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Context: Joint hypermobility (JH) represents the extreme of the normal range of motion or a condition for a group of genetically determined connective tissue disorders. Generalized joint hypermobility (GJH) is suspected when present in all four limbs and the axial skeleton, scored in prepubescent children and adolescents by a Beighton Score (BS) ≥ 6. Parameters are also used to identify GJH in hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSDs). The purpose of this study is to characterize children with JH based on the location of variables in the BS ≥ 6 and identify children with JH in the axial skeleton, upper limbs (ULs), and lower limbs (LLs) simultaneously., Methods: We analyzed 124 medical records of one- to nine-year-old children with JH by BS., Results: The characterization of GJH by combinations of the axial skeleton, ULs, and LLs simultaneously totaled 25.7%. BS = 6 and BS = 8 consisted of variables located in ULs and LLs. BS = 7 included the axial skeleton, ULs, and LLs. BS ≥ 6 represents the majority of the sample and predominantly girls., Conclusions: BS ≥ 6 represents the majority of the sample and predominantly girls. Most characterized children with GJH present BS = 6 and BS = 8 with variables located only in ULs and LLs, a condition that does not imply the feature is generalized. In children, BS = 7 and BS = 9 characterize GJH by including the axial skeleton, ULs, and LLs. These results draw attention to the implications for defining the diagnosis of hEDS and HSDs.

Histone modifications are an epigenetic mechanism, and the dysregulation of these proteins is known to be associated with the initiation and progression of cancer. In the search for the development of new and more effective drugs, histone modifications were identified as possible therapeutic targets. Histone methyltransferase (HMT) inhibitors correspond to the third generation of epigenetic drugs capable of writing or deleting epigenetic information. This systematic review summarized the development and prospect for the use of different HMT inhibitors in cancer therapy. An electronic search was applied across CENTRAL, Clinical Trials, Embase, LILACS, LIVIVO, Open Gray, PubMed, Scopus, and Web of Science. Based on the title and abstracts, two authors independently selected eligible studies. After the complete reading of the articles, based on the eligibility criteria, 11 studies were included in the review. Different inhibitors of HMT have been explored in multiple clinical studies, and have shown considerable anti-tumor effects. However, few phase 2 studies have been completed and/or have available results. The most advanced clinical trials mainly include tazemetostat, an Enhancer of zeste homolog 2 (EZH2) inhibitor approved for follicular lymphoma (FL). The use of HMT inhibitors has presented, so far, concise results in the treatment of hematological cancers, moreover, the adverse effects presented after the use of these medicines (alone or in combination) did not show a high level of risk for the patient. These findings, in addition to ongoing clinical studies, can represent a promising future regarding the use of HMT inhibitors in treating different types of cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

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 ** p 101 = 0.009, t -test ** p 139 = 0.009, t -test ** p 144 = 0.002, and t -test *** p 199 = 0.0006). Overall, our study enabled an improved understanding of the role of ZEB1-suppressed miRNAs in CSC biology.

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 (CO) ) and decreased the levels of caspase-3 p12 and methylenetetrahydrofolate reductase in the treated groups. The results demonstrated that trisomy factor causes morphofunctional abnormalities in the OB of Ts (CO) mice. Moreover, VD3 could represent a therapeutic target to attenuate morphological and molecular alterations in OB., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

