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1.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34859258

RESUMO

Malignant mesothelioma is a highly aggressive tumor, and an effective strategy for its treatment is not yet available. Long non­coding RNAs (lncRNAs) have been reported to be associated with various biological processes, including the regulation of gene expression of cancer­related pathways. Among various lncRNAs, plasmacytoma variant translocation 1 (PVT1) acts as a tumor promoter in several human cancers, but its mechanism of action has not yet been elucidated. Increased PVT1 expression was identified in ACC­MESO­1, ACC­MESO­4, CRL­5915, and CRL­5946 mesothelioma cell lines. PVT1 expression was investigated in mesothelioma cell lines by reverse transcription­quantitative polymerase chain reaction and its functional analysis by cell proliferation, cell cycle, cell migration, and cell invasion assays, as well as western blot analysis of downstream target genes. Knockdown of PVT1 expression in these cell lines by small interfering RNA transfection resulted in decreased cell proliferation and migration and increased the proportion of cells in the G2/M phase. The results of reverse transcription­quantitative polymerase chain reaction analysis revealed that PVT1 knockdown in mesothelioma cell lines caused the downregulation of Forkhead box M1 (FOXM1) expression, while the results of western blot analysis revealed that this knockdown reduced FOXM1 expression at the protein level. In addition, combined knockdown of PVT1 and FOXM1 decreased the proliferation of mesothelioma cell lines. In conclusion, PVT1 and FOXM1 were involved in the proliferation of cancer cells. Therefore, PVT1­FOXM1 pathways may be considered as candidate targets for the treatment of malignant mesothelioma.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica , Mesotelioma Maligno/genética , RNA Longo não Codificante/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Mesotelioma Maligno/patologia
2.
IJU Case Rep ; 4(6): 397-402, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34755067

RESUMO

Introduction: Metastatic urothelial carcinomas are common in lung, liver, and lymph nodes. We present rare secondary tumor of the prostate metastasized from upper tract urothelial carcinoma. Case presentation: An 87-year-old man was diagnosed as urothelial carcinoma of left upper tract and bladder. Only transurethral resection of bladder tumor was performed as palliative therapy to control hematuria. Thereafter, the tumor of left upper tract showed aggressive progression with multiple metastases involving lymph nodes and bilateral lungs. Finally, autopsy revealed swelling of left kidney due to tumor growth and systemic cancer disseminations involving bilateral lungs and renal hilar lymph nodes. In addition, prostate tumor was found incidentally. Histological examination including immunohistochemistry revealed the prostate tumor as metastatic tumor from urothelial carcinoma of left renal pelvis. Conclusion: We reported rare secondary tumor of the prostate, derived from upper tract urothelial carcinoma. Further consideration would be required to provide better knowledge of the disease.

3.
Intern Med ; 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34544945

RESUMO

This is the first report describing primary pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with the high expression of IgG4. The histological findings were compatible with the diagnostic criteria for MALT lymphoma and IgG4-related respiratory disease (IgG4-RRD). An unfixed sample for Southern blotting was not obtained since computed tomography findings showed multiple lung cysts, which is rare in patients with MALT lymphoma. However, polymerase chain reaction using paraffin sections showed the clonality of the immunoglobulin heavy chain variable region gene rearrangement, confirming a diagnosis of MALT lymphoma. This is an instructive case in which primary pulmonary MALT lymphoma was histologically compatible with IgG4-RRD.

