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Photodynamic therapy (PDT) is a procedure used in cancer therapy that has been shown to be useful for certain indications. Considerable evidence suggests that PDT might be superior to conventional modalities for some indications. In this report, we examine the relationship between PDT responsiveness and autophagy, which can exert a cytoprotective effect. Autophagy is an essential physiological process that maintains cellular homeostasis by degrading dysfunctional or impaired cellular components and organelles via a lysosome-based pathway. Autophagy, which includes macroautophagy and microautophagy, can be a factor that decreases or abolishes responses to various therapeutic protocols. We systematically discuss the mechanisms underlying cell-fate decisions elicited by PDT; analyse the principles of PDT-induced autophagy, macroautophagy and microautophagy; and present evidence to support the notion that autophagy is a critical mechanism in resistance to PDT. A combined strategy involving autophagy inhibitors may be able to further enhance PDT efficacy. Finally, we provide suggestions for future studies, note where our understanding of the relevant molecular regulators is deficient, and discuss the correlations among PDT-induced resistance and autophagy, especially microautophagy.
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Antineoplásicos/uso terapêutico , Autofagia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/patologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: Accurate assessment of liver functional reserve pre-operatively is vital for safe hepatic resection. The ALBI score is a new model for assessing liver function. This study aimed to evaluate the value of combining ALBI score with sFLR in predicting post-operative morbidity and PHLF in HCC patients who underwent hepatectomy. METHODS: Patients undergoing three-dimensional CT reconstruction prior to hepatectomy for HCC between January 2015 and January 2017 were enrolled. The values of the CP score, ALBI score and sFLR in predicting post-operative outcomes were evaluated. RESULTS: A total of 229 HCC patients were enrolled; 24 (10.5%) experienced major complications and 21 (9.2%) developed PHLF. The incidence of major complications and PHLF increased with increasing ALBI grade. The ALBI grade classified patients with CP grade A into two subgroups with different incidences of PHLF (P=.029). sFLR and ALBI scores were identified as independent predictors of PHLF. The AUC values for the CP score, ALBI score, sFLR and sFLR×ALBI for predicting major complications were 0.600, 0.756, 0.660 and 0.790 respectively. The AUC values of the CP score, ALBI score, sFLR and sFLR×ALBI for predicting PHLF were 0.646, 0.738, 0.758 and 0.884 respectively. CONCLUSIONS: The ALBI score showed superior predictive value of post-operative outcomes over CP score, and the combination of sFLR and ALBI score was identified as a stronger predictor of post-operative outcomes than the sFLR or ALBI score alone.
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Carcinoma Hepatocelular/cirurgia , Hepatectomia , Hepatite B/complicações , Falência Hepática/mortalidade , Neoplasias Hepáticas/cirurgia , Adolescente , Adulto , Idoso , Bilirrubina/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/virologia , China/epidemiologia , Feminino , Humanos , Fígado/fisiopatologia , Falência Hepática/sangue , Falência Hepática/etiologia , Neoplasias Hepáticas/virologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Albumina Sérica , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Underlying liver function is a major concern when applying surgical resection for hepatocellular carcinoma (HCC). We aimed to explore the capability of the albumin-bilirubin (ALBI) grade to predict post-hepatectomy liver failure (PHLF) and long-term survival after hepatectomy for HCC patients with different Barcelona Clinic Liver Cancer (BCLC) stages. METHODS: Between January 2010 and December 2014, 338 HCC patients who were treated with liver resection were enrolled. The predictive accuracy of ALBI grade system for PHLF and long-term survival across different BCLC stages was examined. RESULTS: A total of 26 (7.7%) patients developed PHLF. Patients were divided into BCLC 0/A and BCLC B/C categories. ALBI score was found to be a strong independent predictor of PHLF across different BCLC stages by multivariate analysis. In terms of overall survival (OS), it exhibited high discriminative power in the total cohort and in BCLC 0/A subgroup. However, differences in OS between ALBI grade 1 and 2 patients in BCLC B/C subgroup were not significant (P = 0.222). CONCLUSION: The ALBI grade showed good predictive ability for PHLF in HCC patients across different BCLC stages. However, the ALBI grade was only a significant predictor of OS in BCLC stage 0/A patients and failed to predict OS in BCLC stage B/C patients.
