Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response.

Macrophages play a pivotal role in orchestrating the immune response against pathogens. While the intricate interplay between macrophage activation and metabolism remains a subject of intense investigation, the role of glutamate oxaloacetate transaminase 1 (Got1) in this context has not been extensively assessed. Here, we investigate the impact of Got1 on macrophage polarization and function, shedding light on its role in reactive oxygen species (ROS) production, pathogen defense, and immune paralysis. Using genetically modified mouse models, including both myeloid specific knockout and overexpression, we comprehensively demonstrate that Got1 depletion leads to reduced ROS production in macrophages. Intriguingly, this impairment in ROS generation does not affect the resistance of Got1 KO mice to pathogenic challenges. Furthermore, Got1 is dispensable for M2 macrophage differentiation and does not influence the onset of LPS-induced immune paralysis. Our findings underscore the intricate facets of macrophage responses, suggesting that Got1 is dispensable in discrete immunological processes.

PSMD11 promotes the proliferation of hepatocellular carcinoma by regulating the ubiquitination degradation of CDK4.

BACKGROUND: The 26S proteasome non-ATPase regulatory subunit 11 is a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins, and PSMD11 plays a key role in the regulation of embryonic stem cell proteasome activity. However, the role of PSMD11 in hepatocellular carcinoma has not been studied. In this study, it was found that the expression of PSMD11 in HCC tissues was significantly higher than that in para-cancerous tissues, and was associated with poor prognosis. The results of in vitro experiments showed that PSMD11 knockdown could effectively inhibit the proliferation and apoptosis of hepatoma cell lines, and flow cytometry showed that the G0/G1 phase was significantly prolonged. Through protein spectrometry, immunoprecipitation and in vitro experiments, it was found that PSMD11 can promote the proliferation of hepatocellular carcinoma through regulating the ubiquitination of CDK4 and enhancing its protein stability. This study explores the mechanism of action of PSMD11 in hepatocellular carcinoma and provides new insights for the treatment of hepatocellular carcinoma.

The Value of Chemokine and Chemokine Receptors in Diagnosis, Prognosis, and Immunotherapy of Hepatocellular Carcinoma.

Background: Chemokines and chemokine receptors (CCRs) are involved in a variety of anti-tumour and pro-tumour immune processes in vivo, such as angiogenesis, metastasis, proliferation and invasiveness, and influence patient prognosis and response to therapy. Methods: CCRs differentially expressed in HCC and associated with prognosis were extracted from TCGA and GEO databases, and the obtained CCRs were then used to construct signature genes, and the signature gene were selected for expression validation as well as functional experiments to explore the role of CCRs in the treatment and prognosis of HCC. Results: We constructed a prognostic model including five CCRs (CCL20, CCL23, CCR3, CCR10, and CXCR3) and validated the expression of signature genes. The model's risk score is an independent prognostic factor for HCC. We have also developed prognostic model nomograms for clinical use. In addition, we validated that CCR3 expression is associated with poor prognosis in HCC, and the proliferation and migration ability of HCC cells was significantly inhibited after interfering with the expression of CCR3 in MHCC-LM3. We also looked at differences in pathway enrichment, immune infiltration and immune checkpoints. Finally, we found that risk scores were also correlated with drug sensitivity, the high-risk group had a better sensitivity to sorafenib. Conclusion: The CCRs-related gene signature may better assess HCC prognosis and response to immunotherapy and tyrosine kinase inhibitors such as sorafenib in HCC, providing prospective solutions for diagnosis and treatment.

PAFAH1B3 is a KLF9 target gene that promotes proliferation and metastasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A.

In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.

BarH-Like Homeobox 2 Suppresses Cell Proliferation, Invasion, and Angiogenesis in Hepatocellular Carcinoma by Activating N-Acetylgalactosaminyltransferase 4.

