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Serratierte Läsionen im Kolorektum stellen eine Problemzone für Kliniker und Pathologen dar; dies liegt zum einen an der noch nicht allgemein bekannten Nomenklatur, zum anderen an dem noch nicht abschließend geklärten Progressionsrisiko der verschiedenen serratierten Polypen. Mittlerweile gilt als akzeptiert, dass neben der klassischen Adenom-Karzinom-Sequenz ein alternativer serratierter und ein sogenannter gemischter Karzinogeneseweg existiert; diese Karzinogenesewege sind in Bezug auf die präinvasiven Vorstufen, die molekularen Pfade und die Prognose der Karzinome heterogen. Bei den serratierten Adenokarzinomen lassen sich ein Niedrigrisiko-Subtyp (Häufigkeit <20%, mit meist proximaler Lokalisation, dem sessilen serratierten Adenom als Vorläuferläsion, BRAF-Mutation, hoher Mikrosatelliteninstabilität, CpG-Methylierung/hMLH1-Ausfall und einer 5-Jahres-Überlebensrate von >70%) sowie ein Hochrisiko-Subtyp (Häufigkeit >80%, mit meist distaler Lokalisation, dem traditionellen serratierten Adenom als Vorläuferläsion, KRAS-Mutation, niedriger Mikrosatelliteninstabilität/mikrosatellitenstabil, CpG-Methylierung/ p53-Akkumulation und einer 5-Jahres-Überlebens-Rate von <30%) unterscheiden. Eine molekular pathologische Bestimmung des Mikrosatellitenstatus und einer BRAF-oder KRAS-Mutation in Verbindung mit einer hMLH1-und p53-Immunhistochemie lässt eine bessere Unterscheidung dieser beiden Typen zu und wird klinisch zunehmend relevant. / Serrated Lesions of the Colorectum – a Pathological or a Pathologist’s Problem? The classification and treatment of serrated lesions in the lower gastrointestinal tract remains a difficult task for clinicians and surgical pathologists; on the one hand, due to the inconsistent nomenclature of serrated lesions in the lower gastrointestinal tract and, on the other hand, due to the poor understanding of the underlying mechanisms and risk factors for progression of these lesions. It is widely accepted that in addition to the classic adenoma-carcinoma sequence a recently discovered serrated or mixed pathway is important in colorectal carcinogenesis. These two pathways are heterogeneous with regard to precursor lesions, molecular mechanisms and prognosis. Depending on their molecular signature, serrated colorectal adenocarcinomas, for instance, can be subdivided into a low-risk (frequency <20%, often with proximal location, the sessile serrated adenoma as a precursor lesion, BRAF mutation, high microsatellite instability, CpG methylation/hMLH1 loss and a 5-year survival rate of >70%) and a high-risk subtype (frequency >80%, often with distal location, the traditional serrated adenoma as a precursor lesion, KRAS mutation, low microsatellite instability/microsatellite stable, CpG methylation/ p53 accumulation and a 5-year survival rate of <30%). The evaluation of the microsatellite status as well as the detection of BRAF or KRAS mutations together with immunohistochemistry for hMLH1 and p53 will allow a discrimination between these two subtypes and will become increasingly important in the future. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Serratierte Läsionen im Kolorektum stellen eine Problemzone für Kliniker und Pathologen dar; dies liegt zum einen an der noch nicht allgemein bekannten Nomenklatur, zum anderen an dem noch nicht abschließend geklärten Progressionsrisiko der verschiedenen serratierten Polypen. Mittlerweile gilt als akzeptiert, dass neben der klassischen Adenom-Karzinom-Sequenz ein alternativer serratierter und ein sogenannter gemischter Karzinogeneseweg existiert; diese Karzinogenesewege sind in Bezug auf die präinvasiven Vorstufen, die molekularen Pfade und die Prognose der Karzinome heterogen. Bei den serratierten Adenokarzinomen lassen sich ein Niedrigrisiko-Subtyp (Häufigkeit <20%, mit meist proximaler Lokalisation, dem sessilen serratierten Adenom als Vorläuferläsion, BRAF-Mutation, hoher Mikrosatelliteninstabilität, CpG-Methylierung/hMLH1-Ausfall und einer 5-Jahres-Überlebensrate von >70%) sowie ein Hochrisiko-Subtyp (Häufigkeit >80%, mit meist distaler Lokalisation, dem traditionellen serratierten Adenom als Vorläuferläsion, KRAS-Mutation, niedriger Mikrosatelliteninstabilität/mikrosatellitenstabil, CpG-Methylierung/ p53-Akkumulation und einer 5-Jahres-Überlebens-Rate von <30%) unterscheiden. Eine molekular pathologische Bestimmung des Mikrosatellitenstatus und einer BRAF-oder KRAS-Mutation in Verbindung mit einer hMLH1-und p53-Immunhistochemie lässt eine bessere Unterscheidung dieser beiden Typen zu und wird klinisch zunehmend relevant. / Serrated Lesions of the Colorectum – a Pathological or a Pathologist’s Problem? The classification and treatment of serrated lesions in the lower gastrointestinal tract remains a difficult task for clinicians and surgical pathologists; on the one hand, due to the inconsistent nomenclature of serrated lesions in the lower gastrointestinal tract and, on the other hand, due to the poor understanding of the underlying mechanisms and risk factors for progression of these lesions. It is widely accepted that in addition to the classic adenoma-carcinoma sequence a recently discovered serrated or mixed pathway is important in colorectal carcinogenesis. These two pathways are heterogeneous with regard to precursor lesions, molecular mechanisms and prognosis. Depending on their molecular signature, serrated colorectal adenocarcinomas, for instance, can be subdivided into a low-risk (frequency <20%, often with proximal location, the sessile serrated adenoma as a precursor lesion, BRAF mutation, high microsatellite instability, CpG methylation/hMLH1 loss and a 5-year survival rate of >70%) and a high-risk subtype (frequency >80%, often with distal location, the traditional serrated adenoma as a precursor lesion, KRAS mutation, low microsatellite instability/microsatellite stable, CpG methylation/ p53 accumulation and a 5-year survival rate of <30%). The evaluation of the microsatellite status as well as the detection of BRAF or KRAS mutations together with immunohistochemistry for hMLH1 and p53 will allow a discrimination between these two subtypes and will become increasingly important in the future. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Over 80% of colorectal cancers (CRCs) are sporadic/randomly arising tumors. Interval CRCs represent a subset of sporadic tumors that develop within 6-36 months after a negative colonoscopy. Interval CRCs are suggested to exhibit altered biological properties that contribute to rapid growth and proliferation. We hypothesize that chromosomal instability (CIN), or aberrant chromosome numbers, contributes to the etiology of Interval CRCs. We have assembled a Manitoban cohort of Interval and sporadic (control) CRC tumor samples, and established a fluorescence in situ hybridization approach to characterize CIN by enumerating specific chromosomes. The results of this study indicate that 75% of Interval CRCs exhibit a CIN phenotype, making CIN the most prevalent contributor to genomic instability in Interval CRCs. Only once we grasp a better understanding of the tumorigenic pathways through which Interval CRCs develop, can we tailor screening strategies and treatment options to specifically identify and combat this subset of sporadic CRC.

