Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 199
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Control Release ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31756395

RESUMO

Malignancies treated by insoluble targeted agents show low dose exposure and therapeutic responses, therefore easily develop drug resistance. Nanoparticle-modified drugs might disrupt chemoresistance by increasing dose exposure and altering resistance pathways, as administrated via the intravenous route to maximize efficacy. Herein, we proposed a self-assembled nanocapsulation strategy to construct a nanocomplex with multiarm polymer and novel dendrimer series (MAP-mG3) for encapsulating insoluble inhibitors by nucleotide lock. MAP-mG3 delivering the mammalian target of rapamycin (mTOR) inhibitor OSI-027 (MAP-mG3/OSI-027) showed higher loading capacity, enhanced solubility, controlled release, and increased intracellular tumoral accumulation. MAP-mG3/OSI-027, more efficiently than the free targeted agents, attenuated mTOR phosphorylation and inhibited growth of pancreatic cancer cells. In addition, MAP-mG3/OSI-027 reverted chemoresistance to OSI-027 in drug resistance pancreatic cancer by increasing intracellular dose exposure, as well as regulating ABCB1 expression and compensatory pathways. The optimized nanocapsulation design provides an effective strategy to engineer and reactivate insoluble targeted agents for chemoresistant applications.

2.
Br J Cancer ; 121(9): 786-795, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31588122

RESUMO

BACKGROUND: The progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumour microenvironment. Most tumour-associated macrophages (TAMs) are M2 phenotype macrophages, which normally show anti-inflammatory functions in numerous disorders. Previously, we found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation with hepatoma cell-derived debris; however, the molecular mechanism was unclear. METHODS: In vitro and in vivo experiments were employed to investigate the molecular mechanism. Using pancreatic cancer cell lines, mouse models and human tissues, we obtained a general picture of tumour cell-derived debris promoting metastasis of pancreatic cancer by inducing inflammation via TAMs. RESULTS: We showed that M2 macrophage-derived inflammation also exists in PDAC. Debris from PDAC cells induced potent IL-1ß release by M2 macrophages via TLR4/TRIF/NF-κB signalling, and this effect was further boosted by IgG that was also derived from PDAC cells. Increased IL-1ß promoted epithelial-mesenchymal transition and consequent metastasis of PDAC cells. A selective COX-2 inhibitor, celecoxib, enhanced the anti-tumoural efficacy of gemcitabine. CONCLUSIONS: These data revealed a pro-inflammatory mechanism in PDAC, which indicated that IL-1ß and COX-2 could be therapeutic targets of an anti-inflammatory strategy to treat PDAC.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31563597

RESUMO

BACKGROUND: The enhanced recovery after surgery (ERAS) protocol is an evidence-based perioperative care program aimed at reducing surgical stress response and accelerating recovery. However, a small proportion of patients fail to benefit from the ERAS program following pancreaticoduodenectomy. This study aimed to identify the risk factors associated with failure of ERAS program in pancreaticoduodenectomy. METHODS: Between May 2014 and December 2017, 176 patients were managed with ERAS program following pancreaticoduodenectomy. ERAS failure was indicated by prolonged hospital stay, unplanned readmission or unplanned reoperation. Demographics, postoperative recovery and compliance were compared of those ERAS failure groups to the ERAS success group. RESULTS: ERAS failure occurred in 59 patients, 33 of whom had prolonged hospital stay, 18 were readmitted to hospital within 30 days after discharge, and 8 accepted reoperation. Preoperative American Society of Anesthesiologists (ASA) score of ≥III (OR = 2.736; 95% CI: 1.276-6.939; P = 0.028) and albumin (ALB) level of <35 g/L (OR = 3.589; 95% CI: 1.403-9.181; P = 0.008) were independent risk factors associated with prolonged hospital stay. Elderly patients (>70 years) were on a high risk of unplanned reoperation (62.5% vs. 23.1%, P = 0.026). Patients with prolonged hospital stay and unplanned reoperation had delayed intake and increased intolerance of oral foods. Prolonged stay patients got off bed later than ERAS success patients did (65 h vs. 46 h, P = 0.012). Unplanned reoperation patients tended to experience severer pain than ERAS success patients did (3 score vs. 2 score, P = 0.035). CONCLUSIONS: Patients with high ASA score, low ALB level or age >70 years were at high risk of ERAS failure in pancreaticoduodenectomy. These preoperative demographic and clinical characteristics are important determinants to obtain successful postoperative recovery in ERAS program.