BarH-like homeobox 2 (BARX2) has been identified to play a key role in the development of multiple cancers. Meanwhile, BARX2 may be an independent prognostic biomarker for patients suffering from hepatocellular carcinoma (HCC). Nevertheless, the regulatory role of BARX2 in HCC is still unclear and needs to be unveiled. In this study, the expressions of BARX2 and N-acetylgalactosaminyltransferase 4 (GALNT4) were evaluated by quantitative real-time PCR (qRT-PCR) as well as western blot. Besides, the abilities of cells to proliferate, migrate, invade, and angiogenesis were assessed with CCK-8, colony formation, wound-healing, Transwell, and tube formation assays, separately. Cell apoptosis was determined by flow cytometry analysis. The binding relationship between BARX2 and GALNT4 was predicted by JASPAR website and verified using Chromatin immunoprecipitation (ChIP) and luciferase report assay. It was discovered that BARX2 was reduced in HCC cell lines, while its overexpression greatly repressed cell proliferation, migration, invasion, and angiogenesis and promoted cell apoptosis in HuH7 and MHCC97-H cells. BARX2 could bind to GALNT4 promoter and positively regulate GALNT4 expression. In addition, GALNT4 deficiency partly abolished the inhibitory effects of BARX2 on the progression of HCC. In summary, this study highlights that BARX2 may hold promise for serving as a potential therapeutic target, facilitating the development of a novel therapeutic strategy against HCC.

Signature construction and molecular subtype identification based on immune-related genes for better prediction of prognosis in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) immunotherapy is a focus of current research. We established a model that can effectively predict the prognosis and efficacy of HCC immunotherapy by analyzing the immune genes of HCC. METHODS: Through the data mining of hepatocellular carcinoma in The Cancer Genome Atlas (TCGA), the immune genes with differences in tumor and normal tissues are screened, and then the univariate regression analysis is carried out to screen the immune genes with differences related to prognosis. The prognosis model of immune related genes is constructed by using the minimum absolute contraction and selection operator (lasso) Cox regression model in the TCGA training set data, The risk score of each sample was calculated, and the survival was compared with the Kaplan Meier curve and the receiver operating characteristic (ROC) curve to evaluate the predictive ability. Data sets from ICGC and TCGA were used to verify the reliability of signatures. The correlation between clinicopathological features, immune infiltration, immune escape and risk score was analyzed. RESULTS: Seven immune genes were finally determined as the prognostic model of liver cancer. According to these 7 genes, the samples were divided into the high and low risk groups, and the results suggested that the high-risk group had a poorer prognosis, lower risk of immune escape, and better immunotherapy effect. In addition, the expression of TP53 and MSI was positively correlated in the high-risk group. Consensus clustering was performed to identify two main molecular subtypes (named clusters 1 and 2) based on the signature. It was found that compared with cluster 1, better survival outcome was observed in cluster 2. CONCLUSION: Signature construction and molecular subtype identification of immune-related genes could be used to predict the prognosis of HCC, which may provide a specific reference for the development of novel biomarkers for HCC immunotherapy.

Pancancer analysis of oncogenic BARX2 identifying its prognostic value and immunological function in liver hepatocellular carcinoma.

The transcription factor BarH-like homeobox 2 (BARX2), a member of the Bar-like homeobox gene family, is involved in cell proliferation, differentiation, immune responses and tumorigenesis. However, the potential role of BARX2 in the development of liver hepatocellular carcinoma (LIHC) remains unclear. Therefore, we aimed to study the biological role of BARX2 in hepatocellular carcinoma. Through the UALCAN, GTEx PORTAL, TIMER 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and STRING public databases, the BARX2 mRNA level, prognostic value, coexpressed genes, associated differentially expressed genes, DNA methylation and functional enrichment of LIHC patients were studied. The relationships between BARX2 expression and various clinical or genetic parameters of LIHC patients were determined using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and BEAT LIHC databases. In addition, the biological function of BARX2 in LIHC was studied in vitro. Through large-scale data mining, our study showed that BARX2 was differentially expressed between different normal and tumour tissues.BARX2 expression in LIHC tissues was significantly lower than that in corresponding controls, especially in patients with T2-4 stage disease. In patients with LIHC, overexpression of BARX2 was an independent poor prognostic factor associated with poor cytogenetic risk and gene mutations. Genomic hypermethylation of the BARX2 gene was associated with upregulated BARX2 expression and poor overall survival (OS) in LIHC. Functional enrichment analysis showed that BARX2 had an immunomodulatory role and was involved in the inflammatory response in LIHC occurrence. In conclusion, the oncogene BARX2 may serve as a new biomarker and prognostic factor for patients with LIHC. The immunomodulatory function of BARX2 deserves further validation in LIHC.

