Trends and predictions for survival and mortality in individuals with Down syndrome in Brazil: A 21-year analysis.

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.

Polymorphisms of interleukin 6 in Down syndrome individuals: a case-control study.

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, São José do Rio Preto, SP, Brazil, and 188 individuals without DS attended at the Pediatric Service of Hospital de Base de São José 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.

Role of MTHFR C677T and MTR A2756G polymorphisms in thyroid and breast cancer development.

Folate metabolism is essential for DNA synthesis and repair. Alterations in genes that participate in folate metabolism can be associated with several types of malignant neoplasms, including thyroid and breast cancer. In the present case-control study, we examined the association between methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) and methionine synthase (MTR A2756G, rs1805087) polymorphisms and risk for thyroid and breast cancer. Polymerase chain reaction-restriction fragment length technique was used to determine the specific genotypes in the genes of interest. Statistical analysis was performed by multiple logistic regression test. We found an association between MTHFR C677T polymorphism and risks to both thyroid (OR = 2.50; 95%CI = 1.15-5.46; P = 0.02) and breast cancer (OR = 2.53; 95%CI = 1.08-5.93; P = 0.03). Tobacco consumption and high body mass index were also associated with thyroid cancer. In addition, increased age (≥50 years) and alcohol consumption were found to be associated with breast cancer. Our results indicated that MTHFR C677T is significantly associated with thyroid and breast cancer risks. Thus, these factors may be used as potential prognostic markers for thyroid and breast cancers.

Cancer stem cells in head and neck cancer: A Mini Review.

Head and neck cancer (HNC) is a multifaceted and genomically complex disease and rapidly emerging preclinical and clinical studies have provided a broader landscape of signaling. It is being realized that intra-tumor heterogeneity, genetic and epigenetic mutations considerably challenge wide ranging therapeutics and patients frequently develop locoregional recurrences, second primary tumours and distant metastases. Using high-throughput technologies, it has been revealed that existence of different subpopulations of cells within tumor mass with different phenotypic and functional properties with distinct tumour-initiating potential is responsible to HNC resistance. In light of accumulating evidence reported in recent years, it is now known that different intracellular proteins and cell surface markers have been used to study CSCs. This review provides an overview of CSC biomarkers in HNC treatment and their potential as therapeutic targets in improving the diagnosis, prognosis and treatment of HNC patients for new therapeutic strategies with information about estimation of prognosis and treatment decision. Further studies regarding biomarkers are necessary to determine the specific role of CSCs in HNC which could be useful in development of new therapeutic strategies to eliminate CSCs and maximize clinical outcome. Furthermore, CD44 still need more research in HNC once the studies show contradictions. Studies using lineage tracing and deep sequencing will provide a comprehensive understanding of CSC model and extent to which it is accountable for resistance against therapeutics and carcinogenesis.

A case-control study of CYP2E1 (PstI) and CYP1A1 (MspI) polymorphisms in colorectal cancer.

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.

Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR 677T allele.

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.

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome.

Individuals with Down syndrome (DS) carry three copies of the Cystathionine ß-synthase (CßS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.

Sensitivity of human laryngeal squamous cell carcinoma Hep-2 to metrotexate chemoterapy.

AIM: Methotrexate (MTX) is an antifolate agent that acts inhibiting purine and pyrimidine synthesis. The objective of the study was to evaluate the viability of Hep-2 human laryngeal cancer cells to the treatment with MTX chemotherapy in vitro. METHODS: Cultured Hep-2 cells were treated with 0.25, 25.0 and 75 µM MTX for 24 h, and their viability was evaluated with Bcl-2-FITC antibody in flow cytometry. RESULTS: The numbers of viable Hep-2 cells after 24 h treatment with 0.25, 25.0 and 75.0 uM MTX were 85.43%, 22.46% and 8.42%, respectively (p < 0.05). Therefore, MTX possesses a dose-dependent effect on viability of Hep-2 cells in vitro. CONCLUSION: The highest MTX concentration is associated with highest tumor cell sensitivity of human laryngeal cancer cells of Hep-2 line.

VEGF gene alternative splicing: pro- and anti-angiogenic isoforms in 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.

Chromosome breakpoint distribution in nonmelanoma skin cancers.

We have identified chromosome regions that may be sites of genes activated as a result of chromosomal rearrangements observed in 61 of the 86 skin tumors referenced in the literature. The data showed that most of the breakpoints were distributed throughout the genome and some tended to cluster. Highest frequencies of breakpoints were observed in chromosomes with high relative length, except chromosomes 14 and 15 that were often affected in malignant tumors, despite their size. Our work provides a starting point for more detailed studies that may allow identification of these genes as important keys in the development and progression of skin cancers.

Cytogenetic study of neoplastic and nonneoplastic cells of the skin.

We describe the cytogenetic study of six neoplastic and eight nonneoplastic skin samples from sun-exposed body sites or sites close to tumors. The cytogenetic findings revealed that chromosome rearrangements are common in sun-exposed normal skin, similar to the situation in cutaneous tumors, and suggest that such karyotypic abnormalities might be indicative of the genetic instability caused by specific mutations and resulting from carcinogenic exposure of the tissue.