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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

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.

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.

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

Background Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease caused by mutations in APOE, the gene which encodes apolipoprotein E. LPG mainly affects Asian individuals, however occasional cases have also been described in Americans and Europeans. Herein we report two unrelated Brazilian patients with LPG in whom genetic analyses revealed the APOE-Osaka/Kurashiki variant. Case presentation - case 1 A 29-year-old Caucasian male sought medical attention with complaints of face swelling and foamy urine for the last 3 months. He denied a family history of kidney disease, consanguinity, or Asian ancestry. His tests showed proteinuria of 12.5 g/24 h, hematuria, serum creatinine 0.94 mg/dL, albumin 2.3 g/dl, total cholesterol 284 mg/dL, LDL 200 mg/dL, triglycerides 175 mg/dL, and negative screening for secondary causes of glomerulopathy. A kidney biopsy revealed intraluminal, laminated deposits of hyaline material in glomerular capillaries consistent with lipoprotein thrombi. These findings were confirmed by electron microscopy, establishing the diagnosis of LPG. His apolipoprotein E serum level was 72 mg/dL and genetic analysis revealed the APOE pathogenic variant c.527G > C, p.Arg176Pro in heterozygosis, known as the Osaka/Kurashiki mutation and positioned nearby the LDL receptor binding site. Case 2 A 34-year-old Caucasian man sought medical assessment for renal dysfunction and hypertension. He reported intermittent episodes of lower-limb edema for 3 years and a family history of kidney disease, but denied Asian ancestry. Laboratorial tests showed BUN 99 mg/dL, creatinine 10.7 mg/dL, total cholesterol 155 mg/dL, LDL 79 mg/dL, triglycerides 277 mg/dL, albumin 3.1 g/dL, proteinuria 2.7 g/24 h, and negative screening for secondary causes of glomerulopathy. His kidney biopsy was consistent with advanced chronic nephropathy secondary to LPG. A genetic analysis also revealed the Osaka/Kurashiki variant. He was transplanted a year ago, displaying no signs of disease relapse. Conclusion We report two unrelated cases of Brazilian patients with a diagnosis of lipoprotein glomerulopathy whose genetic assessment identified the APOE-Osaka/Kurashiki pathogenic variant, previously only described in eastern Asians. While this is the second report of LPG in Latin America, the identification of two unrelated cases by our medical team raises the possibility that LPG may be less rare in this part of the world than currently thought, and should definitely be considered when nephrotic syndrome is associated with suggestive kidney biopsy findings.

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.

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.

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.

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.

Objective. The aim of the study was to investigate the expression patterns of a specific set of genes involved in the inflammation process in children with Down Syndrome (DS) and children without the syndrome (control group) to identify differences that may be related to the immune abnormalities observed in DS individuals.Method. RNA samples were obtained from peripheral blood, and gene expression was quantified using the TaqMan® Array Plate Human Inflammation Kit, which facilitated the investigation into 92 inflammation-related genes and four reference genes using real-time polymerase chain reaction (qPCR).Results. Twenty genes showed differential expression in children with DS; 12 were overexpressed (PLA2G2D,CACNA1D,ALOX12,VCAM1,ICAM1,PLCD1,ADRB1,HTR3A,PDE4C,CASP1,PLA2G5,andPLCB4), and eight were underexpressed (LTA4H,BDKRB1,ADRB2,CD40LG,ITGAM,TNFRSF1B,ITGB1,andTBXAS1). After statistically correcting for the false discovery rate, only the genesBDKRB1andLTA4Hshowed differential expression, and both were underexpressed within the DS group.Conclusion. DS children showed differential expression of inflammation-related genes that were not located on chromosome 21 compared with children without DS. TheBDKRB1andLTA4Hgenes may differentiate the case and control groups based on the inflammatory response, which plays an important role in DS pathogenesis.

