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BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by a complex pathogenesis that confers aggressive malignancy, leading to a lack of dependable biomarkers for predicting invasion and metastasis, which results in poor prognoses in patients with HCC. Glycogen storage disease (GSD) is an uncommon metabolic disorder marked by hepatomegaly and liver fibrosis. Notably, hepatic adenomas in GSD patients present a heightened risk of malignancy compared to those in individuals without the disorder. In this investigation, PON1 emerged as a potential pivotal gene for HCC through bioinformatics analysis. METHODS: Transcriptomic profiling data of liver cancer were collected and integrated from TCGA and GEO databases. Bioinformatics analysis was conducted to identify mutated mRNAs associated with GSD, and the PON1 gene was selected as a key gene. Patients were grouped based on the expression levels of PON1, and differences in clinical characteristics, biological pathways, immune infiltration, and expression of immune checkpoints were compared. RESULTS: The expression levels of the PON1 gene showed significant differences between the high-expression group and the low-expression group in HCC patients. Further analysis indicated that the PON1 gene at different expression levels might influence the clinical manifestations, biological processes, immune infiltration, and expression of immune checkpoints in HCC. Additionally, immunohistochemistry (IHC) results revealed high expression of PON1 in normal tissues and low expression in HCC tissues. These findings provide important clues and future research directions for the early diagnosis, prognosis, immunotherapy, and potential molecular interactions of HCC. CONCLUSION: Our investigation underscores the noteworthy prognostic significance of PON1 in HCC, suggesting its potential pivotal role in modulating tumor progression and immune cell infiltration. These findings establish PON1 as a novel tumor biomarker with significant implications for the prognosis, targeted therapy, and immunotherapy of patients with HCC.
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2-Methyl-4-nitroaniline (MNA), an intermediate in the synthesis of azo dyes, is widely distributed in various environmental media and organisms. Although there is speculation regarding MNA's potential to be hepatotoxic, the underlying mechanisms of its hepatotoxicity and its definitive diagnostic process remain largely unexplored. In this research. In the present study, we initially predicted the toxicity and possible toxic effect pathways of MNA using ProTox-II, and found that MNA binds to the PPARγ receptor (binding energy ï¼6.118â¯kcal/mol) with a potential PPARγ agonist effect. Subsequently, in vivo exposure evaluation was conducted on Wistar rats to assess the impact of MNA after a 90-day exposure period, by detecting serum biochemical indexes, hematological indexes, urinary indexes, inflammatory factors, liver histopathological observations and liver tissue PPARγ mRNA expression. The results showed that MNA causes liver function abnormalities, liver histopathological changes and inflammatory response, along with a pronounced increase in PPARγ mRNA levels. This study suggests that the hepatotoxic mechanism of MNA may be related to its possible upregulation of PPARγ expression, increased liver dysfunction and inflammatory responses. Based on these results, the benchmark dose lower limit (BMDL) of 1.503â¯mg/kg for male Wistar rats was also established, providing a vital benchmark for determining the safety threshold of MNA. Our data highlight the hepatotoxic mechanism of MNA and contribute to a better understanding of its potential etiological diagnosis.
Subject(s)
Aniline Compounds , Chemical and Drug Induced Liver Injury , Liver , PPAR gamma , Rats, Wistar , Animals , Aniline Compounds/toxicity , Male , Liver/drug effects , Liver/pathology , Liver/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Administration, Oral , PPAR gamma/genetics , PPAR gamma/metabolism , Rats , Molecular Docking Simulation , Dose-Response Relationship, DrugABSTRACT
Background: Immunotherapy plays a significant role in the treatment of hepatocellular carcinoma (HCC). Members of the S100 protein family (S100s) have been widely implicated in the pathogenesis and progression of tumors. However, the exact mechanism by which S100s contribute to tumor immunity remains unclear. Methods: To explore the role of S100s in HCC immune cells, we collected and comparatively analyzed single-cell RNA sequencing (scRNA-seq) data of HCC and hepatitis B virus-associated HCC. By mapping cell classification and searching for S100s binding targets and downstream targets. Results: S100A6/S100A11 was differentially expressed in tumor T cells and involved in the nuclear factor (NF) κB pathway. Further investigation of the TCGA dataset revealed that patients with low S100A6/S100A11 expression had a better prognosis. Temporal cell trajectory analysis showed that the activation of the NF-κB pathway is at a critical stage and has an important impact on the tumor microenvironment. Conclusion: Our study revealed that S100A6/S100A11 could be involved in regulating the differentiation and cellular activity of T-cell subpopulations in HCC, and its low expression was positively correlated with prognosis. It may provide a new direction for immunotherapy of HCC and a theoretical basis for future clinical applications.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , RNA-Seq , S100 Calcium Binding Protein A6 , S100 Proteins , Humans , Biomarkers, Tumor , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/etiology , Cell Cycle Proteins , Computational Biology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Liver Neoplasms/genetics , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , NF-kappa B/metabolism , Prognosis , S100 Calcium Binding Protein A6/genetics , S100 Calcium Binding Protein A6/metabolism , S100 Proteins/genetics , S100 Proteins/metabolism , Signal Transduction , Single-Cell Analysis , Tumor Microenvironment/immunology , Tumor Microenvironment/geneticsABSTRACT
