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Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.
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OBJECTIVE: Selecting interventions for patients with solitary hepatocellular carcinoma (HCC) remains a challenge. Despite gross classification being proposed as a potential prognostic predictor, its widespread use has been restricted due to inadequate studies with sufficient patient numbers and the lack of established mechanisms. We sought to investigate the prognostic impacts on patients with HCC of different gross subtypes and assess their corresponding molecular landscapes. DESIGN: A prospective cohort of 400 patients who underwent hepatic resection for solitary HCC was reviewed and analysed and gross classification was assessed. Multiomics analyses were performed on tumours and non-tumour tissues from 49 patients to investigate the mechanisms underlying gross classification. Inverse probability of treatment weight (IPTW) was used to control for confounding factors. RESULTS: Overall 3-year survival rates varied significantly among the four gross subtypes (type I: 91%, type II: 80%, type III: 74.6%, type IV: 38.8%). Type IV was found to be independently associated with poor prognosis in both the entire cohort and the IPTW cohort. The four gross subtypes exhibited three distinct transcriptional modules. Particularly, type IV tumours exhibited increased angiogenesis and immune score as well as decreased metabolic pathways, together with highest frequency of TP53 mutations. Patients with type IV HCC may benefit from adjuvant intra-arterial therapy other than the other three subtypes. Accordingly, a modified trichotomous margin morphological gross classification was established. CONCLUSION: Different gross types of HCC showed significantly different prognosis and molecular characteristics. Gross classification may aid in development of precise individualised diagnosis and treatment strategies for HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Prospective Studies , Multiomics , PrognosisABSTRACT
BACKGROUND: Previously published work has demonstrated that combining gemcitabine with irreversible electroporation (IRE) results in increased drug delivery to pancreatic adenocarcinoma cells in vivo. This study assessed the efficacy of IRE + gemcitabine and IRE + FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), the impact of the superior regimen on survival, and the safety of electrochemotherapy in human subjects. METHODS: Histologic analysis was performed after in vitro and in vivo treatment of S2013 and Panc-1 pancreatic cancer cells and S2013 orthotopic tumors, respectively, and levels of apoptotic machinery and cell cycle proteins were evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: Electrochemotherapy (ECT) with IRE and FOLFIRINOX resulted in increased tumor cells apoptosis compared with gemcitabine, gemcitabine + IRE, and FOLFIRINOX alone, and significantly improved overall survival when compared with mice treated with IRE or FOLFIRINOX. Increased tumor cell apoptosis, caspase-3 mRNA, active caspase-3 protein, and decreased cell proliferation were noted at the time of death or euthanasia in the ECT group compared with folinic acid alone. In five patients, ECT with either FOLFIRINOX or gemcitabine was well-tolerated and resulted in no dose-limiting toxicities. CONCLUSIONS: ECT thus results in synergistic antitumor activity compared with either treatment modality used alone, resulting in increased tumor cell apoptosis as well as decreased tumor cell proliferation and improved overall survival. Pilot data suggest that ECT represents a promising modality for the treatment of patients with locally advanced pancreatic cancer. TRIAL REGISTRATION: The human subject portion of this work was conducted as part of an investigator-initiated clinical trial at the University of Louisville (NCT03484299).
