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1.
Chin J Cancer Res ; 35(6): 645-659, 2023 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-38204447

RESUMEN

Objective: The aim of this study was to prospectively compare double-tract reconstruction (DTR) and esophagogastrostomy (EG) after proximal gastrectomy (PG) regarding the incidence of reflux esophagitis, quality of life (QOL), nutritional status and surgical safety. Methods: This study was a randomized controlled trial. Patients eligible for PG were enrolled and randomly assigned to the EG group and DTR group. The characteristics of patients, parameters for surgical safety, incidence of reflux esophagitis, nutrition status and QOL were collected and compared between the two groups. Univariate analysis and multivariate analysis were performed to determine the significant factors affecting the incidence of reflux esophagitis after PG. Results: Thirty-seven patients of the EG group and 36 patients of the DTR group were enrolled. The incidence of reflux esophagitis was significantly lower in the DTR group than in the EG group (8.3% vs. 32.4%, P=0.019). The DTR group demonstrated a more favorable QOL than the EG group after PG. The nutritional status was balanced within the EG group and the DTR group. The operation time was longer in the DTR group than in the EG group (191 min vs. 221 min, P=0.001), while surgical safety was similar in the two groups. Conclusions: Our research demonstrated that DTR is superior to EG after PG in terms of the incidence of reflux esophagitis and provides a more satisfactory QOL without increasing surgical complications or sacrificing nutritional status.

2.
Am J Pathol ; 191(9): 1651-1667, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34129844

RESUMEN

Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de los Conductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Receptor Notch1/metabolismo , Factores de Transcripción/metabolismo , Adulto , Anciano , Animales , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Proto-Oncogenes Mas , Proteínas Señalizadoras YAP
3.
Ann Surg Oncol ; 28(11): 6665-6672, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33783640

RESUMEN

OBJECTIVE: The aim of this study was to create a risk-scoring model to preoperatively predict the incidence of lymph node metastasis (LNM) in early gastric cancer (EGC) patients to guide treatment. METHODS: To construct the risk-scoring model, we retrospectively analyzed a primary cohort of 548 EGC patients. Univariate analysis and logistic regression were performed. A risk-scoring model for predicting LNM in EGC patients was developed based on preoperative factors, and another cohort of 73 patients was then analyzed to validate the model. RESULTS: In the primary cohort, LNM was pathologically confirmed in 72 (13.1%) patients. In the multivariate analysis, the presence of ulceration and tumor size on gastroscopy, undifferentiated histological type, and presence of enlarged lymph nodes on computed tomography or endoscopic ultrasonography were independent risk factors for LNM. A 17-point risk-scoring model was developed to predict LNM risk. The cut-off score of the model was 8, and the area under the receiver operating characteristic curve (AUC) of the model was 0.835 [95% confidence interval (CI) 0.784-0.886]. In the validation cohort, the AUC of the model was 0.829 (95% CI 0.699-0.959). CONCLUSIONS: We developed and validated an effective 17-point risk-scoring model that could preoperatively predict LNM for EGC patients.


Asunto(s)
Neoplasias Gástricas , Gastrectomía , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía , Metástasis Linfática , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/cirugía
4.
BMC Cancer ; 21(1): 216, 2021 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-33653317

RESUMEN

BACKGROUND: HIPEC is an emerging procedure to treat peritoneal metastasis of gastric cancer. Data about HIPEC in locally advanced gastric cancer is scarce. The purpose of this trial is to evaluate the safety and toxicity of prophylactic HIPEC with cisplatin for patients with locally advanced gastric cancer. METHODS: From March 2015 to November 2016, a prospective, randomized phase II trial was conducted. After radical gastrectomy, patients in the experimental group underwent HIPEC with cisplatin followed by adjuvant chemotherapy with SOX regime. Patients in the other group were treated with SOX regime alone. Postoperative complications and patient survival were compared. RESULTS: In total, 50 patients were eligible for analyses. No significant difference was found in the incidence of postoperative complications including anastomotic/intestinal leakage, liver dysfunction, bone marrow suppression, wound infection and ileus (P > 0.05). Mean duration of hospitalization after radical gastrectomy was 11.7 days. 12.2 days in experimental group and 10.8 days in control group respectively (P = 0.255). The percentage of patients with elevated tumor markers was 12.1% in experimental group, which was significantly lower than 41.2% in control group (P = 0.02). 3-year RFS of patients who treated with or without prophylactic HIPEC were 84.8 and 88.2% respectively (P = 0.986). In the multivariate analysis, pathological T stage was the only independent risk factor for the RFS of patients (P = 0.012, HR =15.071). CONCLUSION: Additional intraoperative HIPEC with cisplatin did not increase postoperative complications for locally advanced gastric cancer after curative surgery. Prophylactic HIPEC with cisplatin was safe and tolerable, while it did not reduce the risk of peritoneal recurrence in this trial, supporting further studies to validate the efficacy of it. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000038331. Registered 18 September 2020 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=59692 .


