RESUMO
BACKGROUND: Plasma is an ionised gas that is typically generated in high-temperature laboratory conditions. However, recent progress in atmospheric plasmas has led to the creation of cold plasmas with ion temperature close to room temperature. METHODS: Both in-vitro and in-vivo studies revealed that cold plasmas selectively kill cancer cells. RESULTS: We show that: (a) cold plasma application selectively eradicates cancer cells in vitro without damaging normal cells; and (b) significantly reduces tumour size in vivo. It is shown that reactive oxygen species metabolism and oxidative stress responsive genes are deregulated. CONCLUSION: The development of cold plasma tumour ablation has the potential of shifting the current paradigm of cancer treatment and enabling the transformation of cancer treatment technologies by utilisation of another state of matter.
Assuntos
Melanoma Experimental/terapia , Gases em Plasma/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Transplante de Neoplasias , Transdução de Sinais , Temperatura Cutânea , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance, we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and quantitative methylation specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage design consisting of discovery and prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. Promoter methylation of KIF1A (κ = 0.64), HOXA9 (κ = 0.60), NID2 (κ = 0.60), and EDNRB (κ = 0.60) had a moderate to substantial agreement with clinical diagnosis in the discovery screen. HOXA9 had 68% sensitivity, 100% specificity, and a 0.81 Area Under the Curve (AUC). NID2 had 71% sensitivity, 100% specificity, and a 0.79 AUC. In the prevalence screen, HOXA9 (κ = 0.82) and NID2 (κ = 0.80) had an almost perfect agreement with histologic diagnosis. HOXA9 had 85% sensitivity, 97% specificity, and a 0.95 AUC. NID2 had 87% sensitivity, 95% specificity, and a 0.91 AUC. A HOXA9 and NID2 gene panel had 94% sensitivity, 97% specificity, and a 0.97 AUC. In saliva, from OSCC cases and controls, HOXA9 had 75% sensitivity, 53% specificity, and a 0.75 AUC. NID2 had 87% sensitivity, 21% specificity, and a 0.73 AUC. This phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Moléculas de Adesão Celular/genética , Metilação de DNA , Proteínas de Homeodomínio/genética , Neoplasias Bucais/genética , Neoplasias Orofaríngeas/genética , Saliva/metabolismo , Proteínas de Ligação ao Cálcio , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/prevenção & controle , Diagnóstico Precoce , Humanos , Cinesinas/genética , Boca/metabolismo , Boca/patologia , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/prevenção & controle , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/prevenção & controle , Regiões Promotoras Genéticas , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: Two separate molecular pathways have been proposed for the early carcinogenic events observed in the oral cavity and pharynx: one is associated with chemical etiological factors such as smoking and drinking, and the other one is associated with HPV insertion. OBJECTIVE: A proof-of-principle study was performed to ascertain if global DNA methylation could be used to distinguish between the early molecular changes in premalignant oral lesions. METHODS: Personal histories of tobacco and alcohol use were obtained by questionnaire. HPV insertion in tumor tissue was detected by polymerase chain reaction (PCR). Global DNA methylation levels were obtained using HPLC for fraction separation and mass spectrometry for quantification. Predictive simulations were performed to explore potential associations between different etiological factors and the global DNA methylation index. Significance of results was ascertained using Pearson's Chi-squared test. RESULTS: The global methylation index was found to be 4.28 (95% CI, 4.1, 4.4) in an oral cancer case series. Pearson's chi squared test showed no statistically significant difference between cases that had smoking (p = 0.21), drinking (p = 0.31) or HPV insertion (p = 0.34) as etiologic risk factors, when compared to cases that did not. An inverse significant association between smoking and DNA methylation was observed. As the smoking effect increases, the global methylation index decreases, In addition, no associations between the probability of DNA methylation and drinking, or DNA methylation and HPV insertion were observed in simulations. CONCLUSIONS: The global DNA methylation index was shown to vary for oral cancer cases with different etiologies. Smoking was inversely correlated with DNA methylation levels when generalized linear model simulations were performed. Future studies should look at global DNA methylation alterations associated to the progression from normal to premalignant oral epithelium tissue in a cohort of smokers and nonsmokers.
