Presumed TP53 mosaicism: variants detected using a NGS hereditary cancer multigene panel

Aims/Context: NGS multigene panels are routinely used to identify germline pathogenic variants in cancer susceptibility genes. In addition, NGS allows the identification of low-level mosaicism events that may not be detectable by conventional Sanger sequencing. We describe two cases of presumed TP53 mosaic variants detected by NGS on blood-derived DNA, and confirmed by ARMS-PCR and Sanger sequencing. Case 1: female, 87 years old, colon cancer at 83 and metachronous breast cancer at 86, no history of familial cancer. Case 2: female, 75 years old, ovarian cancer at 71, local relapse at 74. Methods: NGS using TruSight® Cancer Sequencing Panel and TruSight® Rapid Capture kit (Illumina) and paired-end sequencing on MiSeq® platform (Illumina). Bioinformatic analysis with MiSeq Reporter, Enrichment, VariantStudio, VEP, Alamut Visual, VarAFT, VarSome and IGV. ARMS-PCR and Sanger sequencing were used to confirm the TP53 variants. Results and Conclusions: Two cases of presumed TP53 mosaic variants were studied. Case 1: the missense alteration TP53: c.764T>G, p.(Ile255Ser) was detected with a variant allele frequency (VAF) of 26% (39/150 reads). This variant is described in ClinVar as a somatic alteration, classified as likely pathogenic. It is not reported in gnomAD and VarSome software classified it as a variant of uncertain significance. Case 2: missense variant TP53: c.524G>A, p.(Arg175His) detected with a VAF of 15% (10/58 reads). This variant is described as pathogenic in HGMD Professional, LOVD and ClinVar, in association with Li-Fraumeni syndrome. These two cases seem to represent TP53 mosaicism, supported by: i) VAF lower than 30%, ii) detection at the sensitivity limit of Sanger sequencing and iii) confirmation by ARMS-PCR. Confirming this hypothesis by studying tumor and other tissue samples and offspring analysis (underway in both cases), is essential for disease diagnosis, assessing recurrence risk and genetic counseling. The hypothesis of acquired aberrant clonal expansion limited to the hematologic compartment, versus a germline variant should be considered in similar cases, and confirmatory methodologies are mandatory.info:eu-repo/semantics/publishedVersio

Large scale railway renewal planning with a multiobjective modeling approach

Conferência realizada na Filândia, Helsinquia, de 20-24 de agosto de 2018A multiobjective modeling approach for managing large scale railway infrastructure asset renewal is presented. An optimized intervention project schedule is obtained considering operational constraints in a three objectives model: evenly spreading investment throughout multiple years, minimizing total cost, minimizing work start postponements on higher priority railway sections. The MILP model was based on a real world case study; the objectives and constraints specified by an infrastructure management company. Results show that investment spreading greatly influences the other objectives and that total cost fluctuations depend on the overall condition of the railway infrastructure. The model can produce exact efficient solutions in reasonable time, even for very large-sized instances (a test network of similar size to the USA railway network, the largest in the world). The modeling approach is therefore a very useful, practical methodology, for generating optimized solutions and analyzing trade-offs among objectives, easing the task of ultimately selecting a solution and produce the works schedule for field implementation.info:eu-repo/semantics/publishedVersio

Thermodynamic analysis and optimization of a scramjet engine with thermal management system