Asunto(s)
Gastrectomía , Quimioterapia Intraperitoneal Hipertérmica/métodos , Neoplasias Gástricas/terapia , Anciano , Anciano de 80 o más Años , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Gastrectomía/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Prospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología
5.
Gastrointest Endosc ; 94(3): 642-650, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33798538

RESUMEN

BACKGROUND AND AIMS: Now that the debate about the safety and effectiveness of laparoscopic versus open surgery is over, attention has turned to innovations that can verify whether minimizing the impact of laparoscopy on the abdominal wall can further reduce pain, improve patient comfort, lead to superior cosmesis, and reduce morbidity. The aim of this study was to further explore the application value of totally laparoscopic right hemicolectomy with transcolonic natural orifice specimen extraction (NOSE) and to evaluate the short-term efficacy of transcolonic NOSE surgery for resecting specimens of ascending colon cancer. METHODS: From January 2016 to May 2017, a retrospective study was conducted in Guangxi. Propensity score matching was used to minimize the bias from nonrandomized treatment assignment. Patients were followed up through May 2020. RESULTS: Forty-nine patients underwent totally laparoscopic right hemicolectomy with transcolonic NOSE and 116 patients laparoscopic right hemicolectomy with mini-laparotomy (ML) procedures at our institution. After propensity score matching, each group included 45 patients, and all covariate imbalances were alleviated. The transcolonic NOSE group and the ML group did not differ significantly in terms of baseline clinical characteristics. The transcolonic NOSE group was associated with a shorter time to first flatus (NOSE vs ML: 1.8 ± .5 vs 3.2 ± .8, P = .032), a shorter length of hospital stay (11.3 ± 2.5 days vs 13.0 ± 3.1 days, P = .034), a shorter time to first liquid intake (2.6 ± .8 vs 3.8 ± .9, P = .068), less pain (1.8 ± .8 vs 4.2 ± .7, P = .013), less analgesia requirement (6 [13.3%] vs 21 [46.7%], P = .001), and lower C-reactive protein levels on postoperative day 1 (3.6 ± 1.7 vs 8.2 ± 2.2, P = .001) and postoperative day 3 (NOSE 2.4 ± 1.4 vs M: 4.6 ± 1.7 [P = .013]) than the ML group. The median follow-up was 28.4 months (interquartile range, 18.0-36.0). The 3-year overall survival rates were similar between the transcolonic NOSE group and the ML group. CONCLUSIONS: In total, laparoscopic right hemicolectomy with transcolonic specimen extraction appears to be safe for selected patients with ascending colon cancer as a minimally invasive surgery.


Asunto(s)
Neoplasias del Colon , Laparoscopía , China , Colectomía , Colon Ascendente , Neoplasias del Colon/cirugía , Humanos , Laparotomía , Tiempo de Internación , Puntaje de Propensión , Estudios Retrospectivos , Resultado del Tratamiento
6.
Gastric Cancer ; 24(1): 45-59, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32572790

