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1.
Cancer Sci ; 112(6): 2335-2348, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33931930

RESUMO

Lysosomal degradation plays a crucial role in the metabolism of biological macromolecules supplied by autophagy. The regulation of the autophagy-lysosome system, which contributes to intracellular homeostasis, chemoresistance, and tumor progression, has recently been revealed as a promising therapeutic approach for pancreatic cancer (PC). However, the details of lysosomal catabolic function in PC cells have not been fully elucidated. In this study, we show evidence that suppression of acid alpha-glucosidase (GAA), one of the lysosomal enzymes, improves chemosensitivity and exerts apoptotic effects on PC cells through the disturbance of expression of the transcription factor EB. The levels of lysosomal enzyme were elevated by gemcitabine in PC cells. In particular, the levels of GAA were responsive to gemcitabine in a dose-dependent and time-dependent manner. Small interfering RNA against the GAA gene (siGAA) suppressed cell proliferation and promoted apoptosis in gemcitabine-treated PC cells. In untreated PC cells, we observed accumulation of depolarized mitochondria. Gene therapy using adenoviral vectors carrying shRNA against the GAA gene increased the number of apoptotic cells and decreased the tumor growth in xenograft model mice. These results indicate that GAA is one of the key targets to improve the efficacy of gemcitabine and develop novel therapies for PC.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , alfa-Glucosidases/genética , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , Masculino , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno/farmacologia , Fatores de Tempo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
2.
J Surg Res ; 226: 157-165, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29661282

RESUMO

BACKGROUND: Blood transfusion has been reported to be associated with immunomodulation and poor oncologic outcomes in several malignancies. The aim of the study is to investigate the influence of the use of fresh frozen plasma (FFP) on long-term outcomes in patients with colorectal liver metastases (CRLM) after hepatic resection. MATERIALS AND METHODS: The study comprised 127 patients who had undergone first hepatic resection for CRLM between April 2000 and December 2013. We retrospectively investigated the influence of the use of FFP on disease-free survival as well as overall survival and assessed the impact of such a practice on postoperative inflammation markers. RESULTS: In multivariate analysis, more than four lymph node metastases of the primary cancer (P = 0.001), bilobar distribution (P = 0.002), and perioperative FFP transfusion (P = 0.005) were independent risk factors for cancer recurrence, while more than four lymph node metastases of the primary cancer (P < 0.001), presence of neoadjuvant chemotherapy (P = 0.002), and perioperative FFP transfusion (P = 0.004) were independent risk factors for poor overall survival. In patients who underwent FFP transfusion, tumor size (P = 0.004), anatomic resection (P < 0.001), duration of operation (P = 0.039), and intraoperative blood loss (P < 0.001) were significantly greater. Moreover, FFP transfusion was associated with a higher white blood cell level on postoperative day 3 (P < 0.001) and day 5 (P = 0.010) and lower serum C-reactive protein level on postoperative day 1 (P < 0.001) and day 3 (P = 0.017). CONCLUSIONS: Perioperative FFP transfusion is independently associated with poor long-term outcomes in patients with CRLM after hepatic resection. FFP may have an influence on postoperative inflammation because of its immunosuppressive effects.


Assuntos
Transfusão de Componentes Sanguíneos/métodos , Perda Sanguínea Cirúrgica , Neoplasias Colorretais/patologia , Inflamação/diagnóstico , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/análise , Intervalo Livre de Doença , Feminino , Hepatectomia/efeitos adversos , Humanos , Inflamação/sangue , Inflamação/etiologia , Inflamação/imunologia , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Duração da Cirurgia , Período Perioperatório , Plasma/imunologia , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
3.
J Surg Res ; 206(1): 1-8, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27916347

