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1.
Cancer Immunol Immunother ; 72(10): 3175-3189, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37382632

RESUMO

Dendritic cell (DC)-based immunotherapy has been applied to glioblastoma (GBM); however, biomarkers informing response remain poorly understood. We conducted a phase I/IIa clinical trial investigating tumor-fused DC (TFDC) immunotherapy following temozolomide-based chemoradiotherapy in patients with newly diagnosed GBM and determined prognostic factors in patients receiving TFDC immunotherapy. Twenty-eight adult patients with GBM isocitrate dehydrogenase (IDH) wild-type (IDH-WT) were enrolled; 127 TFDC vaccine injections (4.5 ± 2.6 times/patient) were administered. Patients with GBM IDH-WT had a respectable 5-year survival rate (24%), verifying the clinical activity of TFDC immunotherapy, particularly against O6-methylguanine-DNA methyltransferase (MGMT) unmethylated GBM (5-year survival rate: 33%). To identify novel factors influencing overall survival (OS) in GBM IDH-WT treated with TFDC immunotherapy, clinical parameters were assessed and comprehensive molecular profiling involving transcriptome and exome analyses was performed. MGMT promoter methylation status, extent of tumor resection, and vaccine parameters (administration frequency, DC and tumor cell numbers, and fusion ratio) were not associated with survival following TFDC immunotherapy. Old age and pre- and post-operative Karnofsky performance status were significantly correlated with OS. Low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were correlated with better prognosis. We validated the activity of TFDC immunotherapy against GBM IDH-WT, including chemoresistant, MGMT promoter unmethylated cases. The identification of molecular biomarkers predictive of TFDC immunotherapy efficacy in GBM IDH-WT will facilitate the design of and patient stratification in a phase-3 trial to maximize treatment benefits.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Glioblastoma/terapia , Glioblastoma/tratamento farmacológico , Prognóstico , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/uso terapêutico , Células Dendríticas , Imunoterapia Ativa , Metilação de DNA , NF-kappa B/genética
2.
Pediatr Surg Int ; 39(1): 264, 2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37672099

RESUMO

PURPOSE: Tunneled central venous catheters (TCVs) are commonly used for pediatric chemotherapy. Recently, peripherally inserted central catheters (PICCs) have been used instead. Although PICC has the advantages of simpler insertion and fewer severe complications, there is little information on the efficacy of PICC compared to TCV in pediatric chemotherapy. METHODS: Patients, aged younger than 18 years, with primary malignancy who received chemotherapy with PICC or TCV at our institution from December 2007 to August 2022 were included in the study. We retrospectively compared PICC and TCV using medical records. RESULTS: Within the observation period, 133 catheters (73 PICCs and 60 TCVs) were inserted. The median indwelling time was 99 days for PICCs and 182 days for TCVs, with TCVs being significantly longer (p < 0.001). There were no significant differences in the incidence of complications, such as infections, thrombosis, obstruction, or mechanical accidents. Comparing patients treated with PICC (PICC group) versus those with TCV (TCV group), the time from diagnosis to insertion was significantly shorter in the PICC group (p < 0.001). In the PICC group, none of the patients required general anesthesia, and chemotherapy was completed with PICC only. CONCLUSION: PICC can be an alternative to TCV in pediatric chemotherapy.


Assuntos
Cateteres Venosos Centrais , Humanos , Criança , Idoso , Estudos Retrospectivos , Anestesia Geral , Prontuários Médicos , Pacientes
3.
Prostate ; 79(9): 1043-1052, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30998834

