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Bakgrund: Kolorektalcancer är den tredje vanligaste cancerdiagnosen i världen. En av behandlingsmetoderna är operation, där det kan ske via ett evidensbaserat vårdprogram, kallad ERAS. Programmet har som syfte att påskynda återhämtningsprocessen och därmed en kortare vistelse på sjukhus. Syfte: Syftet med studien var att beskriva patienters upplevelse av delaktighet vid operation via ett evidensbaserat vårdprogram. Metod: En kvalitativ litteraturstudie baserat på tio kvalitativa artiklar som analyserades via Fribergs femstegsmodell. Resultat: Resultatet visade på att vissa patienter inte upplever sig delaktiga vid sin operationsresa, medan vissa patienter upplevde att information delgivningen var tillräcklig. Detta visar på hur viktigt det är att individanpassa vården. Detta för att ge patienter bästa möjliga förutsättningar för att ge en sådan bra vård som möjligt. Konklusion: Att opereras utifrån ERAS ger bra operationsresultat. En del av patienterna som ingår i ERAS programmet upplever dock minskad delaktighet på grund av att informationen inte var personcentrerad. Studien bidrar till att uppmärksamma behovet av personcentrerad vård och patientundervisning. En brist på detta kan leda till minskad tillit till sjuksköterskan. Brist på individanpassad information kan bidra till ökad stress hos patienten, vilket kan leda till längre återhämtningstid som belastar vården. / Background: Colorectal cancer is the third most common cancer diagnosis in the world. One of the treatment methods is surgery, which can be done via ERAS. The aim of the program is to speed up the recovery process and thus a shorter stay in hospital. Aim: The aim of the study was to describe patients' experience of participation in surgery via ERAS. Method: A qualitative literature study based on ten qualitative articles that were analyzed via Friberg's five-step model. Findings: The results showed that some patients did not feel involved in their surgical journey, while some patients felt that the information provision was sufficient. This shows how important it is to tailor care to the individual. This is to give patients the best possible conditions to provide such good care as possible. Conclusion: Surgery based on ERAS gives good results. Some of the patients who are part of the ERAS program experience reduced participation because the information was not person-centered. As a lack of this can lead to reduced trust in the nurse. A lack of individually tailored information can contribute to increased stress in the patient, which can lead to longer recovery times than burden care.

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Bakgrund: Att få cancer kan rubba den grundläggande tilliten i tillvaron. Sexuell hälsa är en viktig aspekt av individens övergripande livskvalitet och välbefinnande. Patienter med kolorektalcancer får ofta biverkningar av behandlingen som kan påverka den sexuella funktionen och deras livskvalitet.   Syfte: Att beskriva vilka sexuella problem patienter kan drabbas av efter att ha behandlats för kolorektalcancer och hur det kan påverka deras livskvalitet.    Metod: En allmän litteraturöversikt valdes som metod med vetenskapliga kvantitativa artiklar. Artikelsökningar har skett i databaserna CINAHL, PubMed och PsycINFO. Artiklarna kvalitetsgranskades för att bedöma för risk för bias med hjälp av SBU:s granskningsmallar.     Resultat: 15 artiklar inkluderades och resultatet presenteras utifrån tre teman: ”Manlig sexuell dysfunktion”, ”Kvinnlig sexuell dysfunktion” och ” Försämrad sexuell funktion och dess påverkan på livskvalitén”. Till teman ”Manlig sexuell dysfunktion” samt teman ”Kvinnlig sexuell dysfunktion” kunde tre respektive fem subteman identifieras. Samtliga studier bedömdes ha medel eller hög metodologisk kvalitet och låg risk för bias.    Slutsats: Resultaten visade att både kirurgisk och medicinsk cancerbehandling negativt påverkade patienternas sexualitet och livskvalitet. Specialistsjuksköterskor har en viktig roll att erbjuda stöd till patienter kring sexuell hälsa genom samtal.   Nyckelord: kolorectal cancer, livskvalité, sexuell dysfunktion, sexuell funktion. / Background: Getting cancer has a negative influence on life. Sexual health is an important aspect of an individual's overall quality of life and well-being. Patients with colorectal cancer often experience side effects from the treatment that may affect sexual function and their quality of life. Aim: To describe what sexual problems patients may suffer from after being treated for colorectal cancer and how it can affect their quality of life. Method: A general literature review was chosen as the method where quantitative articles were included. The searches have been made in the databases CINAHL, PubMed and PsycINFO. Articles were quality reviewed for risk of bias using SBU's review templates.  Results: 15 articles were included and the results are presented based on three themes: "Male sexual dysfunction", "Female sexual dysfunction" and "Impaired sexual function and its impact on quality of life". For the themes "Male sexual dysfunction" and the themes "Female sexual dysfunction" three and five subthemes could be identified, respectively. All studies were assessed as medium or high methodological quality and low risk of bias. Conclusion: The results showed that both surgical and medical cancer treatment negatively affected the patients' sexuality and quality of life. Specialist nurses have an important role in offering support to patients about sexual health through conversation

