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1.
Medicine (Baltimore) ; 98(26): e16016, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261505

RESUMO

Spontaneous bacterial peritonitis (SBP) is one of the most frequent and severe complications in patients with decompensated cirrhosis. Early antibiotic therapy is extremely important for successful treatment and reducing mortality. Prostaglandin E2 (PGE2) is a regulator of the immune response and infection. This study aimed to explore whether ascitic PGE2 could be used as a marker for diagnosing SBP and predicting in-hospital mortality.Patients with cirrhosis and ascites undergoing abdominal paracentesis were enrolled in our study. Demographic, clinical, and laboratory parameters were recorded at the time of paracentesis and ascitic PGE2 levels were determined by ELISA. The correlation between ascitic PGE2 level and SBP as well as in-hospital mortality were analyzed.There were 224 patients enrolled, 29 (13%) patients diagnosed as SBP based on the current guideline criteria. The ascitic PGE2 level of patients with SBP [32.77 (26.5-39.68) pg/mL] was significantly lower than that of patients without SBP [49.72 (37.35-54.72) pg/mL]. In ROC analysis, the AUC of ascitic PGE2 for the diagnosis of SBP was 0.75, and the AUC of ascitic PGE2 combined with WBC and ascitic PGE2 combined with neutrophils were 0.90 and 0.90, respectively, which were significantly higher than that of ascitic PGE2. In multivariate analysis, ascites PGE2≤32.88 pg/mL (OR: 9.39; 95% CI: 1.41-67.44, P = .026), hepatic encephalopathy (OR: 18.39; 95% CI: 3.00-113.13, P = .002) and a higher MELD score (OR: 1.25; 95% CI: 1.05-1.40, P = .009) remained independent predictors of in-hospital mortality.Ascitic PGE2 level is likely to be a valuable marker in prediction of in-hospital mortality in patients with decompensated cirrhosis, and its value in diagnosis of SBP was not superior to other inflammatory indicators.


Assuntos
Líquido Ascítico/metabolismo , Infecções Bacterianas/metabolismo , Dinoprostona/metabolismo , Mortalidade Hospitalar , Cirrose Hepática/complicações , Peritonite/metabolismo , Área Sob a Curva , Ascite/complicações , Ascite/metabolismo , Ascite/mortalidade , Infecções Bacterianas/complicações , Infecções Bacterianas/mortalidade , Biomarcadores/metabolismo , Feminino , Humanos , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Peritonite/complicações , Peritonite/mortalidade , Prognóstico , Estudos Prospectivos , Curva ROC
2.
Cancer Sci ; 110(9): 2933-2940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278877

RESUMO

Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Ascite/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/patologia , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Ascite/etiologia , Linhagem Celular Tumoral/transplante , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Estimativa de Kaplan-Meier , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Distribuição Tecidual , Resultado do Tratamento
3.
J Ethnopharmacol ; 241: 112034, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31226385

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine boasts a 440-year-long history of treating refractory ascites via combinations of herbal medicines, called formulae. Xiaozhang Tie (XT) is a proprietary herbal-compound-based formula that has been proven to be very effective in the treatment of cirrhosis-associated ascites in clinical practice, but the mechanism of action of XT remains unknown. AIM OF THE STUDY: In this study, we used a metabolomics-based systematic method to elucidate the mechanism of XT in the treatment of cirrhotic ascites. METHODS: Decompensated liver cirrhosis was induced in rats by intraperitoneal injection of Carbon tetrachloride (CCl4). Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) combined with pattern recognition approaches were used to determine differentiating metabolites relevant to XT treatment. Biomarkers were further validated by a targeted quantitative method and by the results from serum and urine analyses. Pathway analysis and correlation network construction were used to reveal the therapeutic targets associated with XT treatment, and the potential mechanisms were verified by the results from biochemical, histopathological and immunohistochemical assays. RESULTS: XT synergistically mediated the abnormalities of amino acid metabolic pathways in cirrhotic rats. XT significantly elevated the arginine levels, reduced the serum nitric oxide (NO) levels and alleviated the gastrointestinal motility disorder of cirrhotic rats. This effect of XT has been confirmed by the inhibition of the activities of inducible NO synthase and neuronal NO synthase in the small intestine. CONCLUSIONS: These results reveal that XT promotes gastrointestinal motility by acting on multiple targets in multiple pathways, of which the L-arginine/NO pathway is most affected.


