Colon cancer is a significant risk factor for development of venous thromboembolism (VTE). We assessed trend and outcomes of VTE among hospitalized patients with colon cancer from a Nationwide Inpatient Sample. VTE is associated with higher inpatient mortality and disability but not with length of stay. Hospitalization related to VTE in colon cancer is increasing but mortality continues to decline. Introduction Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalized patients with colon cancer. We assessed nationwide population-based trends in rates of hospitalization and mortality from VTE among patients with colon cancer to determine its impact. Methods We queried the Nationwide Inpatient Sample (NIS) database entries from 2003 to 2011 to identify patients with colon cancer. Bivariate group comparisons between hospitalized patients with colon cancer with VTE to those without VTE were made. Multivariate logistic regression analysis was used to obtain adjusted odds ratios. The Cochrane-Armitage test for linear trend was used to assess occurrences of VTE and mortality rates among patients with colon cancer. Results The total number patients with colon cancer was 1,502,743, of which 41,394 (2.75%) had VTE. The median age of the study population was 69 years; 51.5% were women. After adjusting for potential confounders, compared with those without VTE, patients with colon cancer with VTE had significantly higher inpatient mortality (6.26% vs. 5.52%, OR 1.15, P < .001) and greater disability at discharge (OR 1.38, P < .001), but were not associated with longer length of stay (LOS) or cost of hospitalization. From 2003 to 2011, despite an increase in hospitalization rate with VTE in patients with colon cancer, their mortality steadily declined. Conclusion VTE in hospitalized patients with colon cancer is associated with a significantly higher inpatient mortality and greater disability, but not with longer LOS or cost of hospitalization. Furthermore, even though there has been a trend toward more frequent hospitalizations in this patient population, their mortality continues to decline.

Selected drugs are being utilized as models of putative colon carcinogens in a study of the influence of major types of dietary fiber upon drug pharmacokinetics. Adult, male Wistar rats were pretreated with standardized, isocaloric hydrated gelatin diets containing no fiber or 15% (w/w) cellulose, lignin, hemicellulose (metamucil), or pectin for 30 days. An additional group was fed lab chow ad libitum as a reference control. The pharmacokinetics of acetaminophen, FD & C Red No. 2 and mirex were examined following oral administration in three separate experiments. Among fiber types, pectin and hemicellulose (Metamucil) caused higher peak plasma concentrations of acetaminophen and faster rates of absorption. There was no effect of fiber type on the rate of acetaminophen elimination as determined by the interpretation of the plasma data using the computer programs AUTOAN2 and NONLIN69. Minimal quantities of Red No. 2 were absorbed from the rat intestinal tract, but its microbial metabolite, naphtionic acid, was readily taken up. Pectin produced a 5-fold higher peak plasma concentration of naphthionic acid than control animals on fiber free diet. Cellulose feeding lowered peak plasma concentration of naphthionic acid compared to the fiber control animals. Lack of any fiber in the diet produced a prolonged peak plasma concentration of napthionic acid. The metabolism of Red No. 2 to naphtionic acid by rat cecal contents was augmented by pectin feeding, alone among fiber types. Red No. 2 decreased intestinal transit times in all diet groups, including controls, with there being no difference in transit times between fiber-fed and control animals. Hemicellulose and pectin feeding lowered peak plasma concentrations of mirex compared to control and cellulose fed animals. Lignin, however produced higher peak plasma concentrations of mirex and a 4-fold higher rate of mirex elimination when compared to the fiber-free control group. These differential effects of specific fiber types upon the absorption and disposition of acetaminophen, Red No. 2 and mirex were not consistantly related to the chemical binding-capacities of the fibers of their water-holding capacities.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18853号 / 医博第3964号 / 新制||医||1007(附属図書館) / 31804 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 泰広, 教授 武田 俊一, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

