Pre and Post-high-intensity Interval Training Delays Colon Tumor Onset in a Syngeneic Mouse Model.

BACKGROUND/AIM: High-intensity interval training (HIIT) can trigger transient anti-tumor cytotoxicity through the mobilization of natural killer cells (NK cells) and myokines. Yet, the effects of HIIT on tumor development and microenvironment are unclear. MATERIALS AND METHODS: Male C57/BL6 mice were administered either MC38 of syngeneic colon cancer cells or vehicle in a single subcutaneous injection. Before injection, the training group completed four weeks of the HIIT program (progressive swimming training, 3/week, 10-12 min, 4-6% of body weight for overload). Following injection, trained mice continued to exercise for two additional weeks. RESULTS: Pre and post-HIIT training was effective in preventing tumor onset (p=0.0065), maintaining body weight gain, and counteracting splenomegaly by 40% compared to the tumor group. However, HIIT had no impact on suppressing tumor growth, modifying final tumor volume, or significantly changing tumor proliferation (Ki-67), connective tissue content, or DNA double-strand damage detected by phospho-histone gamma-H2AX (γ-H2AX). CONCLUSION: Pre and post-HIIT program is feasible for mice carrying a subcutaneous syngeneic tumor and effective in delaying tumor burden; however, HIIT did not alter colon tumor endpoints.

ALCAM is a biomarker of tumor aggressiveness and worse prognosis in glottic laryngeal squamous cell carcinoma.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the second most frequent head and neck tumor. Prognosis of patients with LSCC has not improved in recent decades, showing a need for the identification of prognostic biomarkers and new therapeutic targets. Recently, we showed that ALCAM overexpression was associated with glottic LSCC prognosis. OBJECTIVES AND METHODS: Aiming to validate the prognostic value of ALCAM, we evaluate the ALCAM protein levels by immunohistochemistry in 263 glottic LSCC surgically treated with neck dissection. RESULTS: ALCAM was expressed in 48.7% and overexpressed in 36.5% of glottic LSCC samples. ALCAM overexpression was associated with lymph node metastasis (p = 0.030), lymphovascular involvement (p = 0.0002), high-grade tumors (p = 0.025), and tumor relapse (p = 0.043). Multivariate survival analyses showed an overfitting between ALCAM overexpression and lymph node metastasis as a prognostic variable. CONCLUSIONS: High ALCAM expression was associated with an aggressive glottic LSCC profile.

Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population.

The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Interleukin 6 and Interleukin 1ß hypomethylation and overexpression are common features of apical periodontitis: A case-control study with gingival tissue as control.

OBJECTIVES: Apical periodontitis is a periradicular tissue disorder that usually arises from infection by microorganisms in the root canal system resulting in local bone resorption. This usually involves the dysregulation of inflammatory mediators, which can be mediated by epigenetic mechanisms. Thus, the objective of this study was to evaluate Interleukin 6 (IL6) and Interleukin 1ß (IL1ß) and DNA methylation and gene expression levels in apical periodontitis. METHODS: Gene expression was analyzed in 60 participants using quantitative polymerase chain reaction, while the methylation levels of IL6 and IL1ß promoters were analyzed in 72 patients using pyrosequencing. All statistical analyzes were performed using the GraphPad Prism software version 8.0. The p value was considered statistically significant when < 0.05. RESULTS: A significantly higher IL6 and IL1ß expression levels were observed in cases relative to controls (fold-changes of 27.4 and 11.43, respectively, and p < 0.0001). By comparing the same groups, lower promoter methylation levels were observed for both genes in cases (methylation percentage delta relative to controls of -24.57% and -16.02%, respectively, and p < 0.0001). A significant inverse correlation between gene expression and promoter methylation was observed for both IL6 (p = 0.0002) and IL1ß (p = 0.001). Neither IL6 expression nor promoter methylation were significantly associated with cases' age, smoking history, alcohol consumption history or sex. For IL1ß, alcoholic cases showed lower methylation level relative to non-alcoholic cases (p = 0.01), while females showed higher methylation levels relative to males (p = 0.03). CONCLUSIONS: Our data suggest a role for DNA methylation in IL6 and IL1ß upregulation in apical periodontitis.