Pancreatic cancer (PC) is a malignant digestive system tumor with a very poor prognosis. N6-methyladenosine (m6A) is mediated by a variety of readers and participates in important regulatory roles in PC. Based on TCGA_PAAD, ICGC_AU_PAAD, ICGC_CA_PAAD, GSE28735 and GSE62452 datasets, We mapped the multi-omics changes of m6A readers in PC and found that m6A readers, especially IGF2BP family genes, had specific changes and were significantly associated with poor prognosis. An unsupervised consensus clustering algorithm was used to explore the correlation between specific expression patterns of m6A readers in PC and enrichment pathways, tumor immunity and clinical molecular subtypes. Then, the principal component analysis (PCA) algorithm was used to quantify specific expression patterns and screen core genes. Machine learning algorithms such as Bootstrapping and RSF were used to quantify the expression patterns of core genes and construct a prognostic scoring model for PC patients. What's more, pharmacogenomic databases were used to screen sensitive drug targets and small molecule compounds for high-risk PC patients in an all-around and multi-angle way. Our study has not only provided new insights into personalized prognostication approaches, but also thrown light on integrating tailored risk stratification with precision therapy based on IGF2BP2-mediated m6A modification patterns.
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Breast cancer (BC) has emerged as an extremely destructive malignancy, causing significant harm to female patients and society at large. Proteomic research holds great promise for early diagnosis and treatment of diseases, and the integration of proteomics with genomics can offer valuable assistance in the early diagnosis, treatment, and improved prognosis of BC patients. In this study, we downloaded breast cancer protein expression data from The Cancer Genome Atlas (TCGA) and combined proteomics with genomics to construct a proteomic-based prognostic model for BC. This model consists of nine proteins (HEREGULIN, IDO, PEA15, MERIT40_pS29, CIITA, AKT2, CD171 DVL3, and CABL9). The accuracy of the model in predicting the survival prognosis of BC patients was further validated through risk curve analysis, survival curve analysis, and independent prognostic analysis. We further confirmed the impact of differential expression of these nine key proteins on overall survival in BC patients, and the differential expression of the key proteins and their encoding genes was validated using immunohistochemical staining. Enrichment analysis revealed functional associations primarily related to PPAR signaling pathway, steroid hormone metabolism, chemokine signaling pathway, DNA conformation changes, immunoglobulin production, and immunoglobulin complex in the high- and low-risk groups. Immune infiltration analysis revealed differential expression of immune cells between the high- and low-risk groups, providing a theoretical basis for subsequent immunotherapy. The model constructed in this study can predict the survival of BC patients, and the identified key proteins may serve as biomarkers to aid in the early diagnosis of BC. Enrichment analysis and immune infiltration analysis provide a necessary theoretical basis for further exploration of the molecular mechanisms and subsequent immunotherapy.
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Background: APOBEC family play an important role in cancer mutagenesis and tumor development. The role of APOBEC family in lung adenocarcinoma (LUAD) has not been studied comprehensively. Materials and methods: The expression data of pan-cancer as well as LUAD was obtained from public databases. The expression level of APOBEC family genes was analyzed in different normal and cancer tissues. APOBEC mutagenesis enrichment score (AMES) was utilized to evaluate the APOBEC-induced mutations and the relation of APOBEC with genomic instability. Gene set enrichment analysis was used to identify differentially enriched pathways. Univariate Cox regression and Lasso regression were applied to screen key prognostic genes. The immune cell infiltration was estimated by CIBERSORT. RT-qPCR assay, CCK-8 and Transwell assay were conducted to explore gene expression and lung cancer cell invasion. Results: Cancer tissues had significantly altered expression of APOBEC family genes and the expression patterns of APOBEC family were different in different cancer types. APOBEC3B was the most aberrantly expressed in most cancer types. In LUAD, we observed a significantly positive correlation of AMES with intratumor heterogeneity (ITH), tumor neoantigen burden (TNB), and tumor mutation burden (TMB). High AMES group had high mutation counts of DNA damage repair pathways, and high enrichment of cell cycle and DNA repair pathways. We identified four prognostic genes (LYPD3, ANLN, MUC5B, and FOSL1) based on AMES, and constructed an AMES-related gene signature. The expressions of four genes were enhanced and accelerated the invasion ability and viability of lung cancer cells. Furthermore, we found that high group increased oxidative stress level. Conclusions: APOBEC family was associated with genomic instability, DNA damage-related pathways, and cell cycle in LUAD. The AMES-related gene signature had a great potential to indicate the prognosis and guide immunotherapy/chemotherapy for patients suffering from LUAD.