RESUMEN

BACKGROUND: Long non-coding RNA (lncRNA) ASB16 antisense RNA 1 (ASB16-AS1) is recognized as an oncogene in several cancer types, but its relation to GC is unknown. Tripartite motif containing 37 (TRIM37) has been proven to accelerate the development of gastric cancer (GC), whereas the molecular mechanism assisted ASB16-AS1 and TRIM37 in regulating GC progression remains unclear. METHODS: Differentially expressed lncRNAs in GC samples were analyzed based on Gene Expression Omnibus (GEO) data. CCK-8 and colony formation assays were applied to determine the proliferative ability of GC cells. Stem cell-like phenotype of GC cells was assessed by sphere formation assay and flow cytometry analysis. Luciferase reporter assay, RNA immunoprecipitation (RIP), pulldown, and co-immunoprecipitation (Co-IP) were performed to verify the interplay of RNA molecules. RESULTS: ASB16-AS1 was upregulated in GC samples according to GEO data and qRT-PCR analysis. ASB16-AS1 strengthened the proliferative ability and stem cell-like characteristics in GC cells. More importantly, ASB16-AS1 encouraged GC cell growth in vivo. Mechanistically, ASB16-AS1 strengthened TRIM37 expression by sequestering miR-3918 and miR-4676-3p. ASB16-AS1 activated NF-kappa B (NF-κB) pathway by cooperating with ATM serine/threonine kinase (ATM) to induce TRIM37 phosphorylation. CONCLUSION: In summary, ASB16-AS1 exerted oncogenic functions in GC through modulating TRIM37 expression at both mRNA and protein levels.


Asunto(s)
Repetición de Anquirina/genética , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética , Carcinogénesis/genética , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Proliferación Celular/genética , Cisplatino , Resistencia a Medicamentos/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genética , FN-kappa B/metabolismo , Células Madre Neoplásicas , Fosforilación/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/genética , Regulación hacia Arriba/genética
7.
Jpn J Clin Oncol ; 50(1): 20-28, 2020 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-31665375

RESUMEN

OBJECTIVES: Anastomotic leakage (AL) after anterior resection always leads to longer hospital stays, decreased quality of life and even increased mortality. Despite extensive research, no consensus on the world well-concerned surgical-related risk factors exists. We therefore conducted a meta-analysis of the available published literature to identify the effects of surgical-related risk factors for AL after anterior resection for rectal cancer, hoping to provide more information and improved guidance for clinical workers managing patients with rectal cancer who are at a high risk for AL. METHODS: In this study, the relevant articles were systematically searched from EMBASE, MEDLINE, PubMed, WangFang (Database of Chinese Ministry of Science & Technology), Chinese National Knowledge Infrastructure Database and China Biological Medicine Database. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were calculated. Meta-analysis was performed using of RevMan 5.3 software. RESULTS: A total of 26 studies met the inclusion criteria and comprised 34238 cases. Analysis of these 26 studies showed that no defunctioning stoma was highly correlated with AL (pooled OR = 1.28, 95%CI: 1.05-1.57, P = 0.01, random effect), and intraoperative blood transfusion was significantly associated with AL (pooled OR = 1.64, 95%CI: 1.34-2.02, P = 0.02, random effect). However, the AL was not associated with type of anastomosis, type of surgery, technique of anastomosis, level of inferior mesenteric artery ligation, operation time and splenic flexure mobilization. CONCLUSIONS: Depend on this meta-analysis, no defunctioning stoma and intraoperative blood transfusion are the major surgical-related risk factors for AL after resection for rectal cancer. Because of the inherent limitations of the research, future prospective randomized controlled trials will need to confirm this conclusion.


Asunto(s)
Fuga Anastomótica/etiología , Neoplasias del Recto/cirugía , Reacción a la Transfusión/etiología , Anastomosis Quirúrgica/efectos adversos , Transfusión Sanguínea , China , Humanos , Ligadura , Masculino , Oportunidad Relativa , Calidad de Vida , Factores de Riesgo , Estomas Quirúrgicos/efectos adversos
8.
Am J Pathol ; 188(4): 995-1006, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29378174

RESUMEN

Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors.


Asunto(s)
Linaje de la Célula , Neoplasias Hepáticas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Animales , Conductos Biliares/patología , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Femenino , Vía de Señalización Hippo , Humanos , Masculino , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Notch/metabolismo , Transcripción Genética , Proteínas ras/metabolismo
9.
J Exp Bot ; 70(21): 6277-6291, 2019 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-31504730