RESUMO

BACKGROUND: Because of difficulties with early diagnosis, most patients with pancreatic cancer receive chemotherapy. The National Comprehensive Cancer Network guidelines (version 2.2015) suggest therapy with gemcitabine (GEM) plus nab-paclitaxel (nPTX) as a category 1 recommendation for metastatic pancreatic ductal adenocarcinoma. According to the results of many studies, the activation of chemotherapeutic agents-induced nuclear factor-κB (NF-κB) causes chemoresistance. Hence, we hypothesized that the addition of nafamostat mesilate (NM), a potent NF-κB inhibitor, to GEM/nPTX therapy could enhance the antitumor effect in the treatment of pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: In vitro, we assessed NF-κB activity and apoptosis under treatment with NM alone (80 µg/mL), with GEM/nPTX, or with a combination of NM and GEM/nPTX in human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and AsPC-1). In vivo, orthotopic pancreatic cancer mice (BALBc nu/nu) were divided into four groups: control (n = 13), NM (n = 13), GEM/nPTX (n = 13), and triple combination (n = 13). NM (30 mg/kg) was delivered intraperitoneally three times a week, and GEM/nPTX was injected intravenously once a week to orthotopic pancreatic cancer model mice. In the triple combination group, mice received NM followed by GEM/nPTX on the first day to avoid GEM/nPTX-induced NF-κB activation. RESULTS: In vitro and in vivo, NM inhibited GEM/nPTX-induced NF-κB activation, and a synergistic effect of apoptosis was observed in the triple combination group. Furthermore, tumor growth was significantly suppressed in the triple combination group compared with the other groups. CONCLUSIONS: NM enhances the antitumor effect of GEM/nPTX chemotherapy for orthotopic pancreatic cancer by inhibition of NF-κB activation.


Assuntos
Albuminas/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Guanidinas/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Albuminas/farmacologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Benzamidinas , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Esquema de Medicação , Guanidinas/farmacologia , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , Paclitaxel/farmacologia , Neoplasias Pancreáticas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
4.
Zootaxa ; 5405(4): 577-590, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38480169

RESUMO

Three new species of ascothoracidan crustaceans, Dendrogaster danni sp. nov., Dendrogaster tanabensis sp. nov., and Dendrogaster jinshomaruae sp. nov. are described from the sea around the Kii Peninsula on the Pacific coast of central Japan. They are found in the coelomic cavities of the sea stars, Neoferdina japonica Oguro & Misaki, 1986., Henricia sp., and Coronaster volsellatus (Sladen, 1889), respectively. Morphological examinations and DNA barcoding analyses of these new species are reported in this study. The emergence of Dendrogaster from their host sea stars is also noted. These findings represent the 11th to 13th species of Dendrogaster that infest Japanese sea stars.


Assuntos
Parasitos , Estrelas-do-Mar , Animais , Japão , Crustáceos
5.
Trauma Case Rep ; 43: 100761, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36660402

RESUMO

Traumatic intrathoracic foreign bodies are said to occur in many cases when the patient himself/herself is aware of the trauma. However, at the time of injury, the patient may sometimes be accompanied by loss of consciousness. We report a case of traumatic intrathoracic foreign body that was difficult to diagnose due to loss of consciousness at the time of injury. A 51-year-old female was brought to our emergency department with a fall trauma due to loss of consciousness while bathing. The head computed tomography and electrocardiogram showed no abnormalities, and the laceration of approximately 3 cm in length was found on the left side thorax, and it was sutured and the patient was sent home. Four days later, she returned to our hospital with a complaint of left anterior chest pain, and chest X-ray showed a left degree pneumothorax and mediastinal emphysema. She underwent semi-emergency thoracoscopic removal of the foreign body, and was discharged from the hospital on the fourth postoperative day. She had progressive supranuclear palsy, and her memory at the time of injury was not clear due to loss of consciousness caused by central autonomic neuropathy, and she also had dementia, making it difficult to interview her. She had no thoracic symptoms, and the glass fragment that had strayed into the thoracic cavity was not exposed outside the body, making the diagnosis difficult at the time of initial examination. When a patient with loss of consciousness is difficult to interview at the time of injury, it is advisable to perform an imaging examination appropriate for the site of injury, taking into consideration the presence of foreign bodies.

