Dissertations / Theses on the topic 'Human primary liver cancer'
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1
曹德良 and De-liang Cao. "Over-expression of aldose reductase and a novel aldose reductase-like gene in human primary liver cancers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1996. http://hub.hku.hk/bib/B31234616.
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Cao, De-liang. "Over-expression of aldose reductase and a novel aldose reductase-like gene in human primary liver cancers /." Hong Kong : University of Hong Kong, 1996. http://sunzi.lib.hku.hk/hkuto/record.jsp?B17506438.
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Ladep, Nimzing. "Primary liver cancer : epidemiological and biomarker discovery studies." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24683.
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With previous reports indicating changes in mortality, risk factors and management of primary liver cancer (PLC), evaluation of current trends in the incidence and mortality rates was indicated. Late diagnosis has been implicated to be a major contributor to the high fatality rates of PLC. This work aimed at: • studying trends of PLC by subcategories globally in general, and in England and Wales, in particular; • investigating liver-related morbidities of HIV infected patients in an African setting; and • discovering urinary biomarkers of hepatocellular carcinoma. The World Health Organisation (WHO) and Small Area Health Statistics Unit (SAHSU) databases were interrogated respectively, in order to achieve the first aim. The second aim was achieved through utilisation of databases of an African-based HIV treatment programme- AIDS Prevention Initiative in Nigeria (APIN), located in Jos, Nigeria. The European Union-funded Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) case-control study in three West African countries was the platform through which urinary metabolic profiling was accomplished. Proton nuclear magnetic resonance spectroscopy (NMR) and parallel ultra-performance liquid chromatography mass spectrometry (UPLC-MS) were used for biomarker discovery studies. Mortality rates of intrahepatic bile duct carcinoma (IHBD) increased in all countries that were studied. Misclassification of hilar cholangiocarcinoma accounted for only a small increase in the rate of IHBD in England and Wales. With over 90% screening rate for viral hepatitides, the rates of hepatitis B (HBV), hepatitis C (HCV) and HBV/HCV in HIV-infected patients in the APIN programme were 17.8%, 11.3% and 2.5% respectively. There was attenuated immune response as well as significantly lower survival observed in HBV/HIV co-infection, relative to HIV mono-infected patients (p=0.0097). Whereas single urinary metabolites, including acetylcarnitine, N-acetylglutamate, betaine aldehyde, 3'-sialyllactose, methionine among others possessed high discriminatory power to diagnose HCC, a combination of three metabolites: 3'-sialyllactose, methionine and 9-decenoylcarnitine significantly outperformed serum alpha-fetoprotein (AFP) in the diagnosis of HCC in a cirrhosis population (area under the receiver operating characteristic curve; [urinary panel= 0.96] compared to [AFP = 0.64]). This work informs a critical assessment of current control strategies in the prevention of HCC, and potentially assists in the development of more affordable means of early detection of PLC for most affected regions of the world.
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Hubbard, J. G. H. "Primary tamoxifen therapy in human breast cancer." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341491.
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Clifford, Steven Curtis. "Determinants of chemosensitivity in human primary bladder cancer." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239771.
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Collier, Jane Davina. "Molecular mechanisms in human hepatocellular carcinoma." Thesis, University of Newcastle Upon Tyne, 1993. http://hdl.handle.net/10443/693.
