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Budd-Chiari syndrome (B-CS) is a rare and lethal condition characterized by hepatic venous outflow tract blockage. Gut microbiota has been linked to numerous hepatic disorders, but its significance in B-CS pathogenesis is uncertain. First, we performed a case-control study (Ncase = 140, Ncontrol = 63) to compare the fecal microbiota of B-CS and healthy individuals by metagenomics sequencing. B-CS patients' gut microbial composition and activity changed significantly, with a different metagenomic makeup, increased potentially pathogenic bacteria, including Prevotella, and disease-linked microbial function. Imbalanced cytokines in patients were demonstrated to be associated with gut dysbiosis, which led us to suspect that B-CS is associated with gut microbiota and immune dysregulation. Next, 16S ribosomal DNA sequencing on fecal microbiota transplantation (FMT) mice models examined the link between gut dysbiosis and B-CS. FMT models showed damaged liver tissues, posterior inferior vena cava, and increased Prevotella in the disturbed gut microbiota of FMT mice. Notably, B-CS-FMT impaired the morphological structure of colonic tissues and increased intestinal permeability. Furthermore, a significant increase of the same cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, IL-17F, and IL-13) and endotoxin levels in B-CS-FMT mice were observed. Our study suggested that gut microbial dysbiosis may cause B-CS through immunological dysregulation. IMPORTANCE: This study revealed that gut microbial dysbiosis may cause Budd-Chiari syndrome (B-CS). Gut dysbiosis enhanced intestinal permeability, and toxic metabolites and imbalanced cytokines activated the immune system. Consequently, the escalation of causative factors led to their concentration in the portal vein, thereby compromising both the liver parenchyma and outflow tract. Therefore, we proposed that gut microbial dysbiosis induced immune imbalance by chronic systemic inflammation, which contributed to the B-CS development. Furthermore, Prevotella may mediate inflammation development and immune imbalance, showing potential in B-CS pathogenesis.
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Síndrome de Budd-Chiari , Citocinas , Disbiose , Microbioma Gastrointestinal , Disbiose/microbiologia , Disbiose/imunologia , Microbioma Gastrointestinal/fisiologia , Síndrome de Budd-Chiari/imunologia , Síndrome de Budd-Chiari/microbiologia , Síndrome de Budd-Chiari/patologia , Humanos , Animais , Camundongos , Masculino , Estudos de Casos e Controles , Feminino , Citocinas/metabolismo , Citocinas/imunologia , Citocinas/genética , Adulto , Transplante de Microbiota Fecal , Pessoa de Meia-IdadeRESUMO
Objective: This study examines the effects of the 3S2E nursing management mode on patients with severe pneumonia in the intensive care unit's respiratory function, psychological status, and quality of life (ICU). Methods: According to a random number table, 82 ICU patients with severe pneumonia who were admitted between March 2021 and March 2022 were enrolled and assigned to the control and observation class (n = 41, respectively) in a 1 : 1 ratio. The observation class added 3S2E manner in addition to ordinary breastfeeding, whereas the control class received treatment in the usual nursing mode. The two groups' preintervention and postintervention times for mechanical ventilation, white blood cell count (WBC) recovery, duration of hospital stay, problems, respiratory function, psychological state, and living quality were compared. Results: Fever time abatement, mechanical ventilation time, WBC recovery time, and length of hospital stay in the observation category were found to be shorter in comparison with the control class (P < 0.05). In contrast to the other group, the observation group had fewer issues (P < 0.05). Both teams' oxygenation indices and SaO2 were higher after the intervention (P < 0.05), with the observation team's index being higher than the control group's index. The total SAS and SDS scores of the two groups were less in the postintervention period than in the preintervention period, with the observational class having lower postintervention SAS and SDS ratings than the comparison group (P < 0.05). The postintervention ratings in the observation class were higher than those in the control, and the World Health Organization Quality of Life (WHOQOL) scale scores in the 2 categories were greater after the intervention than they were before (P < 0.05). Conclusion: 3S2E nursing management model improves respiratory function, alleviates negative emotions, and improves living quality in ICU patients with severe pneumonia.
