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We have hypothesized that dietary modulation of intestinal miRNA expression may contribute to the chemoprotective effects of nutritional bioactives (fish oil and pectin). Using a rat colon carcinogen model, we determined miRNAs-let-7d, miR-15b, miR-107, miR-191 and miR-324-5p were modulated by fish oil + pectin. We also demonstrated that BACE1 and PTEN are targets of miR-107 and miR-21, respectively. To further elucidate the biological effects of diet and carcinogen on miRNAs, we integrated global miRNAs, total and polysomal gene expression datasets obtained from the above mentioned study and used four computational approaches. We demonstrated that polysomal profiling is tightly related to microRNA changes when compared with total mRNA profiling. In addition, diet and carcinogen exposure modulated a number of microRNAs and complementary gene expression analyses showed that oncogenic PTK2B, PDE4B, and TCF4 were suppressed by the chemoprotective diet at both the mRNA and protein levels. To determine the function of select diet and colon carcinogen modulated miRNAs and to validate their targets, we carried out a series of loss and gain of function experiments along with luciferase reporter assays. We verified that PDE4B and TCF4 are direct targets of miR-26b and miR-203, respectively. PTK2B was determined to be an indirect target of miR-19b. In addition, microRNA physiological function was assessed by examining effects on apoptosis and cell proliferation. To better understand how the colonic stem cell population responds to environmental factors such as diet and carcinogen, we investigated the chemoprotective effects of dietary agents on miRNAs in colonic stem cells obtained from Lgr5-EGFP-IRES-creERT2 knock in mice injected with AOM. We demonstrated that based on relative expression of miR-125a-5p, miR-190b and miR-191 in stem cells vs. daughter cells and differentiated cells, these miRNAs may be stem cell specific miRNAs. We also identified miR-21 to be significantly reduced in stem cells compared to differentiated cells and selectively modulated by these dietary agents in stem cells. In summary, our results indicate for the first time that fish oil plus pectin protect against colon tumorigenesis in part by modulating a subset of miRNAs and their target genes (mRNAs) implicated in the regulation of the colon stem cell niche and tumor development.

The colonoscope is an important tool in diagnosis and management of diseases of the colon. One of the ongoing challenges with this device is that the colonoscope may form a loop together with the colon during the procedure. The result of the loop is that further insertion of the scope in the colon may not be possible. The loop may also cause risks of perforation of the colon and pain in the patient. There are currently several existing devices to overcome loop formation in colonoscopy, some of which have been introduced in clinical work. However, empirical assessment shows that these devices do not work very well. This is the motivation for the research presented in this thesis. In this thesis, a new paradigm of thinking, “doctor-assisted colonoscopy,” is proposed to overcome loop formation. In this new approach, the physician’s role is enhanced with new information that is acquired by sensors outside the human body and inferred from the mathematical model. It is referred to as a kinetic model due to the fact that this model describes the kinetic behaviour of the scope. This thesis is devoted to development of this kinetic model. In this study, the model of the colonoscope and the model of the colon are developed based on the Timoshenko beam theory, and parameters in both models are determined by the experiments. The following conclusions then are made: (1) self-locking of the colonoscope is the most basic cause for a loop to occur, while structural instability of the colonsocope is dependent on the self-locking; (2) both the scope and the colon can be well represented with the Timoshenko beam elements and the Linear Complementary Problem (LCP) formulation derived from Signorini’s law, and Coulom’s law for representation of interactions between the colon and scope is adequate; (3) there are effects from the location, looping, and tip deflection of the scope on flexural rigidity of the scope. Approximately, the flexural rigidity of the CF-Q160L colonoscope ranges from 300 to 650 N•cm2, and its accuracy is proven by a good agreement between the model predicted result and experimental result; (4) Rayleigh damping for the CF-Q160L colonoscope depends more on the mass matrix [M] of the colonoscope than the stiffness matrix [K], which is evident by the large coefficient value of “alpha” (0.3864) and the small coefficient value of “beta” (0.0164). The contributions of this thesis are: (1) the finding that the main cause of the loop is not structural instability of the colonoscope but rather self-locking of the colonoscope, which could lead to design of a “new-generation” colonoscope to avoid the loop; (2) a systematic evaluation of the existing colonoscopy technologies based on the well-proven Axiomatic Design Theory (ADT), which will serve as a guideline for the development of future new colonoscopes in future; (3) an approach to developing a kinetic model of the colonoscope useful to modeling similar objects such as a catheter guide-wire; (4) a novel ex-vivo colonoscopy test-bed with the kinetic and kinematic measurements useful for validation of new designs in colonoscopy technology and also useful for training physicians who perform the colonoscopy procedure; and (5) a new paradigm of thinking for colonoscopy called “doctor-assisted colonoscopy,” which has potential applications to other medical procedures such as catheter-based procedures.

Final publication is available at http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=26018088 / Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(医科学) / 甲第19635号 / 医科博第73号 / 32671 / 京都大学大学院医学研究科医科学専攻 / (主査)教授 妹尾 浩, 教授 渡邊 直樹, 教授 椛島 健治 / 学位規則第4条第1項該当

El diagnóstico histológico de los pólipos colorrectales determina la conducta que tomará el médico especialista con el paciente. Con la aparición de nuevos pólipos en los últimos años, la clasificación histológica se ha tornado más compleja y amplia. Nuestro objetivo es actualizar los conceptos en el diagnóstico histológico de pólipos de colon de una manera clara y de fácil comprensión, especialmente para gastroenterólogos y patólogos.

Objetivo: Determinar la prevalencia y factores de riesgo de síndrome de intestino irritable en estudiantes e internos de medicina de la Universidad Ricardo Palma. Materiales y Métodos: Estudio observacional, analítico, de corte transversal. La población estuvo conformada por los estudiantes e internos de medicina de la Universidad Ricardo Palma durante los meses de Julio y Agosto del 2016. Se realizó un muestreo aleatorio estratificado y se añadió criterios de inclusión y exclusión para obtener el tamaño total de una muestra significativa (207 alumnos). Los datos fueron recolectados mediante una ficha de recolección de datos basadas en los protocolos seguidos por STEPwise. Asimismo, se utilizó la escala de HADS para la detección de ansiedad/depresión clínica. Para el diagnostico de Síndrome de Intestino Irritable se hizo uso del cuestionario autoevaluativo según criterios de ROMA III. Resultados: El sexo femenino fue el género predomínate dentro de los estudiantes de medicina (66.2 %). La edad promedio de la población de estudio fue de 22.23 años. Se halló una prevalencia de 24% de Síndrome de Intestino Irritable. La variedad predominante fue el subtipo mixto (52%), seguido de los subtipos de diarrea (24%), estreñimiento (20%) y no especificado (4%) respectivamente. Los predictores de SII con significancia estadística hallados durante la presente investigación fueron la presencia de ansiedad borderline (p=0.001; OR=4.505; IC 95%: 1.84-11.01), seguido de la presencia de Ansiedad Clínica (p=0.005; OR: 4.332; IC 95%: 1.54-12.12) y el antecedente de enfermedad crónica (p=0.012; OR=2.805; IC 95%: 1.26-6.24) Conclusiones: El sexo femenino, no practicar ejercicio regularmente, dormir menos de 6 horas, el antecedente de enfermedad crónica, el estrés emocional y tanto la ansiedad borderline como la ansiedad clínica son factores de riesgo para el desarrollo de Síndrome de Intestino Irritable. El antecedente de enfermedad crónica, la presencia de ansiedad borderline o clínica calificaron como predictores de esta entidad al ser estadística mente significativos.