Class of 2017 Abstract / Objectives: To determine if the addition of oral alvimopan, liposomal bupivacaine and intravenous acetaminophen as part of a comprehensive enhanced recovery after surgery (ERAS) program decreases length of stay, recovery time and narcotic/acetaminophen use without affecting colorectal surgery patient outcomes. Methods: Patients were compared before and after the implementation of alvimopan, liposomal bupivacaine and intravenous acetaminophen with an ERAS program. The primary outcome was hospital length of stay (measured in hours). Secondary outcomes included change in time to first meal, bowel sounds, and bowel movement (measured in hours), pain scores (visual analog scale 0-10), opioid use (measured in morphine equivalent milligrams), and acetaminophen use (measured in mg). Results: Thirty-seven individuals were included in the pre implementation population and fifty one patients were included in the post implementation population. The mean length of stay decreased from 124.3 hours to 100.2 hours (P equals 0.13) with the addition of the ERAS program with the three medications. The 24 hour morphine equivalent intervals for seventy-two hours following surgery decreased from 125.8 mg (day 1), 81.9 mg (day 2) and 44.5 mg (day 3) to 44.3 mg (day 1), 22.8 mg (day 2) and 13.2 mg (day 3) (P less than 0.005 for each one). Conclusions: The addition of alvimopan, liposomal bupivacaine and intravenous acetaminophen as part of a comprehensive ERAS program decreased length of stay but not significantly. However, the addition of these three medications with the ERAS program changes was associated with a statistically significant decrease in opioid use.

Le corépresseur nucléaire NCOR1 est impliqué dans la régulation transcriptionnelle en interagissant avec les récepteurs à hormones thyroïdiennes et rétinoïques ainsi qu’avec les facteurs de transcription AP-1 et NF-κB au niveau des gènes cibles impliqués dans la réponse inflammatoire intestinale. Par une approche d’immunoprécipitation (IP) couplée à la spectrométrie de masse, CHD8 a été découverte pour agir de manière complémentaire à NCOR1. CHD8 est impliquée dans le remodelage de la chromatine et dans la régulation du cycle cellulaire. Ainsi, le projet de recherche visait à comprendre l’interaction et les rôles fonctionnels de CHD8 et de NCOR1 ainsi que l’impact physiologique de la perte d’expression de NCOR1 face à un stress épithélial. Pour commencer, nous avons confirmé l’interaction entre CHD8 et NCOR1 dans différents types cellulaires tels que les 18Co, Caco-2/15 et HT-29. Ensuite, nous avons diminué l’expression de NCOR1 et CHD8 dans les cellules HT-29 et Caco-2/15 à l’aide de shRNA et nous avons observé une diminution de croissance cellulaire intermédiaire pour la perte de CHD8 comparativement à une diminution plus drastique pour NCOR1. L’effet intermédiaire sur la croissance cellulaire peut être dû à un effet de compensation par la petite forme de CHD8 (CHD8S) puisque le shRNA utilisé cible uniquement la grande forme de CHD8 (CHD8L). Avec cette diminution commune de croissance cellulaire, une question s’est imposée à savoir quelle est l’implication de l’interaction entre CHD8 et NCOR1 dans ce phénomène. Nous avons séparé NCOR1 en protéines correspondant à ces différents domaines et par IP suivies d’immunobuvardages, nous avons déterminé que le premier domaine de répression de NCOR1 (RD1) interagissait avec la forme complète de CHD8 au niveau du noyau. Nous avons ensuite utilisé un modèle murin où il y a une perte d’expression de NCOR1 (NCOR1ΔE11ΔCEI) avec l’aide d’un modèle où la Cre-recombinase est exprimée sous le promoteur de la villine. Nous avons ensuite traité les souris NCOR1ΔE11ΔCEI et contrôles au DSS 3% afin d’induire des lésions aux cellules épithéliales intestinales. Ceci permet l’étude de la suceptibilité au DSS des souris contrôles et NCOR1ΔE11ΔCEI. Ainsi, CHD8 et NCOR1 ont des rôles fonctionnels communs qui pourrait être attribué à leur interaction, CHD8-NCOR1 (RD1). Cette nouvelle mécanistique permettrait donc de réguler la transcription de certains gènes cibles impliqués dans le cancer colorectal.

Although there is consistent evidence of an inverse association between physical activity and colorectal cancer (CRC), it is unclear whether physical activity has to be lifelong in order to protect against CRC, or whether there are critical time periods in which physical activity is most protective. This thesis investigated the association between recreational physical activities in specific age periods and across the lifetime and CRC risk in data from a population-based case control study (n=1395) in Newfoundland and Labrador. There were no significant associations between recreational physical activity at any age period or across the lifetime. Lack of association with activity in early adulthood is consistent with other studies in which this has been investigated. Lack of association in later life and across the lifetime may in part be explained by low levels of recreational physical activity, with only 30% of participants meeting World Cancer Research Fund cancer prevention recommendations.

