In Krebszellen induzieren Onkogene und Chemotherapie zelluläre Seneszenz. Dabei handelt es sich um einen terminalen Wachstumsarrest, bei dem durch Trimethylierung der Aminosäure Lysin an Position 9 (K9) des Histons H3 (H3K9me3) die Aktivierung S-Phase-relevanter Gene epigenetisch blockiert ist. Obwohl Therapie-induzierte Seneszenz (TIS) das Gesamtüberleben von Mäusen mit einer Lymphomerkrankung verbessert, stellt eine Elimination seneszenter Zellen aufgrund weiterhin bestehender und neu erworbener tumorigener Eigenschaften ein wichtiges therapeutisches Ziel dar. Die Arbeit zeigt anhand des transgenen Eμ-myc Mausmodells, in dem TIS in Abhängigkeit von der H3K9-Histonmethyltransferase Suv39h1 durch Chemotherapie induziert wird, dass TIS-Zellen in vitro und in vivo einer metabolischen Reprogrammierung unterliegen, die therapeutisch genutzt werden kann. TIS-kompetente Lymphome erhöhen im Gegensatz zu TIS-kompromittierten, Suv39h1- defizienten Lymphomen den Glukoseumsatz und die Produktion von ATP. Diese Umstellung des Stoffwechsels erfolgt als Antwort auf eine erhöhte Proteotoxizität, die durch Bestandteile des Seneszenz-assoziierten sekretorischen Phänotyps (SASP) hervorgerufen wird. SASP-Faktoren lösen in TIS-Zellen erhöhten Stress im endoplasmischen Retikulum (ER) aus und forcieren die Fehlfaltung von Proteinen, die nach vermehrter Ubiquitinierung durch Autophagie unter Energieverbrauch abgebaut werden. Deshalb sind stark SASP-exprimierende TIS-Lymphome im Vergleich zu genetisch durch die Inhibition des Transkriptionsfaktors NfκB veränderten und dadurch SASP-supprimierten TIS-Lymphomen empfindlich gegenüber der Inhibition des Glukosestoffwechsels oder der Blockade von Autophagie. Beides führt zur Elimination von TIS Zellen durch Caspase-12- und Caspase-3-abhängige, ER-initiierte Apoptose. Folglich erwirkt die pharmokologische Inhibition dieser veränderten Stoffwechselbedürfnisse nach TIS Induktion eine Tumorregression und ein verbessertes Gesamtüberleben in vivo. Zusammenfassend zeigen diese Ergebnisse eine katabole Stoffwechsellage seneszenter Zellen, die therapeutisch durch konzeptionell neue „synthetisch-letale“, metabolische Therapien eliminiert werden können. Damit wird erstmals in der Krebstherapie ein Tumor-selektives Seneszenzprogramm zusammen mit der Blockade von Stoffwechselwegen genutzt. / Cellular senescence is a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3) in response to oncogene activation and anticancer chemotherapy. Although therapy-induced senescence (TIS) improves long-term outcome, senescent tumor cells acquire potentially harmful characteristics. Therefore, their quantitative elimination presents a therapeutic opportunity. In this thesis the Eμ-myc transgenic mouse lymphoma model, in which TIS depends on the H3K9 histone methyltransferase Suv39h1, is used to show mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS- competent lymphomas but not TIS-incompetent Suv39h1- lymphomas displayed increased glucose turnover and higher ATP production. The thesis demonstrates that this was due to massive proteotoxic stress, which is a consequence of the enhanced production of secretory proteins - referred to as the senescence-associated secretory phenotype (SASP) - of senescent cells. Consequently, SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, for example due to the inhibition of the transcription factor NfκB, were more sensitive to blocking glycolysis or autophagy, which lead to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic liabilities upon TIS induction in vivo prompted tumor regression and improved treatment outcome further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting. Thus, this treatment approach for the first time combines the inhibition of a tumor-specific senescence program with the interference of a metabolic pathway.

