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1.
Nat Commun ; 12(1): 174, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420030

RESUMO

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.


Assuntos
Imunossupressores/farmacologia , Neoplasias Hepáticas/imunologia , Neutrófilos/metabolismo , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pâncreas/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/imunologia , Receptores Purinérgicos P2X/metabolismo
2.
Environ Sci Technol ; 55(3): 1604-1614, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33427447

RESUMO

The occurrence of high-level tigecycline resistance tet(X) variant genes represents a new transferable resistance crisis to food safety and human health. Here, we investigated the abundance of tet(X)-variant genes [tet(X), tet(X1) to tet(X6)] in 33 samples collected from layer manures, manured/un-manured soils, and corresponding lettuce from three provinces in China. The results showed the occurrence of tet(X)/(X2), tet(X3), and tet(X4) in 24 samples. The detection rate of tet(X)/(X2) (23/24) is higher than that of tet(X3) (7/24) and tet(X4) (2/24), and tet(X)/tet(X2) and tet(X3) were found to be enriched and more abundant in most manured soil and several lettuce samples from manured soils than that from manure samples. Twenty six tigecycline-resistant bacteria were isolated, and tet(X)-variant genes were found to be disseminated not only by bacterial clone spreading but also via multidrug resistance plasmids. The total concentrations of tet(X)-variant genes showed significantly positive correlations (R = 0.683, p < 0.001) with ISCR2. Two veterinary tetracyclines (tetracycline and oxytetracycline) and other classes of antimicrobials (enrofloxacin, azithromycin, thiamphenicol, and florfenicol) showed significant correlations with the total concentrations of tet(X)-variant genes (R = 0.35-0.516, p < 0.05). The findings indicate the transmission of tet(X)-variant genes from layer manures to their receiving environmental soils and lettuce and highlight the contribution of veterinary antimicrobials to the spread of tet(X)-variant genes.

3.
Cancer Res ; 80(10): 1991-2003, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32098780

RESUMO

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.


Assuntos
Acetilcolina/metabolismo , Carcinoma Ductal Pancreático/patologia , Invasividade Neoplásica/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/fisiologia
4.
Chin Clin Oncol ; 8(2): 20, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31070040

RESUMO

Pancreatic neuroendocrine neoplasms (P-NENs) are a group of pathologically and clinically heterogeneous tumors. In the past several decades, the incidence has been increasing. In 2010, the WHO presented a new classification dividing P-NENs into well-differentiated neuroendocrine tumors (NETs) and poorly-differentiated neuroendocrine carcinomas (NECs). Surgery is the primary and most important treatment for P-NENs, and is also the only possible curative procedure. By the 2018 NCCN guideline, observation can be considered for <1 cm, low-grade asymptomatic nonfunctional P-NETs. And for patients who are not suitable for surgery, somatostatin analogues, targeted therapy, radionuclides, ablation therapies, (chemo)embolisation and chemotherapy should be considered to improve and maintain a good quality of life. More than one hundred years has passed since termed, and in recent years, more and more molecule mechanism about P-NENs have been discovered. With the addition of several new agents, survival improved over the time. All this made P-NENs great promise.


Assuntos
Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Qualidade de Vida , Terapia Combinada , Humanos , Prognóstico
5.
Medicine (Baltimore) ; 98(17): e15351, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027116

RESUMO

BACKGROUND: On-pump coronary artery bypass grafting (ON-PCABG) and off-pump coronary artery bypass grafting (OF-PCABG) greatly affect myocardial metabolism (MCMB). However, no study has systematically explored and compared the impacts of ON-PCABG and OF-PCABG on MCMB. This study will aim to explore and to compare the effects of ON-PCABG and OF-PCABG on MCMB systematically. METHODS: We will conduct the comprehensive literature search from the following electronic databases from inception to the present: Cochrane Library, EMBASE, MEDILINE, CINAHL, AMED and 4 Chinese databases without language restrictions. This systematic review will only concern randomized controlled trials (RCTs) and case-control studies of ON-PCABG and OF-PCABG on MCMB. The methodological quality of each entered study will be assessed by using Cochrane risk of bias tool. RESULTS: Primary outcomes include myocardial cellular markers, myocardial lactate, oxygen utilization, pyruvate, and intramyocardial concentrations of glucose, urea and lactate. Secondary outcome comprises of glutathione, superoxide dismutase, myeloperoxidase, and oxidative stress and any other complications post surgery. CONCLUSION: This study will provide a high-quality synthesis and will assess and compare the effects of ON-PCABG and OF-PCABG on MCMB based on the current relevant literature evidence. DISSEMINATION AND ETHICS: The results will be submitted to peer-reviewed journals for publication. This study does not require ethic approval, because it only analyzes the data from published literature. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019125381.