4.
World J Gastroenterol ; 25(32): 4749-4763, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31528099

RESUMO

BACKGROUND: Liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Socioeconomic development, indicated by the Human Development Index (HDI), is closely interconnected with public health. But the manner in which social development and medical advances influenced liver cancer patients in the past decade is still unknown. AIM: To investigate the influence of HDI on clinical outcomes for patients with existing liver cancer from 2008 to 2018. METHODS: The HDI values were obtained from the United Nations Development Programme, the age-standardized incidence and mortality rates of liver cancer were obtained from the GLOBOCAN database to calculate the mortality-to-incidence ratio, and the estimated 5-year net survival of patients with liver cancer was provided by the CONCORD-3 program. We then explored the association of mortality-to-incidence ratio and survival with HDI, with a focus on geographic variability across countries as well as temporal heterogeneity over the past decade. RESULTS: From 2008 to 2018, the epidemiology of liver cancer had changed across countries. Liver cancer mortality-to-incidence ratios were negatively correlated and showed good fit with a modified "dose-to-inhibition response" pattern with HDI (r = -0.548, P < 0.0001 for 2018; r = -0.617, P < 0.0001 for 2008). Cancer survival was positively associated with HDI (r = 0.408, P < 0.01) and negatively associated with mortality-to-incidence ratio (r = -0.346, P < 0.05), solidly confirming the interrelation among liver cancer outcome indicators and socioeconomic factors. Notably, in the past decade, the HDI values in most countries have increased alongside a decreasing tendency of liver cancer mortality-to-incidence ratios (P < 0.0001), and survival outcomes have simultaneously improved (P < 0.001), with significant disparities across countries. CONCLUSION: Socioeconomic factors have a significant influence on cancer outcomes. HDI values have increased along with improved cancer outcomes, with significant disparities among countries.

5.
J Gastrointest Surg ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31468329

RESUMO

BACKGROUND: The ligation of the splenic vein (SV) during pancreaticoduodenectomy (PD) may result in sinistral portal hypertension (SPH). This study aimed to identify the collateral pathways that formed postoperatively and evaluate the impact of omentum and arc of Barkow preservation in PD. METHODS: Patients who underwent PD between January 2013 and May 2018 at the Second Affiliated Hospital of Zhejiang University were enrolled in this retrospective study. PD was performed with preservation of the greater omentum and arc of Barkow. Venous collaterals, spleen size, and platelet count were evaluated before and after surgery. RESULTS: In total, 330 patients underwent PD, of whom, 43 patients who underwent superior mesenteric vein (SMV)/portal vein (PV) reconstruction and splenic vein (SV) ligation were selected. No patient developed severe gastrointestinal bleeding. Three collateral routes were identified: the left gastric route, the colic marginal route, and the first jejunal route. Seventeen patients developed splenomegaly. Twenty-three patients developed thrombocytopenia. However, none of them developed gastrointestinal bleeding or other clinical complaints. CONCLUSION: Although subclinical SPH developed after SV ligation, postoperative gastrointestinal bleeding was uncommon.

6.
Cancer Immunol Res ; 7(10): 1580-1590, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399419

RESUMO

PD-1 (CD279)-PD-L1 (CD274) inhibitory signaling is critical for cancer immune evasion, and thus has become one of the major targets in anticancer immunotherapy. There are several studies that demonstrate the potent effects of posttranslational modifications of CD274 on immune inactivation and suppression, such as ubiquitination, phosphorylation, glycosylation, and palmitoylation. However, the regulatory mechanisms for CD274 deubiquitination are still largely unclear. Here, we identified ubiquitin-specific protease 22 (USP22) as a novel deubiquitinase of CD274. USP22 directly interacted with the C terminus of CD274, inducing its deubiquitination and stabilization. Across multiple cancer types, USP22 was highly expressed and frequently altered in liver cancer, closely correlating with poor prognosis of these patients. Genetic depletion of USP22 inhibited liver cancer growth in an immune system-dependent manner, increased tumor immunogenicity and tumor-infiltrating lymphocytes, and improved therapeutic efficacy of CD274-targeted immunotherapy and CDDP-based chemotherapy in mice. We demonstrate that targeting USP22 is a promising strategy to potentiate anticancer immunity for CD274-amplified cancer.