6.
PLoS One ; 16(9): e0257019, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34473771

RESUMO

Nuclear factor kappa B (NF-κB) is a transcriptional factor that can be activated by radiotherapy and chemotherapy. The synthetic protease inhibitor nafamostat mesilate (NM) inhibits NF-κB activity and exerts antitumor actions in various types of cancer. In the present study, we hypothesized that NM might enhance the antitumor action of radiotherapy on gallbladder cancer (GBC) cells by inhibiting radiation-induced NF-κB activity. Thus, we investigated the correlation between radiotherapy and NF-κB activity in GBC cells. We assessed the in vitro effects of radiotherapy with or without NM on NF-κB activity, apoptosis of GBC cells (NOZ and OCUG-1), induction of apoptotic cascade, cell cycle progression, and viability of GBC cells using four treatment groups: 1) radiation (5 Gy) alone; 2) NM (80 µg/mL and 40 µg/mL, respectively) alone; 3) combination (radiation and NM); and 4) vehicle (control). The same experiments were performed in vivo using a xenograft GBC mouse model. In vitro, NM inhibited radiation-induced NF-κB activity. Combination treatment significantly attenuated cell viability and increased cell apoptosis and G2/M phase cell cycle arrest compared with those in the other groups for NOZ and OCUG-1 cells. Moreover, combination treatment upregulated the expression of apoptotic proteins compared with that after the other treatments. In vivo, NM improved the antitumor action of radiation and increased the population of Ki-67-positive cells. Overall, NM enhanced the antitumor action of radiotherapy on GBC cells by suppressing radiation-induced NF-κB activity. Thus, the combination of radiotherapy and NM may be useful for the treatment of locally advanced unresectable GBC.


Assuntos
Benzamidinas/administração & dosagem , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/radioterapia , Guanidinas/administração & dosagem , NF-kappa B/antagonistas & inibidores , Inibidores de Proteases/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada/métodos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Surgery ; 166(6): 991-996, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31353078

RESUMO

BACKGROUND: Liver metastasis is a common problem after pancreatectomy for pancreatic cancer. In pancreatic cancer cells, nuclear factor-κB is activated constitutively. Nuclear factor-κB activates matrix metalloproteinase-2/9, which plays an important role in cancer metastasis. Because the serine protease inhibitor FUT-175 suppresses nuclear factor-κB, we hypothesized that perioperative treatment with FUT-175 for pancreatic cancer may help to prevent liver metastasis. METHODS: We compared in vitro cell viability, cell invasiveness, nuclear factor-κB signaling, and the expression levels of matrix metalloproteinase signals between the control group (C group) and the FUT-175 group (F group) using the murine pancreatic cancer cells PAN02. In addition, we evaluated the in vivo effect of pretreatment with FUT-175 using an established model of liver metastasis in mice. Metastatic liver lesions were assessed with magnetic resonance imaging. Liver recurrence and overall survival were evaluated. Also, the antimetastatic effect of systemic administration of FUT-175 was examined. RESULTS: FUT-175 did not suppress the cell viability of PAN02 cells at or after 24 hours of treatment (P > .05); however, cell invasion was suppressed in the F group compared with the C group (P < .05). The levels of nuclear factor-κB activation, membrane type-1 (MT-1) matrix metalloproteinase (MMP)/matrix metalloproteinase-14 (MMP-14), and matrix metalloproteinase-2/9 (MMP-2/9) were lower in the F group compared with the C group. In vivo, both disease-free and overall survivals were prolonged in the F group compared with the C group. Systemic administration was also effective in suppressing the number of metastases. CONCLUSION: Perioperative treatment with FUT-175 may help to prevent early liver metastasis after pancreatectomy for pancreatic cancer.


