RESUMO
Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the ß-catenin-binding domain. Ninety-one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.
Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , Humanos , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Mutação em Linhagem Germinativa , beta Catenina/metabolismo , Células Germinativas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteína Axina/genéticaRESUMO
BACKGROUND: During the last century, life expectancy has doubled. As a result, senior patients with cancer are more frequently referred for possible surgery. Pancreatic surgery is a complex surgery associated with significant postoperative morbidity. Surgical decision-making in the elderly population can be difficult because outcomes in the elderly are poorly defined. Our objective is to characterize differences in mortality and morbidity for pancreatic surgery in the elderly population. METHODS: A retrospective review of all patients undergoing pancreatic head surgery in our tertiary referral center from 2015 to 2021 was conducted. Analysis was performed for the entire cohort, classifying patients into three age groups: <70 years, 70-79 years, and ≥80 years. Data from these three groups were compared, including comorbidity, oncologic outcomes and postoperative complications. RESULTS: A total of 326 patients underwent pancreatic head resection. The 90-day mortality increased from 2.9% to 5.3% to 15.4% with increasing age (p = 0,015). There were no differences among the three groups in terms of postoperative morbidity. There was no difference in disease-free survival (DFS), but overall survival was better in patients under 70 years (p = 0,046). CONCLUSION: Compared to younger patients, patients over 80 years old have a higher risk of mortality despite similar postoperative morbidity.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório , Neoplasias , Neoplasias Pancreáticas , Humanos , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Neoplasias/complicações , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Comorbidade , Morbidade , Estudos Retrospectivos , Fatores EtáriosRESUMO
BACKGROUND: Heterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS. METHODS: We report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5. RESULTS: Genomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis. CONCLUSION: Our results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Adulto , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Metilação de DNA/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , França/epidemiologia , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-IdadeRESUMO
Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo de Erro de Pareamento de DNA , Éxons , Feminino , Efeito Fundador , França/epidemiologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Beta-catenin, encoded by the CTNNB1 gene, plays an important role in cell proliferation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Our study was conducted on 26 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Twenty three cases were from a series of 925 tumors (2.48%). The hospital files and pathological data, from surgical samples (nâ¯=â¯16), small biopsies (nâ¯=â¯5) and trans-bronchial fine needle aspirations (nâ¯=â¯5), were reviewed. Immunohistochemistry was performed with an anti-beta-catenin antibody. There were 10 female and 16 male patients aged 52 to 83. Eleven of 25 patients were no-smoking or light smokers. Three cases were diagnosed while under treatment with EGFR tyrosine kinase inhibitor. There were 25 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas had a papillary component and were TTF1-positive. One case was a well-differentiated fetal adenocarcinoma. Eleven cases (42%) with CTNNB1 mutations showed associated EGFR mutations. The frequency of CTNNB1 mutations was higher among EGFR mutated carcinomas. Immunohistochemistry showed heterogeneous nuclear or cytoplasmic abnormal expression. Our study shows that CTNNB1 mutations mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are often associated with EGFR mutations and possibly interfer in the mechanism of resistance to tyrosine kinase inhibitors. Our experience suggests that immuno-histochemistry cannot be used for screening.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , beta Catenina/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer. A subset of patients with a history of LS shows no causal germline pathogenic alteration and are identified as having Lynch-like syndrome (LLS). Alu retrotransposons are the most abundant mobile DNA sequences in the human genome and have been associated with numerous human cancers by either disrupting coding regions or altering epigenetic modifications or splicing signals. We report a family first classified as having LLS by Sanger sequencing analysis. Next-generation sequencing (NGS) analysis identified an AluY5a insertion in MLH1 exon 6 that led to exon skipping. This splicing alteration inducing a pathogenic frameshift was found in patients who developed colorectal adenocarcinomas. Retroelement insertion might thus be an important but underestimated mechanism of cancer genetics that could be systematically tested in patients with a phenotype suggesting LS to accurately assess family risk and surveillance approaches.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 1 Homóloga a MutL/genética , Mutagênese Insercional , Análise de Sequência de DNA/métodos , Adulto , Elementos Alu , Éxons , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , FenótipoRESUMO
BACKGROUND: Discovering over-represented approximate motifs in DNA sequences is an essential part of bioinformatics. This topic has been studied extensively because of the increasing number of potential applications. However, it remains a difficult challenge, especially with the huge quantity of data generated by high throughput sequencing technologies. To overcome this problem, existing tools use greedy algorithms and probabilistic approaches to find motifs in reasonable time. Nevertheless these approaches lack sensitivity and have difficulties coping with rare and subtle motifs. RESULTS: We developed DiNAMO (for DNA MOtif), a new software based on an exhaustive and efficient algorithm for IUPAC motif discovery. We evaluated DiNAMO on synthetic and real datasets with two different applications, namely ChIP-seq peaks and Systematic Sequencing Error analysis. DiNAMO proves to compare favorably with other existing methods and is robust to noise. CONCLUSIONS: We shown that DiNAMO software can serve as a tool to search for degenerate motifs in an exact manner using IUPAC models. DiNAMO can be used in scanning mode with sliding windows or in fixed position mode, which makes it suitable for numerous potential applications. AVAILABILITY: https://github.com/bonsai-team/DiNAMO .
Assuntos
Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Motivos de Nucleotídeos , Análise de Sequência de DNA/métodos , Software , Algoritmos , Imunoprecipitação da Cromatina , HumanosRESUMO
PURPOSE: Constitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far. METHODS: We designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations. RESULTS: This strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5'-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription. CONCLUSION: This is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Epigênese Genética , Predisposição Genética para Doença , Proteína 1 Homóloga a MutL/genética , Adulto , Alelos , Elementos Alu/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Metilação de DNA/genética , Feminino , Haplótipos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genéticaRESUMO
Functional specialization of cells and tissues in metazoans require specific gene expression patterns. Biological processes, thus, need precise temporal and spatial coordination of gene activity. Regulation of the fate of messenger RNA plays a crucial role in this context. In the present review, the current knowledge related to the role of RNA-binding proteins in the whole mRNA life-cycle is summarized. This field opens up a new angle for understanding the importance of the post-transcriptional control of gene expression in cancer cells. The emerging role of non-classic RNA-binding proteins is highlighted. The goal of this review is to encourage readers to view, through the mRNA life-cycle, novel aspects of the molecular basis of cancer and the potential to develop RNA-based therapies.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Estabilidade de RNA , RNA Mensageiro/genética , Animais , Humanos , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/terapia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Processamento Pós-Transcricional do RNA , Splicing de RNA , Transporte de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcrição GênicaRESUMO
The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.
Assuntos
Biomarcadores Tumorais , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metilação de DNA , Mucina-5AC/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/genética , Pólipos do Colo/patologia , Neoplasias Colorretais/diagnóstico , Feminino , Expressão Gênica , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas ras/genéticaRESUMO
BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Resistencia a Medicamentos Antineoplásicos , Testes Genéticos , Mutação em Linhagem Germinativa , Linfócitos/efeitos dos fármacos , Instabilidade de Microssatélites , Síndromes Neoplásicas Hereditárias/diagnóstico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Células CACO-2 , Estudos de Casos e Controles , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Células HCT116 , Hereditariedade , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Endonuclease PMS2 de Reparo de Erro de Pareamento , Reação em Cadeia da Polimerase Multiplex , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Proteínas Nucleares/genética , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Transfecção , Adulto JovemRESUMO
BACKGROUND: The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma. METHODS: Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics. RESULTS: 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation. CONCLUSIONS: Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Doenças Urogenitais Masculinas/genética , Diagnóstico Pré-Natal , Criança , Pré-Escolar , Fibrose Cística/complicações , Fibrose Cística/patologia , Feminino , Heterozigoto , Humanos , Lactente , Recém-Nascido , Infertilidade Masculina/complicações , Infertilidade Masculina/genética , Masculino , Doenças Urogenitais Masculinas/complicações , Doenças Urogenitais Masculinas/patologia , Mutação , Taxa de Mutação , Fenótipo , Suor/química , Ducto Deferente/anormalidades , Ducto Deferente/patologiaRESUMO
This is a protocol for a Cochrane Review (prototype). The objectives are as follows: This systematic review aims to summarize the available scientific literature on the effect of mindfulness-based approaches in children and adults with Chronic Tic Disorder (CTD) or Tourette Disorder (TD). More specifically, the research question is: What is the effectiveness of mindfulness-based interventions in reducing tic severity and improving overall functioning, quality of life, and co-occurring symptoms in children and adults with CTD or TD?
RESUMO
Background/Objectives: Tourette Syndrome (TS), Obsessive Compulsive Disorder (OCD), and Body-Focused Repetitive Behaviors (BFRB) are three disorders that share many similarities in terms of phenomenology, neuroanatomy, and functionality. However, despite the literature pointing toward a plausible spectrum of these disorders, only a few studies have compared them. Studying the neurocognitive processes using Event-Related Potentials (ERPs) offers the advantage of assessing brain activity with excellent temporal resolution. The ERP components can then reflect specific processes known to be potentially affected by these disorders. Our first goal is to characterize 'when' in the processing stream group differences are the most prominent. The second goal is to identify 'where' in the brain the group discrepancies could be. Methods: Participants with TS (n = 24), OCD (n = 18), and BFRB (n = 16) were matched to a control group (n = 59) and were recorded with 58 EEG electrodes during a visual counting oddball task. Three ERP components were extracted (i.e., P200, N200, and P300), and generating sources were modelized with Standardized Low-Resolution Electromagnetic Tomography. Results: We showed no group differences for the P200 and N200 when controlling for anxiety and depressive symptoms, suggesting that the early cognitive processes reflected by these components are relatively intact in these populations. Our results also showed a decrease in the later anterior P300 oddball effect for the TS and OCD groups, whereas an intact oddball effect was observed for the BFRB group. Source localization analyses with sLORETA revealed activations in the lingual and middle occipital gyrus for the OCD group, distinguishing it from the other two clinical groups and the controls. Conclusions: It seems that both TS and OCD groups share deficits in anterior P300 activation but reflect distinct brain-generating source activations.
RESUMO
Background: Tourette syndrome (TS) and Chronic Tic Disorder (CT) are neurodevelopmental conditions involving motor and/or phonic tics. Youth with tics may encounter feelings of isolation, diminished self-esteem and quality of life, and academic difficulties. A growing body of scientific literature suggests sex differences in youth with tics, but findings have been mixed so far. Because symptom severity peaks around puberty, understanding sex differences in tic manifestations and associated symptoms during this critical period is essential. Therefore, we aimed to assess sex differences related to tic symptoms, action planning styles, quality of life, and externalizing/internalizing symptoms in youth with tics. Methods: Our sample consisted of 66 youths with tics (19 girls) aged 7-14 (mean = 10 years). Youths were assessed with clinical interviews, as well as self- and parent-reported inventories evaluating tic symptoms, psychological profiles, and quality of life. Results: While no differences in tic symptoms were found, girls exhibited lower functional inflexibility, reduced overall functional planning effectiveness, and higher impairment in the psychological well-being subscale than boys. Additionally, girls had reduced general life satisfaction and social self-esteem. Boys reported more explosive outbursts, higher levels of hyperactivity, and more difficulties with self-concept. Conclusions: Our analyses suggested differences in several manifestations associated with tics. This introduces new perspectives that refine our understanding of sex differences. A better understanding of sex differences in tic disorders may eventually improve outcomes for all individuals living with these conditions.
RESUMO
(1) Background: Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Attention deficit and hyperactivity disorder (ADHD) is a common comorbidity of TS that adds further impairment. Cognitive-behavioural therapy (CBT) has shown efficacy in treating tics, yet its effectiveness in individuals with TS and comorbid ADHD remains unclear. Also, it is suggested that ADHD characteristics like executive dysfunction and inattention could hinder the response to CBT. This study aims to compare the response to CBT for tics and its maintenance six months post-therapy among TS individuals with and without ADHD symptoms. (2) Methods: In this study, 55 TS participants who completed 14-week CBT for tics were split into high (TS+) or low (TS-) ADHD symptomatology groups. Outcomes were evaluated using the Yale Global Tic Severity Scale (YGTSS) regarding global tic severity and motor and vocal tic frequency post-CBT and at a 6-month follow-up. (3) Results: No significant group difference was found regarding improvements post-CBT (n = 55), nor the maintenance six months later (n = 45). (4) Conclusions: ADHD symptoms may not hinder the response to CBT or its maintenance, suggesting that TS individuals with ADHD symptoms may not require specialized CBT interventions.
RESUMO
Numerous lung cell lines are currently used as in vitro models for pharmacological and toxicological studies. However, no exhaustive report about the metabolic capacities of these models in comparison with those of lung tissues is available. In the present study, we used a high-throughput quantitative real-time reverse transcription-polymerase chain reaction strategy to characterize the expression profiles of 380 genes encoding proteins involved in the metabolism and disposition of xenobiotics in 10 commonly used lung cell lines (A549, H292, H358, H460, H727, Calu-1, 16HBE, 1 HAEO, BEAS-2B, and L-132) and four primary cultures of human bronchial epithelial cells. Expression results were then compared with those previously obtained in human nontumoral and tumoral lung tissues. Our results revealed disparities in gene expression between lung cell lines or when comparing lung cell lines with primary cells or lung tissues. Primary cell cultures displayed the highest similarities with bronchial mucosa in terms of transcript profiling and therefore seem to be the most relevant in vitro model for investigating the metabolism and bioactivation of toxicants and drugs in bronchial epithelium. H292 and BEAS-2B cell lines, which exhibited the highest homology in gene expression pattern with primary cells and the lowest number of dysregulated genes compared with nontumoral lung tissues, could be used as surrogates for toxicological and pharmacological studies. Overall, our study should provide references for researchers to choose the most appropriate in vitro model for analyzing the cellular effects of drugs or airborne toxicants on the airway.
Assuntos
Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Xenobióticos/metabolismo , Biotransformação/genética , Brônquios/metabolismo , Linhagem Celular , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Cultura Primária de Células , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Background: Although the COVID-19 pandemic has increased the incidence of distress in youth, some children show increased resilience, emphasizing the need to better understand the predictors of distress in youth. Objective: This longitudinal study aimed to assess the combined impact of known socio-emotional predictors of stress-related psychopathology, namely anxiety sensitivity, anxiety trait, intolerance to uncertainty, and rumination, on COVID-related distress in healthy youth. Method: A total of 92 parent-child dyads that previously participated in a laboratory-based experiment assessing observational fear learning in families between 2017 and 2019 (T0) were recontacted. Of them, 84 children aged between 9 and 14 agreed to participate. They completed online questionnaires in June 2020 (T1), September 2020 (T2), December 2020 (T3), and March 2021 (T4). Participants were free of mental illness at T0 and T1. To create a socio-emotional composite score (SECS), we measured anxiety sensitivity (Childhood Anxiety Sensitivity Index) at T0, trait anxiety (Trait subscale of the State-Trait Anxiety Inventory for Children (STAI-C)), intolerance to uncertainty (Intolerance of Uncertainty Scale for Children), and trait rumination (Children's Response Style Scale) at T1 and created a weighted z-score. To assess symptoms of anxiety, post-traumatic stress (PTS), and depression in reaction to COVID-19, participants completed the State subscale of the STAI-C, the Children's Revised Impact of Event Scale, and the Children's Depression Inventory at T1-T4. Three general linear models were run with sex, age group (9-11 and 12+ years old), and SECS as predictors. Results: Analyses revealed a SECS*Time interaction, with higher SECS predicting elevated anxiety symptoms at T1 and T4, and elevated PTS symptoms at T1 and T2. Conclusion: These results suggest that healthy youth endorsing high levels of socio-emotional vulnerability to psychopathology have a higher risk of suffering from anxiety and PTS, but not depressive symptoms, in the year following a major stressor.
Antecedentes: Aunque la pandemia de COVID-19 ha aumentado la incidencia de angustia en jóvenes, algunos niños muestran una mayor resiliencia, relevando la necesidad de comprender mejor los predictores de la angustia en los jóvenes.Objetivo: Este estudio longitudinal tuvo como objetivo evaluar el impacto combinado de los predictores socioemocionales conocidos de la psicopatología relacionada con el estrés, como son la sensibilidad a la ansiedad, rasgos ansiosos, intolerancia a la incertidumbre y rumiación, en la angustia relacionada con COVID en jóvenes sanos.Método: 92 díadas de padres e hijos que participaron previamente en un experimento de laboratorio que evaluó el aprendizaje del miedo observacional en familias entre 2017 y 2019 (T0) fueron contactados nuevamente. Participaron 84 niños de entre 9 y 14 años. Completaron cuestionarios en línea en junio de 2020 (T1), septiembre de 2020 (T2), diciembre de 2020 (T3) y marzo de 2021 (T4). Los participantes estaban libres de enfermedad mental en T0 y T1. Para crear una puntuación socioemocional compuesta (SECS), medimos la sensibilidad a la ansiedad (Índice de sensibilidad a la ansiedad infantil) en T0, rasgo de ansiedad (subescala de rasgo del Inventario de ansiedad estado-rasgo para niños (STAI-C)), intolerancia a la incertidumbre (escala de intolerancia a la incertidumbre para niños) y rasgo de rumiación (Escala de estilo de respuesta en niños) en T1 y se creó una puntuación z ponderada. Para evaluar los síntomas de ansiedad, estrés postraumático (PTS) y depresión en reacción al COVID-19, los participantes completaron la subescala de estado de STAI-C, la escala de impacto de eventos para niños revisada, y el inventario de depresión infantil en T1T4. Se ejecutaron tres modelos lineales generales con sexo, grupo de edad (911 y 12+ años) y SECS como predictores.Resultados: Los análisis revelaron una interacción entre el tiempo y la puntuación socioemocional compuesta (SECS), donde un SECS más alto predice síntomas de ansiedad elevados en T1 y T4, y síntomas elevados de PTS (Estrés post traumático) en T1 y T2.Conclusión: Estos resultados sugieren que la juventud sana que presenten altos niveles de vulnerabilidad socioemocional a la psicopatología, tiene un mayor riesgo desufrir de ansiedad y síndrome de estrés postraumático, pero no síntomas depresivos, en el año siguiente a un evento estresante mayor.