7.
HPB (Oxford) ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31272847

RESUMO

BACKGROUND: The utility of the proposed alternative fistula risk score (a-FRS) for predicting risk of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD) has not been validated widely. METHODS: This retrospective analysis included data of patients undergoing open and laparoscopic PD during March 2012-May 2018 in our institution. The predictive abilities of a-FRS and original-FRS were compared. Risk factors for CR-POPF were also evaluated by multivariate regression analysis. RESULTS: Of the 370 patients, 80 (21.62%) developed CR-POPF. The incidences of CR-POPF in patients classified as low risk, intermediate risk, and high risk by a-FRS were 5.88%, 24.38%, and 57.69%, respectively (R2 = 0.97). The incidences of CR-POPF in patients classified as negligible risk, low risk, intermediate risk, and high-risk by original-FRS were 0%, 8.62%, 21.51%, and 52.50%, respectively (R2 = 0.92). The area under the ROC curve (AUC) was 0.74 for a-FRS vs. 0.70 for original-FRS. The a-FRS performed better than original-FRS for prediction of CR-POPF in open PD patients (AUC: 0.74 vs. 0.69) and was comparable with original- FRS in laparoscopic PD patients (AUC: 0.70 vs. 0.72). CONCLUSIONS: The a-FRS appears to be an accurate and convenient tool for predicting occurrence of CR-POPF after PD.

8.
Chem Commun (Camb) ; 55(63): 9363-9366, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31317136

RESUMO

We developed a biodegradable, oncosensitive, megamer-based delivery system for miRNA therapy. The miRNA nanotherapeutics, activatable by stepwise stimulation of acidity and reduction mimicking tumor microenvironment, efficiently improve liver-specific miR-122 expression, increasing the possibility of translational application of miR-122 therapy against liver cancer.


Assuntos
Portadores de Fármacos/química , MicroRNAs/química , Nanopartículas/química , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Dendrímeros/química , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Transplante Heterólogo
9.
Gut ; 68(11): 2019-2031, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31227589

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice. DESIGN: We harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings. RESULTS: Tumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis. CONCLUSION: There is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Antígenos Comuns de Leucócito/metabolismo , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral
10.
Int J Surg ; 68: 27-34, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31195148

RESUMO

BACKGROUND: Management strategies for grade-C postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy (PD) vary. The aim of this study was to evaluate surgical indications, approaches, and outcomes of grade-C POPF following PD. MATERIALS AND METHODS: The clinical data of grade-C POPF patients from 9 high-volume institutions between January 1, 2012 and December 31, 2016 were retrospectively reviewed. The indications and outcomes of different surgical strategies were analyzed. Risk factors for unfavorable outcomes were evaluated by multivariate regression analysis. RESULTS: Out of 5115 patients that underwent PD, 68 were diagnosed as grade-C POPF, and 53 underwent re-laparotomy. Pancreas-preserving surgical strategies were mostly used in this cohort (96.2%). Postoperative hospital stay in the external wirsungostomy group tended to be shorter than the other two major surgical approaches (20 days vs. 38 days and 34.5 days). Mortality and morbidity were comparable among different surgical strategies. Prolonged high drain amylase level prior to the development of grade-C POPF was negatively associated with unfavorable outcomes after re-laparotomy (OR: 0.20, 95% CI: 0.05-0.82). CONCLUSION: Pancreas-preserving approaches were preferred for grade-C POPF in this multicenter database, although the choice of definite procedure differed according to different clinical scenarios. Longstanding high amylase drainage may predict better outcomes after re-laparotomy.