This work will first introduce the problems related to the colorectal cancer - its epidemiology and screening possibilities. Next the main topic is addressed - i.e. to ascertain the influence of national screening programmes for colorectal cancer on really observed data of lethality and incidence of this disease. Group of so-called APC models was selected as a useful tool for this purpose. Applying these methods on data of The National Oncological Registry of the Czech Republic for the period between 1980 till 2009 this work aims to prove expected reducing effect of area-wide screening programme on incidence and lethality related to colorectal cancer. Using the AP model and data of previous period before the screening introduction (i.e. 1980-1999) the values of incidence and lethality were predicted for the period in question (i.e. 2000-2009). Mere comparison of this predicted values with really observed data showed that real lethality and incidence was significantly lower in both sexes as compared to the model without the screening intervention. Difference between predicted and real data corroborates positive influence of colorectal cancer screening.

Master of Science / Food Science Institute / Kelly J. K. Getty / The United States Department of Agriculture’s Food Safety and Inspection Service require that processors of ready-to-eat (RTE) meat and poultry products implement post- processing intervention strategies for controlling Listeria monocytogenes. The objective of our study was to determine the effect of packaging methods and storage time on reducing L. monocytogenes in shelf-stable meat snacks. Commercially available kippered beef steak strips (14 × 2.5 cm rectangle piece) and turkey tenders (4 × 4 cm square piece) were dipped into a five-strain L. monocytogenes cocktail, and dried at 23°C until a water activity of approximately 0.80 was achieved. Inoculated samples were packaged with four treatments: 1) vacuum, 2) nitrogen flushed with oxygen scavenger, 3) heat sealed with oxygen scavenger, and 4) heat sealed without oxygen scavenger. Samples were stored at 23°C and evaluated for L. monocytogenes levels at 0, 24, 48, and 72 h. Initial levels (time 0) of L. monocytogenes were approximately 5.7 log CFU/cm[superscript]2 for steak and tenders. For kippered beef steak, there was no interaction among packaging treatments and storage times (P > 0.05) whereas, storage time was different (P <0.05). A 1 log reduction of L. monocytogenes was observed at 24 and 48 h at 23°C for all packaging treatments and a 2.1 log CFU/cm[superscript]2 reduction occurred at 72 h. A 1 log CFU/cm[superscript]2 reduction of L. monocytogenes was observed after 24 h of storage for turkey tenders for all packaging treatments. After 48 h of storage time turkey tenders showed >1 log CFU/cm [superscript]2 reduction of L. monocytogenes for all packaging treatments except for vacuum packaged where only 0.9 log CFU/cm[superscript]2 reduction was observed. Log reductions at 72 h for all packaging treatments for turkey tenders ranged from 1.5 to 2.2. Processors of kippered beef steak and turkey tenders could use vacuum, nitrogen-flushing, or heat sealed with an oxygen scavenger packaging methods and hold product 24 h prior to shipping to reduce potential L. monocytogenes numbers by ≥1 log. However, processors should be encouraged to hold packaged product a minimum of 72 h to enhance the margin of safety for L. monocytogenes control.

