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1.
Cells ; 9(3)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120837

RESUMO

The SRC kinase family comprises non-receptor tyrosine kinases that are ubiquitously expressed in all cell types. Although Src is reportedly activated in pulmonary and renal fibrosis, little is known regarding its role in liver fibrosis. This study investigated whether the inhibition of Src protects against liver fibrosis. The expression of Src was upregulated in thioacetamide (TAA)-induced fibrotic mouse liver and cirrhosis of patients, and phospho-Src was upregulated during activation of hepatic stellate cells (HSC). In addition, Src inhibition reduced the expression of α-smooth muscle actin (αSMA) in primary HSCs and suppressed transforming growth factor ß (TGF-ß)-induced expression of connective tissue growth factor (CTGF) in hepatocytes. Src inhibitor Saracatinib also attenuated TAA-induced expression of type I collagen, αSMA, and CTGF in mouse liver tissues. The antifibrotic effect of Src inhibitors was associated with the downregulation of smad3, but not of signal transducer and activator of transcription 3 (STAT3). In addition, Src inhibition increased autophagy flux and protected against liver fibrosis. These results suggest that Src plays an important role in liver fibrosis and that Src inhibitors could be treat liver fibrosis.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Células Estreladas do Fígado/enzimologia , Células Estreladas do Fígado/patologia , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Quinases da Família src/antagonistas & inibidores , Animais , Autofagia , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Células Cultivadas , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Cirrose Hepática/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Tioacetamida , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima , Quinases da Família src/metabolismo
2.
HPB (Oxford) ; 22(8): 1139-1148, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31837945

RESUMO

BACKGROUND: IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. METHODS: Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. RESULTS: Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the "Jang & Kim's modified anatomical classification," 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010-4.433]). CONCLUSIONS: This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.


Assuntos
Neoplasias dos Ductos Biliares , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares , Estudos de Coortes , Humanos , República da Coreia/epidemiologia
3.
Cells ; 8(11)2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739636

RESUMO

Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis is unknown. Here, we examined whether clusterin had protective effects against hepatic fibrosis using in vitro and in vivo models. Clusterin was upregulated in the livers of human cirrhotic patients and in thioacetamide (TAA)-induced and bile duct ligation mouse models of liver fibrosis. Loss and overexpression of clusterin promoted and attenuated hepatic fibrosis after TAA injection, respectively. In addition, we found that clusterin attenuates hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Smad3 signaling pathways. Thus, clusterin plays an important role in hepatic fibrosis.


Assuntos
Clusterina/genética , Células Estreladas do Fígado/citologia , Cirrose Hepática/metabolismo , Proteína Smad3/metabolismo , Tioacetamida/efeitos adversos , Animais , Linhagem Celular , Clusterina/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Técnicas de Inativação de Genes , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Masculino , Camundongos , Transdução de Sinais , Regulação para Cima
4.
Hepatol Int ; 13(4): 490-500, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31214875

RESUMO

BACKGROUND: Although molecular characterization of iCCA has been studied recently, integrative analysis of molecular and clinical characterization has not been fully established. If molecular features of iCCA can be predicted based on clinical findings, we can approach to distinguish targeted treatment. We analyzed RNA sequencing data annotated with clinicopathologic data to clarify molecular-specific clinical features and to evaluate potential therapies for molecular subtypes. METHODS: We performed next-generation RNA sequencing of 30 surgically resected iCCA from Korean patients and the clinicopathologic features were analyzed. The RNA sequences from 32 iCCA resected from US patients were used for validation. RESULTS: Patients were grouped into two subclasses on the basis of unsupervised clustering, which showed a difference in 5-year survival rates (48.5% vs 14.2%, p = 0.007) and similar survival outcome in the US samples. In subclass B (poor prognosis), both data sets were similar in higher carcinoembryonic antigen and cancer antigen 19-9 levels, underlying cholangitis, and bile duct-type pathology; in subclass A (better prognosis), there was more frequent viral hepatitis and cholangiolar-type pathology. On pathway analysis, subclass A had enriched liver-related signatures. Subclass B had enriched inflammation-related and TP53 pathways, with more frequent KRAS mutations. CCA cell lines with similar gene expression patterns of subclass A were sensitive to gemcitabine. CONCLUSIONS: Two molecular subtypes of iCCA with distinct clinicopathological differences were identified. Knowledge of clinical and pathologic characteristics can predict molecular subtypes, and knowledge of different subtype signaling pathways may lead to more rational, targeted approaches to treatment.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Genes Neoplásicos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , República da Coreia/epidemiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Regulação para Cima , Gencitabina
5.
Evol Bioinform Online ; 15: 1176934319831306, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30833809