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Albuminas/metabolismo , Bilirrubina/metabolismo , Carcinoma Hepatocelular/mortalidade , Hepatectomia/mortalidade , Falência Hepática/mortalidade , Neoplasias Hepáticas/mortalidade , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Hepatectomia/efeitos adversos , Humanos , Falência Hepática/etiologia , Falência Hepática/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: This study investigated UGP2 (uridine diphosphate-glucose pyrophosphorylase-2) and CFL1 (cofilin-1) expression in pancreatic ductal carcinoma (PDC), paracancerous tissue (PT), benign lesions (BL), and normal tissue (NT) and their clinicopathological significance. METHODS: Surgical specimens, which were collected from 106 cases of pancreatic ductal carcinoma, 35 cases of paracancerous tissues, 55 cases of benign lesions and 13 cases of normal pancreatic tissues, were fixed with 4% formaldehyde to prepare conventional paraffin-embedded sections. EnVision immunohistochemical was used to stain for UGP2 and CFL1. Kaplan-Meier survival analysis was performed to assess the correlation of expression pattern with survival. RESULTS: We found that positive UGP2 and CFL1 expression in PDC were significantly higher than those in PT, BL, and NT. In PT and BL with positive UGP2 and CFL1 expression, mild to severe atypical hyperplasia or intraepithelial neoplasia of grades II-III was observed in ductal epithelium. Positive UGP2 and CFL1 expression in cases with high differentiation, no lymph node metastasis, no surrounding invasion, and TNM (tumor-node-metastasis) staging I or/and II were significantly lower than those in cases with poor differentiation, lymph node metastasis, surrounding invasion, and TNM stage III and/or IV. Positive UGP2 expression in male patients was significantly lower than that in female patients. UGP2 and CFL1 expression in PDC were positively correlated. Kaplan-Meier survival analysis showed the degree of differentiation, tumor maximal diameter, TNM stage, lymph node metastasis, and surrounding invasion, and UGP2 and CFL1 expression were closely related to the average survival time of patients with PDC. The survival time of patients with positive UGP2 and CFL1 expression was significantly shorter than that of patients with negative expression. Cox multivariate analysis showed that poor differentiation, tumor maximal diameter ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, and positive UGP2 and CFL1 expression was negatively correlated with the postoperative survival rate and positively correlated with the mortality of patients with PDC. CONCLUSION: Positive expression of UGP2 and CFL1 can serve a valuable prognostic factor in pancreatic cancer.
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Adenocarcinoma/secundário , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/secundário , Cofilina 1/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , UTP-Glucose-1-Fosfato Uridililtransferase/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/cirurgia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Pâncreas/metabolismo , Pâncreas/cirurgia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Prognóstico , Taxa de SobrevidaRESUMO
Activation of apoptotic signalling in endothelial cells contributes to the detrimental effects of a variety of pathological stimuli. In investigating the molecular events underlying the anti-apoptotic effect of human plasma in cultured human endothelial cells, we unexpectedly uncovered a novel mechanism of apoptosis suppression by human plasma through an interaction between two previously unrelated proteins. Human plasma inhibited hypoxia-serum deprivation-induced apoptosis and stimulated BADS136 and AktS473 phosphorylation. Akt1 silencing reversed part (~52%) of the anti-apoptotic effect of human plasma, suggesting the existence of additional mechanisms mediating the anti-apoptotic effect other than Akt signalling. Human plasma disrupted the interaction of BAD with protein phosphatase 1 (PP1). Mass spectrometry identified fourteen PP1-interacting proteins induced by human plasma. Notably, a group of serine protease inhibitors including plasminogen activator inhibitor 1 (PAI1), a major inhibitor of fibrinolysis, were involved. Silencing of PAI1 attenuated the anti-apoptotic effect of human plasma. Furthermore, combined Akt1 and PAI1 silencing attenuated the majority of the anti-apoptotic effect of human plasma. We conclude that human plasma protects against endothelial cell apoptosis through sustained BAD phosphorylation, which is achieved by, at least in part, a novel interaction between PP1 with PAI1.
