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1.
Artigo em Inglês | MEDLINE | ID: mdl-38088372

RESUMO

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are being increasingly used to treat advanced malignancies. ICI-induced pancreatic injury (ICI-PI), which is an immune-related adverse event that may be a risk factor for ICI-associated pancreatitis, is not well documented in the literature. METHODS: Consecutive patients who received ICIs for advanced malignancies from August 2015 through October 2022 were analyzed with regard to the incidence of ICI-PI based on the Common Terminology Criteria for Adverse Events and ICI-associated pancreatitis. The imaging, clinical, and pathological findings of ICI-associated pancreatitis were also assessed. RESULTS: This study enrolled 843 patients. In multivariable analyses, dual or simultaneous immunotherapy and ≥10 cycles of ICI administration were significant predictive factors for all grades of pancreatic injury, including grade ≥ 3. Notably, patients who received simultaneous immunotherapy exhibited a higher incidence of grade ≥ 3 pancreatic injuries compared to those receiving asynchronous immunotherapy in univariable analysis (p = 0.032). One-fifth of the patients (16/70) with grade ≥ 3 pancreatic injuries had imaging evidence of pancreatitis similar to mild acute pancreatitis. ICI-associated pancreatitis was observed in 5.7% (48/843) of patients, including 1.8% (15/843) with moderate-to-severe pancreatitis (grade ≥ 2). Symptomatic cases (0.36%, 3/843) were treated with steroids with favorable outcomes. Immunohistochemistry for CD4 and CD8 revealed greater infiltration of CD8+ than CD4+ lymphocytes. CONCLUSION: Simultaneous immunotherapy and dual immunotherapy are risk factors for ICI-PI. Although most patients diagnosed with ICI-PI and ICI-associated pancreatitis were asymptomatic and had a low mortality likelihood, long-term outcomes, including endocrine and exocrine function should be carefully monitored.

2.
Cancer Sci ; 114(12): 4571-4582, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37770812

RESUMO

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Biomarcadores , Linhagem Celular , Modelos Animais de Doenças , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Interferência de RNA
3.
mBio ; 14(4): e0099223, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37366623

RESUMO

Identification of the mechanisms of viral evasion from human antibodies is crucial both for understanding viral pathogenesis and for designing effective vaccines. Here we show in cell cultures that an N-glycan shield on the herpes simplex virus 1 (HSV-1) envelope glycoprotein B (gB) mediated evasion from neutralization and antibody-dependent cellular cytotoxicity due to pooled γ-globulins derived from human blood. We also demonstrated that the presence of human γ-globulins in mice and immunity to HSV-1 induced by viral infection in mice significantly reduced replication in their eyes of a mutant virus lacking the glycosylation site but had little effect on the replication of its repaired virus. These results suggest that an N-glycan shield on a specific site of HSV-1 envelope gB mediated evasion from human antibodies in vivo and from HSV-1 immunity induced by viral infection in vivo. Notably, we also found that an N-glycan shield on a specific site of HSV-1 gB was significant for HSV-1 neurovirulence and replication in the central nervous system of naïve mice. Thus, we have identified a critical N-glycan shield on HSV-1 gB that has dual impacts, namely evasion from human antibodies in vivo and viral neurovirulence. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latent and recurrent infections in humans. To produce recurrent infections that contribute to transmission of the virus to new human host(s), the virus must be able to evade the antibodies persisting in latently infected individuals. Here, we show that an N-glycan shield on the specific site of the envelope glycoprotein B (gB) of HSV-1 mediates evasion from pooled γ-globulins derived from human blood both in cell cultures and mice. Notably, the N-glycan shield on the specific site of gB was also significant for HSV-1 neurovirulence in naïve mice. Considering the clinical features of HSV-1 infection, these results suggest that the glycan shield not only facilitates recurrent HSV-1 infections in latently infected humans by evading antibodies but is also important for HSV-1 pathogenesis during the initial infection.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Animais , Camundongos , Herpesvirus Humano 1/fisiologia , Reinfecção , Proteínas do Envelope Viral/genética , Anticorpos Neutralizantes , gama-Globulinas
4.
Nat Cell Biol ; 25(3): 453-466, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36918692

