RESUMO
BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.
Assuntos
Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologiaRESUMO
Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Lapatinib/uso terapêutico , Receptor ErbB-2/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sistema Livre de Células , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
PURPOSE: The influence of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the histone deacetylase inhibitor PXD101 on survival of thyroid carcinoma cells was investigated. METHODS: SW1736, TPC-1, 8505C and BCPAP human thyroid carcinoma cells were used. To assess cell survival, cell viability, the percentage of viable cells and dead cells, cytotoxic activity, ATP levels and FACS analysis were measured. To validate the impact of gemigliptin combined with PXD101, the interactions were estimated by obtaining combination index in cells treated with two agents. RESULTS: In cells treated with gemigliptin or PXD101, cell viability, the percentage of viable cells and ATP levels were reduced, and the percentage of dead cells and cytotoxic activity were elevated. In cells treated with both gemigliptin and PXD101, compared with PXD101 alone, cell death was augmented, and all of the combination index values were lower than 1.0, suggesting the synergism between gemigliptin and PXD101. The percentage of apoptotic cells, and the protein levels of Bcl2 and cleaved poly (ADP-ribose) polymerase were elevated, and the protein levels of xIAP and survivin were reduced. The protein levels of phospho-Akt and phospho-AMPK were elevated, and cell migration was reduced. CONCLUSIONS: Our results demonstrate that gemigliptin induces cytotoxicity in thyroid carcinoma cells. Moreover, gemigliptin has a synergistic activity with PXD101 in the induction of cell death through involvement of Bcl2 family proteins, xIAP and survivin as well as mediation of Akt and AMPK in thyroid carcinoma cells.
Assuntos
Biomarcadores Tumorais/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Piperidonas/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/patologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular , Humanos , Transdução de Sinais , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Células Tumorais CultivadasRESUMO
Benign esophageal tumors are rare; complete surgical resection is essential for the management of the submucosal tumors. Larger, symptomatic, or non-diagnostic lesions should be resected for both diagnostic and therapeutic indications. Video-assisted thoracic surgery has become a popular treatment in the field of thoracic surgery; however, thoracoscopic esophageal surgery may lead to an increase in operative complications. The effect and safety of thoracoscopic surgery for esophageal submucosal lesions were evaluated. A retrospective study evaluated patients undergoing thoracoscopic treatment of benign submucosal tumors. Between March 2011 and December 2013, 17 patients underwent thoracoscopic resection of benign submucocal tumors. Intraoperative esophagoscopy was performed for tumor localization by transillumination and confirmation of mucosal integrity after enucleation in every patient. Median patient age was 47 years (range 30-65). The median surgery time was 170 minutes (range 80-429). The median tumor size was 3.8 cm (range 1.3-9). The median hospital stay was 4 days (range 2-12). There were 16 leiomyoma and 1 neurogenic tumor. There was one case of conversion to thoracotomy because of residual tumor after enucleation. Mucosal injuries occurred in three patients, two accidentally and one intentionally; each patient was treated with primary repair and confirmed integrity with flexible esophagoscopy at operating room. The small sized tumor with intraoperative esophagoscopy could be localized. Esophagoscopic assistance was necessary in eight patients to have better idea where to make myotomy. There were no major morbidities such as postoperative leakage or mortality. Esophageal submucosal tumors can be treated safely with thoracoscopic surgery. However, intraoperative esophagoscopy allows accurate tumor localization, direction of esophageal access incision, and decreases complications during VATS enucleation of esophageal submucosal tumors.
