No description available.

Intestinal cylindrical growth peaks in mice a few weeks after birth, simultaneously with crypt fission activity. It nearly stops after weaning and cannot be reactivated later. Transgenic mice expressing Cd97/Adgre5 in the intestinal epithelium develop a mega-intestine with normal microscopic morphology in adult mice. Here, we demonstrate premature intestinal differentiation in Cd97/Adgre5 transgenic mice at both the cellular and molecular levels until postnatal day 14. Subsequently, the growth of the intestinal epithelium becomes activated and its maturation suppressed. These changes are paralleled by postnatal regulation of growth factors and by an increased expression of secretory cell markers, suggesting growth activation of non-epithelial tissue layers as the origin of enforced tissue growth. To understand postnatal intestinal growth mechanistically, we study epithelial fate decisions during this period with the use of a 3D individual cell-based computer model. In the model, the expansion of the intestinal stem cell (SC) population, a prerequisite for crypt fission, is largely independent of the tissue growth rate and is therefore not spontaneously adaptive. Accordingly, the model suggests that, besides the growth activation of non-epithelial tissue layers, the formation of a mega-intestine requires a released growth control in the epithelium, enabling accelerated SC expansion. The similar intestinal morphology in Cd97/Adgre5 transgenic and wild type mice indicates a synchronization of tissue growth and SC expansion, likely by a crypt density-controlled contact inhibition of growth of intestinal SC proliferation. The formation of a mega-intestine with normal microscopic morphology turns out to originate in changes of autonomous and conditional specification of the intestinal cell fate induced by the activation of Cd97/Adgre5.

Milk fat globule membrane surrounds the fat droplets of milk. It is a biopolymer containing primarily membrane glycoproteins and polar lipids which contribute to its properties as a possible neutraceutical. The aims of the studies were to determine if dietary milk fat globule membrane: (1) confers protection against colon carcinogenesis; and (2) promotes gut mucosal integrity while decreasing inflammation compared to diets containing corn oil or anhydrous milk fat. Aim 1. Three dietary treatments differing only in the fat source were formulated: (1) AIN-76A, corn oil; (2) AIN-76A, anhydrous milk fat; and (3) AIN-76A, 50% milk fat globule membrane, 50% anhydrous milk fat. Each diet was formulated to contain 50 g/kg diet of fat and to be identical in macro and micro nutrient content. To assess protection against colon carcinogenesis, male, weanling Fischer-344 rats were randomly assigned to one of the three dietary treatments. Animals were injected with 1,2-dimethylhydrazine once per week at weeks 3 and 4. After 13 weeks animals were sacrificed, colons were removed, and aberrant crypt foci were counted by microscopy. Rats fed the milk fat globule membrane diet (n = 16) had significantly fewer aberrant crypt foci (20.9 ± 5.7) compared to rats fed corn oil (n = 17) or anhydrous milk fat (n = 16) diets (31.3 ± 9.5 and 29.8 ± 11.4 respectively; P < 0.05). Aim 2. Male BALB/c mice were randomly assigned to one of two diets: AIN- 76A, corn oil or AIN-76A, 50% milk fat globule membrane, 50% anhydrous milk fat. After 5 weeks mice were injected with saline vehicle control or lipopolysaccharide and gavaged with dextran-FITC. To assess gut mucosal integrity and inflammation, serum samples were assayed for dextran-FITC 24 and 48 hours after gavage, and a panel of 16 cytokine concentrations was analyzed. Serum concentrations of IL-6, IL-10, IL-17, MCP-1, IFNγ, and TNFα decreased and gut permeability decreased 45% in lipopolysaccharide challenged mice fed milk fat globule membrane diet compared to control diet at 24 hours (P < 0.05). Overall, the results of these aims suggest that diets containing milk fat globule membrane are protective against colon carcinogenesis, inhibit the inflammatory response, and protect against gastrointestinal stress.