RESUMO

BACKGROUND: Androgen receptor variants (AR-vs), especially AR-v7 and AR-v 5, 6, and 7 exon-skipped (AR-v567es), are reportedly key players in the development of castration-resistant prostate cancer (CRPC). We previously established a mouse xenograft model (JDCaP) from a metastatic skin lesion from a Japanese patient with CRPC and that was revealed to exhibit androgen sensitivity. In the present study, we established multiple castration-resistant xenograft models from JDCaP mice to investigate the biological features of CRPC. METHODS: Tissue from JDCaP mice was transplanted into male and female nude mice, and after serial passaging, castration-resistant sublines (JDCaP-CR2M and JDCaP-CR4M in male mice, JDCaP-CR2F and JDCaP-CR4F in female mice) were established. We investigated anti-androgen and testosterone sensitivity and the messenger RNA expression pattern of full-length AR and AR-vs. In addition, we compared AR protein levels of patient specimens among primary, local-recurrent, and two skin-metastatic tumors. RESULTS: All JDCaP-CR sublines showed continuous growth following the administration of bicalutamide, although the effects of testosterone varied among sublines. Parental JDCaP and JDCaP-CR2M, JDCaP-CR4M, and JDCaP-CR4F sublines expressed AR-v7, whereas JDCaP-CR2F exhibited elevated AR-v567es expression resulting from genomic deletion, which was confirmed by DNA sequencing. Moreover, we confirmed AR-v7 expression in the tumor of the original patient after androgen-deprivation therapy. CONCLUSIONS: Each JDCaP-CR subline showed different AR-v-expression patterns, with JDCaP-CR2F expressing AR-v567es due to genomic deletion. Our results indicated that AR-vs emerged after androgen-deprivation therapy and appeared essential for acquisition of castration resistance.


Assuntos
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Animais , Antineoplásicos/farmacologia , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nitrilas/farmacologia , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Testosterona/farmacologia , Compostos de Tosil/farmacologia
4.
Prostate ; 79(1): 3-8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30051483

RESUMO

BACKGROUND: TMPRSS2:ERG fusion is the most common genetic event in prostate cancer (PCa). However, its association with prognosis is controversial. Overexpression of serine protease inhibitor Kazal-type 1 (SPINK1) was almost exclusively defined in ERG-negative PCa in most studies. This study aimed to determine the association between ERG and SPINK1 expression and the biological aggressiveness of PCa by analyzing their expression in incidental and metastatic cohorts. METHODS: A total of 143 cystoprostatectomy specimens of invasive bladder cancer and 98 biopsy specimens from de novo metastatic PCa were analyzed. The prostate gland of cystoprostatectomy specimens was fixed and sliced in step sections. Immunohistochemistry of ERG and SPINK1 was conducted, and the results were correlated with the clinicopathological characteristics of the patients. RESULTS: The overall prevalence of incidental cancer was 32.2% (46/143). The frequencies of both ERG and SPINK1 expression were not significantly different between incidental and metastatic cohorts (15.2% and 14.3%; P = 1.00, and 6.5% and 12.2%; P = 0.38, respectively). In the metastatic cohort, any pre-treatment factors were not significantly associated with the frequencies of ERG and SPINK1 expression. However, SPINK1 expression was significantly associated with a shorter time to castration-resistant PCa (CRPC) (P = 0.048). Meanwhile, overall survival was not significantly associated with the expression status of ERG and SPINK1 (P = 0.71). CONCLUSIONS: ERG and SPINK1 expression may not have significant influence on the metastatic behavior of PCa. SPINK1 expression was significantly associated with a shorter time to CRPC in metastatic PCa. The expression profile of ERG and SPINK1 may be a useful predictor for effect of androgen deprivation therapy in patients with metastatic castration-sensitive PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica , Achados Incidentais , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Inibidor da Tripsina Pancreática de Kazal/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Estudos de Coortes , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/epidemiologia , Regulador Transcricional ERG/biossíntese , Regulador Transcricional ERG/genética , Inibidor da Tripsina Pancreática de Kazal/genética
5.
Pancreatology ; 19(1): 88-96, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30416041

RESUMO

BACKGROUND/OBJECTIVES: Pancreatic cancer consists of various subpopulations of cells, some of which have aggressive proliferative properties. The molecules responsible for the aggressive proliferation of pancreatic cancer may become molecular targets for the therapies against pancreatic cancer. METHODS: From a human pancreatic cancer cell line, MIA PaCa-2, MIA PaCa-2-A cells with an epithelial morphology and MIA PaCa-2-R cells with a non-epithelial morphology were clonogenically isolated by the limiting dilution method. Gene expression of these subpopulations was analyzed by DNA microarray. Gene knockdown was performed using siRNA. RESULTS: Although the MIA PaCa-2-A and MIA PaCa-2-R cells displayed the same DNA short tandem repeat (STR) pattern identical to that of the parental MIA PaCa-2 cells, the MIA PaCa-2-A cells were more proliferative than the MIA PaCa-2-R cells both in culture and in tumor xenografts generated in immunodeficient mice. Furthermore, the MIA PaCa-2-A cells were more resistant to gemcitabine than the MIA PaCa-2-R cells. DNA microarray analysis revealed a high expression of claudin (CLDN) 7 in the MIA PaCa-2-A cells, as opposed to a low expression in the MIA PaCa-2-R cells. The knockdown of CLDN7 in the MIA PaCa-2-A cells induced a marked inhibition of proliferation. The MIA PaCa-2-A cells in which CLDN7 was knocked down exhibited a decreased expression of phosphorylated extracellular signal-regulated kinase (p-Erk)1/2 and G1 cell cycle arrest. CONCLUSIONS: CLDN7 may be expressed in the rapidly proliferating and dominant cell population in human pancreatic cancer tissues and may be a novel molecular target for the treatment of pancreatic cancer.