Assuntos
Neoplasias Esofágicas/cirurgia , Esofagoscopia/métodos , Esôfago/cirurgia , Leiomioma/cirurgia , Neoplasias de Tecido Nervoso/cirurgia , Cirurgia Torácica Vídeoassistida/métodos , Adulto , Idoso , Neoplasias Esofágicas/patologia , Feminino , Humanos , Leiomioma/patologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Mucosa/cirurgia , Neoplasias de Tecido Nervoso/patologia , Duração da Cirurgia , Estudos RetrospectivosRESUMO
SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells. After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Indóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/patologia , Fator de Transcrição CHOP/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Técnicas de Silenciamento de Genes , Humanos , Carcinoma Anaplásico da Tireoide , Proteína Supressora de Tumor p53/metabolismoRESUMO
SU6656 is a small-molecule indolinone that selectively inhibits Src family kinase and induces death of cancer cells. The aim of the present study was to investigate the influence of SU6656 on cell survival and to assess the role of p21 and PI3K/Akt signaling in cell survival resulting from SU6656 treatment in anaplastic thyroid carcinoma (ATC) cells. When 8505C, CAL62, and FRO ATC cells were treated with SU6656, the viability of 8505C and CAL62 ATC cells decreased only after treatment with SU6656 at a dosage of 100 µM for 72 h, while the viability of FRO ATC cells decreased after treatment with SU6656 in a concentration- and time-dependent manner. Cell viability was not changed by pretreatment with the broad-spectrum caspase inhibitor z-VAD-fmk. Phospho-Src protein levels were reduced, and p21 protein levels were elevated. Phospho-ERK1/2 protein levels were multiplied without alteration of total ERK1/2, total Akt, and phospho-Akt protein levels. Regarding FRO ATC cells, the decrement of cell viability, the increment of cleaved PARP-1 protein levels, and the decrement of phospho-Src protein levels were shown in p21 siRNA- or LY294002-pretreated cells compared to SU6656-treated control cells. ERK1/2 siRNA transfection did not affect cell viability and protein levels of cleaved PARP-1, p21, and Akt. In conclusion, these results suggest that SU6656 induces caspase-independent death of FRO ATC cells by overcoming the resistance mechanism involving p21 and Akt. Suppression of p21 and Akt enhances the cytotoxic effect of SU6656 in FRO ATC cells.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/fisiopatologia , Caspases/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Aim of the present study was to evaluate the effect of apigenin in combination with BRAFV600E inhibitor PLX4032 on cell survival, and to investigate the influence of Akt inhibition on the combined effect of apigenin and PLX4032 in ATC cells harboring BRAFV600E. In 8505C and FRO cells harboring BRAFV600E, after treatment of apigenin and PLX4032, the cell viability decreased, and the percentage of dead cells increased in a time- and concentration-dependent manner, respectively. In apigenin- and PLX4032- treated cells, compared with apigenin alone-treated cells, the cell viability was lessened, and the percentage of dead cells was multiplied. In the addition of PLX4032 to apigenin, compared with the treatment of apigenin alone, the protein levels of cleaved PARP-1 and cleaved caspase-3 were elevated, and phospho-ERK protein levels were reduced, and the protein levels of total ERK, c-Myc, BRAF, phospho-Akt, phospho-p70S6K and phospho-4EBP1 were not varied. Compared with the treatment of PLX4032 alone, phosphop70S6K protein levels were reduced, and the other protein levels were not altered. Phospho-ERK protein levels were reduced only in 8505C cells. Under the co-treatment of apigenin and PLX4032, administration of the PI3K inhibitor wortmannin further decreased the cell viability, and increased the percentage of dead cells. In conclusion, our results suggest that PLX4032 augments apigenin-induced cytotoxicity in ATC cells harboring BRAFV600E. Moreover, Akt suppression potentiates the combined effect of apigenin and PLX4032 in ATC cells harboring BRAFV600E.
Assuntos
Apigenina/farmacologia , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Androstadienos/farmacologia , Apigenina/uso terapêutico , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Carcinoma Anaplásico da Tireoide , Vemurafenib , WortmaninaRESUMO
The prevalence of gastroesophageal reflux disease (GERD) has increased recently in Asia-Pacific countries. However, little is known about its prevalence and clinical characteristics in GERD patients with atypical symptoms in Asia. The aim of this study was to investigate the clinical characteristics of GERD in patients who had laryngeal symptoms in Korea. Data were gathered retrospectively from patients who presented with atypical symptoms, such as throat discomfort, globus pharyngeus, hoarseness, and chronic cough. They underwent a 24-hour ambulatory intraesophageal pH monitoring and filled in a validated reflux questionnaire. Overall, 128 patients (36 men and 92 women) with laryngeal symptoms were included. Of these 128, 43 patients (34%) had erosive esophagitis or pathological reflux from 24-hour ambulatory pH monitoring, and 24 (19%) had a positive Bernstein test or positive symptom index from 24-hour pH monitoring. Sixty-one patients (48%) had no evidence of reflux esophagitis on upper endoscopy and pathological acid reflux on 24-hour pH monitoring. Fifty-six patients (44%) had weekly heartburn or regurgitation. Typical symptoms and dyspepsia were significantly more common in patients with GERD who had laryngeal symptoms than non-GERD. Fifty-two percent of patients had laryngeal symptoms that were associated with GERD. The presence of typical reflux symptoms and dyspepsia are risk factors for GERD in patients who present with laryngeal symptoms.