11.
Oncogene ; 38(28): 5740-5741, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31068668

RESUMO

Following publication of this article the Authors noted mislabelling in Figure 2k. The label ITGA2 had been duplicated and CDH1 had been omitted. The correct version of the figure is included below.

12.
Can J Gastroenterol Hepatol ; 2019: 9780952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058114

RESUMO

Patients undergoing liver transplantation (LT) are at a high risk of dermatological complications compared to the general population as a result of long-term use of immunosuppressant. However, the risk is not as high as other solid organ transplantations (SOT), particularly for skin cancer. The liver is considered as an immune privileged organ since it has a low prevalence of humoral rejection in contrast to other SOT, and thus, LT requires a minimal amount of immunosuppressants compared to other SOT recipients. However, because of the large volume of the liver, patients with LT have higher donor lymphocytes that sometimes may trigger graft-versus-host-disease, yet it is rare. On the other hand, the vast majority of the nonspecific dermatological lesions linked with cirrhosis improve after removal of diseased liver or due to the immunosuppressant used after LT. Nevertheless, dermatological infections related to bacteria, viruses, and fungus after LT are not uncommon. Additionally, the incidence of IgE-mediated food allergies develops in 12.2% of LT patients and may present as life-threatening conditions such as urticaria and/or angioedema and hypersensitivity. Moreover, skin malignancies after LT are a matter of concern. Thus, posttransplant dermatological care should be provided to all LT patients for any suspicious dermatological lesions. Our goal is to give an outline of the dermatological manifestation associated with LT for the clinicians by collecting the published data from all archived case reports.

14.
J Zhejiang Univ Sci B ; 20(4): 355-362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30932380

RESUMO

OBJECTIVE: This study demonstrated that dexamethasone (DEX) protects the endothelial glycocalyx from damage induced by the inflammatory stimulus tumor necrosis factor-α (TNF-α) during severe acute pancreatitis (SAP), and improves the renal microcirculation. METHODS: Ninety mice were evenly divided into 3 groups (Sham, SAP, and SAP+DEX). The SAP mice model was established by ligature of pancreatic duct and intraperitoneal injection of cerulein. Renal perfusion and function, and morphological changes of the glycocalyx were evaluated by laser Doppler velocimetry, electron microscopy, and histopathology (hematoxylin and eosin (H&E) staining), respectively. Serum levels of syndecan-1 and TNF-α were assessed by enzyme-linked immunosorbent assay (ELISA). The protective effects of dexamethasone on the glycocalyx and renal microcirculation were evaluated. RESULTS: Significantly high levels of serum TNF-α were detected 3 h after the onset of SAP. These levels might induce degradation of the glycocalyx and kidney hypoperfusion, resulting in kidney microcirculation dysfunction. The application of dexamethasone reduced the degradation of the glycocalyx and improved perfusion of kidney. CONCLUSIONS: Dexamethasone protects the endothelial glycocalyx from inflammatory degradation possibly initiated by TNF-α during SAP. This is might be a significant discovery that helps to prevent tissue edema and hypoperfusion in the future.


Assuntos
Dexametasona/farmacologia , Endotélio Vascular/metabolismo , Glicocálix/efeitos dos fármacos , Rim/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Doença Aguda , Animais , Modelos Animais de Doenças , Edema/metabolismo , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação , Perfusão , Substâncias Protetoras/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Cancer Lett ; 452: 237-243, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30905814

RESUMO

The identification of circulating tumor cells (CTCs) relies on epithelial tumor cell markers. In the present study, we aimed to determine whether cell-surface vimentin could be a biomarker to isolate CTCs in pancreatic ductal adenocarcinoma (PDAC). Vimentin was identified as highly expressed on the surface of mesenchymal-phenotype pancreatic tumor cells. Vimentin+ CTCs were detected in 76% of patients with PDAC (76/100) using CTCs enriched via a microfluidic assay. A cut-off value of two vimentin+ CTCs distinguished patients with PDAC from healthy individuals. Combined vimentin+ CTCs and Carbohydrate antigen 19-9 provided favorable diagnostic potency, with an area under the curve of 0.968. Vimentin+ CTCs counts correlated with the change in tumor burden for patients undergoing resection. Significantly reduced CTC counts were observed after chemotherapy in subjects that responded to treatment. Preoperatively higher CTCs counts correlated with shortened recurrence-free survival. Taken together, vimentin+ CTCs could be a reliable biomarker in pancreatic cancer. The enrichment of mesenchymal CTCs complements the strategy of capturing epithelial CTCs, allowing a more thorough interrogation of the biology and clinical significance of CTCs in PDAC.