4.
JTO Clin Res Rep ; 2(2): 100126, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34589986

RESUMO

Introduction: The International Association for the Study of Lung Cancer proposed a new grading criteria for invasive adenocarcinoma. However, its utility has not been validated. Methods: Patients who underwent complete resection of lung adenocarcinoma were included in this study. Then, they were divided into the following three groups on the basis of the criteria recently proposed by the International Association for the Study of Lung Cancer: grade 1, lepidic predominant tumor, with less than 20% of high-grade patterns; grade 2, acinar or papillary predominant tumor, with less than 20% of high-grade patterns; and grade 3, any tumor with greater than or equal to 20% of high-grade patterns. Results: Recurrence-free survival (RFS) was significantly different among the proposed grades (p < 0.001). The RFS of patients upgrading from current grade 2 (papillary or acinar predominant tumor) to proposed grade 3 (5-y RFS, 65.2%) was significantly worse than that of patients with proposed grade 2 (77.1%, hazard ratio = 1.882, 95% confidence interval: 1.236-2.866) but not significantly different from that of patients with grade 3 in both the current (micropapillary or solid predominant tumor) and proposed criteria (53.2%, hazard ratio = 0.761, 95% confidence interval: 0.456-1.269). Among patients with pathologic stage 0 or I, RFS was well stratified by the new grading system (p < 0.001) but not among patients with stage II or III (p = 0.334). In the multivariable analysis, the new grading was not a predictive factor of RFS. Conclusions: Although the proposed grading system well stratified RFS in patients with pathologic stage 0 or I lung adenocarcinoma, there is room for improvement.

5.
BMC Pulm Med ; 21(1): 186, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078355

RESUMO

BACKGROUND: Acute exacerbation (AE) of interstitial pneumonia (IP) is the most fatal complication after lung resection for lung cancer. To improve the prognosis of lung cancer with IP, the risk factors of AE of IP after lung resection should be assessed. S100 calcium-binding protein A4 (S100A4) is a member of the S100 family of proteins and is a known marker of tissue fibrosis. We examined the usefulness of S100A4 in predicting AE of IP after lung resection for lung cancer. METHODS: This study included 162 patients with IP findings on preoperative high-resolution computed tomography scan who underwent curative-intent lung resection for primary lung cancer between April 2007 and March 2019. Serum samples were collected preoperatively. Resected lung tissue from 76 patients exhibited usual IP (UIP) pattern in resected lung were performed immunohistochemistry (IHC). Relationship between S100A4 and the incidence of AE of IP and short-term mortality was analyzed. RESULTS: The receiver operating characteristic area under the curve for serum S100A4 to predict postoperative AE of IP was 0.871 (95% confidence interval [CI], 0.799-0.943; P < 0.001), with a sensitivity of 93.8% and a specificity of 75.3% at the cutoff value of 17.13 ng/mL. Multivariable analysis revealed that a high serum S100A4 level (> 17.13 ng/mL) was a significant risk factor for AE of IP (odds ratio, 42.28; 95% CI, 3.98-449.29; P = 0.002). A 1-year overall survival (OS) was significantly shorter in patients with high serum levels of S100A4 (75.3%) than in those with low serum levels (92.3%; P = 0.003). IHC staining revealed that fibroblasts, lymphocytes, and macrophages expressed S100A4 in the UIP area, and the stroma and fibrosis in the primary tumor expressed S100A4, whereas tumor cells did not. CONCLUSIONS: Serum S100A4 had a high predictive value for postoperative AE of IP and short-term mortality after lung resection.


Assuntos
Doenças Pulmonares Intersticiais/sangue , Neoplasias Pulmonares/cirurgia , Pulmão/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Modelos Logísticos , Pulmão/cirurgia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/mortalidade , Neoplasias Pulmonares/complicações , Masculino , Complicações Pós-Operatórias , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Taxa de Sobrevida
6.
Transl Lung Cancer Res ; 10(2): 766-775, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33718020

