Search

We investigate patients undergoing treatment for head and neck cancer (HNC) who had mucositis. The most were male, literate, white, smokers and and alcoholics. Mucositis is associated with age over 65 years and alcohol (age:OR:0.52;CI:0.37 0.74;p = 0.000/Alcohol:OR:1.90;CI:1.25–2.87;p = 0.002). There is significance for oropharyngeal site (OR:1.58;CI:1.02–2.43;p = 0.039), advanced clinical stage (OR:2.39;CI:1.18–4.85;p = 0.016) and chemotherapy (OR:0.61;CI: 0.41–0.91;p = 0.016) with mucositis. Grade 1 mucositis was present in 55.2% of patients, followed by 23.6% with grade 2 and 21.1% with grade 3. A total of 57.09% of patients with mucositis were submitted to lasertherapy and the mean time between the beginning of the treatment and the complaint of mucositis was six months; the mean time between the complaint of mucositis and the beginning of lasertherapy was 33 days. Normality test showed that there is a difference in the groups: mucositis Initial degree (K2 = 55.17

Cancer biologists have focused on studying cancer stem cells (CSCs) because of their ability to self-renew and recapitulate tumor heterogeneity, which increases their resistance to chemotherapy and is associated with cancer relapse. Here, we used two approaches to isolate CSCs: the first involved the metabolic enzyme aldehyde dehydrogenase ALDH, and the second involved the three cell surface markers CD44, CD117, and CD133. ALDH cells showed a higher zinc finger E-box binding homeobox 1 (ZEB1) microRNA (miRNA) expression than CD44/CD117/133 triple-positive cells, which overexpressed miRNA 200c-3p: a well-known microRNA ZEB1 inhibitor. We found that ZEB1 inhibition was driven by miR-101-3p, miR-139-5p, miR-144-3p, miR-199b-5p, and miR-200c-3p and that the FaDu Cell Line inhibition occurred at the mRNA level, whereas HN13 did not affect mRNA expression but decreased protein levels. Furthermore, we demonstrated the ability of the ZEB1 inhibitor miRNAs to modulate CSC-related genes, such as TrkB, ALDH, NANOG, and HIF1A, using transfection technology. We showed that ALDH was upregulated upon ZEB1-suppressed miRNA transfection (Mann–Whitney ** p101 = 0.009, t-test ** p139 = 0.009, t-test ** p144 = 0.002, and t-test *** p199 = 0.0006). Overall, our study enabled an improved understanding of the role of ZEB1-suppressed miRNAs in CSC biology.

Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), results in a broad range of phenotypes. However, the determinants contributing to the complex and variable phenotypic expression of DS are still not fully known. Changes in microRNAs (miRNAs), short non-coding RNA molecules that regulate gene expression post-transcriptionally, have been associated with some DS phenotypes. Here, we investigated the genome-wide mature miRNA expression profile in peripheral blood mononuclear cells (PBMCs) of children with DS and controls and identified biological processes and pathways relevant to the DS pathogenesis. The expression of 754 mature miRNAs was profiled in PBMCs from six children with DS and six controls by RT-qPCR using TaqMan® Array Human MicroRNA Cards. Functions and signaling pathways analyses were performed using DIANA-miRPath v.3 and DIANA-microT-CDS software. Children with DS presented six differentially expressed miRNAs (DEmiRs): four overexpressed (miR-378a-3p, miR-130b-5p, miR-942-5p, and miR-424-3p) and two downregulated (miR-452-5p and miR-668-3p). HSA21-derived miRNAs investigated were not found to be differentially expressed between the groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed potential target genes involved in biological processes and pathways pertinent to immune response, e.g., toll-like receptors (TLRs) signaling, Hippo, and transforming growth factor β (TGF-β) signaling pathways. These results suggest that altered miRNA expression could be contributing to the well-known immunological dysfunction observed in individuals with DS. Supplementary Information The online version contains supplementary material available at 10.1007/s13577-022-00672-x.

This study was performed to investigate the relationship between polymorphisms in microsomal epoxide hydrolase (mEH; Tyr113His and His139Arg substitution) and glutathione S-transferase (GST; GSTM1 deletion, GSTT1 deletion, and GSTP1.Ala114Val substitution) and their correlation with clinico-histopathological features in hepatocellular carcinoma (HCC).We evaluated environmental risk factors and genetic alterations in 556 individuals (86 cases and 470 controls). PCR multiplex for GSTM1 and GSTT1, polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) for GSTP1, and real-time PCR for mEH were performed. Statistical analyses were performed using multiple logistic regression tests.Age over 48 years (p p = 0.021) were the predictors of increased risk of developing HCC. GSTP1.Ala114Val for all regression models (p GSTT1 null genotype (odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.21–0.87, p = 0.019) were predictors of an increased risk of developing HCC. Polymorphic GSTT1, GSTM1, GSTP1.Ala114Val, and mEH.His139Arg and wild-type mEH.Tyr113His (OR = 5.04; 95% CI = 1.59–16.04; p = 0.006) were associated with HCC.Age over 48 years, alcohol consumption, and the presence of polymorphic variants of GSTP1 and GSTT1 were associated with the risk of developing HCC. This study was performed to investigate the relationship between polymorphisms in microsomal epoxide hydrolase (mEH; Tyr113His and His139Arg substitution) and glutathione S-transferase (GST; GSTM1 deletion, GSTT1 deletion, and GSTP1.Ala114Val substitution) and their correlation with clinico-histopathological features in hepatocellular carcinoma (HCC). We evaluated environmental risk factors and genetic alterations in 556 individuals (86 cases and 470 controls). PCR multiplex for GSTM1 and GSTT1, polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) for GSTP1, and real-time PCR for mEH were performed. Statistical analyses were performed using multiple logistic regression tests. Age over 48 years (p p = 0.021) were the predictors of increased risk of developing HCC. GSTP1.Ala114Val for all regression models (p GSTT1 null genotype (odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.21–0.87, p = 0.019) were predictors of an increased risk of developing HCC. Polymorphic GSTT1, GSTM1, GSTP1.Ala114Val, and mEH.His139Arg and wild-type mEH.Tyr113His (OR = 5.04; 95% CI = 1.59–16.04; p = 0.006) were associated with HCC. Age over 48 years, alcohol consumption, and the presence of polymorphic variants of GSTP1 and GSTT1 were associated with the risk of developing HCC.

