Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Front Oncol ; 12: 950418, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387243

RESUMO

Background: Peritoneal sarcomatosis (PS) could occur in patients with retroperitoneal sarcomas (RPS). This study aimed to expand the understanding of PS on its characteristics and prognostic role, and develop a nomogram to predict its occurrence preoperatively. Methods: Data of 211 consecutive patients with RPS who underwent surgical treatment between 2011 and 2019 was retrospectively reviewed. First, the clinicopathological characteristics of PS were summarized and analyzed. Second, the disease-specific survival (DSS) and recurrence-free survival (RFS) of patients were analyzed to evaluate the prognostic role of PS. Third, preoperative imaging, nearly the only way to detect PS preoperatively, was combined with other screened risk factors to develop a nomogram. The performance of the nomogram was assessed. Results: Among the 211 patients, 49 (23.2%) patients had PS with an incidence of 13.0% in the primary patients and 35.4% in the recurrent patients. The highest incidence of PS occurred in dedifferentiated liposarcoma (25.3%) and undifferentiated pleomorphic sarcoma (25.0%). The diagnostic sensitivity of the preoperative imaging was 71.4% and its specificity was 92.6%. The maximum standardized uptake value (SUVmax) was elevated in patients with PS (P<0.001). IHC staining for liposarcoma revealed that the expression of VEGFR-2 was significantly higher in the PS group than that in the non-PS group (P = 0.008). Survival analysis (n =196) showed significantly worse DSS in the PS group than in non-PS group (median: 16.0 months vs. not reached, P < 0.001). In addition, PS was proven as one of the most significant prognostic predictors of both DSS and RFS by random survival forest algorithm. A nomogram to predict PS status was developed based on preoperative imaging combined with four risk factors including the presentation status (primary vs. recurrent), ascites, SUVmax, and tumor size. The nomogram significantly improved the diagnostic sensitivity compared to preoperative imaging alone (44/49, 89.8% vs. 35/49, 71.4%). The C-statistics of the nomogram was 0.932, and similar C-statistics (0.886) was achieved at internal cross-validation. Conclusion: PS is a significant prognostic indicator for RPS, and it occurs more often in recurrent RPS and in RPS with higher malignant tendency. The proposed nomogram is effective to predict PS preoperatively.

2.
J Surg Oncol ; 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36444482

RESUMO

BACKGROUND AND OBJECTIVES: Resection of retroperitoneal sarcoma (RPS) en bloc with pancreas is challenging and controversial. This single-center retrospective study aimed to analyze the impact of pancreatic resection (PR) and its different types on short- and long-term outcomes in patients with RPS. METHODS: Data from 242 consecutive patients with RPS who underwent surgical treatment at the Peking University Cancer Hospital Sarcoma Center between January 2010 and February 2021 were analyzed. Out of these, 90 patients underwent PR, including pancreaticoduodenectomy (PD) in 31 and distal pancreatectomy (DP) in 59. RESULTS: Patients in the PR group had a higher major morbidity (37.8% vs. 14.5%) and mortality (8.9% vs. 1.3%) than those in the non-PR group, with a similar 5-year overall survival (OS) rate (46.9% vs. 53.6%). Patients in the PD and DP groups had a slight difference in major morbidity (48.4% vs. 32.2%), mortality (6.4% vs. 10.2%), and 5-year OS rates (43.3% vs. 49.3%). The PR type was not an independent risk factor for major morbidity or OS. CONCLUSIONS: PR in RPS resection was associated with increased morbidity and mortality with minimal influence on survival. Patients with RPS undergoing PD and DP showed slight differences in terms of safety and OS.