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Hepatocellular carcinoma (HCQ is one of the commonest cancers worldwide. There is, however, a marked geographical variation in incidence and it has been suggested that the pathogenesis may vary in different parts of the world. A retrospective analysis of 110 HCC patients was initially undertaken which confirmed that only 29% of British patients had markers of hepatitis B infection, suggesting a possible role for other environmental agents in the pathogenesis, and that 80% of patients had underlying cirrhosis. The nature of the strong relationship between HCC and cirrhosis has not been established but it has been postulated that increased hepatocyte turnover in the cirrhotic liver may predispose to DNA damage by environmental mutagens. Cell proliferation is required to express the strongly promutagenic DNA base lesion 0'-methylguanine, produced by alkylating agents, as a mutation. &- methylguanine is repaired by the DNA repair enzyme 06-methylguanine-DNA methyltTansferase (06-MT). A microassay was developed which could reliably measure 06-MT levels in liver biopsy samples. Using this approach 06-MT levels were found to be significantly lower in cirrhotic liver when compared to non-cirrhotic and normal liver tissue. No correlation was found between lymphocyte and liver levels from individual patients with liver disease indicating that the deficiency in DNA repair is disease-a nd tissue-specific. Three polyclonal antibodies were subsequently raised to 06-MT peptides and characterised by immunoblotting in an attempt to establish the tissue distribution of the enzyme in liver. Although none of the antisera were able to detect &-MT in tissue sections they were used to analyse structural differences in the enzyme between cirrhotic and non-cirrhotic liver using SDS-PAGE followed by immunoblotting and fluorography. A band of M, 24,000r,e presentingn ative enzyme, was visualised by fluorography in all liver extracts. Densitometry of these bands correlated with the enzyme activity determined by the direct enzyme assay, validating the assay findings. Other small molecular weight bands were seen in all liver extracts and comparison with immunoblots suggested that these bands represent C-terminal truncated enzyme. The spectrum of smaller molecular weight enzyme forms was similar in cirrhotic and non-cirrhotic liver. It was, thus, concluded that although 06-MT levels were lower in'cirrhosis this was not accounted for by structural differences in the enzyme. DNA mutations (G to A) produced by the failure to repair 06-methylguanine are known to activate oncogenes and turnour suppressor genes such as p53. However only 5/55 (9%) of HCC expressed mutant p53. Other factors potentially involved in hepatocarcinogenesis include the growth factor TGF-a and a growth factor receptor encoded by the c-erb B-2 proto-oncogene. Expression of TGF-a and the C-erbB -2 oncoprotein were seen in 8/28 (28%) and 2/26 (8%) of HCC respectively, findings which differ from those observed in HCC from the Far East. Deficient DNA repair by &-MT provides one possible reason why cirrhosis is an important risk factor for the development of HCC. However, failure to repair 06-mothylguanine does not result in mutations within the p53 gene in British HCC. Furthermore, the finding of low expression of mutant p53, TGF-a and the c-erb B-2 oncoprotein in HCC from Britain compared to HCC from the Far East and Africa suggests geographical differences in the molecular mechanisms involved in hepatocarcinogenesis between areas of high and low HCC prevalence.
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Chan, Chun-Fai. "Study of cancer vaccine candidates for human hepatocellular carcinoma (HCC) /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202004%20CHAN.
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AOKI, KUNIO, RYUICHIRO SASAKI, and ZHU-MIN HUANG. "Trends in Mortality from Primary Liver Cancer, Cirrhosis of the Liver, Virus Hepatitis, and Other Liver Diseases 1968-1984 in Japan." Nagoya University School of Medicine, 1987. http://hdl.handle.net/2237/17497.
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Easom, Nicholas James Wilson. "Interactions between tumour and natural killer cells in primary and secondary liver cancer." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042188/.
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Natural killer (NK) cells are implicated in tumour surveillance and control in a number of settings. The liver contains large numbers of NK cells and hepatocellular carcinoma (HCC) has been shown to express various ligands that permit interactions with NK cells, some of which have been shown to have prognostic significance. Similar prognostic associations have been shown for colorectal cancer, a tumour which commonly metastasizes to the liver. However the mechanistic underpinning of these effects is unclear. This thesis describes a survey of soluble NKG2D ligand expression in patients with HCC caused by chronic hepatitis B (CHB), patients with CHB without cancer, and healthy controls. ULBP1 was found to be raised in HCC patients; where it was associated with poor survival, and in active CHB; where it was associated with hepatitis B viral load. ULBP1 was not seen in secondary liver tumours, suggesting that this protein may be useful as a biomarker of severe disease or to monitor treatment response. The other NKG2D ligands MICA, MICB, ULBP2 and ULBP3 were not found to be elevated in patient serum. Soluble NKG2D ligands did not affect NKG2D expression by circulating NK cells. Tumour infiltrating NK cells have the potential to be important effector cells, but are functionally defective. This work builds on recent advances in the understanding of liver-resident NK cells to characterise the functional defect in primary and secondary liver cancers, using human ex vivo intrahepatic and tumour-infiltrating NK cells. Using an in vitro model of HCC we have investigated the mechanisms for this defect and examine the potential for IL- 15 to restore NK cell cytotoxicity and cytokine production. Ex-vivo tumourinfiltrating NK cells had reduced NKG2D expression, IFNγ production and degranulation potential compared with paired intrahepatic NK cells, but maintained expression of NKp46. We were able to recapitulate this phenotype by co-culture with an HCC cell line, but were not able to protect NK cells from NKG2D downregulation and functional inhibition by NKG2D blockade. However, IL-15 was able to restore function after HCC exposure. This model may serve as an in-vitro assay for future therapeutics targeting tumour-infiltrating NK cells.