Assuntos
Arginina/metabolismo , Ascite/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Cirrose Hepática Experimental/tratamento farmacológico , Óxido Nítrico/metabolismo , Animais , Ascite/metabolismo , Ascite/fisiopatologia , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/fisiopatologia , Masculino , Metabolômica , Fitoterapia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Toxicol In Vitro ; 60: 305-312, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31207347

RESUMO

The objective of study was to examine the role of MBZ on malignant ascites cells and the involvement of C-MYC. Comet assay was used to assess the genotoxic effects of MBZ in AGP01 cells and human lymphocytes; differential staining by ethidium bromide and acridine orange, caspase 3/7 and flow cytometry assay was done to access the mechanisms of apoptosis and cell cycle analysis of MBZ in AGP01 cells. C-MYC amplification, C-MYC mRNA and C-MYC protein expression were evaluated by FISH, RT-qPCR and Western blotting, respectively. In addition, cytotoxicity of MBZ was evaluated in AGP01 and AGP01 shRNA MYC by MTT. MBZ significantly increased the damage index and no produced in human lymphocytes. MBZ caused remarkable cell cycle arrest in G0/G1 and G2/M phases at 0.5µM and 1.0 µM, respectively and induced significantly apoptosis in higher concentrations. Additionally, MBZ (0.5 µM and 1.0 µM) increased caspase 3 and 7 activities. MBZ decreased signals, C-MYC mRNA and C-MYC protein expression in AGP01 cells. MBZ induced lower cell viability in AGP01 cells compared AGP01 shRNA MYC in the same concentration. Therefore, our results show the evidence of C-MYC gene as one of the pathways by which MBZ induces cell death in gastric cancer cells.


Assuntos
Ascite/tratamento farmacológico , Mebendazol/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Apoptose/efeitos dos fármacos , Ascite/genética , Ascite/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Linfócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
5.
Cancer Sci ; 110(8): 2658-2666, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199029

RESUMO

Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.


Assuntos
Fibrina/metabolismo , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Ascite/metabolismo , Ascite/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Peritônio/metabolismo , Peritônio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
BMC Cancer ; 19(1): 406, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039761

RESUMO

BACKGROUND: CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 is released from the cell surface into malignant ascites and blood vessels. Previous studies have shown that both tumor and surrounding mesothelial cells may express MUC16. Although little is known about the regulation of MUC16 expression in these cells, recent evidence suggest that inflammatory cytokines may stimulate MUC16 expression. Because malignant ascites is a pro-inflammatory environment, we investigated whether OC ascites stimulate the expression and release of MUC16 by human peritoneal mesothelial cells (HPMCs). METHODS: HPMCs were isolated from peritoneal lavages of women operated for conditions other than cancer. MUC16 protein expression was determined by immunoblot, immunofluorescence or immunohistochemistry depending on the experiments. The release of MUC16 from the cell surface was measured using EIA and MUC16 mRNA expression by ddPCR. RESULTS: We show that high-grade serous ascites from patients with OC (n = 5) enhance MUC16 expression in HPMCs. Malignant ascites, but not benign peritoneal fluids, stimulate the release of MUC16 in HPMCs in a dose-dependent manner, which is abrogated by heat inactivation. Moreover, we establish that ascites-induced MUC16 expression occurs at the post-transcriptional level and demonstrate that ascites-induced MUC16 expression is mediated, at least partially, through an Akt-dependent pathway. A cytokine array identified upregulation of several cytokines and chemokines in ascites that mediate MUC16 upregulation versus those that do not, including CCL7, CCL8, CCL16, CCL20, CXCL1, IL-6, IL-10, HGF and IL-1 R4. However, when individually tested, none of these factors affected MUC16 expression or secretion. Concentrations of CA125 in the serum of a given patient did not correlate with the ability of its corresponding ascites to stimulate MUC16 release in HPMCs. CONCLUSIONS: Collectively, these data indicate that mesothelial cells are an important source of MUC16 in the context of ovarian cancer and malignant ascites is a strong modulator of MUC16 expression in HPMCs and uncover the Akt pathway as a driving factor for upregulation of MUC16. Factors in ascites associated with enhanced MUC16 expression and release remains to be identified.