Assuntos
Claudinas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Claudinas/genética , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Neoplasias Experimentais , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno
6.
Nihon Hinyokika Gakkai Zasshi ; 108(2): 87-95, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-29669982

RESUMO

(Objective) To determine whether the plakin family proteins periplakin, desmoplakin, plectin, and envoplakin could be markers of urothelial carcinoma of the upper urinary tract. (Materials and methods) Fifty-seven surgical specimens were obtained from patients with urothelial carcinoma of the upper urinary tract, who were admitted to the Jikei University Hospital between April 2000 and December 2005. The expression of plakin family proteins in cancerous and normal tissues was investigated using immunohistochemistry, and its association with clinicopathological parameters was analyzed. (Results) The expression of periplakin, envoplakin, and desmoplakin was significantly lower in cancerous tissue than in normal urothelium (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). Strong desmoplakin expression in cancerous tissue was significantly associated with poor cancer-specific survival and overall survival (P = 0.023 and P = 0.034, respectively, compared with cancerous tissue with slight or less desmoplakin expression). Furthermore, strong plectin expression was significantly associated with poor metastasis-free survival (P = 0.034, compared with cancerous tissue with slight or less plectin expression). (Conclusion) Plakin family, particularly desmoplakin was suggested to be a prognostic marker of urothelial carcinoma of the upper urinary tract.

7.
Cancer Sci ; 107(5): 682-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26920337

RESUMO

Although rituximab, a chimeric monoclonal antibody that specifically binds to CD20, has significantly improved the prognosis for diffuse large B cell lymphoma (DLBCL), one-third of DLBCL patients demonstrate resistance to rituximab or relapse after rituximab treatment. Thus, a novel approach to rituximab-based treatment is likely to be required to improve the efficacy of DLBCL treatment. As complement dependent cytotoxicity (CDC) is a key mechanism mediating rituximab's tumoricidal activity, rituximab binding to CD20 on tumor cells is a critical factor for effective rituximab-based treatments against DLBCL. We found that gemcitabine (GEM), but not lenalidomide (LEN) or azacitidine (AZA), can upregulate CD20 expression in TK and KML-1 cells, two human DLBCL cell lines. Treatment of TK and KML-1 cells with GEM enhanced CD20 expression at both the mRNA and protein levels. CD20 upregulation by GEM treatment was accompanied by increased rituximab binding to CD20. In TK cells, GEM treatment synergistically increased rituximab-mediated CDC activity in a dose-dependent manner. In KML cells, GEM treatment also induced upregulation of complement regulatory proteins, possibly leading to resistance to CDC. Treatment with LEN, a drug that did not upregulate CD20, did not enhance rituximab-mediated CDC activity. GEM treatment activated nuclear factor-kappa B (NF-kB) signaling in these cells. Furthermore, a specific inhibitor to NF-kB suppressed GEM-induced CD20 upregulation, indicating that GEM-induced NF-kB activation is closely associated with CD20 upregulation. These results suggest that when used in combination, GEM might enhance the antitumor efficacy of rituximab against DLBCL due to its unique ability to upregulate CD20.