CXCL16 is an interferon-inducible chemokine of the CXC-subfamily and functions as an adhesion molecule, when membrane bound, and a chemoattractant when soluble. Upregulation of cell associated CXCL16 (cCXCL16) in colorectal cancer is associated with increased tumor infiltrating lymphocytes and good prognosis. ADAM10 and ADAM17 are metalloproteinases responsible for cleaving CXCL16, releasing soluble CXCL16 (sCXCL16) and contributing to proliferation and migration of mesangial cells, in kidney inflammatory disease. We hypothesize that cCXCL16 is a substrate for ADAM10 and ADAM17 cleavage in colorectal cancer, releasing sCXCL16, which mediates cell proliferation. To this end, we first identified CXCL16 in the human colon carcinoma cell line, RKO, by immunohistochemistry. cCXCL16 was found in the membrane, cytoplasm and nucleus. We treated RKO, in vitro, with an inflammatory cytokine mix containing 1.4 nM rhIFN[gamma], 2.0 nM rhTNF[alpha] and 2.0 nM rhIL1[beta] to increase the cleavage of cCXCL16 to sCXCL16. Overnight incubation with the cytokine mix significantly (P=.004) increased the release of sCXCL16 compared to normal conditions. To confirm that a metalloproteinase is responsible for the cleavage of cCXCL16, we used a broad spectrum metalloproteinase inhibitor, GM6001, in combination with inflammatory stimulation, in cell culture. We assayed the supernatant using ELISA for sCXCL16. GM6001 at 100 [mu]M decreased sCXCL16 to levels indistinguishable from the background. Using siRNA, we knocked down the expression of ADAM10 and ADAM17, independently, to determine if the activity of each on cCXCL16 was mediated by inflammatory stimulation. It was shown that ADAM10 constitutively cleaved cCXCL16, and ADAM17 cleavage activity was induced by inflammatory stimulation. To determine if sCXCL16 increased colorectal cancer cell (CRC) proliferation through ligand-receptor binding, we treated cells with a range of rhCXCL16 from 3.125-100 ng/mL. rhCXCL16 did not increase RKO proliferation at doses up to 100 ng/mL. We used GM6001, to inhibit the cleavage of cCXCL16 into sCXCL16 then performed an ATPase assay and 6 day cell cycle analysis, under inflammatory stimulation. Increased cleavage of cCXCL16 induced by inflammatory stimulation with the cytokine mix containing 1.4 nM rhIFN[gamma], 2.0 nM rhTNF[alpha] and 2.0 nM rhIL1[beta], increased RKO proliferation and reduced apoptosis. We conclude that ADAM10 and ADAM17 cleavage of cCXCL16 to sCXCL16 is increased by ADAM17 activation with inflammatory stimulation. The cleavage of the extracellular portion from cCXCL16 is associated with increased proliferation and decreased apoptosis of colorectal cancer cells.

no / Chemotherapy drugs usually inflict a lethal dose to tumour cells with the consequence that these cells are being killed by cell death. However, each round of chemotherapy also causes damage to normal somatic cells. The DNA cross-linking agent oxaliplatin which causes DNA double-strand breaks and vinflunine which disrupts the mitotic spindle are two of these chemotherapy drugs which were evaluated in vitro using peripheral lymphocytes from colorectal cancer patients and healthy individuals to determine any differential response. Endpoints examined included micronucleus (MN) induction using the cytokinesis-blocked micronucleus (CBMN) assay and pancentromeric fluorescence in situ hybridisation. Also, survivin expression was monitored since it regulates the mitotic spindle checkpoint and inhibits apoptosis. Oxaliplatin produced cytogenetic damage (MN in binucleated cells) via its clastogenic but also previously unknown aneugenic action, possibly through interfering with topoisomerase II, whilst vinflunine produced MN in mononucleated cells because of incomplete karyokinesis. Survivin expression was found to be significantly reduced in a concentration-dependent manner by not only oxaliplatin but surprisingly also vinflunine. This resulted in large numbers of multinucleated cells found with the CBMN assay. As survivin is upregulated in cancers, eliminating apoptosis inhibition might provide a more targeted chemotherapy approach; particularly, when considering vinflunine, which only affects cycling cells by inhibiting their mitotic spindle, and alongside possibly other pro-apoptotic compounds. Hence, these newly found properties vinflunine – the inhibition of survivin expression - might demonstrate a promising chemotherapeutic approach as vinflunine induces less DNA damage in normal somatic cells compared to other chemotherapeutic compounds. / Saudi Arabian Government

