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Conventional treatments have shown a limited efficacy for pancreatic cancer, and immunotherapy is an emerging option for treatment of this highly fatal malignancy. Neoantigen is critical to improving the efficacy of tumor-specific immunotherapy. The cancer and peripheral blood specimens from human leukocyte antigen (HLA)-A0201 positive pancreatic cancer patient were subjected to next-generation sequencing and bioinformatics analyses were performed to screen high-affinity and highly stable neoepitopes. The activation of cytotoxic T lymphocytes (CTLs) by the mutBCL2A111-20 neoepitope targeting B-cell lymphoma 2-related protein A1 (BCL2A1) mutant epitope was investigated, and the cytotoxicity of mutBCL2A111-20 neoepitope-specific CTLs to pancreatic cancer cells was evaluated. The mutBCL2A111-20 neoepitope was found to present a high immunogenicity and induce CTLs activation and proliferation, and was cytotoxic to mutBCL2A111-20 neoepitope-loaded T2 cells and pancreatic cancer PANC-1-Neo and A2-BxPC-3-Neo cells that overexpressed mutBCL2A111-20 neoepitopes, appearing a targeting neoepitope specificity. In addition, high BCL2A1 expression correlated with a low 5-year progress free interval (PFI) among pancreatic cancer patients. Our findings provide experimental supports to individualized T-cell therapy targeting mutBCL2A111-20 neoepitopes, and provide an option of immunotherapy for pancreatic cancer.
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Hepatocellular carcinoma (HCC) exhibits high incidence and mortality rates in China. Most cases are often diagnosed at late stages and require multi-strategy therapies. In recent years, immune checkpoint inhibitors (ICIs), particularly programmed cell death protein 1 (PD-1) antibodies, have demonstrated effectiveness in comprehensive HCC treatment. However, the efficacy and prognosis vary greatly among patients. Screening suitable patients and predicting outcomes are crucial for improving the efficacy of ICIs. Although PD-L1 expression levels in tumor cells have been used as predictors of PD-1/PD-L1 antibody therapy, they may not consistently correlate with clinical response in some studies; thus, exploring new biomarkers is necessary. The neutrophil-to-lymphocyte ratio (NLR) emerged as a new predictor of ICI immunotherapy efficacy, and its application in HCC is worth exploring. This study utilizes the Cancer Genome Atlas Liver Hepatocellular Carcinoma Collection (TCGA-LIHC) project in the Genomic Data Commons (GDC) database for methylation and transcriptome data analysis. The correlation between NLR and ICI immunotherapy efficacy for HCC was evaluated, identifying differentially expressed genes. Analysis revealed 74 up-regulated and 445 down-regulated genes in the high-NLR group compared to the low-NLR group. NLR-related differential methylation analysis identified 68 hypermethylated and 65 hypomethylated probes in the NLR high group. Furthermore, a machine learning model using 27 intersecting genes predicted PD-1 antibody therapy efficacy, achieving an AUC value of 0.813. In summary, we established a predictive model for HCC immunotherapy based on 27 genes related to differential expressions and NLR-associated methylation, showing significant potential for clinical research potential in this field.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Neoplasias Hepáticas/patología , Neutrófilos/patología , Linfocitos/patologíaRESUMEN
Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive malignant tumor arising within the liver, with a 5-year survival rate of only 20-40% after surgery. The role of interleukin-8 (IL-8) in ICC progression remains elusive. A transcriptomic approach based on IL-8 stimulation first revealed significant upregulation of the prometastatic gene CD97 and key epithelial-mesenchymal transition (EMT) factors E-cadherin and vimentin. Immunohistochemistry of 125 ICC tissues confirmed the positive correlation between IL-8 and CD97. Multivariable Cox regression indicated that they are both independent predictors of ICC prognosis. Mechanistically, IL-8 treatment induced CD97 expression at 50 and 100 ng/ml in QBC-939 and QBE cells, respectively. Moreover, the induction of cell migration and invasion upon IL-8 treatment was attenuated