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Apoptose , Células Endoteliais/metabolismo , Plasma/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Proteína Fosfatase 1/metabolismo , Hipóxia Celular , Citoproteção , Inativação Gênica , Humanos , Modelos Biológicos , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Specific visualization of body parts is needed during surgery. Fluorescence-guided surgery (FGS) uses a fluorescence contrast agent for in vivo tumor imaging to detect and identify both malignant and normal tissues. There are several advantages and clinical benefits of FGS over other conventional medical imaging modalities, such as its safety, effectiveness, and suitability for real-time imaging in the operating room. Recent advancements in contrast agents and intraoperative fluorescence imaging devices have led to a greater potential for intraoperative fluorescence imaging in clinical applications. Photodynamic therapy (PDT) is an alternative modality to treat tumors, which uses a light-sensitive drug (photosensitizers) and special light to destroy the targeted tissues. In this review, we discuss the fluorescent contrast agents, some newly developed imaging devices, and the successful clinical application of FGS. Additionally, we present the combined strategy of FGS with PDT to further improve the therapeutic effect for patients with cancer. Taken together, this review provides a unique perspective and summarization of FGS.
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Neoplasias/terapia , Fotoquimioterapia/métodos , Meios de Contraste/uso terapêutico , Fluorescência , Humanos , Linfonodos/patologiaRESUMO
Pancreatic ductal adenocarcinoma is a highly malignant tumor with poor prognosis, and the biomarkers for the early diagnosis, targeting therapy, and prognosis are still not clinically available. This study investigated the expression of forkhead box P1 and forkhead box O3a proteins in human pancreatic ductal adenocarcinoma tumor tissues and pancreatic tissues with and without benign lesions using immunohistochemical staining. Results showed that the positive rates of forkhead box P1 and forkhead box O3a protein expression were significantly lower in pancreatic ductal adenocarcinoma tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (p < 0.01). Pancreatic tissues with negative forkhead box P1 and forkhead box O3a protein expression exhibited dysplasia or intraepithelial neoplasia. The positive rates of forkhead box P1 and forkhead box O3a expression were significantly lower in cases with tumor mass >5 cm, lymph node metastasis, invasion to surrounding tissues and organs, and tumor-node-metastasis III + IV stage disease compared to cases with tumor mass ⩽5 cm (p < 0.05), no lymph node metastasis (p < 0.001 and p = 0.001, respectively), no invasion (p = 0.003 and p = 0.004, respectively), and tumor-node-metastasis I or II stage disease (p < 0.05). Kaplan-Meier survival analysis showed that pancreatic ductal adenocarcinoma patients with negative forkhead box P1 and forkhead box O3a expression survived significantly shorter than patients with positive forkhead box P1 and forkhead box O3a expression (p = 0.000). Cox multivariate analysis revealed that negative forkhead box P1 and forkhead box O3a expression was an independent poor prognosis factor in pancreatic ductal adenocarcinoma patients. The area under the curve of a receiver operating characteristic curve was 0.642 for forkhead box P1 (95% confidence interval: 0.553-0.730) and 0.655 for forkhead box O3a (95% confidence interval: 0.6568-0.742). Loss of forkhead box P1 and forkhead box O3a protein expression is associated with carcinogenesis, progression, and poor prognosis in patients with pancreatic ductal adenocarcinomas.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Proteína Forkhead Box O3/genética , Fatores de Transcrição Forkhead/genética , Proteínas Repressoras/genética , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma Ductal Pancreático/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PrognósticoRESUMO
PURPOSE: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. METHODS: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. RESULTS: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. CONCLUSION: mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.