Orientador: Dirlei Antonio Berto / Banca: Ana Silvia Alves Meira Tavares Moura / Banca: Caio Abércio da Silva / Resumo: Foram realizados dois experimentos: no primeiro utilizaram-se 96 leitões desmamados com idade média de 21 dias, num delineamento em blocos com arranjo fatorial dos tratamentos 2 x 2 ( duas fontes de carboidratos e duas classes de peso ao desmame). No segundo foram utilizados 48 leitões, num delineamento em blocos com arranjo fatorial 2 x 2 x 2 x 3 (duas classes de pesos ao desmame x duas fontes de carboidratos x duas porções do intestino delgado x três épocas de abate). Portanto, no modelo estatístico foram usados os efeitos fixos de peso, fontes de carboidratos, porções do intestino delgado, épocas de abate e suas respectivas interações; e o efeito aleatório de blocos. O objetivo deste estudo foi avaliar os efeitos da substituição da lactose pela maltodextrina nas rações de leitões desmamados, com diferentes pesos, sobre o consumo diário de ração, ganho diário de peso, conversão alimentar, incidência de diarreia, altura das vilosidades, profundidade das criptas e espessura de mucosa. No primeiro experimento, nos períodos de 0 a 17 e 0 a 29 dias após o desmame constatou-se efeito da classe de peso, no ganho diário de peso e no consumo diário de ração dos leitões, ou seja, os animais mais pesados ao desmame apresentaram maiores consumo diário de ração e ganho diário de peso em relação aos animais mais leves. No segundo experimento, verificou-se que a maltodextrina determinou aumentos na espessura média da mucosa intestinal dos leitões, independente do peso, e na profundidade média das criptas apenas nos animais leves. A maltodextrina pode ser usada como uma alternativa para substituir a lactose nas rações de leitões desmamados, pois não afeta negativamente o desempenho e a maioria dos parâmetros morfométricos do intestino. / Abstract: Two trials were conducted: in the first trial, were used, 96 weaning pigs at the age of about 21 days, in a 2 × 2 factorial arrangement (two sources of carbohydrate: lactose and maltodextrin and two weaning weight classes: light, from 4,50 to 5,20 kg, and heavy, from 5,90 to 6,60 kg). In the second trial, 48 pigs, in a 2 x 2 x 2 x 3 factorial arrangement (two weaning weight classes x two sources of carbohydrate x two portions of the small intestine x three slaughter times). Therefore, in the statistical model the fixed effect of weight, sources of carbohydrate, portions of the small intestine, times of slaughter and its respective interactions; and the random effect of blocks. The objective of this study was to evaluate the effects of maltodextrin diets in weaning pigs of different weights on feed intake, feed:gain ratio, weight gain, diarrhea incidence, villus height, crypt depth and mucous membrane height. In the first trial, from 0-17 days and from 0-29 days after the weaning effects of weight classes, were detected on daily weight gain, and daily feed intake. The heaviest animals at weaning showed the best results. In the second trial, we verified that maltodextrin determined an increase in the average thickness of the intestinal mucosa, regardless of weight classes, and the increase in the average depth of the crypt, only in the highter animals. Maltodextrin can be used as an alternative to lactose in diets of weaning pigs, as it doesn't affect negatively the performance neither the morfometric parameters of the intestine. / Mestre

No description available.

