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In this two-part dissertation, several different strategies are developed to attempt concise synthesis of complex natural products. In the first part, a concise total synthesis of garsubellin A, is reported. Starting from commercially available 2-methyl cyclopentenone, this synthesis of garsubellin A was enabled by a series of powerful C-C bond forming reactions, including a tandem oxy-Cope/methylation reaction, a diketene annulation, a ring expansion reaction and a novel regioselective prenyl coupling reaction. Meanwhile, a novel palladium catalyzed Wacker-type oxidation was developed to construct the characteristic tetrahydrofuran ring of garsubellin A. As we hoped this synthetic strategy could serve as a modular synthetic solution of diverse PPAP meroterpenes, an enhanced substrate scope of the diketene reaction was reported.In the second part of this dissertation, our synthetic studies of acutumine is described. In this chapter, a background introduction is first given, including the isolation and structure determination of acutumine alkaloids, biosynthetic studies, bioactivates of acutumine family, and the prior synthetic studies of (–)-acutumine. Meanwhile, several different strategies for achieving a concise total synthesis of (–)-acutumine were developed and discussed in this dissertation. A novel [3+2] cyclization protocol was developed, which, in three steps, converts commercially available starting materials to a [3.3.0] aza-bicyclic intermediate. From this advanced bicyclic intermediate, a series of efforts to transfer this advanced bicyclic intermediate to (–)-acutumine was explored and reported.

Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimer's disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)‐garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2‐ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelve‐step, protecting group‐free synthetic route has enabled the syntheses of both the natural (−)‐garsubellin A and its unnatural (+)‐antipode for biological evaluations., The first enantioselective total synthesis of garsubellin A establishes the absolute stereostructure of the plant‐derived meroterpene that enhances the choline acetyltransferase enzyme responsible for the biosynthesis of the neurotransmitter acetylcholine. The 12‐step, protecting group‐free synthesis features use of a dithiolane for efficient construction of the bridged and fused ring system.

Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients.

[Purpose]: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. [Methods]: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. [Results]: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies, This work was funded by the Spanish Ministry of Science and Innovation, cofunded by FEDER funds (SAF2016-80888-R, SAF2015-68016-R, Severo Ochoa SVP-2014-068895 contract [L.M.-P.]); Instituto de Salud Carlos III (PI16/00563, PI16/00588, PI14/00613, PI19/00553, CIBERONC CB16/12/00234, CIBERESP, Sara Borrell contract [P.M.]); Government of Catalonia [AGAUR 2017SGR1282, CERCA Program]; and Fundación Olga Torres. This study was facilitated by COST Action CA17118, supported by COST (European Cooperation in Science and Technology).

This paper will analyze “PPAP,” created and performed by Pikotaro, Japanese musician, and performer, released in 2016. It received worldwide views and listens, revealing its universality, modernity, and problem1). The two fundamental concerns of this paper are world music and ethnomusicology 2). This paper contains five sections. Section 1 (“Introduction”) shows the object of this research. Section 2 gives an outline of PPAP and introduces its short history from creation to acceptance. Section 3 (“Analysis”) classifies the piece into seven portions and discusses their constructions and elements. Section 4 (“Consideration”) shows the meaning of the analysis and clarifies the characteristics of the piece. Section 5 (“Conclusion”) examines the universality, modernity, and problem of PPAP.

The automotive industry is one of the main drivers of industrial production and is well known for high-quality criteria. In the past, original equipment manufacturers (OEMs) pushed forward the main processes of new vehicle production. Today, OEM transfers a great deal of high-level engineering tasks to suppliers. As automotive industries are highly automated robot lines, constituting serial production in millions, the smallest error in a delivered product/component causes the downtime for the whole line. In these situations, it is necessary to validate another supplier of the same component, which can last a very long time. This paper presents a quality management model for incoming components in the automotive industry which can recognize possible risks in the early phase of the component prototype development. The model is successfully applied in a company that produces components for OEM, which will be presented in the second part of the paper.