Assuntos
Guanidinas/administração & dosagem , Neoplasias Hepáticas/prevenção & controle , NF-kappa B/antagonistas & inibidores , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Animais , Benzamidinas , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Intervalo Livre de Doença , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Assistência Perioperatória/métodos , Transdução de Sinais/efeitos dos fármacos
9.
Anticancer Res ; 39(11): 6325-6332, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704863

RESUMO

BACKGROUND/AIM: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. PATIENTS AND METHODS: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or older; n=16). RESULTS: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. CONCLUSION: Hepatic resection for HCC and CRLM in patients aged 80 years and older may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and older, hepatic resection may be effective when negative surgical margins can be achieved.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Comorbidade , Intervalo Livre de Doença , Feminino , Hepatectomia/mortalidade , Hepatectomia/estatística & dados numéricos , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Margens de Excisão , Complicações Pós-Operatórias , Análise de Sobrevida , Resultado do Tratamento
10.
Anticancer Res ; 39(9): 5143-5148, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519626

RESUMO

BACKGROUND/AIM: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. PATIENTS AND METHODS: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or over; n=16). RESULTS: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. CONCLUSION: Hepatic resection for HCC and CRLM in patients aged 80 years and over may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and over, hepatic resection may be effective when negative surgical margins can be achieved.


Assuntos
Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Estadiamento de Neoplasias , Complicações Pós-Operatórias , Prognóstico , Resultado do Tratamento
11.
Anticancer Res ; 38(2): 987-992, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29374731

RESUMO

BACKGROUND: The purpose of this study was to evaluate the prognostic index of the preoperative platelet to albumin ratio (PAR) in patients who underwent primary resection for cholangiocarcinoma. PATIENTS AND METHODS: A total of 59 patients were divided into two groups: those with PAR ≥72.6×103 or <72.6×103 according to the area under the receiver operating characteristics curve. RESULTS: PAR was significantly inversely associated with overall (OS) and disease-free (DFS) survival on univariate analysis. PAR showed significance on multivariate analysis for OS (hazard ratio=6.232, 95% confidence interval=1.283-30.279, p=0.023), along with tumor differentiation (p=0.009), nodal involvement (p=0.001), intraoperative blood loss (p=0.001), and serum carcinoembryonic antigen (CEA) (p=0.012). High PAR was also significantly associated poor DFS on multivariate analysis (hazard ratio(HR)=4.422, 95% confidence interval(CI)=1.168-16.732, p=0.029), along with tumor differentiation (p=0.009). CONCLUSION: PAR is a useful prognostic index for OS and DFS in patients with cholangiocarcinoma after primary resection. By accumulating cases prospectively, this new index may be a reference for use before neoadjuvant chemotherapy.


Assuntos
Albuminas/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Plaquetas/patologia , Colangiocarcinoma/patologia , Hepatectomia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/cirurgia , Biomarcadores Tumorais/análise , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
12.
Oncotarget ; 9(20): 15292-15301, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29632644

RESUMO

INTRODUCTION: Nuclear factor κB (NF-κB) plays an important role in cancer progression and causes therapeutic resistance to chemotherapy. Pomalidomide, a third-generation immunomodulating drug derived from thalidomide, has been approved for uncontrolled multiple myeloma. We hypothesized that pomalidomide may inhibit the anticancer agent-induced NF-κB activity and enhance chemosensitization of combination chemotherapy with gemcitabine and S1 (Gem/S1) in pancreatic cancer. METHODS: In vitro, we assessed NF-κB activity, induction of caspase cascade, cell apoptosis and cell proliferation using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). In vivo, we established an orthotopic xenograft mouse model for human pancreatic cancer by injection of PANC-1 cells. At 5 weeks after injection, the animals were randomly divided into four groups and treated with Gem (100 mg/kg) /S1 (10 mg/kg), with oral administration of pomalidomide (0.5 mg/kg), with combination of gemcitabine, S1, and pomalidomide or vehicle only. RESULTS: Although chemotherapeutic agents induced NF-κB activation in pancreatic cancer cells, pomalidomide inhibited anticancer agent-induced NF-κB activation (p < 0.01). Of the four groups tested for the apoptosis-related caspase signals and apoptosis under both in vitro and in vivo conditions, Gem/S1/Pomalidomide group demonstrated the strongest activation of the caspase signals and proapoptotic effect. In Gem/S1/Pomalidomide group, cell proliferation and tumor growth were slower than those in other groups both in vitro and in vivo (p < 0.01). There were no obvious adverse effects except for thrombocytosis by using pomalidomide. CONCLUSIONS: Pomalidomide promotes chemosensitization of pancreatic cancer by inhibiting chemotherapeutic agents-induced NF-κB activation.