In the present study, we sought to identify the factors during the pregnancy of systemic lupus erythematosus (SLE) patients that could be linked to the presence and proliferation of male fetal cells (MFC) and the possible relation between these factors and development of lupus nephritis (LN). We evaluated 18 healthy women (control group) and 28 women affected by SLE. Genomic DNA was extracted from peripheral blood and quantified using the technique of quantitative real-time polymerase chain reaction (qPCR) for specific Y chromosome sequences. The amount of MFC was significantly higher in the SLE group compared with the controls (SLE 252 ± 654 vs control 2.13 ± 3.7; P = 0.029). A higher amount of MFC was detected among multiparous SLE patients when compared with the control group (SLE 382 ± 924 vs control 0.073 ± 0.045; P = 0.019). LN was associated with reduced amount of MFC (LN 95.5 ± 338 vs control 388 ± 827; P = 0.019) especially when they have delivered their child before age 18 (LN 0.23 ± 0.22 vs control 355 ± 623; P = 0.028). SLE patients present a higher amount of MFC, which may increase with the time since birth of the first male child. LN patients showed an inverse correlation with MFC, suggesting that the role of the cells may be ambiguous during the various stages of development of the disease.

Functional polymorphisms in promoter regions can produce changes in the affinity of transcription factors, thus altering the messenger ribonucleic acid (mRNA) expression levels of inflammatory cytokines associated with the risk of cancer development. The goal of this study was to evaluate the influence that polymorphisms in the cytokine genes known as TNF-α-308 G/A (rs1800629), TNF-α-857 C/T (rs1799724), IL-8-251 T/A (rs4073), IL-8-845 T/C (rs2227532), and IL-10-592 C/A (rs1800872) have on changes to mRNA expression levels and on the risks of chronic gastritis (CG) and gastric cancer (GC). A sample of 723 individuals was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Relative mRNA expression levels were measured using quantitative real-time PCR (qPCR). Polymorphisms TNF-α-308 G/A and IL-8-251 A/T were not associated with risks of these gastric lesions. However, TNF-α-857 C/T, IL-8-845 T/C, and IL-10-592 C/A were found to be associated with a higher risk of GC, and IL-10-592 C/A was found to be associated with a higher risk of CG. The relative mRNA expression levels (RQ) of TNF-α, IL-8, and IL-10 were markedly downregulated in the CG group (median RQs = 0.128, 0.247, and 0.614, respectively), while the RQ levels of TNF-α in the GC group were upregulated (RQ = 2.749), but were basal for IL-8 (RQ = 1.053) and downregulated for IL-10 (RQ = 0.179). When the groups were stratified according to wild-type and polymorphic alleles, only for IL-8-845 T/C the polymorphic allele was found to influence the expression levels of this cytokine. IL-8-845 C allele carriers were significantly upregulated in both groups (GC and CG; RQ = 3.138 and 2.181, respectively) when compared to TT homozygotes (RQ = -0.407 and 0.165, respectively). In silico analysis in the IL-8 promoter region revealed that the presence of the variant C allele in position -845 is responsible for the presence of the binding sites for two transcription factors (REL and CREB1), which are involved in increased gene expression. Polymorphic alleles were not shown to have any effect on the expression levels of TNF-α and IL-10. Taken together, our findings provide evidence for an association of TNF-α-857 C/T, IL-8-845 T/C, and IL-10-592 C/A with a higher risk of gastric cancer and also demonstrate the influence that the polymorphic C allele of IL-8-845 has on changes to the gene expression levels of this cytokine.

Polymorphisms in genes encoding P450 cytochrome enzymes may increase the risk of sporadic colorectal cancer (SCRC). Here we investigated the association between SCRC and CYP2E1 (PstI) and CYP1A1 (MspI) polymorphisms in a case-control study. Moreover, we sought to determine any possible associations between this disease and the sociodemographic factors. We included 273 individuals (74 patients and 199 controls); the gender, age, tobacco usage, and alcohol consumption of the included subjects, and the clinico-histopathological parameters of the tumors, were analyzed. Molecular analyses were performed using PCR-RFLP. The effect of polymorphisms on SCRC development, and the association between this disease and sociodemographic factors were determined by multiple-logistic regression analyses. The combined genotype was also evaluated. Statistically significant differences between the patients and controls regarding the male gender (odds ratio, OR = 0.19, 95% confidence interval, CI = 0.08-0.46; P ≤ 0.05) and age ≥44 years (median = 44; OR = 96.84, 95%CI = 21.78-430.49; P ≤ 0.05) were observed. The evaluated polymorphisms were not associated with SCRC (PstI-CYP2E1: OR = 0.93, 95%CI = 0.30-2.85; P = 0.897; MspI-CYP1A1: OR = 0.75, 95%CI = 0.35-1.61; P = 0.463); the combined genotypes were not associated with the risk of disease. Thus, individuals aged ≥44 years are more sensitive to SCRC, while men are less susceptible. Additionally, polymorphisms in CYP2E1 (PstI) and CYP1A1 (MspI) were not associated with SCRC in the evaluated Brazilian population.

Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs-Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95% confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I(2). Publication bias was estimated using Begg's test and Egger's linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy-Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I(2) test values ranging from 8 to 89%. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS.

Aims 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 (Aβ42) can favor the development of renal abnormalities in DS. We evaluated the effects of vitamin D3 (VD3) supplementation on morphofunctional aspects and the repercussions on the presence and localization of Aβ42, methylenetetrahydrofolate reductase (MTHFR), caspase-3 p12, and P-glycoprotein (Pgp) in the renal tissue of DS mouse model. Main methods Twenty 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 VD3, Ts(VD3), and Wt(VD3). All the groups were treated for 10 weeks. At 24 weeks, the protocol experimental was interrupted. The kidney was weighed, collected, and processed for immunochemical analysis for Aβ42, Caspase-3 p12, MTHFR, and Pgp proteins. All data were analyzed statistically. Key findings Our results showed that VD3 promoted an increase in caspase-3 p12, MTHFR, and Pgp, and consequently contributed to reduced Aβ42 in the renal tissue of a mouse model of DS. Furthermore, VD3 treatment affected the plasma creatinine and urea levels and contributed to the attenuation of the dilation of Bowman's space observed in trisomic mice. Significance Finally, the results showed that VD3 may activate specific mechanisms involved in reduced Aβ42 and tissue repair in the kidneys of a mouse model for Down syndrome.

Folate is an essential nutrient with important roles in the synthesis, repair, and DNA methylation. Polymorphisms in genes encoding enzymes involved in folate metabolism can change these processes and modulate cancer development. We investigated DNMT3B C46359T (rs2424913) and SHMT1 C1420T (rs1979277) polymorphisms related to folate pathway in head and neck cancer (HNC) risk and the association of the disease with gender, risk factors and clinical histopathological parameters. A case–control study was conducted in 725 individuals (237 patients with HNC and 488 control individuals). Real-time PCR technique was performed for genotyping. Chi square and multiple logistic regression tests were used for statistical analysis. Male gender (OR 1.80; 95 % CI 1.11–2.94; P

Inter-individual variations to methotrexate (MTX) outcome have been attributed to different expression profiles of genes related to folate metabolism. To elucidate the mechanisms of variations to MTX outcome, we investigated MTHFR, DHFR, TYMS, and SLC19A1 gene expression profiles by quantifying the mRNA level of the genes involved in folate metabolism to MTX response in laryngeal cancer cell line (HEP-2). For this, three different concentrations of MTX (0.25, 25, and 75 μmol) were added separately in HEP-2 cell line for 24 h at 37 °C. Apoptotis quantification was evaluated with fluorescein isothiocyanate-labeled Bcl-2 by flow cytometry. Real-time quantitative PCR technique was performed by quantification of gene expression with TaqMan® Gene Expression Assay. ANOVA and Bonferroni’s post hoc tests were utilized for statistical analysis. The results showed that the numbers of apoptotic HEP-2 cells with 0.25, 25.0, and 75.0 μmol of MTX were 14.57, 77.54, and 91.58 %, respectively. We found that the expression levels for MTHFR, DHFR, TYMS, and SLC19A1 genes were increased in cells with 75.0 μmol of MTX (p

Câncer de cabeca e pescoco e o quinto tipo de câncer mais comum e a taxa de sobrevivencia nao tem mudado nos ultimos anos. Objetivo: Determinar os fatores de risco, causas, tratamento e prevencao do câncer de cabeca e pescoco. Metodo: Nos detalhamos os fatores de risco, causas, tratamento e prevencao da doenca por meio de pesquisa nos bancos de dados PUBMED, MEDLINE e SciELO. Resultados: Alcool e fumo ainda sao os principais fatores de risco. Outros fatores podem influenciar o desenvolvimento do carcinoma de cabeca e pescoco. A opcao de tratamento principal e terapia cirurgica e sua utilizacao seguida por radioterapia e uma pratica comum de tratamento em fases iniciais da doenca. Existem terapias que visam agir em componentes moleculares geneticos especificos para o desenvolvimento do tumor. A cessacao do cigarro, limitacao de ingestao de alcool, evitar a exposicao a fumaca do cigarro, a carcinogenicos ambientais, deteccao precoce de infeccao por HPV, manutencao da saude bucal, bons habitos alimentares e controle do stress podem ser medidas de prevencao da doenca. Conclusao: Investigacoes adicionais sao necessarias para completa compreensao do desenvolvimento do carcinoma de cabeca e pescoco e isso ira fornecer novos caminhos e melhora na intervencao e abordagens terapeuticas.

