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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
561

Operationssjuksköterskors erfarenheter av att vårda ERAS patienter perioperativt : En kvalitativ intervjustudie / Operating room nurses’ experiences in caring of ERAS patients perioperative : A qualitative interview study

Rustami, Golan, Podvorica Stublla, Agnesa January 2023 (has links)
Bakgrund: Patienter med kolorektalcancer vårdas enligt enhanced recovery after surgery (ERAS) vårdprogram. ERAS är ett evidensbaserat vårdprogram som syftar till att effektivisera och förbättra vårdkvalitén genom hela den perioperativa vårdprocessen. Den perioperativa dialogen är nyckeln till god vårdrelation inom ERAS för att motverka vårdlidande. Operationssjuksköterskans funktion är betydelsefull i vårdandet av dessa patienter. Syfte: Belysa operationssjuksköterskors erfarenheter av att vårda patienter som genomgår kolorektalkirurgi inom ERAS vårdprogram perioperativt. Metod: En kvalitativ studie där åtta operationssjuksköterskor intervjuades. Insamlade data analyserades med hjälp av en kvalitativ innehållsanalys. Resultat: Informanternas upplevelser av att vårda patienter enligt ERAS vårdprogram var positivt. ERAS vårdprogram ansågs vara strukturerat och effektivt. ERAS resulterade i total optimering hos patienter som ska genomgå kolorektalkirurgi. Flera fördelar kunde identifieras med ERAS vårdprogrammet dock framkom det att operationssjuksköterskornas delaktighet var minimal. Däremot hade operationsteamets samverkan en central betydelse i arbetet med ERAS vårdprogram. Konklusion: Arbetet och resultaten inom kirurgisk vård har förbättrats avsevärt efter implementeringen av ERAS. ERAS skapar goda förutsättningar för patienterna i deras vård. / Background: Patients with colorectal cancer gets treatment within the ERAS program. It is an evidence-based program with the purpose of making the care more effective through the perioperative process. The perioperative dialogue is the key to a good care relationship within the ERAS to counteract care suffering. The role of the operating room nurse is significant in the care of these patients. Aim: The perioperative experience from operating room nurses when they are taking care of patients with colorectal cancer within the ERAS program. Method: A quality based study with interviews from eight operating room nurses. Collected data which was analyzed with the help of a quality based content analysis.  Result: the experience of taking care of patients within ERAS were positive by the informants. ERAS is considered being a structured and effective program. It resulted in an optimization with patients undergoing colorectal surgical. A lot of positive things were identified within ERAS, although the participation of operating room nurses were minimal. However were the cooperation of the surgical team important within the ERAS program.  Conclusion: The work and result within surgical care has improved significantly since the introduction of ERAS. The program creates good conditions for patients in healthcare.
562

Upplevelsen av patientdelaktighet

Fornander, Elisabet, Götulf, Lina January 2008 (has links)
I ett alltmer välinformerat samhälle, ökar individens kunskap om hälso- och sjukvård samt om patientens rättigheter och skyldigheter. Detta ställer krav på sjuksköterskor att arbeta aktivt för ökad patientdelaktighet. Syftet med denna pilotstudie var att undersöka patientens upplevelse av patientdelaktighet på en cytostatikamottagning på ett sjukhus i södra Sverige. Datainsamling skedde med hjälp av enkät, utdelad på mottagningen. Materialet bearbetades med kvalitativ innehållsanalys, vilket resulterade i två huvudkategorier: Kommunikation mellan patient och sjuksköterska och hantering av sjukdomsupplevelsen. Resultatet visade på att upplevelse av patientdelaktighet uppnås och upprätthålls genom god information från professionell vårdpersonal, att patientens kunskap och synpunkter beaktas samt att dennes känslor visas hänsyn. / In an increasingly well-informed society, the individual’s knowledge about health care as well as knowledge about patient rights and obligations increases. This increases the demand on nurses to work actively towards patient participation. The aim of this pilot study was to examine the patient’s experience of patient participation in a chemotherapy ward at a hospital in southern Sweden. A data collection took place by using a questionnaire. The material was processed using qualitative content analysis, which resulted in two main categories: Communication between patient and nurse and handling the experience of illness. The result showed that the experience of patient participation is achieved and maintained by good information from a professional nursing staff, which consider the patient’s knowledge and opinions and take his or her feelings into account.
563