RESUMO

Background: The histological classification of non-small cell lung cancer (NSCLC) is essential in determining new cancer-specific targeted therapies. However, the accurate typing of poorly differentiated is difficult, particularly for poorly differentiated squamous cell carcinoma and adenocarcinoma of the lung with limited immunohistochemical markers. Thus, novel immunohistochemical markers are required. We assumed the possibility of the immunohistochemical expression of glypican-1 in lung squamous cell carcinoma. Methods: The microarray dataset GSE43580 from Gene Expression Omnibus database were analyzed for confirming the gene expression of glypican-1 in lung squamous cell carcinoma. We immunohistochemically investigated the use of glypican-1 as a novel positive diagnostic marker for lung squamous cell carcinoma. Glypican-1 expression in 63 cases of poorly differentiated lung squamous cell carcinoma and 60 cases of solid predominant lung adenocarcinoma was investigated by immunohistochemistry. Additionally, we compared glypican-1 expression with the expressions of p40, cytokeratin 5/6, thyroid transcription factor-1 (TTF-1), and napsin A. Results: All 63 cases of lung squamous cell carcinoma showed glypican-1 expression. In contrast, only 2 cases of lung adenocarcinoma showed glypican-1 expression. The sensitivity, specificity, and diagnostic accuracy of glypican-1 expression for differentiating lung squamous cell carcinoma from lung adenocarcinoma were 100%, 96.7%, and 98.4%, respectively. These were similar to those of p40 and significantly better than those of CK 5/6. Conclusions: We recommend the use of glypican-1 as an additional positive marker of lung squamous cell carcinoma.

7.
Ann Thorac Surg ; 112(3): 935-943, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33144104

RESUMO

BACKGROUND: This study aimed to investigate the prognosis after segmentectomy as compared with lobectomy for small-sized lung adenocarcinoma with spread through air spaces (STAS). METHODS: This retrospective study included 609 patients who underwent lobectomy or segmentectomy with lymph node dissection for clinical stage IA lung adenocarcinoma between April 2011 and March 2020 at Hiroshima University Hospital. Patient characteristics and prognosis after segmentectomy and lobectomy were investigated. RESULTS: STAS was detected in 293 patients (48.1%). The recurrence-free survival (RFS) rate was significantly worse with STAS-positive adenocarcinoma than with STAS-negative adenocarcinoma both in patients who underwent lobectomy (5-year RFS, 68.2% vs 90.2%; P < .001) and in patients who underwent segmentectomy (5-year RFS, 81.3% vs 93.0%; P = .003). Among the patients with STAS, there was no significant difference in RFS between patients who underwent lobectomy (5-year RFS, 68.2%) and those who underwent segmentectomy (5-year RFS, 81.3%; P = .225). In a multivariable analysis using propensity score to adjust clinical patient characteristics, segmentectomy was not found to be an independent prognostic factor of RFS (hazard ratio 0.732, P = .326) among patients with STAS. Among the patients with STAS, only 1 patient (1%) with insufficient resection margin (0.5 mm) had local recurrence and 1 patient (1%) with invasive mucinous adenocarcinoma had recurrence in preserved lobe after segmentectomy. CONCLUSIONS: Spread through air spaces was a poor prognostic factor in patients with clinical stage IA lung adenocarcinoma. Prognosis after segmentectomy was comparable with that of lobectomy in lung adenocarcinoma with STAS without increasing locoregional recurrence.


Assuntos
Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
8.
Am J Surg Pathol ; 44(9): 1259-1265, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496433

RESUMO

The differential diagnosis of epithelioid mesothelioma from lung adenocarcinoma using immunohistochemistry is improving. However, immunohistochemical markers with high sensitivity and specificity have yet to be identified. In this study, we investigated the utility of sex-determining region Y box 6 (SOX6) as a novel immunohistochemical marker, identified by analyzing previous gene expression data. Immunohistochemically, SOX6 expression was present in 53 of 54 (98%) cases of epithelioid mesothelioma, compared with its expression in only 5 of 69 (7%) cases of lung adenocarcinoma. The sensitivity and specificity of SOX6 expression for differentiating epithelioid mesothelioma and lung adenocarcinoma were 98% and 93%, respectively. SOX6 expression showed similar sensitivity and far better specificity than those of calretinin or podoplanin (D2-40). In addition, SOX6 expression was more sensitive than Wilms' tumor 1 expression. The combination of SOX6 with other markers showed comparable or better sensitivity and specificity relative to other combinations. In particular, the sensitivity of positivity for both SOX6 and calretinin (96%) and the specificity of positivity for both SOX6 and Wilms' tumor 1 (93%) were higher than those of the other combinations. In conclusion, SOX6 is a novel candidate immunohistochemical marker for differentiating epithelioid mesothelioma from lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/química , Biomarcadores Tumorais/análise , Células Epitelioides/química , Imuno-Histoquímica , Neoplasias Pulmonares/química , Mesotelioma/química , Fatores de Transcrição SOXD/análise , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Células Epitelioides/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Transcrição SOXD/genética
9.
Oncol Lett ; 19(6): 4161-4168, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32382354

