RESUMO
Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules inâ vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P-F and P-N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.
Assuntos
Neoplasias , Pró-Fármacos , Antivirais/farmacologia , Humanos , Fosfatos , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.
Assuntos
Células Epiteliais/metabolismo , Fator de Transcrição GATA4/genética , Regulação da Expressão Gênica , Junções Intercelulares/genética , Sistema de Sinalização das MAP Quinases/genética , Fatores de Transcrição SOXB1/genética , Animais , Células Cultivadas , Feminino , Fator de Transcrição GATA4/metabolismo , Mucosa Gástrica/metabolismo , Queratina-7/genética , Queratina-7/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Transgênicos , Fatores de Transcrição SOXB1/metabolismoRESUMO
OBJECTIVES: Although simultaneous occurrences of autoimmune pancreatitis (AIP) and cancer are occasionally observed, it remains largely unknown whether cancer and AIP occur independently or these disorders are interrelated. The aim of this study was to examine the relationship between AIP and cancer. METHODS: We conducted a multicenter, retrospective cohort study. One hundred and eight patients who met the Asian diagnostic criteria for AIP were included in the study. We calculated the proportion, standardized incidence ratio (SIR), relative risk, and time course of cancer development in patients with AIP. We also analyzed the clinicopathological characteristics of AIP patients with cancer in comparison with those without cancer. RESULTS: Of the 108 AIP patients, 18 cancers were found in 15 patients (13.9%) during the median follow-up period of 3.3 years. The SIR of cancer was 2.7 (95% confidence interval (CI) 1.4-3.9), which was stratified into the first year (6.1 (95% CI 2.3-9.9)) and subsequent years (1.5 (95% CI 0.3-2.8)) after AIP diagnosis. Relative risk of cancer among AIP patients at the time of AIP diagnosis was 4.9 (95% CI 1.7-14.9). In six of eight patients whose cancer lesions could be assessed before corticosteroid therapy for AIP, abundant IgG4-positive plasma cell infiltration was observed in the cancer stroma. These six patients experienced no AIP relapse after successful cancer treatment. CONCLUSIONS: Patients with AIP are at high risk of having various cancers. The highest risk for cancer in the first year after AIP diagnosis and absence of AIP relapse after successful treatment of the coexisting cancers suggest that AIP may develop as a paraneoplastic syndrome in some patients.
Assuntos
Doenças Autoimunes/complicações , Neoplasias/etiologia , Pancreatite/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunoglobulina G/sangue , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Pancreatite/diagnóstico , Pancreatite/imunologia , Estudos Retrospectivos , Medição de Risco , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND AND STUDY AIMS: Biliary complications are one of the most serious morbidities after liver transplantation. Inside-stent is a plastic stent placed above the sphincter of Oddi without endoscopic sphincterotomy against biliary strictures. Our aims were to analyze the long-term efficacy of inside-stent placement in patients with biliary stricture after living donor liver transplantation. PATIENTS AND METHODS: Ninety-four patients who experienced biliary stricture that employed duct-to-duct reconstruction were treated with inside-stent placement. Treatment outcomes, including stricture resolution, recurrence, inside-stent patency, and morbidity rate were evaluated retrospectively. RESULTS: Ninety-two patients could be evaluated. Resolution of stricture was eventually observed in 81 of 92 patients with an average of 1.4 sessions of endoscopic retrograde cholangiography. Of the 81 patients who achieved the resolution of the stricture, recurrent biliary stricture that required intervention occurred in 8 patients. Conversely, stricture remission was achieved 73 patients (90.1 %) during 53 months follow-up after stent removal. Median duration of patency of the initial stent was 189 (range 2-1228) days. Stent dislocation occurred in 10 patients. Adverse event related to inside-stent placement was pancreatitis in 18 cases (mild 13, moderate 5). CONCLUSIONS: Inside-stent placement achieved long-term patency and high remission rate in patients with biliary stricture after liver transplantation.
Assuntos
Colestase/cirurgia , Transplante de Fígado/efeitos adversos , Adolescente , Adulto , Idoso , Anastomose Cirúrgica/efeitos adversos , Criança , Colestase/etiologia , Constrição Patológica/etiologia , Constrição Patológica/cirurgia , Endoscopia do Sistema Digestório/efeitos adversos , Endoscopia do Sistema Digestório/métodos , Feminino , Humanos , Transplante de Fígado/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Esfíncter da Ampola Hepatopancreática/cirurgia , Stents , Resultado do Tratamento , Adulto JovemRESUMO
A 41-year-old man was admitted to our hospital because of multiple liver tumors. Colonoscopy showed a mass lesion in the cecum. He was given a diagnosis of endocrine cell carcinoma by immunostaining technique, and received chemotherapy of CAPOX regimen for 3 courses. After that, he underwent second-line chemotherapy of EP(CDDP/VP-16)regimen due to deterioration of his performance status(PS), and his tumor marker NSE. He then showed dramatically improved PS, and improvement in the size of liver mets and NSE(4. 3mg/mL).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ceco/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias das Glândulas Endócrinas/tratamento farmacológico , Adulto , Biópsia , Cisplatino/uso terapêutico , Neoplasias do Colo/patologia , Neoplasias das Glândulas Endócrinas/patologia , Etoposídeo/uso terapêutico , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
A 70-year-old woman who underwent proximal gastrectomy for gastric cancer (poorly-differentiated adenocarcinoma) of Stage IIIB at age 46 visited our hospital April 2004 because of exacerbated pain by movement in the buttocks since November 2003. She showed multiple bone metastasis by CT (computerized tomography). Pancreas cancer or gallbladder cancer was suspected by CT, and a high tumor marker score (CA19-9 18,625 U/mL, DUPAN-II 15,000 U/ mL elevations were acknowledged). Although her symptoms were severe with performance status (PS) 4, she was administered combination chemotherapy with gemcitabine and cisplatin. After 2 cycle therapy, her PS was improved to 2, but the tumor markers had elevated. So we changed the chemotherapy menu to S-1 and gemcitabine. Her tumor markers lowered and PS was improved to 1. There was a remarkable response to this chemotherapy, and the result of CT and bone scintigraphy suggested that her bone metastasis was improved. Because of hematologic relapse due to DIC at 1 year after the first treatment, she was readmitted to our hospital and later died. The autopsical result revealed recurrence of gastric cancer 23 years post-operatively.