Assuntos
Antígenos CD20/metabolismo , Proteínas do Sistema Complemento/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Rituximab/farmacologia , Regulação para Cima/efeitos dos fármacos , Azacitidina/farmacologia , Linhagem Celular Tumoral , Proteínas do Sistema Complemento/imunologia , Desoxicitidina/farmacologia , Humanos , Lenalidomida , Linfoma de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , NF-kappa B/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Gencitabina
8.
BMC Cancer ; 15: 726, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26475267

RESUMO

BACKGROUND: Although pancreatic ductal adenocarcinomas (PDAs) widely express HER2, the expression level is generally low. If HER2 expression in PDA cells could be enhanced by treatment with a given agent, then combination therapy with that agent and trastuzumab emtansine (T-DM1), a chemotherapeutic agent that is a conjugate of trastuzumab, might lead to significant antitumor effects against PDA. METHODS: Cell proliferation was examined by spectrophotometry. HER2 expression was examined by flow cytometry, immunoblot and quantitative reverse transcription polymerase chain reaction. T-DM1 binding to cells was examined by flow cytometry and enzyme-linked immunosorbent assay. RESULTS: Out of 5 tested human PDA cell lines, including MIA PaCa-2, three showed increases in HER2 expression after gemcitabine (GEM) treatment. The binding of T-DM1 to GEM-treated MIA PaCa-2 cells was higher than to untreated MIA PaCa-2 cells. Treatment with GEM and T-DM1 showed synergic cytotoxic effects on MIA PaCa-2 cells in vitro. Cells in the G2M phase of the cell cycle were retained after GEM treatment and showed higher levels of HER2 expression, possibly contributing to the synergic effect of GEM and T-DM1. CONCLUSIONS: Combined treatment with GEM and T-DM1 might confer a potent therapeutic modality against PDA as a result of GEM-mediated HER2 up-regulation.


Assuntos
Adenocarcinoma/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Receptor ErbB-2/biossíntese , Adenocarcinoma/genética , Adenocarcinoma/patologia , Ado-Trastuzumab Emtansina , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Maitansina/administração & dosagem , Maitansina/análogos & derivados , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Receptor ErbB-2/genética , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
9.
Cancer Immunol Immunother ; 63(5): 459-68, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24627093

RESUMO

Vaccination of BALB/c mice with dendritic cells (DCs) loaded with the lysate of induced vascular progenitor (iVP) cells derived from murine-induced pluripotent stem (iPS) cells significantly suppressed the tumor of CMS-4 fibrosarcomas and prolonged the survival of CMS-4-inoculated mice. This prophylactic antitumor activity was more potent than that of immunization with DCs loaded with iPS cells or CMS-4 tumor cells. Tumors developed slowly in mice vaccinated with DCs loaded with iVP cells (DC/iVP) and exhibited a limited vascular bed. Immunohistochemistry and a tomato-lectin perfusion study demonstrated that the tumors that developed in the iVP-immunized mice showed a marked decrease in tumor vasculature. Immunization with DC/iVP induced a potent suppressive effect on vascular-rich CMS-4 tumors, a weaker effect on BNL tumors with moderate vasculature, and nearly no effect on C26 tumors with poor vasculature. Treatment of DC/iVP-immunized mice with a monoclonal antibody against CD4 or CD8, but not anti-asialo GM1, inhibited the antitumor activity. CD8(+) T cells from DC/iVP-vaccinated mice showed significant cytotoxic activity against murine endothelial cells and CMS-4 cells, whereas CD8(+) T cells from DC/iPS-vaccinated mice did not. DNA microarray analysis showed that the products of 29 vasculature-associated genes shared between genes upregulated by differentiation from iPS cells into iVP cells and genes shared by iVP cells and isolated Flk-1(+) vascular cells in CMS-4 tumor tissue might be possible targets in the immune response. These results suggest that iVP cells from iPS cells could be used as a cancer vaccine targeting tumor vascular cells and tumor cells.


Assuntos
Vacinas Anticâncer/farmacologia , Células Dendríticas/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Neoplasias Experimentais/terapia , Vacinação/métodos , Animais , Fibrossarcoma/terapia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia
10.
Surg Case Rep ; 10(1): 133, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38806890