Molecular subtype identification and signature construction based on Golgi apparatus-related genes for better prediction prognosis and immunotherapy response in hepatocellular carcinoma.

Introduction: The Golgi apparatus (GA) is the center of protein and lipid synthesis and modification in normal cells and is involved in regulating various cellular process as a signaling hub, the dysfunction of which can lead to the development of various pathological conditions, including tumors. Mutations in Golgi apparatus-related genes (GARGs) are prevalent in most tumors, and their mutations can make them pro-tumor metastatic. The aim of this study was to analyze the predictive role of GARGs in the prognosis and immunotherapeutic outcome of hepatocellular carcinoma. Methods: We used TCGA, GEO and ICGC databases to classify hepatocellular carcinoma samples into two molecular subtypes based on the expression of GARGs. Signature construction was then performed using GARGs, and signature genes were selected for expression validation and tumor phenotype experiments to determine the role of GARGs in the prognosis of hepatocellular carcinoma. Results: Using the TCGA, GEO and ICGC databases, two major subtypes of molecular heterogeneity among hepatocellular carcinoma tumors were identified based on the expression of GARGs, C1 as a high-risk subtype (low survival) and C2 as a low-risk subtype (high survival). The high-risk subtype had lower StromalScore, ImmuneScore, ESTIMATEScore and higher TumorPurity, indicating poorer treatment outcome for ICI. Meanwhile, we constructed a new risk assessment profile for hepatocellular carcinoma based on GARGs, and we found that the high-risk group had a worse prognosis, a higher risk of immune escape, and a higher TP53 mutation rate. Meanwhile, TME analysis showed higher tumor purity TumorPurity and lower ESTIMATEScore, ImmuneScore and StromalScore in the high-risk group. We also found that the high-risk group responded more strongly to a variety of anticancer drugs, which is useful for guiding clinical drug use. Meanwhile, the expression of BSG was experimentally found to be associated with poor prognosis of HCC. After interfering with the expression of BSG in HCC cells SMMC-7721, the proliferation and migration ability of HCC cells were significantly restricted. Discussion: The signature we constructed using GARGs can well predict the prognosis and immunotherapy effect of hepatocellular carcinoma, providing new ideas and strategies for the treatment of hepatocellular carcinoma.

Comprehensive Analysis of Cellular Senescence-Related Genes in Prognosis, Molecular Characterization and Immunotherapy of Hepatocellular Carcinoma.

BACKGROUND: Cellular senescence is a tumor suppressive response in which the cell cycle is in a state of permanent arrest and can inhibit tumor cell proliferation. In recent years, induction of cellular senescence has been shown to be important for antitumor therapy, and the link between cellular senescence and clinical prognosis and immunotherapy of hepatocellular carcinoma is still unknown. METHODS: We performed enrichment analysis of genes in three cellular senescence gene sets, screened for gene sets significantly enriched in hepatocellular carcinoma and extracted genes from them. Signature were constructed using senescence-related genes, and their expression was verified at the protein and RNA levels. Survival, clinical staging and grading, immune infiltration, immunotherapy, and drug sensitivity were also analyzed between risk groups. RESULTS: The q-PCR and immunohistochemistry results revealed significant differences in the expression of the signature genes between normal and tumor tissues. Significant differences in clinicopathological features, prognosis and immune infiltration were observed between risk groups. In the low-risk group, better OS and lower TMB scores were demonstrated, while the high-risk group had higher immune checkpoint expression, as well as lower risk of immune escape. In addition, we found that the High-risk group was more sensitive to sorafenib. CONCLUSION: In summary, the signature constructed using aging-related genes can reliably predict patient prognosis and immunotherapy efficacy, providing a new idea for immune system therapy of hepatocellular carcinoma.

Comprehensive Analysis of Prognostic Value and Immune Infiltration of Ficolin Family Members in Hepatocellular Carcinoma.

