Introduction: Joint hypermobility (JH) is mobility beyond the normal range of motion. JH can be an isolated finding or a characteristic of a syndrome. Characteristics related to the sitting position with atypical body positions, such as sitting in splits (S), with the foot on the head (F), in W (W), in a concave shape (C), episodes of dislocations, and subluxations, suggest impacts on body mechanics since childhood, with damage to the conformation of the joints. Objectives: Identify preclinical signs of JH, in addition to Beighton Score (BS), through signs that are easily recognized early by pediatricians and family members to avoid possible joint deformities in the future. Methods: The medical records of 124 children (59.7% girls) between one and nine years old were analyzed. JH was assessed using the BS, a history of luxations/subluxations, and the concave (C), “W”, “splits” (S), and foot (F) on head sitting positions. Results: The concave sitting position was the most common, followed by W, F, and S in decreasing order. A total of 52.4% of the children had BS > 6, with a higher prevalence among girls (60.8%) compared to boys (40.0%); a difference statistically significant (p = 0.024, Fisher’s exact test). Thirty-two patients (27.4%) had luxations/subluxations with the higher scores. Conclusions: Sitting in S, F, W, and C positions are preclinical phenotypic characteristics of JH, easily identified by pediatricians and family members to prevent possible joint deformities. BS ≥ 6 is more frequently observed in all positions. The majority of the total sample has BS > 6, with a significant female gender influence. Among those with a history of occasional joint dislocations and subluxations, half of them have the highest BS scores.

Hypoxia in the tumor environment leads to an activation of genotypes that favors the tumor, promoting angiogenesis, epithelial-mesenchymal transition, cell invasion, and metastasis. It is considered a prognostic factor related to the progression and aggressiveness of Head and Neck Cancer (HNC). Hypoxia-inducible factor (HIF) is the main gene activated by hypoxia and has been associated with tumor advancement. Thus, this work aims to evaluate the performance of the compounds Acriflavine, Resveratrol, Topotecan, and RNA interference (siRNA) as HIF inhibitors as well as a therapeutic approach. Molecular docking results have suggested that the evaluated compounds present potential interactions with HIF-1α and HIF-2α. In vitro analysis, they demonstrated that treatments with Acriflavine and Topotecan caused a decrease in the gene expression of HIFs in the HN13 cell line (carcinoma of the oral cavity). Furthermore, treatments performed with siRNAs effectively inhibited gene expression of HIFs in HN13 and FaDu (carcinoma of the pharynx) cell lines. Considering the role of hypoxia and HIFs in tumor aggressiveness; the present study shows the potential of the evaluated compounds as a therapeutic use for the prevention of tumor progression in head and neck cancer.

Head and neck cancer (HNC) is one of the most common types of cancer in the world, characterized by resistance to conventional therapies and an unfavorable prognosis due to the presence of tumor stem cells (TSCs). TSCs are cell subpopulations with high potential for invasion, migration, and metastasis, being responsible for the initiation and dissemination of cancer. This study aimed to evaluate the efficacy of treatments with cetuximab and paclitaxel, alone and in combination, in TSCs from oral cavity (SCC-28) and hypopharynx (FADU) cancer cell lines. In addition, the influence of the gene and protein expression of EGFR, NTRK2 (TRKB), KRAS, and HIF-1α on the response to treatments was investigated. TSCs were identified based on ALDH staining, and cell viability assays (MTS) indicated that both TSCs and non-TSCs showed resistance to cetuximab monotherapy, while paclitaxel, either alone or in combination with cetuximab, was more effective in reducing cell viability. Real-time PCR and Western blot analysis revealed increased expression of KRAS and HIF-1α in TSCs, suggesting their possible association with treatment resistance. The results of this study point to specific molecular factors that influence therapeutic responses in HNC, with an emphasis on the efficacy of drug combinations to overcome TSC resistance. The identification of these molecular mechanisms may provide guidelines for the development of more targeted and effective therapies against HNC, improving clinical management and patient prognoses.