RESUMO

BACKGROUND: Biliary obstruction due to compression by a B-cell solid tumor occurs rarely. A few reports have described biliary reconstruction surgery for obstructive jaundice caused by Burkitt's lymphoma. However, there are no detailed reports on pediatric cases. We report a pediatric case of obstructive jaundice due to malignant lymphoma treated with biliary reconstruction surgery. CASE PRESENTATION: A 5-year-old girl presented to our hospital with a massive abdominal tumor that caused biliary stricture. Chemotherapy was initiated after an open tumor biopsy. However, endoscopic biliary stent placement was performed owing to elevated bilirubin levels. We treated the patient with chemotherapy for 9 months while endoscopically replacing the biliary stent every few months. She achieved complete tumor remission. However, sclerotic lymph nodes were persistent on the dorsal side of the cholecystic duct junction, and biliary stricture at the same site had changed to stent-dependent biliary obstruction. Therefore, we performed choledochojejunostomy and retrocolic Roux-en-Y reconstruction 15 months after initial admission. There were no postoperative complications or tumor recurrences, and the bilirubin level remained low. Histopathologically, the resected bile duct wall was fibrotic and thick, and the bile duct lumen narrowed. CONCLUSIONS: Biliary reconstruction is effective to achieve long-term biliary patency in pediatric patients with stent-dependent biliary obstruction due to malignant lymphoma. However, the decision on when to stop biliary stent replacement and proceed to biliary reconstruction surgery is a matter of debate. Further case studies are required to address this issue.

11.
Pathol Int ; 62(11): 742-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23121605

RESUMO

To investigate and characterize ERG oncoprotein expression in Japanese patients with prostate cancer (PCa), we evaluated 92 index tumors from Japanese patients who had undergone radical prostatectomy for PCa, using an antibody-based detection method to determine ERG expression. Expression status was compared with clinicopathological findings including patient age, body mass index and preoperative prostate-specific antigen (PSA) levels, specimen Gleason score, pathological stage, positive surgical margin, size of index tumor, prostatic volume, zonal origin of index tumor and biochemical failure. Overall, ERG protein was expressed in 16.3% (15/92) of the index tumors, but not in benign glands. Younger patient age, lower Gleason score and negative surgical margins were found to be independently associated with its expression in the multivariate analysis (P= 0.015, 0.003 and 0.038, respectively). ERG expression was not associated with biochemical failure. Though not statistically significant, ERG expression was more frequently observed in peripheral zone than in transition zone cancers (28.2% vs 10%, respectively). In conclusion, ERG protein was less frequently expressed in this Japanese PCa cohort compared with Western reports. ERG expression was associated with a less aggressive tumor phenotype, and its biological significance needs to be further investigated.


Assuntos
Adenocarcinoma/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Transativadores/metabolismo , Adenocarcinoma/diagnóstico , Fatores Etários , Idoso , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Próstata/metabolismo , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/diagnóstico , Taxa de Sobrevida , Análise Serial de Tecidos , Regulador Transcricional ERG
12.
Front Oncol ; 12: 898614, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35785200

RESUMO

Background: Previously, we reported that bevacizumab (Bev) produces histological and neuroradiographic alterations including changes in tumor oxygenation, induction of an immunosupportive tumor microenvironment, and inhibition of stemness. To confirm how those effects vary during Bev therapy, paired samples from the same patients with newly diagnosed glioblastoma (GBM) who received preoperative neoadjuvant Bev (neoBev) were investigated with immunohistochemistry before and after recurrence. Methods: Eighteen samples from nine patients with newly diagnosed GBM who received preoperative neoBev followed by surgery and chemoradiotherapy and then autopsy or salvage surgery after recurrence were investigated. The expression of carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1 alpha (HIF-1α), nestin, and Forkhead box M1 (FOXM1) was evaluated with immunohistochemistry.For comparison between neoBev and recurrent tumors, we divided the present cohort into two groups based on neuroradiographic response: good and poor responders (GR and PR, respectively) to Bev were defined by the tumor regression rate on T1-weighted images with gadolinium enhancement (T1Gd) and fluid-attenuated inversion recovery images. Patterns of recurrence after Bev therapy were classified as cT1 flare-up and T2-diffuse/T2-circumscribed. Furthermore, we explored the possibility of utilizing FOXM1 as a biomarker of survival in this cohort. Results: A characteristic "pseudo-papillary"-like structure containing round-shaped tumor cells clustered adjacent to blood vessels surrounded by spindle-shaped tumor cells was seen only in recurrent tumors. Tumor cells at the outer part of the "pseudo-papillary" structure were CA9-positive (CA9+)/HIF-1α+, whereas cells at the inner part of this structure were CA9-/HIF-1α+ and nestin+/FOXM1+. CA9 and HIF-1α expression was lower in T1Gd-GR and decreased in the "T2-circumscribed/T2-diffuse" pattern compared with the "T1 flare-up" pattern, suggesting that tumor oxygenation was frequently observed in T1Gd-GR in initial tumors and in the "T2-circumscribed/T2-diffuse" pattern in recurrent tumors. FOXM1 low-expression tumors tended to have a better prognosis than that of FOXM1 high-expression tumors. Conclusion: A "pseudo-papillary" structure was seen in recurrent GBM after anti-vascular endothelial growth factor therapy. Bev may contribute to tumor oxygenation, leading to inhibition of stemness and correlation with a neuroimaging response during Bev therapy. FOXM1 may play a role as a biomarker of survival during Bev therapy.