Assuntos
Ascite/metabolismo , Antígeno Ca-125/genética , Antígeno Ca-125/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias Ovarianas/metabolismo , Regulação para Cima , Ascite/genética , Ascite/patologia , Linhagem Celular Tumoral , Citocinas/genética , Células Epiteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Peritônio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
7.
PLoS One ; 14(4): e0214333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30946755

RESUMO

BACKGROUND: Peritoneal tuberculosis (TB) remains difficult to diagnose because of its non-specific clinical features and the lack of efficient microbiological tests. As delayed diagnosis is associated with high mortality rates, new diagnostic tools are needed. METHODS AND FINDINGS: We investigated for 24 patients prospectively enrolled with a possible diagnosis of peritoneal TB, the diagnostic value of the analysis of IFN-γ production by peritoneal fluid lymphocytes in response to a short in vitro stimulation with mycobacterial antigens. The patients were classified in two groups: non-TB and confirmed or highly probable TB. Diagnosis of TB was based on microbiological and histopathological criteria and/or a favorable response to anti-TB treatment. The IFN-γ production by peritoneal CD4+ T lymphocytes was analyzed by flow cytometry after an overnight in vitro stimulation with three different mycobacterial antigens, purified protein derivative (PPD), heparin-binding haemagglutinin (HBHA) or early-secreted-antigen-target-6 (ESAT-6). The percentages of PPD-, HBHA- or ESAT-6-induced IFN-γ-producing peritoneal fluid CD4+ T lymphocytes were higher in the TB group than in the non-TB group (p = 0.0007, p = 0.0004, and p = 0.0002 respectively). Based on cut-off values determined by ROC curve analysis of the results from TB and highly probable TB compared to those of non-TB patients, the sensitivity of these three tests was 100% with a specificity of 92%. CONCLUSIONS: The analysis of mycobacterial-induced IFN-γ production by peritoneal lymphocytes is a promising tool to reliably and rapidly diagnose peritoneal TB. Further studies should be performed on larger cohorts of patients in high-TB-incidence countries to confirm the clinical value of this new diagnostic approach for peritoneal TB.


Assuntos
Antígenos de Bactérias/imunologia , Ascite/metabolismo , Linfócitos T CD4-Positivos/imunologia , Interferon gama/biossíntese , Mycobacterium tuberculosis/imunologia , Peritônio/patologia , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Adolescente , Adulto , Idoso , Proteínas de Bactérias/imunologia , Bélgica/epidemiologia , Feminino , Humanos , Incidência , Lectinas/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Tuberculina/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia
8.
Clin Chim Acta ; 494: 116-122, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30904547

RESUMO

Metalloproteinases and their extracellular matrix metalloproteinase inducer (EMMPRIN) play an essential role in the regulation of signaling from growth factors receptors and adhesion molecules, cell motility and extracellular matrix degradation. The aim of the study was to evaluate the relationship between the levels of small extracellular vesicles (sEVs) metalloproteinases, such as ADAM10, ADAM17, MMP2, MMP9 and EMMPRIN and ascites volume and peritoneal canceromatosis index in advanced ovarian cancer patients (OCPs). The subpopulations of metalloproteinases at the surface of sEVs of borderline ovarian tumor patients (BOTPs) (n = 20, 36.5 ±â€¯2.5 years) and previously untreated advanced OCPs (n = 35, 56.5 ±â€¯2.5 years) were evaluated using flow cytometry. The metalloproteinase subpopulations of CD9-positive sEVs isolated from plasma of BOTPs and OCPs appeared to be quite similar. However, a significant difference in the expression of ADAM-metalloproteinases in ascites sEVs was found between BOTPs and OCPs. The level of sEVs metalloproteinases in OCPs significantly depended on the ascites volume. A statistically significant relationship between the level of ADAM10+/ADAM17- subpopulation in plasma sEVs and the peritoneal canceromatosis index was found (R = 0.66, p < .05). The levels of metalloproteinases and EMMPRIN in circulating sEVs, as well as the assessment of individual subpopulations may be promising approaches to OCPs managing.