A pesquisa Letalidade da ação policial e teoria interacional: análise integrada do sistema paulista de segurança pública visa dimensionar os fatores associados a letalidade policial. Dada a complexidade da ação policial, que envolve aspectos criminais, sociais e institucionais, a pesquisa propõe a formulação de um modelo teórico penológico que unifique diferentes tradições das Ciências Sociais. O modelo teórico interacional, adotado na tese, integra em uma dimensão analítica as premissas presentes nas teorias racionalista, contextual, institucional e ecológica. Tal estratégica metodológica é necessária, porque os modelos paradigmáticos selecionam um único parâmetro analítico para correlacionar com a ação policial e essa simplificação do comportamento policial não encontra suporte na realidade. Nesse sentido, encontrar uma alternativa as preposições teóricas clássicas foi o principal objetivo desse trabalho. Como estratégia de comprovação empírica do modelo teórico interacional foram utilizadas técnicas de regressão multivariadas, que permitem o teste simultâneo de validade das hipóteses alternativas e a verificação das interações entre os modelos teóricos e as variáveis independentes. A base empírica foi coletada junto a Comissão de Letalidade Policial da Secretaria de Segurança Pública do Estado de São Paulo. A amostra é de 1.111 casos de letalidade de não-policias registradas no Estado, entre 2001 e 2003 / The objective of the research Lethality of police action and interaction theory: integrated analysis of São Paulo public security system is to understand factors connected with police lethality. As police action is a complex issue, with criminal, social and institutional aspects, the study aims to formulate a penal theoretical model able to unify different traditions of Social Sciences. The interaction theoretical model adopted in the thesis integrates in an analytical dimension the premises presented in the rational, contextual, institutional and ecological thesis. This methodological strategy is necessary because the traditional models select only one parameter to police action. This simplification of police behavior does not find basis in social reality. The main proposal of this work was to find as alternative to classical theory propositions. As empiric form to check strategy of interaction theory model, the author used multiple regression techniques that permit simultaneous test of alternative hypothesis validation and the verification of interaction between theoretical models and independent variables. The empiric basis was the São Paulo State Public Security Secretary of Police Lethality Committee with 1.111 lethality non-policeman cases in the State in 2001-2003

Made available in DSpace on 2016-08-10T10:53:39Z (GMT). No. of bitstreams: 1 DJALMA ANTONIO DA SILVA JUNIOR.pdf: 3848227 bytes, checksum: 1904d70387982421a30c0d626079c004 (MD5) Previous issue date: 2012-05-04 / Dengue is a major re-emerging diseases in the world, provided mainly by environmental and economic changes in the social space organized. With increasing national incidence of severe forms and deaths, it is necessary to better understand the real magnitude of the disease at the local level, aiming to characterize the demographic distribution of dengue cases in the city of Goiânia, from 2001 to 2009. This is a descriptive and transversal epidemiological study whose data were provided by the Department of Epidemiology Municipal Health Secretariat of Goiânia, and extracted the information about the variables of the form of the Information System for Notifiable Diseases. In the analyzed period were 124,629 dengue cases reported, affecting more females, caucasians, living in urban areas with the highest incidence in age from 15 to 24 years (p<0.001). During the study period, was identified the three serotypes DENV 1, DENV 3 and DENV 2, the latter being identified in all the years of the series, alternating with the other. There was no preference for a particular serotype of gender, race and age of infected individuals. Of 124,629 cases of dengue, 4.4% required hospitalization with greater involvement of the age group 5- 14 years (p=0.04), those with a more favorable course of the disease, unlike the hospitalized population over 55 years whose mortality rate was above 5.6% (p=0.04). The DENV serotype 2 was most related to the infections that led to hospitalization (p<0.001). Goiânia is figured as an urban center with a high incidence of dengue in all years of the series, especially in 2008 when they accounted for 36.6% of all reported cases and 75% of deaths in the Midwest. The dengue fever was the most prevalent clinical form (99.7%). Cases with complications (Dengue Hemorrhagic Fever and Dengue Shock Syndrome), had increasing reports since the