3.
Front Surg ; 9: 956384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36157408

RESUMO

The outcomes of patients with primary retroperitoneal sarcoma (RPS) are significantly superior to those with recurrence. En bloc resection of tumor and adjacent organs is recommended in primary RPS. However, whether en bloc resection of tumor and adjacent organs can benefit recurrent patients or some recurrent patients is unclear. We compared the outcomes of patients with primary RPS, first recurrence (RPS-Rec1), and ≥2 recurrences (≥RPS-Rec2) to evaluate the value and criteria for en bloc resection of tumor and adjacent organs in recurrent cases. We evaluated the safety of en bloc resection of tumor and adjacent organs by assessing operation time, blood loss volume, postoperative morbidities (POM), and efficacy by comparing local recurrence and peritoneal metastasis (LR-PM), distant metastasis, progression-free survival (PFS), and overall survival (OS). A total of 101, 47, and 30 patients with primary RPS, RPS-Rec1, and ≥RPS-Rec2 were included, respectively. Recurrent RPS invaded more adjacent organs and surrounding fat tissue than primary RPS. The operation time, amount of blood loss, incidence of grade III-V POM, LR-PM rate, PFS, and OS in the RPS-Rec1 group were similar to those of the primary group, both of which were significantly superior to those of the ≥RPS-Rec2 group. Macroscopically incomplete resection and high-grade RPS rather than first recurrence were independent risk factors for LR-PM, PFS, and OS. In conclusion, the safety and efficacy of en bloc resection of tumor and adjacent organs in RPS-Rec1 were comparable with those in primary RPS but significantly superior to those of ≥RPS-Rec2. For RPS-Rec1, comparable outcomes to patients with primary RPS can be achieved, particularly in those in whom a macroscopically complete resection is achieved.

4.
J Surg Oncol ; 126(7): 1288-1298, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35943840

RESUMO

BACKGROUND AND OBJECTIVES: Retroperitoneal sarcomas (RPSs) are difficult to manage, rare malignant tumors. This single-center, retrospective study aimed to analyze the treatment algorithm and outcomes of aggressive surgical treatment in patients with primary and recurrent RPS. METHODS: Data of 242 consecutive patients with RPS who underwent surgical treatment at the Peking University Cancer Hospital Sarcoma Center between January 2010 and February 2021 were collected and analyzed. Indications for surgery were based on the treatment algorithm. RESULTS: A total of 145 patients with primary RPS and 97 with recurrent RPS were included. The recurrent cohort comprised more patients with multifocal tumors than the primary cohort (64.9% vs. 15.2%). R0/R1 resection was achieved in 94.5% and 81.4% of the primary and recurrent RPS cases, respectively. Major complication rates in the primary and recurrent cohorts were 17.9% and 30.9%, respectively. During a median follow-up of 51 months, the estimated 5-year overall survival, local recurrence, and distant metastasis rates for patients with primary and recurrent RPS were 61.0% versus 37.1%, 47.4% versus 71.3%, and 18.4% versus 17.6%, respectively. CONCLUSIONS: Aggressive surgical treatment achieved good local control and long-term survival in patients with primary RPS, whereas the prognosis in patients with recurrence were significantly worse.


Assuntos
Neoplasias Retroperitoneais , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Algoritmos , Recidiva Local de Neoplasia/patologia , Neoplasias Retroperitoneais/patologia , Estudos Retrospectivos , Sarcoma/patologia , Taxa de Sobrevida , Resultado do Tratamento , Tomada de Decisão Clínica
5.
Mol Med Rep ; 25(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35014686

RESUMO

Long non­coding RNAs can regulate the malignant tumor phenotype either as tumor suppressors or oncogenes. The present study investigated the underlying mechanism of LINC00238 in liver cancer. LINC00238 was identified as a downregulated molecule in The Cancer Genome Atlas liver hepatocellular carcinoma dataset through Gene Expression Profiling Interactive Analysis software. Through gain­ and loss­of­function experiments, LINC00238 was confirmed as a tumor suppressor that could not only decrease cell viability, migration and invasion in vitro, but also tumorigenesis and tumor metastasis in vivo. By cytoplasmic and nuclear RNA isolation, LINC00238 was confirmed to be predominantly cytoplasmic. Mechanistically, RNA pull­down assays showed that LINC00238 sponged microRNA (miR)­522 and then reversed the inhibitory effects on two downstream targets, secreted frizzled related protein 2 and dickkopf1. Collectively, LINC00238 was identified as a tumor suppressor that acts via sponging miR­522 followed by silencing of downstream targets, suggesting that LINC00238 may have a key role in suppressing the malignant phenotype of liver cancer cells.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Linhagem Celular , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Galinhas , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Modelos Biológicos , Fenótipo , Prognóstico
6.
Cancer Manag Res ; 13: 6157-6167, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34385843