Oral Lichen Planus and Oral Squamous Cell Carcinoma share key oncogenic signatures.

To investigate similarities in the gene profile of Oral Lichen Planus and Oral Squamous Cell Carcinoma that may justify a carcinogenic potential, we analyzed the gene expression signatures of Oral Lichen Planus and Oral Squamous Cell Carcinoma in early and advanced stages. Based on gene expression data from public databases, we used a bioinformatics approach to compare expression profiles, estimate immune infiltrate composition, identify differentially and co-expressed genes, and propose putative therapeutic targets and associated drugs. Our results revealed gene expression patterns related to processes of keratinization, keratinocyte differentiation, cell proliferation and immune response in common between Oral Lichen Planus and early and advanced Oral Squamous Cell Carcinoma, with the cornified envelope formation and antigen processing cross-presentation pathways in common between Oral Lichen Planus and early Oral Squamous Cell Carcinoma. Together, these results reveal that key tumor suppressors and oncogenes such as PI3, SPRR1B and KRT17, as well as genes associated with different immune processes such as CXCL13, HIF1A and IL1B are dysregulated in OLP.

Genome-Wide DNA Methylation Profiling of Esophageal Squamous Cell Carcinoma from Global High-Incidence Regions Identifies Crucial Genes and Potential Cancer Markers.

Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumor-specific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and South America. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Δß) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, PAX9, SIM2, and THSD4, had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization. SIGNIFICANCE: This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world identifies functionally relevant and robust DNAme events that could serve as potential tumor-specific markers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2612/F1.large.jpg.

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We examined the genome-wide DNA methylation profile of PDAC in an exploratory cohort including the comparative analyses of tumoral and non-tumoral pancreatic tissues (PT). Pathway enrichment analysis was used to choose differentially methylated (DM) CpGs with potential biological relevance. Additional samples were used in a validation cohort. DNA methylation impact on gene expression and its association with overall survival (OS) was investigated from PDAC TCGA (The Cancer Genome Atlas) data. Pathway analysis revealed DM genes in the calcium signaling pathway that is linked to the key pathways in pancreatic carcinogenesis. DNA methylation was frequently correlated with expression, and a subgroup of calcium signaling genes was associated with OS, reinforcing its probable phenotypic effect. Cluster analysis of PT samples revealed that some of the methylation alterations observed in the Calcium signaling pathway seemed to occur early in the carcinogenesis process, a finding that may open new insights about PDAC tumor biology.

Association of DNA sequence-independent genetic regulatory mechanisms with apical periodontitis: A scoping review.

OBJECTIVE: Different studies in the last decade have proposed that gene expression alterations that are independent of the DNA sequence may also play an important role in periapical disease. The present study aimed to assess the available evidence supporting a relationship between these alterations and apical periodontitis through a scoping review. DESIGN: Specific strategies were developed for different databases (MEDLINE via PubMed, Cochrane Library, Scopus, Web of Science, and Virtual Health Library) and a search performed by March 1st, 2019. The evidence sources were selected according to the eligibility criteria and underwent a critical appraisal of methodological quality. RESULTS: The initial search retrieved 212 references, with eight eligible articles after the removal of replicates and application of exclusion criteria. Five studies identified altered DNA methylation on inflammatory response genes (FOXP3, CXCL3, FADD, MMP2, MMP9, IFNG, IL4, IL12) on AP patients. Three others identified the alterations on the expression of several microRNAs (miR-29b, 106b, 125b, 143, 146a, 155, 198) during AP. No evidence was identified regarding mechanisms of histone methylation, or of epigenetic heritability or stability. CONCLUSIONS: There is available evidence for the involvement of different genetic regulatory mechanisms independent of changes in DNA sequence in the development or severity of apical periodontitis. However, due to methodological limitations, further research must be performed before novel therapies and diagnostic tools for AP may arise from these data.