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We investigated the effects of gut microbiota and serum metabolite levels in patients with Budd-Chiari syndrome (B-CS) and their importance for guiding clinical management strategies. In total, 214 B-CS patients (93 untreated and 121 treated) and 41 healthy controls were enrolled. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography-mass spectrometry. The gut microbiota of the patients showed abundance of Campylobacter and low levels of Saccharomyces, Deinococcus, and Thiomonas (P < 0.05). Thirty metabolites, including taurocholate and (R)-3-hydroxybutyric acid, were identified in the patients (VIP > 1, P < 0.05 and FC > 1.2 or FC < 0.83). Random forest (RF) models showed that serum metabolome could effectively identify B-CS from healthy controls and RF-metabolomics exhibited perfect discrimination (AUC = 100%, 95% CI: 100% - 100%), which was significantly higher than that achieved by RF-metagenomics (AUC = 58.48%, 95% CI: 38.46% - 78.5%). Campylobacter concisus and taurocholate showed significant positive correlation in patients with clinical manifestations (P < 0.05). Actinobacteria levels were significantly higher in untreated patients than in treated patients (P < 0.05). Campylobacter and Veillonella levels were significantly higher in treated patients than in healthy controls (P < 0.05). We identified major alterations in the gut microbiota and serum metabolome of patients with B-CS. Faecal metagenomics- and serum metabolomics-guided management strategies are required for patients with B-CS.
Assuntos
Síndrome de Budd-Chiari , Campylobacter , Humanos , Metabolômica , MetagenômicaRESUMO
BACKGROUND: Delayed gastric emptying (DGE) is the main complication after pancreaticoduodenectomy (PD), but the mechanism is still unclear. The aim of this study was to elucidate the role of complete resection of the gastric antrum in decreasing incidence and severity of DGE after PD. METHODS: Sprague-Dawley rats were divided into three groups: expanded resection (ER group), complete resection (CR group), and incomplete resection (IR group) of the gastric antrum. The tension (g) of remnant stomach contraction was observed. We analyzed the histological morphology of the gastric wall by different excisional methods after distal gastrectomy. Moreover, patients underwent PD at our department between January 2012 and May 2016 were included in the study. These cases were divided into IR group and CR group of the gastric antrum, and the clinical data were retrospectively analyzed. RESULTS: The ex vivo remnant stomachs of CR group exhibited much greater contraction tension than others (P < 0.05). The contraction tension of the remnant stomach increased with increasing acetylcholine concentration, while remained stable at the concentration of 10 × 10-5 mol/L. Furthermore, 174 consecutive patients were included and retrospectively analyzed in the study. The incidence of DGE was significantly lower (3.5% vs. 21.3%, P < 0.01) in CR group than in IR group. In addition, hematoxylin-eosin staining analyses of the gastric wall confirmed that the number of transected circular smooth muscle bundles were higher in IR group than in CR group (8.24 ± 0.65 vs. 3.76 ± 0.70, P < 0.05). CONCLUSIONS: The complete resection of the gastric antrum is associated with decreased incidence and severity of DGE after PD. Gastric electrophysiological and physiopathological disorders caused by damage to gastric smooth muscles might be the mechanism underlying DGE.
Assuntos
Gastroparesia , Pancreaticoduodenectomia , Animais , Esvaziamento Gástrico , Gastroparesia/epidemiologia , Gastroparesia/etiologia , Gastroparesia/prevenção & controle , Humanos , Incidência , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Antro Pilórico/diagnóstico por imagem , Antro Pilórico/cirurgia , Ratos , Ratos Sprague-Dawley , Estudos RetrospectivosRESUMO
Gut microbiota is associated with liver diseases. However, gut microbial characteristics of Budd-Chiari syndrome (B-CS) have not been reported. Here, by MiSeq sequencing, gut microbial alterations were characterized among 37 health controls, 20 liver cirrhosis (LC) patients, 31 initial B-CS patients (B-CS group), 33 stability patients after BCS treatment (stability group) and 23 recurrent patients after BCS treatment (recurrence group). Gut microbial diversity was increased in B-CS versus LC. Bacterial community of B-CS clustered with controls but separated from LC. Operational taxonomic units (OTUs) 421, 502 (Clostridium IV) and 141 (Megasphaera) were unique to B-CS. Genera Escherichia/Shigella and Clostridium XI were decreased in B-CS versus controls. Moreover, nine genera, mainly including Bacteroides and Megamonas, were enriched in B-CS versus LC. Notably, Megamonas could distinguish B-CS from LC with areas under the curve (AUCs) of 0.7904. Microbial function prediction revealed that L-amino acid transport system activity was decreased in B-CS versus both LC and controls. Furthermore, OTUs 27 (Clostridium XI), 137 (Clostridium XIVb) and 40 (Bacteroides) were associated with B-CS stability. Importantly, genus Clostridium XI was enriched in stability group versus both recurrence group and B-CS group. Also, PRPP glutamine biosynthesis was reduced in stability group versus recurrence group, but was enriched in stability group versus B-CS group. In conclusion, specific microbial alterations associated with diagnosis and prognosis were detected in B-CS patients. Correction of gut microbial alterations may be a potential strategy for B-CS prevention and treatment.