Objective: To determine the clinical validity of family history (FH) in colorectal cancer (CRC) risk classification. Methods: The Assessment of Risk of Colon Tumors In Canada case-control dataset was used to develop regression models associating risk factors with CRC in Ontario adults. Two regression models (‘clinically-driven’ based on a previously published tool, and data-driven) examined discrimination between CRC cases and controls, with and without the inclusion of FH as a risk variable. Discrimination was assessed using the area under the receiver operator characteristics curve. Results: For males, with the addition of FH, there were statistically significant yet quantitatively modest improvements in both models (3.7% clinically-driven, 6.8% data-driven). For females, while FH was a statistically significant predictor of CRC status in the data-driven model, the improvement in discrimination was not significant in either model. Conclusion: FH provides very small improvement in model discrimination beyond other standard CRC risk factors.

Class of 2017 Abstract / Objectives: To determine if the addition of oral alvimopan, liposomal bupivacaine and intravenous acetaminophen as part of a comprehensive enhanced recovery after surgery (ERAS) program decreases length of stay, recovery time and narcotic/acetaminophen use without affecting colorectal surgery patient outcomes. Methods: Patients were compared before and after the implementation of alvimopan, liposomal bupivacaine and intravenous acetaminophen with an ERAS program. The primary outcome was hospital length of stay (measured in hours). Secondary outcomes included change in time to first meal, bowel sounds, and bowel movement (measured in hours), pain scores (visual analog scale 0-10), opioid use (measured in morphine equivalent milligrams), and acetaminophen use (measured in mg). Results: Thirty-seven individuals were included in the pre implementation population and fifty one patients were included in the post implementation population. The mean length of stay decreased from 124.3 hours to 100.2 hours (P equals 0.13) with the addition of the ERAS program with the three medications. The 24 hour morphine equivalent intervals for seventy-two hours following surgery decreased from 125.8 mg (day 1), 81.9 mg (day 2) and 44.5 mg (day 3) to 44.3 mg (day 1), 22.8 mg (day 2) and 13.2 mg (day 3) (P less than 0.005 for each one). Conclusions: The addition of alvimopan, liposomal bupivacaine and intravenous acetaminophen as part of a comprehensive ERAS program decreased length of stay but not significantly. However, the addition of these three medications with the ERAS program changes was associated with a statistically significant decrease in opioid use.

Le corépresseur nucléaire NCOR1 est un répresseur transcriptionnel qui régule l’expression génique en s’associant à des récepteurs nucléaires ou à des facteurs de transcription comme AP-1 et NF-B. Ce projet de recherche visait à déterminer comment NCOR1 régule la prolifération et la réponse inflammatoire dans les cellules épithéliales intestinales (CEIs). Nous avons utilisé deux modèles murins de délétion du gène Ncor1 (Ncor1ID et Ncor1Exon11) ainsi que la Cre-recombinase sous le contrôle du promoteur du gène Vil1 (12.4KbVilCre) afin d’invalider le gène Ncor1 au niveau des CEIs (Ncor1IDΔCEI et Ncor1Exon11ΔCEI). Nous avons induit une réponse inflammatoire dans les CEIs en utilisant de l’IL-1 et du LPS. Nous avons observé que l’expression de NCOR1 est augmentée dans les CEIs lors de la réponse inflammatoire. Nous avons également traité les souris invalidées pour le gène Ncor1 avec du DSS afin d’induire une colite chimique expérimentale. Nous avons observé que les animaux Ncor1IDΔCEI et Ncor1Exon11ΔCEI sont plus susceptibles que les témoins. Nous avons analysé l’expression génique chez les animaux Ncor1IDΔCEI et Ncor1Exon11ΔCEI. L’analyse des gènes modulés dans les animaux Ncor1IDΔCEI a révélé que l’expression de la Retnlb est augmentée chez ces animaux, ce qui suggère un dérèglement dans la microflore. Dans les animaux Ncor1Exon11ΔCEI, nous avons noté que l’expression du gène Ido1, un puissant immunosuppresseur, est augmentée et permettrait possiblement à ces animaux de se maintenir dans un état homéostatique en absence de stress. Lorsque nous avons diminué l’expression de NCOR1 dans les CEIs à l’aide de shARN (shNCOR1_655), nous avons observé que celles-ci arrêtent de proliférer et sont sénescentes. De plus, nous avons remarqué une induction de molécules inflammatoires associées au SASP dans ces cellules. Nous avons analysé le transcriptome des cellules shNCOR1_655. Nous avons identifié le facteur de pluripotence SOX2 comme étant induits lorsque l’expression de NCOR1 est diminuée. Finalement, nous avons utilisé la technologie SILAC et la spectrométrie de masse afin de déterminer la composition du complexe de répression de NCOR1 dans les CEIs. Nous avons identifié de nouveaux partenaires d’interaction potentiels de NCOR1.

