75 research outputs found
Dissection of genetic associations with language-related traits in population-based cohorts
No full textThe author was supported by the Wellcome Trust [076566/Z/05/Z]; [075491/Z/04] and the Medical Research Council [G0800523/86473].Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations.Peer reviewe
Recommended from our members
Analysis of Defects in Transcriptional Regulation Mechanisms in High-Grade Serous Ovarian Cancer and Their Correlation with Clinic-Pathological Features
No full textHigh grade serous epithelial ovarian cancer (HGS-EOC) is the most lethal gynaecological disease, usually diagnosed at advanced stages. Although most HGS-EOC patients are initially sensitive to therapy, about 20% of them does not respond to front-line platinum (Pt)-based chemotherapy, relapsing within 6 months from treatment. No molecular biomarkers are as yet available in the clinical practice to discriminate, at the time of diagnosis, the patients who will respond or not to first-line Pt treatment. The identification of a molecular signature associated with intrinsic Pt resistance would allow to select patients who will not respond to Pt compound, thus avoiding ineffective treatment and related toxicities.
In this thesis, defects in transcriptional regulation mechanisms associated to intrinsic Pt resistance were investigated using two different omic approaches – microarray and RNA sequencing. Moreover, considering the correlation between defects in DNA repair Homologous Recombination and Pt sensitivity, we have started to develop an academic assay which exploits high-throughput DNA sequencing to evaluate Homologous Recombination Deficiency (HRD).
Results obtained from three independent HGS-EOC cohorts (n=1080) indicate that the combined expression profile of three genes – PRKG1, SDF2L1 and PPP1R12A – could represent an independent prognostic biomarker for Pt response and survival. In addition, 25 transcripts, 16 of which are unknown or partially known variants, have been identified that are differentially expressed between Pt-sensitive and Pt-resistant patients. These results, once validated, integrated and associated with the HRD status, could identify a molecular signature applicable in the clinical setting to enable stratification of patients at time of diagnosis, allowing to choose the best therapeutic option
Regional and temporal heterogeneity of epithelial ovarian cancer tumor biopsies: implications for therapeutic strategies
No full textStage III/IV epithelial ovarian cancer (EOC) is a systemic disease. The clonal relationship among different tumor lesions at diagnosis (spatial heterogeneity) and how tumor clonal architecture evolves over time (temporal heterogeneity) have not yet been defined. Such knowledge would help to develop new target-based strategies, as biomarkers which can adjudge the success of therapeutic intervention should be independent of spatial and temporal heterogeneity. The work described in this paper addresses spatial and temporal heterogeneity in a cohort of 71 tumor biopsies using targeted NGS technology. These samples were taken from twelve high grade serous (HGS) and seven non HSG-EOC, both at the time of primary surgery when the tumor was naïve to chemotherapy and after chemotherapy. Matched tumor lesions growing in the ovary or at other anatomical sites show very different mutational landscapes with branched tumor evolution. Mutations in ATM, ATR, TGFB3, VCAM1 and COL3A1 genes were shared across all lesions. BRCA1 and BRCA2 genes were frequently mutated in synchronous lesions of non HGS-EOC. Relapsed disease seems to originate from resistant clones originally present at the time of primary surgery rather than from resistance acquired de novo during platinum based therapy. Overall the work suggests that EOC continues to evolve. More detailed mapping of genetic lesions is necessary to improve therapeutic strategies
Exome sequencing in an Italian family with Alzheimer’s disease points to a role for seizure-related gene 6 (SEZ6) rare variant R615H
No full textAbstract Background The typical familial form of Alzheimer’s disease (FAD) accounts for about 5% of total Alzheimer’s disease (AD) cases. Presenilins (PSEN1 and PSEN2) and amyloid-β (A4) precursor protein (APP) genes carry all reported FAD-linked mutations. However, other genetic loci may be involved in AD. For instance, seizure-related gene 6 (SEZ6) has been reported in brain development and psychiatric disorders and is differentially expressed in the cerebrospinal fluid of AD cases. Methods We describe a targeted exome sequencing analysis of a large Italian kindred with AD, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology. Results We overexpressed R615H mutation in H4-SW cells, finding a reduction of amyloid peptide Aβ(1–42). Sez6 expression decreased with age in a mouse model of AD (3xTG-AD), but independently from transgene expression. Conclusions These results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models
Liquid Biopsy in the Clinical Management of High-Grade Serous Epithelial Ovarian Cancer—Current Use and Future Opportunities
No full textThe lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical decisions. To overcome these issues, liquid biopsy has emerged as a very promising tool for HGS-EOC. The analysis of circulating tumor DNA appears to be feasible and studies assessing specific pathogenic mutations (i.e., TP53) or copy number alterations have shown a sufficient degree of sensitivity and specificity to be realistically used to monitor the effectiveness of antitumor therapy. Liquid biopsy can also provide potential important information on the mechanisms of sensitivity and resistance, e.g., by the determination of the reversion of BRCA mutations. Perspective studies are needed to test whether the application of liquid biopsy will significantly improve HGS-EOC management and patients’ survival
Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP-1 and TIMP-2 and tumor thrombospondin-1
No full textTrabectedin is a marine natural product, approved in Europe for the treatment of soft tissue sarcoma and relapsed ovarian cancer. Clinical and experimental evidence indicates that trabectedin is particularly effective against myxoid liposarcomas where response is associated to regression of capillary networks. Here, we investigated the mechanism of the antiangiogenic activity of trabectedin in myxoid liposarcomas. Trabectedin directly targeted endothelial cells, impairing functions relying on extracellular matrix remodeling (invasion and branching morphogenesis) through the upregulation of the inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2. Increased TIMPs synthesis by the tumor microenvironment following trabectedin treatment was confirmed in xenograft models of myxoid liposarcoma. In addition, trabectedin upregulated tumor cell expression of the endogenous inhibitor thrombospondin-1 (TSP-1, a key regulator of angiogenesis-dependent dormancy in sarcoma), in in vivo models of myxoid liposarcomas, in vitro cell lines and primary cell cultures from patients' myxoid liposarcomas. Chromatin Immunoprecipitation analysis showed that trabectedin displaced the master regulator of adipogenesis C/EBPβ from the TSP-1 promoter, indicating an association between the up-regulation of TSP-1 and induction of adipocytic differentiation program by trabectedin. We conclude that trabectedin inhibits angiogenesis through multiple mechanisms, including directly affecting endothelial cells in the tumor microenvironment--with a potentially widespread activity--and targeting tumor cells' angiogenic activity, linked to a tumor-specific molecular alteration
Link to dataset related to article "Liquid Biopsy in the Clinical Management of High-Grade Serous Epithelial Ovarian Cancer-Current Use and Future Opportunities "
No full textThis record contains raw data related to article “"Liquid Biopsy in the Clinical Management of High-Grade Serous Epithelial Ovarian Cancer-Current Use and Future Opportunities"
The lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical decisions. To overcome these issues, liquid biopsy has emerged as a very promising tool for HGS-EOC. The analysis of circulating tumor DNA appears to be feasible and studies assessing specific pathogenic mutations (i.e., TP53) or copy number alterations have shown a sufficient degree of sensitivity and specificity to be realistically used to monitor the effectiveness of antitumor therapy. Liquid biopsy can also provide potential important information on the mechanisms of sensitivity and resistance, e.g., by the determination of the reversion of BRCA mutations. Perspective studies are needed to test whether the application of liquid biopsy will significantly improve HGS-EOC management and patients' survival
Liquid biopsy in the clinical management of high-grade serous epithelial ovarian cancer—current use and future opportunities
No full textReview
The lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical decisions. To overcome these issues, liquid biopsy has emerged as a very promising tool for HGS-EOC. The analysis of circulating tumor DNA appears to be feasible and studies assessing specific pathogenic mutations (i.e., TP53) or copy number alterations have shown a sufficient degree of sensitivity and specificity to be realistically used to monitor the effectiveness of antitumor therapy. Liquid biopsy can also provide potential important information on the mechanisms of sensitivity and resistance, e.g., by the determination of the reversion of BRCA mutations. Perspective studies are needed to test whether the application of liquid biopsy will significantly improve HGS-EOC management and patients’ survival
Agroecological practices supporting food production and reducing food insecurity in developing countries - Volume 2: A study on scientific literature in 9 countries
No full textThis report represents a second step in structuring existing knowledge about agroecology as farming and food system in support of the EC Knowledge Centre on Food and Nutrition Security (https://ec.europa.eu/knowledge4policy/global-food-nutrition-security_en). It complements the report “Agroecological practices supporting food production and reducing food insecurity in developing countries” (Paracchini et al., 2020 ) in which scientific literature has been screened, selected and synthesized for 17 developing countries. An identical protocol has been applied to a new set of nine countries (Bolivia, Burundi, Cameroon, Colombia, Cote d’Ivoire, Gambia, Nigeria, Pakistan, Uganda). In total, agroecological practices have been analysed on the basis of 278 selected documents (papers and reports) which have been synthesized and used to derive country-specific and general conclusions.Approximately 50% of the analysed papers report a positive contribution of agroecological practices to food security, mostly due to improved yields, improved resilience, enhanced diversification of production, and better economic situation of producers. Overall, agroecology contribution to food security in these regions needs to be further investigated. In fact, most country reports lack of quantifiable data and direct measurement of the relationship between the use of agroecological practices and food security. The availability of useful publications was limited for several countries
Pleural mesothelioma: Long-term progression-free survival with Tumor Treating Fields (TTFields) therapy case reports
No full text- …
