Clinical exome performance for reporting secondary genetic findings.

BACKGROUND : Reporting clinically actionable incidental genetic findings in the course of clinical exome testing is recommended by the American College of Medical Genet- ics and Genomics (ACMG). However, the performance of clinical exome methods for reporting small subsets of genes has not been previously reported. METHODS : In this study, 57 exome data sets performed as clinical (n ! 12) or research (n ! 45) tests were retrospec- tively analyzed. Exome sequencing data was examined for adequacy in the detection of potentially pathogenic variant locations in the 56 genes described in the ACMG incidental findings recommendation. All exons of the 56 genes were examined for adequacy of sequencing coverage. In addition, nucleotide positions annotated in HGMD (Human Gene Mutation Database) were examined. RESULTS : The 56 ACMG genes have 18336 nucleotide variants annotated in HGMD. None of the 57 exome data sets possessed a HGMD variant. The clinical exome test had inadequate coverage for " 50% of HGMD vari- ant locations in 7 genes. Six exons from 6 different genes had consistent failure across all 3 test methods; these exons had high GC content (76%–84%). CONCLUSIONS : The use of clinical exome sequencing for the interpretation and reporting of subsets of genes requires recognition of the substantial possibility of inadequate depth and breadth of sequencing coverage at clinically relevant locations. Inadequate depth of coverage may contribute to false-negative clinical ex- ome results

Modellazione funzionale di un freno a tamburo

Scopo di questo lavoro è la costruzione di un modello matematico implementato in Matlab-Simulink che sia in grado di prevedere il comportamento termomeccanico di un freno a tamburo, in particolare di un freno Simplex a ganascie flottanti: questo può essere utile sia in fase di progettazione per ottimizzare un determinato obiettivo, sia in fase di integrazione dei sistemi frenanti di tipo "passivo" con sistemi di tipo "attivo". Il modello sviluppato è stato suddiviso in un blocco che descrive il comportamento meccanico ed in un blocco che descrive il comportamento termico. I due blocchi interagiscono fra di loro e con l’esterno, ricevendo informazioni(pressione idraulica, velocità del veicolo e velocità di rotazione della ruota) e fornendone altre (momento frenante, assorbimento idraulico, temperatura freno). Il modello meccanico esegue un’analisi dinamica e statica del freno. Il modello termico calcola la temperatura del tamburo e della ganascia senza fare alcuna ipotesi su come si ripartisce la potenza termica tra tamburo e guarnizione: ciò è ottenuto tramite una opportuna discretizzazione del componente

ANALISI DINAMICA DI VEICOLI Studio di uno scooter basculante a tre ruote. Revisione critica dell'handling diagram.

L'attività di modellazione e simulazione nel campo della dinamica del veicolo va assumendo un'importanza sempre più crescente in campo industriale perchè permette la diminuzione dei tempi e dei costi di un determinato prodotto. Il lavoro presentato nella tesi si inserisce all’interno di questo contesto e lo fa seguendo due filoni principali. Il primo, di carattere più applicativo, verrà discusso nella prima parte della tesi e riguarda la modellazione di una nuova tipologia di scooter introdotta nel mercato dalla Piaggio & C. SpA qualche anno fa. La caratteristica evidente di questa categoria di scooter è quella di possedere due ruote anteriori ed una posteriore. L'obiettivo è quello di investigare, mediante la realizzazione di modelli, le diversità che eventualmente intercorrono tra tale tipo di scooter ed uno di tipo tradizionale con una sola ruota anteriore. Tra i risultati prevale l'effetto di maggiore tenuta di strada presentato dall'anteriore dell'MP3. La seconda parte della tesi è invece di carattere più teorico e va ad interessare le fondamenta della dinamica dell'autoveicolo ed, in particolare, il concetto di sottosterzo e il diagramma di maneggevolezza. L'obiettivo è quello di capire se tali strumenti, largamente usati, continuano a rimanere validi per veicoli che non rientrano all'interno della categoria rappresentata dal modello monotraccia da cui essi traggono origine. Si fa riferimento, tanto per fare qualche esempio, a veicoli con differenziale bloccato o parzialmente bloccabile o a veicoli che possiedono più di due assali