Assuntos
Ponte de Artéria Coronária sem Circulação Extracorpórea , Ponte de Artéria Coronária/métodos , Miocárdio/metabolismo , Humanos , Metanálise como Assunto , Complicações Pós-Operatórias , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
World J Gastroenterol ; 25(14): 1684-1696, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011254

RESUMO

BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Neuroendócrino/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Neoplasias Gástricas/imunologia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Evasão Tumoral/imunologia
7.
Am J Cancer Res ; 9(2): 363-377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906634

RESUMO

Secreted Frizzled-Related Protein 4 (SFRP4), a member of secreted frizzled-related protein family, has been found as a vital modulator in cell proliferation, cell self-renew and apoptosis through Wnt signaling transduction pathway. In the present study, we re-analyzed the expression pattern of SFRPs in Gene Expression Omnibus (GEO) datasets and evaluated the expression of SFRP4 at protein level in both KrasG12D/+; Trp53R172H/+; Pdx1-Cre; (KPC) mice and human pancreatic ductal adenocarcinoma (PDAC) tissue. We found that the expression of SFRP4 increased gradually in PanINs and PDAC lesions in KPC mice and high expression of SFRP4 was much more common in tumor lesions compared to the adjacent non-tumor tissues. Then we performed Kaplan-Meier survival and Cox regression analysis and found that high expression of SFRP4 in the serum and tumor lesions predicted poor prognosis for pancreatic cancer patients. Furthermore, we demonstrated that SFRP4 positively correlated with FOXP3+ Treg cells infiltration while the down-regulation of SFRP4 in tumor cells impaired the production of cytokines and the recruitments of T cells. This study suggested that SFRP4 can be a novel prognostic biomarker and potential therapeutic target for pancreatic cancer.

8.
J Cancer ; 8(16): 3154-3165, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158787

RESUMO

FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. What's more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo. Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. It's of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC.

9.
Cell Cycle ; 16(17): 1622-1629, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28749252

RESUMO

Dickkopf-1(DKK-1), the downstream target of ß-catenin/T-cell factor, participates in a negative feedback loop in the Wnt signaling and reported as an important biomarker in many tumors. In this study, we analyzed the expression of DKK-1 in pancreatic ductal adenocarcinoma (PDAC) patients at both mRNA and protein levels. We used real-time PCR to detect the expression of DKK-1 in 32 PDAC and paired adjacent non-tumor tissues, results suggested that the expression of DKK-1 was increased in PDAC tissues. We found the similar results in the analysis of 3 independent microarray data sets. Immunohistochemical staining of 311 pairs of PDAC tissues suggested that DKK-1 expression was significantly associated with T classification (P = 0.039) and lymph node metastasis (P = 0.035). Furthermore, Kaplan-Meier analysis for DKK-1 expression demonstrated that patients with higher DKK-1 level had shorter overall survival (OS) and relapse-free survival (RFS) time in Ren Ji cohort and online PDAC database at both mRNA and protein levels. Univariable and multivariable Cox regression analysis confirmed that DKK-1 as well as lymph node metastasis and histology were independent predictors of OS in patients with PDAC. This study demonstrated that DKK-1 may be a predictor for prognosis in PDAC patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida , Regulação para Cima/genética
10.
Gastroenterology ; 153(1): 277-291.e19, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28315323

RESUMO

BACKGROUND & AIMS: Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. METHODS: We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses. RESULTS: In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B-LYN-p85 complex, which increased PI3K-Akt-mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. CONCLUSIONS: Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Serotonina/metabolismo , Idoso , Animais , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Inativação Gênica , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Ácido Láctico/biossíntese , Masculino , Camundongos , Pessoa de Meia-Idade , Monoaminoxidase/análise , Transplante de Neoplasias , Pâncreas/química , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor 5-HT2B de Serotonina/genética , Serotonina/análise , Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Transdução de Sinais , Estresse Fisiológico , Serina-Treonina Quinases TOR/metabolismo , Análise Serial de Tecidos , Transcriptoma , Triptofano Hidroxilase/análise , Ureia/análogos & derivados , Ureia/uso terapêutico , Quinases da Família src/metabolismo
11.
World J Gastroenterol ; 23(3): 516-524, 2017 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-28210088

RESUMO

AIM: To provide more information and therapeutic methods about gastric neuroendocrine carcinomas (G-NECs) which occur rarely but are highly malignant and clinically challenging. METHODS: We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria. RESULTS: Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half (48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases (72.09%), and liver metastasis was found in 6 cases (13.95%). Follow-up information was got for 40 patients. Twenty-three die of this disease with a median survival of 31 mo (range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR (30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence. CONCLUSION: G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/cirurgia , Quimioterapia Adjuvante/métodos , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Taxa de Sobrevida
12.
Sci Rep ; 6: 33535, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27628540