beginning of the series, especially in the years 2008 and 2009, occurred when recirculation of DENV 1 and DENV 2, respectively, also providing a high case fatality. The spatial distribution of deaths from dengue in Goiânia, showed that the administrative districts of Campinas and the Centre had the highest prevalence (22.2% and 17.1%) respectively. / A dengue é uma das principais doenças reemergentes no mundo, proporcionada principalmente pelas mudanças ambientais e econômicas no espaço social organizado. Com o aumento da incidência nacional das formas graves e de óbitos, torna-se necessário um melhor entendimento da real magnitude da doença a nível local, tendo como objetivo a caracterização da distribuição demográfica dos casos de dengue no município de Goiânia, no período de 2001 a 2009. Trata-se de um estudo epidemiológico descritivo e transversal, cujo dados foram fornecidos pelo Departamento de Epidemiologia da Secretaria Municipal de Saúde de Goiânia, sendo extraídas as informações referentes as variáveis da ficha do Sistema de Informação de Agravos de Notificação. No período analisado foram notificados 124.629 casos de dengue, comprometendo mais indivíduos do sexo feminino, da raça branca, que residiam na zona urbana, com maior incidência na etária de 15 a 24 anos (p<0,001). Durante o período de estudo, foram identificados os três sorotipos DENV 1, DENV 2 e DENV 3, sendo este último identificados em todos os anos da série, com alternância dos demais. Não houve preferências de um determinado sorotipo quanto ao sexo, a raça e a idade dos indivíduos infectados. De 124.629 casos de dengue, 4,4% necessitaram de hospitalização com acometimento maior do grupo etário de 5 a 14 anos (p=0,04), estes com uma evolução mais favorável da doença, ao contrário da população hospitalizada acima de 55 anos, cuja taxa de mortalidade esteve acima de 5,6% (p=0,04). O sorotipo DENV 2 foi o mais relacionado com as infecções que motivaram a hospitalização (p<0,001). Goiânia figurou-se como centro urbano de alta incidência de dengue em todos os anos da série, principalmente em 2008, quando foi responsável por 36,6% de todos os casos notificados e 75% dos óbitos da região Centro-Oeste. A dengue clássica foi a forma clínica com maior prevalência (99,7%). Os casos com complicações (Febre Hemorrágica da Dengue e Síndrome do Choque da Dengue), tiveram notificação crescente desde o início da série, em especial nos anos de 2008 e 2009, quando ocorreu a recirculação do DENV 2 e DENV 1, respectivamente, proporcionando também uma alta letalidade de casos. A distribuição espacial dos óbitos pela dengue em Goiânia, revelou que os distritos administrativos do Centro e de Campinas foram os de maior prevalência (22,2% e 17,1%) respectivamente.

Made available in DSpace on 2016-08-10T10:54:47Z (GMT). No. of bitstreams: 1 NICOLY AGUIAR.pdf: 1322443 bytes, checksum: 65dbdd6f424841fb3d62e00660fd042b (MD5) Previous issue date: 2015-08-28 / Visceral leishmaniasis (VL) is considered a neglected disease and has expanded and urbanized. The objectives of this study were to describe the demographic characteristics of visceral leishmaniasis; Assess the incidence rate; Describe the mortality rate and mortality and correlate average annual temperature and mean annual rainfall with the incidence rate. It is a descriptive, retrospective, ecological epidemiological study of the use of secondary data for the period 2007-2012 developed in the two most populous urban centers in the State of Tocantins, obtained from the Information Resulting System Notification and Secretary of State Tocantins Health. The average temperature in degrees Celsius and rainfall in millimeters were provided by the National Institute of Meteorology. It was adopted as a criterion for inclusion municipalities with a population in excess of 100,000 in this case Palmas and Araguaína. 358 reports of confirmed cases of VL in those over 15 years of age were analyzed. The highest incidence of the disease occurred among people of Masculine sex (70.7 %%), residing in urban areas (99.03%), and the brown race the most affected (85.5%). The age group with the highest incidence was between twenty to thirty-four years (40.2%). There was a significant difference (p <0.05) between variables. The most widely used diagnostic criterion was the Lab (98.3%). The highest incidence rate occurred in 2008, followed by a significant downward trend in cases (p <0.001). The greatest mortality and lethality coefficients occurred in 2008 and 2010. The clinical course for healing occurred in most patients (90.2%). The percentage of co-infected with HIV observed in this study was 4.5%. The weather conditions did not influence the epidemiology of the disease. It is concluded that LV is a disease with urban characteristics, endemic, with a