Submitted by Michele Mologni (mologni@unoeste.br) on 2019-01-29T18:40:59Z No. of bitstreams: 1 Sandra Cristina Genaro.pdf: 1632390 bytes, checksum: 89f6ec224705d20a5ce967976b70a4c3 (MD5) / Made available in DSpace on 2019-01-29T18:40:59Z (GMT). No. of bitstreams: 1 Sandra Cristina Genaro.pdf: 1632390 bytes, checksum: 89f6ec224705d20a5ce967976b70a4c3 (MD5) Previous issue date: 2018-11-22 / Among the existing types, colorectal cancer (CRC) affects approximately one million people per year, considered the second most common cause of death among women and the third most prevalent in men. Risk factors are genetic syndromes; inflammatory bowel diseases; family history; sedentary lifestyle; obesity, low fiber, high saturated fats, smoked foods or built-in food, excess red meat (> 300g/week), preparation mode in high temperatures and on the ember; medications; smoking, and excessive alcohol. These factors alter the intestinal microbiome which is colonized by pathogenic bacteria capable of provoking a local inflammatory response that, in chronic cases, activates carcinogenic components. Probiotics have increasingly attracted the attention of researchers in order to understand their action in the intestinal microbiota, aiding in the prevention and treatment of colorectal cancer. The objective of this study was to evaluate the effect of a probiotic In aggressiveness of the chemically induced colorectal tumor in rats. Twenty-five male Fisher 344 rats, 250 g, receiving ration and water ad libitum, were randomly divided into 5 groups (5 rats/group): GControl, without treatment; GTumor, tumor induction; GTumor + 5FU, tumor induction, 5-fluorouracil applied; GTumor + prob, tumor induction, supplemented with probiotic; GTumor + 5-FU + prob, tumor induction, applied 5-fluorouracil, supplemented with probiotic. For tumor induction, the animals received four intraperitoneal injections of the carcinogen 1.2-dimethylhidrazine (DMH) at the dose of 20 mg/kg body weight, being two applications per week, for four consecutive week. A 15-day interval was given and DMH applications were repeated for another four week. After 5 weeks of the last dose of the carcinogen, the treatment was initiated for ten consecutive weeks, applying a weekly dose of 15 mg/kg body weight of 5-fluorouracil, Intraperitoneal route and commercial probiotic containing Lactobacillus and Bifidobacterium at the dose of 1x109 UFC, administered by gavage, daily. Datas were analyzed by the analysis of variance One Way and the averages compared by the test of Dunnett. Used Software Statistical GraphPad Prism. The histopathologic analyses evaluated by the Chi-square ratio test. It was considered type-I error of 5% as statistically significant. Compared to the GTumor, the GTumor + prob (P < 0,0373) and GTumor + 5-FU + prob (P < 0,0003) showed attenuating effect on the aggressiveness of the colorectal tumor, with a reduction in the count of Aberrant Crypts Foci; and lower percentage of malignant neoplastic lesions in the GTumor + prob (40% of low-grade tubular adenoma, 40% of carcinoma in situ, 20% of low-grade adenocarcinoma) and GTumor + 5-FU + prob (40% of low-grade tubular adenoma and 60% of carcinoma in situ). The suplementation with probiotic has the potential to decrease the formation of aberrant crypts and mitigate the progression of tumor malignancy, potentializing the antitumor effect of 5-fluorouracil chemotherapy in the colic segments. / O câncer colorretal (CCR) acomete aproximadamente um milhão de pessoas por ano, considerado a segunda causa de morte mais comum entre mulheres e a terceira mais prevalente em homens. Os fatores de risco incluem as síndromes genéticas; doenças inflamatórias intestinais; história familiar; sedentarismo; obesidade, alimentação pobre em fibras, rica em gorduras saturadas, alimentos defumados ou embutidos, carne vermelha em excesso (>300g/sem), modo de preparação em altas temperaturas e na brasa; medicamentos; tabagismo e bebida alcoólica em excesso. Esses fatores levam a alteração da microbiota intestinal a qual é colonizada por bactérias patogênicas capazes de provocar uma resposta inflamatória local que, em casos crônicos, ativam componentes cancerígenos. Os