O mercado competitivo e cada vez mais globalizado exige que as organizações tenham uma relação com seus fornecedores que possibilite agregar valor e garantir qualidade a seus produtos. Neste contexto este estudo busca compreender as principais falhas no processo de elaboração da documentação de PPAP para a entrega junto ao primeiro lote de produção para uma empresa do ramo metalmecânico da Serra Gaúcha. A pesquisa realizada é qualitativa, sendo aplicada a seis fornecedores, atuantes em ramos variados de mercado, utilizou-se como instrumento de coleta de dados um questionário semiestruturado aplicado durante entrevistas presenciais e por telefone, nos meses de outubro e novembro de 2018. Os dados obtidos foram analisados por técnicas de análise de conteúdo, onde identificou-se que ocorrem falhas tanto originárias dos fornecedores quanto da empresa focal, principalmente relacionadas a troca de informações e aos prazos de desenvolvimento. Sugeriu-se também possibilidades de melhorias para a empresa focal, tomando por base as sugestões e críticas citadas pelos fornecedores entrevistados. Como conclusão, observou-se que as principais ações para a melhoria do processo de elaboração e entrega das documentações de PPAP junto ao primeiro lote de produção devem partir da empresa cliente, possibilitando assim ganhos neste processo e na relação com os fornecedores. DOI: 10.18226/23190639.v8n1.03 Julian Perboni Copetti*, Universidade de Caxias do Sul (UCS). Brasil.E-mail: julian_copetti@hotmail.com Ivandro Cecconello, Universidade de Caxias do Sul (UCS). Brasil.E-mail: iceccone@ucs.br Submetido: Março 2019Aceito: Novembro 2019*Contato para Correspondência

Purpose Germline pathogenic variants in the exonuclease domain (ED) of polymerasesPOLEandPOLD1predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence ofPOLEandPOLD1variants in hereditary cancer are evaluated in this study. Methods POLEandPOLD1were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. Results Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies

Projeto submetido para obtenção do grau de Mestre em Engenharia de Produção Nesta tese de mestrado é apresentada uma revisão bibliográfica no âmbito da regulamentação da manutenção aeronáutica, das ferramentas do planeamento avançado da qualidade do produto (APQP) e por fim os princípios e documentação utilizada no processo de aprovação para fabricação de peças (PPAP) no setor automóvel e no setor de fabricação aeronáutica, sendo assim possível de desenvolver o processo de aprovação para manutenção de peças (MPAP), de forma a garantir um processo de integração e gestão robusto. Nesta tese de mestrado também é demonstrado que o setor de manutenção aeronáutica é diferente e muito específico, sendo evidenciada a enorme importância e o impacto que o processo de gestão da lista de capacidades (LC) tem numa Organização de Manutenção bem como na implementação de um processo PPAP no setor de manutenção aeronáutica. Sem o processo de gestão da lista de capacidades implementado e a funcionar de forma robusta o processo de aprovação para manutenção de peças não poderá ser implementado. Assim, ainda nesta tese de mestrado são demonstradas as implementações de melhorias e os seus ganhos de forma a que o processo de gestão da lista de capacidades seja mais fácil de garantir e manter, tornando-o num processo de aprovação de componentes ágil e robusto, que diferencia as situações que carecem de aprovação/reaprovação, os diferentes níveis de detalhe e os conteúdos de cada nível de aprovação. This master thesis presents a bibliographic revision in the scope of the aeronautical maintenance regulation, considering the advanced product quality planning tools (APQP) and finally the principles and documentation used in the Production Part Approval Process (PPAP) in the automotive sector and in the aeronautical manufacturing sector. This master thesis gives visibility of a Maintenance Part Approval Process (MPAP) possible to develop, in order to ensure a robust integration and management process in place at aeronautical industry. In this master thesis it is also demonstrated that the aeronautical maintenance sector is very specific, highlighting the huge importance and the high impact that the Capacity List management (LC) process has in a Maintenance Organization as well as the implementation of a MPAP process. Without having a capability list management process in place, a robust functional MPAP approval process for parts maintenance cannot be implemented. In this master thesis it is also demonstrated improvements implementations and their gains, having the possibility to verify that the capacity list management process becomes easier to guarantee and maintain. As a conclusion, a robust component approval process makes a very positive difference in situations that is required the approval / disapproval on different levels of detail and several contents of each approval level.