16.
J Surg Res ; 239: 67-75, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30818080

RESUMO

BACKGROUND: Pancreaticoduodenectomy (PD) is a complex procedure with a morbidity rate of 40%-50%. We evaluated the incidence, associated factors, etiologic characteristics, and outcome of pyogenic liver abscess (PLA), a rare infectious complication of PD. METHODS: We retrospectively assessed the data of patients who underwent PD (n = 326) between January 2012 and February 2017 at a single institution. Patients who developed PLA after PD were matched (1:3) for age, sex, and pathologic diagnosis with patients without PLA after PD. Patients who developed PLA without abdominal operation history (n = 77) were also reviewed in the same period. RESULTS: Eleven patients (3.4%) developed PLA after PD; diabetes (5/11, 45.5% versus 4/33, 12.1%; P = 0.031) increased the risk of PLA after PD. The preoperative and postoperative fasting blood glucose (FBG) was significantly higher in PLA+ group than PLA- group: preoperative FBG (median: 7.39 versus 4.49; P < 0.01), postoperative FBG (median: 8.98 versus 5.68; P < 0.01). The occurrence of multiple liver abscess was significantly higher in patients with PLA after PD than patients who developed PLA without abdominal operation history (7/11 versus 22/77; P = 0.036). Microbial pus culture was positive in eight patients with PLA after PD (n = 8/11) and in forty-one patients who developed PLA without abdominal operation history (n = 41/77). Klebsiella pneumoniae was the most commonly isolated microorganism in PLA patients with or without a history of PD (5/8, 62.5% versus 34/41, 82.9%; P = 0.333). CONCLUSIONS: Patients with diabetes (including impaired fasting plasma glucose) have a higher risk of developing PLA after PD. Multiple liver abscess was the most common type of PLA after PD; K pneumoniae should be covered when empirically treated patients with PLA.

17.
Surg Laparosc Endosc Percutan Tech ; 29(3): e29-e33, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889057

RESUMO

BACKGROUND: Situs inversus (SI) is a rare congenital anomaly characterized by the transposition of thoracic and abdominal viscera. Laparoscopic pancreaticoduodenectomy (LPD) is increasingly used in patients with periampullar and pancreatic carcinomas. For patients with SI, LPD can be more complicated because of reversed anatomy and possible other associated anomalies that have not been expected before surgery. CASE PRESENTATION: A female patient with SI totalis presented with inappetence, vomiting, and weight loss for 2 months. Imaging modalities and angiography revealed a mass in the periampullary region without obvious vascular abnormalities. The mass was successfully resected via LPD based on an elaborate preoperative plan. The surgical pathology report demonstrated adenocarcinoma of the duodenal papilla. The patient has been followed up for 4 months and no tumor recurrence or long-term complications were observed. CONCLUSION: LPD is technically difficult but feasible in patients with SI.