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Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Mutação , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND Almost all hepatic cancer cells have resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. c-FLIPL and RIP-1 are apoptotic negative regulatory factors. This study investigated the role of c-FLIPL and RIP-1 in hepatic cancer cell resistance to TRAIL-induced apoptosis. MATERIAL AND METHODS HepG2 cells were treated by TRAIL, RIP-1 siRNA, and/or BY11-7082. Cell viability was detected by MTT assay. Cell apoptosis was tested by flow cytometry. DISC component proteins, RIP-1, and p-p65 were measured by Western blot. Caspase-8 and caspase-3 were determined by spectrophotometry. RESULTS Single TRAIL treatment showed no significant impact on cell proliferation and apoptosis. HepG2 cells expressed high levels of RIP1 and c-FLIPL, while a high concentration of TRAIL upregulated RIP-1 and c-FLIPL expression but not DR4 and DR5. Single TRAIL treatment did not obviously activate caspase-8 and caspase-3. RIP-1 or c-FLIPL siRNA markedly induced cell apoptosis and enhanced caspase-8 and caspase-3 activities. Combined transfection obviously increased apoptotic cells. TRAIL markedly upregulated RIP-1 expression and enhanced p-p65 protein. Downregulating RIP-1 and/or BAY11-7082 significantly reduced NF-kB transcriptional activity, blocked cells in G0/G1 phase, weakened proliferation, elevated caspase-8 and caspase-3 activities, and promoted cell apoptosis. CONCLUSIONS TRAIL can enhance RIP1 and c-FLIPL expression in HepG2 cells. High expression of RIP1 and c-FLIPL is an important reason for TRAIL resistance. Downregulation of RIP1 and c-FLIPL can relieve caspase-8 suppression, activate caspase-3, and promote cell apoptosis. TRAIL mediates apoptosis resistance through upregulating RIP-1 expression, enhancing NF-kB transcriptional activity, and weakening caspase activity.
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Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Regulação para Baixo/efeitos dos fármacos , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , NF-kappa B/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologiaRESUMO
BACKGROUND: The purpose of this case series is to investigate the relationship between splenic thickness (ST) and postoperative outcomes after hepatic resection in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients. METHODS: The clinical data of 320 patients with HBV-associated HCC who had undergone liver resection were retrospectively analyzed. The value of ST in predicting postoperative outcomes was evaluated. RESULTS: A total of 320 patients were enrolled in the study. An increase in ST was significantly associated with an increase in portal vein diameter (PVD), indocyanine green retention rate 15 min (ICG R15), and total bilirubin (TBIL); however, it was negatively correlated with platelet count (PLT). Post-hepatectomy liver failure (PHLF) occurred in 35 (10.9%) patients. Multivariate logistic regression analysis showed that ST was an independent predictor of morbidity and mortality after hepatectomy. Meanwhile, ST was associated with an almost sixfold increased risk for developing perioperative complications (OR 5.678; 95% CI 2.873 to 11.224; P < 0.001) and almost 13-fold increased risk for mortality after hepatectomy (OR 13.007; 95% CI 1.238 to 136.627; P = 0.033).The area under the receiver operating characteristic (ROC) curve (AUC) of ST for predicting the incidence of PHLF was 0.754 (95% confidence interval (CI) 0.667 to 0.841; P < 0.001), with a sensitivity of 57.1% and a specificity of 82.5%, which were significantly greater than those of the ICG R15 level (AUC 0.670; 95% CI 0.560 to 0.779; P < 0.001). The critical value of ST was 43.5 mm. CONCLUSIONS: ST, which is an easy, inexpensive, and routinely available perioperative marker, showed a favorable predictive value for postoperative outcomes in HBV-associated HCC patients.
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Carcinoma Hepatocelular/cirurgia , Falência Hepática/epidemiologia , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Baço/patologia , Adulto , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Feminino , Hepatectomia/efeitos adversos , Vírus da Hepatite B/isolamento & purificação , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/cirurgia , Fígado/virologia , Falência Hepática/etiologia , Testes de Função Hepática , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Veia Porta/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Baço/diagnóstico por imagemRESUMO
OBJECTIVE: To explore the effects of protoporphyrin IX (PpIX)-mediated photodynamic therapy (PDT) on induction of apoptosis and death in colon cancer cell and the underlying mechanisms.â© Methods: The cell killing effect of PDT on HCT116 cell was determined by cell counting kit (CCK). The cells were divided into a control group, a single light group, a single PpIX group, and a PDT group. Hoechst 33342 and flow cytometry was used to assess the cell apoptosis. Western blot was employed to analyze the expressions of bcl-2, bax, and caspase-3. Reactive oxygen species (ROS) was detected by flow cytometry.â© Results: The viability of HCT116 cell was decreased gradually with the increase of irradiation dose (P<0.05). Compared to the other 3 groups, ROS production, the number of apoptotic cells and the protein expressions of bax and caspase-3 in PDT group increased, while bcl-2 expression was decreased (P<0.05).â© Conclusion: PpIX-mediated PDT can enhance the apoptosis in HCT116 cell, which may be related to mitochondrial apoptosis pathway.