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BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication and results in prolonged hospitalization and high mortality. The present study aimed to evaluate the safety and effectiveness of total closure of pancreatic section for end-to-side pancreaticojejunostomy in pancreaticoduodenectomy (PD). METHODS: This was a prospective randomized clinical trial comparing the outcomes of PD between patients who underwent total closure of pancreatic section for end-to-side pancreaticojejunostomy (Group A) vs those who underwent conventional pancreaticojejunostomy (Group B). The primary endpoint was the incidence of pancreatic fistula. Secondary endpoints were morbidity and mortality rates. RESULTS: One hundred twenty-three patients were included in this study. The POPF rate was significantly lower in Group A than that in Group B (4.8% vs 16.7%, P<0.05). About 38.3% patients in Group B developed one or more complications; this rate was 14.3% in Group A (P<0.01). The wound/abdominal infection rate was also much higher in Group B than that in Group A (20.0% vs 6.3%, P<0.05). Furthermore, the average hospital stays of the two groups were 18 days in Group A, and 24 days in Group B, respectively (P<0.001). However, there was no difference in the probability of mortality, biliary leakage, delayed gastric emptying, and pulmonary infection between the two groups. CONCLUSION: Total closure of pancreatic section for end-to-side pancreaticojejunostomy is a safe and effective method for pancreaticojejunostomy in PD.
Assuntos
Fístula Pancreática/prevenção & controle , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Pancreaticojejunostomia/métodos , Idoso , China/epidemiologia , Feminino , Humanos , Incidência , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Fístula Pancreática/diagnóstico , Fístula Pancreática/mortalidade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/mortalidade , Pancreaticojejunostomia/efeitos adversos , Pancreaticojejunostomia/mortalidade , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Bromodomain 4 (BRD4) is an epigenetic regulator that, when inhibited, has anti-cancer effects. In this study, we investigated whether BRD4 could be a target for treatment of human hepatocellular carcinoma (HCC). We show that BRD4 is over-expressed in HCC tissues. Suppression of BRD4, either by siRNA or using JQ1, a pharmaceutical BRD4 inhibitor, reduced cell growth and induced apoptosis in HCC cell lines while also slowing HCC xenograft tumor growth in mice. JQ1 treatment induced G1 cell cycle arrest by repressing MYC expression, which led to the up-regulation of CDKN1B (P27). JQ1 also de-repressed expression of the pro-apoptotic BCL2L11 (BIM). Moreover, siRNA knockdown of BIM attenuated JQ1-triggered apoptosis in HCC cells, suggesting an essential role for BIM in mediating JQ1 anti-HCC activity.
Assuntos
Azepinas/farmacologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Carcinoma Hepatocelular/prevenção & controle , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/prevenção & controle , Proteínas Nucleares/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/genética , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Imunoprecipitação da Cromatina , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cancer testis antigens (CTAs) are selectively expressed in malignant cells and can serve as ideal targets for immunotherapy. We investigated the expressions of MAGE-A3, MAGE-A4, MAGE-C2 and NY-ESO-1 to determine if combinatorial expressions of CTAs might be as potential prognostic markers for patients with hepatocellular carcinoma (HCC). In tumor tissues of 142 HCC patients, the mRNA expressions of MAGE-A3, MAGE-A4, MAGE-C2 and NY-ESO-1 were 78.9%, 33.8%, 74.6% and 14.1% respectively. Furthermore, the expressions of MAGE-A3, MAGE-A4 and combination of MAGE-A3, MAGE-A4 and NY-ESO-1 (CTAs-A3/A4/NY) showed positive correlations with serum AFP, tumor stages and Ki-67 (P < 0.05). In addition, mRNA expressions of CTAs were significantly consistent with protein expressions of CTAs by immunohistochemistry (P > 0.05). Receiver operating characteristic curves (ROC) analysis showed that CTAs-A3/A4/NY had larger areas under ROC curve (0.768), specificity (99.1%), Youden's index (44.6), positive predictive value (90.9%) and negative predictive value (89.9%) for predicting HCC recurrence than other CTAs. Moreover, the combinatorial expression of CTAs-A3/A4/NY was significantly associated with HCC recurrence by Kaplan-Meier analysis (HR = 69.36, P < 0.01) and multivariate Cox analysis (RR = 17.11, P < 0.01). The combinatorial expression of CTAs-A3/A4/NY mRNA promotes the predictive accuracy of HCC recurrence and itself may be a potential target for immunotherapy of HCC as well.