Biological Random Walks: multi-omics integration for disease gene prioritization

Motivation: Over the past decade, network-based approaches have proven useful in identifying disease modules within the human interactome, often providing insights into key mechanisms and guiding the quest for therapeutic targets. This is all the more important, since experimental investigation of potential gene candidates is an expensive task, thus not always a feasible option. On the other hand, many sources of biological information exist beyond the interactome and an important research direction is the design of effective techniques for their integration. Results: In this work, we introduce the Biological Random Walks (BRW) approach for disease gene prioritization in the human interactome. The proposed framework leverages multiple biological sources within an integrated framework. We perform an extensive, comparative study of BRW's performance against well-established baselines. Availability and implementation: All code is publicly available and can be downloaded at \url{https://github.com/LeoM93/BiologicalRandomWalks}. We used publicly available datasets, details on their retrieval and preprocessing are provided in the supplementary material

An overview of technologies and devices against COVID-19 pandemic diffusion: virus detection and monitoring solutions

none5siThe year 2020 will remain in the history for the diffusion of the COVID-19 virus, originating a pandemic on a world scale with over a million deaths. From the onset of the pandemic, the scientific community has made numerous efforts to design systems to detect the infected subjects in ever-faster times, allowing both to intervene on them, to avoid dangerous complications, and to contain the pandemic spreading. In this paper, we present an overview of different innovative technologies and devices fielded against the SARS-CoV-2 virus. The various technologies applicable to the rapid and reliable detection of the COVID-19 virus have been explored. Specifically, several magnetic, electrochemical, and plasmonic biosensors have been proposed in the scientific literature, as an alternative to nucleic acid-based real-time reverse transcription Polymerase Chain Reaction (PCR) (RT-qPCR) assays, overcoming the limitations featuring this typology of tests (the need for expensive instruments and reagents, as well as of specialized staff, and their reliability). Furthermore, we investigated the IoT solutions and devices, reported on the market and in the scientific literature, to contain the pandemic spreading, by avoiding the contagion, acquiring the parameters of suspected users, and monitoring them during the quarantine period.openR. de Fazio, A. Sponziello, D. Cafagna, R. Velazquez, P. Viscontide Fazio, R.; Sponziello, A.; Cafagna, D.; Velazquez, R.; Visconti, P

Risk stratification of neck lesions detected sonographically during the follow-up of differentiated thyroid cancer

Context: The European Thyroid Association (ETA) has classified post-treatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence. Objective: To assess this classification's ability to predict the growth and persistence of such lesions during active post-treatment surveillance of patients with differentiated thyroid cancer (DTC). Design: Retrospective, observational study Setting: Thyroid cancer center, large Italian teaching hospital. Patients: Center referrals (2005–2014) were reviewed and patients selected with pathologically confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on ≥2 consecutive post-treatment neck sonograms; subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with ≥1 lesion classified as ‘suspicious’) and group I (‘indeterminate’ lesions only). We recorded baseline and follow-up clinical data through 30 June 2015. Main Outcomes: Patients with growth (> 3 mm, largest diameter) of ≥1 lesion during follow-up, patients with ≥1 persistent lesion at the final visit. Results: The cohort included 58 (9%) of the 637 DTC cases screened. A total of 113 lesions were followed (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 years), group I had significantly lower rates than group S of lesion growth (8% vs. 36%, p=0.01) and persistence (64% vs. 97%, p=0.014). Median time to scan normalization: 2.9 years. Conclusions: The ETA's evidence-based classification of sonographically detected neck abnormalities can help identify PTC patients eligible for more relaxed follow-up

Reduced expression of THRβ in papillary thyroid carcinomas: relationship with BRAF mutation, aggressiveness and miR expression