RESUMO

Cladosporium phlei, which causes purple eyespot disease, has been focused on as a source of phleichrome from the perylenequinone group of pigments. Although this agent is important in photodynamic therapy, there are no genome sequences for the species. Here, we sequenced the genome of C. phlei and reported the draft sequence. The total length of the draft genome was approximately 31.8 Mb, and 9571 genes were predicted. Phylogenetic analysis showed that Cladosporium sphaerospermum, Rachicladosporium sp., and Rachicladosporium antarcticum were closely related, and this result corresponded to the taxonomic data. In addition to the draft genome sequence, we report four candidates of new polyketide synthase (PKS) genes, involved in the production of perylenequinone-group pigments.

6.
J Pathol Transl Med ; 52(5): 339-343, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30008197

RESUMO

Laparoscopic cholecystectomy is a widely used treatment method for most cholelithiasis and is a relatively safe procedure. Foreign body granulomatous reaction to bile or gallstone spillage during laparoscopic cholecystectomy has rarely been reported. We report a case of bile granuloma after laparoscopic cholecystectomy, which mimicked peritoneal seeding. A 59-year-old Korean man presented with right upper quadrant pain. He underwent laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis. Pathologic examination revealed an incidental adenocarcinoma invading the lamina propria with acute cholecystitis and cholelithiasis. After 3 months, follow-up abdominal computed tomography revealed a subhepatic nodule, which showed hypermetabolism on positron emission tomography-computed tomography. Suspecting localized peritoneal seeding, wedge resection of the liver, wedge resection of the transverse colon, and omentectomy were performed. Pathologic examination of the resected specimens revealed multiple bile granulomas. Awareness of bile granuloma mimicking malignancy is noteworthy for patient management to reduce unnecessary procedure during postoperative surveillance.

7.
Pathol Res Pract ; 214(7): 1031-1039, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29699904

RESUMO

Yes-associated protein (YAP) is a nuclear effector of the cell-density sensing Hippo pathway and interacts with Src homology phosphotyrosine phosphatase 2 (SHP2), which controls cell proliferation and survival. The tumor promoting/suppressing activities of YAP and SHP2 during liver tumorigenesis remain controversial. This study aimed to investigate the tumorigenic roles of YAP and SHP2 in hepatocellular carcinogenesis. Cell density associated subcellular distributions of YAP and SHP2 in normal human hepatocytes (THLE-2) and hepatocellular carcinoma (HCC) cells (SK-Hep1, SNU-182) were investigated by Western blotting and cell block immunohistochemistry. The effects of YAP knockdown on proliferation, migration and invasion were studied using YAP-specific siRNAs. The prognostic significance of YAP and SHP2 expressions was investigated immunohistochemically using a tissue microarray (TMA) from 50 HCC cases. High-cell density decreased the nuclear expression of YAP and SHP2 in normal hepatocytes as compared with low-cell density. However, in HCC cells, nuclear YAP and SHP2 were observed regardless of cell density. Nuclear YAP influenced SHP2 expression and cell proliferation. In particular, YAP knockdown impacted nuclear levels of SHP2 protein in SK-Hep1 cells. In HCC tissues, nuclear YAP expression was elevated and cytoplasmic SHP2 expression was diminished as compared with adjacent non-tumor tissues. Notably, these expressions were found to be significantly associated with poor recurrence-free and overall survival rate in patients with HCC. Consequently, the tumor promoting role of YAP is involved in SHP2 which functions as a tumor promoter in vitro but as a tumor suppressor in vivo. YAP and SHP2 can be unfavorable prognostic markers in HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Fosfoproteínas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Adulto , Idoso , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP
8.
Int J Surg Pathol ; 26(6): 507-513, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29532690