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Antígenos de Neoplasias/imunologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Testiculares/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Testículo/imunologia , Testículo/metabolismo , Testículo/patologiaRESUMO
BACKGROUND: Collateralized intra- and extra-hepatic routes in patients with Budd-Chiari syndrome (BCS) were important. This study aimed to investigate the feasibility and clinical outcomes of the staged management of BCS based on the degree of compensation provided by intra- or extra-hepatic collateral circulations. METHODS: A total of 103 adult patients with BCS caused by co-obstruction of the inferior vena cava (IVC) and main hepatic veins (MHVs) between March 2001 and October 2009 were enrolled in this study. Based on the pathological classification and degree of hemodynamic compensation by collateral circulations, treatment priority for IVC hypertension was determined in the first-stage treatment. Patients were deemed eligible for second-stage treatment when the first-stage treatment failed to relieve. RESULTS: Imaging results revealed that most patients had collateral circulations to different extents. Based on the degree of compensation provided by these collateral circulations, 74 patients underwent single-stage treatment for IVC hypertension, i.e., radiologic intervention (RI) for 61 patients and surgical procedures (SPs) for 13. One patient was treated for portal hypertension. Twenty-nine patients underwent second-stage treatment (25 underwent RI and SP, and 4 only SP). The general morbidity and mortality after all procedures were 8.3% and 1.5%, respectively. After a median follow-up of 35 months, 4 patients underwent second-stage treatment and 7 underwent recanalization of the IVC/MHVs. Two patients died of hepatocellular carcinoma and 1 died of graft obstruction. CONCLUSION: Staged management produces excellent outcomes for patients with BCS caused by co-obstruction of the IVC and MHVs.
Assuntos
Angioplastia com Balão , Síndrome de Budd-Chiari/terapia , Veias Hepáticas/cirurgia , Procedimentos Cirúrgicos Vasculares , Veia Cava Inferior/cirurgia , Adulto , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/instrumentação , Angioplastia com Balão/mortalidade , Síndrome de Budd-Chiari/diagnóstico , Síndrome de Budd-Chiari/etiologia , Síndrome de Budd-Chiari/mortalidade , Síndrome de Budd-Chiari/fisiopatologia , Síndrome de Budd-Chiari/cirurgia , Circulação Colateral , Estudos de Viabilidade , Feminino , Veias Hepáticas/fisiopatologia , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Hipertensão Portal/terapia , Circulação Hepática , Masculino , Pessoa de Meia-Idade , Stents , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/mortalidade , Veia Cava Inferior/fisiopatologia , Pressão Venosa , Adulto JovemRESUMO
Small-molecule Bcl-2/Bcl-xL inhibitor Navitoclax represents a promising cancer therapeutic since preclinical and clinical studies with Navitoclax have demonstrated strong anticancer activity in several types of cancers. However, because Navitoclax has a low binding affinity to Mcl-1, anticancer activity by Navitoclax is often attenuated by the elevated expression of Mcl-1 in hepatocellular carcinoma (HCC) and other cancers, posing a serious problem for its potential clinical utilities. Therefore, approaches that suppress the expression of Mcl-1 are urgently needed to overcome Navitoclax-resistance in these cancers. Here, we reported that aspirin markedly suppressed Mcl-1 expression, and significantly enhanced Navitoclax-mediated cell viability inhibition and apoptosis induction in HCC cells. We further showed that aspirin robustly enhanced Navitoclax-triggered cytosolic cytochrome c release, activation of initiator caspase-9 and effector caspase-3, and cleavage of PARP. Importantly, the cell death induction by the combination could be rescued by a cell-permeable caspase-9 inhibitor Z-LEHD-FMK, indicative of an indispensable role of mitochondrial apoptosis pathway during the combination effect. Taken together, our study suggests that aspirin can be used to enhance Navitoclax-mediated anticancer activity via suppression of Mcl-1. Since aspirin is one of the most commonly used medicines, our findings therefore have translational impacts on Navitoclax-based therapy for HCC.