Objectives: To identify psychosocial and motor aspects related to joint hypermobility (JH) in a sample from almost all Brazilian states by age range and sex; to characterize JH by the Beighton total score ≥4, ≥5, and ≥6 according to sex and age and atypicality in the sitting position and in the hands; identify, in the total sample, manifestations of "growing pain" and its location, fatigue, attention deficit, anxiety, insomnia, drowsiness, apathy, depression, delay in walking, not crawling or crawling differently, school performance, spatial orientation and/or temporally impaired, social isolation, and being stigmatized as "lazy/clumsy/apathetic"., Methods: This retrospective, observational, quantitative, and cross-sectional study used data obtained through analyses of descriptive and inferential crossings between 2012 and 2020 of 482 medical records of individuals between 1 and 76 years of age, from most Brazilian states. All patients previously diagnosed with "joint hypermobility syndrome" (JHS) and "Ehlers-Danlos syndrome hypermobility type" (EDS-HT) had their medical records reassessed, following the guidelines established in 2017. The analysis of GJH was performed using the updated method by Beighton method; atypical characteristics were investigated in the hands and the ability to sit in the "W" and the "concave" positions. The characteristics and manifestations of "growing pain" and its location were analyzed in the total sample, fatigue, insomnia, drowsiness, apathy, depression, social isolation, attention deficit, anxiety, stigmatization as "lazy," clumsy/restless, impaired school performance, and spatial and/or temporal orientation. Descriptive and inferential statistical methods were used, such as Mean, Median, Mode, Standard Deviation, Standard Error, Maximum Value, Minimum Value, Komolgorov-Smirnov , Significance, Relative Value, Absolute Value, Mann-Whitney U , and Correlation of Spearman ., Results: JH in the total sample predominated in the upper limbs, the majority were women, represented by 352 (73.02%), 15 years old or older with 322 (66.80%), 312 (64.73%) had a Beighton total score ≥6, which decreased as the age increased. Always sitting in the "concave" position was represented by 54.15% and the ability to sit in the "W" position by 39.21%; signs on the hands totaled between 27.59 and 44.19% with a significant correlation between the variables. Among the characteristics, fatigue predominated, followed by an awkward/clumsy/restless individual, attention deficit, anxiety and stigmatized as "lazy," insomnia, drowsiness, apathy, depression, impaired spatial and/or temporal orientation, and social isolation. From the total sample, pain in the lower limbs was reported by 55.81% and having or having had "growing pain" was reported by 36.93%, delay in walking occurred in 19.92%, 15.35% did not crawl or crawled differently, and for 12.86%, school performance was impaired. Higher Beighton total scores showed a trend towards motor implications and correlation between variables. Ability to still sit in the "concave" position was possible for 54.15% and to sit in the "W" position for 39.21%., Conclusion: In the total sample, the JH characteristic prevails in the upper limbs of female children, adolescents and adults, with a total Beighton score ≥6. Most sit in the "concave" position and less than half also sit in the "W" position and with atypical hand postures. The higher Beighton scores, which include the upper limbs, show a tendency to not crawl or crawl differently, delayed ambulation, and impaired school performance. The predominance of JH in the upper limbs is suggestive of a justification for not crawling or crawling differently. Characteristics of atypical motor performance in hands and sitting posture, in addition to fatigue, pain since childhood, anxiety, apathy, depression, sleep disorders, stigmatization, attention deficit, spatial and/or temporal orientation impairment, and social isolation are characteristics. suggestive of psychosocial implications at different ages. Future studies with motor and psychosocial aspects of people with JH will help to identify the phenotype of this population and consequent guidance for clinical management based on the motor and psychosocial aspects of people with JH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lamari, Lamari, Araujo-Filho, Medeiros, Pugliesi Marques and Pavarino.)

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., (© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.)

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., (© 2021. Japan Human Cell Society.)

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  < 0.001) and alcohol consumption (OR = 1.60, 95% CI = 1.13-2.27, p  = 0.008) were associated to the development of breast cancer, while smoking and null genotypes GSTM1 and GSTT1 presented no association. GSTM1 and GSTT1 polymorphisms presented no relationship with the clinical and histopathological parameters or molecular subtypes of breast cancer. Ninety-two percent of tumours were invasive ductal, 66% were grade II, 65% were larger than 2 cm, the stages II (35.3%) and III (31.2%) were the most prevalent, and 47.7% were molecular subtype luminal B.Individuals aged ≥ 50 years and alcohol consumers have more chance to developing breast cancer. GSTM1 and GSTT1 polymorphisms are not associated to the risk of breast cancer.