RESUMO

Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte , Interferon Tipo I , Proteínas de Membrana , Animais , Humanos , Adenosina Trifosfatases/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/metabolismo , Microautofagia , Transporte Proteico , Transdução de Sinais , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
5.
PLoS One ; 18(2): e0281605, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36758010

RESUMO

BACKGROUND: Endoscopic transpapillary gallbladder drainage (ETGBD) has been reported as an alternative procedure for acute cholecystitis but remains a challenging procedure. AIMS: To elucidate the efficacy of a strategic approach for ETGBD that utilizes a four-step classification system and the optional use of 'Three-pillar' assistance with the following devices: cholangioscopy (SpyGlass DS, SG), a flex-type guidewire (Flex-GW), and a 3-Fr microcatheter (3-Fr Micro). METHODS: A total of 115 patients undergoing ETGBD were studied retrospectively. Characteristics and technical outcomes were compared between conventional ETGBD technique (Classical ETGBD, N = 50) and strategic ETGBD with optional Three-pillar assistance (Strategic ETGBD, N = 65). RESULTS: SG-assistance (15/65, 23.1%) was as an excellent troubleshooter in Category 1 (failure to identify the cystic duct [CD] orifice) and Category 2 (failure to advance the GW across the CD takeoff due to unfavorable angle). Flex-GW (19/65, 29.2%) worked for Category 3b (failure of GW access to the GB due to multiple tortuosities). 3-Fr Micro (11/65, 16.9%) was effective for Category 3a (failure of GW access to the GB due to CD obstruction) and Category 4 (failure of drainage stent insertion to the GB). The overall technical success rate was significantly higher for Strategic ETGBD (63/65, 96.9%) compared with Classical ETGBD (36/50, 72.0%) (p = 0.0001). CONCLUSIONS: Strategic ETGBD, which includes the Three-pillar assistance options of SG in the initial steps, Flex-GW for tortuous CD, and 3-Fr Micro for stenotic CD, achieved a significantly higher success rate than for Classical ETGBD.


Assuntos
Colecistite Aguda , Laparoscopia , Humanos , Vesícula Biliar , Estudos Retrospectivos , Colecistite Aguda/cirurgia , Drenagem/métodos , Stents
6.
Microbiol Immunol ; 67(3): 114-119, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36606601

RESUMO

Wild-type herpes simplex virus (HSV) strains infrequently mediate cell-cell fusion in cell cultures and barely induce large multinucleated cells. In this study, we established a system to quantify infrequent cell-cell fusion induced by wild-type HSV strains. The established system clarified that the HSV-1 envelope glycoprotein B and its N-glycosylation at asparagine at position 141 were required for efficient cell-cell fusion. This study provides a link between cell-cell fusion induced by wild-type HSV-1 and viral pathogenesis in vivo.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Herpesvirus Humano 1/genética , Glicosilação , Fusão Celular , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
7.
Intern Med ; 62(4): 545-551, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35831103

RESUMO

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.


Assuntos
Doenças Autoimunes , Pancreatite Autoimune , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatite , Masculino , Humanos , Pessoa de Meia-Idade , Pancreatite Autoimune/diagnóstico por imagem , Pancreatite/diagnóstico por imagem , Biópsia por Agulha Fina/métodos , Doenças Autoimunes/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Ultrassonografia de Intervenção , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pancreáticas
8.
Cancer Sci ; 114(1): 295-305, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36168845

RESUMO

Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study reports the results of a global investigation of exosomal microRNAs (miRNAs) in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty-eight bile samples collected during ERCP (45 BTC and 43 noncancer control samples) were enrolled in this study. Eleven BTC samples and nine control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size-controlled macroporous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D-Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D-Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR-451a and miR-3619-3p were identified as reproducible upregulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR-3619-3p expression in bile reflects poorer prognosis of BTCs (hazard ratio = 2.89). The MPG-extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile-derived miRNA analysis with miR-451a and miR-3619-3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis.


Assuntos
Neoplasias do Sistema Biliar , Exossomos , MicroRNAs , Humanos , MicroRNAs/metabolismo , Prognóstico , Bile/metabolismo , Perfilação da Expressão Gênica/métodos , Biomarcadores Tumorais/genética , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/genética , Biomarcadores , Exossomos/genética , Exossomos/metabolismo
9.
Front Oncol ; 12: 963314, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36212467

RESUMO

Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA.