13.
Asian J Endosc Surg ; 14(3): 594-597, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33305500

RESUMO

Acute appendicitis during pregnancy may lead to increased maternal and fetal risks. Laparoscopic appendectomy is commonly performed during pregnancy. Compared with open appendectomy in pregnant women, laparoscopic appendectomy has shown non-inferior safety for pregnancy outcomes and superior safety for surgical outcomes. Over the last few decades, the occurrence of twin pregnancy has been increasing. Performing an operation on a patient with a twin pregnancy is more difficult than with a singleton pregnancy. Only a few operations of this kind have been reported. Here, we present a case of a 20-week twin pregnant woman who presented with acute appendicitis. Laparoscopic appendectomy was performed, and no maternal complications occurred. This report contributes to discussions on the safety of the laparoscopic approach for appendicitis during twin pregnancies.


Assuntos
Apendicectomia/métodos , Apendicite , Laparoscopia , Complicações na Gravidez , Gravidez de Gêmeos , Adulto , Apendicite/cirurgia , Feminino , Humanos , Gravidez , Complicações na Gravidez/cirurgia , Segundo Trimestre da Gravidez , Estudos Retrospectivos
14.
Surg Case Rep ; 7(1): 126, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34014419

RESUMO

BACKGROUND: Traumatic esophageal injury leads to severe complications such as mediastinitis, pyothorax, and tracheoesophageal fistula. Although prompt diagnosis and treatment are required, there are no established protocols to guide diagnosis or treatment. In particular, thoracic esophageal injury tends to be diagnosed later than cervical esophageal injury because it has few specific symptoms. We report a case of thoracic esophageal injury caused by a cervical stab wound; the patient was stabbed with a sharp blade. CASE PRESENTATION: A 74-year-old woman was attacked with a knife while sleeping at home. The patient was taken to the emergency room with an injury localized to the left section of her neck. She was suspected of a left jugular vein and recurrent laryngeal nerve injury from cervical hematoma and hoarseness. On the day following the injury, computed tomography revealed a thoracic esophageal injury. Emergency surgery was performed for an esophageal perforation and mediastinal abscesses. Although delayed diagnosis resulted in suture failure, the patient was able to resume oral intake of food a month later following enteral feeding with a gastrostomy. Esophageal injuries due to sharp trauma are rare, and most are cervical esophageal injuries. There are very few reports on thoracic esophageal injuries. CONCLUSIONS: The possibility of thoracic esophageal injury should always be considered when dealing with neck stab wounds, particularly those caused by an attack.

15.
Am J Pathol ; 174(6): 2044-50, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19435788

RESUMO

Using high molecular-weight proteomic analysis, we previously showed that Staphylococcal nuclease domain-containing protein 1 (SND1) is highly expressed in recurrent androgen-insensitive prostate cancer tissues. SND1 is a component of the RNA-induced splicing complex that mediates RNA interference, leading to degradation of specific mRNAs. The objective of this study was to further characterize SND1 expression and to investigate its biological potential in prostate cancer. Radical prostatectomy specimens were obtained from 62 prostate cancer patients. SND1 immunohistochemical staining patterns were evaluated using an in-house polyclonal antibody. We confirmed SND1 mRNA expression in prostate cancer cells using an in situ hybridization technique. To determine the importance of SND1 mRNA, we knocked down SND1 in vitro with small interfering RNA and observed a significant decrease in cell growth. SND1 was expressed in 60 of 62 prostate cancers (97%), appearing in the cytoplasm as small, granular structures; it was also present at high levels in prostate cancer specimens, while in hyperplasia specimens and normal epithelium, it was weakly or negatively expressed. SND1 expression intensity increased with increasing grade and aggressiveness of the cancer. As SND1 mRNA was overexpressed in cancer cells, the growth of these cells was suppressed following SND1 knockdown in vitro, thus representing a promising prostate cancer biomarker and therapeutic target.