Down syndrome (DS) individuals present impaired adaptive immune system. However, the etiology of the immunological deficiency in these individuals is not completely understood. This study investigated the frequency of interleukin 6 polymorphisms (rs1800795, rs1800796, and rs1800797) in individuals with DS and individuals without the syndrome. The study included 282 individuals, 94 with DS attended at the General Genetics Outpatient Service of Hospital de Base, Sao Jose do Rio Preto, SP, Brazil, and 188 individuals without DS attended at the Pediatric Service of Hospital de Base de Sao Jose do Rio Preto, SP, Brazil. Genotyping was performed by allelic discrimination technique by real-time polymerase chain reaction using TaqMan SNP Genotyping Assays (Applied Biosystems). There was no difference in the genotype frequency between individuals with and without DS for the evaluated polymorphisms (P > 0.05). The frequency of interleukin 6 polymorphisms did not differ significantly between individuals with and without DS in the casuistic analyzed.

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G , MTHFD1 G1958A , CBS 844ins68 , TC2 C776G and A67G , SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ⩾49 years ( P P = 0.03), tobacco habit ( P MTHFR 1298AC/CC ( P = 0.028), MTR 2756AG/GG ( P = 0.010) and RFC1 80AG/GG ( P = 0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 ( P = 0.005); age ⩾49 years and MTR 2756 AG/GG ( P = 0.004) and RFC1 80AG/GG ( P = 0.006) genotypes; male gender and MTHFR 1298 AC/CC ( P = 0.030), MTR 2756 AG/GG ( P = 0.006) and RFC1 80 AG/GG ( P = 0.009); tobacco non-habit and MTHFD1 1958GA/AA ( P = 0.040); tobacco and MTHFR 1298 AC/CC ( P = 0.054) and MTR 2756 AG/GG ( P = 0.010); alcohol non-consume and RFC1 80 AG/GG ( P = 0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours ( P = 0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

Evidencias epidemiologicas sugerem que variantes geneticas que codificam enzimas envolvidas no metabolismo do folato podem modular o risco de câncer de cabeca e pescoco por alterar a metilacao, sintese de DNA e estabilidade genomica. OBJETIVOS: Realizar uma revisao bibliografica sobre polimorfismos geneticos envolvidos no metabolismo do folato e o risco de câncer de cabeca e pescoco. METODOLOGIA: Realizou-se uma busca eletronica na base de dados Medline, selecionando estudos em câncer de cabeca do pescoco e polimorfismos envolvidos no metabolismo do folato. RESULTADOS: A associacao do polimorfismo MTHFR C677T no risco dessa neoplasia foi avaliada em nove estudos e tres deles mostraram associacao com essa doenca. Os polimorfismos MTR A2756G e MTRR A66G e RFC1 A80G tambem foram associados com aumento de risco para o câncer de cabeca e pescoco. O polimorfismo MTHFD1 G1958A nao mostra associacao com o risco dessa doenca e os resultados da avaliacao do polimorfismo MTHFR A1298C nesse tipo de neoplasia sao contraditorios. Outros polimorfismos envolvidos no metabolismo do folato ainda nao foram estudados nesse tipo de neoplasia. CONCLUSAO: Concluimos que polimorfismos envolvidos no metabolismo do folato podem modular o risco desse tipo de tumor, no entanto, esses resultados precisam ser comprovados em diferentes populacoes.