Predictors of Survival After Head and Neck Squamous Cell Carcinoma in South America: The InterCHANGE Study.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) incidence is high in South America, where recent data on survival are sparse. We investigated the main predictors of HNSCC survival in Brazil, Argentina, Uruguay, and Colombia. METHODS: Sociodemographic and lifestyle information was obtained from standardized interviews, and clinicopathologic data were extracted from medical records and pathologic reports. The Kaplan-Meier method and Cox regression were used for statistical analyses. RESULTS: Of 1,463 patients, 378 had a larynx cancer (LC), 78 hypopharynx cancer (HC), 599 oral cavity cancer (OC), and 408 oropharynx cancer (OPC). Most patients (55.5%) were diagnosed with stage IV disease, ranging from 47.6% for LC to 70.8% for OPC. Three-year survival rates were 56.0% for LC, 54.7% for OC, 48.0% for OPC, and 37.8% for HC. In multivariable models, patients with stage IV disease had approximately 7.6 (LC/HC), 11.7 (OC), and 3.5 (OPC) times higher mortality than patients with stage I disease. Current and former drinkers with LC or HC had approximately 2 times higher mortality than never-drinkers. In addition, older age at diagnosis was independently associated with worse survival for all sites. In a subset analysis of 198 patients with OPC with available human papillomavirus (HPV) type 16 data, those with HPV-unrelated OPC had a significantly worse 3-year survival compared with those with HPV-related OPC (44.6% v 75.6%, respectively), corresponding to a 3.4 times higher mortality. CONCLUSION: Late stage at diagnosis was the strongest predictor of lower HNSCC survival. Early cancer detection and reduction of harmful alcohol use are fundamental to decrease the high burden of HNSCC in South America.

A reversible, switchable pH-driven quaternary ammonium pillar[5]arene nanogate for mesoporous silica nanoparticles.

Here we describe the assembly and pH-driven operation of two nanocarriers based on non-functionalized (MCM-41) and carboxylate-functionalized (MCM-41-COOH) containers loaded with the anticancer drug doxorubicin (DOX) and capped by quaternary ammonium pillar[5]arene (P[5]A) nanogates. MCM-41 and MCM-41-COOH containers were synthesized and transmission and scanning electron microscopies showed nanoparticles with spherical morphology and dimensions of 85 ± 13 nm. The nanochannels of MCM-41 loaded with DOX were gated through the electrostatic interactions between P[5]A and the silanolate groups formed at the silica-water interface, yielding the MCM-41-DOX-P[5]A nanocarrier. The second nanocarrier was gated through the electrostatic interactions between the carboxylate groups mounted on the surface of MCM-41 and P[5]A, resulting in the MCM-41-COO-DOX-P[5]A nanocarrier. The DOX release profiles from both nanocarriers were investigated by UV-vis spectroscopy at different pH values (2.0, 5.5 and 7.4) and also in the presence of ions, such as citrate3- (19 mmol L-1) and Zn2+ (1.2 and 50 mmol L-1) at 37 °C. MCM-41-COO-DOX-P[5]A can be turned on and off eight times through the formation and breaking of electrostatic interactions. In vitro studies show that MCM-41-COO-DOX-P[5]A can penetrate and release DOX in the nucleus of human breast adenocarcinoma MCF-7 cancer cells leading to a pronounced cytotoxic effect. Therefore, the fabricated nanocarrier based on a water-soluble cationic pillar[5]arene nanogate, which is reversibly opened and closed by electrostatic interactions, can be considered as a promising drug transport and delivery technique for future cancer therapy.

How pathological criteria can impact prognosis of tongue and floor of the mouth squamous cell carcinoma.

other: Pathological parameters have been indicated as tumor prognostic factors in oral carcinoma. OBJECTIVE: The objective of this study was to investigate the impact of pathological parameters on prognosis of patients affected only by tongue and/or floor of the mouth squamous cell carcinoma (SCC). METHODOLOGY: In total, 380 patients treated in the Brazilian National Cancer Institute (INCA) from 1999 to 2006 were included. These patients underwent radical resection followed by neck dissection. The clinical and pathological characteristics were recorded. The Kaplan-Meier method and Cox proportional hazards model were used in survival analysis. Overall survival (OS), cancer-specific survival (CSS) and disease-free interval (DFI) were estimated. Cox residuals were evaluated using the R software version 3.5.2. Worst OS, CSS and DFI were observed in patients with tumors in advanced pathological stages (p<0.001), with the presence of perineural invasion (p<0.001) and vascular invasion (p=0.005). RESULTS: Advanced pathological stage and the presence of a poorly differentiated tumor were independent prognostic factors for OS and CSS. However, advanced pathological stage and perineural invasion were independent predictors of a shorter OS, DFI and CSS. CONCLUSION: Pathological stage and perineural invasion were the most significant pathological variables in survival analysis in tongue and/or floor of the mouth SCC.

