ABSTRACT
BACKGROUND: Gallbladder cancer is the sixth most common malignant gastrointestinal tumor. Radical surgery is currently the only effective treatment, but patient prognosis is poor, with a 5-year survival rate of only 5-10%. Establishing an effective survival prediction model for gallbladder cancer patients is crucial for disease status assessment, early intervention, and individualized treatment approaches. The existing gallbladder cancer survival prediction model uses clinical data-radiotherapy and chemotherapy, pathology, and surgical scope-but fails to utilize laboratory examination and imaging data, limiting its prediction accuracy and preventing sufficient treatment plan guidance. AIMS: The aim of this work is to propose an accurate survival prediction model, based on the deep learning 3D-DenseNet network, integrated with multimodal medical data (enhanced CT imaging, laboratory test results, and data regarding systemic treatments). METHODS: Data were collected from 195 gallbladder cancer patients at two large tertiary hospitals in Shanghai. The 3D-DenseNet network extracted deep imaging features and constructed prognostic factors, from which a multimodal survival prediction model was established, based on the Cox regression model and incorporating patients' laboratory test and systemic treatment data. RESULTS: The model had a C-index of 0.787 in predicting patients' survival rate. Moreover, the area under the curve (AUC) of predicting patients' 1-, 3-, and 5-year survival rates reached 0.827, 0.865, and 0.926, respectively. CONCLUSIONS: Compared with the monomodal model based on deep imaging features and the tumor-node-metastasis (TNM) staging system-widely used in clinical practice-our model's prediction accuracy was greatly improved, aiding the prognostic assessment of gallbladder cancer patients.
Subject(s)
Gallbladder Neoplasms , Humans , Gallbladder Neoplasms/diagnostic imaging , Gallbladder Neoplasms/therapy , Neoplasm Staging , Retrospective Studies , China , PrognosisABSTRACT
BACKGROUND: Gallbladder cancer is associated with late diagnosis and poor prognosis. Current study aims to develop a prognostic nomogram for predicting survival of gallbladder cancer patients after surgery. METHODS: Two large cohorts were included in this analysis. One consisted of 1753 gallbladder cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database, and the other consisted of 239 patients from Shanghai Renji hospital. Significant prognostic factors were identified and integrated to develop the nomogram. Then the model was subjected to bootstrap internal validation and external validation. RESULTS: Univariate and multivariate analysis indicated that age, tumor histology, T-stage, N-stage and M-stage were significant prognostic factors, which were all included to build the nomogram. The model showed good discrimination, with a concordance index (C-index) of 0.724 (95% CI, 0.708-0.740), and good calibration. Application of the nomogram in the validation cohort still presented good discrimination (C-index, 0.715 [95% CI 0.672-0.758]) and good calibration. In the primary cohort, the C-index of the nomogram was 0.724, which was significantly higher than the Nevin staging system (C-index = 0.671; P < 0.001) and the 8th TNM staging system (C-index = 0.682; P < 0.001). In the validation cohort, the C-index of the nomogram was 0.715, which was also higher than the Nevin staging system (C-index = 0.692; P < 0.05) and the 8th TNM staging system (C-index = 0.688; P = 0.06). CONCLUSIONS: The proposed nomogram resulted in more-accurate prognostic prediction for patients with gallbladder cancer after surgery.
Subject(s)
Gallbladder Neoplasms , Nomograms , China , Gallbladder Neoplasms/surgery , Humans , Neoplasm Staging , Prognosis , SEER ProgramABSTRACT
OBJECTIVE: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE). DESIGN: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies. RESULTS: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment. CONCLUSIONS: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.
