RESUMO
BACKGROUND & AIMS: Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear. METHODS: We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established diethylnitrosamine/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdhf/fLyz2cre) or Kupffer cells (Xdhf/fClec4fcre). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux. RESULTS: We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment, especially hypoxia. Using HCC-inflicted mice (Xdhf/fLyz2cre and Xdhf/fClec4fcre), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8+ T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of α-ketoglutarate was enhanced within XOR-depleted macrophages. XOR inhibited α-ketoglutarate production by interacting with IDH3α catalytic sites (K142 and Q139). The increased IDH3α activity caused increased adenosine and kynurenic acid production in TAMs, which enhanced the immunosuppressive effects of TAMs and CD8+ T cells. CONCLUSIONS: The XOR-IDH3α axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs. IMPACT AND IMPLICATIONS: Immunotherapies have been widely applied to the treatment of hepatocellular carcinoma (HCC), but to date they have been associated with unsatisfactory efficacy. The tumor microenvironment of HCC is full of different infiltrating immune cells. Tumor-associated macrophages (TAMs) are vital components in the tumor microenvironment and are involved in HCC progression. Herein, we confirm the downregulation of XOR expression in TAMs isolated from human HCC. The loss of XOR in monocyte-derived macrophages increases IDH3 activity and results in an increase in α-ketoglutarate production, which can promote M2-like polarization. Additionally, XOR-null TAMs derived from monocytes promote CD8+ T-cell exhaustion via the upregulation of immunosuppressive metabolites, including adenosine and kynurenic acid. Given the prevalence and high rate of incidence of HCC and the need for improved therapeutic options for patients, our findings identify potential therapeutic targets that may be further studied to develop improved therapies.
RESUMO
Circular RNA has been revealed to participate in multiple biological functions and contribute to various diseases' progression. This study aims to clarify the role of circ_0003028 and its potential molecular mechanism in hepatocellular carcinoma (HCC). The levels of circ_0003028, miR-498, and ornithine decarboxylase 1 (ODC1) mRNA were examined by quantitative real-time PCR. The cell proliferation ability was detected via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, colony formation, and 5-ethynyl-2'-deoxyuridine assays. The apoptotic rate was evaluated through flow cytometry. The migration and invasion capacity was tested by using wound healing assay and transwell assay. The protein levels of E-cadherin, N-cadherin, and vimentin were measured by western blot assay. The ceRNA regulatory mechanism of circ_0003028 was observed via dual-luciferase reporter and RNA pull-down assays. The mice xenograft models were constructed to confirm the oncogenicity of circ_0003028 in HCC in vivo . Circ_0003028 and ODC1 were upregulated, whereas miR-498 was downregulated in HCC tissues and cells. Circ_0003028 knockdown inhibited cell proliferation and metastasis, and promoted apoptosis. MiR-498 was a direct target of circ_0003028, and inhibition of miR-498 reversed the inhibitory effect of circ_0003028 silencing on HCC progression. Moreover, ODC1 was a direct target of miR-498 and ODC1 overexpression abated the anticancer roles of miR-498 in HCC. Additionally, circ_0003028 regulated ODC1 expression by sponging miR-498. Finally, we found that circ_0003028 could induce epithelial-mesenchymal transition of HCC cells by exosome pathway. In brief, the results demonstrated that circ_0003028 exerted tumourigenicity roles via miR-498/ODC1 signaling axis, providing a promising biomarker and therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Animais , Camundongos , RNA Circular/genética , Carcinoma Hepatocelular/genética , Ornitina Descarboxilase/genética , Neoplasias Hepáticas/genética , Proliferação de Células , MicroRNAs/genética , Linhagem Celular TumoralRESUMO
BACKGROUND: Hydrocephalus caused by spontaneous intracerebral hemorrhage (ICH) is an independent risk factor with adverse effects on the progression of the disease. Until now, the choice of intraventricular catheter placement and intraventricular fibrinolysis (IVF) has been mainly based on the personal experience of the neurosurgeon. OBJECTIVE: We will introduce the clinical effect of the new external ventricular drainage (EVD), an independent innovation of our medical center, on ICH patients, hoping to inspire more neurosurgeons to apply our method. METHODS: In this open retrospective study, We analyzed the clinical data, radiological manifestations, and prognostic scores of 10 patients with the spontaneous intracerebral hemorrhage who received transfrontal lateral ventricle puncture and drainage under laser navigation in our hospital. RESULTS: A total of 10 patients with an average age of 58.10±9.97 years were enrolled for emergency surgery. All operations were completed according to the consensus specifications. It took 11.25±3.81 days for the intracranial pressure to return to normal. On admission, patients had a median GCS of 10. The median preoperative GCS was 8. The median GCS at discharge score was 15. At discharge, the median NIHSS score was 4. After 6 months of follow-up, patients had a median NIHSS score of 4. At discharge, the median ADL score of patients was 85. After 6 months of follow-up, the median ADL score of the patients was 95. CONCLUSION: In treating patients with ICH, the emergency treatment of transfrontal external ventricular drainage combined with OMMAYA sac implantation under laser navigation is a surgical method worthy of further study.