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OBJECTIVE: Several randomized controlled trials (RCTs) have explored the impact of 17ß-estradiol plus norethisterone acetate administration on blood pressure and inflammation markers, however, their findings have often been contradictory. Thus, we conducted a systematic review and meta-analysis of RCTs to assess the effects of this drug combination on systolic blood pressure (SBP), diastolic blood pressure (DBP) and C-reactive protein (CRP) concentrations. METHODS: The Cochrane Library, PubMed/Medline, Scopus, and Google Scholar were searched to identify relevant published RCTs. The pooled mean change and standard deviation (SD) of the outcomes were calculated using the STATA software (version 14) for Statistical Computing. RESULTS: A total of 18 publications were included in the current meta-analysis. In total, there were 12 RCT arms on SBP, 12 RCT arms on DBP, and 6 RCT arms on CRP levels. The administration of 17ß-estradiol plus norethisterone acetate intake increased SBP (WMD: 3.48 mmHg, 95% CI: 0.73, 6.23, P = 0.013), particularly in subjects aged ≥ 60 years (WMD: 5.89 mmHg, 95% CI: 1.71, 10.07, P = 0.006) or with a body mass index (BMI) < 30 kg/m2 (WMD: 6.55 mmHg, 95% CI: 2.64, 10.46, P = 0.012), as well as in the RCTs which lasted ≥ 6 months (WMD: 6.47 mmHg, 95% CI: 3.03, 9.90, P < 0.001),when 17ß-estradiol dosages were ≥ 2 mg/day (WMD: 4.12 mmHg, 95% CI: 1.03, 7.22, P = 0.009; I2 = 99%, P < 0.001) and in RCTs conducted on healthy postmenopausal women (WMD: 4.22 mmHg, 95% CI: 0.43, 8.01, P = 0.02; I2 = 94%, P < 0.001). DBP decreased following this drug combination in the RCTs which lasted < 6 months (WMD: -1.42 mmHg, 95% CI: -2.27, -0.57, P = 0.001). CRP concentrations increased following the use of this drug combination (WMD: 1.01 mg/L, 95% CI: 0.62, 1.41, P < 0.001), especially in participants aged < 60 years (WMD: 1.22 mg/L, 95% CI: 0.77, 1.68, P < 0.001) or with a BMI < 30 kg/m2 (WMD: 0.97 mg/L, 95% CI: 0.67, 1.27, P < 0.001), as well as in RCTs with a duration of ≥ 6 months (WMD: 1.15 mg/L, 95% CI: 0.57, 1.73, P < 0.001), when 17ß-estradiol dosages were ≥ 2 mg/day (WMD: 0.97 mg/L, 95% CI: 0.67, 1.27, P < 0.001; I2 = 55%, P = 0.107) and in RCTs conducted on healthy postmenopausal women (WMD: 1.22 mg/L, 95% CI: 0.77, 1.68, P < 0.001; I2 = 90%, P < 0.001). CONCLUSION: The administration of 17ß-estradiol plus norethisterone acetate increases SBP and CRP concentrations and, when prescribed for less than 6 months, decreases DBP. However, despite being statistically significant, the impact of this drug combination on SBP and DBP is not clinically relevant as the variation in blood pressure values was low.