13.
Oncotarget ; 9(21): 15780-15791, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29644009

RESUMO

BACKGROUND: Chemotherapy with gemcitabine and nab-paclitaxel (gemcitabine/nab-paclitaxel) is recommended for unresectable pancreatic cancer. However, the therapeutic efficacy is attenuated by the antitumor agent-induced activation of nuclear factor-κB (NF-κB). Thalidomide inhibits NF-κB activation, therefore, we hypothesized that pomalidomide, a third-generation IMiD, would also inhibit NF-κB activation and enhance the antitumor effects of gemcitabine/nab-paclitaxel. METHODS: In vitro, we assessed NF-κB activity and apoptosis in response to pomalidomide alone, gemcitabine/nab-paclitaxel, or combination of pomalidomide and gemcitabine/nab-paclitaxel in human pancreatic cancer cell lines (PANC-1 and MIA PaCa-2). In vivo, we established orthotopic model and the animals were treated with oral pomalidomide and injection of gemcitabine/nab-paclitaxel. RESULTS: In pomalidomide and gemcitabine/nab-paclitaxel group, gemcitabine/nab-paclitaxel-induced NF-κB activation was inhibited and apoptosis was enhanced in comparison with those in the other groups both in vitro and in vivo. Especially, this study revealed for the first time that pomalidomide enhances p53 on pancreatic cancer cells. The tumor growth in the pomalidomide and gemcitabine/nab-paclitaxel group was significantly slower than that in the gemcitabine/nab-paclitaxel group. Moreover, pomalidomide induced G0/G1 cell cycle arrest and suppressed angiogenesis. CONCLUSIONS: Pomalidomide enhanced the antitumor effect of gemcitabine/nab-paclitaxel by inhibition of NF-κB activation. This combination regimen would be a novel strategy for treating pancreatic cancer.

14.
Surgery ; 164(3): 404-410, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29754978

RESUMO

BACKGROUND: Liver function in patients with hepatocellular carcinoma is generally graded according to the Child-Pugh system; however, some variables in the Child-Pugh grade are subjective. We developed a novel, objective score called the prothrombin time-international normalized ratio to albumin ratio. The aim of this study was to evaluate the prognostic value of this new score in patients with hepatocellular carcinoma after hepatic resection. METHODS: The study comprised 199 patients who underwent elective hepatic resection for hepatocellular carcinoma between January 2003 and December 2014. We investigated retrospectively the relation between prothrombin time-international normalized ratio to albumin ratio, disease-free survival, and overall survival and compared the value of liver functional reserve between prothrombin time-international normalized ratio to albumin ratio and Child-Pugh grade. RESULTS: The optimal cut-off level of the prothrombin time-international normalized ratio to albumin ratio was 0.288. In multivariate analysis, the independent and significant predictors of cancer recurrence consisted of hepatitis C virus infection (P = .043), preoperative retention rate of indocyanine green at 15 minutes ≥15% (P = .039), the presence of multiple tumors (P = .001) or microvascular invasion (P < .001), and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .022). The independent predictors of poor overall survival were microvascular invasion (P = .001) and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .001). In patients with a high prothrombin time-international normalized ratio to albumin ratio, pathologic liver cirrhosis (P < .001), postoperative ascites (P = .039), and postoperative liver failure (P = .040) were greater than for their counterparts. CONCLUSION: The prothrombin time-international normalized ratio to albumin ratio may reflect liver function and may be a novel indicator of poor long-term outcome in patients with hepatocellular carcinoma after hepatic resection.