Subject(s)
Adenocarcinoma/genetics , Barrett Esophagus/genetics , DNA Methylation , Esophageal Neoplasms/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Antineoplastic Agents/pharmacology , Barrett Esophagus/drug therapy , Barrett Esophagus/metabolism , Barrett Esophagus/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , DNA, Neoplasm/genetics , ErbB Receptors/metabolism , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Gene Silencing , Genome-Wide Association Study/methods , Humans , Mutation , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Protein Tyrosine Phosphatase, Non-Receptor Type 13/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 13/genetics , Receptor, ErbB-2/metabolism , Signal Transduction/geneticsABSTRACT
As the most important detoxifying enzymes in liver, glutathione S-transferases (GSTs) can protect hepatocytes against carcinogens. We conducted a large cohort study to investigate the prognostic value of single nucleotide polymorphisms (SNPs) in seven encoding genes of GSTs for hepatocellular carcinoma (HCC). Twelve SNPs were genotyped and correlated with overall survival in 469 HCC patients. The median follow-up time of all patients was 21 (range 3-60) months, and the median survival time was 22 months. By the end of the study, 135 (28.8 %) patients were alive. Only rs4147581 in GSTP1 gene exhibited a significant association with survival of HCC patients (P = 0.006), with its mutant allele bearing a significantly lower risk of death (hazard ratio, 0.71; 95 % confidence interval 0.53-0.90), compared with the homozygous wide-type. A longer median survival time in patients with rs4147581 mutant allele was noticed than those homozygous wide-type (P = 0.03), and there was a marked adverse effect on survival conferred by smoking exposure in these patients. Conclusively, our findings provide supporting evidence for a contributory role of GSTP1 rs4147581 polymorphism in predicting the prognosis of HCC.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/mortality , Glutathione S-Transferase pi/genetics , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Alleles , Carcinoma, Hepatocellular/pathology , Female , Follow-Up Studies , Genotype , Humans , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Risk Factors , Tumor Burden , Young AdultABSTRACT
BACKGROUND: Numerous literature suggest that the preoperative neutrophil to lymphocyte ratio (NLR) is correlated to the prognosis of various cancers. However, the prognostic significance of NLR in gallbladder carcinoma (GBC) remains to be determined. METHODS: Data from 316 GBC patients with surgical treatment were reviewed retrospectively. A receiver operating characteristic (ROC) curve was performed to determine an optimal cut-off value for NLR. The Kaplan-Meier method and Cox regression proportional hazard model were performed to evaluate prognostic factors. RESULTS: The optimal cut-off point for NLR was 2.61 according to the ROC curve. According to the univariable analysis, NLR, differentiation and TNM stage were associated with GBC prognosis. GBC patients with NLR > 2.61 have worsened 5-year overall survival (OS) compared to patients with NLR ≤ 2.61 (P < 0.001). Multiple analyses indicated that NLR (hazard ratio (HR) 1.65; 95 percent confidence interval (95% CI) 1.25-2.17), differentiation (HR 1.25; 95% CI 0.97-1.62) and TNM stage (HR 3.79; 95% CI 2.09-6.87) were independent prognostic factors for GBC. GBC patients in stage III/IV, NLR > 2.61 exhibited worse OS compared to patients with NLR ≤ 2.61 (P < 0.05). A prognostic evaluation model based on the independent prognostic factors was established. CONCLUSION: NLR is associated with GBC prognosis and is a potential prognostic marker for GBC, not only preoperatively but also postoperatively.
Subject(s)
Carcinoma/immunology , Gallbladder Neoplasms/immunology , Lymphocytes/immunology , Neutrophils/immunology , Aged , Area Under Curve , Carcinoma/mortality , Carcinoma/pathology , Carcinoma/surgery , Chi-Square Distribution , Female , Gallbladder Neoplasms/mortality , Gallbladder Neoplasms/pathology , Gallbladder Neoplasms/surgery , Humans , Kaplan-Meier Estimate , Lymphocyte Count , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Predictive Value of Tests , Proportional Hazards Models , ROC Curve , Retrospective Studies , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Some genetic alterations of glutathione S-transferase omega 2 (GSTO2) have been reported to increase the risk of many malignancies, including hepatocellular carcinoma (HCC); however, their prognostic capability remained unresolved in HCC patients treated with transarterial chemoembolization (TACE). To fill this gap, we genotyped three well-defined polymorphisms in GSTO2 to assess whether they can predict overall survival among 228 HCC patients under TACE treatment. The median follow-up time and survival time were 22.0 months (range 3.0-60.0) and 19.2 months, respectively. Only one of three polymorphisms examined, rs157077, was significantly associated with overall survival of TACE-treated HCC (P = 0.003), and its mutant allele conferred a higher risk of death than its wild homozygotes (hazard ratio 1.58, 95 % confidence interval 1.17-2.14). Moreover, carriers of this mutant allele had higher tissue GSTO2 expression, reinforcing the prognostic capability of GSTO2 rs157077 for HCC, especially in combination with age and tumor-node-metastasis (TNM) stage. Taken together, we for the first time provided evidence supporting the prognostic role of GSTO2 in the progression of TACE-treated HCC.
