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.

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.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24196号 / 医博第4890号 / 新制||医||1060(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊藤 貴浩, 教授 妹尾 浩, 教授 永井 純正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24883号 / 医博第5017号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中島 貴子, 教授 石見 拓, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Metformin is the most common type 2 diabetes therapy, and may also reduce colorectal cancer growth. Currently, two mechanisms driving reduced cancer growth are considered: 1) Regulation of glucose and insulin levels, which may support cancer growth, and 2) Direct entry into cancer cells to activate the AMP-activated kinase (AMPK) protein, and inhibit cell growth pathways. The gut microbiome is the community of commensal microorganisms in the gastrointestinal tract. It is also affected by metformin, and may elevate production of short-chain fatty acids (SCFAs). Therefore, this thesis aimed to clarify how metformin may inhibit colorectal cancer growth and if the microbiome is involved. The hyperglycemic-responsive, murine-derived MC38 colon cancer cell line was used to test these effects. This model was confirmed to experience growth stimulation caused by high-fat diet (HFD) feeding in mice. Daily i.p. injections of metformin (100mg/kg) had no measurable effect on glucose and insulin sensitivity, or MC38 tumor growth. Oral metformin (250mg/kg) improved glucose tolerance and inhibited MC38 tumor growth in HFD-fed mice. To see if the gut microbiome is required for this effect, the antibiotic ampicillin was used to limit the gut microbiome. The addition of ampicillin blunted metformin’s glucose sensitization and tumor inhibition effects. A fecal microbiome transfer model was then used to isolate the role of the microbiome. Conventional mice fed HFD and gavaged with feces from metformin-treated donors experienced no glucose or insulin tolerance improvements. However, tumor growth was decreased by 30%, and serum SCFAs concentrations were elevated. The SCFA butyrate inhibited in vitro MC38 colony growth, but did not activate AMPK. These data suggest that metformin alters the gut microbiome, and fecal transfer from metformin-treated animals can uncouple MC38 tumor growth inhibition from the glucose homeostasis effects of metformin. These novel findings support a new mechanism for metformin to prevent cancer growth and development. / Thesis / Doctor of Philosophy (PhD) / Metformin is the most commonly used type 2 diabetes therapy, and may also reduce colorectal cancer growth. Anti-cancer effects may be caused by: 1) decreased glucose and insulin levels, which support cancer growth; or 2) entry into cancer cells to directly decrease cell growth. The gut microbiome, microorganisms that live symbiotically in the gastrointestinal tract, is also affected by metformin. This thesis aimed to clarify how metformin can inhibit cancer, and if the microbiome is involved. Mice treated with metformin had improved glucose metabolism and decreased colorectal tumor growth; when an antibiotic was introduced, this effect was lost. A fecal microbiome transfer model was used to determine if the microbiome is driving this effect. Mice receiving feces from metformin treated mice also experienced tumor growth inhibition. This suggests that the gut microbiome is involved in the anti-cancer effects of metformin, and is a new potential mechanism of action.