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Cunha, Virgínia Filipa Pereira Monteiro da. "Human adipose tissue primary cultures and impact in prostate cancer." Master's thesis, Universidade de Aveiro, 2009. http://hdl.handle.net/10773/8985.
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Mestrado em Biologia Aplicada - Molecular e CelularProstate cancer (Pca) is one of the most frequent diagnosed neoplasies and the second cause of cancer-related death in the world, in men. Between others risk factors, obesity has been associated to Pca although the innerent mechanisms to this association remain to be clear. With this work, throuhg in vitro studies, we wish to contribute to the understanding of the impact of white adipose tissue and its sub-fractions (adipocytes and stromal vascular fraction), from visceral and periprostatic anatomic regions, in celular proliferation, apoptosis and invasion of castration sensitivity (LNCaP) and castration resistant (PC-3) prostate cells. With the purpose of obtaining answers directly from humam studies, were performed visceral and periprostatic adipose tissue primary cultures obtained during urologic surgeries (radical prostatectomy and prostatic adenomectomy) (n=16). Adipose tissue was used to make primary organotipical cultures (WAT) and after collagenase digestion adipocytes and SVF primary cultures. Sobrenatants and infranatants of each culture were collect and used as conditioned medium representing adipokines production. LNCaP and PC-3 cell lines were stimulated with these mediums and apoptosis, proliferation and invasion were evaluated, in vitro. This study model represent a potential form for analyze the impact of adipose tissue in tumor cells, allowing to evaluate adipose tissue-tumor interactions. The results show that adipose tissue promotes tumor cells proliferation, that periprostatic adipose tissue increase apoptosis in obese individuals and that SVF subfraction suppresses invasion of PC-3 cells through a direct effect in tumor cells.
O Cancro da próstata (CaP) é uma das neoplasias mais frequentemente diagnosticadas e a segunda causa de morte por cancro no mundo nos homens. Entre outros factores de risco, a obesidade tem sido frequentemente associada a CaP, embora permaneçam por esclarecer os mecanismos subjacentes a esta associação. Com o presente trabalho pretendeu-se através de estudos in vitro, contribuir para a compreensão do impacto do tecido adiposo branco e suas sub-fracções (adipócitos e fracção vascular estromal), com origens anatómicas periprostática e viceral, na proliferação, apoptose, e invasão celular de células de cancro da próstata sensíveis à castração (LNCaP) e resistentes à castração (PC-3). Com o propósito de obter respostas directamente através de estudos em humanos, foram efectuadas culturas primárias de tecido adiposo periprostático e visceral obtido durante cirurgias urológicas (prostatectomia radical e adenomectomia prostática) (n=16). O tecido adiposo foi utilizado para realizar culturas primárias organotípicas (tecido adiposo total fraccionado) e após digestão com colagenase culturas primárias de adipócitos e de células da fracção vascular estromal do tecido adiposo. Foram colhidos sobrenadantes e infranadantes destas culturas de tecido adiposo e utilizados como meios condicionados representativos da produção de adipocinas. As linhas celulares LNCaP e PC-3 foram estimuladas com estes meios e avaliados a apoptose, proliferação celular e invasividade tumoral in vitro. Este modelo de estudo representa um potencial meio para análise do impacto do tecido adiposo nas células tumorais, permitindo avaliar as interacções tecido adiposo-tumor. Os resultados evidenciam que o tecido adiposo promove a proliferação das células tumorais, que o tecido adiposo periprostático aumenta a apoptose em indivíduos obesos e que os SVF suprimem a invasão das PC-3 através de um efeito directo nas células tumorais.