Subject(s)
Carcinoma, Hepatocellular/genetics , Glutathione Transferase/genetics , Liver Neoplasms/genetics , Prognosis , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Embolization, Therapeutic , Female , Genotype , Glutathione Transferase/biosynthesis , Hepatitis B Surface Antigens/blood , Humans , Kaplan-Meier Estimate , Liver Cirrhosis/blood , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Male , Middle Aged , Neoplasm Staging , Polymorphism, Single NucleotideABSTRACT
Although previous evidence indicates close involvement of CD147 in the pathogenesis of liver fibrosis, the underlying molecular mechanisms and its therapeutic value remain largely unknown. In the present study, we investigated the biological roles of CD147 in liver fibrosis and assessed its therapeutic value as a target molecule in the CCl4-induced liver fibrosis mouse model. We found that CD147 was highly expressed in both hepatocytes and SECs (sinusoidal endothelial cells) in fibrotic liver tissues. Additionally, it was significantly associated with the fibrosis stage. TGF-ß1 (transforming growth factor ß1) was found to be mainly responsible for the up-regulation of CD147. Bioinformatic and experimental data suggest a functional link between CD147 expression and VEGF-A (vascular endothelial growth factor A)/VEGR-2 (VEGF receptor 2) signalling-mediated angiogenesis in fibrotic liver tissues. Furthermore, we observed that the CD147-induced activation of the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway promotes the production of VEGF-A in hepatocytes and expression of VEGFR-2 in SECs, which was found to enhance the angiogenic capability of SECs. Finally, our data indicate that blocking of CD147 using an mAb (monoclonal antibody) attenuated liver fibrosis progression via inhibition of VEGF-A/VEGFR-2 signalling and subsequent amelioration of microvascular abnormality in the CCl4-induced mouse model. Our findings suggest a novel functional mechanism that CD147 may promote liver fibrosis progression via inducing the VEGF-A/VEGFR-2 signalling pathway-mediated cross-talk between hepatocytes and SECs. New strategies based on the intervention of CD147 can be expected for prevention of liver fibrosis.
Subject(s)
Basigin/metabolism , Endothelial Cells/metabolism , Hepatocytes/metabolism , Liver Cirrhosis/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Animals , Cell Line , Cell Movement , Cell Proliferation , Disease Progression , Humans , Mice , Neovascularization, Pathologic/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Transforming Growth Factor beta1/metabolism , Up-RegulationABSTRACT
BACKGROUND AND AIM: Although the influence of cigarette smoking on the incident risk of liver cancer has been determined, the association between smoking and liver cancer mortality remains uncertain. METHODS: We searched Pubmed, EmBase, and Web of Science databases to obtain eligible studies. Hazard ratio (HR) value and 95% confidential intervals (CI) were pooled by using a random-effects model, and dose-response analyses were conducted to quantify associations between smoking and mortality from liver cancer. RESULTS: A total of 27 articles involving four million participants from seven countries by retrieval (published 1986-2014) were finally included. Pooled HR values for liver cancer mortality was 1.45 (95% CI: 1.33-1.59), 1.22 (95% CI: 1.11-1.34) and 1.16 (95% CI: 1.01-1.32) for current, former, and ever smokers, respectively, when compared with nonsmokers. The risk increased by 7.1% (95% CI: 1.4-13.2) for per additional 10 cigarettes per day and by 5.2% (95% CI: 0.02-11.2) for per additional 10 pack-years. In our population recruiting 597 patients with liver cancer, smoking status was further identified as a significant determinant factor of tumor size and serum level of gamma-glutamyl transpeptidase, but not a significant prognostic factor. CONCLUSIONS: Cigarette smoking, especially current smoking, significantly increased mortality risk from liver cancer.