Assuntos
Drenagem , Hidrocefalia , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Drenagem/efeitos adversos , Hemorragia Cerebral/cirurgia , Hidrocefalia/cirurgia , Hidrocefalia/etiologia , Ventrículos Laterais , Resultado do TratamentoRESUMO
Metal-catalyzed C-H glycosylation reactions with glycosyl chloride donors have emerged as a useful strategy for the synthesis of C-glycosides. Previously, palladium and nickel complexes were reported to catalyze C-H glycosylation reactions using amide-linked bidentate auxiliaries. Herein, a ruthenium-catalyzed ortho C-H glycosylation reaction of arenes with various glycosyl chloride donors using a monodentate pyridine directing group is developed. Preliminary mechanistic studies indicated that two-electron oxidative addition and reductive elimination of ruthenocycle intermediate led to the glycosylation products.
Assuntos
Cloretos , Rutênio , Catálise , Glicosilação , PiridinasRESUMO
Gastric cancer (GC) is the most frequent digestive system malignant tumour and the second most common cause of cancer death globally. Cancer stem cell (CSC) is a small percentage of cancer cells in solid tumours that have differentiation, self-renewal and tumorigenic capabilities. They have an active participation in the initiation, development, metastasis, recurrence and resistance of tumours to chemotherapy and radiotherapy. Gastric cancer stem cells (GCSCs) have been shown to be correlated with GC initiation and metastasis. In this study, we found that TAK1 expression level in GC tissues was significantly increased compared to the adjacent non-cancerous tissues by RT-qPCR, Western blot and immunohistochemistry. TAK1 has been identified as a critical molecule that promoted a variety of malignant GC phenotypes both in vivo and in vitro and promoted the self-renewal of GCSCs. Mechanistically, TAK1 was up-regulated by IL-6 and prevented the degradation of yes-associated protein (YAP) in the cytoplasm by binding to YAP. Thus, TAK1 promoted the SOX2 and SOX9 transcription and the self-renewal and oncogenesis of GCSCs. Our findings provide insights into the mechanism of self-renewal and tumorigenesis of TAK1 in GCSCs and have broad implications for clinical therapies.
Assuntos
Carcinogênese/genética , MAP Quinase Quinase Quinases/genética , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOXB1/genética , Neoplasias Gástricas/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Autorrenovação Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Interleucina-6/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Fator de Crescimento Transformador beta/genética , Proteínas de Sinalização YAP/genéticaRESUMO
BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self-renewal and maintenance of liver CSCs remain poorly understood. APPROACH AND RESULTS: We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in human HCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin-specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch-like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2-related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15-mediated Nrf2-KEAP1 signaling to block liver CSCs and tumor propagation. CONCLUSION: We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.