Assuntos
Esofagite Péptica/diagnóstico , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/diagnóstico , Adulto , Tosse/etiologia , Dispepsia/etiologia , Monitoramento do pH Esofágico , Esofagite Péptica/complicações , Feminino , Refluxo Gastroesofágico/fisiopatologia , Azia/etiologia , Rouquidão/etiologia , Humanos , Refluxo Laringofaríngeo/etiologia , Masculino , Pessoa de Meia-Idade , Faringite/etiologia , Estudos Retrospectivos , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Endoscopic submucosal dissection is gaining popularity in the treatment of early gastric cancer. This study aimed to identify clinicopathological factors predictive of lymph node metastasis in patients with the poorly differentiated early gastric cancer to assess the feasibility of using endoscopic submucosal dissection for these cancers. METHODS: The records of patients with poorly differentiated early gastric cancer who had undergone gastric cancer surgery between January 2002 and December 2009 were reviewed. Associations between clinicopathological factors and the presence of lymph node metastasis were analysed by univariable and multivariable logistic regression analysis. RESULTS: Some 1005 patients were included in the analysis. Univariable analysis indicated that lymph node metastasis was associated with sex, ulceration, tumour size, depth of invasion, macroscopic type, lymphatic invasion and venous invasion. Logistic regression revealed that lymph node metastasis was significantly associated with sex, tumour size, depth of tumour invasion and lymphatic involvement. In the group with none of these risk factors (men with mucosal tumour no larger than 2 cm in size, with no lymphatic involvement), lymph node metastasis was present in four (3·2 per cent) of 124 patients. CONCLUSION: In the present study 3·2 per cent of patients who were negative for all identified risk factors had lymph node metastasis. The use of endoscopic submucosal dissection should be considered carefully in the treatment of poorly differentiated early gastric cancer.
Assuntos
Adenocarcinoma/cirurgia , Gastrectomia/métodos , Gastroscopia/métodos , Neoplasias Gástricas/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Excisão de Linfonodo/métodos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Análise de Regressão , Fatores de Risco , Neoplasias Gástricas/patologiaRESUMO
Bolus transit through the esophagus has not been validated by videoesophagram in patients with dysphagia and changes in impedance with abnormal barium transit have not been described in those patients. The aim of this study was to compare esophageal impedance findings with barium esophagram measurements in patients with dysphagia. The consecutive patients with dysphagia underwent conventional multichannel esophageal impedance manometry, after which a barium videoesophagram was performed simultaneously with multichannel esophageal impedance manometry using a mean of three swallows of barium. Esophageal emptying patterns shown in the esophagogram were classified by the degree of intraesophageal stasis and presence of intraesophageal reflux. Bolus transit patterns in impedance were classified as complete and incomplete transit. Sixteen patients (M : F = 8 : 8, mean age, 47 years) were enrolled. Their manometric diagnosis were normal (n= 6), ineffective esophageal motility (n= 1), diffuse esophageal spasm (DES; n= 2), and achalasia (n= 7). Sixty-three swallows were analyzed. According to impedance analysis, 21/22 swallows with normal barium emptying showed complete transit (96%) and 31/32 swallows with severe stasis showed incomplete transit (97%). Nine swallows with mild stasis showed either complete or incomplete transit patterns in impedance. Swallows with mild barium stasis and complete transit in impedance were observed in patients who had received treatment (two patients with achalasia with history of esophageal balloonplasty and a patient with DES after nifedipine administration). Impedance reflected severe stasis with retrograde barium movement and described typical bolus transit patterns in patients with achalasia and DES. In conclusion, impedance-barium esophagram concordance is high for swallows with normal esophageal emptying and for severe barium stasis in patients with dysphagia.
Assuntos
Transtornos de Deglutição/diagnóstico por imagem , Deglutição , Impedância Elétrica , Esôfago/diagnóstico por imagem , Trânsito Gastrointestinal , Adulto , Sulfato de Bário , Transtornos de Deglutição/fisiopatologia , Esôfago/fisiopatologia , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Radiografia , Gravação em VídeoAssuntos
Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Súbita/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adulto , Idoso , Glicemia , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Súbita/diagnóstico , Perda Auditiva Súbita/etiologia , Humanos , Hiperglicemia/complicações , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Endoscopic resection of early gastric cancer is a relatively new and attractive treatment, but occasionally fails to remove all cancer lesions completely. This study aimed to elucidate clinicopathological factors that could be helpful in predicting residual tumour in the surgical specimen after incomplete endoscopic submucosal dissection (ESD). METHODS: Patients who underwent gastrectomy because of incomplete ESD between August 2004 and August 2008 were analysed. Clinicopathological characteristics were reviewed retrospectively from prospectively collected medical records. Patients were classified into groups with and without residual tumour. Pathology results following gastrectomy were compared with those of incomplete ESD. RESULTS: A total of 118 patients were included. The incidence of residual tumour in the surgical specimen was 24·6 per cent after incomplete ESD. Elevated/flat-type cancers, large tumours (at least 2 cm) and those limited to the mucosa had significantly higher incomplete ESD rates. Cancer limited to the mucosa and the presence of tumour in the lateral margin were associated with residual tumour in the surgical specimen (both P = 0·001). CONCLUSION: Radical gastrectomy should be performed if pathological examination reveals a positive lateral resection margin after ESD.