Mutations and alterations in the expression of VEGFA, KRAS, and NFE2L2 oncogenes play a key role in cancer initiation and progression. These genes are enrolled not only in cell proliferation control, but also in angiogenesis, drug resistance, metastasis, and survival of tumor cells. MicroRNAs (miRNAs) are small, non-coding regulatory RNA molecules that can regulate post-transcriptional expression of multiple target genes. We aimed to investigate if miRNAs hsa-miR-17-5p, hsa-miR-140-5p, and hsa-miR-874-3p could interfere in VEGFA, KRAS, and NFE2L2 expression in cell lines derived from head and neck cancer (HNC). FADU (pharyngeal cancer) and HN13 (oral cavity cancer) cell lines were transfected with miR-17-5p, miR-140-5p, and miR-874-3p microRNA mimics. RNA and protein expression analyses revealed that miR-17-5p, miR-140-5p and miR-874-3p overexpression led to a downregulation of VEGFA, KRAS, and NFE2L2 gene expression in both cell lines analyzed. Taken together, our results provide evidence for the establishment of new biomarkers in the diagnosis and treatment of HNC.

To investigate the association between sociodemographic factors and variables related to oral health services in oral and oropharyngeal cancer mortality in Brazil, between 2000 and 2019. This study had an ecological design. Standardized mortality rates were compared between age group, sex, and regions. Age–Period–Cohort analysis was applied. Oral health services variables were analyzed in correlation tests. Survival analysis included Kaplan–Meier estimators, log-rank tests, and Cox regression. The mortality rate increased with age and was higher in men. Southeast and south regions had the highest rates for men, and the northeast and southeast had it for women. Age–Period–Cohort analysis showed a slight increase in female deaths and an increasing trend in the annual percent change in mortality for men over age 55. In survival analysis, males, Black individuals and southern residents were more strongly associated with death. The correlation between oral health teams’ coverage was high and negative, while the number of dental specialty centers and soft tissue biopsies had a high and positive correlation. Mortality and survival patterns were dependent on sex, age, geographic region and race/ethnicity. It was observed that preventive and diagnostic procedures were not being performed, which may be related to the increase in mortality.

Background: Folate is essential for DNA synthesis, repair, and methylation. Polymorphisms in genes associated with folate metabolism may alter these processes and, consequently, modulate cancer development. Aim: We aimed to assess DNMT3B -149C/T (rs2424913), DNMT3B -283T/C (rs6087990), DNMT3B -579G/T (rs2424909), DHFR 19-pb ins/del (rs70991108), SHMT1 1420C/T (rs1979277), and TYMS 28-bp tandem repeat (rs34743033) polymorphisms with risk of head and neck cancer. Methods: A case-control study was conducted in 1,086 Brazilian individuals. Real-time and conventional polymerase chain reactions-PCR were performed for genotyping the polymorphisms. Results: The single nucleotide polymorphism (SNP), DNMT3B -283T/C, revealed a higher risk of head and neck squamous cell carcinoma (HNSCC) when compared with the C group in the codominant (p < 0.001), dominant (p

BACKGROUND Regional heterogeneities and sociodemographic characteristics affect mortality and population survival in Brazil. However, for individuals with Down syndrome (DS) this information remains unknown. In this study, we analysed survival and mortality rates among DS individuals in the five Brazilian geographic regions. In addition, we investigated whether there is an association between mortality and sociodemographic factors across administrative regions. METHODS Data between 1996 and 2016, comprising 10 028 records of deaths of individuals with DS, were collected from database records of the Department of Informatics of the Unified Health System. Data on race/ethnicity, sex, age and years of schooling were defined for the association analyses. Survival data were analysed according to the Kaplan-Meier method and Cox regression model. RESULTS The number of deaths among people with DS has increased in recent years. Children are more susceptible to death, especially in the first years of life. Individuals living in the northern region, Indigenous women and people with no years of schooling have higher mortality. In the Southeast and South region, for White and Yellow, survival is related to a higher level of education. Ethnic factors and years of schooling influence risk for mortality across the administrative regions. CONCLUSIONS These findings show that sociodemographic characteristics affect survival and are associated with the risk of mortality for people with DS. In addition, this suggests that differences in access to health services among Brazilian regions, especially in the first years of life, may affect the survival of individuals with DS.