by CD97 RNA interference, and the expression of EMT-associated genes was dramatically inhibited. To determine whether CXCR1 or CXCR2 are downstream effectors of IL-8, siCXCR2 was applied and shown to significantly attenuate the oncogenic effects of IL-8 by inhibiting the phosphorylation of PI3K/AKT. Finally, the induction of CD97 expression by the PI3K pathway was verified by treatment with the inhibitor LY294002. In vivo, the significant tumor growth and lung metastasis effects induced by intraperitoneal injection of IL-8 were greatly inhibited by silencing CD97 in nude mice. Collectively, the study presents a novel mechanism of the IL-8-CXCR2-PI3K/AKT axis in regulating CD97 expression, which leads to ICC metastasis mainly through EMT. The study may provide alternatives for targeting the tumor microenvironment in metastatic ICC.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Animales , Ratones , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Colangiocarcinoma/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Interleucina-8 , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Microambiente Tumoral , HumanosRESUMEN
Protein sulfoconjugation, or sulfation, represents a critical post-translational modification (PTM) process that involves the attachment of sulfate groups to various positions of substrates within the protein peptides or glycoproteins. This process plays a dynamic and complex role in many physiological and pathological processes. Here, we summarize the importance of sulfation in the fields of oncology, virology, drug-induced liver injury (DILI), inflammatory bowel disease (IBD), and atherosclerosis. In oncology, sulfation is involved in tumor initiation, progression, and migration. In virology, sulfation influences viral entry, replication, and host immune response. In DILI, sulfation is associated with the incidence of DILI, where altered sulfation affects drug metabolism and toxicity. In IBD, dysregulation of sulfation compromises mucosal barrier and immune response. In atherosclerosis, sulfation influences the development of atherosclerosis by modulating the accumulation of lipoprotein, and the inflammation, proliferation, and migration of smooth muscle cells. The current review underscores the importance of further research to unravel the underlying mechanisms and therapeutic potential of targeting sulfoconjugation in various diseases. A better understanding of sulfation could facilitate the emergence of innovative diagnostic or therapeutic strategies.
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Aterosclerosis , Enfermedades Inflamatorias del Intestino , Humanos , Péptidos/metabolismo , GlicoproteínasRESUMEN
BACKGROUND: The primary aim of the present study was to explore risk factors for portal vein system thrombosis following splenectomy. METHODS: A systematic search of PubMed, Embase and Cochrane libraries was conducted to identify original studies that fulfilled the inclusion criteria. Raw data on potential risk factors for portal vein system thrombosis after splenectomy were extracted for meta-analysis. Subsequently, a sensitivity analysis was conducted to verify the stability of the results. RESULTS: Eighteen studies with 626 thrombosis events from 1807 splenectomy met the inclusion criteria. Larger spleen volume (SMD 0.44, P = 0.000), broader splenic vein diameter (WMD 2.30, P = 0.000), broader portal vein diameter (WMD 2.08, P = 0.000), a lower velocity of portal blood flow (WMD -0.91, P = 0.001), decreased platelet count (WMD -5.14, P = 0.007), decreased white blood cell (WMD -0.40, P = 0.027), decreased haemoglobin (WMD -9.14, P = 0.002), ascites (OR 1.81, P = 0.003) and bleeding history before surgery (OR 1.88, P = 0.002) were identified to be factors that exacerbated the risk of portal vein system thrombosis after splenectomy. Sex, age, preoperative prothrombin time, postoperative platelet count, postoperative D-dimer, operation time and intraoperative blood loss, did not increase the risk of thrombosis. CONCLUSION: Larger spleen volume, broader splenic vein diameter, broader portal vein diameter, a lower velocity of portal blood flow, ascites, bleeding history before surgery, decreased platelet count, white blood cell and haemoglobin may increase the risk of portal vein system thrombosis.