predominance of males and records of people who are in an economically active age group with high incidence rate, when compared to other studies. The association was not significant between the average rainfall and the incidence rate, as well as between temperature and the incidence rate. / A leishmaniose Visceral (LV) é considerada uma doença negligenciada e tem se expandido e urbanizado. Os objetivos deste estudo foram: Descrever as características demográficas da Leishmaniose visceral; Avaliar o coeficiente de incidência; Descrever o coeficiente de mortalidade e letalidade e correlacionar temperatura anual média e pluviosidade anual média com o coeficiente de incidência. Trata-se de um estudo epidemiológico descritivo, retrospectivo, ecológico com a utilização de dados secundários referentes ao período de 2007 a 2012 desenvolvido no dois centros urbanos mais populosos do Estado do Tocantins, obtidos do Sistema de Informação de Agravos de Notificação e Secretaria de Estado da Saúde do Tocantins. As médias de temperatura em graus Celsius e de precipitação pluviométrica em milímetros foram fornecidas pelo Instituto Nacional de Meteorologia. Foi adotado como critério de inclusão municípios com população acima de 100.000 habitantes, neste caso, Palmas e Araguaína. Foram analisados 358 notificações de casos confirmados de LV em maiores de 15 anos de idade. A maior incidência da doença ocorreu entre pessoas do sexo masculino (70,7%%), residentes na zona urbana (99,03%), sendo a raça parda a mais acometida (85,5%). A faixa etária com maior incidência foi entre vinte a trinta e quatro anos (40,2%). Houve diferença significativa (p<0,05) entre as variáveis estudadas. O Critério diagnóstico mais usado foi o Laboratorial (98,3%). O maior coeficiente de incidência ocorreu em 2008, seguido de uma tendência significativa de diminuição dos casos (p< 0,001). Os maiores coeficientes de mortalidade e letalidade ocorreram nos anos de 2008 e 2010. A evolução clínica para a cura ocorreu na maioria dos pacientes (90,2%). O percentual de coinfectados com o HIV observados nesse estudo foi de 4,5%. A condição climática não influenciou na epidemiologia da doença. Conclui-se que a LV é uma doença com características urbana, endêmica, com predileção pelo sexo masculino e com registros de pessoas que encontram-se numa faixa etária economicamente ativa e com alto coeficiente de incidência, quando comparado a outros estudos. A associação não foi significativa entre a precipitação pluviométrica média e o coeficiente de incidência, assim como entre temperatura e o coeficiente de incidência.

Os trocadores de calor tubulares são muito utilizados para o processamento térmico de alimentos líquidos viscosos por possuírem um maior diâmetro hidráulico em comparação aos trocadores de calor a placas. O cálculo da letalidade neste tipo de trocador está diretamente relacionado ao perfil de velocidade e à distribuição do tempo de residência (DTR). Para escoamento laminar de fluidos viscosos, Newtonianos e não-Newtonianos, geralmente adota-se um perfil de velocidade laminar e de lei de potência, respectivamente. No entanto, algumas características do equipamento como irregularidades na tubulação, a corrugação do tubo ou as curvas podem modificar o perfil de velocidade ideal. Esse desvio da idealidade pode ser caracterizado através da determinação experimental da distribuição do tempo de residência do processo. Este trabalho teve como objetivo a determinação experimental da DTR de fluidos viscosos em um equipamento bitubular de processamento térmico e o ajuste do perfil de velocidade associado. Modelos clássicos de DTR foram ajustados aos dados, assim como foram propostos e testados novos modelos generalizados de DTR, a fim de caracterizar o escoamento laminar não ideal em tubos. A determinação da DTR experimental foi realizada para vazões entre 10 e 50 L/h utilizando água, solução de carboximeticelulose 1,0% (pseudoplástico) e mistura glicerina/água 80%. Os dados de DTR foram obtidos através de duas técnicas: condutimétrica e colorimétrica. A primeira técnica baseia-se na injeção de solução saturada de cloreto de sódio e detecção online por um condutivímetro, porém, não apresentou resultados satisfatórios mostrando que o método não é adequado para fluidos viscosos. Já a segunda técnica utilizada se baseia na injeção de corante e posterior detecção em espectrofotômetro. Os modelos que melhor se ajustaram aos dados experimentais para os três fluidos estudados foram os modelos generalizados y-laminar e exponencial. A letalidade foi calculada a partir da distribuição de temperatura no trocador de calor em estado estacionário e do tempo médio de residência obtido experimentalmente e permitiu detectar o sobreprocessamento no processo estudado. / Tubular heat exchangers