The KiSS-1 metastasis-suppressor gene (KiSS-1) product (metastin, kisspeptin) is reported to act after binding with the natural ligand of a G-protein coupled receptor and this gene product inhibits chemotaxis, invasion, and metastasis of cells. The aim of this study was to evaluate the Q36R polymorphism of KiSS-1 in patients with head and neck cancer and to compare the results with healthy individuals and its association with clinicopathological parameters. Gender, age, smoking and alcohol consumption were analyzed for 744 individual (252 head and neck cancer patients and in 522 control individuals). The molecular analysis of these individuals was made after extraction of genomic DNA using the SSCP-PCR technique. This study did not reveal any significant differences in genotype frequencies between healthy individuals and patients with head and neck cancer or with the clinical parameters. This study showed an increase frequency of the Q36R polymorphism in pharyngeal cancer.

Tumor growth and progression depend on angiogenesis, a process of new blood vessels formation from a preexisting vascular endothelium. Tumors promote angiogenesis by secreting or activating angiogenic factors that stimulate endothelial proliferation and migration and capillary morphogenesis. The newly formed blood vessels provide nutrients and oxygen to the tumor, increasing its growth. Thus, angiogenesis plays a key role in cancer progression and development of metastases. An important growth factor that promotes angiogenesis and participates in a variety of physiological and pathological processes is the vascular endothelial growth factor (VEGF-A or VEGF). Overexpression of VEGF results in increased angiogenesis in normal and pathological conditions. The existence of an alternative site of splicing at the 3' untranslated region of the mRNA results in the expression of isoforms with a C-terminal region which are downregulated in tumors and may have differential inhibitory effects. This suggests that control of splicing can be an important regulatory mechanism of angiogenesis in cancer.

Neurofibromatosis type 1 (NF1) is a hereditary disease with a dominant autosomal pattern. In children and adolescents, it is frequently associated with the appearance of T2-weighted hyperintensities in the brain’s white matter. MRI with diffusion tensor imaging (DTI) is used to detect white matter abnormalities by measuring fractional anisotropy (FA). This study employed DTI to evaluate the relationship between FA patterns and the findings of T2 sequences, with the aim of improving our understanding of anatomical changes and microstructural brain abnormalities in individuals with NF1. Forty-four individuals with NF1 and 20 control subjects were evaluated. The comparative analysis of FA between NF1 and control groups was based on four predetermined anatomical regions of the brain hemispheres (basal ganglia, cerebellum, pons, thalamus) and related the presence or absence of T2-weighted hyperintensities in the brain, which are called unidentified bright objects (UBOs). The FA values between the groups demonstrated statistically significant differences (P ≤ 0.05) for the cerebellum and thalamus in patients with NF1, independent of the occurrence of UBOs. Diffusion tensor MR imaging confirms the influence of UBOs in the decrease of FA values in this series of patients with NF1. Additionally, this technique allows the characterization of microstructural abnormalities even in some brain regions that appear normal in conventional MR sequences.

Different routes for the administration of bone marrow-derived cells (BMDC) have been proposed to treat the progression of chronic renal failure (CRF). We investigated whether (1) the use of bovine pericardium (BP) as a scaffold for cell therapy would retard the progression of CRF and (2) the efficacy of cell therapy differently impacts distinct degrees of CRF. We used 2/3 and 5/6 models of renal mass reduction to simulate different stages of chronicity. Treatments consisted of BP seeded with either mesenchymal or mononuclear cells implanted in the parenchyma of remnant kidney. Renal function and proteinuria were measured at days 45 and 90 after cell implantation. BMDC treatment reduced glomerulosclerosis, interstitial fibrosis and lymphocytic infiltration. Immunohistochemistry showed decreased macrophage accumulation, proliferative activity and the expression of fibronectin and α-smooth muscle-actin. Our results demonstrate: (1) biomaterial combined with BMDC did retard the progression of experimental CRF; (2) cellular therapy stabilized serum creatinine (sCr), improved creatinine clearance and 1/sCr slope when administered during the less severe stages of CRF; (3) treatment with combined therapy decreased glomerulosclerosis, fibrosis and the expression of fibrogenic molecules; and (4) biomaterials seeded with BMDC can be an alternative route of cellular therapy.

Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk because folate participates in DNA methylation and synthesis. We therefore conducted a case–control study of 853 individuals (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell carcinoma risk. Interactions between these two polymorphisms and risk factors and clinical histopathological parameters were also evaluated. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the polymorphisms and Chi-square test and multiple logistic regression were used for statistical analyses. The variables age ≥49 years, male gender, tobacco habits and alcohol consumption, MTHFR 1298 AC or CC genotypes, combined genotypes with two or more polymorphic alleles and 677T and 1298C polymorphic alleles were associated with increased risk for this disease (P

O polimorfismo C677T do gene metilenotetra-hidrofolato redutase (MTHFR) pode ser um fator de risco para o carcinoma espinocelular de cabeça e pescoço devido a alterações nos níveis de folato que podem induzir alterações na metilação intracelular, promovendo a carcinogênese. OBJETIVO: Avaliar o polimorfismo MTHFR C677T em pacientes com carcinoma espinocelular de cabeça e pescoço e em indivíduos sem história de neoplasia e verificar a associação desta doença com as características clínico-patológicas. CASUÍSTICA E MÉTODOS: Estudo retrospectivo no qual foram avaliados gênero, idade, tabagismo, etilismo e parâmetros clínico-histopatológicos em 200 indivíduos (100 com a doença e 100 sem história de neoplasia). A análise molecular foi realizada pela técnica de PCR- RFLP e os testes qui-quadrado de Pearson e Regressão Logística Múltipla foram utilizados para análise estatística. RESULTADOS: Não houve associação entre o polimorfismo MTHFR C677T e a doença (p=0,50). Diferenças significantes entre o grupo de pacientes e o grupo controle foram observadas para idade superior a 50 anos, hábito tabagista e gênero masculino (p

Reduced folate carrier is an essential folate transporter and the A80G polymorphism in reduced folate carrier 1 gene (rs1051266) has been shown to be associated with alterations in folate metabolism and consequently cancer development. We evaluated the association of this polymorphism with head and neck squamous cell carcinoma risk in a case-control study of 322 head and neck carcinoma patients and 531 individuals without cancer in a Brazilian population and association of this polymorphism with clinical histopathological parameters, and gender and lifestyle factors. The PCR-RFLP technique was used to genotype the polymorphism and multiple logistic regression was used for comparison between the groups and for interaction between the polymorphism and risk factors and clinical histopathological parameters. We observed association between the RFC1 A80G polymorphism and the risk of this disease. Male gender, tobacco habit and RFC1 AG or GG genotypes may be predictors of this disease (P0.05). The genotype, 80AG or GG was associated with for50 years, male gender and non alcohol consumption (P ≤ 0.05). The polymorphism did not show any association with the primary site, aggressiveness, lymph node involvement or extension of the tumor. In conclusion tobacco and male gender are associated with etiology of this disease and our data provide evidence that supports an association between the RFC1 A80G polymorphism and head and neck squamous cell carcinoma risk, male gender, alcohol non consumption and age over 50 years. However, further studies of folate and plasma concentrations may contribute to the better understanding of the factors involved in the head and neck squamous cell carcinoma etiology.

CONTEXT AND OBJECTIVE: Polymorphisms in genes involved in folate metabolism may modulate the maternal risk of Down syndrome (DS). This study evaluated the influence of a 19-base pair (bp) deletion polymorphism in intron-1 of the dihydrofolate reductase (DHFR) gene on the maternal risk of DS, and investigated the association between this polymorphism and variations in the concentrations of serum folate and plasma homocysteine (Hcy) and plasma methylmalonic acid (MMA). DESIGN AND SETTING: Analytical cross-sectional study carried out at Faculdade de Medicina de São José do Rio Preto (Famerp). METHODS: 105 mothers of individuals with free trisomy of chromosome 21, and 184 control mothers were evaluated. Molecular analysis on the polymorphism was performed using the polymerase chain reaction (PCR) through differences in the sizes of fragments. Folate was quantified by means of chemiluminescence, and Hcy and MMA by means of liquid chromatography and sequential mass spectrometry. RESULTS: There was no difference between the groups in relation to allele and genotype frequencies (P = 0.44; P = 0.69, respectively). The folate, Hcy and MMA concentrations did not differ significantly between the groups, in relation to genotypes (P > 0.05). CONCLUSIONS: The 19-bp deletion polymorphism of DHFR gene was not a maternal risk factor for DS and was not related to variations in the concentrations of serum folate and plasma Hcy and MMA in the study population. CONTEXTO E OBJETIVO: Polimorfismos em genes do metabolismo do folato podem modular o risco materno para síndrome de Down (SD). Este estudo avaliou a influência do polimorfismo de deleção de 19 pares de base (pb) no íntron 1 do gene dihidrofolato redutase (DHFR) no risco materno para SD e investigou a associação entre esse polimorfismo e variações nas concentrações de folato sérico, homocisteína (Hcy) e ácido metilmalônico (MMA) plasmáticos. TIPO DE ESTUDO E LOCAL: Estudo transversal analítico realizado na Faculdade de Medicina de São José do Rio Preto (Famerp). MÉTODOS: 105 mães de indivíduos com trissomia livre do cromossomo 21 e 184 mães controles foram avaliadas. A análise molecular do polimorfismo foi realizada pela reação em cadeia da polimerase (PCR) por diferença de tamanho dos fragmentos. O folato foi quantificado por quimioluminescência, e Hcy e MMA foram determinados por cromatografia líquida/espectrometria de massas sequencial. RESULTADOS: Não houve diferença entre os grupos em relação às frequências alélica e genotípica (P = 0,44; P = 0,69, respectivamente). As concentrações de folato, Hcy e MMA não mostraram diferença significativa entre os genótipos, entre grupos (P > 0,05). CONCLUSÕES: O polimorfismo de deleção de 19 pb do gene DHFR não é um fator de risco materno para SD e não está relacionado com variações nas concentrações de folato sérico, Hcy e MMA plasmáticos na população estudada.