Assuntos
Ascite/metabolismo , Vesículas Extracelulares/enzimologia , Metaloproteases/metabolismo , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/metabolismo , Adulto , Ascite/sangue , Ascite/patologia , Feminino , Citometria de Fluxo , Humanos , Pessoa de Meia-Idade , Neoplasias Peritoneais/patologia , Propriedades de Superfície
9.
J Pharmacol Sci ; 139(4): 373-376, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30857764

RESUMO

To investigate the relationship between the exposure and efficacy of tolvaptan, we measured pharmacokinetics of total drug at 7 days after repeated doses of 3.75 mg/day tolvaptan in 16 patients with hepatic edema. Nine patients (56.3%) were responders, which were defined as those with body weight reduction of >1.5 kg/week. Serum albumin levels were significantly lower in responders than in non-responders (P = 0.031). However, the pharmacokinetics varied greatly among individuals and was not relevant to the clinical response.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Ascite/tratamento farmacológico , Ascite/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Tolvaptan/farmacocinética , Tolvaptan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/sangue , Ascite/complicações , Edema/complicações , Feminino , Humanos , Cirrose Hepática/complicações , Hepatopatias/complicações , Masculino , Pessoa de Meia-Idade , Albumina Sérica/metabolismo , Tolvaptan/sangue , Resultado do Tratamento
10.
Int J Mol Sci ; 20(1)2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30609691

RESUMO

The role of the epithelial-mesenchymal transition (EMT) in ovarian cancer cell progression is unquestioned. In this report, we describe that malignant ascites, fluid that accumulates in the peritoneal cavity in a large group of patients with ovarian cancer, stimulate EMT in two representative ovarian cancer cell lines (A2780, SKOV-3). In addition, we identify the ascites-derived mediators of EMT and signaling pathways initiated in the cancer cells that underlie this phenomenon. Finally, we demonstrate that EMT induced in the cancer cells in response to the malignant ascites contributes to their increased transmesothelial invasion. Altogether, our study provides new insight into the mechanistic aspects of the malignant ascites-dependent exacerbation of the intraperitoneal progression of ovarian cancer.


Assuntos
Ascite/patologia , Transição Epitelial-Mesenquimal , Neoplasias Ovarianas/patologia , Ascite/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Células Cultivadas , Feminino , Humanos , Invasividade Neoplásica , Neoplasias Ovarianas/metabolismo , Transdução de Sinais
11.
Int J Obes (Lond) ; 43(1): 158-168, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717278

RESUMO

BACKGROUND/OBJECTIVES: A high body mass index increases the risk of severe pancreatitis and associated mortality. Our aims were: (1) To determine whether obesity affects the release of extracellular nucleosomes in patients with pancreatitis; (2) To determine whether pancreatic ascites confers lipotoxicity and triggers the release of extracellular nucleosomes in lean and obese rats. METHODS: DNA and nucleosomes were determined in plasma from patients with mild or moderately severe acute pancreatitis either with normal or high body mass index (BMI). Lipids from pancreatic ascites from lean and obese rats were analyzed and the associated toxicity measured in vitro in RAW 264.7 macrophages. The inflammatory response, extracellular DNA and nucleosomes were determined in lean or obese rats with pancreatitis after peritoneal lavage. RESULTS: Nucleosome levels in plasma from obese patients with mild pancreatitis were higher than in normal BMI patients; these levels markedly increased in obese patients with moderately severe pancreatitis vs. those with normal BMI. Ascites from obese rats exhibited high levels of palmitic, oleic, stearic, and arachidonic acids. Necrosis and histone 4 citrullination-marker of extracellular traps-increased in macrophages incubated with ascites from obese rats but not with ascites from lean rats. Peritoneal lavage abrogated the increase in DNA and nucleosomes in plasma from lean or obese rats with pancreatitis. It prevented fat necrosis and induction of HIF-related genes in lung. CONCLUSIONS: Extracellular nucleosomes are intensely released in obese patients with acute pancreatitis. Pancreatitis-associated ascitic fluid triggers the release of extracellular nucleosomes in rats with severe pancreatitis.