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Obara, Akio. "DEPTOR-related mTOR suppression is involved in metformin’s anti-cancer action in human liver cancer cells." Kyoto University, 2015. http://hdl.handle.net/2433/200493.
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Pang, Wen-chi Roberta, and 彭詠枝. "The role of Pin1 in the pathogenesis of human hepatocellularcarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36905847.
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The Best PhD Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize,2005-2006published_or_final_version
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Medicine
Doctoral
Doctor of Philosophy
13
Campbell, Andrew M. "Microsphere distribution and radiation dosimetry in human liver following Yttrium-90 microsphere therapy." Thesis, Curtin University, 2000. http://hdl.handle.net/20.500.11937/1742.
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The microscopic distribution of microspheres and the resulting radiation dose deposition patterns in human liver following hepatic arterial infusion of 90Y labelled microspheres have been investigated. Tissue samples from normal liver, the tumour periphery and tumour centre were taken from a patient following infusion of 3 GBq of 32 pm diameter resin microspheres labelled with 90Y as treatment for an 80 millimetre diameter metastatic liver tumour. Microspheres were found to deposit inhomogeneously in tissues, preferentially lodging in a region approximately 6 mm wide around the periphery of the tumour. A relative concentration of microspheres of 50 to 70 times that of normal hepatic parenchyma and 65 to 94 times that in the tumour centre was measured in this region. The deposition of microspheres in the tumour periphery was not uniform, and cluster analysis showed that the spheres could be classified into clusters. The number of microspheres in a cluster was skewed towards low numbers and cluster sizes varied from 20 pm to 1500 pm. Microsphere deposition in normal liver was demonstrated to be non-uniform, there being significant variations in concentration over distances on the order of 3 to 4 millimetres. The observed microsphere distributions in three dimensions were used to calculate radiation dose patterns, and the results showed that heterogeneous doses were delivered to all tissues. Within the tumour periphery average doses ranged from 200 Gy to 600 Gy with minimum doses between 70 Gy and 190 Gy. The maximum and minimum doses for the tumour centre sample were 920 Gy and 3.7 Gy respectively, the median dose was 5.8 Gy. In the normal liver sample the median dose was 7.3 Gy with maximum and minimum doses of 753 Gy and 5 Gy respectively. Less than 1% of the normal liver tissue volume received more than 30 GY, the level above which complications have resulted for whole liver exposure using external beam radiotherapy. These calculations suggest that preferential deposition of microspheres in the well vascularised periphery of large tumours will lead to a high proportion of the tumour volume receiving a therapeutic dose, with most of the normal liver tissue being spared substantial damage.
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Ng, Lui, and 吳磊. "Actopaxin: a novel regulator of cell migration and invasion in human hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47752610.
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Invasion and metastasis are the major causes of treatment failure and high mortality rate in hepatocellular carcinoma (HCC) patients. Cell motility is crucial to tumor invasion and metastasis, requiring the ability of tumor cells to interact with extracellular matrix, which is regulated by integrins and integrin-associated molecules at the focal adhesions. Recent studies have demonstrated the role of β1 integrin (CD29) overexpression in HCC and its correlation with cancer cell invasiveness and metastastic potential, as well as its protective role against cancer cells against chemotherapeutic drug-induced apoptosis, yet the mechanism is not fully known. Focal adhesion proteins serve as binding platforms for additional cytoskeletal and signaling molecules in the CD29 signaling pathway. Recently, Actopaxin has been demonstrated to form complex with numerous molecules at the focal adhesions, including ILK, which interacts with the cytoplasmic tail of CD29. Through these interactions, Actopaxin has been shown to regulate different cellular events, including cell survival, spreading and cell migration. In this study, the role of Actopaxin in HCC was investigated. In particular, its role in the regulation of tumor invasion and metastasis of HCC cells was demonstrated.
