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1.
BMC Gastroenterol ; 20(1): 319, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993498

RESUMO

BACKGROUND: Pancreatic juice cytology (PJC) is a tool for diagnosing malignant intraductal papillary mucinous neoplasm (IPMN); however, the accuracy is insufficient using the conventional method. Liquid-based cytology (LBC) improves the cell recovery rate, and almost all cells can be evaluated. We evaluated the efficacy of PJC with LBC for malignant IPMN. METHODS: We retrospectively analyzed 90 patients with suspected malignant IPMN who underwent PJC before pancreatectomy. PJC with smear and LBC methods was conducted in 52 patients (between June 2003 to December 2011) and 38 patients (between January 2012 to December 2018). Based on the imaging studies, all of the patients were classified according to the international consensus guidelines for IPMN revised in 2017. RESULTS: Of the 90 patients, 43 (48%) had malignant IPMN (high-grade dysplasia or invasive carcinoma), and the remaining patients had non-malignant IPMN (intermediate- or low-grade dysplasia). LBC increased the accuracy of PJC for the diagnosis of malignant IPMN (smear method: 56% [29/52] vs. LBC method: 76% [29/38]; P = 0.044). In a multivariate analysis, LBC was a significant factor influencing the accurate diagnosis of PJC (odds ratio: 3.52; P = 0.021). Furthermore, LBC increased the accuracy of PJC for malignant IPMN in patients with worrisome features (smear method: 66% [19/29] vs. LBC method: 93% [14/15]; P = 0.043). CONCLUSIONS: LBC increases the accuracy of PJC for diagnosing malignant IPMN compared with the conventional smear method.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Humanos , Suco Pancreático , Neoplasias Pancreáticas/diagnóstico , Estudos Retrospectivos
2.
Biosci Biotechnol Biochem ; 73(11): 2488-93, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19897899

RESUMO

Hamartin and tuberin interact directly to regulate cell growth negatively. In this study, far-western blotting revealed that hamartin binds directly Heat shock protein 70 (Hsp70), even in the absence of tuberin. While the hamartin-tuberin complex acts as a sensor for a variety of types of stress, it is unclear how the complex is regulated under stress conditions. We found that the hamartin-Hsp70 interaction is stabilized during heat shock. On the other hand, tuberin underwent degradation through phosphorylation in an Akt-dependent manner. Furthermore, we found that when Hsp70 expression was inhibited by N-formyl-3,4-methylenedioxy-benzylidene-gamma-butyrolactam (KNK437), Akt phosphorylation on site Ser308 diminished and tuberin was not phosphorylated at Thr1462 during heat shock. We conclude that both hamartin and Hsp70 increase in response to heat shock, whereas tuberin is phosphorylated and thereafter degraded via the PI3K/Akt pathway. Through this pathway, hamartin-Hsp70 plays a crucial role as a scaffolding protein that transfers the Akt signal to tuberin.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Western Blotting , Células COS , Chlorocebus aethiops , Proteínas de Choque Térmico HSP70/análise , Masculino , Camundongos , Fosforilação , Ratos , Análise Espectral , Treonina , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/química
3.
Biochem Biophys Res Commun ; 368(1): 132-7, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18230340

RESUMO

The products of the TSC1 (hamartin) and TCS2 (tuberin) tumor suppressor genes negatively regulate cell growth by inhibiting mTOR signaling. Recent research has led to the postulation that tuberin and/or hamartin are involved in tumor migration, presumably through Rho activation. Here we show that LEF-8 cells, which contain a Y1571 missense mutation in tuberin, express higher Rac1 activity than tuberin negative and positive cells. We also provide evidence of obvious lamellipodia formation in LEF-8 cells. Since the production of TSC2(Y1571H) cannot form a hetero-complex with hamartin, we further analyzed another mutant, TSC2(R611Q), which also lacks the ability to form a complex with hamartin. Introducing both forms of mutated TSC2 into COS-1 cells increased Rac1 activity as well as cell motility. We also found these two mutants interacted with Rac1. We further demonstrated that the introduction of mutated TSC2 into COS-1 cells can generate higher reactive oxygen species (ROS). These results indicate that loss-of-function mutated tuberin can activate Rac1 and thereby increase ROS production.


Assuntos
Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Linhagem Celular , Movimento Celular , Chlorocebus aethiops , Ativação Enzimática , Camundongos , Mutação/genética , Ligação Proteica , Ratos , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas rac1 de Ligação ao GTP/genética
4.
Mol Clin Oncol ; 2(5): 719-724, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25054036

RESUMO

To determine the efficacy of postoperative adjuvant chemotherapy with docetaxel + cisplatin + 5-fluorouracil (DCF) in lymph node metastasis-positive esophageal cancer, we retrospectively analyzed 139 patients with stage II/III (non-T4) esophageal cancer with lymph node metastasis (1-6 nodes), who did not receive preoperative treatment and underwent three-field lymph node dissection in the Juntendo University Hospital between December, 2004 and December, 2009. The tumors were histologically diagnossed as squamous cell carcinoma. The patients were divided into two groups, a surgery alone group (S group, 88 patients) and a group that received postoperative DCF therapy (DCF group, 51 patients). The disease-free and overall survival were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as N1 and N2, according to the TNM classification. There were no significant differences between the S and DCF groups regarding clinicopathological factors other than intramural metastasis and main tumor location. The presence of intramural metastasis, blood vessel invasion and the number of lymph nodes were identified as prognostic factors. The 5-year disease-free and overall survival were 55.8 and 57.3%, respectively, in the S group and 52.8 and 63.0%, respectively, in the DCF group. These differences were not considered to be statistically significant (P=0.789 and 0.479 for disease-free and overall survival, respectively). Although there were no significant differences in disease-free and overall survival between the S and DCF groups in N1 cases, both disease-free and overall survival were found to be better in the DCF group (54.2 and 61.4%, respectively) compared to the S group (29.6 and 28.8%, respectively) in N2 cases (P=0.029 and 0.020 for disease-free and overall survival, respectively). Therefore, postoperative adjuvant chemotherapy with DCF was shown to improve disease-free and overall survival in moderate lymph node metastasis-positive cases (N2), suggesting that the DCF regimen may be effective as postoperative adjuvant chemotherapy for patients with lymph node metastasis from esophageal cancer.

5.
Nutr Res ; 29(9): 640-7, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19854379

RESUMO

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.


Assuntos
Encéfalo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Deficiências de Ferro , Ferro da Dieta/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Células COS , Chlorocebus aethiops , Desferroxamina/farmacologia , Regulação para Baixo , Masculino , Modelos Animais , Fosforilação , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas/metabolismo , Sideróforos/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
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