Subject(s)
Adenocarcinoma , Antineoplastic Combined Chemotherapy Protocols , Electrochemotherapy , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease Models, Animal , Fluorouracil/administration & dosage , Humans , Irinotecan/administration & dosage , Leucovorin/administration & dosage , Mice , Oxaliplatin/administration & dosage , Pancreatic Neoplasms/drug therapy , Treatment Outcome , GemcitabineABSTRACT
BACKGROUND AND OBJECTIVE: Polycystic liver disease (PCLD) represents a group of genetic disorders that include autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (iPCLD). There is currently no definitive treatment except for liver transplantation. The aim of this study was to assess the expression level of aquaporin 1 (AQP1) on the PCLD cysts with different sizes and provide the potential therapeutic target. METHODS: We collected 3 normal bile ducts, and recruited 8 patients with simple liver cyst disease, 24 patients with ADPKD, and 17 patients with iPCLD. AQP1 expression in different types of cyst walls and in normal bile ducts was detected using real time quantitative PCR, western blot and immunofluorescence staining. We also compared AQP1 expression levels in cysts of different sizes. Besides, ionic concentrations, pH and osmolality of cyst fluid were analyzed. RESULTS: The results showed that AQP1 expression in PCLD cysts was significantly higher than that in simple liver cysts and the normal bile ducts. In addition, a comparable increasing trend was found in cysts of smaller sizes to cysts of larger sizes. pH values, the sodium and chloride concentrations were higher in cyst fluid than that in the serum. CONCLUSIONS: AQP1 was overexpressed in cystic cholangiocytes. A tendency of increased AQP1 protein expression in correlation with the cyst size was also found. These observations offered a direction into the molecular mechanisms of cyst expansion and maybe provide new treatment strategies to reduce fluid secretion into liver cysts.
Subject(s)
Aquaporin 1/metabolism , Cysts/diagnosis , Liver Diseases/diagnosis , Adult , Aged , Biomarkers/metabolism , Blotting, Western , Case-Control Studies , Cysts/metabolism , Cysts/pathology , Female , Fluorescent Antibody Technique , Humans , Liver Diseases/metabolism , Liver Diseases/pathology , Male , Middle Aged , Real-Time Polymerase Chain Reaction , Up-RegulationABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0059604.].
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Heat history monitor: Combination of the sublimation and adsorption processes of specific dyes can be used as a measure of accumulated heat exposure. Mass transfer from the sublimation layer to the adsorption layer strongly depends on temperature and results in a gradual color change in the adsorption layer. The total color change reflects the accumulated heat exposure.
Subject(s)
Coloring Agents/chemistry , Hot Temperature , Adsorption , Azulenes/chemistry , Sesquiterpenes/chemistry , Sesquiterpenes, GuaianeABSTRACT
Background: Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant soft tissue sarcoma with a poor prognosis and no clear effective clinical means for treatment, and there has been no significant progress in research within this field in recent years. This study aimed to investigate the epidemiology, etiology, clinical features, diagnostic modalities, various treatment modalities, and prognosis of retroperitoneal undifferentiated pleomorphic sarcoma and to contribute to the clinical management of this type of disease. In this study, we report a case of undifferentiated pleomorphic sarcoma with a primary origin in the retroperitoneum. Undifferentiated pleomorphic sarcoma occurring in the retroperitoneum is rarely reported. Case description: A 59-year-old man with abdominal distension and pain for 4 months presented to our hospital after the failure of conservative treatment. A 9.6â cm by 7.4â cm mass in the left retroperitoneum was found on a CT scan of the whole abdomen with three degrees of enhancement. After surgical treatment, the tumor and the left kidney were completely removed, and pathological examination and genetic sequencing showed an apparent undifferentiated pleomorphic sarcoma. The patient subsequently declined follow-up treatment and is currently alive and well. Conclusions: At the current level of clinical technology, the treatment of undifferentiated pleomorphic sarcoma is still in the exploratory stage, and the scarcity of clinical cases of this disease may have hindered the acquisition of clinical trials and research data for this disease. At present, the first choice of treatment for undifferentiated pleomorphic sarcoma is still radical resection. In the existing clinical studies, there are no strong data to support the effect of preoperative neoadjuvant chemoradiotherapy and adjuvant chemoradiotherapy in clinical practice. Similar to other diseases, the use of radiotherapy and chemotherapy before and after surgery may be a potential treatment for this disease in the future. Targeted therapy for this disease still needs further exploration, and we need more reports on related diseases to promote future treatment and research on this disease.