This study showed that Actopaxin expression was overexpressed in HCC specimens when compared with the adjacent non-tumorous liver, and that its overexpression positively correlated with tumor size, stage and metastasis in HCC specimens. Actopaxin expression was also correlated with the metastatic potential in HCC cell-lines. Functional studies established that overexpression of Actopaxin conferred invasive phenotypes in primary, non-metastatic HCC cells, whereas down-regulation of Actopaxin could revert the invasive phenotypes and metastatic potential of metastatic HCC cells in vitro and in vivo. Suppression of Actopaxin expression was associated with reduced expression of ILK, PINCH, Paxillin and cdc42, whereas expressions of E-cadherin, β-catenin and GSK3β were induced, indicative of a less invasive and invasive phenotype. Conversely, overexpression of Actopaxin in primary, non-metastasis HCC cells accordingly up-regulated the expression of ILK, PINCH, Paxillin and cdc42, and down-regulation of of E-cadherin, β-catenin and GSK3β, suggestive of an enhanced invasive phenotype. The expression of Actopaxin was found to be correlated with CD29 level, indicating that Actopaxin is a CD29-associated protein and involved in CD29-regulated signaling. Finally, Actopaxin down-regulation enhanced chemosensitivity of of HCC cells towards chemotherapeutic treatment. Treatment with Oxaliplatin was enhanced in Actopaxin-deficient HCC cells, which showed a stronger inhibitory effect on cell proliferation and cell cycle progression, accompanied with induction on apoptosis. The enhanced chemosensitivity effect was a collective result of suppression of Survivin protein, β-catenin and mTOR pathways; and up-regulation of p53.
To conclude, this study demonstrated for the first time that Actopaxin is involved in HCC invasion, metastasis and chemosensitization, providing the basis to further investigate the potential role of this protein or its downstream effectors as a therapeutic target for inhibiting the development of metastasis and enhancing chemotherapy efficacy to combat HCC, and perhaps other invasive cancers.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy
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Ayres, Reuben Christopher Simon. "In vitro investigation into the role of human intrahepatic biliary epithelial cells as targets in primary biliary cirrhosis." Thesis, University of Southampton, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296245.
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Patitucci, Cecilia. "PPARy, a new player in hepatic metabolic adaptation from mouse model to human liver cancer." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB056/document.
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La tumorigenèse est influencée par des facteurs génétiques et environmentaux. La surnutrition est une cause d'obésité et d'accumulation pathologique de lipides dans le foie, la stéatose, qui peut évoluer en stéato-hépatite. Obésité et stéato-hépatite contribuent à l'augmentation de l'incidence du diabète dans le monde entier. Le diabète et l'obésité sont des facteurs de risque pour le cancer du foie (El-Serag et al., Clin Gastroenterol Hepatol, 2006). Cet projet de thèse élucide les mécanismes moléculaires liant l'activation de la voie de signalisation de l'insuline, les maladies du foie gras et le développement du cancer du foie, et il propose de nouvelles stratégies thérapeutiques. La délétion hépato-spécifique du gène codant le suppresseur de tumeurs Phosphatase and tensin homolog (PTEN) est un modèle de cancer du foie associé à la stéatose (Horie et al., J Clin Invest, 2004). Nous avons utilisé ce modèle, où la cascade de signalisation PI3K/mTOR est activée, pour démontrer que l'induction de l'expression du facteur de transcription et récepteur nucléaire Peroxysome Proliferator-Activated Receptor gamma (PPARγ) est responsable de la stéatose et de la glycolyse aérobie (effet Warburg). Son activité est spécifiquement dépendente de l'activité d'un effectuer en aval de la voie PI3K/mTOR, la protéine sérine/thréonine kinase, AKT2 (Panasyuk et al., Nat Comm, 2012). Sur la base de ces observations, nous avons construit l'hypothèse que PPARγ est un important régulateur de la croissance pathologique et du développement des adénocarcinomes hépatiques associés aux stéato-hépatites. Avec mon travail de thèse j'ai pu démontrer que l'expression et l'activité de PPARγ sont essentielles pour le développement du cancer du foie dans le modèle de souris invalidées pour PTEN dans les hépatocytes. Par ailleurs, la délétion de PPARγ dans le foie dépourvu de PTEN joue un rôle protecteur de la tumorigenèse, confirmant que PPARγ est effectivement placé en aval de AKT2. De plus, nous avons découvert que PPARγ est induit dans des échantillons de carcinome hépatocellulaire