Assuntos
Ascite/metabolismo , Nucleossomos/metabolismo , Obesidade/fisiopatologia , Pâncreas/patologia , Pancreatite/fisiopatologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/metabolismo , Índice de Massa Corporal , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Pancreatite/metabolismo , Lavagem Peritoneal , Ratos , Ratos Zucker , Magreza
12.
Reprod Sci ; 26(4): 510-522, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29779470

RESUMO

Ovarian cancer as the most fatal gynecological malignancy is often manifested by excessive fluid accumulation known as ascites or effusion. Ascites-derived microRNAs (miRNAs) may be closely associated with ovarian cancer progression. However, our knowledge of their roles, altered expression, and clinical outcomes remained limited. In this study, large-scale expression profiling of 754 human miRNAs was performed using real-time quantitative polymerase chain reaction and 384-well TaqMan array human miRNA A and B cards to identify differentially expressed miRNAs between extracellular fraction of the ascitic fluid associated with high-grade serous ovarian carcinomas and control plasma. Of the 754 miRNAs, 153 were significantly differentially expressed relative to the controls. Expression of 7 individual miRNAs (miR-200a, miR-200b, miR-200c, miR-141, miR-429, miR-1290, and miR-30a-5p) was further validated in extended sample sets, including serous, endometrioid, and mucinous subtypes. All miR-200 family members and miR-1290 were conspicuously overexpressed, while miR-30a-5p was only weakly overexpressed. The ability of miRNAs expression to discriminate the pathological samples from the controls was strong. Receiver operating characteristic curve analyses found area under the curve (AUC) values of 1.000 for miR-200a, miR-200c, miR-141, miR-429, and miR-1290 and of AUC 0.996 and 0.885 for miR-200b and miR-30a-5p, respectively. Preliminary survival analyses indicated low expression level of miR-200b as significantly related to longer overall survival (hazard ratio [HR]: 0.25, mean survival 44 months), while high expression level was related to poor overall survival (HR: 4.04, mean survival 24 months). Our findings suggested that ascites-derived miRNAs should be further explored and evaluated as potential diagnostic and prognostic biomarkers for ovarian cancer.


Assuntos
Ascite/metabolismo , Biomarcadores Tumorais/genética , MicroRNAs/análise , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Extracelular/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade
13.
Biochem Genet ; 57(1): 159-169, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30073576

RESUMO

Ascites syndrome (AS) is a harmful disease in fast-growing broilers characterized by heart failure and serious fluid accumulation in the abdominal cavity. One of the known functions of zinc transporter ZIP12 is an important regulator in pulmonary hypertension (PH) in rat. Whether chicken ZIP12 is involved in the process of AS need to be explored. Here, chicken ZIP12 was sequenced and expression pattern and histological distribution were detected in broilers of AS induced by intravenous cellulose microparticle injection. Phylogenetic analysis showed that ZIP12 was significantly different between chicken and mammalian. The relative mRNA expression level of ZIP12 in the liver and lung in AS and pre-ascites (PAS) groups were significantly higher (P < 0.01) than that in control. The immunohistological staining using rabbit anti-chicken ZIP12 IgG and integrated optical density analysis showed the positive cells of ZIP12 distributed in detected tissues and the expression level of ZIP12 protein increased in AS and PAS groups compared to control. The results will provide the basic data of ZIP12 in the pathological process of AS in broiler chickens and offer an important reference for prevention and control of the disease.