RESUMO

BACKGROUND: Previous studies have shown that nutrition and systemic inflammation plays an essential role in the development of soft tissue sarcoma. However, few studies have explored the association of clinicopathologic features and local recurrence with nutritional and inflammatory markers in retroperitoneal liposarcoma (RPLS). This study sought to evaluate the prognostic value of the preoperative nutritional and inflammatory markers for local recurrence-free survival (LRFS) among surgical RPLS patients. METHODS: The study included 111 RPLS patients who underwent surgery between May 2010 and June 2019 at the Peking University Cancer Hospital Sarcoma Center. Time-dependent receiver operating characteristic (time-ROC) curve analysis was conducted to evaluate the ability of markers to predict LRFS. The associations of the CONUT-FAR score with clinicopathological variables and LRFS were evaluated. RESULTS: In the time-ROC curve analysis, the CONUT-FAR score was superior to other nutritional and inflammatory markers in predicting LRFS. The CONUT-FAR score was the only nutritional and inflammatory marker that independently predicted LRFS in the multivariate analysis, and patients with a high CONUT-FAR score (> 11) showed significantly decreased LRFS. Although the CONUT-FAR score failed to discriminate patients with low grade (G1) (p = 0.327) or undergoing incomplete (R2) resection (p = 0.072), it stratified patients with high grade (G2 and G3) or undergoing complete resection (R0/R1) into subgroups with significantly distinct LRFS (p < 0.001). The CONUT-FAR score also showed good clinical utility among patients with different clinical characteristics. CONCLUSION: The preoperative CONUT-FAR score reflects both nutritional and inflammatory factors and is an effective predictor of LRFS for surgical RPLS patients.

7.
Contrast Media Mol Imaging ; 2021: 7191363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33505228

RESUMO

This study aimed to evaluate the usefulness of maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) in differentiating the subtypes and tumor grades of retroperitoneal liposarcoma (RPLS). The data of RPLS patients who underwent surgical resection from November 2013 to December 2019 at the sarcoma center of our institute were reviewed. The demographics, clinical features, and SUVmax of 84 patients who underwent preoperative 18F-FDG PET/CT scans were analyzed. Of these, 19 patients (22.6%) were with well-differentiated liposarcoma (WDLPS), 60 patients (71.4%) were with dedifferentiated liposarcoma (DDLPS), and 5 patients (6.0%) were with pleomorphic liposarcoma (PMLPS). The median SUVmax of WDLPS, DDLPS, and PMLPS groups was 2.8 (IQR: 1.9-3.2), 6.2 (IQR: 4.1-11.3), and 4.5 (IQR: 4.0-7.4). The ROC curve suggested 3.8 as an approximate cutoff value of SUVmax for distinguishing WDLPS and non-WDLPS (sensitivity = 0.769; specificity = 0.895). The median SUVmax for FNCLCC Grades 1, 2, and 3 of RPLS was 2.5 (IQR: 1.9-3.2), 4.5 (IQR: 3.2-6.7), and 9.0 (IQR: 6.0-13.3). The ROC curves suggest that SUVmax of ≤3.8 and >5.3 can be used for predicting FNCLCC Grades 1 and 3, respectively. The result showed that 18F-FDG PET/CT exhibited high sensitivity and specificity for identifying the subtypes and FNCLCC grades of RPLS. Additionally, 18F-FDG PET/CT might be a useful complementary imaging modality for guiding suitable biopsy location of RPLS.