Made available in DSpace on 2020-12-10T20:00:39Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-05-15 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) BACKGROUND Toll-like receptor-2 (TLR2) is responsible for recognizing Helicobacter pylori (H. pylori) and activating the immune response. Polymorphisms in TLR2 may modulate gastric carcinogenesis. AIM To evaluate whether the TLR2 19216T/C (rs3804099) and TLR2 -196 to -174 ins/del (rs111200466) polymorphisms contribute to gastric carcinogenesis in the Brazilian population, and to determine the influence of both polymorphisms and H. pylori infection on TLR2 mRNA expression. METHODS DNA was extracted from 854 peripheral blood leukocyte or gastric tissue samples [202 gastric cancer (GC), 269 chronic gastritis (CG), and 383 control/healthy (C)] and genotyped by allele-specific PCR or restriction fragment length polymorphism (RFLP)-PCR. Quantitative polymerase chain reaction by TaqMan(R) assay was used to quantify TLR2 mRNA levels in fresh gastric tissues (48 GC, 36 CG, and 14 C). RESULTS Regarding the TLR2 -196 to -174 polymorphism, the ins/del and del/del genotypes were associated with a higher risk of GC by comparison with the C in all of the analyzed inheritance models (codominant, dominant, recessive, overdominant and log-additive; P < 0.0001). Similarly, an increased risk was observed when comparing the GC and CG groups [codominant (P < 0.0001), dominant (P < 0.0001), recessive (P = 0.0260), overdominant (P < 0.0001) and log-additive (P < 0.0001)]. In contrast, TLR2 19216T/C was associated with a protective effect in the GC group compared to the C group [dominant (P = 0.0420) and log-additive (P = 0.0300)]. Regarding the association of polymorphisms with H. pylori infection, individuals infected with H. pylori and harboring the TLR2 -196 to -174 ins/del polymorphism had an increased risk of gastric carcinogenesis [codominant (P = 0.0120), dominant (P = 0.0051), overdominant (P = 0.0240) and log-additive (P = 0.0030)], while TLR2 19216T/C was associated with a protective effect [codominant (P = 0.0039), dominant (P < 0.0001), overdominant (P = 0.0097) and log-additive (P = 0.0021)]. TLR2 mRNA levels were significantly increased in the GC group (median RQ = 6.95) compared to the CG group (RQ = 0.84, P < 0.0001) and to the normal mucosa group (RQ = 1.0). In addition, both H. pylori infection (P < 0.0001) and the presence of the polymorphic TLR2 -196 to -174del (P = 0.0010) and TLR2 19216 C (P = 0.0004) alleles influenced TLR2 mRNA expression. CONCLUSION The TLR2 -196 to -174 ins/del and TLR2 19216 T/C polymorphisms are strongly associated with GC. TLR2 mRNA expression levels are upregulated in neoplastic tissues and influenced by both the presence of H. pylori and variant genotypes. Univ Sagrado Coracao, Dept Grad Level Res, BR-17011970 Bauru, SP, Brazil Sao Jose do Rio Preto Sch Med, Dept Mol Biol, BR-15090000 Sao Jose Do Rio Preto, SP, Brazil Sao Paulo State Univ, Dept Biol, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil Sao Paulo State Univ, Dept Biol, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil FAPESP: 2013/14022-6 FAPESP: 2014/177161

Made available in DSpace on 2022-04-29T08:32:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-01 Down syndrome (DS) is the most common chromosomal disorder, resulting from the failure of normal chromosome 21 segregation. Studies have suggested that impairments within the one-carbon metabolic pathway can be of relevance for the global genome instability observed in mothers of individuals with DS. Based on the association between global DNA hypomethylation, genome instability, and impairments within the one-carbon metabolic pathway, the present study aimed to identify possible predictors, within the one-carbon metabolism, of global DNA methylation, measured by methylation patterns of LINE-1 and Alu repetitive sequences, in mothers of individuals with DS and mothers of individuals without the syndrome. In addition, we investigated one-carbon genetic polymorphisms and metabolites as maternal predisposing factors for the occurrence of trisomy 21 in children. Eighty-three samples of mothers of children with DS with karyotypically confirmed free trisomy 21 (case group) and 84 of mothers who had at least one child without DS or any other aneuploidy were included in the study. Pyrosequencing assays were performed to access global methylation. The results showed that group affiliation (case or control), betaine-homocysteine methyltransferase (BHMT) G742A and transcobalamin 2 (TCN2) C776G polymorphisms, and folate concentration were identified as predictors of global Alu DNA methylation values. In addition, thymidylate synthase (TYMS) 28-bp repeats 2R/3R or 3R/3R genotypes are independent maternal predisposing factors for having a child with DS. This study adds evidence that supports the association of impairments in the one-carbon metabolism, global DNA methylation, and the possibility of having a child with DS. Unidade de Pesquisa em Genética e Biologia Molecular-UPGEM Departamento de Biologia Molecular Faculdade de Medicina de São José do Rio Preto-FAMERP Hospital Israelita Albert Einstein Molecular Oncology Research Center Barretos Cancer Hospital Universidade Estadual Paulista Júlio de Mesquita Filho Instituto de Biociências Letras e Ciências Exatas de São José do Rio Preto Departamento de Ciências Biológicas Universidade Presbiteriana Mackenzie Discovery-Mackenzie-Núcleo Mackenzie de Pesquisa Núcleo Mackenzie de Pesquisas em Ciência Fé e Sociedade Instituto de Pesquisa Dr. Domingos A. Boldrini Laboratório de Nutrição Departamento de Clínica Médica Faculdade de Medicina de Ribeirão Preto-USP Fleury-Centro de Medicina Diagnóstica Universidade Estadual Paulista Júlio de Mesquita Filho Instituto de Biociências Letras e Ciências Exatas de São José do Rio Preto Departamento de Ciências Biológicas