Orientador: Kléber Pereira Lanças / Banca: Saulo Philipe Sebastião Guerra / Banca: Paulo Roberto Arbex Silva / Banca: Ila Maria Corrêa / Banca: Nilson Salvador / Resumo: As colhedoras atuais de cana-de-açúcar são autopropelidas, com todo acionamento, das peças ativas e locomotoras, hidráulico. O cortador de base é composto por dois discos contra rotativos, com cinco lâminas retangulares cada, que cortam os colmos em sua base por impacto. Um rolo defletor empurra os caules para frente antes do corte para auxiliar na alimentação da máquina. A deflexão e o corte de base por impacto são responsáveis por danos na soqueira e no produto colhido. Estes danos aceleram o processo de deterioração, aumentam o nível de perdas e prejudica a rebrota. O objetivo desta pesquisa foi desenvolver e avaliar um sistema de corte de base que não se baseie no corte por impacto e que possa ser adaptado em qualquer colhedora comercial sem a necessidade de alterações na máquina. Para alcançar o objetivo proposto, foi realizado um estudo cinemático de lâminas curvas e foram conduzidos experimentos de laboratório e campo. Os discos do cortador de base estão sujeitos a dois movimentos, rotação e translação (avanço da colhedora). O estudo cinemático descreve estes movimentos em forma de matrizes. Foram elaborados programas com o uso do software MATLAB para a realização de uma simulação virtual, usada para investigar as configurações alternativas do cortador de base e fornecer subsídios para um desenvolvimento teórico do processo de corte da cana-de-açúcar. No laboratório foi construída uma estrutura de teste que simulava os movimentos de rotação e translação do disco, para cortar uma amostra do caule da cana-de-açúcar. Foram realizados dois experimentos; no primeiro foi utilizado um delineamento estatístico em esquema fatorial onde foi avaliado o passo do serrilhado, o ângulo horizontal da lâmina com inclinação para frente e para trás e a velocidade de corte. Foram analisados os danos no caule, perdas de massa, forças e energia de corte... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The current sugar cane harvesters are self propelled and all transmissions are hydraulic. The basecutting mechanism consists of two rotating discs, with five rectangular blades each, which cut the stalk at its base by impact. A knockdown roller pushes the stem forward before the cut to assist the machine feeding. The deflection and the basecutting by impact are responsible for damage to the stump and harvested product. This damage accelerates the deterioration process, increases the level of losses, damage and reduces the ratoon. The objective of this research was to develop and evaluate a basecutter system that is not based on the impact cut and can be adapted to any commercial harvester without any modification in the machine. To achieve the proposed objective, a cinematic study of curved blades was developed and was also conducted laboratory and field experiments. The basecutter discs are subject to two basic movements, rotation and translation (advancement of the harvester). The cinematic study describes these movements in form of matrices and some programs were written using the MATLAB software and this virtual simulation was used to investigate alternative basecutting configurations and provide knowledge to a theoretical development of the sugarcane cutting process. At the laboratory it was built a test rig that simulates the rotation and translation movements of the disc to cut a sample of sugarcane stalk. Two experiments were conducted: in the first, it was used a factorial statistics design which assessed the pitch of the serration, the horizontal blade angle (backward and forward) and cutting speed. It was analyzed the damage to stem, mass 4 losses, forces and cutting energy. In the second experiment the sample of whole sugarcane was submitted to a bending stress to simulate the effect of deflection roll and it was analyzed the damage to stem, mass loss and consumed energy... (Complete abstract click electronic access below) / Doutor

Made available in DSpace on 2014-06-11T19:31:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-05-23Bitstream added on 2014-06-13T19:20:44Z : No. of bitstreams: 1 mello_rc_dr_botfca.pdf: 1756104 bytes, checksum: 8f837d784813911ebf3c8ca7e85b19c2 (MD5) / As colhedoras atuais de cana-de-açúcar são autopropelidas, com todo acionamento, das peças ativas e locomotoras, hidráulico. O cortador de base é composto por dois discos contra rotativos, com cinco lâminas retangulares cada, que cortam os colmos em sua base por impacto. Um rolo defletor empurra os caules para frente antes do corte para auxiliar na alimentação da máquina. A deflexão e o corte de base por impacto são responsáveis por danos na soqueira e no produto colhido. Estes danos aceleram o processo de deterioração, aumentam o nível de perdas e prejudica a rebrota. O objetivo desta pesquisa foi desenvolver e avaliar um sistema de corte de base que não se baseie no corte por impacto e que possa ser adaptado em qualquer colhedora comercial sem a necessidade de alterações na