18.
Ann Surg ; 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30672792

RESUMO

OBJECTIVE: The aim of the study was to analyze the outcomes of patients who have undergone laparoscopic pancreaticoduodenectomy (LPD) in China. SUMMARY BACKGROUND DATA: LPD is being increasingly used worldwide, but an extensive, detailed, systematic, multicenter analysis of the procedure has not been performed. METHODS: We retrospectively reviewed 1029 consecutive patients who had undergone LPD between January 2010 and August 2016 in China. Univariate and multivariate analyses of patient demographics, changes in outcome over time, technical learning curves, and the relationship between hospital or surgeon volume and patient outcomes were performed. RESULTS: Among the 1029 patients, 61 (5.93%) required conversion to laparotomy. The median operation time (OT) was 441.34 minutes, and the major complications occurred in 511 patients (49.66%). There were 21 deaths (2.43%) within 30 days, and a total of 61 (5.93%) within 90 days. Discounting the effects of the early learning phase, critical parameters improved significantly with surgeons' experience with the procedure. Univariate and multivariate analyses revealed that the pancreatic anastomosis technique, preoperative biliary drainage method, and total bilirubin were linked to several outcome measures, including OT, estimated intraoperative blood loss, and mortality. Multicenter analyses of the learning curve revealed 3 phases, with proficiency thresholds at 40 and 104 cases. Higher hospital, department, and surgeon volume, as well as surgeon experience with minimally invasive surgery, were associated with a lower risk of surgical failure. CONCLUSIONS: LPD is technically safe and feasible, with acceptable rates of morbidity and mortality. Nonetheless, long learning curves, low-volume hospitals, and surgical inexperience are associated with higher rates of complications and mortality.

19.
Nat Cell Biol ; 21(2): 179-189, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664791

RESUMO

Loss of TGF-ß tumour suppressive response is a hallmark of human cancers. As a central player in TGF-ß signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer. However, such genetic alterations are rare in most cancer types and the underlying mechanism for TGF-ß resistance is not understood. Here we describe a mechanism of TGF-ß resistance in ALK-positive tumours, including lymphoma, lung cancer and neuroblastoma. We demonstrate that, in ALK-positive tumours, ALK directly phosphorylates SMAD4 at Tyr 95. Phosphorylated SMAD4 is unable to bind to DNA and fails to elicit TGF-ß gene responses and tumour suppressing responses. Chemical or genetic interference of the oncogenic ALK restores TGF-ß responses in ALK-positive tumour cells. These findings reveal that SMAD4 is tyrosine-phosphorylated by an oncogenic tyrosine kinase during tumorigenesis. This suggests a mechanism by which SMAD4 is inactivated in cancers and provides guidance for targeted therapies in ALK-positive cancers.


Assuntos
Quinase do Linfoma Anaplásico/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/genética , Proteína Smad4/genética , Fator de Crescimento Transformador beta/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação , Proteína Smad4/metabolismo , Transplante Heterólogo , Tirosina/genética , Tirosina/metabolismo
20.
Cancer Sci ; 110(2): 530-539, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30548441

RESUMO

B7-H5 and its cognate receptor CD28H are T lymphocyte second signaling transduction molecules. Here we aimed to explore the function of this pathway in pancreatic cancer in vitro and in vivo, and evaluated the clinical significance in 136 patients with pancreatic ductal adenocarcinoma enrolled from January 2012 to February 2017 in our hospital. Surgical tumor specimens were collected for immunohistochemical staining to evaluate B7-H5 expression. Patients' baseline characteristics, including gender, age, tumor size, tumor location, tumor grading, clinical TNM staging, tumor infiltrating lymphocytes, CA19-9 and chemotherapy treatment, along with the subsequent follow-up data, were documented and analyzed. When co-cultured with T cells, pancreatic cancer PC cells with high B7-H5 expression induced a more potent immune reaction, indicated by elevated cytokine release and increased proliferation of T lymphocytes compared with cells exhibiting low B7-H5 expression. Xenograft pancreatic tumors derived from high B7-H5 expression PC cells exhibited attenuated growth compared to tumors from low B7-H5 expression cells after transfusion with T lymphocytes in immune-deficient mice. Of the 136 PDAC tumor tissues, 93 (68.38%) were strong and 43 (31.62%) were weak B7-H5 expression. Patients with strong B7-H5 expression had significantly longer overall survival than those with weak expression (median: 16.5 vs 11.5 months, P = .017). TNM staging, tumor location and subsequent chemotherapy were also prognostic factors in these patients. Collectively, B7-H5/CD28H is a co-stimulatory signal pathway, and expression of B7-H5 is associated with improved disease prognosis in patients with pancreatic cancer.


Assuntos
Adenocarcinoma/metabolismo , Antígenos B7/metabolismo , Antígenos CD28/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Transdução de Sinais/fisiologia , Adenocarcinoma/patologia , Adulto , Idoso , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Linfócitos T/metabolismo , Linfócitos T/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA