Browsing by Author "Carreira, IM"
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- Array-comparative genomic hybridization as a novel high-throughput approach in bladder cancer treatmentPublication . Neves, AR; Abrantes, AM; Ribeiro, IP; Marques, IA; Marques, V; Tavares da Silva, E; Carreira, IM; Figueiredo, A; Botelho, MF
- Copy number variants prioritization after array-CGH analysis - a cohort of 1000 patientsPublication . Carreira, IM; Ferreira, SI; Matoso, E; Pires, LM; Ferrão, J; Jardim, A; Mascarenhas, A; Pinto, M; Lavoura, N; Pais, C; Paiva, P; Simões, L; Caramelo, F; Ramos, L; Venâncio, M; Ramos, F; Beleza, A; Sá, J; Saraiva, J; Barbosa de Melo, JArray-based comparative genomic hybridization has been assumed to be the first genetic test offered to detect genomic imbalances in patients with unexplained intellectual disability with or without dysmorphisms, multiple congenital anomalies, learning difficulties and autism spectrum disorders. Our study contributes to the genotype/phenotype correlation with the delineation of laboratory criteria which help to classify the different copy number variants (CNVs) detected. We clustered our findings into five classes ranging from an imbalance detected in a microdeletion/duplication syndrome region (class I) to imbalances that had previously been reported in normal subjects in the Database of Genomic Variants (DGV) and thus considered common variants (class IV).
- Early detection and personalized treatment in oral cancer: the impact of omics approachesPublication . Ribeiro, IP; Barroso, L; Marques, F; Melo, JB; Carreira, IMBACKGROUND: Oral cancer is one of the most common malignant lesions of the head and neck. This cancer is an aggressive and lethal disease with no significant improvements in the overall survival in the last decades. Moreover, the incidence of oral HPV-positive tumors is rising, especially in young people. This oral neoplasm develops through numerous molecular imbalances that affect key genes and signaling pathways; however, the molecular mechanisms involved in the pathogenesis and progression of oral tumors are still to be fully determined. In order to improve the quality of life and long-term survival rate of these patients, it is vital to establish accurate biomarkers that help in the early diagnosis, prognosis and development of target treatments. Such biomarkers may possibly allow for selection of patients that will benefit from each therapy modality, helping in the optimization of intensity and sequence of the treatments in order to decrease side effects and improve survival. CONCLUSION: In this review we discuss the current knowledge of oral cancer and the potential role of omics approaches to identify molecular biomarkers in the improvement of early diagnosis, treatment and prognosis. The pursuit to improve the quality of life and decrease mortality rates of the oral patients needs to be centralized on the identification of critical genes in oral carcinogenesis. Understanding the molecular biology of oral cancer is vital for search new therapies, being the molecular-targeted therapies the most promising treatment for these patients.
- Interstitial 287 kb deletion of 4p16.3 including FGFRL1 gene associated with language impairment and overgrowthPublication . Matoso, E; Ramos, F; Ferrão, J; Pires, LM; Mascarenhas, A; Melo, JB; Carreira, IMWe report a male patient with developmental delay carrying an interstitial 4p16.3 deletion of 287 kb, disclosed by oligo array-CGH and inherited from his father with a similar but milder phenotype. This deletion is distal to the Wolf-Hirschhorn syndrome critical regions, but includes the FGFRL1 gene proposed to be a plausible candidate for part of the craniofacial characteristics of Wolf-Hirschhorn syndrome patients. However, the proband lacks the typical facial appearance of the syndrome, but exhibits overgrowth, dysfunction of temporomandibular articulation and a bicuspid aortic valve. Given the pattern of expression of the fibroblast growth factor receptor-like 1 and its involvement in bone and cartilage formation as well as in heart valve morphogenesis, we discuss the impact of its haploinsufficiency in the phenotype.
- Inv21p12q22del21q22 and intellectual disabilityPublication . Oliveira, R; Dória, S; Madureira, C; Lima, V; Almeida, C; Pinho, MJ; Ramalho, C; Matoso, E; Barros, A; Carreira, IM; Moura, CPChromosomal rearrangements are common in humans. Pericentric inversions are among the most frequent aberrations (1-2%). Most inversions are balanced and do not cause problems in carriers unless one of the breakpoints disrupts important functional genes, has near submicroscopic copy number variants or hosts "cryptic" complex chromosomal rearrangements. Pericentric inversions can lead to imbalance in offspring. Less than 3% of Down syndrome patients have duplication as a result of parental pericentric inversion of chromosome 21. We report a family with an apparently balanced pericentric inversion of chromosome 21. The proband, a 23-year-old female was referred for prenatal diagnosis at 16weeks gestation because of increased nuchal translucency. She has a familial history of Down's syndrome and moderate intellectual disability, a personal history of four spontaneous abortions and learning difficulties. Peripheral blood and amniotic fluid samples were collected to perform proband's and fetus' cytogenetic analyses. Additionally, another six family members were evaluated and cytogenetic analysis was performed. Complementary FISH and MLPA studies were carried out. An apparent balanced chromosome 21 pericentric inversion was observed in four family members, two revealed a recombinant chromosome 21 with partial trisomy, and one a full trisomy 21 with an inverted chromosome 21. Array CGH analysis was performed in the mother and the brother's proband. MLPA and aCGH studies identified a deletion of about 1.7Mb on the long arm of inverted chromosome 21q22.11. We believe the cause of the intellectual disability/learning difficulties observed in the members with the inversion is related to this deletion. The recombinant chromosome 21 has a partial trisomy including the DSCR with no deletion. The risk for carriers of having a child with multiple malformations/intellectual disability is about 30% depending on whether and how this rearrangement interferes with meiosis.
- Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 --> qter) detected in an autistic boyPublication . Carreira, IM; Melo, JB; Rodrigues, C; Backx, L; Vermeesch, J; Weise, A; Kosyakova, N; Oliveira, G; Matoso, EBACKGROUND: Inverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders. RESULTS: We present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter --> q26.3::q26.3 --> qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb. CONCLUSION: This is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 --> 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.
- Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control StudyPublication . Diaz, SO; Pinto, JJ; Barros, AS; Morais, E; Duarte, D; Negrão, F; Pita, C; Almeida, MC; Carreira, IM; Spraul, M; Gil, AMThis work assesses the urinary metabolite signature of prematurity in newborns by nuclear magnetic resonance (NMR) spectroscopy, while establishing the role of possible confounders and signature specificity, through comparison to other disorders. Gender and delivery mode are shown to impact importantly on newborn urine composition, their analysis pointing out at specific metabolite variations requiring consideration in unmatched subject groups. Premature newborns are, however, characterized by a stronger signature of varying metabolites, suggestive of disturbances in nucleotide metabolism, lung surfactants biosynthesis and renal function, along with enhancement of tricarboxylic acid (TCA) cycle activity, fatty acids oxidation, and oxidative stress. Comparison with other abnormal conditions (respiratory depression episode, large for gestational age, malformations, jaundice and premature rupture of membranes) reveals that such signature seems to be largely specific of preterm newborns, showing that NMR metabolomics can retrieve particular disorder effects, as well as general stress effects. These results provide valuable novel information on the metabolic impact of prematurity, contributing to the better understanding of its effects on the newborn's state of health.
- NMR metabolomics of human lung tumours reveals distinct metabolic signatures for adenocarcinoma and squamous cell carcinomaPublication . Rocha, CM; Barros, AS; Goodfellow, BJ; Carreira, IM; Gomes, AA; Sousa, V; Bernardo, J; Carvalho, L; Gil, AM; Duarte, IFLung tumour subtyping, particularly the distinction between adenocarcinoma (AdC) and squamous cell carcinoma (SqCC), is a critical diagnostic requirement. In this work, the metabolic signatures of lung carcinomas were investigated through (1)H NMR metabolomics, with a view to provide additional criteria for improved diagnosis and treatment planning. High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (NMR) spectroscopy was used to analyse matched tumour and adjacent control tissues from 56 patients undergoing surgical excision of primary lung carcinomas. Multivariate modeling allowed tumour and control tissues to be discriminated with high accuracy (97% classification rate), mainly due to significant differences in the levels of 13 metabolites. Notably, the magnitude of those differences were clearly distinct for AdC and SqCC: major alterations in AdC were related to phospholipid metabolism (increased phosphocholine, glycerophosphocholine and phosphoethanolamine, together with decreased acetate) and protein catabolism (increased peptide moieties), whereas SqCC had stronger glycolytic and glutaminolytic profiles (negatively correlated variations in glucose and lactate and positively correlated increases in glutamate and alanine). Other tumour metabolic features were increased creatine, glutathione, taurine and uridine nucleotides, the first two being especially prominent in SqCC and the latter in AdC. Furthermore, multivariate analysis of AdC and SqCC profiles allowed their discrimination with a 94% classification rate, thus showing great potential for aiding lung tumours subtyping. Overall, this study has provided new, clear evidence of distinct metabolic signatures for lung AdC and SqCC, which can potentially impact on diagnosis and provide important leads for future research on novel therapeutic targets or imaging tracers.