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1.
FEBS Open Bio ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115931

RESUMO

There are no human cancer cell lines of external auditory canal origin available for research use. This report describes the establishment of a culture condition for external auditory canal squamous cell carcinoma, derived from human tumor tissue. Successive squamous cell carcinoma colonies were dissociated by trypsin, subcultured, and maintained on a feeder layer (MMC-TIG-1-20), yielding a clonally proliferating cell culture. Two morphological types of colony were observed: (a) densely packed colonies and (b) colonies with indistinct boundaries characterized by cell-cell complexes with fibroblast feeder cells. The SCC-like characteristics of these cells were evidenced by positivity for p53, SCCA1/2, cytokeratin, and vimentin, and cancer stem cell properties were indicated by positivity for CD44, CD133, Oct3/4, and alkaline phosphatase (ALP). One of the unique properties of cell cultures is their tendency to form steric colonies in vitro on feeder layer cells. In addition, in the presence of fresh macrophages, the cells very slowly transform to break away from colonies as free cells, a process that resembles the epidermal-mesenchymal transition, whereby cell-cell interactions are weakened and migration activity is enhanced. These factors are purported to play a key role in cancer cell metastasis.

2.
AJR Am J Roentgenol ; 217(2): 411-417, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34076454

RESUMO

OBJECTIVE. The left inferior phrenic vein (LIPV) can be an origin of a gastrorenal shunt from gastric varices. The purpose of our study was to evaluate the angiographic anatomy of the LIPV, particularly anastomoses of the LIPV with the portal vein (PV). SUBJECTS AND METHODS. Of 240 patients with primary aldosteronism who underwent adrenal venous sampling from April 2011 to July 2019, 236 had normal liver and renal function and were included in this study. Of those patients, 214 had evaluable LIPV venography. The angiographic anatomy of the LIPV was classified as type 1 when the subdiaphragmatic transverse part of the LIPV could be visualized or as type 2 when it could not. Type 1 was subclassified into type 1a, which was defined as the transverse part of the LIPV connected with a single vein, or type 1b, which was defined as the transverse part of the LIPV connected with several veins via anastomoses. Type 2 LIPVs were subclassified into type 2a, in which the LIPV had an undeveloped vertical part; type 2b, in which the LIPV had backflow into systemic veins; or type 2c, in which the LIPV had a connection to the PV. The presence of an anastomosis with the PV was defined as the PV being visualizable on LIPV venography. RESULTS. Assessment of LIPV venography revealed type 1 in 71.5% (153/214) of patients, including type 1a (22.4%, 48/214) and type 1b (49.1%, 105/214). Type 2 LIPVs were observed in 28.5% (61/214) of patients, including types 2a (6.5%, 14/214), 2b (11.2%, 24/214), and 2c (10.7%, 23/214). An anastomosis of the LIPV with the PV was found in 28.0% (60/214) of patients, including 10.7% (23/214) with type 2c and 17.3% (37/214) with type 1 with a visible PV. The anastomoses of the LIPV with the PV were of various sizes. CONCLUSION. The angiographic anatomy of the LIPV varied and was commonly formed from several veins connected by anastomoses. An anastomosis between the LIPV and PV, which might be the origin of gastric varices, was found in 28.0% of patients.


Assuntos
Diafragma/anatomia & histologia , Diafragma/irrigação sanguínea , Adulto , Idoso , Angiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Veias/anatomia & histologia
3.
Transl Oncol ; 14(9): 101152, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34134073

RESUMO

In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.