Assuntos
Ascite/induzido quimicamente , Ascite/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Celulose/farmacologia , Galinhas , Regulação da Expressão Gênica/efeitos dos fármacos , Microesferas , Animais , Ascite/genética , Proteínas de Transporte de Cátions/genética , Celulose/administração & dosagem , Celulose/química , Injeções Intravenosas
14.
Mol Oncol ; 13(2): 185-201, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30353652

RESUMO

The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl-LPA species are strongly elevated in ascites versus plasma and are associated with short relapse-free survival. Data derived from transcriptome and secretome analyses of primary ascite-derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2 ) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor-associated macrophages play an essential role as main producers of PLA2 G7 and autotaxin. The latter conclusion is consistent with mass spectrometry-based metabolomic analyses of conditioned medium from ascites cells, which showed that tumor-associated macrophages, but not tumor cells, are able to produce 20:4 acyl-LPA in lipid-free medium. Furthermore, our transcriptomic data revealed that LPA receptor (LPAR) genes are expressed in a clearly cell type-selective manner: While tumor cells express predominantly LPAR1-3, macrophages and T cells also express LPAR5 and LPAR6 at high levels, pointing to cell type-selective LPA signaling pathways. RNA profiling identified cytokines linked to cell motility and migration as the most conspicuous class of LPA-induced genes in macrophages, suggesting that LPA exerts protumorigenic properties at least in part via the tumor secretome.


Assuntos
Lisofosfolipídeos/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Transdução de Sinais , Microambiente Tumoral , Ascite/metabolismo , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Metaboloma , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Resultado do Tratamento , Microambiente Tumoral/genética , Regulação para Cima/genética
15.
Hematol Oncol Stem Cell Ther ; 12(1): 54-59, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28390215

RESUMO

Waldenström's macroglobulinemia is a rare hematology malignancy which often presents with "B symptoms," anemia, and thrombocytopenia. A 46-year-old woman presented with 2 months of abdominal distension accompanied by an unintentional 20-lb weight loss. Her abdominal CT scan demonstrated diffuse carcinomatosis with bilateral ovarian lesions and screening labs revealed a markedly elevated CA-125, suggesting a diagnosis of ovarian cancer. Upon admission for workup, patient was found to have a significant protein gap, later attributed to a markedly elevated IgM. Omental and bone marrow biopsy confirmed the diagnosis of Waldenström's macroglobulinemia, with elevation in CA-125 thought to be secondary to peritoneal irritation. This patient has since been successfully treated with six cycles of bendamusine and rituximab with no evidence of disease on staging scans and normalization of both CA-125 and IgM. To our knowledge, this is the first documented case of Waldenström's macroglobulinemia presenting with symptoms classically associated with ovarian cancer and demonstrates the importance of maintaining a broad differential when evaluating patients with abdominal carcinomatosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ascite , Antígeno Ca-125/metabolismo , Neoplasias Peritoneais , Macroglobulinemia de Waldenstrom , Ascite/diagnóstico , Ascite/tratamento farmacológico , Ascite/metabolismo , Ascite/patologia , Cloridrato de Bendamustina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Rituximab/administração & dosagem , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/metabolismo , Macroglobulinemia de Waldenstrom/patologia
16.
BMC Cancer ; 18(1): 1232, 2018 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-30526541

RESUMO

BACKGROUND: The purpose of this study was to investigate the role of malignant ascites tumor microenvironment in ovarian cancer progression and chemoresistance. METHODS: A total of 45 patients with ovarian cancer and three benign ascites were collected at the time of clinical intervention. Ascites cholesterol levels were quantitated using cholesterol quantitation kit and recurrence free survival (RFS) of ovarian cancer patients were collected. The sensitivity of ovarian cancer cells to cisplatin (CDDP) and paclitaxel (PAC) were assessed by viability assay, flow cytometry and protein expression. Receiver operating characteristics (ROC) curve and Youden index analysis were applied to calculate the optimal cut-off values for ascites cholesterol. Kaplan-Meier curve were applied to compare RFS between high and low ascites cholesterol levels in ovarian cancer patients. RESULTS: Here we show that cholesterol is elevated in malignant ascites and modulates the sensitivity of ovarian cancer cells to CDDP and PAC by upregulating the expression of drug efflux pump proteins, ABCG2 and MDR1, together with upregulation of LXRɑ/ß, the cholesterol receptor. Transfection of LXRɑ/ß siRNA inhibited cholesterol-induced chemoresistance and upregulation of MDR1. In addition, the cholesterol level in malignant ascites was negatively correlated with number of CDDP-induced apoptotic cell death, but not with that of PAC-induced apoptotic cell death. Cholesterol depletion by methyl beta cyclodextrin (MßCD) inhibited malignant ascites-induced chemoresistance to CDDP and upregulation of MDR1 and LXRɑ/ß. For patients with ovarian cancer, high cholesterol level in malignant ascites correlated with short RFS. CONCLUSIONS: High cholesterol in malignant ascites contributes to poor prognosis in ovarian cancer patients, partly by contributing to multidrug resistance through upregulation of MDR1 via activation of LXRɑ/ß.