<p>Colorectal cancer (CRC) is the third most prevalent cancer in the United States and estimated to affect 151,030 people and kill 52,580 people in 2022. Although some populations are more susceptible for CRC due to inherited cancer-causing mutations or having family history of CRC, most CRC cases occur sporadically with accumulation of a series of somatic mutation in tumor suppressor genes, oncogenes, and DNA repair system in the colon. Mutations in the adenomatous polyposis coli <em>(APC)</em> and the Kirsten rat sarcoma viral oncogene homologue <em>(KRAS)</em> are known as cancer driving mutations which are most frequently identified genetic lesions at early stages of sporadic CRC development. To evaluate effective drugs for prevention and treatment, preclinical models of CRC that resemble key features of human CRCs are crucial. Genetically modified mouse models (GEMM) of CRC bearing loss of <em>Apc</em> with or without other mutations, such as oncogenic <em>Kras</em> have been valuable tools to study pathobiology, treatment, and prevention of CRC. However, a major limitation of most <em>Apc</em>-mutant GEMMs is the predominant distribution of tumors in the small intestine rather than in the colon. Previously, a murine model bearing colon-specific mutations in <em>Apc</em> and <em>Kras</em> has been reported to develop colon-specific tumorigenesis in the colon, utilizing the <em>carbonic anhydrase 1 promoter/enhancer-Cre recombinase (CAC)</em> in Cre-LoxP system to restrict <em>Apc</em> knockout and a latent expression of oncogenic <em>Kras</em> in the colon tissue. However, only limited features of this model, so called AKC mouse, have been characterized so far. The lack of in depth understanding of this model could potentially hamper its utility for cancer research. Therefore, in Chapter 2 of this dissertation, I first characterized key aspects of disease-related phenotypes including clinical and histopathological features, tumor-elicited inflammation, the transcriptomic profiles, the gut microbial profiles in the AKC mice. Further, comparative analysis has been made on the transcriptomic profiles between AKC mice and human colon cancers with mutations in <em>APC</em> and <em>KRAS</em> at cancer stage II or below to evaluate the utility of the mouse model for studying human CRCs.</p> <p>Chemoprevention is the use of drugs or natural substances to inhibit initiation and delay of the progression of tumorigenesis, which could be a promising approach to reduce the incidence, mortality, and morbidity of CRC. Delta-tocotrienol (𝛿TE) is a natural analogue of vitamin E which has been shown to have antioxidant, anti-inflammatory and anticancer activities. Although its anticancer effects have been studied in different models of CRCs, including carcinogen-induced models, carcinogen-induced colitis-associated models, and colon cancer xenograft models, it has not been tested in a genetic model of sporadic CRC harboring <em>Apc</em> and <em>Kras</em> mutations. Therefore, in Chapter 3, the antitumor effects of 𝛿TE-rich tocotrienols (𝛿TE/gTE) and the potential mechanisms were investigated in AKC mice. 𝛿TE/𝛾TE-supplementation significantly improved the survival of AKC mice and suppressed tumorigenesis in association with inhibition of cell proliferation in the tumors. Further, the anti-tumor effects were correlated with reduction of pro-inflammatory and pro-tumorigenic cytokines, such as interleukin-1b and granulocyte-macrophage colony stimulating factor (GM-CSF), transcriptional enrichment of pathways involved in fatty acid metabolism, and reduction of diacylglycerol (DG) level in the colon tissue.</p> <p>Finally, AKC mice were used for screening the efficacies of other potential chemoprevention candidates, including aspirin, sulindac, and resveratrol in Chapter 4. Aspirin and sulindac are nonsteroidal anti-inflammatory drugs (NSAIDs) and they are among the most studied chemoprevention agents for CRC. However, the long-term regular use of NSAIDs may cause bleedings in the gastrointestinal organ system or hemorrhagic stroke. For aspirin, although extensive studies have shown its beneficial role in the prevention of primary CRC, there are mixed results for its benefit and harms, which may require further identification of populations who will benefit from the regular use of aspirin for prevention of CRC. Resveratrol is a naturally derived polyphenol, which is known for its antioxidant, anti-inflammatory, and antimicrobial activities with generally good safety profile. In our study, when the dietary supplementation of three compounds alone or in combination with 𝛿TE/gTE were examined for its antineoplastic effects in the AKC mice, only aspirin significantly suppressed tumorigenesis with decreased pro-inflammatory and pro-tumorigenic cytokines in the colon without overt toxicity. We found that sulindac induced serious gastric lesions and potential liver toxicity with some animals died earlier than the rest over the study period. Additionally, in this model, resveratrol was not effective in reducing tumorigenesis, in contrast to a previous study where the workgroup used similar genetic model of CRC but different modality to induce the mutations. Our findings add lines of evidence that depending on the use of different models the test compounds, aspirin, sulindac, and resveratrol may exhibit varying cancer prevention effects. Further research is warranted to identify underlying mechanisms that could explain the heterogenous responses to the test compounds and to optimize the interventions. </p>

No description available.