Subject(s)
Hypertension , Female , Humans , Blood Pressure , Norethindrone Acetate/pharmacology , Randomized Controlled Trials as Topic , InflammationABSTRACT
Li-ion batteries (LIBs) that can operate under low temperature (LT) conditions are essential for applications in orbital missions, subsea areas, and electric vehicles. Unfortunately, severe capacity loss is witnessed due to tremendous kinetic barriers that emerge at LT. Herein, to surmount such kinetic limitations, a low dielectric environment is tamed throughout the bulk electrolyte, which efficaciously brought the Li+ desolvation energy down to 30.76 kJ mol-1 . At the meantime, the adoption of sodium cations (Na+ ) is proposed as a hetero-cation additive, and a Li-Na hybrid and fluoride-rich interphase is further identified via preferential reduction of Na+ -(solvent/anion) clusters, which is found to efficiently facilitate Li+ migration through the LiF/NaF grain boundaries. Based on a N/P ratio of 1.1, the graphite/LiNi0.5 Co0.2 Mn0.3 O2 (NCM) full cell (cathode loading of ≈18.5 mg cm-2 ) delivers a capacity as high as 125.1 mAh g-1 under -20 °C with prolonged cycling to 100 cycles. Finally, a 270 Wh kg-1 graphite/NCM pouch cell is assembled, which affords a discharge capacity of 108.7 mAh g-1 under -40 °C during the initial cycles. With an eye to both fundamental and practical aspects, this work will propel additional advancements and allow LIBs to fill more roles under extreme operation temperatures than ever before.
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Background: Comparing the effects of C-shaped embedded anastomosis and pancreatic duct-jejunal mucosal anastomosis on the incidence of pancreatic fistula after pancreaticoduodenectomy (PD) to find a better pancreaticojejunal anastomosis method that can reduce the occurrence of complications during the operation and benefit the patients. Methods: A retrospective subresearch method was used to select the clinical data of patients who have undergone pancreaticoduodenectomy in our hospital from December 2019 to March 2021. The indicators to be collected for this study include gender, age, body mass index, preoperative liver function (total bilirubin, alanine aminotransferase, and albumin), preoperative comorbidities (diabetes, chronic pancreatitis), and pancreatic condition (texture, pancreatic duct diameter). The patients were divided into two groups according to the method of pancreaticojejunostomy: C-shaped embedded anastomosis group (n = 38) and pancreatic duct-jejunal mucosal anastomosis group (n = 30). The duration of pancreaticojejunostomy, biliary-enteric anastomosis, gastrointestinal anastomosis, intraoperative blood loss, upper abdominal surgery history, pathological type, intraoperative blood loss, pancreaticojejunostomy time, combined pancreatic fistula, biliary fistula, hemorrhage, and abdominal infection were observed and compared. According to the different methods of pancreaticojejunostomy during operation, they were divided into group A: C-shaped embedded pancreaticojejunostomy group (38 cases), and group B: pancreatic duct-jejunal mucosal anastomosis group (30 cases). The postoperative complications were compared between the two groups, and the observed indicators were analyzed with statistical methods. Results: The average pancreaticojejunostomy time in group A was 32.13 ± 4.52 min, and the average pancreaticojejunostomy time in group B was 43.23 + 4.31 min. The difference was statistically significant (p < 0.05). Neither group A nor group B had a grade C fistula. The incidence of biochemical fistula in group A was 21.05% (8/38), and the incidence of biochemical fistula in group B was 13.3% (4/30). The difference was not statistically significant (p > 0.05). The incidence of grade B fistula in group A was 5.20% (2/38), and the incidence of grade B fistula in group B was 26.67% (8/30). The difference was statistically significant (p < 0.05). There were no perioperative deaths in the two groups. Conclusion: According to the results of data analysis, it can be seen that both the two types of pancreaticojejunostomy have good clinical effects, but that in terms of reducing the grade of pancreatic fistula, the C-shaped embedded pancreaticojejunostomy is obviously better and safer. At the same time, the C-shaped embedded pancreaticojejunostomy can shorten the time of pancreaticojejunostomy and is easier to operate, thus worthy of clinical promotion.
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Purpose: Atrial fibrillation (AF) is the most common sustained arrhythmia with a high rate of recurrence after catheter ablation. The gene encoding transcription factor 21 (TCF21) has been linked to coronary artery disease risk by human genome-wide association studies in multiple racial ethnic groups. However, the association of TCF21 with AF remains unclear. Patients and Methods: Circulating leukocytes in patients with paroxysmal AF (PAF) and 92 age-matched controls without a history of cardiovascular disease, AF and other arrhythmias were collected. A total of 224 PAF patients receiving radiofrequency ablation had an 18-month scheduled follow-up study for recurrence of AF. Three single-nucleotide polymorphisms (SNPs) of TCF21 (rs2327429, rs2327433 and rs12190287) were genotyped by PCR, and serum levels of TCF21 were measured by ELISA. Results: More males and smokers were observed in the PAF group compared with controls. C allele of rs2327429, G allele and GG genotype of rs12190287 were markedly associated with the increased onset of PAF. The levels of serum TCF21 were significantly higher in PAF group than those in control group (1.96 ± 0.85 vs 0.86 ± 0.49 ng/mL, P<0.001). Based on logistic regression analysis, we confirmed that risk allele at rs12190287 and serum TCF21 concentration were independently correlated with the incidence of PAF. Furthermore, GG genotype of rs12190287 enhanced the susceptibility of AF recurrence after ablation. Conclusion: G allele and GG genotype of rs12190287 in TCF21 and elevated TCF21 concentration are significantly associated with the onset of PAF and recurrence after ablation.