Assuntos
Endoscopia Gastrointestinal/métodos , Mucosa Gástrica/cirurgia , Gastroscopia/métodos , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Dissecação/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasia Residual , Estudos Prospectivos , Neoplasias Gástricas/patologia , Resultado do TratamentoRESUMO
In thyroid cells, the effects of all- TRANS retinoic acid (ATRA) on sodium/iodide symporter (NIS) and CCAAT/enhancer-binding protein-homologous protein (CHOP) under condition of endoplasmic reticulum (ER) stress have not been evaluated. In the present study, the relationships between NIS, CHOP, and p38 MAPK, and the effects of ATRA on NIS and CHOP expression as well as on p38 MAPK activation under condition of ER stress in thyroid cells were investigated. In FRTL5 thyroid cells, NIS mRNA and protein levels decreased following tunicamycin (TN) treatment, while CHOP mRNA and protein levels increased. In addition, while CHOP mRNA levels decreased after administration of tauro-UDCA and siCHOP, NIS mRNA levels were not altered. After pretreatment with SB203580, NIS mRNA levels decreased in non-TN-treated cells but increased in TN-treated cells. In contrast, CHOP mRNA levels decreased in both non-TN-treated and TN-treated cells. Exposure to ATRA decreased NIS mRNA levels in non-TN-treated cells but increased NIS mRNA levels in TN-treated cells. ATRA decreased CHOP mRNA levels in both non-TN-treated and TN-treated cells although the response was significant only in TN-treated cells. Phospho-p38 MAPK protein levels but not total p38 MAPK protein levels increased in TN-treated cells. ATRA attenuated this increase in phopho-p38 MAPK protein levels. In conclusion, our results demonstrate that ER stress may induce reciprocal changes in NIS and CHOP expression via p38 MAPK in FRTL5 thyroid cells, and that ATRA may attenuate ER stress-induced alterations in NIS and CHOP expression by modulating the phosphorylation of p38 MAPK in FRTL5 thyroid cells.
Assuntos
Retículo Endoplasmático/metabolismo , Simportadores/metabolismo , Glândula Tireoide/metabolismo , Fator de Transcrição CHOP/metabolismo , Animais , Linhagem Celular , Retículo Endoplasmático/genética , Ratos , Simportadores/genética , Fator de Transcrição CHOP/genética , Tretinoína , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Alpha-lipoic acid (ALA) has been shown to modulate cell death via PI3K/Akt signal pathway in various cells. In the present study, the effects of ALA on cell death and PI3K/Akt signal pathway linked to cell death-related proteins during endoplasmic reticulum (ER) stress in FRTL5 thyroid cells were evaluated. In FRTL5 thyroid cells, cell viability increased by ALA pretreatment in tunicamycin (TN)-treated cells. When TN was treated, CCAAT/enhancer-binding protein-homologous protein (CHOP) and Bax protein levels were elevated while Bcl-2 protein levels were reduced. ALA diminished CHOP and Bax protein levels, and augmented Bcl-2 protein levels in TN-treated cells. After exposure to TN, phospho-Akt protein levels were repressed whereas total Akt protein levels were not changed. ALA increased phospho-Akt protein levels but not total Akt protein levels in both non-TN-treated and TN-treated cells. After LY294002 administration in non-TN-treated cells, cell viability was reduced, and CHOP and Bax protein levels were elevated, and Bcl-2 protein levels were reduced. The CHOP, Bcl-2 and Bax protein levels were not different after LY294002 administration in TN-treated cells. LY294002 and wortmannin decreased cell viability, and increased CHOP and Bax protein levels, and decreased Bcl-2 protein levels in ALA-pretreated and TN-treated cells. In conclusion, these results suggest that ER stress may induce cell death by modulating PI3K/Akt signal pathway linked to cell death-related proteins in FRTL5 thyroid cells. Moreover, these findings imply that ALA may ameliorate ER stress-induced cell death by activating PI3K/Akt signal pathway and attenuating changes of cell death-related proteins in FRTL5 thyroid cells.