We investigated the association between methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthetase (MTR A2756G), and methionine synthase reductase (MTRR A66G) polymorphisms involved in folate pathway and breast cancer risk, and the interaction between these polymorphisms and tobacco and alcohol consumption. Furthermore, we evaluated the association between these polymorphisms and clinicopathological variables. This case-control study included 606 Brazilian women, comprising 128 patients with breast cancer and 478 controls. MTHFR and MTR polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and MTRR polymorphisms using real-time PCR. Age ≥50 years (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.65-4.26; p

Introduction Liver cirrhosis (LC) is a heterogeneous liver disease, the last stage of liver fibrosis, and the major risk factor for hepatocellular carcinoma (HCC). Our study aimed to evaluate the expression of microRNAs and the endothelial vascular growth factor (VEGFA) gene in LC and HCC. Material and methods The sample group consisted of 46 tissue samples: 21 of LC, 15 of HCC, and 10 of non-tumoural and non-cirrhotic liver tissue (control group). MiRNAs were chosen based on a mirDIP prediction database as regulators of the VEGFA gene. Gene expression of VEGF and miRNAs was quantified by real-time quantitative polymerase chain reaction. VEGFA protein expression was evaluated by ELISA. Results VEGFA gene expression was significantly overexpressed in LC compared to the control group (p < 0.0001). Hsa-miR-206 (p = 0.0313) and hsa-miR-637 (p = 0.0156) were down-expressed in LC. In HCC, hsa-miR-15b (p = 0.0010), hsa-miR-125b (p = 0.0010), hsa-miR-423-3p (p = 0.0010), hsa-miR-424 (p = 0.0313), hsa-miR-494 (p < 0.0001), hsa-miR-497 (p < 0.0001), hsa-miR-612 (p = 0.0078), hsa-miR-637 (p < 0.0001), and hsa-miR-1255b (p = 0.0156) presented down-expression. Conclusions Overexpression of VEGFA in LC suggests impairment of angiogenesis in this tissue. The differential expression of microRNAs in LC and HCC observed in our study can lead to the evaluation of possible biomarkers for these diseases.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide and is characterized by a fast-paced growth. Like other solid tumors, the HNSCC growth rate results in the development of hypoxic regions identified by the expression of hypoxia-inducible factor 1α (HIF-1α). Interestingly, clinical data have shown that pharmacological induction of intratumoral hypoxia caused an unexpected rise in tumor metastasis and the accumulation of cancer stem cells (CSCs). However, little is known on the molecular circuitries involved in the presence of intratumoral hypoxia and the augmented population of CSCs. Here we explore the impact of hypoxia on the behavior of HNSCC and define that the controlling function of phosphatase and tensin homolog (PTEN) over HIF-1α expression and CSC accumulation are de-regulated during hypoxic events. Our findings indicate that hypoxic niches are poised to accumulate CSCs in a molecular process driven by the loss of PTEN activity. Furthermore, our data suggest that targeted therapies aiming at the PTEN/PI3K signaling may constitute an effective strategy to counteract the development of intratumoral hypoxia and the accumulation of CSCs.—Nascimento-Filho, C. H. V., Webber, L. P., Borgato, G. B., Goloni-Bertollo, E. M., Squarize, C. H., Castilho, R. M. Hypoxic niches are endowed with a protumorigenic mechanism that supersedes the protective function of PTEN.

Individuals with Down syndrome (DS) exhibit impaired olfactory function and are at a higher risk of developing Alzheimer's disease (AD). Olfactory dysfunction may be an early clinical symptom of AD. Recent studies have demonstrated that vitamin D3 (VD3) exerts neuroprotective effects in mouse models of AD. In this study, we investigated the effects of VD3 on the morphology, immunolocalization, and markers involved in neuropathogenic processes, apoptosis, proliferation, cell survival, and clearance of amyloid peptides, along with neuronal markers in the olfactory bulb (OB) of an adult female mouse model of DS. Morphological and molecular analyses revealed that trisomic mice exhibited a volume reduction in the external plexiform layer, a decrease in the number of mitral and granule cells, and an increase in the expression of amyloid-β 42, caspase-3 p12, and P-glycoprotein. VD3 reversed certain morphological abnormalities in the OB of control trisomic mice (Ts

The study was conducted to evaluate the frequency of polymorphisms in GSTM1 and GSTT1 genes in patients with breast cancer compared with individuals without history of cancer, and the association of these polymorphisms with clinical/epidemiological parameters.There were evaluated 752 women (219 patients and 533 controls). Molecular analysis was performed by the Polymerase Chain Reaction (PCR). Statistical analysis was used multiple logistic regression and descriptive statistics.Age ≥ 50 years (OR = 3.22, 95% CI = 2.30-4.51, p

Background: To investigate the influence of sociodemographic factors and variables related to oral health services in oral and oropharyngeal cancer mortality in Brazil. Results: The mortality rate was higher in men than in women; the Southeast and South regions had the highest rates, which increased with age. Regarding APC analysis, men aged 57 years or more and those born from the 1920s to 1955, presented the highest mortality rate, while women born between the 1920s and the 1930s had a higher rate ratio. Kaplan-Meier survival curves and Cox regression showed that black men living in the Midwest region had the lowest survival rate. Considering the correlations, the North and Northeast regions presented mortality rates inversely proportional to FPDC and NSTB, while the Southeast presented it only to FPDC. Conclusions: The sociodemographic variables analyzed exhibited an influence on mortality and survival rates in relation to oral and oropharyngeal cancer. Regarding the oral health services, it was observed that preventive and diagnostic procedures are not being performed, which may be exacerbating the increase in the mortality rates observed.