Assuntos
Carcinoma Hepatocelular , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Hepáticas , Fator 2 Relacionado a NF-E2/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Xantina Desidrogenase/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Autorrenovação Celular , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos , Transdução de Sinais , Células Tumorais Cultivadas , UbiquitinaçãoRESUMO
OBJECTIVE: To explore the preliminary application of three-dimensional (3D) printing technique in preoperative localization of meningiomas in primary hospitals. PATIENTS AND METHODS: The enrolled subjects were 13 patients in the Department of Neurosurgery, Affiliated Hospital of Binzhou Medical College, Shandong Province between December 2018 and June 2020, including CT or MRI data from eight cases of brain meningiomas and five cases of cerebrospinal meningiomas. The Mimics 17.0 software package was applied to reconstruct the 3D images and print out the 3D guide. The authors placed the 3D printed guide on the surgical area for preoperative tumor location. RESULTS: The 3D printed guides for all patients were successfully designed and printed out. Simpson grade I resection was performed on all tumors. No significant hematoma, brain edema, or neurological symptoms were observed in the postoperative patients, and the surgical results were good. CONCLUSIONS: The authors can use 3D printing technology for precise preoperative localization of meningiomas. Grassroots hospitals can also use this technique because of its economic, accurate, and personalized characteristics.
Assuntos
Neoplasias Meníngeas , Meningioma , Hospitais , Humanos , Imageamento Tridimensional , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Impressão TridimensionalRESUMO
C-vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C-vinyl glycosides via Pd-catalyzed directed C-H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C-H bond of allylamines and the δ C-H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio- and stereoselectivity. The resulting C-vinyl glycosides can be further converted to a variety of C-alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C-vinyl glycosides from easily accessible starting materials.
RESUMO
Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in-depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. ß-arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver-specific diseases. However, the role and underlying mechanism of ß-arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down-regulated during liver I/R injury. Hepatocyte-specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro-inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6-mediated Lysine 6-linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.
Assuntos
Hepatopatias/etiologia , Hepatopatias/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , beta-Arrestina 1/genética , beta-Arrestina 1/metabolismo , Animais , Apoptose , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatócitos/metabolismo , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Hepatopatias/patologia , Lisina/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Traumatismo por Reperfusão/patologia , UbiquitinaçãoRESUMO
BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. This study investigated the role of ß-Arrestin1 (ARRB1) in the progression of NASH. METHODS: Liver tissue from patients with NASH and controls were obtained to evaluate ARRB1 expression. NASH models were established in Arrb1-knockout and wild-type mice fed either a high-fat diet (HFD) for 26 weeks or a methionine/choline-deficient (MCD) diet for 6 weeks. RESULTS: ARRB1 expression was reduced in liver samples from patients with NASH. Reduced Arrb1 levels were also detected in murine NASH models. Arrb1 deficiency accelerated steatohepatitis development in HFD-/MCD-fed mice (accompanied by the upregulation of lipogenic genes and downregulation of ß-oxidative genes). Intriguingly, ARRB1 was found to interact with growth differentiation factor 15 (GDF15) and facilitated the transportation of GDF15 precursor (pro-GDF15) to the Golgi apparatus for cleavage and maturation. Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of Arrb1 deletion both in vitro and in vivo. Re-expression of Arrb1 in the NASH models ameliorated the liver disease, and this effect was greater in the presence of pro-GDF15 overexpression. By contrast, the effect of pro-GDF15 overexpression alone was impaired in Arrb1-deficient mice. In addition, the severity of liver disease in patients with NASH was negatively correlated with ARRB1 expression. CONCLUSION: ARRB1 acts as a vital regulator in the development of NASH by facilitating the translocation of GDF15 to the Golgi apparatus and its subsequent maturation. Thus, ARRB1 is a potential therapeutic target for the treatment of NASH. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is associated with the progressive dysfunction of lipid metabolism and a consequent inflammatory response. Decreased ARRB1 is observed in patients with NASH and murine NASH models. Re-expression of Arrb1 in the murine NASH model ameliorated liver disease, an effect which was more pronounced in the presence of pro-GDF15 overexpression, highlighting a promising strategy for NASH therapy.