How pathological criteria can impact prognosis of tongue and floor of the mouth squamous cell carcinoma

Abstract Pathological parameters have been indicated as tumor prognostic factors in oral carcinoma. Objective: The objective of this study was to investigate the impact of pathological parameters on prognosis of patients affected only by tongue and/or floor of the mouth squamous cell carcinoma (SCC). Methodology: In total, 380 patients treated in the Brazilian National Cancer Institute (INCA) from 1999 to 2006 were included. These patients underwent radical resection followed by neck dissection. The clinical and pathological characteristics were recorded. The Kaplan-Meier method and Cox proportional hazards model were used in survival analysis. Overall survival (OS), cancer-specific survival (CSS) and disease-free interval (DFI) were estimated. Cox residuals were evaluated using the R software version 3.5.2. Worst OS, CSS and DFI were observed in patients with tumors in advanced pathological stages (p<0.001), with the presence of perineural invasion (p<0.001) and vascular invasion (p=0.005). Results: Advanced pathological stage and the presence of a poorly differentiated tumor were independent prognostic factors for OS and CSS. However, advanced pathological stage and perineural invasion were independent predictors of a shorter OS, DFI and CSS. Conclusion: Pathological stage and perineural invasion were the most significant pathological variables in survival analysis in tongue and/or floor of the mouth SCC.

Overweight and obesity do not determine worst prognosis in endometrioid endometrial carcinoma.

PURPOSE: The aim of this study was to investigate the impact of body mass index (BMI) on disease-free survival (DFS) and overall survival (OS) in women diagnosed with EEC and treated at the Brazilian National Cancer Institute. METHODS: The study comprised 849 women diagnosed with EEC who underwent surgical treatment between January, 2000 and December, 2011. The demographic and clinical characteristics of these patients were collected from medical records and their nutritional status was based on the BMI criteria. Univariate (OS and DFS) and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazards models, respectively. RESULTS: About 83.2% of patients were obese or overweight at time of diagnosis, with a mean BMI of 31.83. Patients were followed for an average of 34.97 months. There were 111 recurrences (13.1%) and 140 deaths (16.5%), with mean DFS of 51.90 months and mean OS of 52.25 months. There was no significant association between BMI and DFS or OS. In multivariate analysis we did not find an increased hazard of recurrence or death among overweight or obese patients. CONCLUSION: Overweight and obesity had no impact on EEC prognosis on the assessed cohort. Further studies are warranted.

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy.

Esophageal cancer (EC) is one of the most lethal cancers and a public health concern worldwide, owing to late diagnosis and lack of efficient treatment. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are main histopathological subtypes of EC that show striking differences in geographical distribution, possibly due to differences in exposure to risk factors and lifestyles. ESCC and EAC are distinct diseases in terms of cell of origin, epidemiology, and molecular architecture of tumor cells. Past efforts aimed at translating potential molecular candidates into clinical practice proved to be challenging, underscoring the need for identifying novel candidates for early diagnosis and therapy of EC. Several major international efforts have brought about important advances in identifying molecular landscapes of ESCC and EAC toward understanding molecular mechanisms and critical molecular events driving the progression and pathological features of the disease. In our review, we summarize recent advances in the areas of genomics and epigenomics of ESCC and EAC, their mutational signatures and immunotherapy. We also discuss implications of recent advances in characterizing the genome and epigenome of EC for the discovery of diagnostic/prognostic biomarkers and development of new targets for personalized treatment and prevention.

Esophageal squamous cell carcinoma transcriptome reveals the effect of FOXM1 on patient outcome through novel PIK3R3 mediated activation of PI3K signaling pathway.