RESUMO

Malignant pleural mesothelioma is a notorious human malignancy. Despite combination chemotherapy with cisplatin and pemetrexed, the majority of patients with advanced malignant pleural mesothelioma have a poor prognosis. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that regulate various biological processes by binding to the 3'-untranslated region of target gene mRNAs and suppressing their expression. Since abnormal expression patterns of miRNAs are a common feature in human malignancies, a number of them have been researched as potential therapeutic targets. Our previous study demonstrated that microRNA-18a (miR-18a) is upregulated in mesothelioma cell lines compared with in non-neoplastic mesothelial tissues, but its function remains unclear. In the present study, miRNA inhibitor was transfected into mesothelioma cell lines and then analyzed various cellular functions. Mesothelioma cells transfected with the miR-18a inhibitor exhibited lower proliferation and migration rates compared with cells transfected with a negative control inhibitor in proliferation and wound scratch assays, respectively. Additionally, the present study revealed that downregulation of miR-18a increased mesothelioma cell apoptosis. In a chemosensitivity assay, transfection of the miR-18a inhibitor significantly increased the sensitivity of mesothelioma cells to cisplatin but not to pemetrexed. Therefore, miR-18a may be a potential therapeutic target for mesothelioma resistant to cisplatin.

10.
Clin Drug Investig ; 40(6): 567-573, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32314297

RESUMO

BACKGROUND: Factor-Xa inhibitors (FXaIs) are widely used for the treatment of non-valvular atrial fibrillation (NVAF). Although we have previously reported the distribution of the anti-factor Xa activity (AXA) values of three different FXaIs in NVAF patients, the differences in the distribution of AXA values among the different FXaIs in patients with renal impairment (RI) have not been fully elucidated. METHODS: Trough and peak AXA values were measured in 94 patients taking rivaroxaban, 124 patients taking apixaban, and 66 patients taking edoxaban. Of them, we identified 26 patients with moderate RI [creatinine clearance (CrCl) 30-49 mL/min] and 17 patients with severe RI (CrCl 15-29 mL/min) in the rivaroxaban cohort, 37 patients with moderate RI and 17 patients with severe RI in the apixaban cohort, and 21 patients with moderate RI and 9 patients with severe RI in the edoxaban cohort. AXA values were measured using chromogenic AXA assays. Both trough and peak AXA values were compared between patients with moderate RI and those with severe RI in each cohort, and differences in the peak-to-trough ratio among the different drugs were assessed. RESULTS: In the rivaroxaban cohort, the peak AXA value was significantly higher in patients with severe RI than in those with moderate RI. In the apixaban cohort, neither the trough nor peak AXA values significantly differed between patients with moderate RI and those with severe RI. In the edoxaban cohort, the trough AXA value was significantly higher in patients with severe RI than in those with moderate RI, and peak AXA tended to be higher in patients with severe RI. The peak-to-trough ratio of AXA values was significantly lower in patients taking apixaban than in those taking rivaroxaban and edoxaban. CONCLUSION: Among Japanese NVAF patients with RI, the peak or trough AXA values were higher in patients with severe RI than in those with moderate RI when taking rivaroxaban and edoxaban, whereas both the peak and trough AXA values were similar between patients with severe RI and those with moderate RI when taking apixaban. The peak-to-trough ratio of AXA values was the lowest in patients taking apixaban.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Insuficiência Renal/complicações , Rivaroxabana/uso terapêutico , Tiazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Cardiovasc Res ; 116(1): 237-249, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30874788

RESUMO

AIMS: Secreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling. METHODS AND RESULTS: Adipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-ß (TGF-ß) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-ß receptor II (TGF-ßRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-ßRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-ß1 concentration in media from cultured VSMCs and macrophages. CONCLUSION: These data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.


