Generalized Joint Hypermobility: A Statistical Analysis Identifies Non-Axial Involvement in Most Cases.

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.

Effect of ZEB1 Associated with microRNAs on Tumor Stem Cells in Head and Neck Cancer.

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

Use of histone methyltransferase inhibitors in cancer treatment: A systematic review.

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.

Treatment effects of the EGFR pathway drugs on head and neck cancer stem cells.

(1) Head and neck cancer (HNC) is the sixth most common cancer worldwide and show low survival rates and drug resistance, which can be due to the presence of cancer stem cells (CSCs), a small cell population with metastatic potential, invasion and self-renewal ability. (2) Here, seven tumor cells were sorted as CD44+/CD117+/CD133+ or ALDH+, considered as HNC stem cells (HNCSCs), and as CD44-/CD117-/CD133- or ALDH-, considered non-HNCSCs after both cells sorted criteria was compared to evaluate cell migration, invasion, and colony forming assays. These subpopulations were treated with Cetuximab, Paclitaxel, or a combination of both drugs and evaluated for cell viability. Quantitative PCR and western blot were performed to evaluate EGFR, TRKB, KRAS and HIF-1α gene and protein expression. (3) HNCSCs presented more colonies and appeared to be more sensitive to the drug combination when compared with non-HNCSCs, regardless cells sorted criteria and primary tumor subsite. The EGFR, TRKB, KRAS and HIF-1α genes and proteins were upregulated in CSCs compared with non-HNCSCs, thus explaining the drug resistance. (4) This study contributes to the better development of specific therapeutic protocols based on Cetuximab and Paclitaxel drugs in the treatment of HNC in the presence of CSCs and cell proliferation biomarkers.

Vitamin D3 supplementation may attenuate morphological and molecular abnormalities of the olfactory bulb in a mouse model of Down syndrome.

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-ß 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.

Regulation of VEGFA, KRAS, and NFE2L2 Oncogenes by MicroRNAs in Head and Neck Cancer.

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.

Differential microRNA expression profile in blood of children with Down syndrome suggests a role in immunological dysfunction.

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 ß (TGF-ß) signaling pathways. These results suggest that altered miRNA expression could be contributing to the well-known immunological dysfunction observed in individuals with DS.

Association between folate metabolism polymorphisms and breast cancer: a case-control study.

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.

One-carbon metabolism and global DNA methylation in mothers of individuals with Down syndrome.

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.

Evaluation of molecular markers GSTM1 and GSTT1 and clinical factors in breast cancer: case-control study and literature review.

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.

Polymorphisms in xenobiotic metabolism-related genes in patients with hepatocellular carcinoma: a case-control study.

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.

Anti-EGFR treatment effects on laryngeal cancer stem cells.

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".

Gene Polymorphisms Involved in Folate Metabolism and DNA Methylation with the Risk of Head and Neck Cancer.

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 <0.001), and overdominant (p= 0.001) models for T/C and C/C genotypes. DNMT3B -149C/T and DNMT3B -579G/T revealed no association between groups in any model. The DHFR 19-pb ins/del polymorphism protected against HNSCC development compared to the C group by the codominant (p < 0.001), dominant (p < 0.001), and overdominant (p < 0.001) models. In the TYMS, the 3R/3R genotype had a protective effect against HNSCC development compared with the C group by the recessive models (p= 0.009). In contrast, SHMT1 1420 C/T presented no association between the HNSCC and C groups. DHFR 19-pb ins/del polymorphisms protected against oral cavity cancer (p= 0.003), and only TYMS-28 3R/3R decreased the risk of tumor progression (p= 0.023). In the Kaplan-Meier curve, an association was found between DHFR ins/ins and TYMS -28 3R carriers with respect to relapse-free time; further, DNMT3B -579 T and TYMS-28 2R/2R carriers had longer survival times. CONCLUSION: DNMT3B -283T/C is associated with higher risk, whereas DHFR 19-pb ins/del and TYMS 28 3R/3R protect against head and neck cancer. We also highlighted the association of TYMS 3R/3R genotype carriers with relapse-free cancer protection and survival time.

Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer.

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 as regulators of VEGFA and NFE2L2 in cancer.

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.

Glutathione S-transferase Polymorphisms in Head and Neck Squamous Cell Carcinoma Treated with Chemotherapy and/or Radiotherapy.

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.

Signos y síntomas en niños y adolescentes con hipermovilidad articular: un estudio transversal cuantitativo observacional / Signs and symptoms in children and adolescents with joint hypermobility: an observational, quantitative cross-sectional study

Contexto y Objetivo: La hipermovilidad articular (HA) puede representar el ex-tremo del rango normal de movimiento o condición para un grupo de trastornos hereditarios del tejido conectivo, con una variación de 2-64.6% en diferentes poblaciones. El objetivo fue caracterizar la asociación entre HA con las manifestaciones en forma de signos y síntomas.Tipo de Estudio y Ajuste: Estudio transversal cuantitativo observacional en un hospital universitario público.Métodos: Estudio con niños y adolescentes entre 5 y 16 años, de ambos sexos, en asistencia multiprofesional en la clínica ambulatoria de HA y SED en el Hospital Base de São José do Rio Preto y en la Unidad del Proyecto "Gato de Botas", en colaboración con FAMERP. Se utilizó un cuestionario para registrar datos y análisis realizados en base a cálculos de medidas de tendencia central, dispersión y conteos de frecuencia.Resultados: El puntaje 4 obtuvo la frecuencia más alta (45,61%), seguido del puntaje 6 (21,05%). Las manifestaciones musculoesqueléticas y extraesqueléticas fueron frecuentes. La variable de hiperextensión del quinto dedo >90º fue la variable con mayor incidencia, seguida de la aposición del pulgar al tocar la región flexora del antebrazo.Conclusiones: Entre los niños y adolescentes con HA, la mitad o más presentaron manifestaciones musculoesqueléticas o extraesqueléticas.

Background and Aim: Joint hypermobility (JH) may be the extreme of the normal range of motion or a condition for a group of hereditary connective tissue disorders, with a prevalence rate of 2 to 64.6% in different populations. The aim of the present study was to characterize the association between JH and manifestations in the form of signs and symptoms. Study Type and Setting: An observational, quantitative, cross-sectional study was conducted at a public hospital. Methods: This study involved the participation of male and female children and adolescents aged five to 16 years under multidisciplinary care at the JH and Ehlers-Danlos syndrome clinic of the São José do Rio Preto Base Hospital and the "Gato de Botas" Project Unit in partnership with the São José do Rio Preto School of Medicine. A questionnaire was administered for the recording of the data, which were analyzed descriptively, with the calculation of central tendency and dispersion measures as well as the determination of frequencies.Results: Beighton score 4 was the most frequent (45.61%), followed by score 6 (21.05%). Musculoskeletal and extraskeletal manifestations were frequent. Hyperextension of the 5th finger > 90º had a higher occurrence, followed by the thumb touching the flexor region of the forearm. Conclusions: Among children and adolescents with hypermobility, half or more had musculoskeletal or extraskeletal manifestations.

Vitamin D3 increases the Caspase-3 p12, MTHFR, and P-glycoprotein reducing amyloid-ß42 in the kidney of a mouse model for Down syndrome.

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 ß peptide 1-42 (Aß42) 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 Aß42, 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 Aß42, 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 Aß42 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 Aß42 and tissue repair in the kidneys of a mouse model for Down syndrome.

Polymorphisms in MTHFR, MTR, RFC1 and CßS genes involved in folate metabolism and thyroid cancer: a case-control study.

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.

Molecular evaluation of glutathione S transferase family genes in patients with sporadic colorectal 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.