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Immune responses are an integral part of the pathogenesis of pancreatitis. Studies applying the mouse model of pancreatitis induced by partial ligation of the pancreatic duct to explore the pancreatic immune microenvironment are still lacking. The aim of the present study is to explore the macrophage profile and associated regulatory mechanisms in mouse pancreatitis, as well as the correlation with human chronic pancreatitis (CP). In the present study, the mouse model of pancreatitis was induced by partial ligation of the pancreatic duct. Mice in the acute phase were sacrificed at 0, 4, 8, 16, 32, 72 h after ligation, while mice in the chronic phase were sacrificed at 7, 14, 21, 28 days after ligation. We found that the pancreatic pathological score, expression of TNF-α and IL-6 were elevated over time and peaked at 72h in the acute phase, while in the chronic phase, the degree of pancreatic fibrosis peaked at day 21 after ligation. Pancreatic M1 macrophages and pyroptotic macrophages showed a decreasing trend over time, whereas M2 macrophages gradually rose and peaked at day 21. IL-4 is involved in the development of CP and is mainly derived from pancreatic stellate cells (PSCs). The murine pancreatitis model constructed by partial ligation of the pancreatic duct, especially the CP model, can ideally simulate human CP caused by obstructive etiologies in terms of morphological alterations and immune microenvironment characteristics.
Subject(s)
Pancreatitis, Chronic , Animals , Disease Models, Animal , Humans , Macrophages/metabolism , Mice , Pancreas/pathology , Pancreatic Ducts/metabolism , Pancreatic Ducts/pathology , Pancreatic Ducts/surgery , Pancreatitis, Chronic/chemically induced , Pancreatitis, Chronic/metabolism , Pancreatitis, Chronic/surgeryABSTRACT
BACKGROUND: Pancreatic cancer is a highly malignant tumor with poor prognosis. Chronic inflammation contributes to the progression of pancreatic cancer. However, few studies have examined the prognostic role of inflammatory markers in this cancer. Our study sought to analyze the prognostic risk factors of and construct a prognostic index (PI) model using inflammatory markers for pancreatic cancer. METHODS: Forty-eight patients diagnosed with pancreatic cancer at our hospital were selected for this retrospective analysis. Data on the general clinical characteristics, tumor-related features, blood index factors, and treatment methods were collected. The Cox proportional-hazards model was used to analyze the factors affecting the prognosis, and the Kaplan-Meier analysis was used to draw the survival curve. RESULTS: The median overall survival time was 14.5 months, and the 1-, 2-, and 3-year survival rates were 20.83% (10/48), 6.25% (3/48), and 4.17% (2/48), respectively. The univariate analysis showed that tumor grade, vascular invasion, adjacent tissue invasion, lymph node metastasis, tumor-node-metastasis (TNM) stage, the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the lymphocyte-monocyte ratio (LMR) were significantly correlated with the median survival of pancreatic cancer patients (P<0.05). The Cox regression equation showed that tumor grade III-IV (X1), vascular invasion (X2), TNM stage III-IV (X3), a NLR >3.8 (X4), and a PLR >182.1 (X5) were independent risk factors affecting the prognosis of patients with pancreatic cancer (all P<0.05). The prognostic model for pancreatic cancer can be expressed as: PI =3.521X1+4.157X2+1.282X3+2.441X4+6.015X5. Patients with tumor grade I-II, non-vascular invasion, TNM stage I-II, a NLR ≤3.8, and a PLR ≤182.1 exhibited a higher 1-year survival rate. The areas under the receiver operating characteristic (ROC) curves for the NLR >3.8 and the PLR >182.1 were 0.778 and 0.713, respectively. CONCLUSIONS: Tumor grade, vascular invasion, TNM staging, the NLR, and the PLR are independent risk factors affecting the prognosis of pancreatic cancer patients. The NLR and PLR have good clinical value in predicting the survival outcomes of pancreatic cancer patients.