Objective: Ficolin (FCN) family proteins are part of the innate immune system, play a role as recognition molecules in the complement system, and are associated with tumor development. The mechanism of its role in immunotherapy of hepatocellular carcinoma (HCC) is unclear. Methods: In this study, we used the TCGA database, HPA database, Gene Expression Profile Interaction Analysis (GEPIA), Kaplan-Meier plotter, TCGAportal, cBioPortal, GeneMANIA, TIMER, and TISIDB to analyze Ficolin family proteins (FCN1, FCN2 and FCN3, FCNs) in patients with hepatocellular carcinoma for differential expression, prognostic value, genetic alterations, functional enrichment, and immune factor correlation analysis. Results: The expression levels of FCN1/2/3 were significantly reduced in patients with HCC. Among them, FCN3 showed significant correlation with Overall Survival (OS), Progressive Free Survival (PFS) and Relapse Free Survival (RFS) in HCC. FCN1 and FCN3 may be potential prognostic markers for survival in patients with HCC. In addition, the functions of differentially expressed FCNs were mainly related to complement activation, immune response, apoptotic cell clearance and phagocytosis. FCNs were found to be significantly correlated with multiple immune cells and immune factors. Expression of FCN1 and FCN3 differed significantly in the immune and stromal cell component scores of HCC. analysis of the tumor mutation burden (TMB) and microsatellite instability (MSI) of FCNs with pan-cancer showed that FCN3 was significantly correlated with both. Conclusions: Our study provides new insights into the link between the FCN family and immunotherapy for HCC, and FCN3 may serve as a prognostic biomarker for HCC.

Analysis of the Spectrum and Characteristics of Pediatric Cancer Based on Hospital Information Systems in China.

PURPOSE: The purpose of this study was to use the hospital information system to analyze the cancer profile and compare demographics, hospitalization, status of surgery and treatment cost of various cancer categories based on the electronic health record (EHR) of outpatient children with tumors in Shanghai, China. PATIENTS AND METHODS: Information was collected from 3834 inpatients aged 0-18 who were diagnosed with malignant tumors in all 17 hospitals with pediatric wards in the Pudong New District of Shanghai from 2011 to 2016. All patients were classified according to the International Classification of Childhood Cancer-3 (ICCC-3). The chi-squared test was used to compare demographics, hospitalization information, status of surgery and treatment cost according to inpatients' cancer category. RESULTS: In both the malignant non-solid tumor and solid tumor groups, males and those aged 0-4 years were the dominant groups. Lymphocytic leukemia was the most common cancer in all inpatients (n=994, 25.93%), and the acute myeloid leukemia had the longest length of stay of inpatients (median=26.00 days). In both the non-solid and solid tumor groups, patients who received only one type of surgery had an advantage. The highest proportion of patients who had undergone surgery was found in non-Hodgkin lymphoma patients. In terms of total cost, surgical cost and medicine cost, the expenditure of central nervous system tumor patients was the highest. Astrocytoma had the highest total cost. CONCLUSION: Leukemia is common in children with cancer in Pudong and should be given attention. Because the highest financial burden falls on patients with central nervous system tumors and acute myeloid leukemias, the government should take immediate and targeted measures for these cancers in particular.

Iodine-125 seed implantation and allogenic natural killer cell immunotherapy for hepatocellular carcinoma after liver transplantation: a case report.

For advanced hepatocellular carcinoma (HCC) patients, liver transplantation (LT) is an optimal treatment with limitation of high risk of tumor recurrence related to the immunosuppressive chemotherapy as usually recommended. In this study, a 29-year-old man suffered from HCC recurrence after LT. He underwent radiotherapy (total dose: 45 Gy) but had no significant response. Then, he received iodine-125 seed implantation combined with allogenic natural killer (NK) cell immunotherapy. Liver function, immune function, circulating tumor cell counts and computed tomography scans were evaluated to determine the clinical effect. We found that this combined treatment produced enhanced immune function of the patient and reduction in tumor size. This is the first report of an efficacy and safety study about clinical regimen comprising allogenic NK cell immunotherapy combined with iodine-125 seed implantation for the treatment of HCC recurrence after LT.