RESUMO

BACKGROUND: Acetylcholinesterase (AchE) histochemistry has been established as an accurate diagnostic tool for Hirschsprung's disease (HD). In addition, calretinin immunohistochemistry is also reported as a reliable and adjunctive method to diagnose HD. We investigated the diagnostic value of combined AchE histochemistry and calretinin immunohistochemistry in rectal suction biopsies from HD and non-HD patients. METHODS: We retrospectively reviewed 99 rectal suction biopsy specimens including 4 repeat biopsies from 95 patients (34 HD and 61 non-HD). Each specimen was evaluated with hematoxylin-eosin, AchE histochemistry, and calretinin immunohistochemistry. RESULTS: Of 95 patients, only 21 (22.1%) showed some ganglion cells. All 61 non-HD cases revealed no abnormal AchE-positive fibers. Of 34 HD patients, 32 exhibited abnormal AchE fibers, but 2 showed no stained fibers. None of the tissues from the HD patients exhibited calretinin immunoreactivity. Test sensitivity and specificity of AchE histochemistry alone were 93.5% and 100.0%, respectively, while calretinin immunohistochemistry were 100.0% and 85.2%, respectively. CONCLUSIONS: AchE histochemistry is a good diagnostic method for HD, if feasible, and a combination of AchE histochemistry and calretinin immunohistochemistry will help increase the accuracy of the diagnosis of HD.


Assuntos
Acetilcolinesterase/análise , Calbindina 2/análise , Doença de Hirschsprung/diagnóstico , Reto/patologia , Adolescente , Biópsia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Proteínas Ligadas por GPI/análise , Doença de Hirschsprung/patologia , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
9.
Medicine (Baltimore) ; 96(49): e8904, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29245254

RESUMO

RATIONALE: When a gastric spindle cell tumor is observed, the possibility of synovial carcinoma, besides common mesenchymal tumor, should also be considered. PRESENTING CONCERNS OF THE PATIENT: The patient is a 51-year-old American woman who underwent medical check-up at a general hospital. Upper endoscopy showed a 2-cm sized mass covered with intact mucosa, and a central depression located on the posterior wall of the mid body. Biopsy of the mass showed focal atypical cells proliferation in mucosa on hematoxylin & eosin (H&E) staining. Endoscopic ultrasound showed a 17-mm homogenously hypoechoic mass within the submucosal layer. INTERVENTIONS: After diagnostic endoscopic submucosal dissection was performed, H&E and immunohistochemical staining showed synovial sarcoma (SS). To confirm the diagnosis, reverse transcriptase-polymerase chain reaction was performed, revealing a chimeric transcript of the SYT-SSX1 fusion gene. The diagnosis of primary gastric SS was confirmed because no evidence of possible primary lesions or metastatic lesions was observed. Therefore, the patient underwent distal gastrectomy. OUTCOMES: After surgery, the surgical specimen demonstrated no residual tumor cells. The patient received no adjuvant therapy, and there has been no evidence of local recurrence or distant metastasis for 2 months after the operation. LESSONS: When gastric subepithelial tumor is suspicious, we should also consider gastric SS.


Assuntos
Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/cirurgia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgia , Biópsia , Diagnóstico Diferencial , Endossonografia , Feminino , Gastrectomia , Gastroscopia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Sarcoma Sinovial/patologia , Neoplasias Gástricas/patologia
10.
Sci Rep ; 7(1): 9958, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28855656

RESUMO

Peroxisome-proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed. In the present study, we found that Insig2a was upregulated by PPARα in mouse livers and primary hepatocytes during fasting, whereas Insig2a mRNA expression was decreased in the livers of refed mice. A PPAR-responsive element between -126 bp and -114 bp in the Insig2a promoter was identified by a transient transfection assay and a chromatin immunoprecipitation assay; its role in regulation by PPARα was characterised using Pparα-null mice. These results suggest that PPARα is a trans-acting factor that enhances Insig2a gene expression, thereby suppressing SREBP-1c processing during fasting.


Assuntos
Jejum , Regulação da Expressão Gênica , Proteínas de Membrana/metabolismo , PPAR alfa/metabolismo , Processamento de Proteína Pós-Traducional , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Hepatócitos/enzimologia , Fígado/enzimologia , Camundongos
11.
Clin Nucl Med ; 42(8): e365-e366, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28590294

RESUMO

A 77-year-old man with anorexia and weight loss for 6 months received a diagnosis of gastric cancer by endoscopy and referred for F-FDG PET/CT for initial staging. F-FDG PET/CT showed multiple foci of increased FDG uptake with diffuse wall thickening and multiple diverticula. The differential diagnoses were peritoneal seeding and multiple diverticulitis. The patient underwent curative total gastrectomy, and the lesion was diagnosed as poorly differentiated adenocarcinoma by histological examination. He underwent anterior resection of the sigmoid colon for exploration. The nodular lesions of the sigmoid colon were diagnosed by histopathologic examination as chronic diverticulitis caused by a parasitic infection.