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Background: The cancerous microenvironment, characterized by the infiltration of CD4+ and CD8+ T cells, play a critical role in regulating the progression of cancer and treating efficiency of immunotherapy. However, the distribution of these cells and their associated cytokines in the tumor microenvironment of pancreatic cancer (PC) are not yet fully understood. Our study aims to analyze the contents of CD4+IL-17+ and CD8+ T cells in PC and their relationship with the clinicopathological features and survival outcomes of patients. Methods: PC tissues and adjacent tissues were retrospectively collected from 40 patients in our hospital. The expression of CD4, IL-17, and CD8 in histological samples was measured by immunohistochemistry. The correlation between CD4, IL-17, and CD8 expression and clinical characteristics was analyzed using Kaplan-Meier survival analysis. The risk factors affecting the outcome of PC were examined by the Cox proportional hazards model, then a nomogram predicting the survival of PC using these risk factors was established. Results: The content of CD4+IL-17+ T cells in PC tissues was significantly higher than that in adjacent normal tissues, while the number of CD8+ T cells was significantly lower than that in adjacent normal tissues (P<0.01). CD4+ T cells in PC tissues was significantly associated with TNM stage and lymph node metastasis (P<0.05). IL-17 and CD8 were significantly associated with histological grade, TNM stage, local infiltration, and lymph node metastasis (P<0.05). The median survival times (MSTs) of CD4 positive and negative patients were 13.2 and 21.4 months, respectively. The MSTs of IL-17 positive and negative patients were 10.4 and 24.8 months, respectively. The MSTs were 21.9 and 11.8 months for CD8 positive and negative patients, respectively (P<0.05). The Cox regression model demonstrated that TNM staging, lymph node metastasis, and CD4+IL-17+ and CD8+ T cells affected PC prognosis (P<0.05). The nomogram showed that the survival probability was reduced in patients with TNM stage III to IV, lymph node metastasis, high CD4+IL-17+ level, and low CD8+ expression. Conclusions: CD4+IL-17+ and CD8+ T cells in PC tissues are associated with TNM staging, lymph node metastasis, and MST, and can be used as new prognostic indicators for PC.
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Pancreatic cancer (PC) is one of the most lethal malignancies, the mortality and morbidity of which have been increasing over the past decade. Ferroptosis, a newly identified iron-dependent cell death pattern, can be induced by iron chelators and small lipophilic antioxidants. Nonetheless, the prognostic significance of ferroptosis-related lncRNAs in PC remains to be clarified. We obtained the lncRNA expression matrix and clinicopathological information of PC patients from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets in the current study. Firstly, we conducted Pearson correlation analysis to delve into the ferroptosis-related lncRNAs, and univariate Cox analysis was implemented to examine the prognostic values in PC patients. Twenty-three prognostic ferroptosis-related lncRNAs were confirmed and loaded into the least absolute shrinkage and selection operator Cox (LASSO-Cox) analysis, then a ferroptosis-related lncRNA prognostic marker (Fe-LPM) was established in the TCGA dataset. Risk scores of patients were calculated and segregated PC patients into low-risk and high-risk subgroups in each dataset. The prognostic capability of Fe-LPM was also confirmed in the ICGC dataset. Gene set enrichment analysis (GSEA) revealed that several ferroptosis-related pathways were enriched in low-risk subgroups. Furthermore, we adopted a multivariate Cox regression to establish a nomogram based on risk score, age, pathological T stage and primary therapy outcome. A competing endogenous RNA (ceRNA) network was also created relied on four of the twenty-three ferroptosis-related lncRNAs. In conclusion, the eight Fe-LPM can be utilized to anticipate the overall survival (OS) of PC patients, which are meaningful to guiding clinical strategies in PC.
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Immunotherapy has made great progress in hepatocellular carcinoma (HCC), yet there is still a lack of biomarkers for predicting response to it. Cancer stem cells (CSCs) are the primary cause of the tumorigenesis, metastasis, and multi-drug resistance of HCC. This study aimed to propose a novel CSCs-related cluster of HCC to predict patients' response to immunotherapy. Based on RNA-seq datasets from The Cancer Genome Atlas (TCGA) and Progenitor Cell Biology Consortium (PCBC), one-class logistic regression (OCLR) algorithm was applied to compute the stemness index (mRNAsi) of HCC patients. Unsupervised consensus clustering was performed to categorize HCC patients into two stemness subtypes which further proved to be a predictor of tumor immune microenvironment (TIME) status, immunogenomic expressions and sensitivity to neoadjuvant therapies. Finally, four machine learning algorithms (LASSO, RF, SVM-RFE and XGboost) were applied to distinguish different stemness subtypes. Thus, a five-hub-gene based classifier was constructed in TCGA and ICGC HCC datasets to predict patients' stemness subtype in a more convenient and applicable way, and this novel stemness-based classification system could facilitate the prognostic prediction and guide clinical strategies of immunotherapy and targeted therapy in HCC.