Esophageal squamous cell carcinoma (ESCC) presents poor prognosis, and patients diagnosed with this tumor currently lack target treatments. Therefore, in order to identify potential targets for ESCC treatment, we carried out a transcriptome analysis with ESCC and paired nonmalignant surrounding mucosa samples, followed by a master regulator analysis, and further explored the role of the identified central regulatory genes through in vivo and in vitro assays. Among the transcription factors deregulated/enriched in ESCC, we focused on FOXM1 because of its involvement in the regulation of critical biological processes. A new transcriptome analysis performed with ESCC cell lineage TE-1 showed that the modulation of FOXM1 expression resulted in PIK3R3 expression changes, whereas chromatin immunoprecipitation assay revealed that FOXM1 was capable of binding onto PIK3R3 promoter, thus demonstrating that PIK3R3 is a new FOXM1 target. Furthermore, FOXM1 overexpression resulted in the activation of PIK3/AKT signaling pathway through PIK3R3-mediated AKT phosphorylation. Finally, the analysis of the clinic-pathological data of ESCC patients revealed that overexpression of both FOXM1 and PIK3R3 was associated with poor prognosis, but only the latter was an independent prognosis factor for ESCC patients. In conclusion, our results show that FOXM1 seems to play a central role in ESCC carcinogenesis by upregulating many oncogenes found overexpressed in this tumor. Furthermore, PIK3R3 is a novel FOXM1 target that triggers the activation of the PI3K/AKT pathway in ESCC cells.

Ionizing Radiation Deregulates the MicroRNA Expression Profile in Differentiated Thyroid Cells.

BACKGROUND: Ionizing radiation (IR) is a well-known risk factor for papillary thyroid cancer, and it has been reported to deregulate microRNA expression, which is important to thyroid carcinogenesis. Therefore, this study investigated the impact of IR on microRNA expression profile of the normal thyroid cell line (FRTL-5 CL2), as well as its effect on radiosensitivity of thyroid cancer cell lines, especially the human anaplastic thyroid carcinoma cell line (8505c). METHODS: The global microRNA expression profile of irradiated FRTL-5 CL2 cells (5 Gy X-ray) was characterized, and data were confirmed by quantitative real-time polymerase chain reaction evaluating the expression of rno-miR-10b-5p, rno-miR-33-5p, rno-miR-128-1-5p, rno-miR-199a-3p, rno-miR-296-5p, rno-miR-328a-3p, and rno-miR-541-5p in irradiated cells. The miR-199a-3p and miR-10b-5p targets were validated by quantitative real-time polymerase chain reaction, Western blot, and luciferase target assays. The effects of miR-199a-3p and miR-10b-5p on DNA repair were determined by evaluating the activation of the protein kinases ataxia-telangiectasia mutated, ataxia telangiectasia, and Rad3-related and the serine 39 phosphorylation of variant histone H2AX as an indirect measure of double-strand DNA breaks in irradiated FRTL-5 CL2 cells. The impact of miR-10b-5p on radiosensitivity was analyzed by cell counting and MTT assays in FRTL-5 CL2, Kras-transformed FRTL-5 CL2 (FRTL KiKi), and 8505c cell lines. RESULTS: The results reveal that miR-10b-5p and miR-199a-3p display the most pronounced alterations in expression in irradiated FRTL-5 CL2 cells. Dicer1 and Lin28b were validated as targets of miR-10b-5p and miR-199a-3p, respectively. Functional studies demonstrate that miR-10b-5p increases the growth rate of FRTL-5 CL2 cells, while miR-199a-3p inhibits their proliferation. Moreover, both of these microRNAs negatively affect homologous recombination repair, reducing activated ataxia-telangiectasia mutated and Rad3-related protein levels, consequently leading to an accumulation of the serine 39 phosphorylation of variant histone H2AX. Interestingly, the overexpression of miR-10b-5p decreases the viability of the irradiated FRTL5-CL2 and 8505c cell lines. Consistent with this observation, its inhibition in FRTL KiKi cells, which display high basal expression levels of miR-10b-5p, leads to the opposite effect. CONCLUSIONS: These results demonstrate that IR deregulates microRNA expression, affecting the double-strand DNA breaks repair efficiency of irradiated thyroid cells, and suggest that miR-10b-5p overexpression may be an innovative approach for anaplastic thyroid cancer therapy by increasing cancer cell radiosensitivity.