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BACKGROUND: Excess body weight has been found to associate with an increased risk of lymphomas and some metabolic pathways are currently recognized in lymphomagenesis. Bioactive lipid metabolites such as sphingosine-1-phosphate (S1P) have been proposed to play an important role linking obesity and lymphomas. However, the underlying mechanism(s) of S1P signaling in obesity-lymphomagenesis have not been well addressed. METHODS: The gene expression of sphingosine kinase (SPHK), lymphoma prognosis, and S1P production were analyzed using Gene Expression Omnibus (GEO) and human lymphoma tissue array. Obesity-lymphoma mouse models and lymphoma cell lines were used to investigate the S1P/SPHK-YAP axis contributing to obesity-lymphomagenesis. By using the mouse models and a monocyte cell line, S1P-mediated polarization of macrophages in the tumor microenvironment were investigated. RESULTS: In human study, up-regulated S1P/SPHK1 was found in human lymphomas, while obesity negatively impacted progression-free survival and overall survival in lymphoma patients. In animal study, obesity-lymphoma mice showed an aggressive tumor growth pattern. Both in vivo and in vitro data suggested the existence of S1P-YAP axis in lymphoma cells, while the S1P-ALOX15 signaling mediated macrophage polarization towards TAMs exacerbated the lymphomagenesis. In addition, treatment with resveratrol in obesity-lymphoma mice showed profound effects of anti-lymphomagenesis, via down-regulating S1P-YAP axis and modulating polarization of macrophages. CONCLUSION: S1P/S1PR initiated the feedback loops, whereby S1P-S1PR1/S1PR3-YAP signaling mediated lymphomagenesis contributing to tumor aggressive growth, while S1P-ALOX15 signaling mediated TAMs contributing to immunosuppressive microenvironment in obesity-lymphoma. S1P-targeted therapy could be potentially effective and immune-enhancive against obesity-lymphomagenesis.
Subject(s)
Neoplasms , Signal Transduction , Animals , Mice , Humans , Sphingosine-1-Phosphate Receptors/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Disease Models, Animal , Obesity/complications , Obesity/genetics , Tumor Microenvironment , Arachidonate 15-Lipoxygenase , Arachidonate 12-Lipoxygenase/metabolismABSTRACT
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and has become one of the most lethal malignancies in the world. Although chemotherapy remains a cornerstone of cancer therapy, the number of chemotherapeutic drugs approved for HCC is low, and emerging therapeutics are needed. Melarsoprol (MEL) is an arsenic-containing drug, and has been applied in the treatment of human African trypanosomiasis at the late stage. In this study, the potential of MEL for HCC therapy was investigated for the first time using in vitro and in vivo experimental approaches. A folate-targeted polyethylene glycol-modified amphiphilic cyclodextrin nanoparticle was developed for safe, efficient and specific delivery of MEL. Consequently, the targeted nanoformulation achieved cell-specific uptake, cytotoxicity, apoptosis and migration inhibition in HCC cells. Furthermore, the targeted nanoformulation significantly prolonged the survival of mice with orthotopic tumor, without causing toxic signs. This study indicates the potential of the targeted nanoformulation as an emerging chemotherapy option for treating HCC.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Cyclodextrins , Liver Neoplasms , Nanoparticles , Humans , Animals , Mice , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Melarsoprol/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Cyclodextrins/therapeutic use , Folic Acid , Cell Line, Tumor , Polyethylene Glycols/therapeutic useABSTRACT