Subject(s)
Carcinoma, Hepatocellular/therapy , Immunotherapy/methods , Liver Neoplasms/therapy , Machine Learning , Neoplastic Stem Cells/pathology , Carcinoma, Hepatocellular/genetics , Computational Biology , Humans , Liver Neoplasms/genetics , PrognosisABSTRACT
The outcome of pancreatic adenocarcinoma (PAAD) patients is poor, given resistance to gemcitabine. Long noncoding RNA (lncRNA) has been implicated in the carcinogenesis of pancreatic cancer; however, its function and mechanism in PAAD resistance to gemcitabine (GEM) are yet unknown. Herein, we demonstrate that lncRNA DSCR9 is significantly reduced in PAAD in vitro and in vivo. CCK-8, BrdU and flow cytometry assays show that overexpression of DSCR9 markedly suppresses pancreatic cancer cell proliferation and invasion, and promotes apoptosis under gemcitabine treatment. BTG2 acts as a tumor suppressor by reducing the proliferation and invasion of pancreatic cancer cells and increasing gemcitabine-induced apoptosis. Immunofluorescence (IF) staining combined with fluorescence in situ hybridization (FISH) of pancreatic cancer tissues shows that DSCR9 and BTG2 are both increased in pancreatic cancer tissues. Luciferase assay shows that miR-21-5p simultaneously binds to DSCR9 and 3'UTR of BTG2; DSCR9 relieves miR-21-5p-induced inhibition of BTG2 by competing with BTG2 for miR-21-5p binding. Overexpression of miR-21-5p enhances the invasiveness of pancreatic cancer cells by promoting cancer cell proliferation and invasion and attenuating gemcitabine-induced apoptosis. Overexpression of miR-21-5p attenuates the effect of DSCR9 overexpression on BTG2 expression and invasiveness of pancreatic cancer cells. Finally, miR-21-5p expression is increased, while BTG2 expression is decreased in pancreatic cancer tissues. miR-21-5p is negatively correlated with DSCR9 and BTG2. In conclusion, the DSCR9/miR-21-5p/BTG2 axis modulates pancreatic cancer proliferation, invasion, and gemcitabine resistance.
Subject(s)
Adenocarcinoma , Immediate-Early Proteins , MicroRNAs , Pancreatic Neoplasms , RNA, Long Noncoding , Humans , Gemcitabine , MicroRNAs/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , In Situ Hybridization, Fluorescence , Cell Proliferation/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Cell Movement/genetics , Apoptosis , Immediate-Early Proteins/genetics , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Pancreatic NeoplasmsABSTRACT
Background: Pancreatic cancer (PC) is one of the most lethal malignancies and carries a dismal mortality and morbidity. Four types of RNA modification (namely m6A, m1A, APA and A-to-I) could be catalyzed by distinct enzymatic compounds ("writers"), mediating numerous epigenetic events in carcinogenesis and immunomodulation. We aim to investigate the interplay mechanism of these writers in immunogenomic features and molecular biological characteristics in PC. Methods: We first accessed the specific expression pattern and transcriptional variation of 26 RNA modification writers in The Cancer Genome Atlas (TCGA) dataset. Unsupervised consensus clustering was performed to divide patients into two RNA modification clusters. Then, based on the differentially expressed genes (DEGs) among two clusters, RNA modification score (WM_Score) model was established to determine RNA modification-based subtypes and was validated in International Cancer Genome Consortium (ICGC) dataset. What's more, we manifested the unique status of WM_Score in transcriptional and post-transcriptional regulation, molecular biological characteristics, targeted therapies and immunogenomic patterns. Results: We documented the tight-knit correlations between transcriptional expression and variation of RNA modification writers. We classified patients into two distinct RNA modification patterns (WM_Score_high and _low), The WM_Score_high subgroup was correlated with worse prognosis, Th2/Th17 cell polarization and oncogenic pathways (e.g. EMT, TGF-ß, and mTORC1 signaling pathways), whereas the WM_Score_low subgroup associated with favorable survival rate and Th1 cell trend. WM_Score model also proved robust predictive power in interpreting transcriptional and post-transcriptional events. Additionally, the potential targeted compounds with related pathways for the WM_Score model were further identified. Conclusions: Our research unfolds a novel horizon on the interplay network of four RNA modifications in PC. This WM_Score model demonstrated powerful predictive capacity in epigenetic, immunological and biological landscape, providing a theoretical basis for future clinical judgments of PC.