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Apoptose , Fotoquimioterapia , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias do Colo , Humanos , Fármacos Fotossensibilizantes , Protoporfirinas , Espécies Reativas de OxigênioRESUMO
BACKGROUND: Pancreatic cancer ranks as the fourth leading cause of cancer-related mortality in the USA. And gemcitabine has been the standard of care for advanced pancreatic cancer. However, a combined use of gemcitabine plus cisplatin (GemCis) has shown promising efficacies in pancreatic cancer patients. Here, system review and meta-analysis were performed to compare the efficacy and safety of GemCis versus gemcitabine (Gem) alone in the treatment of pancreatic cancer. METHODS: The databases of MEDLINE (PubMed), EMBASE, and Cochrane Library were systematically searched for retrieving the relevant publications prior to 31 September 2014. The primary end point was overall survival (OS) and secondary end points included 6-month survival, 1 year survival, overall response rate (ORR), clinical benefit rate (CBR), time to progression/progression-free survival (TTP/PFS), and toxicities. RESULTS: A total of nine randomized controlled trials involving 1354 patients were included for systematic evaluations. Overall, as compared with Gem alone, GemCis significantly improved the 6-month survival rate (relative risk (RR) = 1.303, 95% confidence interval (CI) 1.090-1.558, P = 0.004), ORR (RR = 1.482, 95% CI 1.148-1.913, P = 0.003), PFS/TTP (hazard ratio (HR) = 0.87; 95% CI 0.78-0.93, P = 0.022), and the overall toxicities (RR = 2.164, 95% CI 1.837-2.549, P = 0.000). However, no significance difference existed in overall survival (HR = 0.90, 95% CI 0.80-1.42, P = 1.02), 1-year survival rate (RR = 0.956, 95% CI 0.770-1.187, P = 0.684), and CBR (RR = 0.854, 95% CI 0.681-1.072, P = 0.175). As for grade III/IV toxicity, seven kinds of toxicities were higher in the GemCis group. However, no significant inter-group statistical differences existed in the incidence of leukopenia, thrombocytopenia, or diarrhea. CONCLUSIONS: Despite a higher incidence of three-fourths toxicity, GemCis offers better outcomes of ORR, PFS/TTP, and 6-month survival, which indicates GemCis may be a promising therapy for pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Humanos , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , GencitabinaRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis. Despite intensive research, markers for the early diagnosis, prognosis, and targeting therapy of PDAC are not available. This study aimed to investigate the protein expressions of Jagged1 and DLL4 in PDAC tumor, benign pancreatic and normal pancreatic tissues, and analyze the associations of the two proteins with the clinical and pathological characteristics of PDAC. METHODS: A total of 106 PDAC tumor tissues and 35 peritumoral tissues were collected from January 2000 to December 2011 at our hospitals. Thirteen normal pancreatic tissues and 55 benign pancreatic specimens were collected at the same period. Immunohistochemical staining was used to measure Jagged1 and DLL4 protein expressions in these tissues. RESULTS: The percentage of positive Jagged1 and DLL4 was significantly higher in PDAC than in normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P<0.01). The higher Jagged1 and DLL4 expressions in PDAC were significantly associated with poor differentiation, maximum tumor size >5 cm, invasion, regional lymph node metastasis, and TNM III/IV disease (P<0.05). In PDAC, Jagged1 expression positively correlated with DLL4 expression. Univariate Kaplan-Meier analysis showed that positive Jagged1 and DLL4 expressions were significantly associated with shorter survival in patients with PDAC. Multivariate Cox regression analysis showed that positive Jagged1 and DLL4 expressions were independent prognostic factors for poor prognosis of patients with PDAC. CONCLUSION: Positive Jagged1 and DLL4 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in patients with PDAC.