RESUMEN

Cytokinins are one of the most important phytohormones and play essential roles in multiple life processes in planta. Root-derived cytokinins are transported to the shoots via long-distance transport. The mechanisms of long-distance transport of root-derived cytokinins remain to be demonstrated. In this study, we report that OsABCG18, a half-size ATP-binding cassette transporter from rice (Oryza sativa L.), is essential for the long-distance transport of root-derived cytokinins. OsABCG18 encodes a plasma membrane protein and is primarily expressed in the vascular tissues of the root, stem, and leaf midribs. Cytokinin profiling, as well as [14C]trans-zeatin tracer, and xylem sap assays, demonstrated that the shootward transport of root-derived cytokinins was significantly suppressed in the osabcg18 mutants. Transport assays in tobacco (Nicotiana benthamiana) indicated that OsABCG18 exhibited efflux transport activities for various substrates of cytokinins. While the mutation reduced root-derived cytokinins in the shoot and grain yield, overexpression of OsABCG18 significantly increased cytokinins in the shoot and improved grain yield. The findings for OsABCG18 as a transporter for long-distance transport of cytokinin provide new insights into the cytokinin transport mechanism and a novel strategy to increase cytokinins in the shoot and promote grain yield.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Citocininas/metabolismo , Grano Comestible/crecimiento & desarrollo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Brotes de la Planta/metabolismo , Transporte Biológico , Grano Comestible/metabolismo , Regulación de la Expresión Génica de las Plantas , Proteínas Fluorescentes Verdes/metabolismo , Mutación/genética , Oryza/anatomía & histología , Oryza/genética , Oryza/crecimiento & desarrollo , Fenotipo , Filogenia , Raíces de Plantas/metabolismo
10.
J Hepatol ; 67(6): 1194-1203, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28733220

RESUMEN

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model. METHODS: We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study. RESULTS: Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. CONCLUSIONS: This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade. Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Neoplasias de los Conductos Biliares/etiología , Neoplasias de los Conductos Biliares/patología , Proteínas de Ciclo Celular , Colangiocarcinoma/etiología , Colangiocarcinoma/patología , Femenino , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/fisiología , Diana Mecanicista del Complejo 2 de la Rapamicina/fisiología , Ratones , Fosfoproteínas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/fisiología , Proteínas Señalizadoras YAP
11.
Chin J Cancer Res ; 29(2): 144-148, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28536493

RESUMEN

BACKGROUND: The ACTS-GC study had shown postoperative adjuvant therapy with S-1 improved survival of patients with locally advanced gastric cancer. Addition of oxaliplatin to S-1 is considered to be acceptable as one of the treatment options for gastric cancer patients after radical gastrectomy with D2 lymph node excision. METHODS: We have commenced a randomized phase III trial in December 2016 to evaluate S-1 plus oxaliplatin compared with S-1 alone in the adjuvant setting for locally advanced gastric cancer. A total of 564 patients will be accrued from 13 Chinese institutions in two years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are 5-year overall survival, proportion of patients who complete the postoperative chemotherapy and incidence of adverse events. ETHIC AND DISSEMINATION: The trial has been approved by the institutional review board of each participating institution and it was activated on December, 2016. The enrollment will be finished in December, 2018. Patient's follow-up will be ended until December, 2023. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02867839. Registered on August 4, 2016.

12.
Hepatology ; 61(1): 200-13, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25145583

RESUMEN

UNLABELLED: Concomitant expression of activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and Ras in mouse liver (AKT/Ras) leads to rapid tumor development through strong activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 functions by regulating p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E-binding protein 1/ eukaryotic translation initiation factor 4E (4EBP1/eIF4E) cascades. How these cascades contribute to hepatocarcinogenesis remains unknown. Here, we show that inhibition of the RPS6 pathway by rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras-induced hepatocarcinogenesis. Combined treatment with rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong antineoplastic effect was successfully recapitulated by ablating regulatory associated protein of mTORC1, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Furthermore, we demonstrate that overexpression of eIF4E, the proto-oncogene whose activity is specifically inhibited by 4EBP1, resulted in hepatocellular carcinoma (HCC) development in cooperation with activated Ras. Mechanistically, we identified the ectonucleoside triphosphate diphosphohydrolase 5/ adenylate kinase 1/cytidine monophosphate kinase 1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in AKT/Ras and Ras/eIF4E livers as well as in human HCC cell lines and tissues. CONCLUSIONS: Complete inhibition of mTORC1 is required to suppress liver cancer development induced by AKT and Ras proto-oncogenes in mice. The mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human HCC.