The microbiome has long been an alluring target to study and recent advancements in microbial detection and omics-technologies has further revolutionized our view of how human diseases are impacted by the microbiome. A member of the human microbiome that has garnered such attention is Fusobacterium nucleatum, a Gram-negative, anaerobic bacterium, that normally inhabits the human oral cavity. Interestingly, F. nucleatum is highly invasive into surrounding cells and tissues of the periodontal pocket (below the gymline) and capable of disseminating throughout the entire body. Because of this, F. nucleatum is associated with a wide variety of diseases, most recently and strikingly, colorectal cancer. Despite the pathogenic potential of F. nucleatum, there is limited knowledge about the molecular mechanisms contributing to the invasive nature and virulence of this oral bacterium. This gap in knowledge can be attributed to the absence of genetic tools and resources to investigate and study host-pathogen interactions of Fusobacterium. Progress in dissecting the role of Fusobacterium in disease has been hindered by a lack of fully sequenced and annotated genomes, and the absence of genetic systems to generate target virulence gene deletions to validate mechanisms contributing to host-pathogen interactions. Breakthroughs discussed in this work focus on developing and expanding the genetic toolkits and resources available for studying F. nucleatum interactions in relation to human health and disease. As part of this work, herein, I introduce FusoPortal, an online database of fully sequenced and annotated Fusobacterium genomes, that enabled the bioinformatic annotation and correction of large protein encoding reading frames, that were previously misannotated. This database features a custom basic local alignment search tool (BLAST) server that establishes this resource as a powerful tool for identifying potential virulence factors that contribute to Fusobacterium pathogenesis. Most notably, FusoPortal facilitated my discovery of DNA uptake machinery involved in natural competence and transformation in F. nucleatum. This work is the first to characterize natural competence in a Fusobacterium species, and also enables the expansion of Fusobacterium genetics utilizing the newly found competence mechanism. The findings within this dissertation encompass a paradigm shift in efficient and robust tools to study F. nucleatum biology and pathogenesis. By creating tools for identifying key genes, proteins, and mechanisms involved in Fusobacterium induced or accelerated diseases, there is the potential to accelerate the development of novel therapeutics and vaccines against the emerging 'oncomicrobe' Fusobacterium nucleatum. / Doctor of Philosophy / The trillions of microbes living on or in the human body, collectively called the microbiome, has long been a captivating target to study and understand its role in human health and disease. Recent advances in technology have revolutionized our view of the individual components of the human microbiome, which has led to a renaissance in understanding how specific bacterial species could be used to modulate human health and fight a myriad of diseases. A member of this microbiome that has garnered such attention is Fusobacterium nucleatum, a bacterium that lives in oxygen free pockets along the gumline in the human mouth. A striking feature of F. nucleatum is its ability to invade surrounding tissue, driving bacterial spread throughout the entire body. This bacterium is associated with a wide variety of diseases, most importantly colon cancer. Although F. nucleatum is implicated in these diseases, we still know very little about the mechanisms used by Fusobacterium to promote disease. This roadblock in studying F. nucleatum can largely be attributed to the lack of molecular tools and resources to investigate and study the interactions between the bacteria and its human host. Therefore, research discussed in this work revolved around developing and resources available for studying F. nucleatum interactions in relation to human health and disease. One such resource developed was FusoPortal, an online website with fully sequenced and annotated genomes. This resource was critical in the bioinformatic annotation and correction of large proteins that were previously misannotated. This website features a tool that allows one to search this complete set of genes for a specific sequence establishing this resource as an important tool for identifying key genes and mechanisms that could influence F. nucleatum ability to infect and cause disease. Most notably, FusoPortal provided the means to discover a bacterial system that can import DNA and integrate it into the bacterial genome, a process called natural competence. This work is the first to characterize natural competence in a Fusobacterium species, and has allowed me to utilize the newly found natural competence mechanism to enhance Fusobacterium genetics. In summary, the findings within this dissertation brings about a new horizon for studying F. nucleatum biology, thereby, providing the framework for creating future therapeutic strategies to treat diseases including colorectal cancer.