Erratum: Allogenic natural killer cell immunotherapy of sizeable ovarian cancer: A case report.

[This corrects the article DOI: 10.3892/mco.2017.1230.].

Allogenic natural killer cell immunotherapy of sizeable ovarian cancer: A case report.

Masses are often detected in the abdomen of patients with sizeable ovarian cancer. There are currently no effective treatments available for late-stage ovarian cancer. Immunotherapy is gaining increasing attention worldwide in the clinical setting due to its ability to eliminate tumor cells and its favorable toxicity profile. We herein report the case of a 60-year-old woman who received allogenic natural killer (NK) cell immunotherapy for a sizeable ovarian carcinoma and achieved a noteworthy response. NK cells were isolated from the donor's peripheral blood mononuclear cells, and the cell numbers were increased to 8-10 billion [corrected]. The activated cells were expanded ex vivo for 14 days prior to intravenous infusion. After six infusions of NK cell therapy >3 months, the level of carbohydrate antigen 125 decreased significantly (from 11,270 to 580 U/ml). Furthermore, the size of the masses in the abdomen was markedly reduced. Overall, the treatment had few adverse effects and it prolonged patient survival. The present data and the patient response suggest that allogenic NK cell immunotherapy is a promising approach for ovarian cancer, with few treatment-related adverse effects. The patient received six intravenous infusions of allogenic HANK cells between March, 2015 and June, 2015, but discontinued in October, 2015 and succumbed to the disease in March, 2016 following relapse.

Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1.

Cellular uptake of platinum-based antitumor drugs is a critical step in the mechanism of the drug action and associated resistance, and deeper understanding of this step may inspire development of novel methods for new drugs with reduced resistance. Human copper transporter 1 (hCtr1), a copper influx protein, was recently found to facilitate the cellular entry of several platinum drugs. In the work reported here, we constructed a Met- and His-rich 20mer peptide (hCtr1-N20) corresponding to the N-terminal domain of hCtr1, which is the essential domain of hCtr1 for transporting platinum drugs. The interactions of the peptide with cisplatin and its analogues, including transplatin, carboplatin, oxaliplatin, and [Pt(L: -Met)Cl(2)], were explored at the molecular level. Electrospray ionization (ESI) mass spectrometry (MS) data revealed that all of the platinum(II) complexes used in present study can bind to hCtr1-N20 in 1:1 and 2:1 stoichiometry. Four Met residues should be involved in binding to cis-platinum complexes on the basis of the tandem MS spectrometry and previously reported data. Time-dependent 2D [(1)H,(15)N] heteronuclear single quantum coherence NMR spectra indicate the reaction of cisplatin with hCtr1-N20 is a stepwise process. The intermediate, however, is transient, which is consistent with the ESI-MS results. Time-dependent ESI-MS data revealed that the geometry and the properties of both the leaving and the nonleaving groups of platinum(II) complexes play essential roles in controlling the reactivity and formation of the final products with hCtr1-N20.

Effect of adenine moiety on DNA binding property of copper(II)-terpyridine complexes.

Two novel copper(ii) terpyridine complexes, [Cu(atpy)(NO(3))(H(2)O)](NO(3)).3H(2)O () and [Cu(ttpy)(NO(3))(2)] () (atpy = 4'-p-N9-adeninylmethylphenyl-2,2':6,2''-terpyridine; ttpy = 4'-p-tolyl-2,2':6,2''-terpyridine) have been prepared and structurally characterized by X-ray crystallography. Both complexes show a CuN(3)O(2) coordination in a square pyramidal (4 + 1) geometry with terpyridine acting as an equatorial ligand. For complex , intermolecular AA base pairing interaction is observed between N(6) and N(1) of adjacent adenines with N(6)N(1) of 3.027(7) A. A molecular dynamics simulation of the DNA binding of two complexes showed that the adenine moiety plays an important role in the intercalation of into DNA. This is verified by UV, fluorescence, circular dichroism and flow linear dichroism studies. The promotional effect from the adenine moiety to the intracellular DNA binding of complex is also confirmed by the inductively coupled plasma mass (ICP-MS) spectrometry data which showed a significant higher copper content in DNA isolated from complex treated MCF-7 and HeLa cells.