The Role of Antioxidants and Pro-Oxidants in Colon Cancer

Stone, William L., Krishnan, Koyamangalath, Campbell, Sharon E., Palau, Victoria E. 15 March 2014 (has links)
This review focuses on the roles antioxidants and pro-oxidants in colorectal cancer (CRC). Considerable evidence suggests that environmental factors play key roles in the incidence of sporadic CRC. If pro-oxidant factors play an etiological role in CRC it is reasonable to expect causal interconnections between the well-characterized risk factors for CRC, oxidative stress and genotoxicity. Cigarette smoking, a high dietary consumption of n-6 polyunsaturated fatty acids and alcohol intake are all associated with increased CRC risk. These risk factors are all pro-oxidant stressors and their connections to oxidative stress, the intestinal microbiome, intestinal microfold cells, cyclooxygenase-2 and CRC are detailed in this review. While a strong case can be made for pro-oxidant stressors in causing CRC, the role of food antioxidants in preventing CRC is less certain. It is clear that not every micronutrient with antioxidant activity can prevent CRC. It is plausible, however, that the optimal food antioxidants for preventing CRC have not yet been critically evaluated. Increasing evidence suggests that RRR-gamma-tocopherol (the primary dietary form of vitamin E) or other "non-alpha-tocopherol" forms of vitamin E (e.g., tocotrienols) might be effective. Aspirin is an antioxidant and its consumption is linked to a decreased risk of CRC.
564

Development of an In Vitro 3-Dimensional Co-Culture Human Colorectal Cancer Model in Microfluidic Devices

Jens, Abby 01 March 2024 (has links) (PDF)
Colorectal cancer is the second most common cause of cancer-related deaths in the United States, with the relative 5-year survival rate for distant stage cancer being only 14%. The most common treatment for colorectal cancer is with chemotherapeutic drugs; however, the discovery of these drugs is costly, time-consuming, and often requires the use of animal models that do not yield results that translate to clinical trials. Due to these shortcomings, researchers seek to develop physiologically relevant in vitro tumor models that more accurately mimic the tumor microenvironment for cheaper and faster high-throughput drug screening. The aim of this research was to develop a colorectal cancer tumor model co-cultured with endothelial and stromal cells, followed by validation with clinically relevant chemotherapeutic agents within microfluidic devices. The first experiment consisted of a lipofection of fibroblasts to yield fluorescently tagged cells that could be later imaged using a fluorescence microscope. The next experiment consisted of a co-culture of tumor, endothelial, and fibroblast cells at varying densities in a twodimensional (2D) culture to determine the optimal plating densities that would yield quantifiable tumor and endothelial network formation. The following experiment used these optimal densities to test the effects of the chemotherapeutic agents oxaliplatin and SN38 on the tumor and endothelial cells in 2D. After the various densities and drug concentrations were tested in 2D, the model was introduced into microfluidic devices. The first experiment in the devices was similar to the first experiment plated in 2D, as it involved the establishment of optimal plating densities of all three cell types within the devices. Similarly, the goal of this experiment was to yield quantifiable tumor and endothelial network formation within the devices. The final experiment performed in this research was the introduction of oxaliplatin and SN38 to the optimized densities v of cells determined from the previous experiment, with the aim of evaluating the effects of these chemotherapeutic agents on the tumor and endothelial cells within microfluidic devices. The two experiments plated in 2D established plating densities to be tested in the devices. These experiments also showed that increasing drug concentrations resulted in reduced tumor count and size and revealed no disruption in the endothelial networks when exposed to oxaliplatin concentrations as high as 50 µM. The final two experiments in microfluidic devices revealed that endothelial network formation is not yet possible within the devices with the current protocols, but that tumor cells still showed dose-dependent responses to drug exposure as they did in 2D. Due to the lack of network formation in this device model, future work is required to allow for endothelial cell organization into networks, to further increase the physiological relevancy of this model to in vivo tumor conditions.
565

