RESUMO
Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after (99)Tc(m) administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease.
Assuntos
Iodo/metabolismo , Vírus do Sarampo/metabolismo , Vírus Oncolíticos/metabolismo , Simportadores/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Animais , Western Blotting , Linhagem Celular Tumoral , Chlorocebus aethiops , Feminino , Terapia Genética/métodos , Humanos , Radioisótopos do Iodo/metabolismo , Radioisótopos do Iodo/uso terapêutico , Vírus do Sarampo/genética , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/metabolismo , Camundongos , Camundongos Nus , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Receptores Virais/metabolismo , Simportadores/genética , Simportadores/metabolismo , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Células Vero , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The iodide-concentrating ability of the thyroid gland is essential to the production of thyroid hormone. We report the nucleotide and amino acid sequence of the mouse sodium iodide symporter (mNIS), which mediates this activity within the thyroid gland. An open reading frame of 1,857 nucleotides codes for a protein of 618 amino acids with 95% identity to rat NIS and 84% identity to human NIS. Transient expression of the mNIS cDNA in Chinese hamster ovary (CHO) cells, a nonthyroid cell line, resulted in sodium-dependent, perchlorate-sensitive iodide uptake. Western blot analysis of membrane preparations of CHO cells transiently transfected with mNIS cDNA showed a band of 90 kd when probed with an antibody directed against rat NIS. mNIS will serve as an important reagent in determining the role of NIS in experimental thyroid diseases and for monitoring the immune response to in animal models of NIS-mediated gene therapy.
Assuntos
Simportadores/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Células CHO , Clonagem Molecular , Cricetinae , DNA Complementar/genética , Expressão Gênica , Humanos , Radioisótopos do Iodo/metabolismo , Camundongos , Dados de Sequência Molecular , Fases de Leitura Aberta , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Simportadores/metabolismo , TransfecçãoRESUMO
The expression levels of three synaptic proteins (synaptophysin, synaptotagmin, and growth-associated protein 43 [GAP43]) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR = 0), mild (early) AD (CDR = 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of >1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD.
Assuntos
Doença de Alzheimer/metabolismo , Proteínas de Ligação ao Cálcio , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sinapses/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Progressão da Doença , Lobo Frontal/química , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Proteína GAP-43/análise , Proteína GAP-43/metabolismo , Humanos , Immunoblotting , Glicoproteínas de Membrana/análise , Proteínas do Tecido Nervoso/análise , Índice de Gravidade de Doença , Sinapses/química , Sinaptofisina/química , Sinaptofisina/metabolismo , SinaptotagminasRESUMO
In order to support the concept that a lesion of the thalamus is sufficient to cause a Korsakoff syndrome, we are presenting 5 patients, all of whom developed the syndrome after sustaining a left (dominant) thalamic infarction. Two patients had pure thalamic strokes followed by a permanent Korsakoff syndrome. One of these patients was studied with neuropsychometric testing, as well as with a modern MRI scan. In 2 other patients, clinical and imaging data indicate that infarction was not limited to the thalamus. Another patient had bilateral thalamic infarcts but only a temporary Korsakoff syndrome. Neuropathological data are needed to elucidate the exact anatomical substrate of dominant thalamic Korsakoff syndrome.