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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.