Manipulation of the bacteria promoting the development of colorectal cancer

Oliero, Manon 03 1900 (has links)
En 2022, le cancer colorectal (CCR) est le deuxième cancer le plus meurtrier au Canada et le troisième dans le monde. Plusieurs facteurs dont l’alimentation, le manque d'activité physique et la génétique, ont été identifiés comme contribuant au développement du CCR. Le microbiote intestinal, une communauté de micro-organismes vivant dans l'intestin de l'hôte, est également associé au développement du CCR, comme particulièrement Escherichia coli productrice de colibactine. Cette génotoxine induit des réticulations inter brin et cassures double brin (DSBs) de l’ADN dans les cellules de mammifères, entraînant des mutations et un risque élevé de développement du CCR. Nous avons pour objectif de contrôler la prolifération et la production de colibactin de la bactérie pks+ E. coli. Nous avons évalué la prévalence des bactéries pks+ et des bactéries bft+ chez des patients atteints de CCR et individus sains de la province de Québec (Canada), en utilisant une cohorte de 156 participants. Nous avons constaté qu'une grande proportion d’individus sains sont colonisés par des bactéries pks+ (42%) et à des niveaux similaires à ceux des patients atteints de CCR (46%). En ce qui concerne la bactérie entérotoxigénique Bacteroides fragilis (ETBF), le gène bft a été détecté chez 21% des contrôles sains et 32% des patients atteints de CCR, et 8% des contrôles sains et 13% des patients atteints de CRC étaient colonisés à la fois par des bactéries pks+ et par ETBF. Comme ces individus sains sont plus susceptibles de développer un CCR, il est vital de fournir des traitements nutritionnels et médicinaux personnalisés pour contrôler la croissance de ces bactéries. Nous avons ensuite étudié l'effet de la supplémentation en prébiotiques sur la génotoxicité des souches de E. coli productrice de colibactine dans un modèle cellulaire. L'inuline et les galacto-oligosaccharides ont augmenté l'expression du gène de la colibactine A chez E. coli pks+, ce qui a été aboli par l'addition de 125 µM de sulfate de fer. La souche de E. coli NC101 (EcNC101) a augmenté les dysplasies et DSBs dans les cellules d'adénocarcinome humain Caco-2, en présence de l'un ou l'autre des oligosaccharides. 6 Nos résultats indiquent que les oligosaccharides aggravent les dommages à l'ADN causés par les bactéries productrices de colibactine. Étant donné la popularité croissante de la supplémentation en prébiotiques et leur facilité d'accès, d'autres études sont nécessaires pour déterminer comment ces prébiotiques peuvent réguler le développement et la progression des tumeurs dans des modèles animaux et chez les humains en présence d'une colonisation par E. coli pks+. Nous avons constaté précédemment que l'inuline avait à la fois des effets protecteurs et des effets promoteurs de tumeurs dans le CCR, et ces divergences peuvent être attribuées à la présence de E. coli pks+. En utilisant le modèle de souris ApcMin/+ de CCR, nous avons cherché à savoir si les bactéries E. coli productrice de colibactine modifiaient la protection conférée par l'inuline contre le développement et la progression des tumeurs. La supplémentation en inuline a conduit à une augmentation de la colonisation par EcNC101, ce qui a entraîné une élévation des DSBs, de la charge tumorale et de la progression tumorale chez les souris ApcMin/+, de manière dépendante à la colibactine. E. coli Nissle 1917 pasteurisé a inhibé la croissance tumorale en inhibant la prolifération de EcNC101 induite par l'inuline. Nos résultats soulignent la nécessité de dépister les bactéries pks+ chez les patients et de leur fournir des conseils nutritionnels préventifs. En résumé, nous avons rapporté que les pré-biotiques, pro-biotiques et post-biotiques peuvent influencer la croissance de E. coli pks+ et/ou la sécrétion de colibactine. Par conséquent, la pertinence de ce projet serait de fournir une thérapie nutritionnelle personnalisée basée sur ces résultats pour les individus colonisés par ces bactéries, qui sont plus enclins à développer un cancer colorectal. / In 2022, colorectal cancer (CRC) was the second deadliest cancer in Canada and the third globally. Factors such as diet, lack of physical activity, and genetics have been identified as contributors to CRC development. The intestinal microbiota, a community of microorganisms living in the host intestine, has been associated with CRC development, particularly the colibactin-producing Escherichia coli. The genotoxin colibactin induces interstrand cross-links (ICLs) double-strand DNA breaks (DSBs) in mammalian cells, resulting in mutations and an elevated risk of CRC development. Therefore, these studies aimed to control the proliferation and production of colibactin of pks+ E. coli. Using a case-control study of 156 participants, we evaluated the prevalence of pks+ bacteria and bft+ bacteria in patients with CRC and healthy controls from the province of Québec (Canada). We found that similar to patients with CRC (46%), a large proportion of healthy controls were colonized by pks+ bacteria (42%). Regarding enterotoxigenic Bacteroides fragilis (ETBF), the bft gene was observed in 21% of healthy controls and 32% of patients with CRC, with 8% of healthy controls and 13% of patients with CRC colonized by both pks+ bacteria and ETBF. Providing personalized dietary and medicinal treatments to control the growth of these bacteria is necessary because these healthy individuals are more likely to develop CRC. The effect of prebiotic supplementation on the genotoxicity of colibactin-producing E. coli strains was investigated in a cellular model. Inulin and galactooligosaccharide increased the expression of the colibactin A gene in pks+ E. coli, which was abrogated by the addition of 125 µM of iron sulfate. E. coli strain NC101 (EcNC101) increased dysplasia and DSBs breaks in human adenocarcinoma Caco-2 cells, in the presence of both inulin and galactooligosaccharide. Our findings indicate that oligosaccharides aggravate DNA damage caused by colibactin-producing bacteria. 4 Given the increasing popularity and accessibility of prebiotic supplementation, more studies are required to determine how these prebiotics may regulate tumor development and progression in animal models and humans in the presence of pks+ E. coli colonization. Inulin has protective and tumor-promoting effects on CRC; these discrepancies may be attributed to the presence of pks+ E. coli. Using the ApcMin/+ mouse model of CRC, we explored whether colibactin-producing E. coli altered the protection conferred by inulin against tumor development and progression. Inulin supplementation increased EcNC101 colonization, resulting in more DSBs, tumor burden, and tumor progression in ApcMin/+ mice, in a colibactin dependant manner. Pasteurized E. coli Nissle 1917 inhibited tumor growth by reversing inulin-driven EcNC101 proliferation. Our findings emphasized the need to screen patients for pks+ bacteria and provide them with preventive dietary counseling. In summary, we reported that prebiotics, probiotics, and postbiotics could influence pks+ E. coli growth, colibactin secretion, or both. Therefore, the significance of this project lies in providing personalized nutritional-based therapy based on the findings for individuals colonized by these bacteria, who are more prone to develop CRC.
566