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Hipertensión Portal , Trombosis , Trombosis de la Vena , Humanos , Vena Porta , Esplenectomía/efectos adversos , Esplenectomía/métodos , Ascitis/complicaciones , Complicaciones Posoperatorias/etiología , Factores de Riesgo , Trombosis de la Vena/epidemiología , Trombosis de la Vena/etiología , Hipertensión Portal/etiología , Trombosis/etiología , HemoglobinasRESUMEN
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein-protein interactions and cellular functions. Solute carrier family 35 member B (SLC35B2) is a key transporter that transports the universal sulfate donor 3'-phosphoadenosine 5'-phosphosulfate into the Golgi apparatus where the protein sulfation occurs. The goal of this study was to determine whether and how the SLC35B2-TPST2 axis of tyrosine sulfation plays a role in PDAC. METHODS: Gene expression was analyzed in PDAC patients and mice. Human PDAC MIA PaCa-2 and PANC-1 cells were used for in vitro studies. TPST2-deficient MIA PaCa-2 cells were generated to assess xenograft tumor growth in vivo. Mouse PDAC cells derived from the KrasLSL-G12D/+;Tp53L/+;Pdx1-Cre (KPC) mice were used to generate Tpst2 knockout KPC cells to evaluate tumor growth and metastasis in vivo. RESULTS: High expressions of SLC35B2 and TPST2 were correlated with poor PDAC patient survival. Knocking down SLC35B2 or TPST2, or pharmacologicically inhibiting sulfation, resulted in the inhibition of PDAC cell proliferation and migration in vitro. TPST2-deficient MIA PaCa-2 cells showed inhibited xenograft tumor growth. Orthotopic inoculation of Tpst2 knockout KPC cells in mice showed inhibition of primary tumor growth, local invasion, and metastasis. Mechanistically, the integrin ß4 was found to be a novel substrate of TPST2. Inhibition of sulfation destabilizes integrin ß4 protein, which may have accounted for the suppression of metastasis. CONCLUSIONS: Targeting the SLC35B2-TPST2 axis of tyrosine sulfation may represent a novel approach for therapeutic intervention of PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Tirosina , Integrina beta4/metabolismo , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Transportadores de Sulfato , Proteínas de la Membrana/metabolismo , Sulfotransferasas/genética , Sulfotransferasas/metabolismoRESUMEN
BACKGROUND: This study aims to investigate whether indocyanine green (ICG) tumor imaging helps determine the safe surgical margin in laparoscopic hepatectomy. PATIENTS AND METHODS: Eighty-six patients with hepatic malignancies [including hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM)] were included in this study. ICG-R15 testing was performed 5-7 days before surgery. Fluorescence staining of the tumor was detected by a fluorescent laparoscope, and the width of fluorescence band surrounding tumor was measured by an electronic vernier caliper. RESULTS: The positive rate of hepatic malignant lesions successfully stained by ICG fluorescence was 96.0% (95/99). HCC with better differentiation demonstrated non-rim fluorescence patterns, while cases with poor differentiation demonstrated rim patterns. CRLM uniformly demonstrated rim pattern. The width of fluorescence surrounding tumors was 0 in HCC with non-rim patterns. The minimum width of fluorescence surrounding tumors in poor differentiated HCC and CRLM were 2.4 ± 1.9 mm and 2.8 ± 2.5 mm, respectively, with no significant difference (P > 0.05). ICG fluorescence imaging revealed eight small lesions, which were not detected preoperatively in seven patients, of which five lesions were confirmed as malignancies by pathology. CONCLUSIONS: Resection along the ICG fluorescence edge can supply a safe surgical margin only for CRLM, but not for HCC. Otherwise, ICG fluorescence tumor imaging can preliminarily determine the pathological type of hepatic malignancies and histological differentiation of HCC and help detect small lesions that cannot be detected preoperatively.
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Carcinoma Hepatocelular , Laparoscopía , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Verde de Indocianina , Hepatectomía/métodos , Estudios Retrospectivos , Márgenes de Escisión , Imagen Óptica/métodos , Laparoscopía/métodosRESUMEN
STING agonist has recently gained much attention for cancer treatment, but the therapeutic potential of STING agonist is hampered by STING-associated tumor immune resistance. In this work, guided by both bioinformatics and computer modeling, we rationally designed a "one stone hits two birds" nanoparticle-based strategy to simultaneously activate STING innate immune response while eliminating STING-associated immune resistance for the treatment of pancreatic ductal adenocarcinoma (PDAC). We discovered that the ultra-small sized micellar system based on gemcitabine-conjugated polymer (PGEM), which showed superior capacity of penetration in pancreatic tumor spheroid model and orthotopic tumor model, could serve as a novel "STING agonist". The activation of STING signaling in dendritic cells (DCs) by PGEM increased both innate nature killer (NK) and adaptive anti-tumor T cell response. However, activation of STING signaling by PGEM in tumor cells also drove the induction of chemokines CCL2 and CCL7, resulting in immune resistance by recruiting tumor associated macrophage (TAM) and myeloid-derived suppressor cells (MDSCs). Through the combination of computer modeling and experimental screening, we developed a dual delivery modality by incorporating a CCR2 (the receptor shared by both CCL2 and CCL7) antagonist PF-6309 (PF) into PGEM micellar system. Our studies demonstrated that PGEM/PF formulation significantly reduced pancreatic tumor burden and induced potent anti-tumor immunity through reversing the CCL2/CCL7-mediated immunosuppression. Moreover, PGEM/PF sensitized PDAC tumors to anti-PD-1 therapy, leading to complete suppression/eradication of the tumors. Our work has shed light to the multi-faceted role of STING activation and provided a novel immunotherapy regimen to maximize the benefit of STING activation for PDAC treatment. In addition, this work paved a new way for bioinformatics and computer modeling-guided rational design of nanomedicine.