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Compostos de Anilina/farmacologia , Aspirina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides , Oligopeptídeos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Interferência de RNARESUMO
OBJECTIVES: This study was conducted to evaluate the clinical value of computed tomographic (CT) angiography for diagnosis and therapeutic planning in patients with pulmonary sequestration. METHODS: Forty-three patients with suspected pulmonary sequestration underwent CT angiography before undergoing digital subtraction angiography or surgery. For each patient, CT angiography was used to determine whether the pulmonary sequestration was suitable for coil embolization, surgical resection or conservative treatment. The treatments planned using CT angiography were compared with actual treatment decisions made or treatments administered using digital subtraction angiography or surgery. RESULTS: Digital subtraction angiography and/or surgery confirmed pulmonary sequestration in 37 patients; six patients had no pulmonary sequestration. The diagnostic performance of CT angiography for pulmonary sequestration in the patient-based evaluation yielded an accuracy of 97.7%, sensitivity of 97.3%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 85.7%. The aberrant systemic artery-based evaluation yielded an accuracy of 98.0%, sensitivity of 97.8%, specificity of 100%, PPV of 100% and NPV of 85.7%. Treatments could be correctly planned using CT angiography with 100% accuracy, sensitivity, specificity, PPV and NPV according to the aneurysm-based evaluation. CONCLUSIONS: We have obtained promising results with a CT angiography-based protocol, rather than a digital subtraction angiography-based protocol, as the only diagnostic and pretreatment planning tool in patients with pulmonary sequestration. The CT angiography-based selection of treatment strategies seems to be safe and effective in the majority of patients with pulmonary sequestration.
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Angiografia Digital/métodos , Sequestro Broncopulmonar/diagnóstico por imagem , Sequestro Broncopulmonar/terapia , Procedimentos Cirúrgicos Pulmonares/métodos , Cirurgia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Sequestro Broncopulmonar/cirurgia , Criança , Pré-Escolar , Embolização Terapêutica , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: The members of inhibitor of apoptosis proteins (IAPs) family are key negative regulators of apoptosis. Overexpression of IAPs are found in hepatocellular carcinoma (HCC), and can contribute to chemotherapy resistance and recurrence of HCC. Small-molecule Second mitochondria-derived activator of caspases (Smac) mimetics have recently emerged as novel anticancer drugs through targeting IAPs. The specific aims of this study were to 1) examine the anticancer activity of Smac mimetics as a single agent and in combination with chemotherapy in HCC cells, and 2) investigate the mechanism of anticancer action of Smac mimetics. METHODS: Four HCC cell lines, including SMMC-7721, BEL-7402, HepG2 and Hep3B, and 12 primary HCC cells were used in this study. Smac mimetic SM-164 was used to treat HCC cells. Cell viability, cell death induction and clonal formation assays were used to evaluate the anticancer activity. Western blotting analysis and a pancaspase inhibitor were used to investigate the mechanisms. RESULTS: Although SM-164 induced complete cIAP-1 degradation, it displayed weak inhibitory effects on the viability of HCC cells. Nevertheless, SM-164 considerably potentiated Apo2 ligand or TNF-related apoptosis-inducing ligand (APO2L/TRAIL)- and Doxorubicin-mediated anticancer activity in HCC cells. Mechanistic studies demonstrated that SM-164 in combination with chemotherapeutic agents resulted in enhanced activation of caspases-9, -3 and cleavage of poly ADP-ribose polymerase (PARP), and also led to decreased AKT activation. CONCLUSIONS: Smac mimetics can enhance chemotherapeutic-mediated anticancer activity by enhancing apoptosis signaling and suppressing survival signaling in HCC cells. This study suggests Smac mimetics are potential therapeutic agents for HCC.