CD1d and NKT cells in intestinal tumor development and hepatic lipid metabolism

Ceriotti, Chiara 17 January 2024 (has links)
Cluster of differentiation 1 (CD1) d ist ein antigenpräsentierendes Glykoprotein, das verschiedene Lipidklassen (z.B. Glycerophospholipide und Sphingolipide) bindet. CD1d zeigt intrazellulär eine Verteilung sowohl im sekretorischen als auch im endolysosomalen Kompartiment und bindet dort endogene (körpereigene) und exogene (körperfremde, z.B. mikrobiellen) Lipide, die an natürliche Killer T-Zellen, eine Gruppe lipidreaktiver T-Zellen, präsentiert werden. Nach Antigenerkennung zeigen NKT-Zellen eine schnelle Zytokinsekretion, was wiederum zu einer breiten Aktivierung anderer angeborener und adaptiver Immunzellpopulationen wie dendritischer Zellen, natürlicher Killerzellen, B-Zellen und konventioneller T-Zellen führt. In meiner Dissertation untersuchte ich die Rolle von CD1d und NKT-Zellen im Kontext der intestinalen Tumorentstehung (Kapitel 1). Darüber hinaus untersuchte ich CD1d-abhängige Effekte auf den hepatischen Lipidmetabolismus, verbunden mit der Frage ob diese Effekte zumindest partiell in NKT-Zell-unabhängiger Weise vermittelt werden (Kapitel 2). CD1d und NKT-Zellen in der intestinalen Tumorentwicklung NKT-Zellen beeinflussen CD1d-abhängig entzündliche Prozesse im Darm sowie die intestinale Tumorentwicklung. Verschiedene Modelle und Strategien, die sich mit der Klärung der Rolle der NKT-Zelluntergruppen in diesen Erkrankungen beschäftigten, zeigten, dass hierbei eine komplexe Regulierung durch spezifische NKT-Zelluntergruppen, nämlich invariante (i)NKT-Zellen und diverse (d)NKT-Zellen, mit teils gegensätzlichen Effekten zu beobachten ist. CD1d zeigt eine ubiquitäre Expression und kann in zellspezifischer Weise in die NKT-Zell-Aktivierung eingreifen. So vermittelt CD1d im Kontext der intestinalen Entzündung regulatorische NKT-Zell-Signale wenn die Antigenpräsentation von intestinalen Epithelzellen (IECs) ausgeht, während CD1d-Signale von professionellen Immunzellen intestinale Entzündung in NKT-Zell-abhängiger Weise fördern. Das Ziel des ersten Teils meiner Arbeit (Kapitel 1) war die Analyse zelltypspezifischer Effekte von CD1d in der Aktivierung von NKT-Zellen im Rahmen der intestinalen Tumorentstehung. Unter Verwendung des Cre-lox-Systems zur Erzeugung von IEC- und myeloidspezifischen CD1d-defizienten Mäusen und der ApcMin/+ und Apcfl/wt-Mausemodelle intestinaler Tumorentwicklung untersuchte ich die Wirkung der zelltypspezifischen CD1d-Deletion auf die NKT-Zell-Immunantwort im Rahmen der intestinalen Tumorentwicklung. Ich konnte dabei zeigen, dass CD1d in NKT-Zell-abhängiger Weise das intestinale Tumorwachstum fördert. Während die intestinal-epitheliale Deletion von CD1d keine Effekte auf die Tumorentwicklung hatte, führte die myeloide Deletion von CD1d zumindest zu einem partiell reduzierten Tumorwachstum. Diese Daten zeigen, dass myeloide Zellen zum CD1d- und NKT-abhängigen Tumorwachstum beitragen. Darüber hinaus ist anzunehmen, dass weitere, bislang uncharakterisierte Zellen zur CD1d-abhängigen Regulation der Tumorentwicklung beitragen. NKT-Zell-unabhängige Effekte von CD1d im hepatischen Lipidmetabolismus. Der zweite Teil meiner Dissertation (Kapitel 2) befasste sich mit der Rolle von CD1d in der Regulierung des hepatischen Fettstoffwechsels unter konstitutiven Bedingungen sowie im Kontext der nichtalkoholischen Fettleberkrankheit (NAFLD). Mausmodelle mit konstitutiver Deletion von CD1d zeigten dabei, dass diese Prozesse in CD1d-abhängiger Weise vermittelt werden. Da die Deletion von CD1d mit einem Verlust von NKT-Zellen verbunden ist, wurde daraus geschlossen, dass NKT-Zellen zur Pathogenese metabolischer und inflammatorischer Veränderungen bei NAFLD beitragen. Ob CD1d auch in NKT-Zell-unabhängiger Weise zur Regulation des hepatischen Metabolismus beitragen kann, wurde bislang nicht untersucht. CD1d wird ubiquitär und abundant von verschiedenen Zelltypen einschließlich Enterozyten, Adipozyten und Hepatozyten exprimiert und interagiert mit verschiedenen Lipidtransferproteinen. Ich untersuchte daher, ob CD1d auch in direkter, NKT-Zell-unabhängiger Weise Einfluss auf den hepatischen Lipidmetabolismus nimmt. Hierzu wurden CD1d-exprimierende und CD1d-defiziente Mäuse auf einem genetischen Hintergrund mit Defizienz des recombination activating gene 1 (Rag1) untersucht, in dem aufgrund der fehlenden VDJ-Rekombination reife T- und B-Zellen einschließlich NKT-Zellen fehlen. Meine Ergebnisse zeigen, dass CD1d den hepatischen Lipidstoffwechsel unter konstitutiven Bedingungen wie auch im Kontext der nicht-alkoholischen Fettleber in einer NKT-Zell-unabhängigen Weise regulieren kann. Die Mechanismen über die diese Regulation vermittelt wird, werden derzeit experimentell untersucht. Zusammenfassend habe ich in dieser Arbeit die Rolle von epithelialem und myeloiden CD1d in der