Assuntos
Colo/parasitologia , Fluordesoxiglucose F18 , Doenças Parasitárias/diagnóstico por imagem , Peritônio/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Idoso , Diagnóstico Diferencial , Diverticulite/diagnóstico por imagem , Gastrectomia , Humanos , Masculino
12.
Tumori ; 103(2): 209-211, 2017 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26350188

RESUMO

AIMS AND BACKGROUND: The incidence rate of colorectal cancer (CRC) increases every year in Korean populations. However, association between the GNAS mutation and colorectal precancerous lesions has not been studied in in Korean populations. To contribute to better understanding of colorectal carcinogenesis, we analyzed GNAS mutation in 100 cancerous and 96 precancerous colorectal lesions. METHODS: The records of colonoscopic polypectomy performed at Dongsan Medical Center between 1999 and 2003 were reviewed retrospectively. Precancerous lesions included 7 villous adenomas, 59 tubular adenomas, and 18 sessile serrated adenomas, and 12 hyperplastic polyps. Keimyung Human Bio-Resource Bank at Dongsan Medical Center provided 100 CRC samples. RESULTS: GNAS mutation was not found in any colorectal cancer or any precancerous colorectal lesions, including villous adenoma, which is thought to harbor the mutation. CONCLUSIONS: The role of GNAS mutation might be limited in colorectal neoplasms of the Korean population.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Cromograninas/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação/genética , Adenoma/genética , Adenoma/patologia , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Pólipos Intestinais/genética , Pólipos Intestinais/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Estudos Retrospectivos
13.
Exp Clin Transplant ; 15(1): 110-113, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26375027

RESUMO

Invasive aspergillosis is one of the most important and fatal complications after liver transplant, especially in patients with involvement of the central nervous system. We present a case of a patient who developed cerebral and pulmonary aspergillosis, coinfected with cytomegalovirus, after liver transplant for toxic fulminant hepatitis. The patient was treated successfully with neurosurgical intervention and voriconazole. Voriconazole is considered more effective in cerebral aspergillosis than other anti-fungal agents due to the greater penetration into central nervous system and higher cerebrospinal fluid and brain tissue levels.


Assuntos
Antifúngicos/uso terapêutico , Abscesso Encefálico/terapia , Doença Hepática Induzida por Substâncias e Drogas/cirurgia , Infecções por Citomegalovirus/terapia , Aspergilose Pulmonar Invasiva/terapia , Transplante de Fígado/efeitos adversos , Abscesso Pulmonar/terapia , Intoxicação Alimentar por Cogumelos/complicações , Neuroaspergilose/terapia , Procedimentos Neurocirúrgicos , Infecções Oportunistas/terapia , Voriconazol/uso terapêutico , Biópsia , Abscesso Encefálico/imunologia , Abscesso Encefálico/microbiologia , Abscesso Encefálico/virologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Aspergilose Pulmonar Invasiva/imunologia , Aspergilose Pulmonar Invasiva/microbiologia , Abscesso Pulmonar/imunologia , Abscesso Pulmonar/microbiologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Intoxicação Alimentar por Cogumelos/diagnóstico , Neuroaspergilose/imunologia , Neuroaspergilose/microbiologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/microbiologia , Infecções Oportunistas/virologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Sci Rep ; 6: 30846, 2016 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-27471054

RESUMO

During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF-1α, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV-infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-α or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication.


Assuntos
Hepacivirus/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Replicação Viral/fisiologia , Adulto , Idoso , Antivirais/farmacologia , Azepinas/farmacologia , Linhagem Celular , Ácido Dicloroacético/farmacologia , Glucoquinase/metabolismo , Glicólise , Hepatócitos/citologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interferon-alfa/farmacologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Interferência de RNA , Ribavirina/farmacologia , Triazóis/farmacologia , Replicação Viral/efeitos dos fármacos
15.
Exp Mol Med ; 48: e213, 2016 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-26940882