Restoration of exhausted hepatitis B virus (HBV)-specific CD8+ T cells is one of the important strategies for inhibition of viral replication. The role of interleukin (IL)-33 to recovery of CD8+ T cell activity is not fully elucidated. We investigated the effect of IL-33 on viral-specific CD8+ T cell responses in chronic hepatitis B (CHB) patients in vitro by both phenotypic and functional analysis. Plasma IL-33 was downregulated in CHB patients, while effective antiviral therapy rescued IL-33 expression. There was no significant difference of IL-33 receptor mRNA relative level in CD8+ T cells between CHB patients and controls. IL-33 induced the proliferation of HBV-specific CD8+ T cells, and reduced programmed death-1 expression on HBV-specific CD8+ T cells. IL-33 promoted the direct cytolytic activity of CD8+ T cells against HepG2.2.15 cells through boosting perforin and granzyme B production. Furthermore, IL-33 administration increased HBV-specific CD8+ T cell-mediated HBV replication and HBV antigen secretion mainly via enhancement of interferon-γ and tumor necrosis factor-α. IL-33 reinvigorated antiviral activity of HBV-specific CD8+ T cells, revealing that IL-33 might contribute to viral clearance in persistent HBV infection.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , CD8-Positive T-Lymphocytes , Hepatitis B/drug therapy , Hepatitis B virus , Humans , Interleukin-33/metabolism , Interleukin-33/therapeutic useABSTRACT
Background: Pancreatic neuroendocrine tumors (pNETs) are rare neuroendocrine neoplasms (NENs) for which little is known about their clinical features, treatment options, and survival prognosis. The purpose of this study is to evaluate the risk factors affecting the overall survival (OS) and cancer-specific survival (CSS) in patients with grade 1 pNETs (G1 pNETs) and to provide a new theoretical basis for clinical diagnosis and treatment. Methods: A retrospective analysis of individuals with G1 pNETs registered in the Surveillance, Epidemiology, End Results (SEER) database was performed. Risk factors affecting OS and CSS were analyzed using Kaplan-Meier analysis, Cox proportional hazards model, and Fine-Gray competing-risk model. Results: A total of 751 patients were included, most of whom were white (77.2%) women (53.9%) under the age of 60 years (54.9%), of whom 66 died of pNETs (8.78%) and 34 died of other causes (4.52%). Patients who were older than 60 years at diagnosis (hazard ratio [HR] = 1.866, 95% confidence interval [CI]: 1.242-2.805) had worse OS. And stage in the regional extent (HR = 1.777, 95% CI: 1.006-3.137) or distance extent (HR = 4.540, 95% CI: 2.439-8.453) had worse OS. Patients who delayed treatment after diagnosis had shorter CSS (delayed treatment < 1 month: HR = 1.933, 95% CI: 0.863-4.333; delayed treatment ≥ 1 month: HR = 2.208; 95% CI:1.047-4.654). Patients with lymph node metastasis (HR = 1.989, 95% CI: 1.137-3.479) or distant metastasis (HR = 5.625, 95% CI: 1.892-16.726) had worse CSS. Acceptance of surgery can significantly improve the patient's OS and CSS. OS (partial pancreatectomy [PP]: HR = 0.350, 95% CI: 0.182-0.672; pancreatectomy and duodenectomy [PD]: HR = 0.426, 95% CI: 0.222-0.815; total pancreatectomy [TP]: HR = 0.495, 95% CI: 0.193-1.267). CSS(PP: HR = 0.148, 95% CI: 0.0054-0.401; PD: HR = 0.332, 95% CI: 0.150-0.730; TP: HR = 0.69, 95% CI: 0.254-1.872). Conclusion: Age and stage were identified as independent risk factors for OS. Delayed treatment, N stage and M stage were independent risk factors for CSS. Only surgery was identified as independent protective factors for OS and CSS.
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With inconsistent findings, evidence has been obtained in recent years that metabolic disorders are closely associated with the development of lymphomas. Studies and multiple analyses have been published also indicating that some solid tumor survivors develop a secondary lymphoma, whereas some lymphoma survivors subsequently develop a second malignant neoplasm (SMN), particularly solid tumors. An interaction between the multiple etiologic factors such as genetic factors and late effects of cancer therapy may play an important role contributing to the carcinogenesis in patients with metabolic diseases or with a primary cancer. In this review, we summarize the current knowledge of the multiple etiologic factors for lymphomagenesis, focusing on the SMN in lymphoma, secondary lymphomas in primary cancers, and the lymphomas associated to metabolic disorders/diseases, which have been received less attention previously. Further, we also review the data of coexistence of lymphomas and hepatocellular carcinoma (HCC) in patients with infection of hepatitis C virus and hepatitis B virus.