Assuntos
Lipossarcoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Retroperitoneais/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Lipossarcoma/diagnóstico , Lipossarcoma/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/administração & dosagem , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/patologia
8.
Int J Med Sci ; 17(18): 3073-3081, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173428

RESUMO

Patient-derived xenograft (PDX) models are effective preclinical cancer models that reproduce the tumor microenvironment of the human body. The methods have been widely used for drug screening, biomarker development, co-clinical trials, and personalized medicine. However, the low success rate and the long tumorigenesis period have largely limited their usage. In the present studies, we compared the PDX establishment between hepatocellular cancer (HCC) and metastatic liver cancer (MLC), and identified the key factors affecting the transplantation rate of PDXs. Surgically resected tumor specimens obtained from patients were subcutaneously inoculated into immunodeficient mice to construct PDX models. The overall transplantation rate was 38.5% (20/52), with the HCC group (28.1%, 9/32) being lower than MLC group (56.2%, 9/16). In addition, HCC group took significantly longer latency period than MLC group to construct PDX models. Hematoxylin and eosin staining results showed that the histopathology of all generations in PDX models was similar to the original tumor in all three types of cancer. The transplantation rate of PDX models in HCC patients was significantly associated with blood type (P=0.001), TNM stage (P=0.023), lymph node metastasis (P=0.042) and peripheral blood CA19-9 level (P=0.049), while the transplantation rate of PDX models in MLC patients was significantly associated with tumor size (P=0.034). This study demonstrates that PDX models can effectively reproduce the histological patterns of human tumors. The transplantation rate depends on the type of original tumor. Furthermore, it shows that the invasiveness of the original liver cancer affects the possibility of its growth in immunodeficient mice.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Fígado/patologia , Microambiente Tumoral , Animais , Carcinoma Hepatocelular/cirurgia , Neoplasias Colorretais/cirurgia , Feminino , Hepatectomia , Humanos , Fígado/cirurgia , Neoplasias Hepáticas/cirurgia , Masculino , Camundongos , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
9.
Toxicol Appl Pharmacol ; 401: 115118, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32619553

RESUMO

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Receptores de Glucocorticoides/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Células A549 , Animais , Antineoplásicos Hormonais/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Carga Tumoral/fisiologia
10.
Am J Transl Res ; 11(5): 3128-3139, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217882

RESUMO

Tumor samples of pancreatic ductal adenocarcinoma patients, who underwent resection surgery, were implanted into NOD/SCID mice to construct pancreatic cancer patient-derived xenograft (PDX) models and explore the biological changes in the different generations of PDXs. Ten PDXs were successfully generated, and the tumor formation rate of F1 PDXs was found to be 38.46%, which was lower than F2 (77.78%) and F3 (71.43%) PDXs. In addition, latent periods of tumorigenesis of F2 and F3 PDXs were significantly shorter, compared to that in F1 PDXs (P<0.05). Comparison of H&E staining of tumor tissue from primary pancreatic cancer and PDXs showed that all three generations of PDXs had similar histopathology to primary pancreatic cancer, indicating that PDXs may well reproduce the histological patterns of primary human cancer. Besides, Ki67 expression was increased in all three generations of PDXs compared to primary tumors of patients, and additionally, EpCAM expression was increased in F3 PDXs. These results were corroborated by the real-time qPCR and western blot results. Therefore, we concluded that PDXs are able to preserve the differentiation degree, morphological characteristics, and structural features of tumor cells. Furthermore, the latent periods of tumorigenesis are shortened after the first generation, which may be attributed to an increase in expression levels of tumor promoters such as Ki67 and EpCAM. PDX models may become an efficient tool for pancreatic cancer research.

11.
Pak J Pharm Sci ; 32(1(Special)): 459-464, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30852485

RESUMO

.To explore the clinicopathological features of solid pseudopapillary neoplasm (SPN) of pancreas and to analyze the related factors of SPNs with aggressive behavior. Clinical data of SPN patients admitted in the Single Center of Peking University Cancer Hospital from January 2007 to September 2017 were retrospectively analyzed. The correlations of clinicopathological features with aggressive SPNs and distant metastasis after curative resection were analyzed using univariate analysis. Twelve of the total 54 SPN patients were diagnosed as aggressive SPNs. Univariate analysis suggested clinical features had no correlations with aggressive SPNs. Patients were followed up for an average of 5.0 years, four of them developed distant metastases. Univariate analysis indicated that distant metastasis of SPNs was correlated with the aggressive behaviors (P=0.031). Moreover, vessels invasion (VI) and Ki-67>4% (P=0.012) were the independent risk factors of distant metastasis of SPNs. The aggressive SPNs, especially VI and Ki-67>4% are the independent factors correlated with distant metastases after SPNs surgery.