are widely used for thermal processing of viscous liquid foods because they have larger hydraulic diameters than the plate heat exchangers. The calculation of lethality in this type of exchanger is directly related to velocity profile and the residence time distribution (RTD). For the laminar flow of viscous fluids, Newtonian and non-Newtonian, generally laminar and power law velocity profiles are used, respectively. However, some features of the equipment as irregularities in the pipe, the corrugation of the pipe or the presence of curves can change the ideal velocity profile. This ideality deviation can be characterized through the experimental determination of the residence time distribution of the process. The aim of this work was the experimental determination of the RTD of a viscous fluid in a bitubular thermal processing equipment and the determination of the associated velocity profile. Classic models of RTD were fitted to the data, as well as were proposed and tested new generalized models of RTD, in order to characterize the non ideal laminar flow in tubes. The experimental determination of RTD was performed to volumetric flow rates between 10 and 50 L/h using water, carboximeticelulose solution 1,0% (pseudoplastic) and glycerin/water mixture 80%. The RTD data were obtained through two techniques: conductimetric and colorimetric. The first technique is based on injection of saturated solution of sodium chloride and online detection with a conductivimeter however, unsatisfactory results showed that the method was not suitable for viscous fluids. The second technique is based on the injection of dye and subsequent detection with a spectrophotometer. The best fitted models to the experimental data for the three studied fluids were: ylaminar and exponential generalized models. The lethality was calculated from the temperature distribution in the heat exchanger at steady state and average residence time obtained experimentally and allowed the evaluation of the overprocessing of this process.

O processamento térmico contínuo usando trocadores de calor é uma forma muito comum de industrialização de alimentos líquidos. Atrelada à inativação de micro-organismos e enzimas pela alta temperatura, está a perda de qualidade do produto; portanto, o estudo e avaliação deste tipo de processo é fundamental para garantir a inocuidade e a melhora da qualidade do produto. Neste trabalho foi desenvolvida a modelagem matemática de um processo térmico contínuo em trocadores bitubulares para determinação da distribuição da temperatura média do produto e da letalidade sobre um atributo de segurança ou qualidade. No modelo, foram considerados os trocadores de aquecimento e de resfriamento, bem como o tubo de retenção. Admitiu-se regime permanente, escoamento pistonado e leva-se em conta a troca de energia com o ambiente. Para a aplicação do modelo, foi adotado um sistema em escala de laboratório com vazão de processamento entre 10 e 50 L/h, trocadores com quatro módulos de troca térmica e área total de 0,13 m² e sistema de indicação e aquisição de dados de temperatura. Como fluidos de trabalho foram usados: mistura de glicerina/água 80 % (Newtoniano) e solução 1 % de carboxi-metil-celulose (CMC, não-Newtoniano). Fluidos e utilidade foram água quente pressurizada e água gelada. Os parâmetros de troca térmica do modelo foram ajustados com sucesso através de ensaios experimentais. Foram ajustados: 1) coeficientes de convecção natural do ar sobre as seções de aquecimento e de resfriamento; 2) parâmetros da correlação de Nusselt x Reynolds para o coeficiente de convecção dos fluidos de trabalho; 3) coeficiente global de troca térmica com o ambiente no tubo de retenção. A validação do modelo ajustado foi realizada através da comparação das distribuições de temperatura experimental com a predição do modelo. A letalidade, levando em conta o tempo espacial no percurso do produto foi calculada e avaliada, indicando importante contribuição da seção de aquecimento e forte influência da elevação de temperatura na entrada do tubo de retenção para compensar as perdas para o ambiente. O modelo proposto mostra-se útil para a avaliação de processos térmicos em sistemas tubulares. / The continuous thermal processing using heat exchangers is a very usual form of industrialization of liquid foods. Linked to the inactivation of microorganisms and enzymes by high temperature is the loss of product quality; thus, the study and evaluation of this type of process is critical to ensure the safety and improve product quality. In this work, it was developed a mathematical model of a continuous process with tubular heat exchangers to determine the distribution of the average temperature of the product and the lethality considering a safety or quality attribute. In the