4.
Oncol Rep ; 45(3): 997-1010, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650666

RESUMO

We previously reported that Hedgehog (Hh) signal was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent years, therapeutics that target Hh signaling have focused on molecules downstream of smoothened (SMO). The three transcription factors in the Hh signal pathway, glioma­associated oncogene homolog 1 (GLI1), GLI2, and GLI3, function downstream of SMO, but their biological role in GBC remains unclear. In the present study, the biological significance of GLI1, GLI2, and GLI3 were analyzed with the aim of developing novel treatments for GBC. It was revealed that GLI2, but not GLI1 or GLI3, was involved in the cell cycle­mediated proliferative capacity in GBC and that GLI2, but not GLI1 or GLI3, was involved in the enhanced invasive capacity through epithelial­mesenchymal transition. Further analyses revealed that GLI2 may function in mediating gemcitabine sensitivity and that GLI2 was involved in the promotion of fibrosis in a mouse xenograft model. Immunohistochemical staining of 66 surgically resected GBC tissues revealed that GLI2­high expression patients had fewer numbers of CD3+ and CD8+ tumor­infiltrating lymphocytes (TILs) and increased programmed cell death ligand 1 (PD­L1) expression in cancer cells. These results suggest that GLI2, but not GLI1 or GLI3, is involved in proliferation, invasion, fibrosis, PD­L1 expression, and TILs in GBC and could be a novel therapeutic target. The results of this study provide a significant contribution to the development of a new treatment for refractory GBC, which has few therapeutic options.


Assuntos
Neoplasias da Vesícula Biliar/patologia , Proteínas Nucleares/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Idoso , Animais , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Transição Epitelial-Mesenquimal , Feminino , Neoplasias da Vesícula Biliar/imunologia , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais
5.
Jpn J Radiol ; 39(1): 84-92, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32918250

RESUMO

PURPOSE: The purpose of this study was to evaluate the safety and feasibility of transarterial fiducial marker implantation for CyberKnife radiotherapy to treat locally advanced pancreatic cancer. MATERIALS AND METHODS: Fifteen pancreatic cancer patients were enrolled for transarterial marker implantation. Embolization platinum coils were implanted as a fiducial marker within 20 mm of the cancer edge, and preferably within 3 mm. The technical success of the implantation was defined as implantation of at least one fiducial marker within 20 mm of the target tumor. Irradiation was performed using the CyberKnife system. RESULTS: For 14 of 15 patients, transarterial implantation was successfully performed, and for 13 of 14 patients, the tracking marker was implanted within 3 mm of the cancer. Tracking instability was observed in two patients, but irradiation was accomplished in all 14 patients. No major complications caused by the implantation procedure were observed. The median overall survival after irradiation was 13.8 months, and the 1- and 2-years survival rates were 62.9% and 32.3%, respectively. CONCLUSION: Transarterial fiducial marker implantation for pancreatic cancer can be safely performed for tracking, and it will be a valuable alternative approach to percutaneous fiducial marker implantation.


Assuntos
Marcadores Fiduciais , Neoplasias Pancreáticas/radioterapia , Radiocirurgia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Cell Immunol ; 358: 104237, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33137650

RESUMO

We previously reported that protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is upregulated in activated lymphocytes, acts as an immune checkpoint. However, the mechanism by which PTPN3 expression is enhanced in activated lymphocytes is unknown. In this study, we analyzed the mechanism of PTPN3 expression in activated lymphocytes with a view for developing a novel immune checkpoint inhibitor that suppresses PTPN3. Through the activation process, lymphocytes showed enhanced NFκB activation as well as increased PTPN3 expression. NFκB enhanced proliferation, migration, and cytotoxicity of lymphocytes. Furthermore, NFκB enhanced PTPN3 expression and tyrosine kinase activation. TGFß reduced PTPN3 expression and NFκB activation in the cancer microenvironment, and suppressed the biological activity of lymphocytes. The results of this study are expected to provide significant implications for improving existing immunotherapy and developing novel immunotherapy.


Assuntos
NF-kappa B/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , NF-kappa B/fisiologia , Fosforilação/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 3/genética , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta/fisiologia
7.
J Immunother ; 43(4): 121-133, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31834207