Asunto(s)
Factor 4E Eucariótico de Iniciación/metabolismo , Neoplasias Hepáticas Experimentales/etiología , Complejos Multiproteicos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína S6 Ribosómica/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Apoptosis , Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Factores Eucarióticos de Iniciación , Humanos , Neoplasias Hepáticas Experimentales/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Complejos Multiproteicos/antagonistas & inhibidores , Proteínas Oncogénicas/metabolismo , Fosfoproteínas/metabolismo , Proto-Oncogenes Mas , Pirofosfatasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Sirolimus , Serina-Treonina Quinasas TOR/antagonistas & inhibidores
13.
Tumour Biol ; 37(8): 10269-78, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26831669

RESUMEN

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal apoptosis inducer and believed to have promise in cancer therapy, yet part of cancer cells exhibit resistance to TRAIL-mediated apoptosis. This necessitates the exploration of agents that resensitizes cancer cells to TRAIL. In our study, we found that Trichostatin A (TSA), an histone deacetylase (HDAC) inhibitor, augmented TRAIL-induced apoptosis in gastric cancer cells in a caspase-dependent manner. Besides, upregulation of DR5 and downregulation of anti-apoptotic proteins including XIAP, Mcl-1, Bcl-2 and Survivin also contributed to this synergism. Noticeably, TSA treatment inhibited Forkhead boxM1 (FOXM1), which expression level showed negative correlation with TRAIL sensitivity. Similarly, silencing of FOXM1 by small interfering RNA (siRNA) resensitized cancer cells to TRAIL and strengthened the TRAIL-augmenting effect of TSA. In addition, we demonstrated the depletion of FOXM1 was a consequence of the inactivation of ERK mediated by TSA. Collectively, it was first shown that TSA potentiated TRAIL sensitivity via ERK/FOXM1 pathway in gastric cancer cells. FOXM1 might serve as a biomarker for predicting sensitivity to TRAIL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Neoplasias Gástricas/patología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Sinergismo Farmacológico , Proteína Forkhead Box M1/metabolismo , Técnicas de Silenciamiento del Gen , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo
14.
BMC Cancer ; 16(1): 765, 2016 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-27716191

RESUMEN

BACKGROUND: Surgery for advanced gastric cancer (AGC) often includes dissection of splenic hilar lymph nodes (SHLNs). This study compared the safety and effectiveness of different approaches to SHLN dissection for upper- and/or middle-third AGC. METHODS: We retrospectively compared and analyzed clinicopathologic and follow-up data from a prospectively collected database at the Peking University Cancer Hospital. Patients were divided into three groups: in situ spleen-preserved, ex situ spleen-preserved and splenectomy. RESULTS: We analyzed 217 patients with upper- and/or middle-third AGC who underwent R0 total or proximal gastrectomy with splenic hilar lymphadenectomy from January 2006 to December 2011, of whom 15.2 % (33/217) had metastatic SHLNs, and from whom 11.4 % (53/466) of the dissected SHLNs were metastatic. The number of harvested SHLNs per patient was higher in the ex situ group than in the in situ group (P = 0.017). Length of postoperative hospital stay was longer in the splenectomy group than in the in situ group (P = 0.002) or the ex situ group (P < 0.001). The splenectomy group also lost more blood volume (P = 0.007) and had a higher postoperative complication rate (P = 0.005) than the ex situ group. Kaplan-Meier (log rank test) analysis showed significant survival differences among the three groups (P = 0.018). Multivariate analysis showed operation duration (P = 0.043), blood loss volume (P = 0.046), neoadjuvant chemotherapy (P = 0.005), and N stage (P < 0.001) were independent prognostic factors for survival. CONCLUSIONS: The ex situ procedure was more effective for SHLN dissection than the in situ procedure without sacrificing safety, whereas splenectomy was not more effective, and was less safe. The SHLN dissection method was not an independent risk factor for survival in this study.


Asunto(s)
Ganglios Linfáticos/patología , Neoplasias Gástricas/cirugía , Femenino , Humanos , Estimación de Kaplan-Meier , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Bazo/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Resultado del Tratamiento
15.
Gastroenterology ; 147(3): 690-701, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24837480