máquina. Para alcançar o objetivo proposto, foi realizado um estudo cinemático de lâminas curvas e foram conduzidos experimentos de laboratório e campo. Os discos do cortador de base estão sujeitos a dois movimentos, rotação e translação (avanço da colhedora). O estudo cinemático descreve estes movimentos em forma de matrizes. Foram elaborados programas com o uso do software MATLAB para a realização de uma simulação virtual, usada para investigar as configurações alternativas do cortador de base e fornecer subsídios para um desenvolvimento teórico do processo de corte da cana-de-açúcar. No laboratório foi construída uma estrutura de teste que simulava os movimentos de rotação e translação do disco, para cortar uma amostra do caule da cana-de-açúcar. Foram realizados dois experimentos; no primeiro foi utilizado um delineamento estatístico em esquema fatorial onde foi avaliado o passo do serrilhado, o ângulo horizontal da lâmina com inclinação para frente e para trás e a velocidade de corte. Foram analisados os danos no caule, perdas de massa, forças e energia de corte... / The current sugar cane harvesters are self propelled and all transmissions are hydraulic. The basecutting mechanism consists of two rotating discs, with five rectangular blades each, which cut the stalk at its base by impact. A knockdown roller pushes the stem forward before the cut to assist the machine feeding. The deflection and the basecutting by impact are responsible for damage to the stump and harvested product. This damage accelerates the deterioration process, increases the level of losses, damage and reduces the ratoon. The objective of this research was to develop and evaluate a basecutter system that is not based on the impact cut and can be adapted to any commercial harvester without any modification in the machine. To achieve the proposed objective, a cinematic study of curved blades was developed and was also conducted laboratory and field experiments. The basecutter discs are subject to two basic movements, rotation and translation (advancement of the harvester). The cinematic study describes these movements in form of matrices and some programs were written using the MATLAB software and this virtual simulation was used to investigate alternative basecutting configurations and provide knowledge to a theoretical development of the sugarcane cutting process. At the laboratory it was built a test rig that simulates the rotation and translation movements of the disc to cut a sample of sugarcane stalk. Two experiments were conducted: in the first, it was used a factorial statistics design which assessed the pitch of the serration, the horizontal blade angle (backward and forward) and cutting speed. It was analyzed the damage to stem, mass 4 losses, forces and cutting energy. In the second experiment the sample of whole sugarcane was submitted to a bending stress to simulate the effect of deflection roll and it was analyzed the damage to stem, mass loss and consumed energy... (Complete abstract click electronic access below)

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The effects of trailing edge flow control on the wakes of a linear cascade of idealized fan blades was investigated experiments with a view to the likely effects on broadband aircraft engine interaction noise. Single and three-component hotwire velocity measurements were made downstream of the cascade for a chord Reynolds number of 390,000 and a Mach number of 0.07. Measurements of the two-point velocity correlation were used extensively to evaluate the impact of various flow control strategies on the organization of the coherent structures of the wakes and their potential to generate noise. A baseline flow was established by measuring the wake downstream of unmodified GE-Rotor-B blades. Four sets of serrated trailing edge blades (with two different serration sizes and with two trailing edge cambers) and three sets of blades with trailing edge blowing (a simple rectangular slot, rectangular slot with Kuethe-vane vortex generators, and rectangular slot with serrated lips) were tested. The serrated trailing edges introduce corrugations into the wake, increase the wake decay and width as well as turbulence levels (possibly because of the blunt trailing edge created at the serration valley). The serrated trailing edges also increase the turbulence scales in the direction perpendicular to the plane of the wake because of the injection of streamwise vorticity. In almost all cases the serrations reduce the spanwise and streamwise turbulence scales. Serrations do not, however, affect the apparent time scale of quasi-periodic structures in the wake, and this appears to limit the potential of this trailing edge treatment to reduce broadband noise. The analysis of the characteristic eddies (obtained from proper orthogonal decomposition combined with linear estimation) revealed that the serrations do not change the qualitative form of the eddies. Trailing edge blowing was found to significantly decrease the wake deficit and width as well as the turbulence levels at all blowing rates. Blowing