Günümüzde iş dünyasındaki yoğun rekabet ortamında kalitenin önemli bir yeri vardır. Bu bağlamda firmaların en değerli birimi olan kalitenin, kurulumu, yönetimi ve iyileştirilmesi sistemli bir şekilde yürütülmelidir. Sistemin kurulabilmesi için yönetim anlayışının amacı, müşteri beklentilerini karşılayabilimek, kâr elde edebilmek, teknolojik yeniliklere ayak uydurarak gelişime açık olmak ve sektörde uzun yıllar kalmayı hedeflemek olmalıdır. Bu çalışmanın amacı, kalitenin ve kalite yönetim sisteminin öneminin anlatılarak, otomotiv sektörünün standardı olan IATF 16949:2016 standardının kurulumu, yönetimi ve sürdürülebilirliği istatistiksel bakış açısıyla irdelenmesidir. Çalışmada IATF 16949:2016 revizyonun getirdiği yenilikler incelenmiş ve istatistiksel olan kalite iyileştirme teknikleri kullanılarak kuruluşlar için örnek olacak uygulamalar yapılmıştır. Çalışmanın uygulanmasında, IATF 16949:2016 KYS'de kalitenin iyileştirilmesine yönelik kullanılan istatistiksel tekniklerden, Ölçüm Sistemleri Analizi (MSA) ve İstatistiksel Proses Kontrol Analizi (SPC) kullanılmıştır. Söz konusu istatistiksel tekniklerde kullanılan veriler Minitab 16'da analiz edilmiş ve analizler 3 ayrı firma için yapılmıştır. Araştırma, kalitenin firma performansıyla doğru orantılı ilişkisi olduğunu desteklemektedir. Nowadays, quality has an important place in the intense competitive environment in the business world. In this context, the establishment, management and improvement of quality, which is the most valuable unit of the companies, should be carried out systematically. In order to establish the system, the aim of management should be to meet customer expectations, to make a profit, to keep pace with technological innovations and to be open to development and to stay in the sector for many years.The aim of this study is to explain the importance of quality and quality management system and to examine the establishment, management and sustainability of the automotive industry standard IATF 16949: 2016 from a statistical point of view. In this study, the innovations brought by IATF 16949: 2016 revision were examined and statistical quality improvement techniques were used and examples were applied for organizations.Measurement Systems Analysis (MSA) and Statistical Process Control Analysis used in the implementation of the study IATF 16949: 2016 is two of the statistical techniques for quality improvement in QMS. The data used from the statistical techniques were analyzed in Minitab 16 and analyzes were conducted in three separate companies. Research supports that quality has a relationship with company performance. 121

[ES] La homologación de los componentes del sector de la automoción se realiza a través de un proceso largo y complejo denominado Part Approval Production Process (PPAP). La realización del mismo no se puede hacer eficientemente sin un sistema de información adecuado debido a la gran cantidad de información y de fuentes de la misma que se manejan. El alcance global del presente trabajo es implementar una mejora del sistema existente para reducir los retrasos recurrentes en la homologación de los componentes de asientos. En primer lugar, el proyecto tratará de plantear el contexto y las etapas del proceso de homologación de un componente. A continuación, se analizará el sistema que se está usando actualmente y se destacarán las incidencias observadas. Tras haber diseñado los requerimientos que tiene que tener el nuevo sistema, se aprovechará el lanzamiento de un nuevo asiento para implementar un nuevo sistema global que pretende facilitar la ejecución del PPAP y los flujos de información. Un análisis de cumplimiento de requerimientos permitirá detectar las oportunidades de mejora y se concluirá el trabajo con la implementación de dos herramientas proporcionando soluciones a corto plazo para resolver incidencias urgentes., [EN] The approval of automotive parts is being carried out through a complex process called Part Approval Production Process (PPAP). Efficient PPAP completion is impossible without an appropriate information system due to the large quantity of information and information sources that have to be dealt with. The global purpose of present paper is implementing an improvement of an existing system in order to reduce automotive seats components approval delays. First of all, general context and process steps of PPAP will be detailed. Then, the analysis of the current information system will be performed, and its inefficiencies will be pointed out. After having designed the requirements new information system must meet, the kick-off of a new seat will be taken advantage of to implement a new global system that is supposed to enhance PPAP execution and communication flow. Afterwards, to highlight the improvement opportunities, fulfilment of requirements will be analysed, and present work will be concluded with the implementation of two information tools offering short-term solutions able to solve urgent issues.