Thermal management of the scramjet engine is one of the key issues of the challenges brought by the development of hypersonic airbreathing vehicles. A Closed Brayton Cycle thermal management system for a regenerative cooled scramjet is introduced with the goal of reducing the hydrogen fuel flow for cooling. Part of the heat absorbed from fuel is converted into other forms of energy to decrease the heat that must be taken away by hydrogen fuel. Reducing this heat increases the fuel heat sink (cooling capacity) without requiring excess fuel for cooling and eliminating the need to search for a new coolant. The proposed thermal cycle reduces the fuel flow for cooling, and this way, the fuel on board assures the cooling requirements for the whole hypersonic vehicle. The basic concept and working principle are introduced: a thermodynamic cycle analysis is performed to demonstrate the system performance gains of Closed Brayton Cycle (CBC) Thermal Management System (TMS) over the conventional system with regenerative cooling. It was shown that the Closed Brayton Cycle Thermal Management Systems presents a high performance gain when compared to conventional regenerative cooling due to the reduction of fuel flow for cooling and additional power output.A evolução dos veículos hipersónicos despoletou diversos desafios, sendo a gestão térmica de um motor scramjet um dos tópicos principais. É apresentado um sistema de gestão térmica designado Closed Brayton Cycle para um motor scramjet regenerativamente arrefecido. Com o objectivo de reduzir o fluxo de combustível para refrigeração do motor e simultaneamente a quantidade de calor que necessita de ser eliminada, uma parte do calor absorvido pelo combustível é convertido em diferentes formas de energia. A redução do fluxo de combustível significa um aumento da capacidade de refrigeração. A necessidade de recorrer a quantidades extra de combustível é eliminada, assim como a necessidade de desenvolvimento de um novo refrigerante. Através da redução do fluxo de combustível para refrigeração, o combustível a bordo da aeronave garante os requisitos de refrigeração para todo o veículo hipersónico. O conceito básico e o principio de operação são apresentados, uma análise termodinámica é efectuada para demonstrar o desempenho do sistema Closed Brayton Cycle relativamente ao sistema convencional com arrefecimento regenerativo. Foi demonstrado que o sistema Closed Brayton Cycle apresenta um ganho de desempenho alto quando comparado com o sistema regenerativo convencional devido à redução do fluxo de combustível e devido também à potência adicional gerada

Bi-objective modeling approach for repairing multiple feature infrastructure systems

A bi-objective decision aid model for planning long-term maintenance of infrastructure systems is presented, oriented to interventions on their constituent elements, with two upgrade levels possible for each element (partial/full repairs). The model aims at maximizing benefits and minimizing costs, and its novelty is taking into consideration, and combining, the system/element structure, volume discounts, and socioeconomic factors. The model is tested with field data from 229 sidewalks (systems) and compared to two simpler repair policies, of allowing only partial or full repairs. Results show that the efficiency gains are greater in the lower mid-range budget region. The proposed modeling approach is an innovative tool to optimize cost/benefits for the various repair options and analyze the respective trade-offs.info:eu-repo/semantics/publishedVersio

Multi-objective model for optimizing railway infrastructure asset renewal

Trabalho inspirado num problema real da empresa Infraestruturas de Portugal, EP.A multi-objective model for managing railway infrastructure asset renewal is presented. The model aims to optimize three objectives, while respecting operational constraints: levelling investment throughout multiple years, minimizing total cost and minimizing work start postponements. Its output is an optimized intervention schedule. The model is based on a case study from a Portuguese infrastructure management company, which specified the objectives and constraints, and reflects management practice on railway infrastructure. The results show that investment levelling greatly influences the other objectives and that total cost fluctuations may range from insignificant to important, depending on the condition of the infrastructure. The results structure is argued to be general and suggests a practical methodology for analysing trade-offs and selecting a solution for implementation.info:eu-repo/semantics/publishedVersio

O ensino superior e o mercado de trabalho

Este ensaio reproduz parte das opiniões expressas no artigo "Employment and Work of British and German Graduates", da autoria de John Brennan, Stina Lyon, Harald Schomburg e Ulrich Teichler (1) sobre a influência do ensino no percurso profissional dos diplomados. Foram tidos em conta outras abordagens à mesma problemática, como a de Christopher Jenks no seu livro "Inequality" (2) e a experiência pessoal do autor

Determinantes dos Custos da Insolvência Financeira.

Os anos noventa foram uma época em que as situações de insolvência empresarial atingiram níveis históricos em muitos dos países desenvolvidos, como nos Estados Unidos da América, Espanha ou Portugal. A experiência portuguesa recente, com os numerosos diplomas legais publicados nos últimos anos procurando contrariar o número crescente de empresas em situação económica difícil, é um bom exemplo da preocupação das autoridades com a eficiência económica dos processos de reestruturação e de falência de um numero crescente de empresas