humains. Ces échantillons sont caractérisés par leur agressivité (haut taux prolifératif et bas niveau de différentiation) et aussi par l'activation de la voie PI3K/AKT. L'analyse des échantillons humains au stade pré-carcinome (adénomes) nous a permis de démontrer que l'ARN de PPARγ est le plus exprimé dans les adénomes caractérisés par un haut degré de stéatose. Ils sont caractérisés par la perte de fonction du facteur de transcription Hepatocyte Nuclear Factor 1α (HNF1α). Nous avons identifié HNF1α comment un nouveau régulateur négatif de la transcription de PPARγ. Nous avons aussi découvert que l'expression et l'activité de HNF1α sont inhibées par AKT2, induisant l'expression de PPARγ et son activité pro-tumorigénique. Finalement, la sensitibilité de PPARγ aux ligands, naturels et exogènes, nous a encouragé à tester des traitements pharmacologiques pour moduler son activation. La stimulation de l'activité de PPARγ avec l'agoniste synthétique Pioglitazone a conduit à une aggravation des symptomes dans le foie. Par contre, son inhibition par un antagoniste sélectif, SR2595, était thérapeutique, resultant en une réduction de signes pré-tumoraux et tumoraux dans le foie des souris invalidé par PTEN. En résumé, nos études chez l'humain et la souris, révèlent une nouvelle signature d'interaction entre les facteurs de transcription HNF1α et PPARγ et la voie de signalisation de l'insuline, suggérant de nouvelles stratégies thérapeutiques possibles pour le traitement d'une sous-classe spécifique de cancer du foie lié aux stéato-hépatitesTumorigenesis is influenced by genetic and environmental factors. Overnutrition leads to obesity and fatty liver disease, contributing to increase diabetes incidence worldwide. Diabetes and obesity are independent risk factors for liver cancer development (El-Serag et al., Clin Gastroenterol Hepatol, 2006). This PhD project elucidates the molecular mechanisms linking activated insulin signalling pathway, fatty liver disease and liver cancer development and proposes novel therapeutic strategies. The hepatocytes-specific deletion of tumour suppressor Phosphatase and tensin homolog (PTEN) is a model of steatosis-associated liver cancer (Horie et al., J Clin Invest, 2004). Using this model of activated PI3K/mTOR signalling, our laboratory discovered that the nuclear receptor transcription factor Proliferator-Activated Receptor gamma (PPARγ) is induced in PTEN-null liver. My group demonstrated that in the liver PPARγ contributes to steatosis and aerobic glycolysis. Its activity specifically requires a downstream effector in the PI3K/mTOR pathway, the serine/threonine-specific protein kinase AKT2 (Panasyuk et al., Nat Comm, 2012). Based on these observations, we hypothesized that PPARγ might be an important regulator of pathological growth and development of steatohepatitis-associated liver adenocarcinomas. In my PhD work, I demonstrated that PPARγ expression and activity is essential for liver cancer in PTEN mutants. Moreover, PPARγ is induced in human samples of Hepatocellular Carcinoma (HCC) characterized by poor differentiation accompanied by the activation of PI3K/AKT pathway. We could attribute to PPARγ a specific role in tumour formation as it is required for abnormal liver growth and steatosis in mice at pre-tumoral age. In addition, deletion of PPARγ in PTEN mutants protected animals form liver tumorigenesis placing PPARγ downstream of activated AKT2. Analysing human samples of pre-carcinoma lesions characterized by high steatotic rate, we demonstrated that PPARγ transcript levels are increased in a specific subgroup of adenomas characterized by loss-of-function mutations in the Hepatocyte Nuclear Factor 1α (HNF1α). We identified HNF1α as a novel direct negative regulator of PPARγ transcription. We also revealed HNF1α expression and activity inhibited by AKT2 and thereby inducing PPARγ pro-tumorigenic action. Finally, the sensitivity of PPARγ to natural and exogenous ligands encouraged us to perform treatments to pharmacologically modulate PPARγ activity. Further activation of PPARγ with its synthetic ligand pioglitazione dramatically aggravates liver disease. While PPARγ inhibition by selective antagonist SR2595 allowed to reduce the pre-tumoral and tumoral signs of PTEN-null mice. In sum, our studies in men and mice reveal a novel pro-tumorigenic network of transcription factors HNF1α and PPARγ downstream of activated insulin signalling pathway, suggesting possible strategies for treatment of a subgroup of steatohepatitis-associated liver cancer
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Campbell, Andrew M. "Microsphere distribution and radiation dosimetry in human liver following Yttrium-90 microsphere therapy." Curtin University of Technology, School of Applied Science, 2000. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=9972.