intestinalen Tumorentstehung charakterisiert. Darüber hinaus konnte ich zeigen, dass CD1d in NKT-Zell-unabhängiger Weise den hepatischen Lipidmetabolismus reguliert.:Zusammenfassung Summary General introduction 1 The CD1 family of antigen presenting proteins 1.1 Structure of CD1 proteins 1.2 Trafficking of CD1 proteins 1.3 Lipid transfer proteins 1.4 CD1 associated lipid repertoire 2 CD1d-restricted T cells 2.1 Lipid antigens presented to CD1 restricted T cells 2.2 NKT cell subsets 2.3 NKT cells in homeostasis and disease Chapter I: CD1d in intestinal tumor development Introduction 1 The role of CD1d and NKT cells in intestinal homeostasis 1.1 The intestine: structure and function 1.2 Immune cell populations in the intestine 1.3 Interplay between iNKT cells and intestinal microbiota 1.3.1 The intestinal microbiota shapes mucosal iNKT cells 1.3.2 Effect of the microbiota on systemic iNKT cells 1.3.3 Bacterial lipid antigens influence iNKT cell-dependent mucosal immunity 1.3.4 Effect of CD1d deficiency on commensals 2 CD1d & NKT cells in cancer 2.1 Enhancing anti-tumor immunity 2.2 Suppressing anti-tumor immunity 3 CD1d & NKT cells in colorectal cancer 3.1 Spontaneous tumorigenesis 3.2 Intestinal inflammation and inflammation-induced cancer Aim of the study Materials and Methods Results 1.1. Validation of the conditional CD1d knockout mouse lines 1.2. Analysis of tumorigenesis in the ApcMin/+ and Apcfl/wt models 1.3. The impact of myeloid cell-specific deletion of CD1d on spontaneous tumor development 1.4. The impact of intestinal epithelial cell specific deletion of CD1d on spontaneous tumorigenesis 1.5. Analysis of constitutive deletion of CD1d in spontaneous tumorigenesis model Discussion Chapter II: CD1d and hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD) Introduction 1 Metabolic diseases as a multi-organ pathology 2 Lipid metabolism and inflammation in metabolic diseases 3 Non alcoholic fatty liver disease (NAFLD) 3.1 Mouse models of NAFLD 4 NKT cells in metabolic diseases 4.1 NKT cells in obesity 4.2 NKT cells in NAFLD 5 Potential NKT cell-independent roles of CD1d Materials and methods Results 2.1 Absence of CD1d on the Rag1-deficient background under constitutive conditions reduces neutral lipid accumulation in the liver 2.2 Deletion of CD1d on a Rag1-deficient background reduces hepatic neutral lipid accumulation in response to a HFD and protects from liver injury 2.3 Choline-deficient HFD as a model of NASH shows no difference between CD1d-deficient Rag1-deficient mice and CD1d-proficient littermates Discussion References Appendix 132 List of abbreviations 132 List of tables 137 List of figures 138 Acknowledgments Anlage 1 Anlage 2 / Cluster of differentiation 1 (CD1) d is an atypical antigen-presenting glycoprotein which binds diverse lipid classes including glycerophospholipids and sphingolipids. Trafficking through secretory and endolysosomal compartments, CD1d broadly surveys the cell for endogenous (self) and exogenous (e.g. microbial) lipids and presents those lipids to a subset of T cells, named natural killer T (NKT) cells. NKT cells exhibit rapid and abundant cytokine secretion upon antigen recognition, leading to a broad activation of other innate and adaptive immune cell populations such as dendritic cells, natural killer cells, B cells, and conventional T cells. My thesis studied CD1d and NKT cells in the context of intestinal tumorigenesis (chapter I) and investigated a novel NKT cell-independent role of CD1d in the regulation of hepatic lipid metabolism (chapter II). CD1d and NKT cells in intestinal tumor development NKT cells modulate intestinal inflammation and tumor development in a CD1d-dependent manner. Different models and strategies have been used to elucidate the role of NKT cell subsets in these processes, highlighting a complexity of regulation by specific NKT cells subsets, namely invariant (i)NKT cells and diverse (d)NKT cells, and other immune cells and mediators in the tumor microenvironment. In addition, CD1d, which is ubiquitously expressed, can elicit cell-type specific effects on NKT cell subsets as shown in intestinal inflammation, where intestinal epithelial cell (IEC) CD1d provide regulatory cues, while CD1d signal from bone marrow-derived cells promote intestinal inflammation. The first part of my thesis (chapter I) aimed at further dissecting potential cell type-specific effects of CD1d in the activation of NKT cells in the context of intestinal tumorigenesis. Using the Cre-lox system to generate IEC- and myeloid-specific CD1d-deficient mice and the ApcMin/+ and Apcfl/wt mouse models of intestinal tumorigenesis, I investigated the effects of cell type-specific CD1d deficiency on iNKT cell immune responses and tumor development. My findings show that CD1d, presumably through iNKT cells, promotes tumor growth as shown in a model of constitutive CD1d