Introdução: O câncer é uma doença multifatorial influenciada por fatores ambientais e genéticos. A progressão tumoral, os mecanismos de plasticidade celular e o desenvolvimento de metástase são coordenados por uma rede complexa de alterações genômicas e epigenômicas, aspectos que representam um grande desafio para o diagnóstico e tratamento da doença. O fator de crescimento endotelial vascular (VEGF) é o principal responsável pela formação de novos vasos sanguíneos a partir de vasos pré-existentes, processo denominado angiogênese. O processo angiogênico desempenha um papel essencial no desenvolvimento e crescimento do tumor. MicroRNAs (miRNAs) são pequenas moléculas de RNA reguladoras não codificantes que podem regular a expressão pós-transcricional de múltiplos genes alvo. Objetivo: Investigar se os miRNAs hsa-miR-140-5p e hsa-miR-874-3p podem interferir na expressão do oncogene VEGFA em linhagens de CCP. Metodologia: As linhas celulares FADU (câncer de faringe) e HN13 (câncer de cavidade oral) foram cultivadas até atingirem a confluência necessária para a transfecção com os mimetizadores dos miRNAs miR-140-5p e miR-874-3p. Foram realizados três experimentos independentes, com posterior extração de RNA sendo submetido ao PCR em tempo real para análise da expressão gênica e de miRNAs. A Técnica de Western Blotting foi utilizada para a avaliar a expressão proteica. Resultados: Após a transfecção, os níveis de expressão do miR-140- 5p (FADU - RQ= 15.620; p= 0.0121 e HN13 - RQ= 3.322; p= 3.322) e miR-874-3p (FADU - RQ= 2.871; p= 0.0313 e HN13 - RQ= 13.265, p= 0.0642) estavam aumentados, em relação ao controle negativo (RQ=1,00), confirmando a eficiência da transfecção. A expressão gênica do VEGFA foi diminuída nas células transfectadas com miR-140-5p (FADU - RQ= 0.5223; p= 0.0015 e HN13 – RQ= 0.4552; p= 0.0019) e miR-874-3p (FADU – RQ= 0.4906; p=

Introdução: O carcinoma hepatocelular (CHC) é o câncer primário de fígado mais frequente, abrangendo 90% dos cânceres hepáticos iniciados no fígado, e 70-80% de todos os cânceres de fígado. Os receptores ativados por proliferadores de peroxissoma (PPARs) são receptores nucleares ativados por ligantes, que atuam como fatores de transcrição, regulando a expressão de genes relacionados ao metabolismo de glicose e lipídios. O PPARγ compreende uma das três isoformas dos PPARs, atuando no processo de regulação da adipogênese, biossíntese e armazenamento de lipídios. As desregulações da expressão desses receptores sinalizam mecanismos que podem favorecer o desenvolvimento de doenças metabólicas hepáticas, e carcinoma hepatocelular. Os microRNAs (miRNAs) são pequenas moléculas de RNA reguladoras não codificantes, que atuam na regulação pós transcricional da expressão de genes-alvo. O miR-17‐5p desempenha um papel fundamental na patogênese de diversos tipos de câncer. Objetivo: Validar a relação entre o gene PPARγ e o miR-17-5p na regulação de sua expressão nas linhagens celulares HepG2 e Huh-7 de CHC. Metodologia: As células das linhagens HepG2 e Huh-7 foram cultivadas até que atingissem confluência de aproximadamente 80% para realização da técnica de transfecção reversa com o mirVanaTM miR-17-5p mimics. A transfecção foi realizada utilizando Lipofectamina RNAiMax. Após período de incubação, as células foram colhidas para extração do RNA, e foram realizadas as análises de expressão gênica e do microRNA por meio de PCR em tempo real (qPCR). Resultado: A expressão gênica do PPARγ apresentou diminuição nas células transfectadas com o miR-17-5p na linhagem de células Huh-7 (RQ=0,5953, p=0,0001), tal como na linhagem de células HepG2 (RQ=0,7677, p=0,0015) em relação ao controle negativo (RQ=1). Conclusão: A mimetização do miR-17-5p culminou na diminuição dos níveis de expressão do gene PPARγ nas células de linhagens HepG2 e Huh-7 de CHC. Logo, é possível que o miR-17-5p regule a expressão deste gene.

Deregulation of VEGFA (Vascular Endothelial Growth Factor A) and NFE2L2 (Nuclear Factor (Erythroid-derived 2)-Like 2), involved in angiogenesis and oxidative stress, can lead to thyroid cancer progression. MiR-17-5p and miR-612 are possible regulators of these genes and may promote thyroid disorders. In order to evaluate the involvement of VEGFA, NFE2L2, hsa-miR-17-5p, and hsa-miR-612 in thyroid pathology, we examined tissue samples from colloid goiter, papillary thyroid cancer (PTC), and a normal thyroid. We found higher levels of VEGFA and NFE2L2 transcripts and the VEGFA protein in goiter and PTC samples than in normal tissue. In the goiter, miR-612 and miR-17-5p levels were lower than those in PTC. Tumors, despite showing lower VEGFA mRNA expression, presented higher VEGFA protein levels compared to goiter tissue. In addition, NRF2 (Nuclear Related Transcription Factor 2) protein levels in tumors were higher than those in goiter and normal tissues. Inhibition of miR-17-5p resulted in reduced NFE2L2 expression. Overall, both transcript and protein levels of NFE2L2 and VEGFA were elevated in PTC and colloid goiter. Hsa-miR-612 showed differential expression in PTC and colloid goiter, while hsa-miR-17-5p showed differential expression only in colloid goiter, suggesting that hsa-miR-17-5p may be a positive regulator of NFE2L2 expression in PTC.