Assuntos
Progressão da Doença , Fator 15 de Diferenciação de Crescimento/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais/genética , beta-Arrestina 1/deficiência , beta-Arrestina 1/metabolismo , Adulto , Animais , Deficiência de Colina/complicações , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Complexo de Golgi/metabolismo , Humanos , Lipogênese/genética , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adulto Jovem , beta-Arrestina 1/genéticaRESUMO
Hepatic ischemia-reperfusion (I/R) injury is a major challenge in liver resection and transplantation surgeries. Previous studies have revealed that guanine nucleotide-binding protein G(i)α2 (GNAI2) was involved in the progression of myocardial and cerebral I/R injury, but the role and function of GNAI2 in hepatic I/R have not been elucidated. The hepatocyte-specific GNAI2 knockout (GNAI2hep-/-) mice were generated and subjected to hepatic I/R injury. Primary hepatocytes isolated from GNAI2hep-/- and GNAI2flox/flox mice were cultured and challenged to hypoxia-reoxygenation insult. The specific function of GNAI2 in I/R-triggered hepatic injury and the underlying molecular mechanism were explored by various phenotypic analyses and molecular biology methods. In this study, we demonstrated that hepatic GNAI2 expression was significantly increased in liver transplantation patients and wild-type mice after hepatic I/R. Interestingly, hepatocyte-specific GNAI2 deficiency attenuated I/R-induced liver damage, inflammation cytokine expression, macrophage/neutrophil infiltration, and hepatocyte apoptosis in vivo and in vitro. Mechanistically, up-regulation of GNAI2 phosphorylates mixed-lineage protein kinase 3 (MLK3) through direct binding, which exacerbated hepatic I/R damage via MAPK and NF-κB pathway activation. Furthermore, blocking MLK3 signaling reversed GNAI2-mediated hepatic I/R injury. Our study firstly identifies GNAI2 as a promising target for prevention of hepatic I/R-induced injury and related liver diseases.-Sun, Q., He, Q., Xu, J., Liu, Q., Lu, Y., Zhang, Z., Xu, X., Sun, B. Guanine nucleotide-binding protein G(i)α2 aggravates hepatic ischemia-reperfusion injury in mice by regulating MLK3 signaling.
Assuntos
Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Hepatopatias/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Células Cultivadas , Regulação para Baixo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/genética , Regulação da Expressão Gênica , Hepatócitos/metabolismo , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Transdução de Sinais , MAP Quinase Quinase Quinase 11 Ativada por MitógenoRESUMO
A mild and convenient method for the synthesis of reverse glycosyl fluorides (RGFs) has been developed that is based on the silver-promoted radical dehydroxymethylative fluorination of carbohydrates. A salient feature of the reaction is that furanoid and pyranoid carbohydrates furnish structurally diverse RGFs bearing a wide variety of functional groups in good to excellent yields. Intramolecular hydrogen atom transfer experiments revealed that the reaction involves an underexploited radical fluorination that proceeds via ß-fragmentation of sugar-derived primary alkoxyl radicals. Structurally divergent RGFs were obtained by catalytic C-F bond activation, and our method thus offers a concise and efficient strategy for the synthesis of reverse glycosides by late-stage diversification of RGFs. The potential of this method is showcased by the preparation and diversification of sotagliflozin, leading to the discovery of a promising SGLT2 inhibitor candidate.