Objectives Human Papillomavirus (HPV) may be a predictive biomarker predictor for clinical outcome and influence treatment decisions in patients with Head and Neck Squamous Cell Carcinoma (HNSCC). Methods We evaluated 253 patients with HNSCC from state of São Paulo, Brazil. The influence of p16INK4a expression was analyzed with epidemiological and clinical variables. Results In total, 32.4% of tumors studied had positive (+) p16INK4a protein expression, and 67.6% had negative. The variables were similar in both groups being the mostly with age under 64-years, male, white race, functional illiterate, smokers and alcoholics. The most affected primary site was oral cavity with T3/T4 tumoral stage, N1/N2/N3 nodals, M0 metastasis and III/IV clinical stage. Patients with oropharyngeal primary site and (+) p16INK4a, clinical staging III and chemotherapy treatment had worse survival. The median time of distant metastasis-free was 38.3-months in oropharyngeal (+) p16INK4a and 15.1-months in negative (−) p16INK4a. Conclusion In the present study, the epidemiological variables are similar in both groups (Positive and negative p16INK4a expression): age under 64-years, male, white, functionally illiterate, smokers and alcoholics. There is no association of p16INK4a expression with primary site, however, the (−) p16INK4a shows better overall survival, higher frequencies in distant metastasis and less free time of the disease. Although the literature shows a greater survival in oropharynx (+) p16INK4a, our results are contradictory. It is suggested that future studies in different regions and with a larger sample size should be carried out to confirm these findings, because the patients who participated in the present study are only from a specific region of Brazil. Level of evidence 2B.

Xia-Gibbs syndrome (XGS) is a rare intellectual disability (ID) syndrome caused by de novo AHDC1 pathogenic variants. We characterized clinical and molecular features of 16 Brazilian patients with XGS. Patient data were collected through semistructured interviews with family members, reanalysis of previous health and genetic assessments, and clinical reports from physicians. Genomic variants and their segregation were validated via Sanger sequencing. Statistical analyses were conducted to evaluate genotype-phenotype associations. Twelve novel AHDC1 causative variants were documented. ID, hypotonia, motor developmental delay, and varied nonspecific facial dysmorphisms were observed in all patients, while speech impairment and autism spectrum disorder were present in nearly all. Three frequent phenotypes, not previously reported, were identified: hyperphagia/food obsession, genital/gonadal alterations in males, and shortening of the Achilles tendon. Additionally, our findings provide statistically significant support for previously reported genotype-phenotype associations between pathogenic variants in the first half of the AHDC1 coding region and the occurrence of epilepsy and scoliosis. We also propose a novel association between N-terminal variants and developmental regression. In summary, our results broaden the clinical phenotype of XGS, with musculoskeletal and genital/gonadal abnormalities highlighting the multisystem involvement in this condition, beyond neurodevelopmental deficits. Comprehensive phenotypic assessments in all identified XGS cases are recommended to accurately recognize and associate novel clinical signs with XGS.

ABSTRACT Gene dysregulation in trisomy 21 can cause disorders of genes that are members of the heat-shock proteins (HSPs) family and contribute to the early onset of Alzheimer’s disease (AD) in Down syndrome (DS). Objective: Investigate in silico differently expressed genes (DEGs) of HSPs and the interaction with microRNAs (miRNAs) located in human chromosome 21 (Hsa21). Methods: Two transcriptome libraries of human brain samples, datasets GSE5390 (DS) and GSE33000 (DA), were extracted from the Gene Expression Omnibus (GEO) and analyzed via GEO2R. DEGs with p-values (Adj p-values) <0.05 were analyzed via STRING. MiRNAs were identified in the miRbase database and analysis of their potential regulation on DEGs was performed using the DIANA tools. Results: HSPE1, HSP90B1, HSPB8 and HSPA13 genes showed a different expression pattern in the transcriptomes of DS. The HSPA13 and HSPA2 genes showed an altered expression profile in the DS and AD datasets. In the predicted protein-protein interactions (PPI), we identified the interaction of HSPE1, HSP90B1, HSPB8 and HSPA13 with other HSP proteins. The miRNA encoded by Hsa21 (hsa-miR-155-5p) interacted with the HSPA13 gene. Conclusion. The results suggest that certain genes encoding members of the HSP family, and in particular the interaction between miR-155-5p and HSPA13, may be associated with AD in DS.

Neurofibromatosis type 1 (NF1) is a syndrome triggered by mutations in the NF1 gene, which alter the neurofibromin protein, a negative regulator of the RAS oncogenic pathway. Due to underreporting, the scarcity of studies on NF1 in Brazil and its importance in public health. This study aimed to assess the clinical and epidemiological characterisation of NF1 in a Reference Hospital in the country and DataSUS. The study analysed the electronic medical records of patients with NF1 and the DataSUS databases. The medical records showed a greater number of female, white and adult patients. There was a high frequency of clinical features adopted by the NIH consensus for the clinical diagnosis of the disease, such as CALMs, dermal neurofibromas and axillary/inguinal ephelides, bone and ophthalmological changes, in addition malignant and benign neoplasms and neurodevelopmental disorders. On the other hand, the data provided by DataSUS shows a disproportionate concentration of NF1 consultations between the country's regions, with a low level of diagnoses of newborn with NF1 and a NF1 mortality rate of 3.06% in the population. There is therefore a need for new public policies on access to diagnosis, treatment and information about the disease for the Brazilian population.