probióticos têm atraído cada vez mais a atenção de pesquisadores com o intuito de compreender a sua ação na microbiota intestinal, auxiliando na prevenção e tratamento do câncer colorretal. O objetivo desse estudo foi avaliar o efeito de um probiótico na agressividade do tumor colorretal induzido quimicamente em ratos. Vinte e cinco ratos machos Fisher 344, 250 g, recebendo ração e água ad libitum, foram divididos aleatoriamente em 5 grupos (5 ratos/grupo): GControle, sem tratamento; GTumor, indução do tumor; GTumor+5FU, indução do tumor, aplicado 5-Fluorouracil; GTumor+Prob, indução do tumor, suplementado com probiótico; GTumor+5-FU+Prob, indução do tumor, aplicado 5-Fluorouracil, suplementado com probiótico. Para indução do tumor colorretal, os animais receberam quatro injeções intraperitoneais do carcinógeno 1,2-dimetilhidrazina (DMH) na dose de 20 mg/kg de peso corporal, sendo duas aplicações por semana, durante quatro semanas consecutivas. Deu-se um intervalo de 15 dias e as aplicações de DMH foram repetidas por mais quatro semanas. Após 5 semanas da última dose do carcinógeno, iniciou-se o tratamento por dez semanas consecutivas, com 5-Fluorouracil: uma dose de 15 mg/kg por semana, via intraperitoneal e probiótico comercial: 1x109 UFC, diariamente, por gavagem. Os dados foram analisados pela Análise de Variância One Way e as médias comparadas pelo teste de Dunnett. Utilizado software estatístico GraphPad Prism. As análises histopatológicas avaliadas pelo teste de proporção Qui-quadrado. Foi considerado erro tipo-I de 5% como estatisticamente significante. Comparados com o GTumor, o GTumor+Prob (p<0,0373) e GTumor+5-FU+Prob (p<0,0003) exibiram efeito atenuante na agressividade do tumor colorretal obervando redução na contagem de Focos de Criptas Aberrantes; e menor porcentagem de lesões neoplásicas malignas no GTumor+Prob (40% de adenoma tubular de baixo grau, 40% de carcinoma in situ, 20% de adenocarcinoma de baixo grau) e GTumor+5-FU+Prob (40% de adenoma tubular de baixo grau e 60% de carcinoma in situ). Concluimos que a suplementação com probiótico tem potencial para diminuir a formação de criptas aberrantes e amenizar a progressão da malignidade do tumor, potencializando o efeito antitumoral da quimioterapia com 5-Fluorouracil nos segmentos cólicos.

Nous assistons au développement rapide des solutions de diffusion de contenus sur des systèmes, où en plus des traditionnelles corruptions de l'information dans les couches basses, se pose le problème des pertes de paquets d'informations. Le besoin de fiabiliser ces systèmes de transmission a conduit à l'émergence de codes correcteurs d'effacements, qui grâce à l'ajout d'informations redondantes, permettent de reconstruire l'information perdue. Dans cette thèse nous abordons le problème de la conception de codes à effacements ayant de bonnes capacités de correction et dont les algorithmes de décodage possèdent une complexité permettant d'atteindre des débits élevés. Pour cela, nous avons choisi de travailler conjointement sur les codes et sur leur implémentation au sein d'un codec logiciel, et plus particulièrement sur les algorithmes de décodage. La première partie de nos travaux montre que des solutions basées sur les codes “Low-Density Parity-Check” (LDPC) permettent d'obtenir d'excellents résultats. En particulier lorsque ces codes sont décodés avec un décodeur hybride IT/ML qui permet d'obtenir des capacités de corrections proches de l'optimal, tout en conservant une complexité acceptable. De plus, nous montrons que grâce à l'utilisation de codes LDPC structurés la complexité du décodage ML peut être largement réduite. Nous étudions ensuite le développement de systèmes combinant un code à effacements et des fonctionnalités cryptographiques. Les systèmes résultants permettent de réduire la complexité globale du système tout en garantissant un niveau de sécurité élevé. Finalement, nous présentons une technique de tolérance aux fautes basée sur des codes correcteurs pour des applications de multiplications matricielles. Cette technique nous permet de construire un système de calcul distribué sur plateforme P2P tolérant efficacement aussi bien les pannes franches que les erreurs malicieuses.