deletion. While epithelial CD1d did not contribute to NKT cell-dependent tumor growth, myeloid deletion of CD1d was associated with a trend towards reduced tumor growth. These results suggest that myeloid CD1d promotes NKT cell-dependent tumor growth and that other, yet uncharacterized cells, have additional contributions to this process. NKT cell-independent roles of CD1d in the regulation of liver metabolism The second part of my thesis (chapter II) tackled the role of CD1d in the regulation of hepatic lipid metabolism under constitutive conditions and in the context of non-alcoholic fatty liver disease (NAFLD), a prevalent metabolic liver disease which is associated, in a subset of individuals, with immune-mediated progression to liver fibrosis and cirrhosis. Inflammation has an important role in the progression of NAFLD and metabolic diseases, and iNKT cells have been linked to these processes. Specifically, constitutive deletion of CD1d, which is associated with loss of NKT cells, has been demonstrated to influence hepatic lipid metabolism and the progression of NAFLD. In this thesis, I investigated whether the effects of CD1d are indeed dependent on NKT cells or whether CD1d has direct, NKT cell-independent effects on liver metabolism. CD1d is expressed ubiquitously and abundantly by various cell types including enterocytes, adipocytes and hepatocytes, and it binds to a plethora of endogenous cellular lipids through the interaction with lipid transfer proteins, which are important regulators of lipid metabolism. To investigate CD1d-mediated effects that are independent from NKT cells, CD1d-proficient and CD1d-deficient mice were analyzed on a recombination activating 1 (Rag1)-deficient background, which lacks mature T and B cells including NKT cells due to the lack of VDJ recombination. My results demonstrate that CD1d can regulate hepatic lipid metabolism in an NKT cell-independent manner under constitutive conditions and in the context of models of NAFDL. The mechanisms by which CD1d can directly regulate hepatic lipid metabolism are currently being addressed. In conclusion, in this thesis I have characterized the cellular contributions to CD1d- and NKT cell-dependent regulation of intestinal tumor development. In addition, I have identified a novel, NKT cell-independent effect of CD1d on hepatic lipid metabolism.:Zusammenfassung Summary General introduction 1 The CD1 family of antigen presenting proteins 1.1 Structure of CD1 proteins 1.2 Trafficking of CD1 proteins 1.3 Lipid transfer proteins 1.4 CD1 associated lipid repertoire 2 CD1d-restricted T cells 2.1 Lipid antigens presented to CD1 restricted T cells 2.2 NKT cell subsets 2.3 NKT cells in homeostasis and disease Chapter I: CD1d in intestinal tumor development Introduction 1 The role of CD1d and NKT cells in intestinal homeostasis 1.1 The intestine: structure and function 1.2 Immune cell populations in the intestine 1.3 Interplay between iNKT cells and intestinal microbiota 1.3.1 The intestinal microbiota shapes mucosal iNKT cells 1.3.2 Effect of the microbiota on systemic iNKT cells 1.3.3 Bacterial lipid antigens influence iNKT cell-dependent mucosal immunity 1.3.4 Effect of CD1d deficiency on commensals 2 CD1d & NKT cells in cancer 2.1 Enhancing anti-tumor immunity 2.2 Suppressing anti-tumor immunity 3 CD1d & NKT cells in colorectal cancer 3.1 Spontaneous tumorigenesis 3.2 Intestinal inflammation and inflammation-induced cancer Aim of the study Materials and Methods Results 1.1. Validation of the conditional CD1d knockout mouse lines 1.2. Analysis of tumorigenesis in the ApcMin/+ and Apcfl/wt models 1.3. The impact of myeloid cell-specific deletion of CD1d on spontaneous tumor development 1.4. The impact of intestinal epithelial cell specific deletion of CD1d on spontaneous tumorigenesis 1.5. Analysis of constitutive deletion of CD1d in spontaneous tumorigenesis model Discussion Chapter II: CD1d and hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD) Introduction 1 Metabolic diseases as a multi-organ pathology 2 Lipid metabolism and inflammation in metabolic diseases 3 Non alcoholic fatty liver disease (NAFLD) 3.1 Mouse models of NAFLD 4 NKT cells in metabolic diseases 4.1 NKT cells in obesity 4.2 NKT cells in NAFLD 5 Potential NKT cell-independent roles of CD1d Materials and methods Results 2.1 Absence of CD1d on the Rag1-deficient background under constitutive conditions reduces neutral lipid accumulation in the liver 2.2 Deletion of CD1d on a Rag1-deficient background reduces hepatic neutral lipid accumulation in response to a HFD and protects from liver injury 2.3 Choline-deficient HFD as a model of NASH shows no difference between CD1d-deficient Rag1-deficient mice and CD1d-proficient littermates Discussion References Appendix 132 List of abbreviations 132 List of tables 137 List of figures 138 Acknowledgments Anlage 1 Anlage 2
567