Esta pesquisa analisa a incorporação do gerenciamento de riscos no processo de desenvolvimento de produtos (PDP) nas empresas de autopeças, fundamentado no Advanced Product Quality Planning (APQP), enfatiza as entregas do projeto de desenvolvimento preconizadas pelo Production Parts Approval Process (PAPP) e realiza uma revisão bibliográfica estabelecendo os fundamentos teóricos para seu desenvolvimento. O método de pesquisa utilizado foi a pesquisa-ação, cujos dados foram coletados por meio de análise documental, entrevistas e observações dos pesquisadores. A incorporação do gerenciamento de riscos no PDP contribui para o processo decisório, principalmente nas etapas de análise de riscos qualitativos e de planejamento de respostas aos riscos, fornecendo maior precisão quanto aos prazos e à identificação das atividades críticas. Os fatores que se destacaram para se obter a precisão dos resultados são: a formação da equipe; a discussão coletiva dos prazos fornecidos, tendo como resultado o comprometimento; o papel do gerente do projeto, propiciando o feedback entre os participantes, e a existência de evidências objetivas do apoio da alta administração. Conclui-se que a formação da equipe influencia no gerenciamento de riscos, sendo preponderante na percepção dos riscos a formação educacional.This research analyzes the incorporation of risk management in the product development process (PDP) in auto parts companies, based on Advanced Product and Quality Planning (APQP), and emphasizes the delivery of project development proposed by the Production Part Approval Process (PPAP) and conducts a review of the literature, establishing the theoretical foundations for its development. The research method used was action research, where data were collected through documentary analysis, interviews and researchers' observations. The incorporation of risk management contributes to the PDP-making processes, especially in the stages of qualitative risk analysis and planning of responses to risk, providing greater accuracy of the time and identification of critical activities. The factors that emerged as most important for guaranteeing the accuracy of the results are: team building; collective discussion of deadlines set, resulting in commitment; the role of project manager, providing feedback from the participants; the existence of objective evidence in support of senior management. It follows that team-building impacts on risk management, as in the perceived risk to ongoing education.