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Objectives: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment (TME). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity. Methods: In vitro human PDAC cell lines MiaPaca2 and S2-013 were treated with 5µ m 3-Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 µ m 5-Azacytidine (5-AZA, a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56/BL7 mice were treated with anti-PD-L1 combined with DZNep and 5-AZA. Short hairpin knockdown (KD) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment (DZNep and 5-AZA). qRT-PCR and microarray assays were performed for the evaluation of Th1-attracting chemokines and cancer-associated antigen induction. Results: Drug treatments induced significant upregulation of gene expressions of Th1-attracting chemokines, CXCL9 and CXCL10, and the cancer-testis antigens, NY-ESO-1, LAGE and SSX-4 (P < 0.05). In orthotopic tumour models, inoculation of PAN02 cells or KPC cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic Pan02-KD model, the anti-PD-L1 treatment also caused significant tumour regression. Conclusion: We demonstrate that immunotherapy for PDAC can be potentiated with epigenetic therapy by increasing cancer-associated antigen expression and increased T-cell trafficking across the immunosuppressive tumour microenvironment via upregulation of the repressed chemokines and increased apoptosis with subsequent tumour regression.
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Irreversible electroporation (IRE) has been postulated to have an off-target effect on lesions not in the tumor-ablative field, possibly through heightened immunologic response. In this study, we evaluated whether combination IRE and immunotherapy would lead to increased tumor necrosis and T cell recruitment to both the treated tumors and tumors outside the local ablative field. An in vitro cell-IRE model was established to evaluate the ability of T lymphocytes (EL4 cell and HH cells) migration in response to Hepatocellular carcinoma (HCC) cells (Hepa1-6 and HepG2) with IRE treatment. An orthotopic HCC mouse model was established by implantation of 1mm^3 sections of Hepa1-6 tumor tissues into the right and left lobes of the liver. The Hepa1-6 cells and HepG2 cells with IRE treatment increased the migration ability of EL4 cell and HH cells, specifically when they were pretreated with immunotherapeutic agents in vitro. In the orthotopic HCC mouse model, IRE+immunotherapy treatment enhanced the necrosis and subpopulation of infiltrated CD8 positive cells, but attenuated the tumor associated inflammatory cells in both IRE target tumor tissues and IRE off-target tumor tissues from the mice with 4 weeks of immunotherapy following IRE. This study provided the evidence that combination of IRE and immunotherapy enhances tumor necrosis and immune responses, not only in the IRE-treated tumor but also in the off-target tumor.
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Background: Nonalcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD) and a potential precursor of hepatocellular carcinoma (HCC). In our previous studies, we found that endocrine fibroblast growth factor 21 (FGF21) played a key role in preventing the development of NASH, however, the FGF15/19 mediated-FGFR4 signaling worsened NASH and even contributed to the NASH-HCC transition. The aim of this study is to determine whether FGF15/FGFR4 signaling could alleviate or aggravate NASH in the FGF21KO mice. Methods: NASH models were established in FGF21KO mice fed with high fat methionine-choline deficient (HFMCD) diet to investigate FGF15/FGFR4 signaling during early stage NASH and advanced stage NASH. Human hepatocytes, HepG2 and Hep3B cells, were cultured with human enterocytes Caco-2 cells to mimic gut-liver circulation to investigate the potential mechanism of NASH development. Results: Significant increase of FGF15 production was found in the liver of the NASH-FGF21KO mice, however the increased FGF15 protein was unable to alleviate hepatic lipid accumulation. In contrast, up-regulated FGF15/19/FGFR4 signaling was found in the FGF21KO mice with increased NASH severity, as evident by hepatocyte injury/repair, fibrosis and potential malignant events. In in vitro studies, blockage of FGFR4 by BLU9931 treatment attenuated the lipid accumulation, up-regulated cyclin D1, and epithelial-mesenchymal transition (EMT) in the hepatocytes. Conclusion: The increased FGF15 in NASH-FGF21KO mice could not substitute for FGF21 to compensate its lipid metabolic benefits thereby to prevent NASH development. Up-regulated FGFR4 signaling in NASH-FGF21KO mice coupled to proliferation and EMT events which were widely accepted to be associated with carcinogenic transformation.