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Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/química , Peptídeos e Proteínas de Sinalização Intercelular/análise , Proteína Jagged-1/análise , Neoplasias Pancreáticas/química , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Proteínas de Ligação ao Cálcio , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Regulação para CimaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with intrinsic resistance to cytotoxic agents. The molecular mechanisms associated with high malignancy and resistance to chemotherapy and radiotherapy have not been fully elucidated. This study investigated the clinicopathological significances of frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) and ATP-binding cassette subfamily G member 2 (ABCG2) expression in PDAC. FRAT1 and ABCG2 protein expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic tissues, and 13 normal pancreatic tissues was measured by immunohistochemistry. FRAT1 and ABCG2 protein was overexpressed in PDAC tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P < 0.01). The percentage of cases with positive FRAT1 and ABCG2 overexpression was significantly higher in PDAC patients with poor differentiation, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with well-differentiated tumor, no lymph node metastasis and invasion, and TNM stage I/II disease (P < 0.05 or P < 0.01). In pancreatic tissues with benign lesions, tissues with positive FRAT1 and ABCG2 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive FRAT1 and ABCG2 expression survived significantly shorter than patients with negative FRAT1 and ABCG2 expression (P < 0.05 or P < 0.001). Cox multivariate analysis revealed that positive FRAT1 and ABCG2 expression was an independent poor prognosis factor in PDAC patients. FRAT1 and ABCG2 overexpression is associated with carcinogenesis, progression, and poor prognosis in patients with PDAC.
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Transportadores de Cassetes de Ligação de ATP/biossíntese , Adenocarcinoma/genética , Biomarcadores Tumorais/biossíntese , Carcinoma Ductal Pancreático/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: Portal hypertension is one of the most important clinical conditions that cause intraoperative intensive hemorrhage in cirrhotic patients undergoing liver transplantation. Pre-transplant portal decompression may reduce the intraoperative bleeding during liver transplantation. METHODS: Splenic artery trunk embolization (SATE) was performed one month prior to liver transplantation. Platelet count, prealbumin, international normalized ratio, and blood flow in the portal vein and hepatic artery were monitored before and one month after SATE. The measurements above were collected on admission and before surgery in the non-SATE patients, who served as controls. We also recorded the intraoperative blood loss, operating time, required transfusion, post-transplant ascites, and complications within three months after operation in all patients. RESULTS: SATE significantly reduced portal venous blood flow, increased hepatic arterial blood flow, normalized platelet count, and improved prealbumin and international normalized ratio in the patients before liver transplantation. Compared to the non-SATE patients, the pre-transplant SATE significantly decreased the operating time, intraoperative bleeding, post-transplant ascites and severe surgical complications. CONCLUSION: Pre-transplant SATE decreases portal pressure, improves liver function reserve, and reduces the surgical risk of liver transplantation effectively in patients with severe portal hypertension.
Assuntos
Embolização Terapêutica/métodos , Hipertensão Portal/terapia , Transplante de Fígado/efeitos adversos , Cuidados Pré-Operatórios/métodos , Artéria Esplênica , Adulto , Ascite/etiologia , Ascite/prevenção & controle , Biomarcadores/sangue , Coagulação Sanguínea , Velocidade do Fluxo Sanguíneo , Perda Sanguínea Cirúrgica/prevenção & controle , Embolização Terapêutica/efeitos adversos , Feminino , Artéria Hepática/fisiopatologia , Artéria Hepática/cirurgia , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/fisiopatologia , Coeficiente Internacional Normatizado , Circulação Hepática , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Contagem de Plaquetas , Pressão na Veia Porta , Veia Porta/fisiopatologia , Veia Porta/cirurgia , Pré-Albumina/metabolismo , Cuidados Pré-Operatórios/efeitos adversos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Epithelial-mesenchymal transitions (EMTs) are essential manifestations of epithelial cell plasticity during tumor progression. Transforming growth factor-ß(TGF-ß) modulates epithelial plasticity in tumor physiological contexts by inducing EMT, which is associated with the altered expression of genes. In the present study, we used DNA micro-array analysis to search for differentially expressed genes in the TGF-ß1 induced gallbladder carcinoma cell line (GBC-SD cells), as compared with normal GBC-SD cells. We identified 225 differentially expressed genes, including 144 that were over-expressed and 81 that were under-expressed in the TGF-ß1 induced GBC-SD cells. NT5E (CD73) is the most increased gene, while the Fc fragment of the IgG binding protein (FcGBP) is the most decreased gene. The expression patterns of these two genes in gallbladder adenocarcinoma and chronic cholecystitis tissue were consistent with the micro-array data. Immunochemistry and clinicopathological results showed that the expression of NT5E and FcGBP in gallbladder adenocarcinoma is an independent marker for evaluation of the disease progression, clinical biological behaviors and prognosis. The data from the current study indicate that differential NT5E and FcGBP expressions could be further evaluated as biomarkers for predicting survival of patients with gallbladder cancer and that NT5E and FcGBP could be promising targets in the control of gallbladder cancer progression.