model, are considered the exchangers for heating and cooling and the holding tube. It was assumed steady state plug-flow and it was taken into account the energy exchange with the ambient air. For the application of the model, it was adopted a laboratory system with processing flow rate between 10 and 50 L/h, exchangers with four heat transfer modules and total area of 0.13 m² and a temperature indication and acquisition system. The working fluids used were: a mixture of glycerol/water 80 % (Newtonian) and a 1 % solution of carboxymethylcellulose (CMC, non-Newtonian). Utility fluids were pressurized hot water and cold water. The heat transfer parameters of the model were adjusted successfully using the experimental data. Were adjusted: 1) the coefficients of natural convection of the air over the heating and cooling sections; 2) the parameters of the Nusselt x Reynolds correlation for the convective coefficient of the working fluid; 3) the overall heat exchange coefficient between the product and the ambient air in the holding tube. The validation of the fitted model was performed by comparing the experimental temperature distributions with the prediction from the model. Lethality, taking into account the space-time in the path of the product was calculated and evaluated, indicating a significant contribution of the heating section and a strong influence on the temperature rise in the entrance of the holding tube to compensate for losses to the surroundings. The model proves useful for the evaluation of thermal processes in tubular systems.

G-quadruplexes are non-canonical nucleic acid secondary structures of increasing biological and medicinal interest due to their proposed physiological functions in transcription, replication, translation and telomere biology. Aberrant G4 formation and stabilisation have been linked to genome instability, cancer and other diseases. However, the specific genes and pathways involved are largely unknown, and the work within this thesis aims to investigate this. Stabilisation of G4s by small molecules can perturb G4-mediated processes and initial studies suggest that this approach has chemotherapeutic potential. I therefore also aimed to identify cell genotypes sensitive to G4-ligand treatment that may offer further therapeutic opportunities. To address these aims, I present the first unbiased genome-wide genetic screen in cells where genes were silenced via short-hairpin RNAs (shRNAs) whilst being treated with either PDS or PhenDC3, two independent G4-stabilising small molecules. I explored gene deficiencies that enhance cell death (sensitisation) or provide a growth advantage (resistance) in the presence of these G4-ligands. Additionally, I present a validation screen, comprising hits uncovered via genome-wide screening, and also the use of this in another cell line of different origin. Sensitivities were enriched in DNA replication, cell cycle, DNA damage repair, splicing and ubiquitin-mediated proteolysis proteins and pathways. Ultimately, I uncovered four synthetic lethalities BRCA1, TOP1, DDX42, GAR1, independent of cell line and ligand. These were validated with three G4-stabilising ligands (PDS, PhenDC3 and CX-5461) using an independent siRNA approach. The latter siRNA methodology was used to screen 12 PDS derivatives with improved medicinal chemistry properties and ultimately identified SA-100-128, as a lead compound. The mechanism behind synthetic lethality with G4-stabilising ligands was explored further for DDX42, which I show has in vitro affinity for both RNA- and DNA-G4s and may represent a previously unknown G4-helicase. Also within this thesis, gene deficiencies that provided a growth advantage to PDS and/or PhenDC3 as uncovered by genome-wide and focused screening were explored. These showed enrichment in transcription, chromatin and lysosome-associated genes. The resistance phenotype of three gene deficiencies, TAF1, DDX39A and ZNF217 was further supported by additional siRNA experiments. Overall, I satisfied the primary aims and established many novel synthetic lethal and resistance interactions that may represent new therapeutic possibilities. Additionally, the results expand our knowledge of G4-biology by identifying genes, functions and subcellular locations previously not known to involve or regulate G4s.

<p>African medicinal plants are commonly used throughout Africa to treat a variety of ailments including wounds and ulcers, cough and chest complaints, gingivitis, fever and gonorrhoea, indication all related to infection and inflammation. In screening several plant species from an inventory of common medicinal plants from both South and West Africa for diverse medicinal purposes, 6 plants were selected because of their interesting and useful ethnomedicinal values.</p>