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Background: Reduced brain volume, impaired cognition, and possibly a range of psychoneurological disorders have been reported in patients with non-alcoholic fatty liver disease (NAFLD); however, no underlying cause has been specified. Here, Mendelian randomization (MR) was employed to determine the causative NAFLD effects on cortical structure. Methods: We used pooled-level data from FinnGen's published genome-wide association study (GWAS) of NAFLD (1908 cases and 340,591 healthy controls), as well as published GWAS with NAFLD activity score (NAS) and fibrosis stage-associated SNPs as genetic tools, in addition to the Enigma Consortium data from 51,665 patients, were used to assess genetic susceptibility in relation to changes with cortical thickness (TH) and surface area (SA). A main estimate was made by means of inverse variance weighted (IVW), while heterogeneity and pleiotropy were detected using MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier to perform a two-sample MR analysis. Results: At the global level, NAFLD reduced SA (beta = -586.72 mm2, se = 217.73, p = 0.007) and several changes in the cortical structure of the cerebral gyrus were found, with no detectable pleiotropy. Conclusion: NAFLD causally affects cortical structures, which supports the presence of an intricate liver-brain axis.
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Diabetes and related metabolic syndrome are common metabolic disorders. Gestational diabetes mellitus (GDM) is rather prevalent in the clinic. Although most GDM resolves after therapeutic intervention and/or after delivery, the long-term health effect of GDM remains to be better understood. The constitutive androstane receptor (CAR), initially characterized as a xenobiotic receptor, was more recently proposed to be a therapeutic target for obesity and type 2 diabetes mellitus (T2DM). In this study, high-fat diet (HFD) feeding was used to induce GDM. Upon delivery, GDM mice were returned to chow diet until the metabolic parameters were normalized. Parous non-GDM control females or metabolically normalized GDM females were then subjected to HFD feeding to induce nongestational obesity and T2DM. Our results showed that GDM sensitized mice to metabolic abnormalities induced by a second hit of HFD. Treatment with the CAR agonist 1,4-bis [2-(3,5 dichloropyridyloxy)] benzene efficiently attenuated GDM-sensitized and HFD-induced obesity and T2DM, including decreased body weight, improved insulin sensitivity, inhibition of hyperglycemia and hepatic steatosis, increased oxygen consumption, and decreased adipocyte hypertrophy. In conclusion, our results have established GDM as a key risk factor for the future development of metabolic disease. We also propose that CAR is a therapeutic target for the management of metabolic disease sensitized by GDM.
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Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Síndrome Metabólico , Animales , Receptor de Androstano Constitutivo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Gestacional/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Humanos , Síndrome Metabólico/complicaciones , Ratones , Obesidad/metabolismo , EmbarazoRESUMEN
The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and ß isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Oxiesteroles , Animales , Carcinoma Hepatocelular/inducido químicamente , Transformación Celular Neoplásica/genética , Interleucina-6 , Neoplasias Hepáticas/inducido químicamente , Ratones , Ratones TransgénicosRESUMEN
Activation of the hepatic stellate cells (HSCs) is a key pathogenic event in liver fibrosis. Protein S-glutathionylation (PSSG) of cysteine residues is a distinct form of oxidative response that modifies protein structures and functions. Glutaredoxin-1 (GLRX) reverses PSSG by liberating glutathione (GSH). In this study, we showed that pirfenidone (PFD), an anti-lung fibrosis drug, inhibited HSC activation and liver fibrosis in a GLRX-dependent manner. Glrx depletion exacerbated liver fibrosis, and decreased GLRX and increased PSSG were observed in fibrotic mouse and human livers. In contrast, overexpression of GLRX inhibited PSSG and liver fibrosis. Mechanistically, the inhibition of HSC activation by GLRX may have been accounted for by deglutathionylation of Smad3, which inhibits Smad3 phosphorylation, leading to the suppression of fibrogenic gene expression. Our results have established GLRX as the therapeutic target of PFD and uncovered an important role of PSSG in liver fibrosis. GLRX/PSSG can be both a biomarker and a therapeutic target for liver fibrosis.