10.
Cancers (Basel) ; 14(17)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36077683

RESUMO

Histological evidence is essential for diagnosing malignant biliary strictures. However, conventional brush cytology remains the primary method used worldwide, despite its low diagnostic sensitivity and accuracy, as it is technically easy, rapid, and cost-effective. The aim of this study was to evaluate the diagnostic performance of a recently introduced endoscopic scraper, the simplicity of which is comparable to that of a conventional brush, by comparing diagnostic yields and the number of collected cells. The sensitivity of the endoscopic scraper when using the cell block technique was significantly higher than when using brush cytology or a brush with the cell block technique (53.6% vs. 30.9%, p < 0.001; 53.6% vs. 31.6%, p = 0.024, respectively). Quantitative digital image analysis of cell block sections revealed that the median number of cells obtained with the endoscopic scraper was significantly higher than when using the brush (1917 vs. 1014 cells, p = 0.042). Furthermore, seven cases (8.3%; 7/84) were diagnosed by immunohistochemical analysis of the cell block section obtained from the endoscopic scraper. Given its simplicity and greater capacity for sample acquisition, use of the endoscopic scraper in conjunction with the cell block technique could replace brush cytology for the histological diagnosis of malignant biliary strictures.

11.
Pancreas ; 51(4): 372-379, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35695793

RESUMO

OBJECTIVES: Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III ß-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. METHODS: We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. RESULTS: High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. CONCLUSIONS: Class III ß-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.


Assuntos
Adenocarcinoma , Albuminas/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Flavonoides , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Tubulina (Proteína)/metabolismo , Gencitabina , Neoplasias Pancreáticas
12.
Sci Rep ; 12(1): 419, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013462

RESUMO

We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r = - 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromograninas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Elementos Nucleotídeos Longos e Dispersos , Masculino , Pessoa de Meia-Idade , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Fenótipo , Proteínas Supressoras de Tumor/genética
13.
Dig Endosc ; 34(3): 632-640, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34716952

RESUMO

With the development of newer devices and technical innovations, pancreaticobiliary endoscopy is expanding to assume more advanced therapeutic roles. As with other devices, slimmed-down "3-Fr microcatheters" are considered to be opening new windows toward entirely new therapeutic techniques for various purposes. Our practical experience with a total of 34 consecutive patients in whom 3-Fr microcatheters were applied during pancreaticobiliary endoscopic procedures clarified the potential roles of this instrument in pancreaticobiliary endoscopy. The major benefits of 3-Fr microcatheters involve their slimness and flexibility. Applications of 3-Fr microcatheters could be categorized into three groups according to the characteristics of usage: (1) utilization as a cannulation catheter for peroral digital cholangioscopy (n = 15); (2) selective advancement through deep flexures or severely stenotic ducts (n = 11); or (3) two-devices-in-one-channel technique (n = 8). The microcatheter worked successfully for cannulation of cholangioscopy in all but one case (14/15, 93.3%). For selective advancement, the microcatheter worked for troubleshooting in 9 of 11 cases (81.8%). With the two-devices-in-one-channel technique, the microcatheter proved satisfactory in all cases (8/8, 100%). In total, the microcatheter was successfully maneuvered in 31 of 34 cases (91.1%), following the failure of procedures using conventional endoscopic techniques. In terms of adverse events, cystic duct injury was only observed in two cases (5.8%), who recovered under conservative observation, because its slimness could minimize the damage. We believe that 3-Fr microcatheters offer effective and safe salvage troubleshooting during various endoscopic pancreaticobiliary procedures that face troublesome situations with conventional strategies.