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<0.001) and alcohol consumption (OR: 1.76; 95% CI: 1.0-2.85; p=0.021) were associated with an increased risk of breast cancer. For MTHFR A1298C, we observed a reduced risk of developing breast cancer in the codominant model (genotype CC-OR: 0.22; 95% CI: 0.06-0.74; p=0.014), recessive model (OR: 0.22; 95% CI: 0.07-0.76 p=0.004), and log-additive model (OR: 0.70; 95% CI: 0.49-0.98; p=0.035). Women aged ≥50 years and those who are alcohol consumers had increased susceptibility to breast cancer, and MTHFR A1298C modulated the risk for this disease. This is the first study to evaluate the association between polymorphisms in folate metabolism and breast cancer in the northwest region of São Paulo State, Brazil.

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  < 0.001) and alcohol consumption ( p  = 0.021) were the predictors of increased risk of developing HCC. GSTP1 .Ala114Val for all regression models ( p  < 0.05), except the recessive model, and the 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.

Laryngeal cancer (LC) is one of the common head and neck neoplasms and is characterized by resistance to conventional therapy and poor prognosis. This may result from the presence of cancer stem cells (CSCs), which form a small population in tumors with metastatic potential, high invasive capacity, self-renewal, and differentiation. This study aimed to evaluate the effectiveness of 5-fluorouracil and cisplatin individually, as well as the combination of cetuximab and paclitaxel in a CSC subpopulation separated with biomarkers related to tumoral growth (CD44, CD117, and CD133). In addition, expression of TrkB, KRAS, HIF-1α, and VEGF -A genes and proteins related to cell proliferation were evaluated in this subpopulation. The CD44, CD133, and CD117 biomarkers were used to analyze the identification and separation of both subpopulations using FACSAria Fusion. Subpopulations positive for CD44, CD133, and CD117 or lacking these biomarkers were classified as laryngeal cancer stem cells (LCSCs) or laryngeal cancer non-stem cells (non-LCSCs), respectively. Matrigel invasion and colony forming assays were performed to confirm CSC presence. Subpopulations were cultured and exposed to 5-fluorouracil, cisplatin, and cetuximab/paclitaxel drugs for 24 h. Cell proliferation was determined using MTS assay. KRAS and TrkB gene expression levels were evaluated using quantitative real time PCR with TaqMan ® Assay in both subpopulations. The non-LCSC subpopulation was considered as the control for relative expression. We found that the LCSC subpopulation demonstrated more resistance to cetuximab and paclitaxel combination chemotherapy when compared with the non-LCSC subpopulation of the cell line. These LCSC subpopulations presented up-regulated expression of KRAS, HIF-1α, and VEGF-A genes and proteins and no TrkB gene expression, but TrkB protein expression was up-regulated in the LC cell line when compared to the non-CSC subpopulation. "In conclusion, the combination of CD44, CD133, and CD117 biomarkers has stem cell properties. Moreover, LCSCs, are capable of resisting treatment and present high KRAS, HIF-1α, and VEGF-A gene expression"., Competing Interests: None., (AJTR Copyright © 2021.)

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., Competing Interests: None

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2020 Termedia & Banach.)

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., (© 2020 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

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.