Purpose Down-regulation of thyroid hormone receptor beta (THRβ) gene has been described in several human malignancies, including thyroid cancer. In this study, we analyzed THRβ mRNA expression in surgical specimens from a series of human papillary thyroid carcinomas (PTCs), characterized by their genotypic and clinical–biological features. Methods Thirty-six PTCs were divided into two groups according to the 2009 American Thyroid Association risk classification (17 low, 19 intermediate), and each group was divided into subgroups based on the presence or absence of the BRAFV600E mutation (21 BRAF mutated, 15 BRAF wild type). Gene expression was analyzed using fluidic cards containing probes and primers specific for the THRβ gene, as well as for genes of thyroperoxidase (TPO), sodium/iodide symporter (NIS), thyroglobulin (Tg) and thyroid stimulating hormone receptor (TSH-R) and for some miRNAs involved in thyroid neoplasia and targeting THRβ. The mRNA levels of each tumor tissue were compared with their correspondent normal counterpart. Results THRβ transcript was down-regulated in all PTCs examined. No significant differences were found between intermediate- vs low-risk PTCs patients, and BRAF-mutated vs BRAF wild-type groups. THRβ expression was directly correlated with NIS, TPO, Tg and TSH-R, and inversely correlated to miR-21, -146a, -181a and -221 expression. Conclusions Our results demonstrate that down-regulation of THRβ is a common feature of PTCs. While it is not associated with a more aggressive phenotype of PTC, it correlates with the reduction of all the markers of differentiation and is associated with overexpression of some miRNAs supposed to play a role in thyroid tumorigenesis

Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells

n this study we analyzed the expression levels of markers of epithelial-to-mesenchymal transition (EMT) in several papillary thyroid carcinomas (PTCs) and the relation with tumor genotypes and clinicopathological characteristics. The role of fibronectin-1 (FN1) was investigated by analyzing the effects of FN1 silencing in two human thyroid cancer cell lines. Most of EMT markers were significantly over-expressed in a group of 36 PTCs. In particular, FN1 mRNA levels were higher in tumor vs non-tumor tissue (117.3, p < 0.001) and also in aggressive and BRAF(V600E) samples. Similar results were observed (and confirmed at the protein level) when FN1 expression was analyzed in a validation group of 50 PTCs and six lymph node (LN) metastases. Silencing of FN1 in TPC-1 and BCPAP thyroid cancer cells significantly reduced proliferation, adhesion, migration, and invasion in both cell lines. Collectively, our data indicate that FN1 overexpression is an important determinant of thyroid cancer aggressiveness

Update on Fundamental Mechanisms of Thyroid Cancer

The incidence of thyroid cancer (TC) has increased worldwide over the past four decades. TC is divided into three main histological types: differentiated (papillary and follicular TC), undifferentiated (poorly differentiated and anaplastic TC), and medullary TC, arising from TC cells. This review discusses the molecular mechanisms associated to the pathogenesis of different types of TC and their clinical relevance. In the last years, progresses in the genetic characterization of TC have provided molecular markers for diagnosis, risk stratification, and treatment targets. Recently, papillary TC, the most frequent form of TC, has been reclassified into two molecular subtypes, named BRAF-like and RAS-like, associated to a different range of cancer risks. Similarly, the genetic characterization of follicular TC has been proposed to complement the new histopathological classification in order to estimate the prognosis. New analyses characterized a comprehensive molecular profile of medullary TC, raising the role of RET mutations. More recent evidences suggested that immune microenvironment associated to TC may play a critical role in tumor invasion, with potential immunotherapeutic implications in advanced and metastatic TC. Several types of ancillary approaches have been developed to improve the diagnostic value of fine needle aspiration biopsies in indeterminate thyroid nodules. Finally, liquid biopsy, as a non-invasive diagnostic tool for body fluid genotyping, brings a new prospective of disease and therapy monitoring. Despite all these novelties, much work remains to be done to fully understand the pathogenesis and biological behaviors of the different types of TC and to transfer this knowledge in clinical practice

Precision oncology for RET-related tumors

Aberrant activation of the RET proto-oncogene is implicated in a plethora of cancers. RET gain-of-function point mutations are driver events in multiple endocrine neoplasia 2 (MEN2) syndrome and in sporadic medullary thyroid cancer, while RET rearrangements are driver events in several non-medullary thyroid cancers. Drugs able to inhibit RET have been used to treat RET-mutated cancers. Multikinase inhibitors were initially used, though they showed modest efficacy and significant toxicity. However, new RET selective inhibitors, such as selpercatinib and pralsetinib, have recently been tested and have shown good efficacy and tolerability, even if no direct comparison is yet available between multikinase and selective inhibitors. The advent of high-throughput technology has identified cancers with rare RET alterations beyond point mutations and fusions, including RET deletions, raising questions about whether these alterations have a functional effect and can be targeted by RET inhibitors. In this mini review, we focus on tumors with RET deletions, including deletions/insertions (indels), and their response to RET inhibitors