Subject(s)
Liver Neoplasms/mortality , Smoking/adverse effects , Biomarkers, Tumor/blood , Cause of Death , Cohort Studies , Confidence Intervals , Databases, Bibliographic , Humans , Incidence , Liver Neoplasms/blood , Liver Neoplasms/pathology , Proportional Hazards Models , Risk , gamma-Glutamyltransferase/bloodABSTRACT
BACKGROUND AND AIM: It was commonly accepted that chemotherapeutic cytotoxicity was the main cause for hepatic failure in hepatocellular carcinoma patients after repeated transarterial chemoembolization (TACE). However, the effect of embolization-induced hypoxia on liver cirrhosis has rarely been concerned. METHODS: Serum levels of alanine aminotransferase, aspartate aminotransferase, and albumin were used to detect liver injury. Hepatic artery ligation was performed in carbon tetrachloride-induced rat hepatic fibrosis model to mimic the effect of hepatic hypoxia on liver fibrosis after TACE. Sirius Red staining and immunohistochemical analysis of alpha-smooth muscle actin (α-SMA) were used to detect the activation of hepatic stellate cells. Moreover, the expression of hypoxia and fibrosis-related molecules were analyzed at protein and/or mRNA level. RESULTS: Patients showed a significant increase in alanine aminotransferase and aspartate aminotransferase (P = 0.006), accompanied by a decrease in albumin (P = 0.005) after repeated TACE. Hepatic artery ligation significantly promoted carbon tetrachloride-induced rat liver fibrosis progression as indicated by Sirius Red and α-SMA staining, as well as increased expression of hypoxia-inducible factor (HIF)-1α, transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF). Conditioned media of hypoxia-treated L02 cells induced the expression of Collagen I and α-SMA in LX-2 cells, which was inhibited by HIF-1α small interfering RNA. Finally, HIF-1α inhibitor LW6 attenuated the hypoxia-induced fibrosis progression in vivo. CONCLUSION: Our data demonstrate that TACE-induced hepatic hypoxia aggravates the fibrosis progression in peritumoral liver tissue, thus leads to the deterioration of liver function. Intervention of HIF-1α might be a valuable strategy to optimize the efficacy and reduce the complication of TACE.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Chemoembolization, Therapeutic/adverse effects , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver/pathology , Adult , Aged , Animals , Cell Hypoxia , Disease Models, Animal , Disease Progression , Epirubicin/administration & dosage , Epirubicin/adverse effects , Female , Fibrosis , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Infusions, Intra-Arterial , Liver Cirrhosis, Experimental , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Hepatocellular carcinogenesis is associated with the progression of cirrhosis, and the latter further aggravates tumor development and prognosis. The aim of the study was to investigate the prognostic values of 12 cirrhosis-relative noninvasive models in hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 363 HCC patients who either underwent partial hepatectomy (PH) or received transcatheter arterial chemoembolization (TCAE). Preoperative data were collected to calculate these indices using the original formulas. Diagnostic accuracy of these models in detection of cirrhosis was evaluated by area under receiver operating characteristic curve (AUC) analysis. Multivariate analyses were performed to assess the independent prognostic significance of the 12 indicators. RESULTS: Aspartate aminotransferase-platelet ratio index (APRI) and Goteborg University Cirrhosis Index (GUCI) were found to be significant in discriminating cirrhotic patients from non-cirrhotic individuals. When the indices were expressed as continuous variables, multivariate analyses indicated that APRI and GUCI were independent indices to predict overall survival in patients underwent PH, with a hazard ratio (HR) value 1.04 (p = 0.005) and 1.07 (p = 0.001), respectively. In the cohort of TACE, APRI and GUCI were independently associated with survival as well. CONCLUSION: Of the 12 indices, APRI and GUCI were relatively accurate predictors of cirrhosis status as well as outcome of HCC. As only a limited study population was enrolled in the current study, larger cohorts are needed to validate our results.