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy. As a factor of resistance, the dense fibrosis of this cancer acts as a barrier to inhibit immune cell infiltration into a tumor. We examined the influence of a Hedgehog signal inhibitor, Patched 1-interacting peptide, on fibrosis, infiltration of immune cells, and immunotherapeutic effects on PDAC. We found that this peptide inhibited proliferation and migration of cancer-associated fibroblasts and cancer cells. Furthermore, this peptide reduced the production of extracellular matrix and transforming growth factor ß1 in cancer-associated fibroblasts and induced expression of HLA-ABC in PDAC cells and interferon-γ in lymphocytes. In vivo, the peptide suppressed fibrosis of PDAC and increased immune cell infiltration into tumors. The combination of this peptide and an anti-programmed death-1 antibody augmented the antitumor effect, and this combination showed the same effect in experiments using cancer cells and autologous lymphocytes. These results indicate that, in addition to the direct effect of tumor suppression, the Patched 1-interacting peptide increases the infiltration of immune cells by reducing fibrosis of PDAC and consequently enhances the effect of immunotherapy. Therefore, treatment with this peptide may be a novel therapy with 2 different mechanisms: direct tumor suppression and enhancing the immune response against PDAC.


Assuntos
Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/patologia , Receptor Patched-1/metabolismo , Peptídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Comunicação Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fibrose , Humanos , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Receptor Patched-1/química , Receptor Patched-1/genética , Peptídeos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Immunol Immunother ; 68(10): 1649-1660, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31562536

RESUMO

It has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting the PTPN3 expression in activated lymphocytes significantly augmented the proliferation, migration, and cytotoxicity through the phosphorylation of zeta-chain-associated protein kinase 70 (ZAP-70), lymphocyte-specific protein tyrosine kinase (LCK), and extracellular signal-regulated kinases (ERK). Lymphocyte activation by PTPN3 inhibition was observed only in activated CD3+ T cells and not in NK cells or resting T cells. In therapy experiments using autologous tumors and lymphocytes, PTPN3 inhibition significantly augmented the number of tumor-infiltrated lymphocytes and the cytotoxicity of activated lymphocytes. Our results strongly imply that PTPN3 acts as an immune checkpoint in activated lymphocytes and that PTPN3 inhibitor may be a new non-antibody-type immune checkpoint inhibitor for cancer therapy.


Assuntos
Pontos de Checagem do Ciclo Celular , Ativação Linfocitária , Neoplasias Ovarianas/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 3/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Feminino , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína-Tirosina Quinase ZAP-70/metabolismo
9.
Sci Rep ; 9(1): 9816, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285536

RESUMO

Tissue amino acid profiles depend on the cell types and extracellular components that constitute the tissue, and their functions and activities. We aimed to characterize the tissue amino acid profiles in several types of pancreatic tumors and lesions. We examined tissue amino acid profiles in 311 patients with pancreatic tumors or lesions. We used newly developed LC-MS/MS methods to obtain the profiles, which were compared with clinicopathological data. Each tumor or lesion presented a characteristic tissue amino acid profile. Certain amino acids were markedly altered during the multistep pancreatic carcinogenesis and pancreatic ductal adenocarcinoma (PDAC) progression. A tissue amino acid index (TAAI) was developed based on the amino acids that were notably changed during both carcinogenesis and cancer progression. Univariate and multivariate survival analyses revealed that PDAC patients with a high TAAI exhibited a significantly shorter survival rate, and these findings were validated using a second cohort. We suggest that tissue amino acid profiles are characteristic for normal tissue type, tumor histological type, and pathological lesion, and are representative of the cancer grade or progression stage in multistep carcinogenesis and of malignant characteristics. The TAAI could serve as an independent prognosticator for patients with PDAC.


Assuntos
Aminoácidos/análise , Carcinoma Ductal Pancreático/patologia , Metabolômica/métodos , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/metabolismo , Cromatografia Líquida , Progressão da Doença , Feminino , Humanos , Masculino , Especificidade de Órgãos , Neoplasias Pancreáticas/metabolismo , Fenótipo , Prognóstico , Estudos Prospectivos , Análise de Sobrevida , Espectrometria de Massas em Tandem
10.
Methods Mol Biol ; 2030: 207-218, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347120