Development of in vivo tumour models for non-invasive proof-of-principle investigation of novel therapeutic agents. Engineering and characterisation of bioluminescent cell reporter systems for in vivo analysis of anti-cancer therapy pharmacodynamics.

O'Farrell, Alice C. January 2011 (has links)
Despite significant advances in cancer treatment, clinical response remains suboptimal and there is a continued requirement for improved chemotherapeutics. The attrition rate for new therapies is high, due principally to lack of in vivo efficacy and poor pharmacodynamics. Consequently better systems are required to determine in vivo preclinical efficiency and drug-target interactions. Engineering of cancer cells to express fluorescent or bioluminescent proteins, either endogenously or under the control of specific gene promoters, and their detection by noninvasive optical imaging has the potential to improve preclinical drug development. In this study, a panel of colorectal cancer cell lines were engineered to express fluorescent and luminescent proteins either constitutively or under control of gene-promoters for the DNA damage response gene p53 or the cell cycle regulator p21, both important pharmacodynamic sensors. These cell lines were characterised for their potential as in vivo models of primary and metastatic tumour therapy response, several showing significant potential. In addition to the development of these models, this study also addressed the pharmacokinetics of different luciferase substrates and identified optimal temporal and dose characteristics for each. Furthermore, a new application for bioluminescent imaging was developed and validated for use in preclinical evaluation of vascular disrupting agents, a new generation of cancer therapeutic. This study demonstrates that despite the dynamic and variable nature of fluorescent and bioluminescent imaging, reproducible results can be obtained if appropriate precautions are taken. The models developed herein will expedite cancer drug development whilst reducing and refining the use of animals in research.
568

Patienternas upplevelser i samband meddiagnosbeskedet kolorektalcancer till början av behandling : En litteraturstudie / Patients' Experiences From the Diagnosis Of Colorectal Cancer To the Initiation Of Treatment : A literature review