Ziel dieser Arbeit war die Isolierung von antitumoral wirksamen Substanzen aus kubanischer Propolis, die in Tieren eine antitumorale Aktivität aufweist. Diese Substanzen kommen als Kandidaten für die Entwicklung von Chemotherapeutika in Betracht, die chemotherapie-refraktäre Krebsstammzellen spezifisch angreifen können. Für diese Absicht wurden als biologisches Untersuchungssystem chemotherapie-resistente und nicht resistente Zelllinien unterschiedlicher Krebsarten etabliert, wobei die resistenten Zelllinien eine Reihe von Charakteristika von Krebsstammzellen aufweisen. Mit diesem System konnten 18 wirksame Substanzen in Reinform isoliert werden. Aufgrund der chemischen Komplexität der kubanischen Propolisspezies wurde sie in drei Areale aufgetrennt, wobei in A acht, in B zwei und in C wiederum acht wirksame Substanzen gefunden worden sind. Areal A enthielt fünf Substanzen, deren Struktur und Namen bereits bekannt sind, dazu eine bisher unbekannte und zwei weitere Verbindungen, bei denen keine Strukturaufklärung möglich war. Die identifizierten Substanzen gehören zu den Flavonoiden, Isoflavonoiden und Chalkonen. In Areal B wurden Nemoroson und Retusapurpurin A identifiziert. In Areal C sind die allermeisten Verbindungen der Gruppe der PPAP zuzuordnen. Das Areal enthält die bereits bekannten Substanzen Propolon A und DEHP, drei bisher unbekannte PPAP, deren Struktur aufgeklärt werden konnte, und drei PPAP-ähnliche Substanzen, von denen aber keine endgültigen Strukturen vorliegen. Molekularbiologische Analysen zur Aufklärung der Wirkmechanismen der isolierten Verbindungen ergaben, dass Laxifloran und Conferol A aus Areal A starke Tubulinpolymerisierungshemmer sind. Die Wirkmechanismen der restlichen Substanzen bleiben offen. Die Wirkmechanismen der Verbindungen aus Areal B sind in der Literatur gut beschrieben und lagen daher nicht im Fokus dieser Arbeit. In Areal C wurde DEHP als starker Hemmer der Topoisomerasen I und II sowie die DNA-Polymerase identifiziert. Für zwei PPAP (CZ4-1-2 und CZ4-2) wurde in den Zellen eine Inhibition der enzymatischen Aktivität der Signaltransduktionselemente c-Raf, MEK1/2 und ERK1/2 beobachtet, was ein wichtiger Wirkmechanismus für diese Substanzen darstellen könnte. Für die restlichen Substanzen konnten bislang keine Wirkmechanismen entschlüsselt werden. Ein bedeutsames Ergebnis dieser Arbeit ist die Identifizierung von neun Verbindungen, die eine deutliche Wirkung in hoch hemotherapie-refraktären Krebszellen zeigen. Diese Eigenschaft ist klinisch relevant, weil solche Substanztypen in Patienten zum Einsatz kommen könnten, die eine Resistenz gegen die Standardtherapien entwickelt haben. Außerdem könnten diese Verbindungen als Leitsubstanzen für die Entwicklung neuartiger Medikamente benutzt werden. Die detaillierte Aufklärung der Wirkweise der Substanzen und die Analyse ihrer Zielstrukturen sollen zukünftige Forschungsschwerpunkte sein, ebenso wie die Untersuchung ihrer akuten und chronischen Toxizität sowie ihrer antitumorale Aktivität im Tiermodell. The aim of this thesis was the isolation of antitumoral active compounds from Cuban propolis. Those compounds are interesting candidates for the development for novel chemotherapeutics, which target the resistant cancer stem cells (CSC). For this purpose we established a broad panel of resistant and non resistant cell lines of different cancer species, in which the resistant cancer cells show properties of CSC. Employing this cell panel and successive HPLC cycles we isolated 18 active substances in a pure form. Due to the chemical complexity the Cuban propolis was divided into three areas, where area A contained eight, area B two and area C eight cytotoxic substances. Five out of the eight substances in area A were already known and are belonging to the chemical classes of flavonoids, isoflavonoids and chalcones (A3-2, A4-6, A5-3 & A6). Additionally there was one un-known xanthone (A4-7) and two substances without a structure (A2-3 & A4-5). Area B consisted of nemorosone (B1) and retusapurpurine A (RNP). Most of the substances in area C were members of the polycyclic polyprenylated acylphloroglucinols (PPAP). Beside of propolone A (C4-2-1) and DEHP (CZ6) there were three unknown PPAP with an identified chemical structure (CZ4-1-1, CZ4-2 & CZ4-3) and another three unidentified compounds (C4-2-2, CZ4-1-2 & CZ5). Molecular biological analyses for the clarification of the mechanism of action of the isolated substances showed that A3-2 and A4-6 were strong inhibitors of tubulin polymerization. The mechanism of action for the other compounds of area A remained unknown. The substances of area B with their mechanism of action were well described in the literature and because of that not in the focus of this thesis. DEHP from area C was a strong inhibitor of topoisomerases I and II as well as of the DNA polymerase. CZ4-1-2 and CZ4-2 blocked the activity of the signal transduction elements c-Raf, MEK1/2 and ERK1/2 in the cells. The mechanisms of action of the remaining area C substances were not identified. A major result of this thesis was the identification of nine compounds, which are highly active in therapy-refractory cancer cells. This is clinical important, because those agents can be used for patients who developed a radio- and chemotherapy-refractory tumor. Furthermore these substances can be used as lead structures for novel drugs. A detailed clarification of the mechanisms of action and identification of the cellular targets of the propolis substances should be the aim and focus of future research, as well as analyses of acute or chronic toxicity and antitumorale activity of the compounds in an in vivo animal model.

Hereditary factors are thought to play are role in 20-30% of all colorectal cancers Around 6% are found as high penetrant disease-causing mutations in genes correlated to hereditary polyposis or hereditary non-polyposis syndromes. The aim of this thesis was to identify new causative genes and variants and also mutation mechanisms in families presenting a polyposis, atypical polyposis or nonpolyposis CRC phenotype. In classical familial adenomatous polyposis (FAP) 100% of the disease-causing mutations were found in patients from the Swedish Polyposis Registry. The mutation underlying the lowered expression of the APC gene in one family was identified by SNP array analysis, the mutation was a split deletion of 61Kb including half of the promoter 1B. Investigation of the significance of this promoter for expression of the APC gene demonstrated considerably higher expression compared with the established promoter 1A. In order to establish a sensitive method for mosaic-mutation detection a comparison of mutation detection methods was performed. Low frequency mosaic mutations were detected down to 1 % by use of massively parallel sequencing (MPS). Whole exome sequencing in four families with attenuated FAP (AFAP), atypical polyposis or non-polyposis syndromes identified two high penetrant disease-causing mutations. One was found in the upstream regulatory region of GREM1and one in the exonuclease domain of POLE. Variants in low-penetrant genes possibly contributing to CRC development were also proposed from the exome sequencing and gene specific analyses of 107 patients. Sixty-seven of these patients were analyzed in a panel of 19 selected CRC predisposing genes. Truncating mutations were found in the BMPR1A and SMAD4 genes in patients with a classical FAP, atypical FAP or non-polyposis phenotype. Classification of found non-synonymous variants was also performed. In summary, using a combination of different molecular screening techniques, 100% of diseasecausing mutations in classical FAP can be found. With MPS it is possible to detect low-frequency mosaic mutations down to 1% by absolute quantification. Whole exome analyses identified mutations in the new causative genes POLE and GREM1. It was also concluded that patients without identified mutations, based on phenotypical CRC classification, can have mutations in genes not included in the primary routine analysis. These results will lead to improved mutation detection analysis for diagnostic and carrier testing.