Fusobacterium are Gram-negative anaerobic bacteria that colonize a variety of eukaryotes including cattle and humans. In humans, Fusobacterium coordinates the central architecture of the oral biofilm by expressing an abundance of outer membrane adhesins that mediate bridging between early and late colonizing bacteria. While Fusobacterium are mostly considered commensal microorganisms, they can also become an opportunistic pathogen that spreads throughout the human body and promote the development of oral and extra-oral infections and diseases including colorectal cancer. Importantly for this work, many Fusobacterium species and strains are recalcitrant to genetic manipulation, the majority of which has led to hindrance in the study of their biology, molecular mechanisms, and pathogenesis. The genetic intractability of Fusobacterium is an obstacle for the development of future treatments for diseases associated with these anaerobic bacteria. Therefore, the creation of tools to enhance genome editing in target species is crucial to understand the molecular mechanisms driving Fusobacterium infections. This dissertation exploits innate and adaptive defense systems present in Fusobacterium for their use as molecular tools for genome editing. Accordingly, we first investigated restriction-modification systems with a focus on the role of DNA methyltransferases and endonucleases in host defense and genetic recalcitrance in several strains of Fusobacterium through bioinformatic and biochemical approaches. Altogether, over 15 DNA methyltransferases were characterized. Most notably, we identified and characterized two type II DNA methyltransferases that are capable of methylating plasmid DNA by treating with purified enzymes in-vitro and coexpression approaches in Escherichia coli strains, enabling an statiscally improved transformation efficiency via electroporation in F. nucleatum. Also contained in this dissertation is the first detailed description of CRISPR-Cas adaptive immunity systems present in Fusobacterium strains. Most of the discovered CRISPR-Cas systems in Fusobacterium belong to Class 1 systems. Nonetheless we identified Type II-A and Type VI-C Class 2 systems. The discovery of Cas9 and Cas13c effectors respectively from these systems will be crucial in the development of a new generation of genome-editing tools in Fusobacterium. The studies included in this dissertation provide the framework for overcoming Fusobacterium genetic recalcitrance by the implementation of host mimicking techniques. By utilizing restriction-modification system enzymes and the adaptive immunity CRISPR-Cas systems, we will gain a better understanding of how Fusobacterium modulates infections and diseases, and ultimately explore the potential of novel therapeutic treatments. / Doctor of Philosophy / The oral cavity has one of the most diverse and largest microbial populations, where microorganisms are capable of colonizing hard surfaces of the teeth and the soft tissues of the oral mucosa. A fundamental member of the oral microbiome is Fusobacterium, a Gram-negative bacterium which coordinates the oral biofilm formation by interacting with other microorganisms. In recent studies, Fusobacterium has been associated with oral and extra-oral infections and diseases including periodontitis, preterm birth, Lemiere syndrome, inflammatory bowel disease and colorectal cancer. Importantly, many Fusobacterium species and strains are challenging to study due to their inability to uptake exogenous DNA and lack of genetic tools, which has hindered the study of their biology, molecular mechanisms and pathogenesis. The challenges in the genetic manipulation of Fusobacterium present a significant obstacle for the development of future treatments for diseases associated with these bacteria. Therefore, the creation of tools to expand bacterial transformation of exogenous DNA and genome editing to more than just one Fusobacterium species is crucial to understand how Fusobacterium is causing these infections. This dissertation explores the presence and utilization of defense systems, which defend bacteria from phage attack, as an alternative to improve Fusobacterium genetics. Accordingly, we first studied a set of over 15 enzymes that recognize a specific DNA pattern and add a methyl group (DNA methyltransferases) to specific nucleotides in several strains of Fusobacterium. We discovered that two of these enzymes improve Fusobacterium's ability of importing and genomically incorporating exogenous DNA after an electric discharge permeabilizes the bacterial membrane. Furthermore, for the first time we have described the composition of CRISPR-Cas bacterial defense systems, that detect invading DNA from viruses and provide protection to Fusobacterium strains. These systems have previously been successfully used as genetic tools to achieve genome editing. Thus, their further characterization is warranted to create novel molecular tools in Fusobacterium. Altogether, these discoveries will lead to a better comprehension of Fusobacterium biology in infections and diseases, while exploring novel therapeutic strategies.

Purpose: Given that CRC Screening disparities in people experiencing homelessness has been heavily understudied, the purpose of this study is to assess how existing knowledge and access to resources about CRC screenings affect the ability to obtain CRC screenings in people experiencing homelessness in Central Florida. Methods: In March 2023, a team of researchers surveyed subjects who do not have stable housing in two Central Florida locations: a local shelter and a resource center serving the predominantly unsheltered. The survey assessed current understanding of CRC screenings and available/lacking resources necessary for completing CRC screening in this population. There was a total sample size of 75 participants, with 36 participants from the shelter and 39 from the service center location. Our inclusion criteria included those who are undomiciled, age 45 and over who speak Spanish or English. Results: The results indicate that there is a statistical difference between those who are screened and not screened when assessing provider counseling (p<0.001), awareness of how to get screened (p<0.001) and access to the same medical provider every visit (p=0.0389). In regard to receipt of CRC screening, there were no statistically significant results when assessing demographics and other resource-related factors. Conclusion: Because data was collected in locations that provided resources, this study may not be representative of all undomiciled individuals in Florida, especially in rural areas. Our results imply a need for provider counseling, patient education and access to a primary care provider. More research needs to be conducted from the physician perspective to understand the context of existing barriers to CRC screening.