FUNDAMENTO: Polimorfismos em genes relacionados ao desenvolvimento da aterosclerose, angiogênese e metabolismo da homocisteína (Hcy) podem ser fatores de risco para a doença arterial coronariana (DAC). OBJETIVO: Avaliar o efeito dos polimorfismos VEGF C-2578A e MTHFR C677T na DAC e a associação desses polimorfismos com a gravidade e a extensão das lesões ateroscleróticas e concentrações de Hcy. MÉTODOS: 244 indivíduos foram avaliados através de angiografia coronariana e incluídos no estudo (145 com DAC e 99 indivíduos-controle). Os polimorfismos VEGF C-2578A e MTHFR C677T foram investigados através das técnicas de PCR-SSCP e PCR-RFLP, respectivamente. Os níveis de homocisteína plasmática foram mensurados através de cromatografia líquida/espectrometria de massa seqüencial (CL/EMS). RESULTADOS: Não houve diferença significante em relação à distribuição de alelos e genótipos entre os grupos, para ambos os polimorfismos. A análise univariada mostrou uma freqüência maior do genótipo VEGF -2578AA no grupo com doença em três vasos (p=0,044). Além disso, o genótipo VEGF -2578CA foi observado mais freqüentemente entre indivíduos com

Objectives Alterations in the enzymes involved in homocysteine (Hcy) metabolism or vitamin deficiency could play a role in coronary artery disease (CAD) development. This study investigated the influence of MTHFR and MTR gene polymorphisms, plasma folate and MMA on Hcy concentrations and CAD development. MMA and folate concentrations were also investigated according to the polymorphisms. Methods Two hundred and eighty-three unrelated Caucasian individuals undergoing coronary angiography (175 with CAD and 108 non-CAD) were assessed in a case–control study. Plasma Hcy and MMA were measured by liquid chromatography/tandem mass spectrometry. Plasma folate was measured by competitive immunoassay. Dietary intake was evaluated using a nutritional questionnaire. Polymorphisms MTHFR and MTR were investigated by polymerase chain reaction (PCR) followed by enzyme digestion or allele-specific PCR. Results Hcy mean concentrations were higher in CAD patients compared to controls, but below statistical significance (P = 0.246). Increased MMA mean concentrations were frequently observed in the CAD group (P = 0.048). Individuals with MMA concentrations >0.5 μmol/l (vitamin B12 deficiency) were found only in the CAD group (P = 0.004). A positive correlation between MMA and Hcy mean concentrations was observed in both groups, CAD (P = 0.001) and non-CAD (P = 0.020). MMA mean concentrations were significantly higher in patients with hyperhomocysteinemia in both groups, CAD and non-CAD (P = 0.0063 and P = 0.013, respectively). Folate mean concentration was significantly lower in carriers of the wild-type MTHFR 1298AA genotype (P = 0.010). Conclusion Our results suggest a correlation between the MTHFR A1298C polymorphism and plasma folate concentration. Vitamin B12 deficiency, reflected by increased MMA concentration, is an important risk factor for the development both of hyperhomocysteinemia and CAD.