Al Robeyi, Soukaina, Al Balout, Ekhlas January 2024 (has links)
Bakgrund: Kolorektalcancer är globalt vanlig och påverkar patienternas livskvalitet negativt. Sjuksköterskor står inför utmaningar att möta patienternas behov på ett tillfredsställande sätt.Syfte: Studien syftar till att belysa vuxna patienters upplevelser i samband med diagnosbeskedet till början av behandling av kolorektalcancer.Metod: En litteraturstudie baserad på 10 kvalitativa artiklar genomfördes med användning av kvalitativ innehållsanalys från PubMed och CINAHL.Resultat: Litteraturstudien resulterade i två huvudkategorier: Emotionella reaktionen och vikten av stöd. Emotionella reaktionen hade subkategorierna tankar och känslor om framtiden, chockreaktion och ångest och osäkerhet. Vikten av stöd hade subkategorierna vikten av familjestöd, vikten av information och vikten av vård.Slutsats: Kolorektalcancerpatienter genomgår emotionella utmaningar och betonar behovet av stöd. Studiens resultat kan öka sjuksköterskors förståelse och förbättra deras möjlighet att ge patienterna ett effektivt och empatiskt bemötande. / Background: Colorectal cancer significantly affects patients' quality of life and poses challenges for nurses in addressing patient needs.Objective: The study aims to illuminate the experiences of adult patients in connection with the diagnosis of colorectal cancer through the beginning of treatment.  Method: Conducted through qualitative content analysis of 10 relevant articles sourced from PubMed and CINAHL databases.Results: The literature study resulted in two main categories: Emotional reactions and the importance of support. Emotional reactions had subcategories of thoughts and feelings about the future, shock reaction, and anxiety and uncertainty. The importance of support included subcategories of the importance of family support the importance of information and the importance of care.  Conclusion: Colorectal cancer patients experience emotional turmoil, affecting their journey from diagnosis to treatment. Understanding these experiences enhances nurses' ability to provide empathetic care.
569

Chromatin-associated functions of the APC tumor suppressor protein

Hankey, William C., IV January 2016 (has links)
No description available.
570

Somatic microsatellite variability as a measure of DNA stability in cancer and DNA  repair disorders

Vaksman, Zalman 07 January 2015 (has links)
Microsatellites (MSTs) are short tandem repeats of motifs, 1 — 6 nucleotide in length, and are considered mutational 'hot-spots' and show a greater degree of somatic variability and population polymorphisms than surrounding DNA sequences. MSTs provide for a unique computational alignment problem for many commonly used algorithms, and therefore required software tools to be developed to specifically address these issues. For this work we developed a novel approach to extract MSTs from next-gen sequencing data that can robustly detect signatures of MST mutation bias and somatic variation occurring in next-gen data including a high frequency of in-phase indels. Somatic variability, novel genomic polymorphisms that arise within a cell population not found in the progenitors, plays a critical role in cellular reprogramming leading to the development and progression of cancer. MST mutation rates are between 10 and 1000 time higher than that of surrounding DNA. MSTs are found ubiquitously throughout the genome including in nearly all transcribed regions and 10-20% of coding genomic regions. Currently the only established DNA repair defect that that has been directly linked to MST instability is replication coupled mismatch repair (MMR). An initial analysis of the utility of the software was conducted with DNA repair impaired cell lines. The results demonstrated the utility in identifying the consequences of DNA repair impairments on genomic stability. There were major objectives of the finding including 1) complimenting genomics of matched DNA samples with in-sample quantification of variation and 2) demonstrating that DNA repair proficient cells and those with different defects in DNA repair can have different somatic MST variability (SMV) profiles that may be potential markers for these defects. DNA repair disorders are debilitating conditions that result in physical and neurological abnormalities robbing the individual of a normal quality of life and life span. The various conditions that fall into this class are known as progeroid disorders and they provide a very important glimpse into the aging process on a genomic level. The conditions for four cohorts analyzed here were; Cockayne's syndrome, caused by the loss of the ERCC8 gene, also known as CSA; xeroderma pigmentosum, caused by the loss of the XPA or XPB genes; Werner syndrome, caused by the loss of the RecQL2 gene; and Rothmond-Thomson syndrome, caused by the loss of the RecQL4 gene. The goal of this project was to determine if impaired excision repair genes CSA or global XPA and B or excision repair supporting helicases BLM or RecQL4 leads to MST destabilization. Comparing cohorts from excision repair disorders with a co-sequenced normal cohort we found that CSA both RecQ helicases had an effect on the exome somatic variability of MSTs. On the other hand the effects of XPA/B were inconclusive. MST instability (MSI), defined as acquired/lost primary alleles in tumors for a small set of microsatellite loci, has been implicated and is a clinically relevant marker for colorectal cancer. Conversely, no clinically actionable genetic markers have been found for liver cancer, a cancer with a very high mortality rate. Here we explore the use SMV defined as the presence of minor alleles at MST loci, as a complementary measure of MSI as a genetic marker for colorectal and liver cancer by analyzing Illumina sequenced genomes from The Cancer Genome Atlas. Our data shows that SMV may distinguish a subpopulation of African American patients with colorectal cancer, ~33% of the population in this study. Further, for liver cancer, a higher rate of SMV may be indicative of earlier age of onset. In conclusion, the work presented here suggests that MSI should be expanded to include SMV, not only instability. / Ph. D.

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