through the simple rectangular slot, at mass flow rates between 1.4 and 2.0% of the total passage through flow, was shown to significantly affect the size, the organization and the strength of the coherent structures. For small blowing rates the strong spanwise eddies near the trailing edge actually appear to be enhanced. For larger blowing rates, however, the turbulent scales are reduced in all directions. The addition of Kuethe vanes on the suction side of the blowing blade results in a low momentum region just downstream of the vanes that may result from flow separation there. This further enhances the shedding and increases the blowing rate needed to overcome it. The serrated blowing blades show the greatest potential to reduce broadband noise as they reduce the turbulence levels and scales without creating potentially detrimental structures. While no acoustic measurements were made, analysis of hypothetical perpendicular and parallel interactions of blades with these wakes has made possible to characterize for the first time the impact of the changes in the eddy structure of these wakes on their potential to generate broadband noise. The serrated trailing edges (especially the larger serrations) actually increase the potential of the wake to generate broadband noise (a direct consequence in the overall increase in turbulence scale and intensity). In contrast, every trailing edge blowing configuration was found to produce large reductions in the potential noise (a maximum of 6dB reduction was obtained at 2.0% blowing). The addition of Kuethe vanes on the suction side of the blowing blades significantly reduced the efficiency of the simple blowing configuration (a result of the increased coherency associated with the shedding of streamwise vorticity by the vanes). The serrated blowing configuration was found to yield reductions similar to the simple blowing configuration. / Ph. D.

The effects of serrated trailing edge designs, designed for noise reduction, on the flow-field downstream of an idealized aircraft engine fan blade row were investigated in detail. The measurements were performed in the Virginia Tech low speed linear cascade tunnel on one set of baseline GE-Rotor-B blades and four sets of GE-Rotor-B blades with serrated trailing edges. The four serrated blade sets consisted of two different serration sizes (1.27 cm and 2.54 cm) and for each different serration size a second set of blades with added trailing edge camber. The cascade row consisted of 8 GE-Rotor-B blades and 7-passages with adjustable tip gap settings. It had an inlet angle of 65.1º, stagger angle of 56.9º and a turning angle of 11.8º. The tunnel was operated with a tip gap setting of 1.65% chord, with a Reynolds number based on the chord of 390,000. Blade loading measurements performed on each set of blades showed that it was slightly dependent on the serration shape. As the serration size was increased the blade loading decreased, but adding droop increased the blade loading. The Pitot-static cross-sections showed that flow-fields near the upper and lower endwalls cascade tunnel were similar with the baseline or the serrated blade downstream of the blade row. In the wake region, the individual trailing edge serrations tips and valleys could be seen. As the wake convected downstream, the individual tips and valleys became less visible and the wake was more uniform in profile. The tip leakage vortex was only minimally affected by the trailing edge serrations. This conclusion was further reinforced by the three-component hot-wire cross-sectional measurements that were performed from the lower endwall to the mid-span of the blade. These showed that the mean streamwise velocity, turbulence kinetic energy and turbulence kinetic energy production in the tip leakage region were nearly the same for all four serrated blades as well as the baseline. The vorticity in this region was a more dependent on the serration shape and as a result increased with serration size compared to the baseline. Mid-span measurements performed with the three-component hot-wire showed the spreading rate of the wake and the decay rate of the wake centerline velocity deficit increased with serration size compared to the baseline case. Drooping of the trailing edge only minimally improved the spreading and decay rates. This improvement in these rates was predicted to reduce the tonal noise at the leading edge of the downstream stator vane because the periodic fluctuation associated with the sweeping of the rotor blade wakes across it, was due to the pitchwise variation in the mean streamwise velocity. The wakes were further compared to the mean velocity and turbulence profiles of plane wakes, which the baseline and the smallest serration size agreed the best. As the serration size was increased and drooping was added, the wakes became less like plane wakes. Spectral plots at the wake centerline in all three velocity directions showed some evidence of coherent motion in the wake as a result of vortex shedding. / Master of Science

Colorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.