Assuntos
Adipocinas/metabolismo , Proliferação de Células , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular , Lesões do Sistema Vascular/metabolismo , Adipocinas/deficiência , Adipocinas/genética , Animais , Modelos Animais de Doenças , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Artéria Femoral/fisiopatologia , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/patologia , Neointima , Fosforilação , Células RAW 264.7 , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Transdução de Sinais , Proteína Smad2/genética , Proteína Smad2/metabolismo , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia , Lesões do Sistema Vascular/fisiopatologia
12.
Ther Adv Cardiovasc Dis ; 13: 1753944719894509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31854243

RESUMO

BACKGROUND: It is known that once heart failure occurs in older patients with diabetes, the overall prognosis is extremely poor. We investigated whether early initiation of SGLT2 inhibitor therapy after admission was beneficial for diabetic patients requiring inpatient treatment for acute heart failure. METHODS: We retrospectively assessed consecutive patients with comorbid diabetes who were admitted to the Department of Cardiology in Tosei General Hospital for treatment of acute heart failure. Patients were divided into two groups: those who initiated SGLT2 inhibitor therapy (SGLT2 inhibitor group; mean age: 73 ± 9 years) and those who did not receive the inhibitors during hospitalization (conventional treatment group; mean age: 75 ± 10 years). RESULTS: No intergroup differences were observed in the distribution of either the severity or classes of heart failure on admission. Glycosylated hemoglobin levels were significantly higher in the SGLT2 inhibitor group (HbA1c: 8.1% ± 0.8%) than in the conventional treatment group (HbA1c: 7.1% ± 0.8%) (p = 0.003). After admission, patients in both groups recovered equally well, and in almost the same period of time, before discharge. The rate of diuretics use at the time of discharge in the SGLT2 inhibitor group (n = 8, 67%) was significantly lower than that in the conventional treatment group (n = 19, 100%) (p = 0.016). In particular, the dose of loop diuretics in the conventional treatment group was 34 ± 4 mg/day while that in the SGLT2 inhibitor group was significantly lower at 13 ± 5 mg/day (p = 0.008). During hospitalization, the incidence of acute kidney injury was significantly higher in the conventional treatment group (n = 11, 58%) than in the SGLT2 inhibitor group (n = 2, 16%) (p = 0.031). CONCLUSIONS: For the treatment and management of heart failure in patients with diabetes, early initiation of SGLT2 inhibitor therapy appears to be effective.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Doença Aguda , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Glicemia/metabolismo , Comorbidade , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobina A Glicada/metabolismo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Intervalo Livre de Progressão , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo
13.
Histopathology ; 74(4): 545-554, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30329165