Assuntos
Carcinoma Hepatocelular/sangue , Coeficiente Internacional Normatizado , Neoplasias Hepáticas/sangue , Tempo de Protrombina , Albumina Sérica , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Intervalo Livre de Doença , Feminino , Hepatectomia , Humanos , Testes de Função Hepática , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento
15.
Cancers (Basel) ; 10(10)2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30336548

RESUMO

Neoadjuvant chemoradiotherapy followed by radical surgery is the standard treatment for patients with locally advanced low rectal cancer. However, several studies have reported that ionizing radiation (IR) activates nuclear factor kappa B (NF-κB) that causes radioresistance and induces matrix metalloproteinase (MMP)-2/-9, which promote tumor migration and invasion. Nafamostat mesilate (FUT175), a synthetic serine protease inhibitor, enhances the chemosensitivity to cytotoxic agents in digestive system cancer cells by inhibiting NF-κB activation. Therefore, we evaluated the combined effect of IR and FUT175 on cell proliferation, migration and invasion of colorectal cancer (CRC) cells. IR-induced upregulation of intranuclear NF-κB, FUT175 counteracted this effect. Moreover, the combination treatment suppressed cell viability and induced apoptosis. Similar effects were also observed in xenograft tumors. In addition, FUT175 prevented the migration and invasion of cancer cells caused by IR by downregulating the enzymatic activity of MMP-2/-9. In conclusion, FUT175 enhances the anti-tumor effect of radiotherapy through downregulation of NF-κB and reduces IR-induced tumor invasiveness by directly inhibiting MMP-2/-9 in CRC cells. Therefore, the use of FUT175 during radiotherapy might improve the efficacy of radiotherapy in patients with CRC.

16.
Anticancer Res ; 37(2): 787-793, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179331

RESUMO

BACKGROUND: The aim of this study was to evaluate a novel prognostic value of preoperative platelet-to-albumin ratio (PAR) in patients resected for pancreatic cancer. PATIENTS AND METHODS: A total of 107 patients who underwent pancreatic resection for pancreatic cancer were studied. The patients were divided into two groups as PAR ≥46.4×103 or <46.4×103 Survival data were analyzed using the log-rank test for univariate analysis and Cox proportional hazards for multivariate analysis. RESULTS: The PAR was a significant prognostic index on univariate analysis for disease-free survival (DFS) and overall survival (OS). The PAR retained its significance on multivariate analysis for OS (hazard ratio(HR)=2.344, 95% confidence interval(CI)=1.188-4.624, p=0.014) along with tumor differentiation and nodal involvement. PAR was a significant independent prognostic index for poor DFS on multivariate analysis (HR=1.971, 95% CI=1.128-3.444, p=0.017). CONCLUSION: The preoperative PAR is a novel significant independent prognostic index for DFS and OS in patients after pancreatic resection with curative intent.


Assuntos
Adenocarcinoma/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Idoso , Plaquetas/metabolismo , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/diagnóstico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pâncreas/patologia , Pâncreas/cirurgia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Contagem de Plaquetas , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Albumina Sérica/metabolismo
17.
Surgery ; 161(6): 1675-1682, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28094003

RESUMO

BACKGROUND: Thrombomodulin, an anticoagulant that inhibits thrombin-induced growth factor promotion, also has an anti-inflammatory effect. Furthermore, thrombomodulin inhibits nuclear factor-kappa B activation, which plays a crucial role in cancer progression. We assessed the antitumor activity of recombinant thrombomodulin for pancreatic cancer. METHODS: A xenograft orthotopic model was established in mice by implantation of human pancreatic cancer cells. The animals were treated with intraperitoneal injection of recombinant thrombomodulin 5 times a week for 4 weeks. Nuclear factor-kappa B activation was evaluated by measuring nuclear localization of the p65. Efficacy of recombinant thrombomodulin on the signal transduction of nuclear factor-kappa B was measured in vitro under preconditioning with thrombin or epidermal growth factor. RESULTS: Tumor growth was suppressed by recombinant thrombomodulin (P < .05). Recombinant thrombomodulin inhibited the expression of IκB kinase ß (P < .05) and pIκBα (P < .01), as well as the activation of nuclear factor-kappa B NF-κB (P < .001). Furthermore, recombinant thrombomodulin inhibited thrombin-induced protease activate receptor 1 and nuclear factor-kappa B activation in vitro (P < .05). The number of Ki67-positive cells was decreased by recombinant thrombomodulin (P < .01). Recombinant thrombomodulin also suppressed body weight loss associated with pancreatic cancer (P < .05). No obvious adverse effects were observed. CONCLUSION: Recombinant thrombomodulin significantly suppressed tumor growth against human pancreatic cancer by blocking thrombin-induced nuclear factor-kappa B activation without adverse effects.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinase I-kappa B/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Trombomodulina/administração & dosagem , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Humanos , Quinase I-kappa B/efeitos dos fármacos , Imuno-Histoquímica , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , Transplante de Neoplasias , Distribuição Aleatória , Valores de Referência , Transdução de Sinais/efeitos dos fármacos
18.
Int J Surg Case Rep ; 25: 7-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27288748