Assuntos
Carcinoma Papilar/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Adolescente , Adulto , Idoso , Carcinoma Papilar/diagnóstico por imagem , Carcinoma Papilar/epidemiologia , Carcinoma Papilar/cirurgia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pâncreas/diagnóstico por imagem , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto Jovem
12.
Med Sci Monit ; 24: 961-969, 2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29449525

RESUMO

BACKGROUND There is no standard surgical approach for the management of retroperitoneal sarcoma. The aim of this clinical study was to describe the experience of an anterior approach to en bloc resection in left-sided retroperitoneal sarcoma with adjacent organ involvement. MATERIAL AND METHODS This retrospective clinical study included 25 patients who were diagnosed with left-sided retroperitoneal sarcoma and underwent tumor resection at a single center between May 2012 and July 2017. All patients had tumors that were adjacent to the left colon, pancreas, left kidney, left adrenal gland, and psoas major; some of the tumors were adjacent to the diaphragm, stomach, and small intestine. An anterior approach was used to remove the left-sided retroperitoneal tumor with the adhesive organs en bloc, an approach that is described in detail. The value of this surgical approach was evaluated based on the histopathological findings, postoperative complications, and patient follow-up. RESULTS The median number of resected organs, in addition to the retroperitoneal tumor, was 8 (range, 6-10). Complete macroscopic tumor resection was achieved in 23 cases (92%). Twenty-four patients (96%) had tumor infiltration of at least one organ or the surrounding fat. Three patients (12%) experienced Grade III and IV postoperative morbidities. The one-year disease-free survival rate was 91.3% among patients with macroscopically complete resections. The one-year overall survival rate was 83.2%. CONCLUSIONS In selected patients, left-sided retroperitoneal sarcoma associated with local organ involvement can be surgically managed using an anterior approach with en bloc resection of adjacent organs.


Assuntos
Especificidade de Órgãos , Neoplasias Retroperitoneais/cirurgia , Sarcoma/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/epidemiologia , Sarcoma/diagnóstico por imagem , Sarcoma/epidemiologia , Tomografia Computadorizada por Raios X
13.
Acta Pharmacol Sin ; 39(3): 472-481, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29119968

RESUMO

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.


Assuntos
Dexametasona/farmacologia , Dexametasona/farmacocinética , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Dexametasona/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Fatores de Tempo
14.
Acta Pharmacol Sin ; 38(9): 1282-1296, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28649130

RESUMO

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg-1·d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg-1·d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Dexametasona/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sulpirida/farmacologia , Animais , Antineoplásicos Hormonais/química , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Dexametasona/química , Antagonistas dos Receptores de Dopamina D2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Relação Estrutura-Atividade , Sulpirida/química , Células Tumorais Cultivadas
15.
Oncotarget ; 8(5): 7766-7776, 2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-27999192

RESUMO

The aim of this study is trying to describe more details of superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, to evaluate biological and prognostic implications of tumor budding in this margin, and to provide more evidence for evaluation of R0 surgery in pancreaticoduodenectomy. 46 patients in 5-years period are included in this study. Immunochemistry and immunofluorescence are used to analyze tumor budding and epithelial-mesenchymal transition. Superior mesenteric artery margin might be described from four aspects including location, gross appearance, microscopic appearance and tumor budding. We find that 1mm rule for R1 surgery is more appropriate to predict prognosis (P = 0.009) than 0mm rule (P = 0.141). Expression of cytokeratin in tumor budding is significantly lower than primary tumor (P = 0.001), and it suggests that tumor budding may participate the procedure of epithelial-mesenchymal transition. High-grade tumor budding and decreasing cytokeratin of tumor budding correlate with distant metastasis and has negative influence on prognosis. So superior mesenteric artery margin might be not only an area that tumor cells may invade, but also a pathway for distant metastasis. It is necessary to evaluate superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Artéria Mesentérica Superior/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/secundário , Movimento Celular , Progressão da Doença , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Margens de Excisão , Artéria Mesentérica Superior/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasia Residual , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/mortalidade , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
Oncotarget ; 7(27): 42461-42473, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27285759