In an experiment to understand colon carcinogenesis, all animals were exposed to a carcinogen while half the animals were also exposed to radiation. Spatially, we measured the existence of aberrant crypt foci (ACF), namely morphologically changed colonic crypts that are known to be precursors of colon cancer development. The biological question of interest is whether the locations of these ACFs are spatially correlated: if so, this indicates that damage to the colon due to carcinogens and radiation is localized. Statistically, the data take the form of binary outcomes (corresponding to the existence of an ACF) on a regular grid. We develop score??type methods based upon the Matern and conditionally autoregression (CAR) correlation models to test for the spatial correlation in such data, while allowing for nonstationarity. Because of a technical peculiarity of the score??type test, we also develop robust versions of the method. The methods are compared to a generalization of Moran??s test for continuous outcomes, and are shown via simulation to have the potential for increased power. When applied to our data, the methods indicate the existence of spatial correlation, and hence indicate localization of damage. Assuming that there are correlations in the locations of the ACF, the questions are how great are these correlations, and whether the correlation structures di?er when an animal is exposed to radiation. To understand the extent of the correlation, we cast the problem as a spatial binary regression, where binary responses arise from an underlying Gaussian latent process. We model these marginal probabilities of ACF semiparametrically, using ?xed-knot penalized regression splines and single-index models. We ?t the models using pairwise pseudolikelihood methods. Assuming that the underlying latent process is strongly mixing, known to be the case for many Gaussian processes, we prove asymptotic normality of the methods. The penalized regression splines have penalty parameters that must converge to zero asymptotically: we derive rates for these parameters that do and do not lead to an asymptotic bias, and we derive the optimal rate of convergence for them. Finally, we apply the methods to the data from our experiment.

In an experiment to understand colon carcinogenesis, all animals were exposed to a carcinogen while half the animals were also exposed to radiation. Spatially, we measured the existence of aberrant crypt foci (ACF), namely morphologically changed colonic crypts that are known to be precursors of colon cancer development. The biological question of interest is whether the locations of these ACFs are spatially correlated: if so, this indicates that damage to the colon due to carcinogens and radiation is localized. Statistically, the data take the form of binary outcomes (corresponding to the existence of an ACF) on a regular grid. We develop score??type methods based upon the Matern and conditionally autoregression (CAR) correlation models to test for the spatial correlation in such data, while allowing for nonstationarity. Because of a technical peculiarity of the score??type test, we also develop robust versions of the method. The methods are compared to a generalization of Moran??s test for continuous outcomes, and are shown via simulation to have the potential for increased power. When applied to our data, the methods indicate the existence of spatial correlation, and hence indicate localization of damage. Assuming that there are correlations in the locations of the ACF, the questions are how great are these correlations, and whether the correlation structures di?er when an animal is exposed to radiation. To understand the extent of the correlation, we cast the problem as a spatial binary regression, where binary responses arise from an underlying Gaussian latent process. We model these marginal probabilities of ACF semiparametrically, using ?xed-knot penalized regression splines and single-index models. We ?t the models using pairwise pseudolikelihood methods. Assuming that the underlying latent process is strongly mixing, known to be the case for many Gaussian processes, we prove asymptotic normality of the methods. The penalized regression splines have penalty parameters that must converge to zero asymptotically: we derive rates for these parameters that do and do not lead to an asymptotic bias, and we derive the optimal rate of convergence for them. Finally, we apply the methods to the data from our experiment.