Assuntos
Biomarcadores Tumorais/análise , Proteínas Nucleares/biossíntese , Neoplasias da Próstata/metabolismo , Idoso , Endonucleases , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Hibridização In Situ , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , RNA Interferente Pequeno , Racemases e Epimerases/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Int Immunopharmacol ; 54: 39-45, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29100036

RESUMO

Programmed cell death ligand-1 (PD-L1) plays a pivotal role in the suppression of antitumour immunity by binding to programmed cell death-1 (PD-1) on tumouricidal cytotoxic T lymphocytes (CTLs), rendering them inactive. As blockade of PD-1/PD-L1 interaction by the monoclonal antibodies induced effective T cell-mediated antitumour response, suppression of PD-L1 expression in tumour cells by the chemical agent might contribute to treatment against malignant tumours. Nafamostat mesilate (NM), a serine protease inhibitor that is frequently used in the clinic, potently suppressed interferon-gamma (IFN-gamma)-induced up-regulation of PD-L1 in cultured human lung cancer cells (HLC-1) at both the messenger RNA (mRNA) and protein levels. Interestingly, suppression of IFN-gamma-induced up-regulation of human leukocyte antigen (HLA)-ABC by NM was limited, suggesting that NM did not block CTL responses to tumour cells. NM treatment did not affect the activation status of signal transducer and activator of transcription (STAT) 1 or the induction of interferon regulatory factor (IRF)-1 expression in IFN-gamma-treated HLC-1 cells. Although NM treatment promoted the phosphorylation of extracellular signal-regulated kinases (Erk) 1/2, an Erk inhibitor, U0126, could not reverse the suppression of PD-L1 up-regulation by IFN-gamma. Suppression of IFN-gamma-induced up-regulation of PD-L1 by NM was not associated with the inhibition of nuclear factor kappa B (NF-kB) or protease-activated receptor (PAR)-1 pathway. Besides HLC-1 cells, NM suppressed IFN-gamma-induced PD-L1 up-regulation in three human pancreatic cancer cell lines. NM could potentiate the antitumour effect of cancer vaccines or immune checkpoint inhibitors by preventing IFN-gamma-induced PD-L1 up-regulation and blocking immune checkpoint suppression.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Guanidinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Serina Proteinase/farmacologia , Antígeno B7-H1/genética , Benzamidinas , Vacinas Anticâncer , Linhagem Celular Tumoral , Antígenos HLA/metabolismo , Humanos , Terapia de Imunossupressão , Interferon gama/metabolismo , Regulação para Cima
17.
PLoS One ; 13(7): e0200499, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30063760

RESUMO

7-Ketocholesterol is a major dietary cholesterol oxidation product found in high concentrations in atherosclerotic plaques, which contribute to the development of atherosclerosis. This study aimed to investigate the effects of 7-ketocholesterol on endothelial inflammation, as well as the underlying mechanisms. Pretreatment of human umbilical vein endothelial cells (HUVEC) with 7-ketocholesterol significantly enhanced the total interactions between human monocytic cells (THP-1 cell line) and TNFα-activated HUVECs under physiological flow conditions, compared to pretreatment with cholesterol (TNFα+50 µM cholesterol: 13.1 ± 0.54 cells/CPF, TNFα+50 µM 7-ketocholesterol: 18.9 ± 0.35 cells/CPF, p < 0.01). 7-Ketocholesterol enhanced the expression of E-selectin, ICAM-1, and VCAM-1 proteins. It also activated p38 mitogen-activated protein kinase (MAPK), and treatment with a p38 MAPK inhibitor inhibited both E-selectin expression via ATF-2 activation and 7-ketocholesterol-induced THP-1 adhesion to HUVECs. These findings suggest that 7-ketocholesterol enhances leukocyte-endothelial interactions by upregulating the expression of adhesion molecules, presumably via the p38 MAPK-dependent pathway.