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Adenocarcinoma/patologia , Idoso , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , RNA Longo não Codificante/metabolismo , Reprodutibilidade dos Testes
13.
Am J Cancer Res ; 6(8): 1820-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27648368

RESUMO

Collagen triple helix repeat containing-1 (CTHRC1), a secreted protein, has been demonstrated as an oncogene in many types of human cancers including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the prognostic value of CTHRC1 in PDAC. In current study, we investigated the expression pattern and underlying clinical significance of CTHRC1 in PDAC. Data from public PDAC microarray datasets, real-time PCR and immunohistochemistry demonstrated that CTHRC1 expression was dramatically increased in PDAC compared with normal tissues at both mRNA and protein level, which was consistent with previous studies. Analysis of its correlation with clinicopathological parameters indicated that high protein expression level of CTHRC1 was significantly associated with lymph node metastasis, vascular invasion and perineural invasion. Kaplan-Meier survival analysis showed that patients with higher CTHRC1 expression exhibited a remarkably shorter overall survival in four different PDAC patient cohorts. Importantly, univariable and multivariable Cox regression analysis revealed that CTHRC1 protein expression level was a significant and independent prognostic factor for overall survival rate of PDAC patients. Together, these data suggested that CTHRC1 is an unfavorable biomarker of prognosis in PDAC and may serve as a potential therapeutic candidate for PDAC treatment.

14.
Medicine (Baltimore) ; 95(15): e3009, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27082545

RESUMO

We have conducted a meta-analysis and systematic review to determine the overall survival, mortality rate, and complete resection rate of neo-adjuvant chemoradiotherapy (CRT) compared with pancreaticoduodenectomy alone in patients with pancreatic adenocarcinoma. Whether neo-adjuvant CRT is beneficial in the treatment of resectable pancreatic cancer or not, it is still a controversial issue. Medline and Cochrane were searched with relevant terms. Eight studies with a total of 833 participants were selected. The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The analysis revealed neo-adjuvant group may have a benefit in the overall survival, as compared with the resection group, although it did not reach statistical significance (pooled hazard ratio = 0.87, 95% confidence interval [CI] = 0.75-1.00, P = 0.051). We found no difference in the in-hospital mortality rate (pooled odds ratio [OR] = 1.27, 95% CI = 0.35-4.58, P = 0.710). The complete resection rate was significantly higher in the neo-adjuvant group than in the resection group (pooled OR = 2.39, 95% CI = 1.21-4.74, P = 0.012). This meta-analysis found that there was no significant difference in the overall survival between patients treated with neo-adjuvant CRT or pancreaticduodenectomy.


Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Quimiorradioterapia Adjuvante/métodos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomia/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica , Mortalidade Hospitalar , Humanos , Análise de Sobrevida
15.
Oncotarget ; 7(4): 4226-40, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26735172

RESUMO

Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients' TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3-related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer.


Assuntos
Adenocarcinoma/secundário , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/secundário , Proteínas de Transporte/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Animais , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Proteínas de Ligação ao Cálcio , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proteínas de Transporte/genética , Moléculas de Adesão Celular , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Am J Transl Res ; 7(9): 1621-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26550461

RESUMO

WNT1 inducible signaling pathway protein 1 (WISP-1) is a member of the CCN family of growth factors and reported to possess an important role in tumorigenesis by triggering downstream events via integrin signaling. However, the exact role of WISP-1 in cancer remains unclear. In this study, we examined the expression pattern of WISP-1 at both mRNA and protein levels and evaluated the prognostic value of WISP-1 in pancreatic ductal adenocarcinoma (PDA). Expression of WISP-1 at mRNA level was upregulated in 17/24 tumor tissues compared to the matched adjacent non-tumor tissues and the result was confirmed by western blotting at protein level. Immunohistochemical staining of 194 pairs of PDA specimens suggested that high expression of WISP-1 is strongly correlated with clinical stage (P=0.003), T classification (P=0.008) and liver metastasis (P=0.012). Consistently, Kaplan-Meier survival curves indicated that patients with high expression of WISP-1 had a shorter survival time independent of clinical stage and lymphatic metastasis status. Moreover, univariate and multivariate analysis confirmed WISP-1 expression, age, classification and liver metastasis as independent prognostic factors for overall survival of PDA patients. Taken together, these results suggest that WISP-1 may serve as a potential prognostic biomarker for PDA.