RESUMEN

BACKGROUND & AIMS: Aberrant activation of ß-catenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with the development of multiple tumor types. Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis. METHODS: We used immunohistochemical analysis to determine expression of ß-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 hepatoblastoma samples. We assessed ß-catenin and Yap1 signaling and interactions in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering RNAs, and effects on proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of ß-catenin (ΔN90/ß-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected, and histological and immunohistochemical analyses were performed. RESULTS: We observed nuclear localization of ß-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples. Yap1 and ß-catenin coprecipitated in hepatoblastoma but not hepatocellular carcinoma cells. Small interfering RNA-mediated knockdown of Yap1 or ß-catenin in hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to coactivate transcription with ß-catenin; ß-catenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and ß-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both proteins, and human hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEA domain factors was required for tumorigenesis in mice. CONCLUSIONS: ß-catenin and the transcriptional regulator Yap1 interact physically and are activated in most human hepatoblastoma tissues; overexpression of activated forms of these proteins in livers of mice leads to rapid tumor development. Further analysis of these mice will allow further studies of these pathways in hepatoblastoma pathogenesis and could lead to the identification of new therapeutic targets.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transformación Celular Neoplásica/metabolismo , Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Fosfoproteínas/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Muerte Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Europa (Continente) , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Hepatoblastoma/genética , Hepatoblastoma/patología , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones , Fosfoproteínas/genética , Unión Proteica , Interferencia de ARN , Transducción de Señal , Factores de Tiempo , Factores de Transcripción , Transcripción Genética , Transfección , Estados Unidos , Proteínas Señalizadoras YAP , beta Catenina/genética
16.
World J Surg Oncol ; 13: 212, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-26126412

RESUMEN

BACKGROUND: Systemic chemotherapy is the key treatment for advanced gastric cancer. The benefit of adjuvant surgery following preoperative chemotherapy in gastric cancer with liver metastasis has not been well established. METHODS: Forty-nine gastric cancer patients diagnosed with synchronous liver metastasis initially treated with chemotherapy were categorized into the following two groups: surgery group: 25 patients who underwent gastrectomy and subsequently received postoperative chemotherapy and control group: 24 patients who received chemotherapy alone. RESULTS: The median overall survival of patients in the surgery group and control group was 20.5 and 9.1 months, respectively, (P = 0.006). The median progression-free survival in the surgery group was 10.9 months, with statistical significance when compared with 5.0 months in the control group (P = 0.001). Multivariate analysis demonstrated that response to chemotherapy was the only independent factor in predicting prognosis. The survival of patients who achieved partial response (PR) was prolonged if they received adjuvant surgery (P = 0.024). No significant difference in the survival of patients underwent combined hepatic resection when compared with patients performed gastrectomy only. CONCLUSIONS: For gastric cancer with synchronous liver metastasis, adjuvant gastrectomy followed by chemotherapy might be beneficial for survival comparing with chemotherapy alone, especially in patients response to initial preoperative chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gastrectomía , Neoplasias Hepáticas/cirugía , Neoplasias Primarias Múltiples/cirugía , Neoplasias Gástricas/cirugía , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Capecitabina/administración & dosificación , Carcinoma de Células en Anillo de Sello/tratamiento farmacológico , Carcinoma de Células en Anillo de Sello/mortalidad , Carcinoma de Células en Anillo de Sello/secundario , Carcinoma de Células en Anillo de Sello/cirugía , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/secundario , Carcinoma de Células Pequeñas/cirugía , Estudios de Casos y Controles , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/mortalidad , Neoplasias Primarias Múltiples/patología , Paclitaxel/administración & dosificación , Pronóstico , Estudios Prospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia
17.
J Cell Biochem ; 115(1): 34-41, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24038122

RESUMEN

UNLABELLED: Transcription Factor E2F-1 plays a critical role in cell cycle regulation and other biological processes in cells. However whether or not it is involved in the multi-drug resistance (MDR) process of gastric cancer has not been fully elucidated yet. To explore the role of E2F-1 in the MDR process of gastric cancer in vitro and in vivo, a cisplatin-resistant gastric cancer cell line with stable downregulation of E2F-1 was established. E2F-1 shRNA led to downregulation of endogenous E2F-1 mRNA and protein. It significantly promoted the sensitivity of SGC7901/DDP cells to cisplatin, doxorubicin, and fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells increased after E2F-1 downregulation. This notion was further supported by the observation that downregulation of E2F-1 blocked entry into the S-phase of the cell cycle. Furthermore, downregulation of E2F-1 significantly increased intracellular accumulation of doxorubicin. In addition, we determined the in vivo effects of E2F-1 small interfering RNA (shRNA) on tumor size, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining. In molecular studies, semiquantitative RT-PCR and western blotting revealed that E2F-1 downregulation could inhibit expression of MDR1, MRP, Bcl-2/Bax, c-Myc, Skp2, Survivin, and Cyclin D1. IN CONCLUSION: E2F-1 may be involved in regulating multiple signaling pathways in reversing MDR, suggesting that E2F-1 may represent a novel target for gastric cancer therapy.