Perfil dos Pacientes com Câncer de Esôfago Diagnosticados entre 2001 e 2010 no Brasil / Profile of Patients with Esophageal Cancer Diagnosed Between 2001 and 2010 in Brazil / Perfil de los Pacientes con Cáncer de Esófago Diagnosticados entre 2001 y 2010 en Brasil

Introdução: O câncer de esôfago é a terceira neoplasia mais comum do trato digestivo e apresenta prognóstico ruim quando diagnosticado em estádios avançados da doença. Objetivo: Descrever as características sociodemográficas, clínicas e de tratamento dos pacientes diagnosticados com câncer de esôfago no Brasil, no período de 2001 a 2010. Método: Estudo transversal de base secundária em pacientes com câncer de esôfago, cadastrados entre 2001 e 2010, nos Registros Hospitalares de Câncer. Foram analisadas as variáveis sociodemográficas, clínicas e de tratamento. Foi realizada análise descritiva utilizando média e desvio-padrão para as variáveis contínuas, e frequência absoluta e relativa para as categóricas. Resultados: Foram incluídos 24.204 pacientes, com média de idade de 60,8 anos (±11,5). A maioria da população era do sexo masculino (78,3%), de baixa escolaridade (75,2%), etilista (62,9%), tabagista (76,0%) e com estádio avançado ao diagnóstico (41,3% em estádio clínico III e 26,9%, IV), sendo o grupo topográfico de maior prevalência o esôfago superior e médio (76,4%). Não foram submetidos a nenhum tratamento oncológico 12,7% dos pacientes. Os tratamentos mais frequentes foram a combinação entre radioterapia e quimioterapia (25,6%) e o tratamento isolado com radioterapia (21,9%). Ao final do primeiro tratamento oncológico, 10,7% estavam sem evidência de doença, 8,4% com remissão parcial, 26,6% com doença estável e, os demais, com doença em progressão ou óbito (54,4%). Conclusão: No Brasil, os casos diagnosticados por câncer de esôfago são, em sua maioria, diagnosticados em estádios avançados da doença, o que representou maior agressividade terapêutica e pior resposta ao tratamento.

Introduction: Esophageal cancer is the third most common neoplasm of the digestive tract and presents poor prognosis when diagnosed in advanced stages of the disease. Objective: To describe the socio-demographic, clinical and treatment characteristics of patients diagnosed with esophageal cancer in Brazil, from 2001 to 2010. Method: A cross-sectional study of patients with esophageal cancer registered between 2001 and 2010 in Hospital-based registries. Socio-demographic, clinical and treatment variables were analyzed. Descriptive analysis was performed using mean and standard deviation for continuous variables, and absolute and relative frequency for categorical variables. Results: A total of 24,204 patients were included, with a mean age of 60.8 years (± 11.5). The majority of the population was male (78.3%), with a low level of schooling (75.2%), alcoholics (62.9%), smokers (76.0%), and had an advanced stage of diagnosis (41.3% in clinical stage III and 26.9% in stage IV), the topographic group being the most prevalent was in the esophagus upper and middle (76.4%). 12.7% of the patients were not submitted to any cancer treatment. The most frequent treatments were the combination of radiotherapy and chemotherapy (25.6%), and treatment alone with radiotherapy (21.9%). At the end of the first cancer treatment, 10.7% had no evidence of disease, 8.4% had partial remission, 26.6% had a stable disease, and the remaining patients had progression or death (54.4%). Conclusion: In Brazil, the cases diagnosed for esophageal cancer are mostly diagnosed in advanced stages of the disease, which represents greater therapeutic aggressiveness and worse response to treatment.