RESUMO

MicroRNAs (miRNAs) have been shown to function as either oncogenes or tumor suppressors by negatively regulating target genes involved in tumor initiation and progression. In this study, we demonstrated that down-regulation of miR-33a-3p in human primary hepatocellular cancer (HCC) specimens was significantly associated with metastases and poor survival. Over-expression of miR-33a-3p in HepG2 cells remarkably suppressed not only cell growth, migration and invasion, but also tumor growth and metastases in the chick embryo chorioallantoic membrane (CAM) assay, and down-regulated Pre-B-Cell Leukemia Homeobox 3 (PBX3) expression. Conversely, inhibition of miR-33a-3p in Bel-7402 cells resulted in increased of cell growth, spreading and invasion. Furthermore, rescue experiments by over-expression PBX3 completely eliminated the inhibitory effects of miR-33a-3p on tumor growth and metastasis, both in vitro and in vivo. The luciferase assay showed that 3'-untranslated regions (3'-UTRs) of PBX3 were inhibited significantly by miR-33a-3p, while mutations in the miR-33a-3p pairing residues rescued the luciferase expression. Taken together, our findings suggest that miR-33a-3p suppressed the malignant phenotype while also inhibiting PBX3 expression in hepatocellular cancer, implying that miR-33a-3p may be a promising biomarkers and therapy target for HCC intervention.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Proteínas Proto-Oncogênicas/metabolismo , Regiões 3' não Traduzidas , Carcinoma Hepatocelular/genética , Movimento Celular , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia
17.
J Cancer Res Clin Oncol ; 139(7): 1211-20, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23576022

RESUMO

PURPOSE: As a novel cell cycle-related gene, p42.3 has been shown to play a key role in the cell proliferation and tumorigenicity of gastric cancer. To date, the association between p42.3 and colorectal cancer (CRC) has not been reported. This study investigated the expression of p42.3 and its potential role in human colorectal cancers. METHODS: Real-time polymerase chain reaction and western blotting were used to evaluate p42.3 mRNA and protein expression in 14 pairs of fresh frozen CRC samples, matched with adjacent normal mucosa. The p42.3 protein was evaluated by immunohistochemistry using CRC tissue microarrays, which included 212 CRC specimens and corresponding normal colorectal mucosa. The expression profiles of p42.3 in CRC tissues were analyzed against clinicopathological factors and post-surgical survival status. The expression profiles of p42.3 were also investigated in six human colon carcinoma cell lines. RESULTS: p42.3 was demonstrated to be over-expressed in colorectal cancer tissues compared with normal mucosa in the 14 tissue pairs (P = 0.011) and was significantly higher in patients with poor tumor differentiation (P = 0.045); patients positive for p42.3 expression had a poorer prognosis than those not expressing this protein (P = 0.033). In a multivariate survival analysis, p42.3 expression was identified as an independent prognostic factor for CRC patients (P = 0.030). CONCLUSIONS: The results indicated that p42.3 might play an important role in the progression of CRC, and it has a great value for assessing CRC patient prognosis after surgery.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares , Prognóstico , Modelos de Riscos Proporcionais , Análise Serial de Tecidos , Adulto Jovem
18.
J Cancer Res Clin Oncol ; 138(12): 2035-44, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22806308