[ES] El objeto del presente proyecto es el estudio y ejecución de un Proceso de Aprobación de Piezas para Producción (PPAP) para la fabricación en grandes series de la matriz 5639 este proyecto es una aplicación real en la empresa en la cual trabajo actualmente. Esta matriz corresponde a un encargo de nuestro cliente Autoliv S.L.

In terms of Quality, more specifically, the Quality Automotive, we emphasize that the Approval Process Production Parts (PPAP) is characterized by evaluating a series of analyzes of various aspects of manufacturing process of production. Also, refers to the way of reporting the results the process, proving that the vendor has the ability to meet production with the level of quality required by the customer. Quality in need of resources that show where the ERP TECNICON BUSINESS SUITE integrates all departments and business processes with versatility provided by a modular and customizable structure, providing opportunities for solutions aimed at improving communication between all areas of an organization, so specific and complete. Thus, the research aims to define and implement the necessary PPAP procedures for TECNICON company in order to meet the needs of its customers. The implementation is aimed at monitoring and guidance of TECNICON Business Suite users directed to customers. The purpose of use of the system by the company is to provide the use of PPAP for their customers. Thus, the PPAP is characterized by the fact that the need for bureaucratic procedure when clients (where customers TECNICON, are to be PPAP suppliers to their customers) request the documentation on the flow of information between them to review and approval of the PPAP. The methodology was defined as action research, since the researcher provides the search directives during the study period in order to find solutions to the problem in TECNICON in Horizontina (RS). As main results, the implementation stands out PPAP procedures for the use of customers TECNICON Company, was completed from the following tools: Study Capability, DPAR, FMEA, Flow Chart, R & R, Dimensional Report, RAA, RIAI and Linearity. No âmbito da Qualidade, mais especificamente da Qualidade Automotiva, destaca-se que o Processo de Aprovação de Peças de Produção (PPAP) caracteriza-se por avaliar uma série de análises de vários aspectos de um processo de manufatura. Além disso, refere-se à maneira de relatar os resultados do processo, provando que o fornecedor tem a capacidade de cumprir a produção com o nível de qualidade exigido pelo cliente. Qualidade que necessita de recursos que a comprovam, onde o ERP TECNICON BUSINESS SUITE integra todos os departamentos. Os processos empresariais, com versatilidade proporcionada por uma estrutura modular e personalizável, oportunizam soluções direcionadas à melhoria na comunicação entre todas as áreas de uma organização de maneira específica e completa. Assim, a pesquisa tem como objetivo definir e implantar os procedimentos necessários do PPAP para a empresa TECNICON com o propósito de atender as necessidades de seus clientes. A implantação está voltada ao monitoramento e à orientação dos usuários do TECNICON BUSINESS SUITE direcionada aos clientes. A finalidade da utilização do sistema pela empresa é de proporcionar o uso do PPAP para seus clientes. Dessa forma, o PPAP se caracteriza pelo fato da necessidade do procedimento burocrático, quando os clientes (onde os clientes da TECNICON, passam a serem fornecedores do PPAP para seus clientes) solicitam a documentação referente ao fluxo de informações entre as mesmas para avaliação e aprovação do PPAP. A metodologia foi definida como pesquisa-ação, uma vez que o pesquisador oferece as diretivas de pesquisa durante todo o período de estudo, no sentido de encontrar as soluções do problema na TECNICON, em Horizontina (RS). Como principais resultados, destaca-se a implantação dos procedimentos PPAP para utilização dos clientes da empresa TECNICON, que foi finalizada a partir das seguintes ferramentas: CEP/Estudo de Capabilidade, DPAR, FMEA, Fluxograma, R&R, Relatório Dimensional, RAA, RIAI e Linearidade.