Assuntos
Ascite/metabolismo , Carcinoma Epitelial do Ovário/patologia , Colesterol/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores X do Fígado/metabolismo , Ascite/patologia , Carcinoma Epitelial do Ovário/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Células Tumorais Cultivadas , Microambiente Tumoral/fisiologia
17.
PLoS One ; 13(10): e0203808, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289914

RESUMO

Ascitic fluid infection is a major cause of morbidity and mortality in cirrhotic patients, requiring early diagnosis and therapy. We aimed to determine predictors of ascitic fluid infection in children with chronic liver disease. The study included 45 children with chronic liver disease and ascites who underwent 66 paracentesis procedures. Full history taking and clinical examination of all patients were obtained including fever, abdominal pain and tenderness and respiratory distress. Investigations included: complete blood count, C-reactive protein, full liver function tests, ascitic fluid biochemical analysis, cell count and culture. Our results showed that patients' ages ranged between 3 months to 12 years. Prevalence of ascitic fluid infection was 33.3%. Gram-positive bacteria were identified in six cases, and Gram-negative bacteria in five. Fever and abdominal pain were significantly more associated with infected ascites (p value = 0.004, 0.006). Patients with ascitic fluid infection had statistically significant elevated absolute neutrophilic count and C-reactive protein. Logistic regression analysis showed that fever, abdominal pain, elevated absolute neutrophilic count and positive C-reactive protein are independent predictors of ascitic fluid infection. Fever, elevated absolute neutrophilic count and positive C-reactive protein raise the probability of ascitic fluid infection by 3.88, 9.15 and 4.48 times respectively. The cut-off value for C-reactive protein for ascitic fluid infection was 7.2 with sensitivity 73% and specificity of 71%. In conclusion, prevalence of ascitic fluid infection in pediatric patients with chronic liver disease and ascites was 33.3%. Fever, abdominal pain, positive C-reactive protein and elevated absolute neutrophilic count are strong predictors of ascitic fluid infection. Therefore an empirical course of first-line antibiotics should be immediately started with presence of any of these predictors after performing ascitic fluid tapping for culture and sensitivity. In absence of these infection parameters, routine ascitic fluid analysis could be spared.


Assuntos
Ascite/microbiologia , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Positivas/diagnóstico , Hepatopatias/microbiologia , Ascite/metabolismo , Líquido Ascítico/microbiologia , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Testes Diagnósticos de Rotina , Feminino , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Positivas/epidemiologia , Humanos , Lactente , Contagem de Leucócitos , Hepatopatias/metabolismo , Modelos Logísticos , Masculino , Paracentese , Prevalência
18.
Nature ; 562(7727): 423-428, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305738

RESUMO

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.