Assuntos
Adesão Celular , Células Endoteliais/citologia , Cetocolesteróis/farmacologia , Leucócitos/citologia , Sistema de Sinalização das MAP Quinases , Selectina E/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/citologia , Oxisteróis/química , Fatores de Risco , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
J Microbiol Methods ; 145: 93-97, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29288674

RESUMO

Cellular glycogen levels reflect the activity of RpoS, an important stress-inducible bacterial sigma factor known to regulate several stress-resistance related genes, such as katE, encoding hydroperoxidase II (HPII), and the glg genes, encoding glycogen synthesis enzymes, in Escherichia coli. In this study, a straightforward assay for measuring glycogen levels and RpoS activity was developed combining the ease and simplicity of qualitative approaches. The assay reagent was a 2% iodine solution (2% iodine/1M NaOH), and the basic principle of this assay is the iodine-glycogen reaction, which produces a reddish brown color that can be measured using a spectrophotometer. A calibration plot using a known amount of glycogen yielded the best linear fit over a range of 10-300µg/assay (R2=0.994). The applicability of the assay for measuring the glycogen level of various samples was assessed using a wild type (WT) E. coli K-12 strain, glycogen- and RpoS-deficient isogenic mutants, and clinical bacterial isolates with or without RpoS activity; the assay generated reproducible results. Additionally, the assay was successfully applied for measuring glycogen levels in human cells. In conclusion, we developed a straightforward and cost-effective assay for measuring glycogen levels, which can be applied for measuring RpoS activity.


Assuntos
Proteínas de Bactérias/metabolismo , Bioensaio/métodos , Escherichia coli K12/fisiologia , Glicogênio/análise , Fator sigma/metabolismo , Proteínas de Bactérias/genética , Catalase/metabolismo , Colorimetria , Escherichia coli K12/efeitos dos fármacos , Escherichia coli K12/genética , Humanos , Iodo/farmacologia , Mutação , Células PC-3 , Sensibilidade e Especificidade , Fator sigma/genética , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética
19.
J Steroid Biochem Mol Biol ; 107(3-5): 163-71, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17681750

RESUMO

Estrogen is known as a major risk factor in tumorigenesis of the endometrium. The aim of this study is to establish stable estrogen-responsive endometrial cancer cell lines and to investigate the mechanism of estrogen action, focusing on cell-cycle regulation. Human wild-type estrogen receptor cDNA was transfected into endometrial cancer cells (Ishikawa) and estrogen-responsive cell lines were cloned. Their estrogen responsiveness was evaluated by the effect of estrogen on cellular growth and progesterone receptor expression. It was quantitatively estimated by immunocytochemistry or immunoblotting how the expression of cell-cycle regulators such as cyclin D1, cyclin E, Cyclin A, p53, p21 and p27 was regulated by estrogen. A cell line stably responsive to estrogen was established, and cells proliferated and the glandular structure was formed by estrogen stimulation. Cyclin D1 expression increased at 6-24h and cyclin A gradually increased until 48h of estrogen treatment compared with untreated cells. On the other hand, p53 and p21 expressions decreased at 6-24h, and p27 gradually decreased until 24h by estrogen. Our results show that the stimulatory effect of estrogen on cell proliferation may be regulated by the up-regulation of cyclin D1 and cyclin A, and down-regulation of p53, p21 and p27. This cell line is useful to clarify the molecular mechanism of estrogen action on endometrial cancer.


Assuntos
Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Neoplasias do Endométrio/patologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Feminino , Humanos
20.
Anticancer Res ; 37(6): 3009-3013, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28551639

RESUMO

BACKGROUND: Bone represents a frequent site of prostate cancer metastasis. As the molecular mechanism remains unclear, an accessible animal model is required. MATERIALS AND METHODS: We established a novel murine metastasis model using near-infrared fluorescent protein iRFP720-labelled prostate cancer (PC3) cells. To clarify transcriptional alterations during metastasis, iRFP720-PC3 cells were intracardially injected into male mice. mRNA expression profiles of metastasis in bone using marrow cancer cells extracted by centrifugal separation and cell sorting were compared with those of parental cells by microarray. Differentially expressed genes were analyzed by pathway analysis. RESULTS: We identified 327 and 197 genes being up- and down-regulated, respectively. Pathway analysis revealed that the p53 signaling pathway, extracellular matrix receptor interaction, Mammalian target of rapamycin signaling pathway, cancer-related pathways, small cell lung cancer, and Escherichia coli infection response were altered. CONCLUSION: iRFP720 is useful for in vivo cell detection/isolation. The results of expression analysis may improve prostate cancer treatment strategies.


Assuntos
Neoplasias Ósseas , Perfilação da Expressão Gênica , Proteínas Luminescentes/metabolismo , Neoplasias da Próstata , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Nus , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/secundário , Receptores de Superfície Celular/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética
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