RESUMO

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) regulates cell growth and tumorigenesis in various cancers. However, the clinical relevance of ERRγ to hepatocellular carcinoma (HCC) remains unclear. Here we examined the clinical significance of ERRγ in HCC and its potential as a therapeutic target. ERRγ levels in tissues from completely resected specimens from 190 HCC patients were examined immunohistochemically and their association with clinical stage and pathological grade was analyzed. Small interfering RNA (siRNA)-mediated knockdown of ERRγ (siRNA-ERRγ) or an ERRγ inverse agonist, GSK5182, were also used to examine the effects of ERRγ inhibition on the proliferation and growth of a human hepatoma cell line, PLC/PRF/5. Immunohistochemical analysis revealed that tumor tissues showed higher levels of ERRγ-positivity than adjacent non-tumor lesions. Tumors showing high levels of ERRγ immunoreactivity also had advanced tumor node metastasis (TNM) and Barcelona Clinic Liver Cancer stages and a higher Edmondson-Steiner grade. In addition, high-level expression of ERRγ in tumors of advanced TNM stage correlated with poorer overall survival. Treatment of PLC/PRF/5 cells with siRNA-ERRγ or GSK5182 inhibited proliferation through G1 arrest, increased expression of p21 and p27 and decreased expression of phosphorylated retinoblastoma protein. GSK5182-induced reactive oxygen species also suppressed the proliferation of PLC/PRF/5 cells. The present study showed that ERRγ expression is clinically significant in HCC; therefore, it can be considered a biomarker for HCC diagnosis. Moreover, the results provide a rationale for the use of ERRγ inhibitors such as GSK5182 as potential therapeutic agents.


Assuntos
Carcinoma Hepatocelular/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Receptores de Estrogênio/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Seguimentos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
16.
BMC Gastroenterol ; 16: 21, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26911927

RESUMO

BACKGROUND: Actual differences of long term outcome of extrahepatic cholangiocarcinoma according to the location of the tumor have not yet been studied. The aim of this study was to evaluate the prognosis and optimal surgical procedure for middle (BD) cancer. METHODS: Among 109 patients with carcinoma of the extrahepatic BD underwent surgical resection, curative resection of extrahepatic BD cancer was performed in 90 patients. They were classified into three groups according to the location of tumors: DISTAL (n = 32), tumor was confined to the intrapancreatic bile duct; MID (n = 20), tumor was located between below the confluence of the hepatic duct bifurcation and suprapancreatic portion of the BD; and DIFFUSE (n = 38), tumor was located diffusely. RESULTS: Tumor involving the middle BD (MID or DIFFUSE) had a higher rate of perineural invasion as compared to the DISTAL group. The overall and disease-free survival rate for the MID or DIFFUSE group was significantly worse than that of DISTAL. In the MID/DIFFUSE group, there was no significant difference of survival according to the type of the operation (pancreaticoduodenectomy or segmental BD resection). The multivariate analysis showed that tumor involving middle BD (MID or DIFFUSE group) and node metastasis were independently poor prognostic factors for the disease free and overall survival. CONCLUSION: Extrahepatic cholangiocarcinoma involving the extrapancreatic BD has a worse prognosis than those confined to the intrapancreatic BD. In patients with tumors confined to the middle BD, BD resection can be considered as an alternative surgical procedure to pancreaticoduodenectomy, if an R0 resection can be accomplished.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Extra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Idoso , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Extra-Hepáticos/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Pancreaticoduodenectomia/mortalidade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos
17.
Medicine (Baltimore) ; 94(26): e1037, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26131811