Abstract In the Western world, colorectal cancer (CRC) is one of the most common cancers and causes of cancer deaths. It is estimated that up to a third of CRCs represent a recently defined subtype, serrated adenocarcinoma (SAC), which develops via the serrated pathway and differs from conventional cancer by molecular, histological, and clinicopathological characteristics. The oncogenic mutation of BRAF V600E is characteristic to the serrated pathway lesions, and VE1 is a novel antibody that has been reported to recognize this mutated BRAF protein. In these studies, two independent cohorts of CRCs and a cohort of 922 colorectal polyps (545 patients) consecutively removed in Oulu University Hospital were utilized to study potential immunohistochemical markers (annexin A10 and VE1) as markers for the serrated pathway lesions, to investigate the presence of ectopic crypt foci (ECF) in different colorectal polyps and CRCs, and to study the network of determinants and the clinical impact of tumor necrosis with special regard to SAC. VE1 immunohistochemistry was found a sensitive and accurate method in the detection of BRAF V600E mutation with potential applications in the recognition of the BRAF V600E-mutated SACs. Annexin A10 immunohistochemistry was indicated to be a marker with high specificity for the serrated pathway lesions. ECF were found to be frequently encountered in addition to traditional serrated adenomas also in the tubular, tubulovillous and villous adenomas. Tumor necrosis in CRC was associated with high tumor stage and inversely associated with the serrated histology. High tumor necrosis percentage correlated with poor survival in CRC independently of other clinicopathological factors. In conclusion, these studies add to the knowledge of the molecular and histological features of SAC and its precursors. The results suggest that VE1 and ANXA10 immunohistochemistry may help in the recognition of the serrated pathway lesions. ECF can be found in other colorectal polyps in addition to traditional serrated adenomas. Tumor necrosis represents a relevant histomorphological prognostic indicator in CRC. / Tiivistelmä Paksu-peräsuolisyöpä on yksi yleisimmistä syövistä länsimaissa. Arviolta kolmasosaa kaikista paksu-peräsuolisyövistä edustava sahalaitainen adenokarsinooma eroaa tavallisesta adenokarsinoomasta molekulaaristen muutostensa sekä histologisten ja kliinispatologisten piirteidensä perusteella. BRAF-onkogeenin V600E-mutaatiota tavataan vain paksu-peräsuolisyövän sahalaitaisen kehittymisreitin muutoksissa ja VE1-immunohistokemian on todettu tunnistavan tämän mutatoituneen BRAF-proteiinin. Tutkimuksessa käytettiin kahta itsenäistä paksu-peräsuolisyöpäaineistoa sekä polyyppiaineistoa, joka käsitti 922 Oulun yliopistollisessa sairaalassa peräkkäisissä kolonoskopioissa poistettua paksu-peräsuolen polyyppia (545 potilasta). Tutkimuksen tarkoituksena oli selvittää kahden immunohistokemiallisen merkkiaineen (VE1 ja annexin A10) spesifisyyttä sahalaitaiselle adenokarsinoomalle ja sen esiastemuutoksille, ektooppisten kryptafokusten esiintymistä paksu-peräsuolen polyypeissa sekä kasvaimen nekroosiin yhteydessä olevia tekijöitä ja nekroosin ennustevaikutusta. VE1-immunohistokemia oli sekä sensitiivinen että spesifinen BRAF V600E-mutaation toteamisessa, minkä vuoksi sitä voidaan käyttää BRAF V600E-mutatoituneiden sahalaitaisten adenokarsinoomien tunnistamisessa. Annexin A10-immunohistokemia osoittautui spesifiseksi sahalaitaisen kehittymisreitin muutosten toteamissa. Ektooppisia kryptafokuksia havaittiin traditionaalisen sahalaita-adenooman lisäksi myös tubulaarisissa, tubulovillooseissa ja villooseissa adenoomissa. Kasvaimen nekroosi oli vähäisempää sahalaitaisessa adenokarsinoomassa sekä matalan levinneisyysasteen kasvaimissa. Runsas nekroosin määrä oli kasvaimen levinneisyydestä riippumatta yhteydessä huonompaan ennusteeseen. Tutkimus lisää tietoa sahalaitaisesta adenokarsinoomasta ja sen esiastemuutoksista. Tulokset osoittavat, että VE1 ja annexin A10 -immuno¬histokemia auttaa sahalaitaisen kehittymisreitin muutosten tunnistamisessa; ektooppisia kryptafokuksia voidaan nähdä traditionaalisten sahalaita-adenoomien lisäksi myös muissa paksu-peräsuolen polyypeissa; lisäksi todettiin, että kasvaimen nekroosin määrällä on vaikutusta paksu-peräsuolisyövän ennusteen arvioinnissa.