Assuntos
Cateterismo , Catéteres , Endoscopia Gastrointestinal , Humanos
15.
Mol Carcinog ; 60(11): 734-745, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34347914

RESUMO

The Cancer Genome Atlas (TCGA) of a pancreatic cancer cohort identified high MST1R (RON tyrosine kinase receptor) expression correlated with poor prognosis in human pancreatic cancer. RON expression is null/minimal in normal pancreas but elevates from pan-in lesions through invasive carcinomas. We report using multiple approaches RON directly regulates HIF-1α, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF-1α are highly co-expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF-1α expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF-1α expression, whereas ectopic RON expression in RON null cells induced HIF-1α expression suggesting the direct regulation of HIF-1α by RON kinase receptor. RON regulates HIF-1α through an unreported transcriptional mechanism involving PI3 kinase-mediated AKT phosphorylation and Sp1-dependent HIF-1α promoter activity leading to increased HIF-1α mRNA expression. RON/HIF-1α modulation altered the invasive behavior of PDAC cells. A small-molecule RON kinase inhibitor decreased RON ligand, MSP-induced HIF-1α expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF-1α expression. RON/HIF-1α co-expression also exists in triple-negative breast cancer cells, a tumor type that also lacks molecular therapeutic targets. This is the first report describing RON/HIF-1α axis in any tumor type and is a potential novel therapeutic target.


Assuntos
Carcinoma Ductal Pancreático/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pancreáticas/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Regulação para Cima , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Regiões Promotoras Genéticas , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação para Cima/efeitos dos fármacos
16.
Sci Rep ; 11(1): 8285, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859301

RESUMO

Endoscopic pancreatic stenting is used to prevent main pancreatic duct obstruction and relieve painful symptoms of chronic pancreatitis. However, the stent typically needs to be exchanged and the rate of adverse events is high. Few studies have evaluated the effect of stent shape on those outcomes. We evaluated the adverse events, stent patency, and total medical cost within 90 days of patients who received an 8.5 French (Fr) physiologically shaped pancreatic stent by comparing these features with those associated with a conventional straight-type stent for ≥ 90 days. The total stent-related adverse event rate was significantly lower for the physiologically shaped pancreatic stent (physiologically shaped, 6.7% [2/30]; straight-type, 50.6% [44/87]; P < 0.001). Stent occlusion was significantly less frequent (P < 0.001) and the total medical costs were significantly lower (P = 0.002) for the physiologically shaped stent. The stent-related adverse event rate was significantly higher for the 10 Fr straight type stent than for the 8.5 Fr physiologically shaped stent (10 Fr, straight-type vs. 8.5 Fr, physiologically shaped: 36.1% [13/36] vs. 6.7% [2/30]; P = 0.007). In conclusion, a physiologically shaped pancreatic stent was superior to a straight-type stent in terms of the patency rate and medical costs.


Assuntos
Endoscopia do Sistema Digestório/métodos , Pancreatite Crônica/cirurgia , Desenho de Prótese , Stents , Adulto , Idoso , Idoso de 80 Anos ou mais , Constrição Patológica/prevenção & controle , Endoscopia do Sistema Digestório/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Dor/prevenção & controle , Ductos Pancreáticos/patologia , Pancreatite Crônica/complicações , Falha de Prótese/etiologia , Stents/efeitos adversos , Stents/economia , Resultado do Tratamento
17.
Carcinogenesis ; 42(7): 940-950, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-33640964

RESUMO

The 5-year survival rate of pancreatic ductal carcinoma (PDAC) patients is <10% despite progress in clinical medicine. Strategies to prevent the development of PDAC are urgently required. The flavonoids Luteolin (Lut) and hesperetin (Hes) may be cancer-chemopreventive, but effects on pancreatic carcinogenesis in vivo have not been studied. Here, the chemopreventive effects of Lut and Hes on pancreatic carcinogenesis are assessed in the BOP-induced hamster PDAC model. Lut but not Hes suppressed proliferation of pancreatic intraepithelial neoplasia (PanIN) and reduced the incidence and multiplicity of PDAC in this model. Lut also inhibited the proliferation of hamster and human pancreatic cancer cells in vitro. Multi-blot and microarray assays revealed decreased phosphorylated STAT3 (pSTAT3) and dihydropyrimidine dehydrogenase (DPYD) on Lut exposure. To explore the relationship between DPYD and STAT3 activity, the former was silenced by RNAi or overexpressed using expression vectors, and the latter was inactivated by small molecule inhibitors or stimulated by IL6 in human PDAC cells. DPYD knock-down decreased, and overexpression increased, pSTAT3 and cell proliferation. DPYD expression was decreased by inactivation of STAT3 and increased by its activation. The frequency of pSTAT3-positive cells and DPYD expression was significantly correlated and was decreased in parallel by Lut in the hamster PDAC model. Finally, immunohistochemical analysis in 73 cases of human PDAC demonstrated that DPYD expression was positively correlated with the Ki-67 labeling index, and high expression was associated with poor prognosis. These results indicate that Lut is a promising chemopreventive agent for PDAC, targeting a novel STAT3-DPYD pathway.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Di-Hidrouracila Desidrogenase (NADP)/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Luteolina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Idoso , Animais , Apoptose , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , Cricetinae , Feminino , Humanos , Masculino , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Fator de Transcrição STAT3/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Gut Liver ; 15(3): 476-485, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33402544