Subject(s)
Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Non-alcoholic Fatty Liver Disease/metabolism , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Signal Transduction , Acrylamides/pharmacology , Animals , Caco-2 Cells , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/metabolism , Diet, High-Fat , Fibroblast Growth Factors/genetics , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Quinazolines/pharmacology , Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 4/geneticsABSTRACT
RATIONALE: Hepatocellular carcinoma (HCC) with intracavitary metastasis extending to the heart, also known as inferior vena cava (IVC) tumor thrombus, is an extremely rare late-stage disease with no effective treatment. In fact, the median survival is reportedly less than 2 months; thus, there is an urgent need for better treatment. PATIENT CONCERNS: In this study, a 48-year-old patient was admitted to our hospital to seek medical treatment for advanced primary HCC with right atrial metastasis. DIAGNOSIS: The patient was diagnosed as primary HCC with a large mass in the right lobe of the liver and intracavitary metastasis to the right atrium. INTERVENTIONS: A new surgical treatment of right hemihepatectomy, complete resection of the involved IVC and the right atrium thrombus, plus reconstruction of the resected IVC using autologous pericardial tube graft were undertaken and successfully performed. OUTCOMES: The patient recovered rapidly, and 14 days after the surgical procedures, he was discharged from the hospital. Notably, serum levels of alpha-fetoprotein dropped to normal range and no clinical signs of recurrence were observed during follow-up. LESSONS: This report highlights an unusual case of right atrial metastasis from HCC. The surgical treatment appeared to be suitable and effective, together with postoperative administration of lenvatinib, a tyrosine kinase multitarget inhibitor selected by performing whole-exome sequencing. These therapies have offered favorable clinical outcomes such as prevention of recurrence and prolongation of patient survival. In addition, clinicians may benefit from our experience for their future treatment of patients with similar clinical conditions.
Subject(s)
Carcinoma, Hepatocellular/surgery , Heart Atria/abnormalities , Neoplasm Metastasis/diagnosis , Carcinoma, Hepatocellular/complications , Heart Atria/surgery , Hepatectomy/methods , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/surgery , Male , Middle Aged , Neoplasm Metastasis/physiopathology , Neoplasm Metastasis/therapy , Tomography, X-Ray Computed/methods , Treatment Outcome , Vena Cava, Inferior/surgeryABSTRACT
Rationale: Hepatocellular carcinoma (HCC) has been increasingly recognized in nonalcoholic steatohepatitis (NASH) patients. Fibroblast growth factor 21 (FGF21) is reported to prevent NASH and delay HCC development. In this study, the effects of FGF21 on NASH progression and NASH-HCC transition and the potential mechanism(s) were investigated. Methods: NASH models and NASH-HCC models were established in FGF21Knockout (KO) mice to evaluate NASH-HCC transition. IL-17A signaling was investigated in the isolated hepatic parenchymal cells, splenocytes, and hepatocyte and HCC cell lines. Results: Lack of FGF21 caused significant up-regulation of the hepatocyte-derived IL-17A via Toll-like receptor 4 (TLR4) and NF-κB signaling. Restoration of FGF21 alleviated the high NAFLD activity score (NAS) and attenuated the TLR4-triggered hepatocyte-IL-17A expression. The HCC nodule number and tumor size were significantly alleviated by treatments of anti-IL-17A antibody. Conclusion: This study revealed a novel anti-inflammatory mechanism of FGF21 via inhibiting the hepatocyte-TLR4-IL-17A signaling in NASH-HCC models. The negative feedback loop on the hepatocyte-TLR4-IL-17A axis could be a potential anti-carcinogenetic mechanism for FGF21 to prevent NASH-HCC transition.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Fibroblast Growth Factors/metabolism , Hepatocytes/metabolism , Interleukin-17/metabolism , Liver Neoplasms/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Toll-Like Receptor 4/metabolism , 3T3 Cells , Animals , Carcinoma, Hepatocellular/pathology , Cells, Cultured , Female , Hepatocytes/pathology , Humans , Kupffer Cells/metabolism , Kupffer Cells/pathology , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/pathology , Prospective Studies , Signal Transduction/physiologyABSTRACT