RESUMO
BACKGROUND: Although hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S-adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis. METHODS: Eighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups. RESULTS: There were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-α between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT and AST than non-cirrhotic patients. CONCLUSIONS: Taken together, our preliminary findings suggest that preoperative administration of SAMe is useful and safe for reducing the HIRI in partial hepatectomy, especially for HCC patients whose disease is associated with chronic HBV infection and cirrhosis.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Hepatite B/cirurgia , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/cirurgia , Traumatismo por Reperfusão/tratamento farmacológico , S-Adenosilmetionina/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/virologia , Feminino , Seguimentos , Hepatite B/complicações , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/virologia , Testes de Função Hepática , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismoRESUMO
HOXA13 is a member of homeobox genes that encode transcription factors regulating embryonic development and cell fate. Abnormal HOXA13 expression was reported in hepatocellular carcinoma (HCC), but its correlation with tumor angiogenesis and prognosis still remain unclear. This study was aimed to uncover the expression, diagnostic and prognostic significance of HOXA13 in HCC. Immunohistochemistry was performed to detect HOXA13 expression in HCC and corresponding paracarcinomatous tissues from 90 patients. Enzyme-linked immunosorbent assay was used to detect serum HOXA13 in 90 HCC patients and 20 healthy volunteers. Receiver operating characteristics was analyzed to calculate diagnostic accuracy of serum HOXA13, alpha-fetoprotein (AFP) and their combination. Immunoreactivity of HOXA13 was detected in 72.2% of HCC, and 12.2% of adjacent non-cancerous samples. HOXA13 expression was significantly associated with tumor size, microvascular invasion, pathological grade, tumor capsula status, AFP level, tumor-node-metastasis stage and positively correlated with VEGF (p < 0.001) and microvessel density (p < 0.001). The combination of serum HOXA13 and AFP had a markedly higher area under the curve than HOXA13 alone. HOXA13 expression was associated with unfavorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001). Multivariate analysis indicated that patients with HOXA13-expressing tumors had a significantly shorter OS (p = 0.030) and DFS (p = 0.005) than those with HOXA13-negative tumors. Thus, HOXA13 expression possibly plays an important role in tumor angiogenesis, progression and prognosis of HCC. Moreover, we demonstrate that serum HOXA13 may serve as a biomarker for early HCC diagnosing and predicting outcome.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Proteínas de Homeodomínio/sangue , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Adulto , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Neovascularização Patológica , Prognóstico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
The radical decarboxylative azidation of structurally diverse uronic acids has been established as an efficient approach to reverse glycosyl azides and rare sugar-derived glycosyl azides under the action of Ag2CO3, 3-pyridinesulfonyl azide, and K2S2O8. The power of this method has been highlighted by the divergent synthesis of 4'-C-azidonucleosides using Vorbrüggen glycosylation of nucleobases with 4-C-azidofuranosyl acetates. The antiviral assessment of the resulting nucleosides revealed one compound as a potential inhibitor of covalently closed circular DNA.
Assuntos
Antivirais , Azidas , Nucleosídeos , Azidas/química , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Estrutura Molecular , Nucleosídeos/química , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , GlicosilaçãoRESUMO
INTRODUCTION: Liver fibrosis is a major cause of morbidity and mortality among in patients with chronic hepatitis. Radiomics, particularly of the spleen, may improve diagnostic accuracy and treatment strategies. External validations are necessary to ensure reliability and generalizability. METHODS: In this retrospective study, we developed 3 radiomics models using contrast-enhanced computed tomography scans from 167 patients with liver fibrosis (training group) between January 2020 and December 2021. Radiomic features were extracted from arterial venous, portal venous, and equilibrium phase images. Recursive feature selection random forest and the least absolute shrinkage and selection operator logistic regression were used for feature selection and dimensionality reduction. Performance was assessed by area under the curve, C-index, calibration plots, and decision curve analysis. External validation was performed on 114 patients from 2 institutions. RESULTS: Twenty-five radiomic features were significantly associated with fibrosis stage, with 80% of the top 10 features originating from portal venous phase spleen images. The radiomics models showed good performance in the validation cohort (C-indices 0.723-0.808) and excellent calibration. Decision curve analysis indicated clinical benefits, with machine learning-based radiomics models (Random Forest score and support vector machine based radiomics score) providing more significant advantages. DISCUSSION: Radiomic features offer significant benefits over existing serum indices for staging virus-driven liver fibrosis, underscoring the value of radiomics in enhancing diagnostic accuracy. Specifically, radiomics analysis of the spleen presents additional noninvasive options for assessing fibrosis, highlighting its potential in improving patient management and outcomes.