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BACKGROUND: Foreign bodies stuck in the throat and esophagus can be discharged through the digestive tract. Esophageal-lodged foreign bodies can cause secondary injury or detrimental response, with hepatic abscess being one such, albeit rare, outcome. Review and discussion of the few case reports on such instances will help to improve the overall understanding of such conditions and aid in differential diagnosis to improve patient outcome. CASE SUMMARY: A 51-year-old female patient with pre-existing diabetes visited our hospital following a 15-d experience of chills and fever. Both plain and enhanced magnetic resonance imaging and color Doppler ultrasound examination of the liver and gallbladder revealed a space-occupying lesion in the caudate lobe of the liver (7.8 cm × 6.0 cm × 5.0 cm). Initially, a malignant tumor was suspected, but differential diagnosis was unable to exclude the possibility of hepatic abscess. Conservative anti-infection therapy produced a less than ideal outcome. Additional examination by hepatobiliary imaging with computed tomography suggested a foreign body present in the upper abdomen and hepatic abscess, and subsequent endoscopy revealed a sinus tract in the anterior wall of the duodenal bulb. Therefore, surgery was performed to remove the object (fishbone) and drain the abscess. After a 2-wk uneventful recovery, the patient was discharged. The final diagnosis was foreign body-induced hepatic abscess of the caudate lobe. CONCLUSION: Differential diagnosis is important for hepatic masses, and systematic examination and physician awareness can aid in diagnosing and curing such rare conditions.
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BACKGROUND & AIMS: Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study was to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis. METHODS: Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2ΔIE) were created and subjected to dextran sodium sulfate-induced colitis and colonic carcinogenesis induced by a combined treatment of azoxymethane and dextran sodium sulfate or azoxymethane alone. RESULTS: The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2ΔIE mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2ΔIE mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids, including the Farnesoid X receptor antagonist bile acid tauro-ß-muricholic acid, and deficiency in the formation of bile acid sulfates in the colon of Papss2ΔIE mice. CONCLUSIONS: We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.
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Neoplasias Asociadas a Colitis/prevención & control , Colitis/prevención & control , Colon/enzimología , Mucosa Intestinal/enzimología , Mucinas/metabolismo , Complejos Multienzimáticos/metabolismo , Sulfato Adenililtransferasa/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Colitis/enzimología , Colitis/genética , Colitis/patología , Neoplasias Asociadas a Colitis/enzimología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/patología , Colon/patología , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Humanos , Mucosa Intestinal/patología , Metaboloma , Metabolómica , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multienzimáticos/genética , Pronóstico , Receptores Citoplasmáticos y Nucleares/metabolismo , Sulfato Adenililtransferasa/genéticaRESUMEN
PURPOSE: Primary hepatic angiosarcoma is a very rare and highly malignant tumor with poor prognosis. It is difficult to diagnose because of the lack of typical clinical features, and the treatment protocols for PHA are also not clear. Therefore, this study wants to find out the clinical characteristics and surgical treatments of primary hepatic angiosarcoma. METHODS: Among 8990 patients diagnosed with primary malignant tumor of the liver from January 2000 to December 2019 in our hospital, only four patients were diagnosed with primary hepatic angiosarcoma. The demographics, clinical manifestation, past history, serology test results, MRI features, pathology, treatment modality and prognosis of four patients were collected and analyzed. RESULTS: Three of four patients had no clinical symptoms, while one patient's symptom was abdominal pain. The levels of tumor markers of all four patients were within the normal reference range and serological tests were negative for hepatitis B and C virus. The MRI imaging findings of all four patients were mixed mass with highly disordered vascular characteristics. All four patients were misdiagnosed preoperatively. One patient who underwent hepatic lobectomy was still alive for about 18 months after surgery. One patient who underwent hepatic lobectomy has survived for only 6 months due to severe pneumonia. The other two patients who received transarterial chemoembolization survived 16 months and 11 months respectively. CONCLUSION: The clinical symptoms of primary hepatic angiosarcoma are not typical, and primary hepatic angiosarcoma is easily misdiagnosed. The typical imaging manifestations are structural disorder and heterogeneous tumor. Hepatic lobectomy and transarterial chemoembolization may be important surgical treatments to improve the prognosis of patients.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Hemangiosarcoma , Neoplasias Hepáticas , Hemangiosarcoma/cirugía , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Estudios RetrospectivosRESUMEN
Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.
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Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver have been extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.