The tropomyosin-related kinase B (TrkB) receptor is a member of the neurotrophic tyrosine kinase receptors family and, together with the brain-derived neurotrophic factor (BDNF), plays an important role in the development of breast cancer, lung cancer, neuroblastoma, colorectal cancer, leukemia, cervical cancer, gallbladder cancer, gastric cancer, kidney cancer, Ewing's sarcoma, esophageal cancer, and head and neck cancer. Overexpression of these two factors has been associated with increased processes involved in carcinogenesis, such as invasion, migration, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, cell proliferation, resistance to apoptosis, resistance to cell death due to loss of adhesion (anoikis), activation of cell proliferation pathways, regulation of tumor suppressor genes, and drug resistance, and is related to advanced clinical stage. Inhibition of the TrkB/BDNF axis using drugs in phase 1 studies, approved drugs, and small interfering RNA (siRNA) are promising strategies for the treatment of various malignant tumors in addition to increasing the sensitivity of cells resistant to chemotherapy, improving the effectiveness of drugs without increasing toxicity. Another factor related to poor cancer prognosis is the presence of cancer stem cells, having effects similar to the high expression of the TrkB/BDNF axis, on cancer. This review aimed to show the role of the TrkB/BDNF axis in several types of cancer, its possible use as a prognostic biomarker, the effects of inhibiting this axis, and its role in the cancer stem cells.

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in post-transcriptional regulation of various genes, and their deregulation can lead to tumorigenesis. They may play the role of oncogenes or tumor suppressors by regulating different genes involved in cellular processes. One of the genes regulated by the miRNAs is the vascular endothelial growth factor A (VEGFA), which is responsible for angiogenesis. Angiogenesis is the process of formation of new blood vessels from pre-existing ones. This process plays an important role in tumor development, since it is responsible for the transport of nutrients required for tumor growth. Several studies have shown an increased expression of VEGFA in various cancers. Another gene regulated by miRNAs, the nuclear factor erythroid 2-like-2 (NFE2L2/NRF2), has a cytoprotective function and regulates cellular defense against oxidative stress. The NFE2L2 is the major regulator of cytoprotective agents and their oxidative damage to cells, which is down-regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the post-transcriptional level. Regulation of the VEGFA and NFE2L2 by miRNAs has been observed in hepatocellular carcinoma and breast, lung, esophageal, endometrial, gastric, and ovarian cancer. This review highlights the role of miRNAs in the regulation of VEGFA and NFE2L2 and their relevance as therapeutic targets in various cancers.

Introduction Polymorphisms in genes coding enzymes involved in folate metabolism may cause alterations in this metabolic pathway and contribute to carcinogenesis, because folate is essential for DNA synthesis, methylation and repair. The objective of this study was to investigate the association of MTHFR 677C>T (rs1801133), MTR 2756A>G (rs1805087), RFC1 80A>G (rs1051266) and CßS 844ins(68) (no rs#) polymorphisms and thyroid cancer development. The association of these polymorphisms with demographic risk factors and clinical histopathological parameters was also evaluated. Material and methods The study is a case-control analysis with a total of 462 individuals (151 patients and 311 controls). Polymerase chain reaction-restriction fragment length polymorphism technique was used for genotyping. The χ2 and multiple logistic regression were utilized for statistical analysis. Results The polymorphisms analysis revealed an association between the MTHFR 677C>T polymorphism (OR = 2.87, 95% CI: 1.50–5.48, p < 0.01, codominant model), (OR = 1.76, 95% CI: 1.18–2.64, p < 0.01, dominant model), (OR = 2.37, 95% CI: 1.28–4.39, p < 0.01, recessive model) and thyroid cancer. RFC1 80A>G polymorphism also was associated with thyroid cancer under recessive mode of inheritance (OR = 1.55; 95% CI: 1.02–2.38; p = 0.04); however, this polymorphism showed Hardy-Weinberg disequilibrium in the control group (χ2 = 24.71, p < 0.001). Furthermore, alcohol (OR = 1.56, 95% CI: 1.36–1.89, p < 0.01) and tobacco consumption (OR = 1.97, 95% CI: 1.28–3.04, p < 0.01) were associated with increased risk for thyroid cancer. The MTR 2756A>G polymorphism showed an association with tumor extent (OR = 2.69, 95% CI: 1.27–5.71, p < 0.01) and aggressiveness (OR = 4.51, 95% CI: 1.67–12.1, p < 0.01). Conclusions MTHFR 677C>T is significantly associated with increased risk for thyroid cancer and MTR 2756A>G is associated with tumor extent and aggressiveness. In addition, alcohol and tobacco consumption were associated with increased risk of thyroid cancer. These results may contribute to a better prognosis for thyroid cancer.