RESUMO

PURPOSE: To investigate matrix metalloproteinase 9 (MMP-9) and WAVE3 expression in human colorectal cancer (CRC) and to evaluate their clinical significance. METHODS: We first performed real-time PCR to evaluate mRNA expression of MMP-9 and WAVE3 in 21 pairs of fresh CRC samples matched with adjacent normal mucosa. Then, MMP-9 and WAVE3 proteins were evaluated by immunohistochemistry on CRC tissue microarrays which included 216 CRC specimens and corresponding normal colorectal mucosa, and their correlation with clinicopathological factors and overall survival after surgery was evaluated. RESULTS: Both real-time PCR and immunohistochemistry evaluation have demonstrated that MMP-9 and WAVE3 were over-expressed in colorectal cancer tissues compared with normal mucosa (p < 0.001). MMP-9 expression was significantly higher in patients with low-grade differentiation and distant metastasis (p = 0.003 and p = 0.005, respectively), and patients with MMP-9-positive expression had a poorer prognosis (p = 0.008). However, patients with WAVE3-positive expression had a better prognosis (p = 0.039) and particularly favorable prognostic factors, including non-lymph node metastasis, non-distant metastasis, and early TNM stage (p = 0.029, 0.021, and 0.003, respectively). In addition, MMP-9-negative/WAVE3-positive patients had the best overall survival (p = 0.021). In multivariate survival analysis, MMP-9 expression and combined expression status of MMP-9/WAVE3 were identified as independent prognostic factors for CRC (p = 0.046 and p = 0.019, respectively). CONCLUSIONS: Combined analysis of MMP-9 and WAVE3 has a significant value for assessing prognosis of CRC patients after surgery.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Metaloproteinase 9 da Matriz/biossíntese , Família de Proteínas da Síndrome de Wiskott-Aldrich/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular/fisiologia , Neoplasias Colorretais/genética , Feminino , Humanos , Imuno-Histoquímica/métodos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias/métodos , Prognóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Adulto Jovem
19.
Hepatogastroenterology ; 58(109): 1182-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21937374

RESUMO

BACKGROUND/AIMS: Liver metastasis is a major factor associated with poor prognosis in patients with colorectal cancer. The objective of this study is to determine the possible indicators in identifying the risk of liver metastasis. METHODOLOGY: We randomly selected 114 colorectal cancer patients with liver metastases and 114 patients without liver metastasis. Several clinicopathological factors were analyzed for the correlation with liver metastasis. PTEN, CapG, MFAP3L, EGFR and HSP-70, chosen from PI3K/ AKT pathway, were evaluated by immunohistochemistry staining. The predictive value of those 5 markers for colorectal liver metastasis was evaluated. RESULTS: Univariate analysis showed that histological type, invasion depth, microscopic tumor embolus and lymph node metastasis were associated with liver metastasis. In multivariate analysis, only microscopic tumor embolus and lymph node metastasis were associated with liver metastasis. PTEN, EGFR, MFAP3L, CapG and HSP-70 were significantly correlated with colorectal liver metastasis. Grouped as a marker set, EGFR, MFAP3L and CapG make an effective predictor for colorectal liver metastasis, wherein the sensitivity and specificity are 92.38% and 94.39%, respectively. CONCLUSIONS: Microscopic tumor embolus and lymph node metastasis are risk factors for colorectal liver metastasis. As a molecular marker set, EGFR, MFAP3L and CapG exhibited both high sensitivity and high specificity in predicting colorectal liver metastasis.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Adulto , Idoso , Proteínas Contráteis/fisiologia , Receptores ErbB/fisiologia , Feminino , Proteínas de Choque Térmico HSP70/fisiologia , Humanos , Masculino , Proteínas dos Microfilamentos/fisiologia , Pessoa de Meia-Idade , Proteínas Nucleares/fisiologia , PTEN Fosfo-Hidrolase/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais
20.
Biotechnol Lett ; 33(4): 805-12, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21190060

RESUMO

Deacetoxy/deacetylcephalosporin C synthase (acDAOC/DACS) from Acremonium chrysogenum is a bifunctional enzyme that catalyzes both the ring-expansion of penicillin N to deacetoxycephalosporin C and the hydroxylation of the latter to deacetylcephalosporin C. The R308 residue located in close proximity to the C-terminus of acDAOC/DACS was mutated to the other 19 amino acids. In the resulting mutant pool, R308L, R308I, R308T and R308V showed significant improvement in their ability to convert penicillin analogs, thus confirming the role of R308 in controlling substrate selectivity, the four amino acids all possess short aliphatic sidechains that may improve hydrophobic interactions with the substrates. The mutant R308I showed the highest reactivity for penicillin G, with 3-fold increase in k(cat)/K(m) ratio and 7-fold increase in relative activity.


Assuntos
Acremonium/enzimologia , Acremonium/genética , Oxirredutases/genética , Cromatografia Líquida de Alta Pressão , Mutagênese , Mutação , Penicilina G/análogos & derivados , Penicilina G/química , Especificidade por Substrato/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...