RESUMO

Background/Aims: Although endoscopic transpapillary gallbladder drainage (ETGBD) has been reported as an alternative procedure for acute cholecystitis, it requires advanced endoscopic techniques. In terms of the certainty of achieving drainage, it remains a challenging procedure. The aim of the current study was to elucidate the practical efficacy of cholangioscopic assistance and to develop a new classification that could be used to evaluate the technical difficulty of ETGBD and provide a theoretical strategy to apply cholangioscopy appropriately for difficult ETGBD. Methods: A total of 101 patients undergoing ETGBD were retrospectively studied. The characteristics and technical outcomes of ETGBD with conventional ETGBD (C-ETGBD) and SpyGlass DS-assisted ETGBD (SG-ETGBD) were evaluated. The characteristics and technique-dependent factors of unsuccessful C-ETGBD/SG-ETGBD were evaluated using the classification based on the steps of the procedure. The predictive factors of successful C-ETGBD/SG-ETGBD were examined. Results: C-ETGBD was successful in 73 patients (72.3%). SG-ETGBD was successful in 11 of 13 patients (84.6%) who had C-ETGBD failure. Optional SG-ETGBD significantly increased the final success rate (94.1%) compared to C-ETGBD alone (p=0.003). ETGBD procedures could be classified into four steps. SG-assistance worked as an excellent troubleshooter in step 1 (failure to identify the cystic duct orifice) and step 2 (failure of guidewire advancement across the downturned angle of cystic duct takeoff). Magnetic resonance cholangiopancreatography could provide predictive information based on the classification. Conclusions: Optional SG-ETGBD achieved a significantly higher success rate than C-ETGBD alone. Step classification is helpful for determining the technical difficulty of ETGBD and developing a theoretical strategy to apply cholangioscopy in a coordinated manner.


Assuntos
Colecistite Aguda , Laparoscopia , Colecistite Aguda/cirurgia , Drenagem , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/cirurgia , Humanos , Estudos Retrospectivos
19.
Cancer Sci ; 112(2): 668-678, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33053268

RESUMO

Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates the progression of various cancers. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX-LPA axis in malignant ascites in PDAC and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380. An in vivo study showed that PF-8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC.


Assuntos
Carcinoma Ductal Pancreático/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Peritoneais/secundário , Diester Fosfórico Hidrolases/metabolismo , Animais , Ascite/metabolismo , Ascite/patologia , Carcinoma Ductal Pancreático/metabolismo , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Pancreáticas
20.
Intern Med ; 60(1): 47-52, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32893228

RESUMO

An 84-year-old man was admitted with epigastralgia. Computed tomography showed contrast-enhanced wall thickness in the cystic duct. An endoscopic examination revealed short irregular stricture in the cystic duct, and per-oral cholangioscopy revealed a reddish papillary tumor at the stricture site. Surgical resection revealed high-grade biliary intraepithelial neoplasia (BilIN) at the stricture site of the cystic duct. To our knowledge, this is the first case of a solitary high-grade BilIN epithelium in the cystic duct detected by per-oral cholangioscopy.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma in Situ , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/cirurgia , Pigmentos Biliares , Carcinoma in Situ/diagnóstico por imagem , Carcinoma in Situ/cirurgia , Ducto Cístico/diagnóstico por imagem , Humanos , Masculino , Tomografia Computadorizada por Raios X
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