Background The skin is the largest organ of the human body. Upon injury, the skin triggers a sequence of signaling pathways that induce epithelial proliferation, migration, and ultimately, the re-establishment of the epithelial barrier. Our study explores the unknown epigenetic regulations of wound healing from a histone perspective. Posttranslational modifications of histones enhance chromatin accessibility and modify gene transcription. Methods Full-thickness wounds were made in the dorsal skin of twenty-four C57/B6 mice (C57BL/6J), followed by the use of ring-shaped silicone splints to prevent wound contraction. Tissue samples were collected at three time points (post-operatory day 1, 4, and 9), and processed for histology. Immunofluorescence was performed in all-time points using markers for histone H4 acetylation at lysines K5, K8, K12, and K16. Results We found well-defined histone modifications associated with the stages of healing. Most exciting, we showed that the epidermis located at a distance from the wound demonstrated changes in histone acetylation, particularly the deacetylation of histone H4K5, H4K8, and H4K16, and hyperacetylation of H4K12. The epidermis adjacent to the wound revealed the deacetylation of H4K5 and H4K8 and hyperacetylation of H4K12. Conversely, the migratory epithelium (epithelial tongue) displayed significant acetylation of H4K5 and H4K12. The H4K5 and H4K8 were decreased in the newly formed epidermis, which continued to display high levels of H4K12 and H4K16. Conclusions This study profiles the changes in histone H4 acetylation in response to injury. In addition to the epigenetic changes found in the healing tissue, these changes also took place in tissues adjacent and distant to the wound. Furthermore, not only deacetylation but also hyperacetylation occurred during tissue repair and regeneration.

AIM To evaluate the association between polymorphisms in glutathione S transferases (GSTs) and the risk of sporadic colorectal cancer (SCRC), tumor progression and the survival of patients. METHODS A case-control study of 970 individuals from the Brazilian population was conducted (232 individuals from the case group with colorectal cancer and 738 individuals from the control group without a history of cancer). PCR multiplex and PCR-RFLP techniques were used to genotype the GST polymorphisms. The tumors were categorized according to the TNM classification: tumor extension (T), affected lymph nodes (N), and presence of metastasis (M). Logistic regression, multiple logistic regression and survival analysis were used to analyze the data. The results are presented in terms of odds ratio (OR) and 95% confidence interval (CI). The level of significance was set at 5% (P ≤ 0.05). RESULTS Age equal to or over 62 years (OR = 8.79; 95%CI: 5.90-13.09, P < 0.01) and female gender (OR = 2.91; 95%CI: 1.74-4.37; P < 0.01) were associated with increased risk of SCRC. Analysis of the polymorphisms revealed an association between the GSTM1 polymorphisms and a risk of SCRC (OR = 1.45; 95%CI: 1.06-2.00; P = 0.02), as well as between GSTT1 and a reduced risk of the disease (OR = 0.65; 95%CI: 0.43-0.98; P = 0.04). An interaction between the presence of the wild-type allele of GSTP1 Ile105Val polymorphism and tobacco consumption on risk of SCRC (OR = 2.33; 95%CI: 1.34-4.05; P = 0.05) was observed. There was an association between the GSTM1 null genotype and the presence of advanced tumors (OR = 2.33; 95%CI: 1.23-4.41; P = 0.009), as well as increased risk of SCRC in the presence of a combination of GSTT1 non-null/GSTM1 null genotypes (OR = 1.50; 95%CI: 1.03-2.19; P = 0.03) and GSTT1 non-null/GSTM1 null/GSTP1 Val* (OR = 1.85; 95%CI: 1.01-3.36, P = 0.04). Combined GSTT1 non-null/GSTM1 null genotypes (OR = 2.40; 95%CI: 1.19-4.85; P = 0.01) and GSTT1 non-null/GSTM1 null/GSTP1 Val* (OR = 2.92; 95%CI: 1.05-8.12; P = 0.04) were associated with tumor progression. Polymorphisms were not associated with the survival of patients with SCRC. CONCLUSION Females aged 62 years or older are more susceptible to SCRC. Polymorphisms of GSTT1 and GSTM1 null genotypes modulated the susceptibility to SCRC in the population studied.

Background/aim The Glutathione S-transferases (GSTs) are important carcinogen-metabolizing enzymes. Polymorphisms involved in these enzymes can modulate the development and treatment of head and neck cancer. To investigate the association of GSTs polymorphisms with head and neck cancer and risk factors, clinical-pathological features, and survival time of the patients treated with chemotherapy and/or radiotherapy. Methods The GST gene polymorphisms were evaluated in 197 cases and 514 controls by PCR-RFLP-Polymerase Chain Reaction Restriction Fragment Length Polymorphism. Results The GSTP-313 was associated with a decreased risk for HNSCC (p=0.050). The GSTP1 haplotype analysis revealed a higher frequency of the AC and AT haplotypes in the case group than in the control group (p=0.013 and p=0.019, respectively), and the opposite for G-C haplotype (p = 0.015). Yet, the different combinations between the genotypes were associated with an increased risk of cancer. The study showed no association between the polymorphisms and primary tumor site, clinical-pathological characteristics, treatment (chemotherapy and/or radiotherapy) and survival time of the patients. Conclusion The GST polymorphisms combination showed an increased risk for carcinogenesis, and studies with larger casuistry can contribute to the clarification of the role in individual patient differences for the response to chemotherapy and/or radiotherapy and identify biomarkers of susceptibility.