RESUMO
Background: Hypertensive intracerebral hemorrhage (HICH) is a severe life-threatening disease, and its incidence has gradually increased in recent years. Due to the particularity and diversity of its bleeding sites, the early treatment of hematoma needs to be more meticulous and accurate, and minimally invasive surgery is often one of the measures that are commonly adopted now. The lower hematoma debridement and the navigation template created by 3D printing technology were compared in the external drainage of a hypertensive cerebral hemorrhage. Then the effect and feasibility of the two operations were explicitly evaluated. Material and methods: We performed a retrospective analysis of all eligible patients with HICH who underwent laser-guided hematoma evacuation or hematoma puncture under 3D-navigated molds at the Affiliated Hospital of Binzhou Medical University from January 2019 to January 2021. A total of 43 patients were treated. Twenty-three patients were treated with laser navigation-guided hematoma evacuation (group A); 20 patients were treated with 3D navigation minimally invasive surgery (group B). A comparative study was conducted between the two groups to evaluate the preoperative and postoperative conditions. Results: The preoperative preparation time of the laser navigation group was significantly shorter than that of the 3D printing group. The operation time of the 3D printing group was better than that of the laser navigation group (0.73 ± 0.26â h vs. 1.03 ± 0.27â h P = 0.00070). In the improvement in the short-term postoperatively, there was no statistically significant difference between the laser navigation group and the 3D printing group (Median hematoma evacuation rate P = 0.14); And in the three-month follow-up NIHESS score, there was no significant difference between the two (P = 0.82). Conclusion: Laser-guided hematoma removal is more suitable for emergency operations, with real-time navigation and shortened preoperative preparation time; hematoma puncture under a 3D navigation mold is more personalized and shortens the intraoperative time course. There was no significant difference in therapeutic effect between the two groups.
RESUMO
Tumor-associated mesenchymal stem cells (MSCs) play a critical role in the growth and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the crosstalk between MSCs and HCC cells is not completely understood. Here, HCC cells were treated with or without conditioned medium of MSCs (CM-MSC), and examined for differential expression of long non-coding RNAs (lncRNAs). Knockdown and overexpression experiments were conducted to explore the function of the lncRNA DNM3OS in MSC-induced HCC growth and metastasis. CM-MSC treatment led to a concentration-dependent induction of DNM3OS in HCC cells. DNM3OS was significantly upregulated in HCC compared to adjacent liver tissues. High DNM3OS expression was associated with TNM stage, vascular invasion, and poor prognosis of HCC patients. Silencing of DNM3OS inhibited HCC cell proliferation and invasion in vitro and tumorigenesis and metastasis in vivo. Overexpression of DNM3OS enhanced HCC cell proliferation, invasion, and metastasis. Biochemically, DNM3OS was mainly localized in the nucleus and physically interacted with KDM6B. The association of DNM3OS with KDM6B induced the expression of TIAM1 through reduction of H3K27me3 at the TIAM1 promoter. TIAM1 overexpression restored the proliferation and invasion of DNM3OS-depleted HCC cells. Our data delineate a mechanism by which MSCs accelerate HCC growth and metastasis through a DNM3OS/KDM6B/TIAM1 axis.
Assuntos
Carcinoma Hepatocelular/patologia , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/química , RNA Longo não Codificante/genética , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genética , Animais , Carcinoma Hepatocelular/genética , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Meios de Cultivo Condicionados/química , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos , Metástase Neoplásica , Transplante de NeoplasiasRESUMO
Gastric cancer metastasis associated long noncoding RNA (GMAN), a long noncoding RNA, is associated with metastasis in gastric cancer. However, its underlying mechanisms in hepatocellular carcinoma (HCC) are unclear. We found that lncRNA-GMAN was significantly overexpressed in HCC tissues. GMAN expression is associated with vascular invasion, histological grade, tumor, node, metastasis (TNM) stage, short overall survival, and disease-free survival. Knockdown of GMAN induced apoptosis and suppressed invasive and migration potential in vitro and vivo, whereas ectopic GMAN expression produced the opposite effect. We also found that the inhibition of apoptosis, rather than promotion of proliferation, was responsible for GMAN-enhanced cellular viability. Mechanistic analyses indicated that GMAN directly combined with eukaryotic translation initiation factor 4B (eIF4B) and promoted its phosphorylation at serine-422 by preventing eIF4B binding and dephosphorization of the protein phosphatase 2A subunit B. The results demonstrated the stability of p-eIF4B and the elevation of mRNA translation and anti-apoptosis-related protein expression, which further induced proliferation and metastasis of HCC. The current study demonstrates that GMAN regulates the progression of HCC by inhibiting apoptosis and promoting the survival of cancer cells.