RESUMO

AIMS: The process of differential diagnosis between epithelioid mesothelioma and lung adenocarcinoma has been progressing; however, there are no absolute immunohistochemical markers with which to definitively diagnose epithelioid mesothelioma. The aim of this study was to search for a novel negative marker of epithelioid mesothelioma. METHODS AND RESULTS: We immunohistochemically studied the applicability of mucin 21 (MUC21), which was identified in our previous study, as a novel, negative diagnostic marker for epithelioid mesothelioma. Seventy epithelioid mesotheliomas and 70 lung adenocarcinomas were investigated for the expression of MUC21, along with other previously reported markers, by the use of immunohistochemistry. MUC21 was expressed in only two of the 70 (3%) epithelioid mesotheliomas, as compared with 67 of the 70 (96%) lung adenocarcinomas. The sensitivity, specificity and accuracy of negative MUC21 expression for differentiating epithelioid mesothelioma from lung adenocarcinoma were 97%, 96%, and 96%, respectively; these are similar to those of carcinoembryonic antigen and claudin-4, and better than those of thyroid transcription factor-1, napsin-A, and mucin 4. CONCLUSION: MUC21 could be used as an additional, novel, negative immunohistochemical marker to differentiate mesothelioma from lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Glicoproteínas de Membrana/biossíntese , Mesotelioma/diagnóstico , Mucinas/biossíntese , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/análise , Mesotelioma Maligno , Mucinas/análise
14.
Circ Res ; 123(12): 1326-1338, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30566056

RESUMO

RATIONALE: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. OBJECTIVE: We investigated the role of myonectin in myocardial ischemic injury. METHODS AND RESULTS: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. CONCLUSIONS: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.


Assuntos
Citocinas/metabolismo , Proteínas Musculares/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Condicionamento Físico Animal/métodos , Animais , Apoptose , Células Cultivadas , AMP Cíclico/metabolismo , Citocinas/genética , Citocinas/farmacologia , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/farmacologia , Músculo Esquelético/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Esfingosina/análogos & derivados , Esfingosina/metabolismo
15.
Front Oncol ; 8: 446, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30406026

RESUMO

Dysregulation of miR-182 and miR-183 has been implicated in the progression of several human cancers. Our previous study showed that miR-182 and miR-183 are upregulated in malignant mesothelioma. However, their biological functions remain unclear. We performed in-situ hybridization to analyze the expression of miR-182 and miR-183 in human tissues. Functional analysis was performed by treatment of two mesothelioma cell lines (ACC-MESO1 and CRL-5915) with miR-182 and miR-183 inhibitors. RT-PCR and western blot analysis were conducted to analyze the expression of FOXO1, a known target of both miR-182 and miR-183. Mesothelioma cells treated with FOXO1 siRNA and miR-182/183 inhibitors were also analyzed by evaluating cell proliferation and invasion, as well as expression of FOXO1 and its downstream targets. We confirmed miR-182 expression in 25/29 cases and miR-183 expression in 29/29 cases of human mesothelioma tissue by in-situ hybridization. Notably, inhibition of miR-182 or miR-183 reduced cell proliferation, invasion, migration, and adhesion abilities of mesothelioma cells. Surprisingly, transfection with both miR-182 and miR-183 inhibitors showed even more effects on cell progression. Furthermore, FOXO1 was identified as a target of miR-182 and miR-183 in mesothelioma cells. Inhibition of miR-182 and miR-183 reduced cell proliferation ability via upregulation of FOXO1 and its downstream targets, namely, p27. Moreover, inhibition of miR-182 and miR-183 reduced the cell invasion properties of mesothelioma cells. Our findings indicated that miR-182 and miR-183 promote mesothelioma cell progression via downregulation of FOXO1 and p27. Targeting the miR-182/183-FOXO1 axis could serve as a novel treatment against malignant mesothelioma.

16.
Geriatr Gerontol Int ; 18(1): 108-114, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28861952

RESUMO

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long-term use of SGLT2 inhibitors in older patients with diabetes. METHODS: A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016. RESULTS: The mean age of the patients was 73.7 ± 10.0 years. During the follow-up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow-up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment. CONCLUSIONS: In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108-114.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Humanos , Japão , Pessoa de Meia-Idade , Resultado do Tratamento
17.
J Arrhythm ; 33(6): 619-623, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29255511

RESUMO

Background: Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated. Methods: Changes in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI. Results: The average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types. Conclusions: PPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered.

18.
FASEB J ; 30(3): 1065-75, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26578687

RESUMO

Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.