Subject(s)
Pancreatic Neoplasms , Tumor Microenvironment , Humans , Tumor Microenvironment/genetics , Pancreatic Neoplasms/genetics , Carcinogenesis , Cluster Analysis , Pancreatic NeoplasmsABSTRACT
OBJECTIVE: To discuss the efficacy of bundled nursing management in nursing of elderly patients with pressure ulcers. METHODS: 148 hospitalized elderly patients with pressure ulcers in our hospital were taken as the study subjects. The study subjects were randomly assigned to the observation group (n=74) and the control group (n=74) using the random number table method. The control group adopted the routine nursing model, while the observation group adopted the bundled nursing. A comparison of the two groups included the cure rate of pressure ulcers, anxiety (using self-rating anxiety scale), depression (using self-rating depression scale), quality of living (using MOS SF-36 scale), sleep quality and patient satisfaction. RESULTS: The cure rate of pressure ulcers in the observation group was greater than that in the control group (P<0.01). The SAS and SDS scores in the observation group were significantly less than those in the control group (P<0.001). The scores of physical function, general health, social function, emotional role, and mental health in the observation group were greater than those in the control group (all P<0.01). The sleep quality scores in the observation group were less than those in the control group (all P<0.001). The nursing satisfaction in the observation group was greater than that in the control group (P<0.05). CONCLUSION: The application of bundled nursing management in the nursing of elderly patients with pressure ulcers is effective, which can promote the cure rate of pressure ulcers, improve the depression or anxiety, quality of living and sleep of patients, and enhance patient satisfaction. It deserves clinical promotion and use.
ABSTRACT
The porous TiO2 coatings containing Ca/P/Ag were separately prepared on titanium (Ti) surface by one-step (micro-arc oxidation) and two-step methods (micro-arc oxidation and cathodic deposition), and then their surface morphology, composition, biological and antibacterial properties were compared. The results showed that the porous coatings containing Ca/P/Ag achieved by different methods showed similar surface morphology and elemental composition, however, by one-step method, silver existed in the coating as silver phosphate, while in the coatings prepared by two-step method, silver existed as metallic silver. Although both coatings showed excellent antibacterial property (the antimicrobial rate is over 99.9%), the surface coating prepared by one-step method had a more suitable release curve of Ag. In addition, the surface coating prepared by one-step method also presented better biological property, which was due to its enhanced surface roughness and hydrophilicity. Combining with its easy operation and long-term antibacterial property, its prospect for clinical application is more promising.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Calcium/chemistry , Phosphorus/chemistry , Silver/chemistry , Titanium/chemistry , Titanium/pharmacology , Electrodes , Oxidation-Reduction , Porosity , Surface PropertiesABSTRACT
INTRODUCTION: This study aimed to evaluate the relationship of plasma microfibrillar-associated protein 4 (MFAP4) to atrial fibrillation (AF) and atrial structural remodelling. MATERIAL AND METHODS: Plasma MFAP4 levels were measured in 92 patients with AF (61 paroxysmal AF (PAF) patients and 31 persistent AF (PersAF) patients) and 71 control subjects without AF. Linear and logistic multivariate regression analyses were performed to determine the potential value of MFAP4 for predicting the incidence of AF and left atrial size. Then, plasma and atrial protein levels of MFAP4 and its association with atrial fibrosis ratio were analysed in an atrial-specific fibrosis rat model. RESULTS: There were significant differences in MFAP4 levels based on clinical group, with a gradient from control (1.71 ±0.53 ng/ml) to PAF (1.98 ±0.53 ng/ml) to PersAF (2.09 ±0.76 ng/ml) (p < 0.01). With multivariate analyses, plasma MFAP4 was found to be an independent determinant of left atrial diameter in AF patients. In atrial fibrosis rats, both plasma MFAP4 and atrial MFAP4 protein levels increased in atrial fibrosis rats and positively correlated with atrial fibrosis severity. CONCLUSIONS: Plasma MFAP4 was increased in patients with AF and was highest in those with PersAF; both plasma MFAP4 and atrial MFAP4 protein expression were directly associated with the extent of LA structural remodelling.