Fusobacterium nucleatum is a Gram-negative, anaerobic bacterium that is a member of the human oral microbiota. Although it is a normal resident of the mouth, it is associated with a number of human diseases including: sepsis, inflammatory bowel disease (IBD), and colorectal cancer (CRC). Despite the important association of F. nucleatum with human health and disease, remarkably little is known about the molecular mechanisms underlying these infections. This knowledge gap can, in part, be attributed to a lack of molecular tools and experimental workflows. Creating the genetic tools to fill this knowledge gap is an imperative undertaking for the future development of treatments for diseases involving F. nucleatum. Previous work in the field has assigned functions to just a handful of Fusobacterium proteins (Fap2, FadA), and only two of those proteins have a well-defined role in the host-pathogen relationship. This dissertation contains work that lays the molecular and genetic foundation for future studies involving F. nucleatum by creating a unique gene deletion system while simultaneously establishing broadly applicable experimental workflows and molecular tools to study initial bacterial attachment and invasion processes crucial to Fusobacterium virulence. Marker-less gene deletions confirm the importance of Fap2 in host-cell attachment and invasion and suggest a lesser role in invasion for FadA, representing a significant revision to the Fusobacterium-host relationship. Also, our system allows for the overexpression and purification of virulence factors directly from Fusobacterium for the first time. This permits us to study aspects of Fusobacterium protein biology that were previously impossible and will provide further insights into the nature of Fusobacterium virulence. A custom suite of molecular tools was also developed to facilitate recombinant expression of these proteins in general laboratory settings using simple E. coli protein expression systems. We have used these new technologies to express and purify a number of potential Fusobacterium virulence factors as detailed in this dissertation. Also contained in this dissertation is the application of these breakthroughs to probe the function of a novel F. nucleatum outer membrane phospholipase, FplA. Phospholipases are important virulence factors in a number of well-studied human pathogens including Pseudomonas aeruginosa and Legionella pneumophila, where they interfere with host cellular signaling processes to increase intracellular bacterial survival. Our data show that FplA is a Class A1 phospholipase (PLA1) with robust catalytic activity capable of binding to and cleaving a number of lipid types. Additionally, we show that it has the ability to bind to important host signaling lipids including phosphatidylinositol 3, 5-bisphosphate and phosphatidylinositol 3, 4, 5-triphosphate. These data suggest FplA may play a role in manipulating the intracellular processes of host cells. Taken together, work in this dissertation provides tools and experimental frameworks for the future study of F. nucleatum pathogenesis while identifying and initially characterizing a new, potentially significant, virulence factor in FplA. / Doctor of Philosophy

Yes / The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC) chemoprevention, alone or in combination with aspirin, which itself has recognized anti-CRC activity. Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials. The seAFOod Polyp Prevention Trial is a randomized, double-blind, placebo-controlled, 2 × 2 factorial ‘efficacy’ study, which will determine whether EPA prevents colorectal adenomas, either alone or in combination with aspirin. Participants are 55–73 year-old patients, who have been identified as ‘high risk’ (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period, malignant change in an adenoma, regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs, regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy. Patients are randomized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo, for approximately 12 months. The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy. Secondary end-points include the number of adenomas (total and ‘advanced’) per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as ‘intermediate risk’ for future surveillance. Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs, resolvin E1 and PGE-M in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination, as well as to discover predictive biomarkers of chemopreventive efficacy. The recruitment target is 904 patients. / Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership

No / Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyp formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA–FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control and resulted in the enrichment of Lactobacillus species in the gut microbiota. Taken together, our data suggest that EPA-FFA is an excellent candidate for CRC chemoprevention in CAC.