Subject(s)
Carcinoma, Hepatocellular/pathology , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Adult , Aged , Area Under Curve , Carcinoma, Hepatocellular/mortality , Female , Humans , Kaplan-Meier Estimate , Liver Cirrhosis/mortality , Liver Neoplasms/mortality , Male , Middle Aged , Multivariate Analysis , Prognosis , Proportional Hazards Models , ROC Curve , Retrospective StudiesABSTRACT
BACKGROUND: Liver transplantation (LT) and liver resection (LR) are currently considered the standard treatment of patients with hepatocellular carcinoma (HCC). However, the outcomes of LT and LR are still inconclusive. DATA SOURCES: MEDLINE, EMBASE, and Cochrane Library were searched for relevant studies. Surgical safety indices such as treatment-related morbidity and mortality, and efficacy indices such as overall and tumor-free survival outcomes were evaluated. Weighted mean differences and odds ratios (ORs) were calculated using a random-effects model. RESULTS: Seventeen studies were included in this meta-analysis. LT achieved significantly higher rates of surgery-related morbidity (OR=1.47; 95% CI: 1.02-2.13) and mortality (OR=2.12; 95% CI: 1.11-4.05). Likewise, the 1-year survival rate was lower in LT (OR=0.86; 95% CI: 0.61-1.20). However, the 3- and 5-year survival rates were significantly higher in LT than in LR and the ORs were 1.12 (95% CI: 0.96-1.30) in 3 years and 1.84 (95% CI: 1.49-2.28) in 5 years. Furthermore, the tumor-free survival rate in LT was significantly higher than that in LR in 1, 3, 5 years after surgery, with the ORs of 1.72 (95% CI: 1.24-2.41), 3.75 (95% CI: 2.94-4.78) and 5.64 (95% CI: 4.35-7.31), respectively. CONCLUSIONS: One-year morbidity and mortality are higher in LT than in LR for patients with HCC. However, long-term survival and tumor-free survival rates are higher in patients treated with LT than those treated with LR.
Subject(s)
Carcinoma, Hepatocellular/surgery , Hepatectomy , Liver Neoplasms/surgery , Liver Transplantation , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Disease Progression , Disease-Free Survival , Hepatectomy/adverse effects , Hepatectomy/mortality , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Liver Transplantation/adverse effects , Liver Transplantation/mortality , Neoplasm Recurrence, Local , Odds Ratio , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Zero-dimensional (0D)-two-dimensional (2D) hybrid photodetectors have received widespread attention due to their outstanding photoelectric performances. However, these devices with high performances mainly employ quantum dots that contain toxic elements as sensitizing layers, which restricts their practical applications. In this work, we used eco-friendly AgInGaS quantum dots (AIGS-QDs) as a highly light-absorbing layer and molybdenum diselenide (MoSe2) as a charge transfer layer to construct a 0D-2D hybrid photodetector. Notably, we observed that MoSe2 strongly quenches the photoluminescence (PL) of AIGS-QDs and decreases the decay time of PL in the MoSe2/AIGS-QDs heterojunction. The MoSe2/AIGS-QDs hybrid photodetector demonstrates a responsivity of 14.3 A W-1 and a high detectivity of 6.4 × 1011 Jones. Moreover, the detectivity of the hybrid phototransistor is significantly enhanced by more than three times compared with that of the MoSe2 photodetector. Our work suggests that 0D-2D hybrid photodetectors with multiplex I-III-VI QDs provide promising potential for future high-sensitivity photodetectors.
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AIM: To elucidate the molecular mechanisms underlying the immunosuppressive effects of emodin isolated from Rheum palmatum L. METHODS: Human T cells were isolated from the peripheral venous blood of 10 healthy adult donors. Cell viability was analyzed with MTT assay. AO/EB and Annexin V/PI staining and DNA damage assay were used to detect cell apoptosis. Fluorescence staining was used to detect the levels of ROS, the mitochondrial membrane potential and intracellular Ca(2+). Colorimetry was used to detect the levels of MDA and total SOD and GSH/GSSG ratio. The expression and activity of caspase-3, -4, and -9 were detected with Western blotting and a fluorometric assay. Western blotting was also used to detect the expression of Bcl-2, Bax, cytochrome C, and endoplasmic reticulum (ER) markers. RESULTS: Emodin (1, 10, and 100 µmol/L) inhibited the growth of human T cells and induced apoptosis in dose- and time dependent manners. Emodin triggered ER stress and significantly elevated intracellular free Ca(2+) in human T cells. It also disrupted mitochondrial membrane potential, and increased cytosolic level of cytochrome C, and the levels of activated cleavage fragments of caspase-3, -4, and -9 in human T cells. Furthermore, emodin significantly increased the levels of ROS and MDA, inhibited both SOD level and GSH/GSSG ratio in human T cells, whereas co-incubation with the ROS scavenger N-acetylcysteine (NAC, 20 µmol/L) almost completely blocked emodin-induced ER stress and mitochondrial dysfunction in human T cells, and decreased the caspase cascade-mediated apoptosis. CONCLUSION: Emodin exerts immunosuppressive actions at least partly by inducing apoptosis of human T cells, which is triggered by ROS-mediated ER stress and mitochondrial dysfunction.