RESUMO

Plasma free amino acid (PFAA) concentrations in humans are affected by various diseases. However, the variations caused are not dramatic, so a high accurate and precise method for analyzing PFAAs is required. The PFAA analysis protocol described in this chapter covers blood sampling, sample pretreatment, amino acid derivatization, and LC-MS analysis. Each procedure is important for accurate and precise quantification.In the protocol, a human blood sample is collected using an EDTA-2Na or 2K vacuum collection tube and then immediately cooled in water mixed with crushed ice. The sample is then centrifuged on cooling to allow a plasma sample to be removed. A stable-isotope-labeled internal standard solution is added to the plasma, and then the plasma is deproteinized with acetonitrile. The amino acids in the plasma are then derivatized using 3-aminopyridyl-N-hydroxysuccinimidyl carbamate (APDS) reagent which is designed for LC-MS analysis. The derivatized amino acids are separated by reverse-phase HPLC and detected by electrospray ionization mass spectrometry. Using this method, 21 amino acids in human plasma can be analyzed with a 12 min cycle. The accuracy and precision are both better than the required criteria given by the US Food and Drug Administration in guidance of Bioanalytical Method Validation.


Assuntos
Aminoácidos/sangue , Carbamatos/química , Cromatografia de Fase Reversa/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Succinatos/química , Aminoácidos/química , Aminoácidos/isolamento & purificação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/instrumentação , Humanos , Indicadores e Reagentes/química , Espectrometria de Massas por Ionização por Electrospray/instrumentação
11.
Eur J Hum Genet ; 27(4): 621-630, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659259

RESUMO

To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography-mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.


Assuntos
Aminoácidos/sangue , Biomarcadores/sangue , Estudo de Associação Genômica Ampla , Metabolômica , Adulto , Aminoácidos/genética , Feminino , Genoma Humano/genética , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
12.
Geriatr Gerontol Int ; 19(3): 254-258, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30561103

RESUMO

AIM: To examine the association between depressive symptoms and plasma amino acid related metaboli in older adults. METHODS: A total of 152 older adults aged ≥65 years, residing in Niigata, Japan, were used for analysis. We evaluated depressive symptoms using the Geriatric Depression Scale-15, which has been validated in older community-dwelling individuals, and used a cut off score of ≥5 to classify participants as having depressive symptoms. We used high-performance liquid chromatography-electrospray ionization mass spectrometry to measure the concentrations of plasma amino acid-related metabolites, and carried out logistic regression analysis to assess the association between depressive symptoms and plasma amino acid-related metabolites. RESULTS: Of the 119 older adults (mean age 76.3 years) included in the analysis, 22 were classified as having depressive symptoms (depressive group). There were no significant differences in physical and cognitive impairments between participants in the depressive and non-depressive groups. The plasma α-aminobutyric acid (AABA) level was significantly lower in the depressive group than in the non-depressive group (P < 0.001). Logistic regression analysis showed the best-fit model, which included AABA, leucine, threonine, hydroxyl proline and histidine levels (area under the receiver operating characteristic curve 0.8346; 95% confidence interval 0.7365-0.9326). In particular, the plasma AABA level was strongly associated with depressive symptoms. CONCLUSIONS: Plasma AABA level is significantly associated with depression symptoms in older community-dwelling adults in Japan. Thus, plasma AABA might serve as a potential marker of depression in older adults aged ≥65 years. Geriatr Gerontol Int 2019; 19: 254-258.


Assuntos
Aminobutiratos/sangue , Depressão/sangue , Vida Independente , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Depressão/diagnóstico , Feminino , Avaliação Geriátrica , Humanos , Japão , Modelos Logísticos , Masculino
13.
Anticancer Res ; 38(8): 4543-4547, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061220