RESUMO

This study assessed whether preoperative maximum standardized uptake value (SUVmax) of metastatic lymph nodes (LNs) measured by F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (F-FDG PET/CT) could improve the prediction of prognosis in gastric cancer.One hundred fifty-one patients with gastric cancer and pathologically confirmed LN involvement who had undergone preoperative F-FDG PET/CT prior to curative surgical resection were retrospectively enrolled. To obtain nodal SUVmax, a transaxial image representing the highest F-FDG uptake was carefully selected, and a region of interest was manually drawn on the highest F-FDG accumulating LN. Conventional prognostic parameters and PET findings (primary tumor and nodal SUVmax) were analyzed for prediction of recurrence-free survival (RFS) and overall survival (OS). Furthermore, prognostic accuracy of survival models was assessed using c-statistics.Of the 151 patients, 38 (25%) experienced recurrence and 34 (23%) died during follow-up (median follow-up, 48 months; range, 5-74 months). Twenty-seven patients (18%) showed positive F-FDG nodal uptake (range, 2.0-22.6). In these 27 patients, a receiver-operating characteristic curve demonstrated a nodal SUVmax of 2.8 to be the optimal cutoff for predicting RFS and OS. The univariate and multivariate analyses showed that nodal SUVmax (hazard ratio [HR] = 2.71, P < 0.0001), pathologic N (pN) stage (HR = 2.58, P = 0.0058), and pathologic T (pT) stage (HR = 1.77, P = 0.0191) were independent prognostic factors for RFS. Also, nodal SUVmax (HR = 2.80, P < 0.0001) and pN stage (HR = 2.28, P = 0.0222) were independent prognostic factors for OS. A predictive survival model incorporating conventional risk factors (pT/pN stage) gave a c-statistic of 0.833 for RFS and 0.827 for OS, whereas a model combination of nodal SUVmax with pT/pN stage gave a c-statistic of 0.871 for RFS (P = 0.0355) and 0.877 for OS (P = 0.0313).Nodal SUVmax measured by preoperative F-FDG PET/CT is an independent prognostic factor for RFS and OS. Combining nodal SUVmax with pT/pN staging can improve survival prediction precision in patients with gastric cancer.


Assuntos
Fluordesoxiglucose F18 , Compostos Radiofarmacêuticos , Neoplasias Gástricas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Prognóstico , República da Coreia/epidemiologia , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade
18.
Nucl Med Mol Imaging ; 49(2): 135-42, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26085859

RESUMO

PURPOSE: Histopathologic features could affect the FDG uptake of primary gastric cancer and detection rate on FDG PET/CT. The aim of this study was to evaluate the FDG uptake of primary gastric cancer by correlating it with the histopathologic features of the tumors. METHODS: Fifty patients with locally advanced gastric adenocarcinoma who were referred for preoperative FDG-PET/CT scans were enrolled in this study. The detection rate of PET/CT and maximum standardized uptake values (SUVmax) of the primary tumor were compared using the WHO, Lauren, Ming and Borrmann classifications and tumor size and location. RESULTS: In 45 of the 50 patients (90 %), the primary gastric tumors were detected by FDG PET/CT. On comparison using the WHO classification, the detection rate and SUVmax of the tubular type were significantly higher than those of the poorly cohesive type. On comparison using the Lauren and Ming classifications, the SUVmaxs of the intestinal type and expanding type were significantly higher than those of the diffuse and infiltrative type, respectively. On comparison using the Borrmann classification and tumor size and location, there was no significant difference in the detection rate and SUVmax of primary gastric tumors. CONCLUSION: This study demonstrates that the poorly cohesive type according to the WHO classification, diffuse type according to the Lauren classification and infiltrative type according to the Ming classification have low FDG uptake in patients with locally advanced gastric carcinoma. Understanding the relationship between primary tumor FDG uptake and histopathologic features would be helpful in detecting the primary tumor by FDG PET/CT in patients with gastric cancer.

19.
Asian Pac J Cancer Prev ; 16(11): 4493-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26107192

RESUMO

Alterations in mitochondrial DNA (mtDNA) have been studied in various cancers. However, the clinical value of mtDNA copy number (mtCN) alterations in gastric cancer (GC) is poorly understood. In the present study, we investigated whether alterations in mtCNs might be associated with clinicopathological parameters in GC cases. mtCN was measured in 109 patients with GC by real-time PCR. Then, correlations with clinicopathological characteristics were analyzed. mtCN was elevated in 64.2% of GC tissues compared with paired, adjacent, non- cancerous tissue. However, the observed alterations in mtCN were not associated with any clinicopathological characteristics, including age, gender, TN stage, Lauren classification, lymph node metastasis, and depth of invasion. Moreover, Kaplan-Meier survival curves revealed that mtCN was not significantly associated with the survival of GC patients. In this study, we demonstrated that mtCN was not a significant marker for predicting clinical characteristics or prognosis in GC.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Mucosa Gástrica/metabolismo , Amplificação de Genes , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Classe I de Fosfatidilinositol 3-Quinases , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida
20.
Int J Med Sci ; 12(4): 349-53, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26019684

RESUMO

Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and sessile serrated adenomas (SSAs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SSAs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR and pyrosequencing. PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs, respectively. KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs. In TAs, PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Amplificação de Genes , Mutação , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenoma/patologia , Idoso , Biomarcadores Tumorais/genética , Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas B-raf/genética
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