Subject(s)
Apoptosis/drug effects , Emodin/pharmacology , Endoplasmic Reticulum Stress/drug effects , Mitochondria/drug effects , Reactive Oxygen Species/metabolism , T-Lymphocytes/drug effects , Apoptosis/physiology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Endoplasmic Reticulum Stress/physiology , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/physiology , Mitochondria/physiology , T-Lymphocytes/physiologyABSTRACT
Objective: To develop and validate an MRI-radiomics nomogram for the prognosis of pancreatic ductal adenocarcinoma (PDAC). Background: "Radiomics" enables the investigation of huge amounts of radiological features in parallel by extracting high-throughput imaging data. MRI provides better tissue contrast with no ionizing radiation for PDAC. Methods: There were 78 PDAC patients enrolled in this study. In total, there were 386 radiomics features extracted from MRI scan, which were screened by the least absolute shrinkage and selection operator algorithm to develop a risk score. Cox multivariate regression analysis was applied to develop the radiomics-based nomogram. The performance was assessed by discrimination and calibration. Results: The radiomics-based risk-score was significantly associated with PDAC overall survival (OS) (P < 0.05). With respect to survival prediction, integrating the risk score, clinical data and TNM information into the nomogram exhibited better performance than the TNM staging system, radiomics model and clinical model. In addition, the nomogram showed fine discrimination and calibration. Conclusions: The radiomics nomogram incorporating the radiomics data, clinical data and TNM information exhibited precise survival prediction for PDAC, which may help accelerate personalized precision treatment. Clinical trial registration: clinicaltrials.gov, identifier NCT05313854.
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Gallbladder cancer (GBC) is a major malignant carcinoma of the biliary tract with extremely poor prognosis. Currently, there is no useful therapy strategies for GBC treatment, indicating the unmet mechanism researches for GBC. In this study, our data showed that SNHG15 expression significantly up-regulated and its high expression associated with poor overall survival of patients suffer from GBC. Functional experiments showed that SNHG15 depletion delayed the proliferation and enhanced the apoptosis of GBC tumor cells under the nutrition stress condition, which further confirmed in the subcutaneous xenograft model and liver metastasis model. Mechanistically, SNHG15 could interact with AMPK and facilitate the phosphorylation of AMPK to Tuberous sclerosis complex TSC2, resulting in mTOR suppression and autophagy enhancement, and finally, conferring the GBC cell sustain proliferation under nutrition stress. Taken together, our findings revealed that SNHG15 promotes GBC tumor progression by enhancing the autophagy under poor nutrition tumor microenvironment, which could be a promising targets for GBC.
Subject(s)
Carcinoma , Gallbladder Neoplasms , Humans , AMP-Activated Protein Kinases/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Tumor Microenvironment , AnimalsABSTRACT
Soy isoflavones are natural tyrosine kinase inhibitors closely associated with decreased morbidity and mortality of various tumors. The activation of tyrosine kinases such as ERBB2 is the mechanism by which cholecystitis transforms into gallbladder cancer (GBC), therefore, it is important to investigate the relationship between long-term exposure to soy isoflavones and the occurrence and progression of GBC. This case-control study (n = 85 pairs) found that the high level of plasma soy isoflavone-genistein (GEN) was associated with a lower risk of gallbladder cancer (≥326.00 ng/mL compared to ≤19.30 ng/mL, crude odds ratio 0.15, 95% CI 0.04-0.59; P for trend = 0.016), and that the level of GEN exposure negatively correlated with Ki67 expression in GBC tissue (n = 85). Consistent with these results, the proliferation of GBC cells was inhibited in the long-term exposure models of GEN in vitro and in vivo. The long-term exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the function of the PTK6-AKT-GSK3ß axis, leading to downregulation of the MCM complex in GBC cells. In summary, long-term exposure to GEN associated with soy products intake might play a certain role in preventing GBC and even inhibiting the proliferation of GBC cells.