RESUMO

BACKGROUND/AIM: Small cell lung cancer (SCLC) is still a deadly type of cancer for which there are few effective therapeutic strategies. Development of a new molecule targeting agent is urgently desired. Previously we showed that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) are new therapeutic targets for pancreatic cancer. In the present study, we analyzed whether RBPJ/MAML3 inhibition could also be a new therapeutic strategy for SCLC. MATERIALS AND METHODS: Using silencing of RBPJ/MAML3, proliferation, invasion, migration and chemosensitivity of SBC-5 cells were investigated. RESULTS: RBPJ/MAML3 inhibition reduced Smoothened and HES1 expression, suggesting that RBPJ/MAML3 signaling was through Hedgehog and NOTCH pathways. In the analysis of cell functions, RBPJ/MAML3 inhibition significantly reduced proliferation and invasiveness via reduction of expression of matrix metalloproteinases. On the other hand, RBPJ/MAML3 inhibition also reduced chemosensitivity to cis-diamminedichlo-roplatinum and gemcitabine. CONCLUSION: These results suggest that RBPJ and MAML3 could be new therapeutic targets for SCLC, however, chemosensitivity may be reduced in combinational use with other chemo-therapeutic agents.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fatores de Transcrição/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Transativadores
14.
Anticancer Res ; 37(12): 6649-6654, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29187440

RESUMO

BACKGROUND/AIM: In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. MATERIALS AND METHODS: In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated. RESULTS: Suppression of liprin-α4 reduced proliferation of pancreatic cancer cells both in vitro and in vivo. Inhibition of liprin-α4 also reduced invasiveness through the suppression of endothelial-mesenchymal transition. Stimulation by liprin-α4 was through phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways. CONCLUSION: Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Hipóxia , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Interferência de RNA , Transdução de Sinais , Transplante Heterólogo
15.
Sci Rep ; 7(1): 14485, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-29101348

RESUMO

Fatty liver disease (FLD) increases the risk of diabetes, cardiovascular disease, and steatohepatitis, which leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Thus, the early detection of FLD is necessary. We aimed to find a quantitative and feasible model for discriminating the FLD, based on plasma free amino acid (PFAA) profiles. We constructed models of the relationship between PFAA levels in 2,000 generally healthy Japanese subjects and the diagnosis of FLD by abdominal ultrasound scan by multiple logistic regression analysis with variable selection. The performance of these models for FLD discrimination was validated using an independent data set of 2,160 subjects. The generated PFAA-based model was able to identify FLD patients. The area under the receiver operating characteristic curve for the model was 0.83, which was higher than those of other existing liver function-associated markers ranging from 0.53 to 0.80. The value of the linear discriminant in the model yielded the adjusted odds ratio (with 95% confidence intervals) for a 1 standard deviation increase of 2.63 (2.14-3.25) in the multiple logistic regression analysis with known liver function-associated covariates. Interestingly, the linear discriminant values were significantly associated with the progression of FLD, and patients with nonalcoholic steatohepatitis also exhibited higher values.


Assuntos
Aminoácidos/sangue , Fígado Gorduroso/sangue , Doenças Metabólicas/sangue , Área Sob a Curva , Biomarcadores/sangue , Comorbidade , Análise Discriminante , Fígado Gorduroso/epidemiologia , Feminino , Humanos , Modelos Lineares , Masculino , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco
16.
BMC Geriatr ; 17(1): 239, 2017 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-29037152

RESUMO

BACKGROUND: Decreased circulating tryptophan (Trp) levels are frequently observed in elderly patients with neurodegenerative disease including Alzheimer's disease. Trp may serve as a potential biomarker for monitoring disease risk in elderly people. We aimed to investigate the association between low plasma Trp levels and olfactory function, which is known to predict age-related diseases including dementia in elderly people. METHODS: A total of 144 healthy elderly Japanese community (≥ 65 years old) dwellers from the Health, Aging and Nutritional Improvement study (HANI study) were the subjects of our analysis. Low Trp levels were classified using the lower limit values of the reference interval according to a previous report. Olfactory function was assessed using a card-type test called Open Essence, which includes 12 odour items that are familiar to Japanese people. The elderly subjects with low circulating Trp levels were compared to a control group with normal plasma Trp levels. RESULTS: We conducted the analyses using 144 people aged 65 years or older (mean age 73.7 ± 5.5 years; 36.1% men). The subjects showed normal serum albumin levels (4.4 ± 0.2 g/dL) and no daily living disabilities. Low plasma Trp levels (low Trp group) were found in 11.1% of the study population. The low Trp group showed a significantly lower correct-answer rate for the items india ink, perfume, curry and sweaty smelling socks than control group (P < 0.05). There was also a significant association between low Trp levels and low olfactory ability, after adjusting for age and sex. CONCLUSIONS: Lower plasma Trp levels were associated with a decrease in olfactory function in functionally competent older individuals. Because olfactory dysfunction predicts age-related diseases, low plasma Trp levels may represent a clinical sign of disease risk in elderly people.