The combination of chemotherapy and phototherapy gives rise to a boom in cancer therapy methodology. An all-in-one nanoplatform is of particular interest for increased safety and efficacy geared toward personalized precision medicine. However, low drug loading efficiency, random dispersion and distribution without visualization are widespread concerns. Here, a reactive oxygen species (ROS) responsive drug delivery system for imaging-guided chemo-phototherapy was developed. Polymeric micelles were designed and synthesized using PTX (drug) and Cypate (fluorescence and photosensitizer) as hydrophobic segments and PEG as hydrophilic ones encapsulating PTX. Furthermore, folic acid, as a targeting moiety, was conjugated to PEG for directed drug delivery. We evaluated the ROS-responsive drug release profiles and chemo-phototherapy application in an anticancer therapy. The results suggest these biocompatible amphiphilic polymer conjugates would be promising for applications in imaging-guided chemo-phototherapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Micelles , Neoplasms/diagnostic imaging , Neoplasms/therapy , Optical Imaging , Phototherapy , Reactive Oxygen Species/metabolism , A549 Cells , Animals , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Drug Liberation , Endocytosis/drug effects , Hep G2 Cells , Humans , Mice, Inbred C57BL , Neoplasms/drug therapy , Paclitaxel/pharmacology , Paclitaxel/therapeutic useABSTRACT
Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) is a negative regulator of NF-κB activity. We previously reported that the paired tandem polymorphic dinucleotides TTâ¯>â¯A (rs148314165, rs200820567 of TNFAIP3) conferred the risk for systemic lupus erythematosus (SLE) in European and Korean populations. We investigated the genetic association of the TTâ¯>â¯A variants, as well as the functional coding variant rs2230926 in exon 3 of TNFAIP3 in 1229 Chinese Han SLE patients and 1608 matched population controls. We further evaluated the role of these variants in regulating expression of the TNFAIP3 gene and NF-κB signaling pathway in their peripheral blood mononuclear cells from Chinese SLE patients. The TTâ¯>â¯A variants and the TNFAIP3 exon 3 coding variant rs2230926 demonstrated significant associations in SLE (PTTâ¯>â¯Aâ¯=â¯8.96â¯×â¯10-12, odds ratio [OR]â¯=â¯2.07, 95% confidence interval [CI]â¯=â¯1.68-2.55). SLE patients carrying the risk A allele showed reduced messenger RNA expression of the TNFAIP3 gene and increased expression of NF-κB1 in PBMCs. Conditional analyses revealed that the TTâ¯>â¯A variants are likely to be causal variants in Chinese Han SLE patients. The TTâ¯>â¯A variants associated with Chinese Han SLE and negatively regulate the expression of the TNFAIP3 gene resulting in enhanced NF-κB activity.
Subject(s)
Genotype , Leukocytes, Mononuclear/physiology , Lupus Erythematosus, Systemic/genetics , Tumor Necrosis Factor alpha-Induced Protein 3/genetics , Adult , Cells, Cultured , China , Cohort Studies , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , NF-kappa B/metabolism , Polymorphism, Single Nucleotide , Risk , Signal Transduction , Young AdultABSTRACT
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel approach for performing liver resection, and the number of clinical applications of this technique has rapidly increased within recent years. ALPPS is important in patients who have insufficient residual liver volume and cannot undergo radical hepatic resection. The most common postoperative complications of ALPPS include biliary fistula and infection. To date, postoperative acute kidney injury following ALPPS has not been reported. The current study reports the case of a 63-year-old patient with hepatitis B-induced cirrhosis who underwent the first stage of ALPPS without completion of the second step. The patient developed postoperative acute kidney injury following ALPPS. The present case study suggests that the use of ALPPS in patients at risk of chronic renal damage should be approached with caution in order to avoid postoperative acute kidney injury. Furthermore, improvements in surgical techniques and skills of the surgeons performing the procedure are required to reduce the surgery duration and improve patient outcomes.