No description available.

Pattern Recognition Receptors (PRRs) are a group of evolutionarily conserved and germline-encoded cellular receptors of the innate immune system that are responsible for recognizing and responding to the entirety of the pathogens a host encounters. The ingenuity of the innate immune system is that with a comparatively miniscule pool of receptors, these receptors are capable of responding to a diverse and large array of pathogens and damage signals. Two highly relevant subsets of PRRs include nucleotide binding domain leucine rich repeat containing (NOD-like) receptors (NLRs) and Toll-like receptors (TLRs). Both NLRs and TLRs have been implicated in several diseases, including autoimmune disorders, inflammatory conditions, and cancer. Mice lacking a specific NLR, NLRP1, are more susceptible to chemically induced colitis and colitis-associated tumorigenesis. We investigated whether the absence of NLRP1 in the gastrointestinal tract influenced the composition of the microbiome, and whether it was responsible for the predisposition of these animals to colitis-associated cancer. By carefully controlling for non-genotype influences, we found that in fact maternal and housing factors were greater predictors over genotype of gut flora composition. This study concluded with a clearer understanding of NLRP1. We next investigated the effectiveness of a novel tumor ablation therapy, termed High-Frequency Irreversible Electroporation (H-FIRE) in a murine model of triple negative breast cancer. The chosen 4T1 model closely mimics aggressive human metastatic triple negative breast cancer, and metastasizes to the same organs. After ablation of the primary mammary tumor, we saw significant improvements in disease burden and metastases, both of which were accompanied by PRR activation within the tumor microenvironment, implicating PRRs in the successful treatment outcome following H-FIRE ablation. Lastly, we generated novel CRISPR-Cas9 plasmids to genetically manipulate the Tlr4 gene of wild type C57Bl/6 mice in order to recapitulate the LPS-hyporesponsive TLR4 protein of C3H/HeJ mice. This proof-of-concept study successfully demonstrated that PRRs can be targets for gene editing purposes, and that nanoparticle delivery leads to enhanced and improved delivery. Collectively, this work attempts to better appreciate the role of PRRs in understanding, treating, and targeting cancer. / Doctor of Philosophy / The work presented here focuses on the role of the immune system in the progression of cancer. Put simply, the properly functioning immune system of a healthy individual should recognize and eliminate mutated or cancerous cells prior to the development of a tumor, thereby implying that the progression to a tumor is due to some dysfunction of the immune system. The immune system is made up of two arms: the innate and adaptive. A key difference between the innate and adaptive immune systems is that upon an infection, the adaptive response is slow and specific while the innate response is rapid and broad. Pattern Recognition Receptors (PRRs) are a group of cellular receptors of the innate immune system that are responsible for recognizing and responding to the entirety of the pathogens a host encounters. The ingenuity of the innate immune system is that with a comparatively miniscule pool of receptors, these receptors are capable of responding to a diverse and large array of pathogens. Two highly relevant PRR families are nucleotide binding domain leucine rich repeat containing (NOD-like) receptors (NLRs) and Toll-like receptors (TLRs). Both NLRs and TLRs have been implicated in several diseases, including autoimmune disorders, inflammatory conditions, and cancer. In this work, we investigated whether the absence of an NLR protein influenced the composition of the microbes that reside within the gastrointestinal tract, and whether this absence was responsible for the predisposition of these animals to colitis-associated cancer. By carefully controlling for all additional influences, we found that in our mice, the other animals with which they shared a cage were more influential on the microbes within the gut, rather than the NLR deficiency. We next investigated a novel tumor ablation therapy in an animal model of breast cancer, which closely mimics human metastatic triple negative breast cancer and metastasizes to the same organs. After treatment of the mammary tumor, we saw significant improvements in disease burden and metastases, both of which were accompanied by PRR activation. Lastly, we manipulated a TLR gene in mice to demonstrate that PRRs can be targeted for therapeutic gene editing. Collectively, this work provides evidence that PRRs are a highly useful tool for improving our understanding of cancer.