RESUMO
PDX1 (pancreatic and duodenal homeobox 1) is overexpressed in pancreatic cancer, and its reduction results in tumor regression. Bi-functional pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) utilizes the endogenous micro-RNA biogenesis pathway to effect cleavage- and non-cleavage-dependent degradation of PDX1 mRNA. We have shown that OFHIRNA-PDX1 reduces pancreatic tumor volume in xenograft models. Thus, we are now exploring biorelevant large animal safety of OFHIRNA-PDX1. Mini pigs were chosen as the biorelevant species based on the similarity of human and pig PDX1 target sequence. In the initial study, animals developed fever, lethargy, hyporexia and cutaneous hyperemia following administration of OFHIRNA-PDX1. Twenty-one days later, the same animals demonstrated less toxicity with a second OFHIRNA-PDX1 infusion in conjunction with a prophylactic regimen involving dexamethasone, diphenhydramine, Indocin and ranitidine. In a new group of animals, PDX1 protein (31 kDa) expression in the pancreas was significantly repressed at 48 and 72 h (85%, P=0.018 and 88%, P=0.013; respectively) following a single infusion of OFHIRNA-PDX1 but recovered to normal state within 7 days. In conclusion, a single intravenous infusion of OFHIRNA-PDX1 in conjunction with premedication in pigs was well tolerated and demonstrated significant PDX1 knockdown.
Assuntos
Proteínas de Homeodomínio/genética , Nanoconjugados , RNA Interferente Pequeno/genética , Transativadores/genética , Animais , Pareamento de Bases , Sequência de Bases , Glicemia , Temperatura Corporal , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Ordem dos Genes , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/metabolismo , Humanos , Insulina/sangue , Camundongos , Nanoconjugados/administração & dosagem , Nanoconjugados/efeitos adversos , Nanoconjugados/química , Plasmídeos/química , Plasmídeos/genética , Isoformas de Proteínas , Interferência de RNA , RNA Interferente Pequeno/química , RNA Interferente Pequeno/metabolismo , Suínos , Transativadores/química , Transativadores/metabolismoRESUMO
INTRODUCTION: Serrated polyps of the large intestine comprise a diverse group of lesions of the colonic mucosa that includes hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. These lesions have been considered precursors of colorectal carcinogenesis associated with microsatellite instability. OBJECTIVE: To determine the prevalence of the MLH1 y MSH2 mutations in serrated polyps and to correlate with morphological and cytoarchitectural characteristics. METHODS: A descriptive study of 164 serrated colorectal polyps was performed. Tissue microarray technique was used to analyze their morphological and cytoarchitectural features and immunohistochemical expression of the MLH1 and MSH2 mutated genes in different regions of the colonic crypts. RESULTS: One-hundred and fifty-nine hyperplastic polyps, 2 sessile serrated adenomas and 3 traditional serrated adenomas were included. There was no significant difference in the immunohistochemical expression between hyperplastic polyps and serrated adenomas for MLH1 and MSH2. Moreover, the degree of expression decreased from the base toward the surface of the crypt where it was negative. This finding was not a sufficient to qualify for microsatellite instability. CONCLUSIONS: The prevalence of the MLH1 and MSH2 mutated genes were similar between hyperplastic polyps and serrated adenomas. No correlation was found with morphological and cytoarchitectural characteristics.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Adulto , Idoso , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Adulto JovemRESUMO
Pulmonary myofibroblastic pseudotumors are rare surgical pathologies, of unknown origin, with benign behavior and a good prognosis if completely resected. We present a 21-year-old male with a solitary pulmonary nodule found during a routine chest X-ray with CT scan confirmation. After a 16-month follow-up, the nodule increased in size and the patient developed mild dyspnea. He underwent an elective left postero-lateral thoracotomy and excision of the mass with an upper lobectomy. Pathologic studies revealed a pulmonary myofibroblastic pseudotumor.