Introduction: Although colorectal cancer (CRC) is the second leading cause of cancer-related deaths among men and women combined in the United States, only 61% of eligible adults are up-to-date with current screening recommendations. Effective screening is hindered by numerous barriers and underutilization of evidence-based interventions. The purpose of this clinical dissertation project was to increase CRC screening in the rural community of Elgin, North Dakota, determine the efficacy of providing targeted educational handouts and endorsement letters, and to identify screening barriers and facilitators. Methods: Educational handouts and screening endorsement letters were developed and distributed to 75 average risk patients (without personal or family history of CRC or certain types of polyps, personal history of inflammatory bowel disease, personal history of receiving radiation to the abdomen or pelvic region, and confirmed or suspected hereditary CRC syndrome). Additional handouts were placed around the community of Elgin. Patients who presented for CRC screening were sent a questionnaire to determine the impact of the interventions. These 75 patients were also contacted via telephone and completed a questionnaire to identify barriers and facilitators and to highlight the effectiveness of the educational handout and the endorsement letter. Results: Five patients contacted the clinic to receive CRC screening. Ninety-seven percent of patients who recalled receiving the endorsement letter and educational handout (n=32) found the material to be informative, 91% of patients appreciated being contacted on behalf of the clinic, and 59% found the handwritten signature on the endorsement letter to be influential. Fifty-one patients identified screening barriers including (in descending order) lack of awareness/knowledge, cost, unpleasant previous experience, embarrassment, lack of motivation, and fear of abnormal findings. Forty-one patients identified screening facilitators including (in descending order) recommending during office visits, providing education on different screening options, sending letter reminders, calling patients, utilizing social media, and sending email reminders. Conclusion: The clinical dissertation project increased CRC screening compliance in Elgin, ND, identified barriers, and highlighted screening facilitators that can be utilized. Future projects should focus efforts on alleviating these barriers via targeted patient education and provider recommendation in order to decrease CRC morbidity and mortality.

L’argument selon lequel les antibiotiques bactéricides stimulent la formation d'espèces réactives de l’oxygène (ROS pour reactive oxygen species) chez certaines bactéries en augmentant leur activité respiratoire est sujet à discussions. Enterococcus faecalis a des propriétés intéressantes pour tester cette hypothèse. La respiration ne s’observe qu’en présence d'hème ou de fumarate. En l'absence d'hème, E. faecalis produit du superoxyde extracellulaire par l’autoxydation d’une demethylmenaquinone (DMK), un composant de sa chaîne respiratoire associé à sa membrane. En raison de cette propriété, E. faecalis est soupçonné de jouer un rôle dans la cancérogenèse colorectale. Nous montrons dans cette étude que les β–lactamines amplifient significativement la production de ROS. Cette augmentation, dépendante de DMK, n'est observée qu'en l'absence de respiration. Nos résultats pourraient également fournir une explication quant au risque accru de cancer colorectal observé chez des patients traités par des β–lactamines, comme le montrent de récentes études cliniques. / The proposal that bactericidal antibiotics stimulate the formation of reactive oxygen species (ROS) by increasing respiration is still a matter of debate. Enterococcus faecalis has interesting properties to test this hypothesis. Respiration occurs only in the presence of heme or fumarate. In the absence of heme, E. faecalis produces extracellular superoxide through autoxidation of demethylmenaquinone (DMK), a component of its respiratory chain. Due to this ability, E. faecalis is suspected to play a role in colorectal carcinogenesis. We show in this study that β–lactam antibiotics increase significantly the production of ROS. This boost of ROS formation is DMK–dependent and only observed in the absence of respiration. Our results could provide a mechanistic explanation for the observed increased risk of colorectal cancer by β–lactam antibiotics in several recent nested case–control studies.

No description available.

Colorectal cancer (CRC) has the 3rd highest incidence and 2nd highest mortality of all cancers in the United States. These numbers have improved with proper screening and the development of new therapies, but CRC continues to evade detection and resist therapy in late stages. The gut microbiome has emerged as a possible explanation for heterogeneity in this disease. In order to help develop screening techniques and accurate, targeted therapies, this review covers the molecular mechanisms by which the microbiome induces CRC. An analysis of current research has confirmed its physiological roles of maintaining intestinal immune homeostasis and metabolizing products produced by the host. When these functions are impaired, CRC can develop. This may occur through damage to the intestinal barrier, inflammation, and production of genotoxins and other metabolites with carcinogenic potential.