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 (Aβ 42 ) can favor the development of renal abnormalities in DS. We evaluated the effects of vitamin D 3 (VD 3 ) supplementation on morphofunctional aspects and the repercussions on the presence and localization of Aβ 42 , 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 VD 3 , 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 Aβ 42 , Caspase-3 p12, MTHFR, and Pgp proteins. All data were analyzed statistically., Key Findings: Our results showed that VD 3 promoted an increase in caspase-3 p12, MTHFR, and Pgp, and consequently contributed to reduced Aβ 42 in the renal tissue of a mouse model of DS. Furthermore, VD 3 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 VD 3 may activate specific mechanisms involved in reduced Aβ 42 and tissue repair in the kidneys of a mouse model for Down syndrome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Differential expression of genes encoding cytochrome P450 (CYP) and other oxygenases enzymes involved in biotransformation mechanisms of endogenous and exogenous compounds can lead to oral tumor development., Objective: We aimed to identify the expression profile of these genes, searching for susceptibility biomarkers in oral squamous cell carcinoma., Patients and Methods: Sixteen oral squamous cell carcinoma samples were included in this study (eight tumor and eight adjacent non-tumor tissues). Gene expression quantification was performed using TaqMan Array Human CYP450 and other Oxygenases 96-well plate (Applied Biosystems) by real time qPCR. Protein quantification was performed by ELISA and IHC methods. Bioinformatics tools were used to find metabolic pathways related to the enzymes encoded by differentially expressed genes. Results. CYP27B1, CYP27A1, CYP2E1, CYP2R1, CYP2J2, CYP2U1, CYP4F12, CYP4X1, CYP4B1, PTGIS, ALOX12, and MAOB genes presented differential expression in the oral tumors. After correction by multiple tests, only the PTGIS (Prostaglandin I2 Synthase) gene presented significant differential expression (P < 0.05). The PTGIS gene and protein were reduced in oral tumors., Conclusion: PTGIS presents downexpression in oral tumors. PTGIS play an important role in the arachidonic acid metabolism. Arachidonic acid and/or metabolites are derived from this pathway, which can influence the regulation of important physiological mechanisms in tumorigenesis process.

Background: Hepatocellular Carcinoma (HCC) is the primary liver cancer with high incidence and mortality rates. Currently one of the major etiologies for liver disease, HCC and liver transplantation is nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the epidemiological, histopathological and clinical aspects of HCC transplant patients, with emphasis on NAFLD etiology. Methods: This study included all HCC patients submitted to liver transplantation from 2010 to 2016 of the University Reference Center. The analyzed variables were age, gender, ethnicity, causes that led to liver transplantation, alpha-fetoprotein (AFP) dosage, histological aspects, recurrence, survival and NAFLD. Results: A total of 60 patients were included in the study being 80% men with a mean age of 58.3 ± 10.6 years. All patients were cirrhotic. The causes that led to the transplantation were the presence of the hepatitis C virus (HCV) (56.6% of the patients), an association of the virus with alcohol (20%), the presence of the hepatitis B virus (HBV) (20%), alcoholic liver disease (ALD) (50.9%) and NAFLD (25%). Of the latter, eight were diagnosed pre-transplantation and seven were NAFLD carriers without a previous diagnosis. Regarding the Edmondson-Steiner histological classification, 58.5% of the patients were classified as grade ≤ II. Conclusions: There is predominance of male patients with a mean age of 58.3 years. Degree ≤ II is the most frequent to the Edmondson-Steiner histological classification in the evaluated casuistic. HCV, ALD and NAFLD is the most common etiological agents found in the study. The (high) underestimated prevalence of NAFLD in the pre-transplanted patients is due to the fact that all patients presented cirrhosis, masking NAFLD signals., (Creative Commons Attribution License)

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., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest.

Immunological impairment is a condition that is often observed in individuals with Down syndrome (DS). The immune response is modulated by pro- and anti-inflammatory cytokines whose expressions could be influenced by genetic polymorphisms. The present study was aimed at evaluating the frequencies of -174G>C, -572G>C, and -597G>A polymorphisms in the interleukin 6 (IL-6) gene and -592C>A, -1082A>G, and -819C>T polymorphisms in the IL-10 gene and the IL-6 and IL-10 serum levels in healthy individuals with and without DS. The authors also aimed to investigate the impact of the genotypes on the interleukin concentrations. The genetic polymorphisms were investigated in 200 DS individuals and 200 controls without DS. The serum measurement of IL-6 and IL-10 was performed in a subgroup (54 cases and 54 controls) by enzyme-linked immunosorbent assay (ELISA). The frequencies of the polymorphisms and haplotypes evaluated were not different between individuals with and without DS. IL-10 concentration was higher in DS children but was not influenced by IL-10 gene polymorphisms. IL-6 genotypes had no influence on IL-6 serum levels. The IL-10 serum levels are increased in DS individuals, but IL-10 polymorphisms are not the main factors that influence the IL-10 expression in DS.