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Antineoplásicos/administração & dosagem , Biomimética , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Mitocondriais , Triazóis/administração & dosagem , Desaminases APOBEC , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citidina Desaminase/metabolismo , Doxorrubicina/administração & dosagem , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/síntese química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas Mitocondriais/administração & dosagem , Proteínas Mitocondriais/síntese química , Proteínas Musculares/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismoRESUMO
OBJECTIVE: To study on the efficacy, prognosis and security of high-intensity focused ultrasound (HIFU) combined with transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). METHODS: Totally 72 HCC patients treated by HIFU from December 2009 to January 2011 were divided into two groups according to treatment methods: 40 cases in HIFU group, 32 cases in TACE + HIFU treatment group (combined group). Then set up a control group include 40 cases treated by only TACE in the same period (TACE group). The improvement of clinical symptoms, AFP, reduce rate of tumor volume, survival rate of 1 year after operation and postoperative complications in front and behind the treatment were analyzed. RESULTS: There was no significant statistical difference on the improvement of clinical symptoms in all these three groups (P > 0.05) after treatment for HCC. There is no significant statistical difference also on reduce rate of tumor volume and decrease rate of AFP in both HIFU group (35.0%, 41.4%) and TACE group (37.5%, 41.9%) (χ² = 0.054, P = 0.816; χ² = 0.002, P = 0.965). Both reduce rate of tumor volume (62.5%) and decrease rate of AFP (72.0%) in combined group were better than HIFU group (χ² = 5.394, P = 0.020; χ² = 5.098, P = 0.024) and TACE group (37.5%, 41.9%) (χ² = 4.448, P = 0.035; χ² = 5.062, P = 0.024). Kaplan-Meier survival curve showed that there was no significant statistical difference on short-term survival rate in the 3 groups. But the long-term survival rate of combined group was better than TACE group and HIFU group. CONCLUSION: TACE combined with HIFU is a effective, safe and noninvasive treatment method to HCC.
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Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Ultrassom Focalizado Transretal de Alta Intensidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do TratamentoRESUMO
Small-molecule cell-permeable Bcl-2/Bcl-xL antagonist ABT-737 has recently emerged as a novel cancer therapeutic agent because it potently induces apoptosis in certain cancer cells. However, since ABT-737 binds to Mcl-1 with low affinity, ABT-737-mediated apoptosis signaling is inhibited in hepatocellular carcinoma (HCC) cells and other solid cancer cells due to the elevated expression of Mcl-1. Accordingly, strategies that target Mcl-1 are explored for overcoming ABT-737-resistance. In this study, we reported that Norcantharidin (NCTD), a small-molecule anticancer drug derived from Chinese traditional medicine blister beetle (Mylabris), induced transcriptional repression of Mcl-1 and considerably enhanced ABT-737-triggered cell viability inhibition and apoptosis in multiple HCC cell lines. Moreover, we observed that the enhancement of ABT-737-mediated apoptosis by NCTD was associated with activation of mitochondrial apoptosis signaling pathway, which involved cytosolic release of cytochrome c, cleavage of caspase-9 and caspase-3. Additionally, knockdown of Bax/Bak, the key effectors permeabilizing mitochondrial outer membrane significantly attenuated the enhancement, indicating mitochondrial apoptosis pathway played an essential role in the execution of the apoptosis. Finally, knockdown of Mcl-1 substantially potentiated ABT-737-mediated apoptotic cell death, confirming the potency of Mcl-1 repression by NCTD in enhancing ABT-737-induced apoptosis. These results therefore suggest that combination treatment with NCTD can overcome ABT-737 resistance and enhance ABT-737 therapeutic efficacy in treating human HCC.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/química , Compostos de Bifenilo/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Nitrofenóis/química , Piperazinas/química , Piperazinas/farmacologia , Sulfonamidas/química , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Budd-Chiari syndrome (B-CS) refers to post-hepatic portal hypertension and/or inferior vena cava hypertension caused by obstruction of blood flow at the portal cardinal hepatic vein. The treatments of B-CS include operations on pathological membrane lesions, shunting and combined operations. Studies have shown that China, Japan, India and South Africa have a high incidence of B-CS. In China, the Yellow River Basin in Henan, Shandong, Jiangsu and Anhui Provinces also have a high incidence, around 10 per 100 000. METHODS: The clinical data of 221 B-CS patients were analyzed retrospectively. We focused on pathological types, surgical methods, effectiveness and complications of treatment, and follow-up. RESULTS: Based on imaging findings such as color ultrasonography, angiography or magnetic resonance angiography, the 221 patients were divided into 3 types (five subtypes): type Ia (72 patients), type Ib (20), type II (72), type IIIa (33), and type IIIb (24). Surgical procedures included balloon membranotomy with or without stent (65 patients), improved splenopneumopexy (18), radical resection of membrane and thrombus (17), inferior vena cava bypass [29, with cavocaval transflow (13) and cavoatrial transflow (16)], mesocaval shunt (41), splenocaval shunt (25), splenoatrial shunt (12), splenojugular shunt (6), and combined methods (8). The complication rate was 9.05% (20/221) and the perioperative death rate was 2.26% (5/221). All of the patients were followed up from 6 months to 5 years. The success rate was 84.6% (187/221), and the recurrence rate was 8.9% (9/101) and 13.5% (13/96) after 1- and 5-year follow-up, respectively. CONCLUSION: The rational choice of surgical treatment based on B-CS pathological typing may increase the success rate and decrease the recurrence.
