RESUMO
The present study evaluated the effects of smoking on the amount of therapeutic doses of radioiodine ((131)I) given to patients with Graves' disease (GB). The study also retrospectively analyzed the relationship between the onset of symptoms of thyroid ophthalmopathy (OT) after treatment with (131)I within 2 years and changes of TSHR-Abs levels, and the impact of prednisone administration before and after the therapy on OT development in both smoking and non-smoking patients. Materials and Methods: The study group included 116 patients, 97 women and 19 men, aged 28 ÷ 77 years (average 51 years) who were diagnosed with GB and treated with therapeutic doses of (131)I. Of the 116 patients treated, 85 patients were given a single dose of (131)I, whereas in 31 patients, due to recurrent hyperthyroidism, there was a need for a second dose of (131)I. In the group of 85 studied patients who received a single therapeutic dose of (131)I, 34 patients were smokers, including 27 women and 7 men, whereas in the group of 31 patients with recurrent hyperthyroidism who received repeated doses of 131I, 21 patients were smokers, 17 women and 4 men. Patients qualified for the therapy with (131)I and diagnosed with mild OT, were given prednisone, administered orally with an initial dose of 0.4 - 0.5 mg/kg daily tapering within 4-6 weeks. Results: The results of the study demonstrated that there was a statistically significant relationship (p<0.05) between cigarette smoking and the number of administered therapeutic doses of (131)I in patients with GD. Smoking patients needed to be given the second therapeutic dose of (131)I more frequently. The relationship between the onset of symptoms of OT in patients with GD and the TSHRAb in serum within two years after (131)I administration was highly significant (p<0.0001). The results obtained in our study showed that efficacy of therapy was lower in smokers with GD when compared with non-smokers Since the increased titer of TSHR-Ab was associated with higher risk of OT development, especially in smokers, its routine measurement after (131)I administration could be considered in all treated patients with GD. Steroid prophylaxis should be recommended for each smoking GD patient with mild OT qualified for (131)I therapy.
Assuntos
Fumar Cigarros/efeitos adversos , Doença de Graves/tratamento farmacológico , Radioisótopos do Iodo/uso terapêutico , Prednisolona/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quimioterapia Combinada , Feminino , Oftalmopatia de Graves/induzido quimicamente , Oftalmopatia de Graves/prevenção & controle , Humanos , Radioisótopos do Iodo/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prednisolona/farmacologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The devastating prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDA) presents an urgent need for the development of therapeutic strategies targeting disseminated tumor cells. Until now, T-cell therapy has been scarcely pursued in PDA, due to the prevailing view that it represents a poorly immunogenic tumor. EXPERIMENTAL DESIGN: We systematically analyzed T-cell infiltrates in tumor biopsies from 127 patients with resectable PDA by means of immunohistochemistry, flow cytometry, T-cell receptor (TCR) deep-sequencing and functional analysis of in vitro expanded T-cell cultures. Parallel studies were performed on tumor-infiltrating lymphocytes (TIL) from 44 patients with metastatic melanoma. RESULTS: Prominent T-cell infiltrates, as well as tertiary lymphoid structures harboring proliferating T-cells, were detected in the vast majority of biopsies from PDA patients. The notion that the tumor is a site of local T-cell expansion was strengthened by TCR deep-sequencing, revealing that the T-cell repertoire in the tumor is dominated by highly frequent CDR3 sequences that can be up to 10,000-fold enriched in tumor as compared to peripheral blood. In fact, TCR repertoire composition in PDA resembled that in melanoma. Moreover, in vitro expansion of TILs was equally efficient for PDA and melanoma, resulting in T-cell cultures displaying HLA class I-restricted reactivity against autologous tumor cells. CONCLUSIONS: The tumor-infiltrating T-cell response in PDA shows striking similarity to that in melanoma, where adoptive T-cell therapy has significant therapeutic impact. Our findings indicate that T-cell-based therapies may be used to counter disease recurrence in patients with resectable PDA.
RESUMO
Aberrant DNA methylation constitutes a well-established epigenetic marker for breast cancer. Changes in methylation early in cancer development may be clinically relevant for cancer detection and prognosis-based therapeutic decisions. In the present study, a combination of methyl-CpG immunoprecipitation (MCIp) and human CpG island (CGI) arrays was applied to compare genome-wide DNA methylation profiles in 10 low-grade in situ and invasive breast cancers against 10 normal breast samples. In total, 214 CGIs were found to be hypermethylated in ≥6 of 10 tumors. Functional term enrichment analyses revealed an overrepresentation of homeobox genes and genes involved in transcription and regulation of transcription. Significant hypermethylation of 11 selected genes in tumor vs. normal tissue was validated in two independent sample sets (45 tumors and 11 controls, 43 tumors and 8 controls) using quantitative EpiTyper technology. In tumors, median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were ≥30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. Using the 90th percentile of methylation levels in normal tissue as cutoff value, 62-92% of in situ samples (n=13), 72-97% of invasive samples from the first validation set (n=32), and 86-100% of invasive samples from the second validation set (n=43) were classified as hypermethylated. Hypermethylation of KLF11 and SIM1 might also be associated with increased risk of developing metastases. In summary, early methylation changes are frequent in the low-grade pathway of breast cancer and may be useful in the development of differential diagnostic and possibly also prognostic markers.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias da Mama/patologia , Brevicam/genética , Proteínas de Ciclo Celular/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Proteínas de Homeodomínio/genética , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neuropeptídeos/genética , Proteínas Repressoras/genética , Proteína 1 Semelhante ao Fator 7 de Transcrição/genética , Fator de Transcrição Brn-3A/genéticaRESUMO
The purpose of this article is to provide an overview on the regulation of transcription in cancer cells. We describe here standard mechanisms of transcription in eukaryotic cells, an influence of common promoter polymorphisms contributing to malignant progression and DNA methylation as significant aspect of gene regulation. We also described transcription factors mechanism of action, and how their alteration can result in cancer.
Assuntos
Neoplasias/genética , Transcrição Gênica , Metilação de DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Polimorfismo Genético , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
The current arsenal of molecular tools for site-directed cleavage of single-stranded DNA (ssDNA) is limited. Here, we describe a method for targeted DNA cleavage that requires only the presence of an A nucleotide at the target position. The procedure involves hybridization of a complementary oligonucleotide probe to the target sequence. The probe is designed to create a deliberate G:A mismatch at the desired position of cleavage. The DNA repair enzyme MutY glycosylase recognizes the mismatch structure and selectively removes the mispaired A from the duplex to create an abasic site in the target strand. Addition of an AP-endonuclease, such as Endonuclease IV, subsequently cleaves the backbone dividing the DNA strand into two fragments. With an appropriate choice of an AP-cleaving enzyme, the 3'- and 5'-ends of the cleaved DNA are suitable to take part in subsequent enzymatic reactions such as priming for polymerization or joining by DNA ligation. We define suitable standard reaction conditions for glycosylase/AP-cleaving enzyme (G/AP) cleavage, and demonstrate the use of the method in an improved scheme for in situ detection using target-primed rolling-circle amplification of padlock probes.