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 CD44 high /CD133 high /CD117 high profile (CSCs) and CD44 low /CD133 low /CD117 low 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., Competing Interests: None.

Background: Alteration in the biotransformation of exogenous compounds can result in production of reactive oxygen species (ROS), which can predispose cells to malignant transformation in the head and neck. This study aimed to evaluate the expression of genes involved in antioxidant metabolism in the oral squamous cell carcinoma (OSCC). Methods: The expression of eighty-four genes was evaluated in OSCC and non-tumor tissues by quantitative real-time polymerase chain reaction using the TaqMan Gene Expression Array. The biological mechanisms related to the differentially expressed genes were investigated using Gene – NCBI, KEGG, UNIPROT and REACTOME databases. Results: Twenty-one genes encoding enzymes involved in antioxidant metabolism were differentially expressed in the OSCC case. Four genes (ATOX1, PRDX4, PRNP, and SOD2) were up-regulated, and seventeen (ALOX12, CAT, CSDE1, DHCR24, DUOX1, DUOX2, EPHX2, GLRX2, GPX3, GSR, GSTZ1, MGST3, PRDX1, OXR1, OXSR1, SOD1, and SOD3) were down-regulated. We identified 14 possible novel biomarkers for OSCC. The differentially expressed genes appeared related to important biological processes involved in carcinogenesis, such as inflammation, angiogenesis, apoptosis, genomic instability, invasion, survival, and cell proliferation. Conclusions: Our study identified novel biomarkers which might warrant further investigation regarding OSCC pathogenesis since the altered expression in the genes can modulate biological processes related to oxidative stress and predispose cells to malignant transformation in the oral cavity., (Creative Commons Attribution License)

Background: Overexpression of proangiogenic vascular endothelial growth factor A family VEGFAxxx is associated with tumor growth and metastasis. The role of the alternatively spliced antiangiogenic family VEGFAxxxb is poorly investigated in head and neck squamous cell carcinomas (HNSCCs). The antiangiogenic isoform binds to bevacizumab and its expression level could influence the treatment response and progression-free survival. In this study, the relative expression of VEGFAxxx and VEGFA165b isoforms and splicing regulatory factors genes was investigated in a series of HNSCCs. Methods: VEGFAxxx, VEGFA165b, SRSF6, SRSF5, SRSF1 and SRPK1 gene expression was quantified by quantitative real time PCR in 53 tissue samples obtained by surgery from HNSCC patients. Protein expression was evaluated by immunohistochemistry. Results: VEGFAxxx and VEGFA165b were overexpressed in HNSCCs. Elevated protein expression was also confirmed. However, VEGFA isoforms demonstrated differential expression according to anatomical sites. VEGFAxxx was overexpressed in pharyngeal tumors while the VEGFA165b isoform was up-regulated in oral tumors. The VEGFA165b isoform was also positively correlated with expression of the splicing regulatory genes SRSF1, SRSF6 and SRSF5. Conclusions: We concluded that VEGFAxxx and VEGFA165b isoforms are overexpressed in HNSCCs and the splicing regulatory factors SRSF1, SRSF6, SRSF5 and SRPK1 may contribute to alternative splicing of the VEGFA gene. The findings for the differential expression of the antiangiogenic isoform in HNSCCs could facilitate effective therapeutic strategies for the management of these tumors., (Creative Commons Attribution License)

Aim: To investigate the contribution of polymorphisms in the CYP1A1 , CYP2E1 and EPHX1 genes on sporadic colorectal cancer (SCRC) risk., Methods: Six hundred forty-one individuals (227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The EPHX1 Tyr113His, EPHX1 His139Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chi-squared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05., Results: Age over 62 years was a risk factor for SCRC development (OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC (OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant (heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant (OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant (OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models (OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant (heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic: OR = 7.32, 95%CI: 1.85-28.96, P < 0.01), dominant (OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive (OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant (OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log-additive models (OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B (C) and CYP2E1*6 (A) polymorphisms was associated with SCRC ( P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113His and EPHX1 His139Arg polymorphisms were not associated with SCRC., Conclusion: In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest.