Asunto(s)
Resistencia a Antineoplásicos , Factor de Transcripción E2F1/genética , Neoplasias Gástricas/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Cisplatino/farmacología , Ciclina D1/genética , Regulación hacia Abajo/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Factor de Transcripción E2F1/metabolismo , Regulación Neoplásica de la Expresión Génica , Genes myc , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Masculino , Ratones , Ratones Desnudos , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Proteínas Quinasas Asociadas a Fase-S/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Survivin
18.
Gastroenterology ; 144(7): 1530-1542.e12, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23419361

RESUMEN

BACKGROUND & AIMS: Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear. METHODS: By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP(S127A)), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients. RESULTS: Human HCC cell lines and mouse hepatocytes that overexpress YAP(S127A) up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not ß-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer. CONCLUSIONS: The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas de Unión al Calcio/fisiología , Carcinoma Hepatocelular/genética , Proteínas de Unión al ADN/fisiología , Hepatocitos/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Neoplasias Hepáticas/genética , Proteínas de la Membrana/fisiología , Proteínas Musculares/fisiología , Fosfoproteínas/fisiología , Receptores Notch/fisiología , Factores de Transcripción/fisiología , Animales , Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína Jagged-1 , Neoplasias Hepáticas/metabolismo , Ratones , Proteínas Serrate-Jagged , Factores de Transcripción de Dominio TEA , Regulación hacia Arriba , Proteínas Señalizadoras YAP
19.
Guang Pu Xue Yu Guang Pu Fen Xi ; 34(1): 111-5, 2014 Jan.
Artículo en Zh | MEDLINE | ID: mdl-24783544

RESUMEN

In the present paper, British Edinburgh FLS920P Steady State and Time-Resolved Fluorescence Spectrometer was applied to measure three dimensional fluorescence spectra of 12 pigment solution samples and the parallel factor algorithm was combined with the excitation-emission matrix to find a way to detect the food colors. In the experiment, making use of CORCONDIA determination method to confirm that the number of the components is 3 in mixed solution, and then by using parallel factor analysis (PARAFAC) algorithms, get the average recoveries of carminum and Allura red were 99.3% +/- 5.0% and 102.2% +/- 5.6%, and the root mean square errors of prediction (RMSEP) were 0.054 and 0.205, respectively. The results show that the method can be applied to determine carminum and Allura red in the mixed solution simultaneously even in the presence of interfering amaranth, which was simple and convenient, rapid, etc, and provides references for synthetic food pigments detection.


Asunto(s)
Algoritmos , Color , Colorantes de Alimentos/análisis , Análisis Factorial , Fluorescencia , Espectrometría de Fluorescencia
20.
Guang Pu Xue Yu Guang Pu Fen Xi ; 34(12): 3307-11, 2014 Dec.
Artículo en Zh | MEDLINE | ID: mdl-25881429

RESUMEN

Three-dimensional fluorescence spectra combined with second-order calibration algorithm based on alternate a weighted residual (ANWE) was applied to the direct concentration determination of carmine in carbonated beverages. Firstly, 3-D fluorescence spectra of carmine and sunset yellow mixed solutions with different concentrations were obtained by employing spectrometer, and analyzed by using ANWE, the correlation coefficient between calibration concentration and the actual concentration was 0.9917, and the average recovery was 100.92%±2.71%. The results show that the ANWE algorithm is reliable. Then, the commercial carbonated soft drinks in 8, 9, 12 and 13 times diluted concentration were detected by using ANWE algorithm, the correlation coefficient between relative concentration and the actual concentration were 0.9930, 0.9930, 0.9932 and 0.7932, respectively, and the contents of carmine in beverage were 38.88, 37.71, 37.68 and 39.65 µg · mL(-1), respectively. The average concentration was (38.48±0.96) µg · mL(-1). Finally, the standard addition method was applied to estimate the prediction accuracy between calibration concentration and the actual concentration was 0.9935, and the average recovery was 102.99%±2.15%. The results can provide a new idea for the rapid content determination of food pigments in commercial beverages.


Asunto(s)
Bebidas Gaseosas/análisis , Carmín/análisis , Colorantes de Alimentos/análisis , Algoritmos , Compuestos Azo , Calibración , Fluorescencia , Espectrometría de Fluorescencia
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