Assuntos
Síndrome de Budd-Chiari/cirurgia , Adolescente , Adulto , Idoso , Síndrome de Budd-Chiari/diagnóstico , Síndrome de Budd-Chiari/mortalidade , China , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/instrumentação , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Recidiva , Estudos Retrospectivos , Stents , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The development of collaterals in Budd-Chiari syndrome has been described and these collaterals play an important role in the presentation of this disease. These collaterals are diagnostic and their use in management strategy has never been evaluated. This study aimed to investigate the indications, feasibility and necessity of invasive treatment for patients with Budd-Chiari syndrome and to determine whether such a strategy is necessary for optimal management. METHODS: Twenty-nine patients who had been treated at our unit were enrolled in this study. Based on physical and biochemical examination, and hemodynamic compensation by collaterals, 18 patients underwent radiological intervention (group A), while the other 11 had no invasive treatment (group B). The related hemodynamic parameters were acquired when percutaneous angiography was performed. RESULTS: In group A, all patients underwent successfully inferior vena cava (IVC) balloon angioplasty with or without stenting. Four patients also underwent hepatic vein angioplasty. In these patients, the mean IVC pressure before and after treatment was statistically different (29.3+/-9.2 vs 15.1+/-4.6 mmHg, P<0.01). The mean IVC pressure was much lower in group B than in group A (12.9+/-2.4 vs 29.3+/-9.2 mmHg, P<0.01), but there was no difference from that of the patients after radiological treatment (12.9+/-2.4 vs 15.1+/-4.6 mmHg, P>0.05). Median follow-up was 32.3 months (mean 21.3 months; range 3-61 months). In the course of follow-up, the patients in group A survived with good systemic status except for re-stenosis in one patient who underwent re-canalization of the IVC. In group B, 10 patients had good systemic status except one patient who had a meso-caval shunt because of deterioration. CONCLUSIONS: The rationale of "early diagnosis and early treatment" is not suitable for all patients with Budd-Chiari syndrome. Satisfactory survival can be achieved in some patients without invasive treatment, who are completely compensated by rich collaterals. Nonetheless, a positive treatment procedure should be performed if the patient's situation worsens in the course of regular follow-up.
Assuntos
Angioplastia com Balão , Síndrome de Budd-Chiari/terapia , Circulação Colateral , Veias Hepáticas/fisiopatologia , Circulação Hepática , Veia Cava Inferior/fisiopatologia , Pressão Venosa , Adulto , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/instrumentação , Anticoagulantes/uso terapêutico , Síndrome de Budd-Chiari/diagnóstico , Síndrome de Budd-Chiari/fisiopatologia , China , Feminino , Veias Hepáticas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Stents , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia Doppler , Veia Cava Inferior/diagnóstico por imagem , Adulto JovemRESUMO
OBJECTIVE: To summarize the clinical experiences in the diagnosis and managements of hepatic veno-occlusive disease (HVOD). METHODS: The clinical and pathologic data of 17 patients with hepatic veno-occlusive disease were analyzed retrospectively. RESULTS: According to the results of imaging examination, clinical data and pathological data, 17 patients HVOD were divided into acute progressive HVOD and chronic HVOD. 2 cases out of the 11 acute progressive cases got improved, 2 cases died after medical treatment and 2 cases died after shunt operation. The 6 chronic HVOD, including 1 case with medical treatment and 5 cases with shunt operation, were cured. CONCLUSION: Liver biopsy was an efficient method for the diagnosis of hepatic veno-occlusive disease. Acute progressive cases of hepatic veno-occlusive disease should be managed with medical treatment and the chronic cases could be treated with shunt surgery if medical treatment were inefficient.