Subject(s)
Carcinoma in Situ , Gallbladder Neoplasms , Humans , Genistein/pharmacology , Gallbladder Neoplasms/metabolism , Case-Control Studies , Cell ProliferationABSTRACT
OBJECTIVE: To compare the outcomes of the transhepatic hilar approach and conventional approach for surgical treatment of Bismuth types III and IV perihilar cholangiocarcinoma. METHODS: We retrospectively reviewed the medical records of 82 patients who underwent surgical resection of Bismuth types III and IV perihilar cholangiocarcinoma from 2008 to 2016. The transhepatic hilar approach and conventional approach was used in 36 (43.9%) and 46 (56.1%) patients, respectively. Postoperative complications and overall survival were compared between the two approaches. RESULTS: Similar clinical features were observed between the patients treated by the conventional approach and those treated by the transhepatic hilar approach. The transhepatic hilar approach was associated with less intraoperative bleeding and a lower percentage of Clavien grade 0 to II complications than the conventional approach. However, the transhepatic hilar approach was associated with a higher R0 resection rate and better overall survival. Multivariate analysis showed that using the transhepatic hilar approach, the Memorial Sloan-Kettering Cancer Center classification, and R0 resection were independent risk factors for patient survival. CONCLUSION: The transhepatic hilar approach might be the better choice for surgical resection of Bismuth types III and IV perihilar cholangiocarcinoma because it is associated with lower mortality and improved survival.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Klatskin Tumor , Bile Duct Neoplasms/surgery , Bismuth , Cholangiocarcinoma/surgery , Hepatectomy , Humans , Klatskin Tumor/surgery , Retrospective Studies , Treatment OutcomeABSTRACT
Background: The mesh infection is mostly related to the gram-negative bacteria, such as Escherichia coli (E. coli) for emergency surgery of incarcerated hernia. However, few study investigated the effects of E. coli concentration, mesh materials and antibiotic prophylaxis on mesh infection after hernioplasty. The aim of this study was to evaluate the bacterial resistance to E. coli for three different materials of mesh, and to measure the minimum E. coli concentration for mesh infection with and without antibiotic prophylaxis in a rat model. Methods: Three types of mesh (polytetrafluoroethylene, polypropylene, and biologic meshes) were used in the repair of an acute ventral hernia rat model in the setting of different concentrations of E. coli loads and antibiotics. At the 8th day after surgery, mesh samples were sent for microbiologic and histologic analyses. Results: The positive rates of bacterial culture increased with E. coli concentration. The biologic mesh showed better bacterial resistance compared to polytetrafluoroethylene mesh and polypropylene mesh when the concentration of E. coli ranges from 106 CFU/ml to 108 CFU/ml (P = 0.002 and P = 0.029, respectively). Prophylactical ceftriaxone treatment could not decrease the colonization rate of E. coli at 106 CFU/ml or 108 CFU/ml in each group (P > 0.05). The scores of neovascularization in polypropylene mesh and biologic mesh were similar, which was higher than that of polytetrafluoroethylene mesh (P < 0.05). Compared with other meshes, biologic mesh showed better tolerance to 106 CFU/ml E. coli with respect to inflammation, depth of inflammation, neovascularization, cellular repopulation and foreign body giant cells. Conclusion: The biologic mesh had better E. coli resistance compared to polytetrafluoroethylene mesh and polypropylene mesh when the E. coli concentration is higher than 106 CFU/ml in rats. Antibiotic prophylaxis was useful when the contamination was not particularly severe.
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[This corrects the article on p. 9497 in vol. 20, PMID: 25071344.].