Assuntos
Retículo Endoplasmático/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Ácido Tióctico/farmacologia , Glândula Tireoide/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Fator de Transcrição CHOP/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
This study was to evaluate the frequency of colorectal neoplasia in renal transplant recipients and to investigate the association with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. We compared the frequency of colorectal neoplasia among renal transplant recipients with that of the healthy subjects. Specimens of colorectal neoplasia were examined for EBV and CMV using in situ hybridization and immunohistochemistry, respectively. Of 796 renal transplantation cohorts, 315 were enrolled. The frequency of colorectal neoplasia among the patients was 22.9%. Compared with the healthy subjects, the odds ratio (OR) for advanced adenoma was 3.32 (95% CI, 1.81-6.10). The frequency of cancer among the patients was 1.9% (OR, 12.0; 95% CI, 1.45-99.7). A long interval between transplantation and colonoscopy was a significant factor in the development of advanced colorectal neoplasia. EBV positivity was detected in 30.6% of colorectal neoplasia specimens from renal transplant recipients, which was higher than that for the controls (p = 0.002). CMV was not detected in any lesions of patients or controls. In conclusion, renal transplant recipients have a significantly increased risk of advanced colorectal neoplasia. EBV was more frequently found in specimens of advanced colorectal neoplasm obtained from the renal transplant recipients.
Assuntos
Neoplasias Colorretais/epidemiologia , Transplante de Rim/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Adenoma/epidemiologia , Adenoma/fisiopatologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Colonoscopia , Neoplasias Colorretais/fisiopatologia , Neoplasias Colorretais/virologia , Citomegalovirus/isolamento & purificação , Progressão da Doença , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imuno-Histoquímica , Hibridização In Situ , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND/AIMS: p12(DOC-1) is a well-known growth suppressor; however, its role in gastric carcinogenesis is still unclear. We investigated the expression of p12(DOC-1) in gastric cancer tissues and its possible correlation with p53 expression, and determined its clinical significance. METHODS: Immunohistochemical staining using the tissue array method was performed on 180 human gastric carcinomas. The clinicopathological features and prognostic significance were analyzed. RESULTS: Of the 180 tissue samples, p53 expression was positive in 85 (47.2%) and p12(DOC-1) expression was negative in 140 (77.8%). The negative expression of p12(DOC-1) was significantly associated with a more advanced depth of tumor invasion and stage (p < 0.05). No apparent correlation was found between p12(DOC-1) and p53 expressions. The 5-year survival rate of the p12(DOC-1)-positive cases (53.7%) was higher than that of the p12(DOC-1)-negative cases (39.3%); however, neither p12(DOC-1) nor p53 expression status had any statistically significant prognostic value. Multivariate analysis revealed that lymph node metastasis, distant metastasis, lymphatic invasion and perineural invasion were independent prognostic factors. CONCLUSIONS: This is the first report that suggests that p12(DOC-1) may be involved in the development and progression of gastric cancer. Further studies are required to clarify its exact role in the mechanism of gastric carcinogenesis.
Assuntos
Carcinoma/metabolismo , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Estômago/patologia , Neoplasias Gástricas/patologia , Adulto JovemRESUMO
Citicoline (cytidine 5'-diphosphocholine) is an important precursor for the synthesis of neuronal plasma membrane phospholipids, mainly phosphatidylcholine. The administration of citicoline serves as a choline donor for the synthesis of acetylcholine. Citicoline has been shown to reduce the neuronal injury in animal models with cerebral ischaemia and in clinical trials of stroke patients. Citicoline is currently being investigated in a multicentre clinical trial. However, citicoline has not yet been examined the context of hypoglycaemia-induced neuronal death. To clarify the therapeutic impact of citicoline in hypoglycaemia-induced neuronal death, we used a rat model with insulin-induced hypoglycaemia. Acute hypoglycaemia was induced by i.p. injection of regular insulin (10 U kg-1 ) after overnight fasting, after which iso-electricity was maintained for 30 minutes. Citicoline injections (500 mg/kg, i.p.) were started immediately after glucose reperfusion. We found that post-treatment of citicoline resulted in significantly reduced neuronal death, oxidative injury and microglial activation in the hippocampus compared to vehicle-treated control groups at 7 days after induced hypoglycaemia. Citicoline administration after hypoglycaemia decreased immunoglobulin leakage via blood-brain barrier disruption in the hippocampus compared to the vehicle group. Citicoline increased choline acetyltransferase expression for phosphatidylcholine synthesis after hypoglycaemia. Altogether, the present findings suggest that neuronal membrane stabilisation by citicoline administration can save neurones from the degeneration process after hypoglycaemia, as seen in several studies of ischaemia. Therefore, the results suggest that citicoline may have therapeutic potential to reduce hypoglycaemia-induced neuronal death.