Aim: To evaluated the association of the risk factors and polymorphisms in MTHFR C677T , MTHFR A1298C , MTR A2756G and MTRR A66G genes., Methods: Patients with cirrhosis ( n = 116), hepatocellular carcinoma (HCC) ( n = 71) and controls ( n = 356) were included. Polymerase chain reaction followed by enzymatic digestion and allelic discrimination technique real-time PCR techniques were used for analysis. MINITAB-14.0 and SNPstats were utilized for statistical analysis., Results: Showed that age ≥ 46 years (OR = 10.31; 95%CI: 5.66-18.76; P < 0.001) and smoking (OR = 0.47; 95%CI: 0.28-0.78; P = 0.003) were associated with cirrhosis. Age ≥ 46 years (OR = 16.36; 95%CI: 6.68-40.05; P < 0.001) and alcohol habit (OR = 2.01; 95%CI: 1.03-3.89; P = 0.039) were associated with HCC. MTHFR A1298C in codominant model (OR = 3.37; 95%CI: 1.52-7.50; P = 0.014), recessive model (OR = 3.04; 95%CI: 1.43-6.47; P = 0.0051) and additive model (OR = 1.71; 95%CI: 1.16-2.52; P = 0.0072) was associated with HCC, as well as MTR A2756G in the additive model (OR = 1.68; 95%CI: 1.01-2.77; P = 0.047), and MTRR A66G in the codominant model (OR = 3.26; 95%CI: 1.54-6.87; P < 0.001), dominant model (OR = 2.55; 95%CI: 1.24-5.25; P = 0.007) and overdominant model (OR = 3.05; 95%CI: 1.66-5.62; P < 0.001). MTR A2756G in the additive model (OR = 1.54; 95%CI: 1.02-2.33; P = 0.042) and smokers who presented at least one polymorphic allele for MTRR A66G (OR = 1.71; 95%CI: 0.77-3.82; P = 0.0051) showed increased risk for cirrhosis. There was no association between clinical parameters and polymorphisms., Conclusion: Age ≥ 46 years, alcohol habit and MTR A2756G , MTHFR A1298C and MTRR A66G polymorphisms are associated with an increased risk of HCC development; age ≥ 46 years, tobacco habit and the MTR A2756G polymorphism are associated with cirrhosis., Competing Interests: Data sharing statement: Patient data and full dataset are available with open accessfrom the corresponding author at analiviagalbiattidias@gmail.com. All Participants gave informed consent for data sharing. For more questions, please contact eny.goloni@famerp.br.

The supernumerary chromosome 21 in Down syndrome differentially affects the methylation statuses at CpG dinucleotide sites and creates genome-wide transcriptional dysregulation of parental alleles, ultimately causing diverse pathologies. At present, it is unknown whether those effects are dependent or independent of the parental origin of the nondisjoined chromosome 21. Linkage analysis is a standard method for the determination of the parental origin of this aneuploidy, although it is inadequate in cases with deficiency of samples from the progenitors. Here, we assessed the reliability of the epigenetic 5mCpG imprints resulting in the maternally (oocyte)-derived allele methylation at a differentially methylated region (DMR) of the candidate imprinted WRB gene for asserting the parental origin of chromosome 21. We developed a methylation-sensitive restriction enzyme-specific PCR assay, based on the WRB DMR, across single nucleotide polymorphisms (SNPs) to examine the methylation statuses in the parental alleles. In genomic DNA from blood cells of either disomic or trisomic subjects, the maternal alleles were consistently methylated, while the paternal alleles were unmethylated. However, the supernumerary chromosome 21 did alter the methylation patterns at the RUNX1 (chromosome 21) and TMEM131 (chromosome 2) CpG sites in a parent-of-origin-independent manner. To evaluate the 5mCpG imprints, we conducted a computational comparative epigenomic analysis of transcriptome RNA sequencing (RNA-Seq) and histone modification expression patterns. We found allele fractions consistent with the transcriptional biallelic expression of WRB and ten neighboring genes, despite the similarities in the confluence of both a 17-histone modification activation backbone module and a 5-histone modification repressive module between the WRB DMR and the DMRs of six imprinted genes. We concluded that the maternally inherited 5mCpG imprints at the WRB DMR are uncoupled from the parental allele expression of WRB and ten neighboring genes in several tissues and that trisomy 21 alters DNA methylation in parent-of-origin-dependent and -independent manners.