Assuntos
Endorribonucleases/metabolismo , Mitocôndrias/metabolismo , Neoplasias Ovarianas/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Proteína 1 de Ligação a X-Box/metabolismo , Sistemas de Transporte de Aminoácidos Básicos , Animais , Ascite/metabolismo , Respiração Celular , Progressão da Doença , Estresse do Retículo Endoplasmático , Feminino , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Glutamina/metabolismo , Glicosilação , Humanos , Interferon gama/biossíntese , Interferon gama/genética , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/patologia , Transdução de Sinais , Taxa de Sobrevida , Linfócitos T/metabolismo , Evasão Tumoral/imunologia , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/biossíntese , Proteína 1 de Ligação a X-Box/deficiência
19.
Biomed Res Int ; 2018: 5484976, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30345303

RESUMO

Almost all the patients with hepatocellular carcinoma (HCC) at advanced stage experience pathological changes of chronic liver cirrhosis, which generally leads to moderate ascites. Recognition of novel biomarkers in malignant ascites could be favorable for establishing a diagnosis for the HCC patients with ascites, and even predicting prognosis, such as risk of distant metastasis. To distinguish the proteomic profiles of malignant ascites in HCC patients from those with nonmalignant liver cirrhosis, an iTRAQ pipeline was built up to analyze the differentially distributed proteins in the malignant ascites from HCC patients (n=10) and benign ascites from hepatic decompensation (HD) controls (n=9). In total, 112 differentially distributed proteins were identified, of which 69 proteins were upregulated and 43 proteins were downregulated (ratio <0.667 or >1.3, respectively) in the malignant ascites. Moreover, 19 upregulated proteins (including keratin 1 protein and rheumatoid factor RF-IP20, ratio>1.5) and 8 downregulated proteins (including carbonic anhydrase 1, ratio<0.667) were identified from malignant ascites samples. Functional categories analyses indicated that membrane proteins, ion regulation, and amino acid metabolism are implicated in the formation of HCC malignant ascites. Pathways mapping revealed that glycolysis/gluconeogenesis and complement/coagulation cascades are the mostly affected cell life activities in HCC malignant ascites, suggesting the key factors in these pathways such as Enolase-1 and fibrinogen are potential ascitic fluid based biomarkers for diagnosis and prognosis for HCC.


Assuntos
Ascite/metabolismo , Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/biossíntese , Proteômica , Ascite/patologia , Ascite/cirurgia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino
20.
J Ovarian Res ; 11(1): 90, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30336783

RESUMO

BACKGROUND: The death-domain-associated protein (DAXX) was originally identified as a protein that binds to the transmembrane death receptor FAS and enhances both FAS-induced and transforming growth factor-ß-dependent apoptosis. In a previous study, we found that nude mice injected with DAXX-overexpressing cells (ES-2-DAXX) accumulated large concentrations of first-generation ascites cells (I ascites cells). The role of DAXX in the development of ascites is unknown. The aim of this study was to analyze the effect of DAXX on proliferation and migration of ascites cells in ovarian cancer in vitro and in vivo. METHODS: Nude mice were housed in cages with a 14:10 h light:dark cycle; water and food were provided ad libitum. ES-2-DAXX cells (1×106) were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, I ascites cells were collected. The I ascites cells were injected intraperitoneally into athymic nude mice (8-week-old female mice). After 4 weeks, II ascites cells were collected and cultured. Ascites cell survival, migration, and colony formation were measured using colony formation and cell growth assays. Immunofluorescent staining revealed the co-localization of DAXX and promyelocytic leukemia protein (PML) in ascites cell nuclei. Western blotting and immunohistochemistry showed that extracellular signal-related kinase (p-ERK) 1/2 and CEBP-ß were highly expressed in tumor tissues formed by II ascites cells. Through immunoprecipitation, we also found that DAXX can interact with CEBP-ß. RESULTS: DAXX enhanced ascites cell survival, migration, and colony formation. DAXX and PML nuclear foci dramatically increased in a passage-dependent manner in ascites cells, DAXX promoted the tumor growth of ascites cells in vivo, increased ascites cell proliferation in vivo, and enhanced ascites cell survival and migration by activating the ERK signalling pathway and integrating with CEBP-ß. CONCLUSIONS: DAXX can interact with CEBP-ß. DAXX can induce ovarian cancer ascites formation by activating the ERK signal pathway and binding to CEBP-ß.


Assuntos
Ascite/metabolismo , Proteínas de Transporte/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos Nus , Chaperonas Moleculares
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