Neurofibromatose (NF), também conhecida como doença de Von Recklinghausen, é uma enfermidade de natureza genética, que pode afetar múltiplos sistemas dos indivíduos. Assim, torna-se importante estudá-la, para que se possa ofertar tratamento e acompanhamento adequados à população envolvida. Identificar e mapear as instituições de apoio aos pacientes com Neurofibromatose e seus familiares, existentes no Brasil. Trata-se de uma pesquisa descritiva exploratória e transversal, com análise qualitativa e quantitativa dos dados. As instituições pesquisadas foram identificadas e incluídas a partir de busca através da Internet, pela técnica “Bola de Neve”. Das 143 entidades localizadas; 10 foram selecionadas e constituíram a amostragem do estudo. Após a autorização e aceite ao Termo de Consentimento Livre e Esclarecido (TCLE), os representantes das instituições preencheram ao questionário semidirigido, de autorresposta, elaborado pelos autores e encaminhado por e-mail. Os dados foram tabulados por meio de estatística descritiva simples e, por agrupamentos semânticos de respostas coincidentes, analisadas por juízes interdependentes, a luz da literatura pertinente. As instituições apresentaram-se de formas distintas com relação à infraestrutura física e humana, bem como, nas atividades/ações desenvolvidas no atendimento aos pacientes e respectivos familiares. Para a maioria das entidades, a prestação de serviços é direcionada a diagnósticos e tratamentos clínicos aos usuários, e o número de atendimentos encontra-se aquém das necessidades da demanda existente. Os dados permitem visualizar o funcionamento e as principais características das instituições avaliadas e indicam a necessidade de incentivar medidas e políticas públicas e privadas de fomento e apoio às mesmas, bem como pesquisas de caráter mais abrangente, de modo a especificar os reais desafios enfrentados pelas entidades/serviços brasileiros de atendimento aos pacientes e familiares com Neurofibromatose.

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.

Enfermeiras, atendentes e assistentes de enfermagem que preparam e aplicam antineoplásicos em unidades hospitalares apresentaram freqüências aumentadas de anomalias e de trocas entre cromátides-irmãs (TCI) em cromossomos de linfócitos periféricos. Não foi detectada associação entre as freqüências desses fenômenos e os tipos de dispositivos de proteção ou o tempo de exposição aos antineoplásicos, possivelmente devido à multiplicidade de variáveis atuantes, o que dificultou a interpretação do papel de fatores isolados. No entanto, foi detectada uma associação entre o grau de escolaridade e a freqüência de anomalias citogenéticas, que é menor nos profissionais de nível superior que naqueles com formação técnica ou prática. Além disso, a freqüência de anomalias cromossômicas e de TCI foram menores quando as profissionais expostas manuseavam menos freqüentemente os antineoplásicos mais tóxicos. A amostra de aplicadores de antineoplásicos analisada, portanto, pertence a um grupo de risco para a ocorrência de lesões no material genético, indicando a necessidade de que sejam sempre observadas as normas de segurança previstas para o manuseio desses compostos e sugerindo a conveniência da monitorização biológica periódica nos indivíduos a eles profissionalmente expostos.

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.

Abstract We investigate patients undergoing treatment for head and neck cancer (HNC) who had mucositis. The most were male, literate, white, smokers and and alcoholics. Mucositis is associated with age over 65 years and alcohol (age:OR:0.52;CI:0.37 0.74;p = 0.000/Alcohol:OR:1.90;CI:1.25–2.87;p = 0.002). There is significance for oropharyngeal site (OR:1.58;CI:1.02–2.43;p = 0.039), advanced clinical stage (OR:2.39;CI:1.18–4.85;p = 0.016) and chemotherapy (OR:0.61;CI: 0.41–0.91;p = 0.016) with mucositis. Grade 1 mucositis was present in 55.2% of patients, followed by 23.6% with grade 2 and 21.1% with grade 3. A total of 57.09% of patients with mucositis were submitted to lasertherapy and the mean time between the beginning of the treatment and the complaint of mucositis was six months; the mean time between the complaint of mucositis and the beginning of lasertherapy was 33 days. Normality test showed that there is a difference in the groups: mucositis Initial degree (K2 = 55.17;<0.000 1), number of lasertherapy (K2 = 112.2; p < 0.0001) and current degree (K2 = 45.50; p < 0.0001). There was significance of the initial and current degrees of mucositis (R = 0.41;p < 0.0001). Pearson's correlation was negative between mucositis current degree and the number of lasertherapy (R= -0.1423;p = 0.072). Patients with mucositis are male, with 65 years, white, literat, smokers and alcoholics. Oropharyngeal cancer and advanced stage are more likely to develop mucositis in the casuistic evaluated. Lasertherapy is effective in treatment of mucositis and can contribute to better life quality for patients with mucositis after treatment for HNC.