Assuntos
Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/patologia , Adulto , Idoso , Feminino , Veias Hepáticas/patologia , Hepatopatia Veno-Oclusiva/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVES: This study evaluated the feasibility and outcomes of percutaneous transhepatic balloon angioplasty (PTBA) of the hepatic vein in the management of Budd-Chiari syndrome (BCS) secondary to hepatic venous outflow obstruction. METHODS: From September 1996 to October 2008, 101 patients (52 males, 49 females) with BCS secondary to occlusion of the hepatic veins were prospectively treated using PTBA of the hepatic vein. Average age was 31.3 years (range, 15-57 years). Nineteen had concurrent inferior vena cava (IVC) obstruction. All the patients presented with symptomatic portal hypertension. PTBA, with or without stenting, was performed after hepatovenography. RESULTS: PTBA was successfully performed in 92 of the 101 patients. Sixty-eight patients underwent PTBA of right hepatic vein, followed by stent placement in two. PTBA was performed in 11 patients with left hepatic vein occlusion and in 13 patients with dominant accessory hepatic vein occlusion. The technical success rate was 92 of 101 (91%). Hepatic venous pressure was significantly decreased after balloon angioplasty/stenting (P < .01, paired t test). Symptoms were significantly improved in the 92 patients who had successful PTBA. Three patients had acute hepatic vein thrombosis during or after PTBA. Two patients sustained intraperitoneal bleeding from the transhepatic puncture track, and one had intrahepatic hematoma. Pulmonary embolism developed in one patient during the operation. All complications were managed nonoperatively. There were no perioperative deaths. Within 1 year, 74 of the 101 patients returned for follow-up, and 51 patients had follow-up at 2 years. The primary patency rates were 84% (62 of 74), 78% (58 of 74), and 76% (39 or 51) at 6, 12, and 24 months after PTBA, respectively. The secondary patency rates were 95% (70 of 74), 92% (68 of 74), and 84% (43 of 51) at 6, 12, and 24 months. CONCLUSIONS: PTBA of the hepatic vein is a safe and effective treatment of BCS. It is currently the most physiologic procedure, and the risk of postoperative encephalopathy is minimized because portal flow is not diverted. Midterm outcomes are satisfactory. Further investigation of the long-term outcomes is needed.
Assuntos
Angioplastia com Balão , Síndrome de Budd-Chiari/terapia , Veias Hepáticas , Adolescente , Adulto , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/instrumentação , Síndrome de Budd-Chiari/complicações , Síndrome de Budd-Chiari/fisiopatologia , Estudos de Viabilidade , Feminino , Veias Hepáticas/diagnóstico por imagem , Veias Hepáticas/fisiopatologia , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Hipertensão Portal/terapia , Masculino , Pessoa de Meia-Idade , Flebografia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Stents , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular , Pressão Venosa , Adulto JovemRESUMO
BACKGROUND: Budd-Chiari syndrome (BCS) refers to posthepatic portal vein hypertension and/or inferior vena cava hypertension syndrome caused by obstruction of the blood flow at the portal cardinal hepatic vein and/or posterior hepatic inferior vena cava. The main surgical treatments of BCS include operations on pathological lesioned membrane, shunt, and combined operations. There are more than ten treatments available and reports on their therapeutic effects vary. As to operations on lesioned membrane, there are Kimura's finger rupture, balloon dilatation and membrane removal. With reference to our experience, the clinical value of membrane resection at normal temperature and under direct vision is discussed. METHODS: A total of 292 patients with BCS undergoing membrane resection at normal temperature and under direct vision from June 1996 to June 2005 were retrospectively analyzed. RESULTS: The short-term therapeutic effect in 256 patients was satisfactory and the effective rate was 87.7% (256/292). Within a week, ascitic fluid disappeared, the liver shrank and edema of the lower extremities was greatly relieved or even disappeared. Perioperative death occurred in 14 patients (4.8%). Of these, 3 had acute heart failure (one during the operation, one after 6 hours and one 7 days later). Six patients had thoracic cavity bleeding within 12 hours after the operation, 3 had acute respiratory distress syndrome (ARDS), 2 had disseminated intravascular coagulation (DIC), and 1 had pulmonary embolism. 158 patients were followed up for 6 months to 12 years, and 12 (7.6%) had recurrences. CONCLUSIONS: After membrane resection at normal temperature and under direct vision, hemodynamics was found to be close to normal, damage was slight, effectiveness was evident and the recurrence rate low. So this method is effective in treating BCS.