Assuntos
Adipocinas/metabolismo , Coração/fisiopatologia , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/metabolismo , Animais , Apoptose/fisiologia , AMP Cíclico/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Transdução de Sinais/fisiologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo
19.
Cardiovasc Res ; 110(1): 107-17, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26714927

RESUMO

AIMS: Obesity is associated with the development of atherosclerosis. We previously demonstrated that omentin is a circulating adipokine that is downregulated in association with atherosclerotic diseases. Here, we examined the impact of omentin on the development of atherosclerosis with gain-of-function genetic manipulations and dissected its potential mechanism. METHODS AND RESULTS: Apolipoprotein E-deficient (apoE-KO) mice were crossed with transgenic mice expressing the human omentin gene (OMT-Tg) mice in fat tissue to generate apoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg mice exhibited a significant reduction of the atherosclerotic areas in aortic sinus, compared with apoE-KO mice despite similar lipid levels. ApoE-KO/OMT-Tg mice also displayed significant decreases in macrophage accumulation and mRNA expression of proinflammatory mediators including tumour necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 in aorta when compared with apoE-KO mice. Treatment of human monocyte-derived macrophages with a physiological concentration of human omentin protein led to reduction of lipid droplets and cholesteryl ester content. Treatment with human omentin protein also reduced lipopolysaccharide-induced expression of proinflammatory genes in human macrophages. Treatment of human macrophages with omentin promoted the phosphorylation of Akt. Inhibition of Akt signalling abolished the anti-inflammatory actions of omentin in macrophages. CONCLUSION: These data document for the first time that omentin reduces the development of atherosclerosis by reducing inflammatory response of macrophages through the Akt-dependent mechanisms.


Assuntos
Aterosclerose/metabolismo , Citocinas/metabolismo , Lectinas/metabolismo , Macrófagos/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Células Cultivadas , Modelos Animais de Doenças , Proteínas Ligadas por GPI/metabolismo , Humanos , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator de Necrose Tumoral alfa/metabolismo
20.
PLoS One ; 10(9): e0137493, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26348726

RESUMO

Obesity-related complications are associated with the development of age-related hearing impairment. ß-Conglycinin (ß-CG), one of the main storage proteins in soy, offers multiple health benefits, including anti-obesity and anti-atherosclerotic effects. Here, to elucidate the potential therapeutic application of ß-CG, we investigated the effect of ß-CG on age-related hearing impairment. Male wild-type mice (age 6 months) were randomly divided into ß-CG-fed and control groups. Six months later, the body weight was significantly lower in ß-CG-fed mice than in the controls. Consumption of ß-CG rescued the hearing impairment observed in control mice. Cochlear blood flow also increased in ß-CG-fed mice, as did the expression of eNOS in the stria vascularis (SV), which protects vasculature. ß-CG consumption also ameliorated oxidative status as assessed by 4-HNE staining. In the SV, lipofuscin granules of marginal cells and vacuolar degeneration of microvascular pericytes were decreased in ß-CG-fed mice, as shown by transmission electron microscopy. ß-CG consumption prevented loss of spiral ganglion cells and reduced the frequencies of lipofuscin granules, nuclear invaginations, and myelin vacuolation. Our observations indicate that ß-CG ameliorates age-related hearing impairment by preserving cochlear blood flow and suppressing oxidative stress.


Assuntos
Antígenos de Plantas/administração & dosagem , Globulinas/administração & dosagem , Obesidade/complicações , Presbiacusia/tratamento farmacológico , Proteínas de Armazenamento de Sementes/administração & dosagem , Proteínas de Soja/administração & dosagem , Soja/química , Animais , Antígenos de Plantas/química , Peso Corporal , Cóclea/irrigação sanguínea , Cóclea/efeitos dos fármacos , Cóclea/patologia , Modelos Animais de Doenças , Globulinas/química , Humanos , Camundongos , Obesidade/tratamento farmacológico , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Presbiacusia/patologia , Proteínas de Armazenamento de Sementes/química , Proteínas de Soja/química
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