RESUMO

Percutaneous drainage, percutaneous transgastric drainage, and endoscopic ultrasound (EUS)-guided transgastric drainage are primarily utilized for drainage of fluid collections dorsal to the stomach. Percutaneous transgastric drainage is performed with computed tomography (CT) guidance, but it requires inflation of a balloon in the stomach, and gastric peristalsis makes it difficult to ensure a reliable puncture route via the stomach. Using endoscopy-assisted CT-guidance, we were able to safely and effectively perform percutaneous transgastric drainage. A 69-year-old man underwent a pancreaticoduodenectomy for cancer of the inferior section of the common bile duct. Postoperative day 5, the amylase value of the drainage fluid was 1,232 IU/L, we diagnosed a pancreatic fistula developed as a result of pancreaticojejunal anastomotic failure and we performed drainage at the drain which was placed in the foramen of Winslow intraoperatively, however fluid collection dorsal to the stomach was detected on a follow-up abdominal CT scan, and the fluid was a high value of amylase, we judged the drain was not working well and the pancreatic fistula occured. Endoscopy-assisted, CT-guided percutaneous transgastric drainage was therefore performed, and the pancreatic fistula was successfully closed the fistula.

19.
Anticancer Res ; 36(4): 2011-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27069195

RESUMO

BACKGROUND/AIM: Pancreatic resection is the only curative treatment for pancreatic and certain biliary malignancies. However, the mortality and morbidity associated with pancreatic resection remain high. PATIENTS AND METHODS: The study included 114 patients with age 70 years or older who underwent pancreatic resection for pancreatic or biliary cancer between 2005 and 2014 at the Jikei University Hospital. We analyzed surgical outcomes, complications, mortality and long-term survival between patients aged 70-79 years (n=97) and those aged 80 years or over (n=17). RESULTS: In patients aged 70 to 79 years, two died in-hospital and 8 required reoperation or interventional radiology (IVR). In patients aged 80 years or over, on the other hand, there was no in-hospital mortality. The incidence of complications and long-term survival were comparable. CONCLUSION: Pancreatic resection for pancreatic and biliary malignancies in patients aged 80 years or over with good general condition and proper selection seems safe and acceptable.


Assuntos
Neoplasias do Sistema Biliar/cirurgia , Neoplasias Pancreáticas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/patologia , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pancreatectomia , Neoplasias Pancreáticas/patologia , Complicações Pós-Operatórias , Análise de Sobrevida
20.
Microscopy (Oxf) ; 65(4): 353-62, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27142511

RESUMO

A new in situ environmental transmission electron microscope (ETEM) was developed based on a 300 kV TEM with a cold field emission gun (CFEG). Particular caution was taken in the ETEM design to assure uncompromised imaging and analytical performance of the TEM. Because of the improved pumping system between the gun and column, the vacuum of CFEG was largely improved and the probe current was sufficiently stabilized to operate without tip flashing for 2-3 h or longer. A high brightness of 2.5 × 10(9) A/cm(2) sr was measured at 300 kV, verifying the high quality of the CFEG electron beam. A specially designed gas injection-heating holder was used in the in situ TEM study at elevated temperatures with or without gas around the TEM specimen. Using this holder in a 10 Pa gas atmosphere and specimen temperatures up to 1000°C, high-resolution ETEM performance and analysis were achieved.

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