Made available in DSpace on 2019-10-06T16:49:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-03-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Objective: This study aimed to evaluate the effect of atorvastatin treatment on reactive oxygen species (ROS) production and tumor angiogenesis in oral squamous cell carcinomas. Material and Methods: An HN13 cell line was treated with 1 µM, 5 µM, and 10 µM of atorvastatin. VEGF-A gene expression was evaluated by quantitative real time PCR. VEGF-A protein expression was quantified from total protein and conditioned media by ELISA. Cellular oxidative stress was measured using 2′,7′-dichlorfluorescein-diacetate (DCFH-DA). Angiogenesis assay was performed using human umbilical vein endothelial cells (HUVEC). The effect of atorvastatin on cell migration was evaluated by wound healing assay. Results: 5 µM and 10 µM of atorvastatin significantly increased VEGF-A gene expression in the HN13 cell line. Intracellular expression of the VEGF-A protein was higher in the cells treated with 5 µM and 10 µM than in the control cells. VEGF-A protein expression was also higher in the conditioned media from the atorvastatin-treated cells than in the media from the DMSO-treated cells. 5 µM and 10 µM of atorvastatin increased oxidative stress. Regarding angiogenesis assay, 5 µM of atorvastatin resulted in higher numbers of branch points, compared to the solvent. 10 µM of atorvastatin treatment resulted in significantly reduced cell migration. Conclusions: This study showed that atorvastatin increases the oxidative stress and angiogenesis in oral squamous cell carcinomas. The decrease of cell migration indicates atorvastatin's inhibitory effect in oral tumors. These results suggest that atorvastatin could increase the intracellular oxidative stress in these cells, leading to a toxic microenvironment and inhibiting their metastasis. Genetics and Molecular Biology Research Unit (UPGEM) São José do Rio Preto Medical School (FAMERP), Av Brigadeiro Faria Lima, 5416, 15090-000, São José do Rio Preto Institute of Biosciences Humanities and Exact Sciences (IBILCE) São Paulo State University (UNESP), R Cristóvão Colombo, 2265, 15054-000, São José do Rio Preto Institute of Biosciences Humanities and Exact Sciences (IBILCE) São Paulo State University (UNESP), R Cristóvão Colombo, 2265, 15054-000, São José do Rio Preto

The overexpression of the amyloid precursor protein (APP) gene, encoded on chromosome 21, has been associated in Down syndrome (DS) with the development of early-onset Alzheimer's disease (EOAD). The increase in APP levels leads to an overproduction of amyloid-β (Aβ) peptide that accumulates in the brain. In response to this deposition, microglial cells are active and generate cascade events that include release cytokines and chemokine. The prolonged activation microglial cells induce neuronal loss, production of reactive oxygen species, neuron death, neuroinflammation, and consequently the development of Alzheimer's disease (AD). The intrinsically deficient immune systems in people with DS result in abnormalities in cytokine levels, which possibly contribute to the development of neurodegenerative disorders such as AD. Knowledge about the biomarkers involved in the process of neurodegeneration and neuroinflamation is important for understanding the mechanisms involved in the incidence and the precocity of AD in individuals with DS.

Renal dysfunction has been reported in individuals with Down syndrome (DS); however, the causes and mechanisms involved remain unknown. Here, we present a proposal for how the triplication of the amyloid beta precursor protein (APP) and, mainly the amyloid β peptide 1-42 (AβTwenty female mice (14-week-old) belonging to the B6EiC3Sn-Rb(12.Ts171665Dn)2Cje/CjeDnJ lineage were divided into four experimental groups (n = 5/group): common diet; trisomy (Ts) and wild-type (Wt); and high doses VDOur results showed that VDFinally, the results showed that VD

Recent evidence suggests that cancer stem cells (CSCs), a small population of cancer cells that are highly tumourigenic, capable of self-renewal and have the ability to differentiate into cells that constitute the tumor, are the “drivers” of local recurrence and metastatic spread and may be associated with resistant to conventional therapy. The objectives of the study are to identify and characterize two head and neck cancer cell lines with regard CD44high/CD133high/CD117high profile (CSCs) and CD44low/CD133low/CD117low profile (Non-CSCs); to investigate the influence of chemotherapy treatment in CSCs and compare with Non-CSCs; to evaluate CD44 and EGFR gene expression in CSCs. Fluorescent-activated cell sorting (FACS) using specific cell surface marker combination (CD44, CD117 and CD133) was performed to isolate CSCs of Non-CSCs from cell lines. The Wound Healing assay was performed to confirm the presence of CSCs. After, the CSCs subpopulation and Non-CSCs were cultured and exposed for 24 h to Cetuximab and Paclitaxel treatment, separately. Cell proliferation was determined by MTS assay. CD44 and EGFR gene expression was quantified by quantitative real time PCR (qPCR) using TaqMan® Assay in both subpopulations. CSCs subpopulation untreated were considered as relative expression control. We firstly characterized CSCs in HN13 and HEP-2 cell lines with CD44, CD133 and CD117 biomarkers. We treated CSCs and Non-CSCs subpopulations with Cetuximab and Paclitaxel treatment and found that CSCs subpopulations demonstrated more resistance to Paclitaxel chemoterapy, when compared with Non-CSCs subpopulations of oral cancer cell line. These CSCs subpopulations presented up-regulation of CD44 gene and down-regulation of EGFR gene in oral cancer cell line, and down-regulation of CD44 gene and up-regulation of EGFR gene in laryngeal cancer cell line when compared with Non-CSCs subpopulations. We conclude that the combination of CD44, CD133 and CD117 biomarkers have stem cell properties in both cell lines. CSCs has ability to resist to Paclitaxel treatment in oral cancer cell line. CSCs present high expression of CD44 gene and down expression of EGFR gene in oral cancer cell line. CSCs in laryngeal cell line present down expression of CD44 gene and high expression of EGFR gene when compared with cells without characteristics of cancer stem cells.