18.
Surg Infect (Larchmt) ; 16(6): 769-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26237502

RESUMO

BACKGROUND: Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of nosocomial infections, which is difficult to treat because of limited susceptibility to antimicrobial agents. In China, isolation rates of P. aeruginosa were observed to increase by year. The incidence of infectious complications after pancreatoduodenectomy (PD) were high. However, there was no data available regarding P. aeruginosa infection in patients undergoing PD. This study evaluated the risk factors and clinical impacts of P. aeruginosa infection on patient after PD. METHODS: 119 patients who underwent PD with post-operative infectious complications were monitored for P. aeruginosa infection. The patients were grouped as P. aeruginosa infection and non-P. aeruginosa infection. Univariable and multivariable analyses were used to identify risk factors for P. aeruginosa infection. RESULTS: 42 (35.3%) of the119 patients were P. aeruginosa positive after PD. The sites of P. aeruginosa infection included (1) abdominal drain fluid (76%); (2) sputum (7%); (3) central line catheter tip cultures (2%); and (4) combination of sites (14%). Pseudomonas aeruginosa isolates were susceptible to Polymyxin B, Amikacin and Gentamicin, resistant to Aztreonam Piperacillin-tazobactam, Imipenem and Ceftazidime. History of diabetes mellitus (OR=2.981, P=0.023), pancreatic fistula (OR=4.699, P=0.001), use of carbapenems (OR=3.236, P=0.013), and fluoroquinolones (OR=2.940, P=0.044), antibiotics, and length of ICU stay (OR=2.133, P=0.022) independently predicted post-operative P. aeruginosa infection. Pseudomonas aeruginosa infection was related to severe post-operative complications, including delayed gastric emptying and post-pancreatectomy hemorrhage, but was not related to not 30-d mortality or a longer post-operative stay. CONCLUSIONS: This analytic study highlights the prevalence and high drug resistance of P. aeruginosa after PD. Pseudomonas aeruginosa infection was related to severe post-operative complications but not 30-d mortality. Measures to combat P. aeruginosa infection would likely decrease the accidence of P. aeruginosa infection and benefit patients' outcomes.


Assuntos
Pancreaticoduodenectomia/efeitos adversos , Infecções por Pseudomonas/epidemiologia , Pseudomonas aeruginosa/isolamento & purificação , Infecção da Ferida Cirúrgica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , China/epidemiologia , Farmacorresistência Bacteriana , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa/efeitos dos fármacos , Estudos Retrospectivos , Fatores de Risco , Infecção da Ferida Cirúrgica/microbiologia , Infecção da Ferida Cirúrgica/mortalidade , Análise de Sobrevida
19.
Sci Rep ; 5: 10575, 2015 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-26015068

RESUMO

Liver kinase B1 (LKB1) has been identified as a critical modulator involved in cell proliferation and polarity. The purpose of the current study was to characterize the expression pattern of LKB1 and assess the clinical significance of LKB1 expression in pancreatic ductal adenocarcinoma (PDAC) patients. LKB1 mRNA expression which was analyzed in 32 PDAC lesions and matched non-tumor tissues, was downregulated in 50% (16/32) of PDAC lesions. Similar results were also obtained by analyzing three independent datasets from Oncomine. Protein expression of LKB1 was significantly reduced in 6 PDAC cell lines and downregulated in 31.3% (10/32) of PDAC lesions compared to matched non-tumorous tissues, as determined by Western blot analysis. Additionally, tissue microarray containing 205 PDAC specimens was evaluated for LKB1 expression by IHC and demonstrated that reduced expression of LKB1 in 17.6% (36/205) of PDAC tissues was significantly correlated with clinical stage, T classification, N classification, liver metastasis and vascular invasion. Importantly, Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of PDAC and found that LKB1 protein expression was one of the independent prognostic factors for overall survival of PDAC patients.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Proteínas Serina-Treonina Quinases/metabolismo , Idoso , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Demografia , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
20.
Opt Express ; 23(6): 7053-61, 2015 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-25837050

RESUMO

In this paper, a multi-layered metallic structure is proposed, which consists of split-ring resonators on both sides of two dielectric substrates. Numerical results reveal that the structure realizes a high magnitude of 0.94, three bands and broadband (more than 8 GHz) asymmetric transmission for linearly polarized wave. These properties are not observed in previous works. In order to better know these transmission properties, the Fabry-Perot like resonance model has been introduced to analyze the enhancement mechanism of asymmetric transmission in the multi-layered structure. The physical mechanism of linearly polarized wave conversion and asymmetric transmission based on electric fields and currents distribution is also analyzed in detail, respectively.

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