Assuntos
Doença de Alzheimer/sangue , Transtornos do Olfato/sangue , Triptofano/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Biomarcadores/sangue , Demência/sangue , Demência/fisiopatologia , Feminino , Humanos , Vida Independente , Japão , Masculino , Transtornos do Olfato/fisiopatologia , Olfato/fisiologia
17.
Anticancer Res ; 37(9): 4987-4992, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28870922

RESUMO

BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. MATERIALS AND METHODS: The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated. RESULTS: TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone. CONCLUSION: These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Apoptose , Proteínas Hedgehog/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , RNA Interferente Pequeno/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Células Tumorais Cultivadas
18.
PLoS One ; 12(9): e0185206, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28934309

RESUMO

BACKGROUND AND PURPOSE: Metabolome analyses have shown that plasma amino acid profiles reflect various pathological conditions, such as cancer and diabetes mellitus. It remains unclear, however, whether plasma amino acid profiles change in patients with sarcopenia. This study therefore aimed to investigate whether sarcopenia-specific changes occur in plasma amino acid profiles. METHODS: A total of 153 community-dwelling and seven institutionalized elderly individuals (56 men, 104 women; mean age, 77.7±7.0 years) were recruited for this cross-sectional analysis. We performed a comprehensive geriatric assessment, which included an evaluation of hand grip strength, gait speed, muscle mass and blood chemistry, including the concentration of 18 amino acids. RESULTS: Twenty-eight of the 160 participants met the criteria for sarcopenia established by the Asian Working Group on Sarcopenia in Older People. Univariate analysis revealed associations between the presence of sarcopenia and a higher plasma concentration of proline and glutamine, lower concentrations of histidine and tryptophan. Multivariable analysis revealed that a higher concentration of proline was the only variable independently associated with sarcopenia. CONCLUSIONS: The plasma concentration of proline may be useful for understanding the underlying pathophysiology of sarcopenia.


Assuntos
Prolina/sangue , População Rural , Sarcopenia/sangue , Idoso , Feminino , Humanos , Vida Independente/estatística & dados numéricos , Japão , Masculino , Análise Multivariada , População Rural/estatística & dados numéricos
20.
Oncotarget ; 8(22): 36211-36224, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28423707

RESUMO

This study aims to demonstrate the clinical and biological significance of Brain derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) signaling in gallbladder cancer (GBC) through a series of in vitro and in vivo experiments. TrkB expression was detected in 63 (91.3%) out of 69 surgically resected primary GBC specimens by immunohistochemistry. TrkB expression in the invasive front correlated with T factor (p=0.0391) and clinical staging (p=0.0391). Overall survival was lower in patients with high TrkB expression in the invasive front than in those with low TrkB expression (p=0.0363). In vitro experiment, we used five TrkB-expressing GBC cell lines with or without K-ras mutation. TrkB-mediated signaling increased proliferation and the invasiveness by inducing epithelial mesenchymal transition, and activating matrix metalloproteinases-2 (MMP-2) and MMP-9. Inhibition of TrkB-mediated signaling also decreased hypoxia-inducible factor-1α, vascular endothelial growth factor A (VEGF-A), VEGF-C, and VEGF-D expression. In vivo experiment, inhibition of TrkB-mediated signaling suppressed tumorigenicity and tumor growth in GBC. These findings demonstrate that TrkB-mediated signaling contributes to the induction of malignant phenotypes (proliferation, invasiveness, angiogenesis, lymphangiogenesis, and tumorigenesis) in GBC, and could be a promising therapeutic target regardless of K-ras mutation status.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neoplasias da Vesícula Biliar/genética , Glicoproteínas de Membrana/genética , Receptor trkB/genética , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estadiamento de Neoplasias , RNA Interferente Pequeno/genética , Receptor trkB/metabolismo , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
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