Assuntos
5'-Nucleotidase/metabolismo , Moléculas de Adesão Celular/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Fator de Crescimento Transformador beta1/farmacologia , 5'-Nucleotidase/genética , Western Blotting , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Neoplasias da Vesícula Biliar/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de SobrevidaRESUMO
BACKGROUND: To establish a model of pancreatic cancer induced by 7,12-dimethylbenzantracene (DMBA) in Sprague-Dawley (SD) rats, and detect the expression of DNA-repair proteins (MGMT, ERCC1, hMSH2, and hMLH1) and their significance in pancreatic cancer and non-cancerous pancreatic tissues of SD rats. METHODS: DMBA was directly implanted into the parenchyma of rat pancreas (group A and group B), and group B rats were then treated with trichostatin A (TSA). The rats in both groups were executed within 3 to 5 months, and their pancreatic tissues were observed by macrography and under microscopy. Meanwhile, the rats in the control group (group C) were executed at 5 months. Immunohistochemistry was used to assay the expression of MGMT, ERCC1, hMSH2, and hMLH1. RESULTS: The incidence of pancreatic cancer in group A within 3 to 5 months was 48.7% (18/37), including 1 case of fibrosarcoma. The incidence of pancreatic cancer in group B was 33.3% (12/36), including 1 case of fibrosarcoma. The mean of maximal diameters of tumors in group A was higher than that in group B (P <0.05). No pathological changes were found in pancreas of group C and other main organs (except pancreas) of group A and group B. No statistical differences were found among the positive rates of MGMT, ERCC1, hMSH2, and hMLH1 in ductal adenocarcinoma and non-cancerous pancreatic tissues of group A (P >0.05). The positive rates of MGMT, ERCC1, hMSH2, and hMLH1 were significantly lower in ductal adenocarcinoma than those in non-cancerous tissues of group B (P ≤0.05). All pancreas of group C had positive expression of MGMT, ERCC1, hMSH2, and hMLH1 and two cases of fibrosarcoma showed a negative expression. CONCLUSIONS: DMBA, directly implanted into the parenchyma of pancreas, creates an ideal pancreatic cancer model within a short time. TSA might restrain DNA damage related to the genesis and growth of pancreatic cancer in rats. The DNA-repair proteins, including MGMT, ERCC1, hMSH2, and hMLH1, might play an important role in the genesis of pancreatic cancer induced by DMBA in rats.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Técnicas Imunoenzimáticas , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Aquaporin-9 (AQP9) is a membrane-span transport protein expressed in the liver. It is located in the cytoplasm membrane of hepatic cells. In addition to water, it is also permeable to glycerol, urea, and other small solutes. Several evidences have revealed that AQP9 is involved in multiple physiological and pathological process of the liver. This paper summarized the expression of AQP9 in the liver and the effect on the physiological and pathological processes of the liver. AQP9 may be defined as a novel target for diagnosis and treatment of hepatic diseases.
Assuntos
Aquaporinas/metabolismo , Fígado/metabolismo , Membrana Celular/metabolismo , Glicerol , Hepatócitos/metabolismo , Humanos , UreiaRESUMO
OBJECTIVE: To explore the technique and effect of liver hanging maneuver in anterior approach for isolated complete liver caudate lobectomy. METHODS: We recruited 17 patients with liver caudate lobe tumor (13 primary hepatocellular carcinoma, 3 cholangiocarcinoma and 1 liver metastasis from colorectal cancer). Isolated complete caudate lobectomy with liver hanging maneuver was performed in 17 patients. RESULTS: All 17 patients were successfully received the above-mentioned operation. The operative time was 166-427 (211.5 ± 20.1) min and the intraoperative blood loss was 372-1 208 (472.7 ± 83.6) mL. There was no operative death. The survival rates of follow up for 1, 3 and 5 years were 76.5%, 52.9% and 23.5%, respectively. CONCLUSION: Liver hanging maneuver for isolated complete resection of the caudate lobe is an ideal approach for liver neoplasms resection.