Introducción: El cáncer de esófago es la tercera neoplasia más común del tracto digestivo y presenta un pronóstico malo cuando se diagnostica en estadios avanzados de la enfermedad. Objetivo: Describir las características sociodemográficas, clínicas y de tratamiento de los pacientes diagnosticados con cáncer de esófago en Brasil, en el período de 2001 a 2010. Método:Estudio transversal de base secundaria en pacientes con cáncer de esófago, registrados entre 2001 y 2010, en los Registros Hospitalarios de Cáncer. Se analizaron las variables sociodemográficas, clínicas y de tratamiento. Se realizó un análisis descriptivo utilizando media y desviación estándar, para las variables continuas, y frecuencia absoluta y relativa para las categóricas. Resultados: Se incluyeron 24.204 pacientes, con una media de edad de 60,8 años (±11,5). La mayoría de la población era del sexo masculino (78,3%), de baja escolaridade (75,2%), etilista (62,9%), tabaquista (76,0%) y con estadio avanzado al diagnóstico (41,3% en estadio clínico III y 26,9% en estadio IV), siendo el grupo topográfico de mayor prevalencia el esófago superior y medio (76,4%). No fueron sometidos a ningún tratamiento oncológico, el 12,7% de los pacientes. Los tratamientos más frecuentes fueron la combinación entre radioterapia y quimioterapia (25,6%), y el tratamiento aislado con radioterapia (21,9%). Al final del primer tratamiento oncológico, el 10,7% estaba sin evidencia de enfermedad, el 8,4% con remisión parcial, el 26,6% con enfermedad estable y los demás, con enfermedad en progresión o muerte (54,4%). Conclusión: En Brasil, los casos diagnosticados por cáncer de esófago son en su mayoría, diagnosticados en estadios avanzados de la enfermedad, lo que representó mayor agresividad terapéutica y peor respuesta al tratamiento.

Role of Dicer1 in thyroid cell proliferation and differentiation.

DICER1 plays a central role in the biogenesis of microRNAs and it is important for normal development. Altered microRNA expression and DICER1 dysregulation have been described in several types of tumors, including thyroid carcinomas. Recently, our group identified a new somatic mutation (c.5438A>G; E1813G) within DICER1 gene of an unknown function. Herein, we show that DICER1 is overexpressed, at mRNA level, in a significant-relative number of papillary (70%) and anaplastic (42%) thyroid carcinoma samples, whereas is drastically downregulated in all the analyzed human thyroid carcinoma cell lines (TPC-1, BCPAP, FRO and 8505c) in comparison with normal thyroid tissue samples. Conversely, DICER1 is downregulated, at protein level, in PTC in comparison with normal thyroid tissues. Our data also reveals that DICER1 overexpression positively regulates thyroid cell proliferation, whereas its silencing impairs thyroid cell differentiation. The expression of DICER1 gene mutation (c.5438A>G; E1813G) negatively affects the microRNA machinery and cell proliferation as well as upregulates DICER1 protein levels of thyroid cells but has no impact on thyroid differentiation. In conclusion, DICER1 protein is downregulated in papillary thyroid carcinomas and affects thyroid proliferation and differentiation, while DICER1 gene mutation (c.5438A>G; E1813G) compromises the DICER1 wild-type-mediated microRNA processing and cell proliferation.

Intrinsic LINE-1 Hypomethylation and Decreased Brca1 Expression are Associated with DNA Repair Delay in Irradiated Thyroid Cells.

Exposure to ionizing radiation greatly increases the risk of developing papillary thyroid carcinoma (PTC), especially during childhood, mainly due to gradual inactivation of DNA repair genes and DNA damages. Recent molecular characterization of PTC revealed DNA methylation deregulation of several promoters of DNA repair genes. Thus, epigenetic silencing might be a plausible mechanism for the activity loss of tumor suppressor genes in radiation-induced thyroid tumors. Herein, we investigated the impact of ionizing radiation on global methylation and CpG islands within promoter regions of homologous recombination (HR) and non-homologous end joining (NHEJ) genes, as well as its effects on gene expression, using two well-established normal differentiated thyroid cell lines (FRTL5 and PCCL3). Our data reveal that X-ray exposure promoted G2/M arrest in normal thyroid cell lines. The FRTL5 cells displayed a slower kinetics of double-strand breaks (DSB) repair and a lower long interspersed nuclear element-1 (LINE-1) methylation than the PCCL3 cells. Nevertheless, acute X-ray exposure does not alter the expression of genes involved in HR and NHEJ pathways, apart from the downregulation of Brca1 in thyroid cells. On the other hand, HR and NHEJ gene expressions were upregulated in radiation-induced senescent thyroid cells. Taken together, these data suggest that FRTL5 cells intrinsically have less efficient DNA DSB repair machinery than PCCL3 cells, as well as genomic instability, which could predispose the FRTL5 cells to unrepaired DSB lesions and, therefore, gene mutations.