Background and Objectives: KRAS, NRAS, BRAF mutations and microsatellite instability (MSI) can be associated with Colorectal Cancer (CRC) development.Material and Methods: We evaluated 828 medical records of CRC patients from a school hospital from January/ 2016 to December/2020. Variables such as age, gender, ethnicity, literacy level, smoking, alcoholism, primary anatomical site, tumor staging, presence of BRAFV600E, KRAS, NRAS mutations and MSI , survival and metastasis were identified. The statistical analyses were performed (p < 0.05 was considered significant).Results: There was a predominance of males (51.93%), whites (90.70%), low education (72.34%), smokers (73.79%), and non-alcoholics (79.10%). Rectum was the most affected site (42.14%), advanced tumor stage was most prevalent (62.07%), and metastasis occurred in (64.61%). Of the enrolled patients; 204 were investigated for BRAF mutation and detected in (2.94%); 216 for KRAS gene and detected in (26.08%); 210 for NRAS gene, and detected in (25.36%); 370 for MSI and detected in (44.68%). A significant association of CRC with NRAS mutation and alcohol habit (p = 0.043) was observed. The presence of MSI was associated with primary site proximal colon (p < 0.000), distal colon (p = 0.001) and rectum (p = 0.010).Conclusion: Patients with CRC are male, over 64 years old, white, with low education, smokers and nonalcoholics. The most affected primary site is rectum in advanced stage with metastasis. CRC is associated with NRAS mutation and alcohol habit, there is increased risk for primary site of proximal colon and MSI; decreased risk for distal colon and rectum in the presence of MSI.

Xia-Gibbs syndrome (XGS) is a syndromic form of intellectual disability caused by heterozygous AHDC1 variants, but the pathophysiological mechanisms underlying this syndrome are still unclear. In this manuscript, we describe the development of two different functional models: three induced pluripotent stem cell (iPSC) lines with different loss-of-function (LoF) AHDC1 variants, derived by reprogramming peripheral blood mononuclear cells from XGS patients, and a zebrafish strain with a LoF variant in the ortholog gene (ahdc1) obtained through CRISPR/Cas9-mediated editing. The three iPSC lines showed expression of pluripotency factors (SOX2, SSEA-4, OCT3/4, and NANOG). To verify the capacity of iPSC to differentiate into the three germ layers, we obtained embryoid bodies (EBs), induced their differentiation, and confirmed the mRNA expression of ectodermal, mesodermal, and endodermal markers using the TaqMan hPSC Scorecard. The iPSC lines were also approved for the following quality tests: chromosomal microarray analysis (CMA), mycoplasma testing, and short tandem repeat (STR) DNA profiling. The zebrafish model has an insertion of four base pairs in the ahdc1 gene, is fertile, and breeding between heterozygous and wild-type (WT) animals generated offspring in a genotypic proportion in agreement with Mendelian law. The established iPSC and zebrafish lines were deposited on the hpscreg.eu and zfin.org platforms, respectively. These biological models are the first for XGS and will be used in future studies that investigate the pathophysiology of this syndrome, unraveling its underlying molecular mechanisms.

Intrachromosomal rearrangements involve a single chromosome and can be formed by several proposed mechanisms. We reported two patients with intrachromosomal duplications and deletions, whose rearrangements and breakpoints were characterized through karyotyping, chromosomal microarray, fluorescence in situ hybridization, whole-genome sequencing, and Sanger sequencing. Inverted duplications associated with terminal deletions, known as inv-dup-del rearrangements, were found in 13q and 15q in these patients. The presence of microhomology at the junction points led to the proposal of the Fold-back mechanism for their formation. The use of different high-resolution techniques allowed for a better characterization of the rearrangements, with Sanger sequencing of the junction points being essential to infer the mechanisms of formation as it revealed microhomologies that were missed by the previous techniques. A karyotype-phenotype correlation was also performed for the characterized rearrangements.