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, and PLCB4), and eight were underexpressed (LTA4H, BDKRB1, ADRB2, CD40LG, ITGAM, TNFRSF1B, ITGB1, and TBXAS1). After statistically correcting for the false discovery rate, only the genes BDKRB1 and LTA4H showed 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. The BDKRB1 and LTA4H genes may differentiate the case and control groups based on the inflammatory response, which plays an important role in DS pathogenesis.

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.

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.

Aim: To evaluate the effect of promoter region polymorphisms of toll-like receptor (TLR)2-196 to -174del and TLR4-1607T/C (rs10759932) on mRNA and protein expression in tumor tissue and of TLR4+896A/G (rs4986790) on colorectal cancer (CRC) risk., Methods: The TLR2-196 to -174del polymorphism was investigated using allele-specific polymerase chain reaction (PCR) and the TLR4-1607T/C and TLR4+896A/G by PCR-restriction fragment length polymorphism (RFLP). We genotyped 434 DNA samples from 194 CRC patients and 240 healthy individuals. The mRNA relative quantification (RQ) was performed in 40 tumor tissue samples by quantitative PCR TaqMan assay, using specific probes for TLR2 and TLR4 genes, and ACTB and GAPDH reference genes were used as endogenous controls. Protein expression was analyzed by immunohistochemistry with specific primary antibodies., Results: No association was found for TLR4-1607T/C and TLR4+896A/G by three statistical models (log-additive, dominant and recessive). However, based on dominant and log-additive models, the polymorphic variant TLR2-196 to -174del was associated with increased CRC risk [dominant: odds ratio (OR) = 1.72, 95%CI: 1.03-2.89; P = 0.038 and log-additive: OR =1.59, 95%CI: 1.02-2.48; P = 0.039]. TLR2 mRNA expression was increased in tumor tissue (RQ = 2.36) when compared to adjacent normal tissue (RQ = 1; P < 0.0001), whereas the TLR4 mRNA showed a basal expression (RQ = 0.74 vs RQ = 1, P = 0.452). Immunohistochemistry analysis of TLR2 and TLR4 protein expression was concordant with the findings of mRNA expression. In addition, the TLR2-196 to -174del variant carriers showed mRNA relative expression 2.19 times higher than wild-genotype carriers. The TLR2 protein expression was also higher for the TLR2-196 to -174del variant carriers [117 ± 10 arbitrary unit (a.u.) vs 95 ± 4 a.u., P = 0.03]. However, for the TLR4 -1607T/C polymorphism no significant difference was found for both mRNA (P = 0.56) and protein expression (P = 0.26)., Conclusion: Our findings suggest that TLR2-196 to -174del polymorphism increases TLR2 mRNA expression and is associated with higher CRC risk, indicating an important role in CRC genetic susceptibility.

Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

Background: Results of magnetic resonance spectroscopy studies in normal-appearing brain and in non-neoplastic brain lesions in individuals with neurofibromatosis type 1 (NF1) have been discrepant., Objective: We used magnetic resonance spectroscopy to analyze the metabolic patterns in the basal ganglia of patients with NF1 and examine their correlation with focal hyperintense lesions in T2-weighted images (T2-weighted hyperintensities)., Methods: We used magnetic resonance spectroscopy data of 42 individuals with NF1 (18 with and 24 without T2- weighted hyperintensities) and 25 controls matched for gender and age. A single-voxel technique was employed by manually placing a region of interest with a uniform size over a predetermined anatomical region including the globus pallidum and putamen (capsulolenticular region). We further analyzed the ratios of choline/creatine, N-acetyl aspartate (NAA)/creatine, and myoinositol/creatine metabolites and the occurrence of T2-weighted hyperintensities in these regions in individuals with NF1., Results: There was a significant difference between the NF1 and control groups with regard to the mean values of myoinositol/creatine and choline/creatine, with higher metabolite values observed in the NF1 group (P < 0.001). Only the myoinositol/creatine ratio was able to discriminate between NF1 subgroups with and without T2-weighted hyperintensities. For the NAA/creatine ratio, there was no significant difference between the NF1 and the control groups., Conclusion: Magnetic resonance spectroscopy allows the characterization of tissue abnormalities not demonstrable in the structural images of individuals with NF1 through choline and myoinositol metabolite analysis. Yet the preserved NAA values argue against demyelination and axonal degeneration occurring in the region, suggesting instead a functional neuronal stability. Taken in association with the findings of lack of clinical manifestations and the known transient nature of T2-weighted hyperintensities in NF1 as demonstrated by other studies, our results support the current histopathologically driven hypothesis that such T2-weighted hyperintensities may be related to intramyelinic edema., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I (2) statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS.

Background: Down syndrome (DS) results from the presence and expression of three copies of the genes located on chromosome 21. Studies have shown that, in addition to overexpression of the Cystathionine β-synthase (CBS) gene, polymorphisms in genes involved in folate/homocysteine (Hcy) metabolism may also influence the concentrations of metabolites of this pathway., Aim: Investigate the association between Dihydrofolate reductase (DHFR) 19-base pair (bp) deletion and Serine hydroxymethyltransferase (SHMT) C1420T polymorphisms and serum folate and plasma Hcy and methylmalonic acid (MMA) concentrations in 85 individuals with DS., Methods: Molecular analysis of the DHFR 19-bp deletion and SHMT C1420T polymorphisms was performed by polymerase chain reaction (PCR) by difference in the size of fragments and real-time PCR allelic discrimination, respectively. Serum folate was quantified by chemiluminescence and plasma Hcy and MMA by liquid chromatography-tandem mass spectrometry., Results: Individuals with DHFR DD/SHMT TT genotypes presented increased folate concentrations (p=0.004) and the DHFR II/SHMT TT genotypes were associated with increased MMA concentrations (p=0.008). In addition, the MMA concentrations were negatively associated with age (p=0.04)., Conclusion: There is an association between DHFR DD/SHMT TT and DHFR II/SHMT TT combined genotypes and folate and MMA concentrations in individuals with DS.

Unlabelled: Although head and neck carcinoma ranks fifth among cancer types, patient survival rates have not changed significantly over the past years., Objective: To determine the risk factors, causes, therapies, and prevention measures for head and neck cancer., Method: Risk factors, causes, therapies, and preventive measures for this disease were searched on databases PUBMED, MEDLINE, and SCIELO., Results: Alcohol and tobacco are still atop risk factors. Other factors may influence the development of head and neck carcinoma. Surgery is the main treatment option, and the addition of radiotherapy following surgery is frequent for patients in the early stages of the disease. Other therapies target specific genetic molecular components connected to tumor development. Disease preventive measures include smoking cessation, limiting alcohol intake, preventing exposure to tobacco smoke and environmental carcinogenic agents, early detection of infection by HPV, maintaining oral health, good eating habits, and managing stress., Conclusion: Additional research is needed for a more thorough understanding of the development of head and neck carcinomas and to shed light on new ways to improve therapeutic approaches and interventions.

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<0.05). Furthermore, we found that 1298 AC or CC genotypes were associated with age≥49 years, tobacco and alcohol habits (P<0.05). Regarding clinical histopathological parameters, the A1298C polymorphism was more frequent in patients with oral cavity as primary site (P<0.05). MTHFR polymorphisms may contribute for increase risk for head and neck carcinoma and the variables age≥49 years, male gender, tobacco and alcohol habits were associated with MTHFR 1298AC or CC genotypes, confirming that individuals with these variables and MTHFR A1298C polymorphism has higher risk for this disease.