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The microscopic distribution of microspheres and the resulting radiation dose deposition patterns in human liver following hepatic arterial infusion of 90Y labelled microspheres have been investigated. Tissue samples from normal liver, the tumour periphery and tumour centre were taken from a patient following infusion of 3 GBq of 32 pm diameter resin microspheres labelled with 90Y as treatment for an 80 millimetre diameter metastatic liver tumour. Microspheres were found to deposit inhomogeneously in tissues, preferentially lodging in a region approximately 6 mm wide around the periphery of the tumour. A relative concentration of microspheres of 50 to 70 times that of normal hepatic parenchyma and 65 to 94 times that in the tumour centre was measured in this region. The deposition of microspheres in the tumour periphery was not uniform, and cluster analysis showed that the spheres could be classified into clusters. The number of microspheres in a cluster was skewed towards low numbers and cluster sizes varied from 20 pm to 1500 pm. Microsphere deposition in normal liver was demonstrated to be non-uniform, there being significant variations in concentration over distances on the order of 3 to 4 millimetres. The observed microsphere distributions in three dimensions were used to calculate radiation dose patterns, and the results showed that heterogeneous doses were delivered to all tissues. Within the tumour periphery average doses ranged from 200 Gy to 600 Gy with minimum doses between 70 Gy and 190 Gy. The maximum and minimum doses for the tumour centre sample were 920 Gy and 3.7 Gy respectively, the median dose was 5.8 Gy. In the normal liver sample the median dose was 7.3 Gy with maximum and minimum doses of 753 Gy and 5 Gy respectively. Less than 1% of the normal liver tissue volume received more than 30 GY, the level above which complications have resulted for ++whole liver exposure using external beam radiotherapy. These calculations suggest that preferential deposition of microspheres in the well vascularised periphery of large tumours will lead to a high proportion of the tumour volume receiving a therapeutic dose, with most of the normal liver tissue being spared substantial damage.
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Zielinski, Nicholas C., and Grant Skrepek. "Mortality and Cost Outcomes of Emergency Department Visits Associated with Primary or Disseminated Liver Cancer in the United States; 2009." The University of Arizona, 2012. http://hdl.handle.net/10150/614537.
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Class of 2012 AbstractSpecific Aims: To evaluate associations between hospital and patient characteristics and mortality and economic outcomes. Included records were of adult patients age 18 years or older with a diagnosis of primary or disseminated liver cancer. Methods: This study was a retrospective cohort design that utilized emergency department discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) National Emergency Department Sample (NEDS). Generalized linear models were used for analyses to assess outcomes of mortality and total charges. Logistic regression was utilized for mortality; gamma regression with log-link was utilized for charges. Main Results: Overall, 239,895 adult records were included in the study with diagnoses of ICD-9 155.x or 197.7. Total charges for all records were over $8.23 billion in 2009. The average age of the case was 65.07 (±13.8) years with 48.7% being female. Mortality (either in the ED or hospital) was 11.1% (n=26,701). The mean length of stay was 6.47 (±6.05) days. Charges for each record were $42,874.50 (±53,956.34). Increased mortality was associated the most with hospital teaching status and primary payer. Increased charges were associated with hospitals located in the Western region. Conclusions: The differences in clinical outcomes were primarily from different payers and economical outcomes differed greatly by the Western region hospital location. Data taken from the nationally-representative investigation reveals that primary and disseminated liver cancer still remains a clinical high burden-of-illness with an 11.1% mortality rate and total charges approaching $10.3 billion dollars.
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Ma, Wei, and 馬威. "Study of the roles of RhoE in human hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205869.
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Hepatocellular carcinoma (HCC) is the seventh most prevalent cancer and the third leading cause of cancer-related mortality globally. Metastasis is a major cause of mortality. HCC is also highly chemoresistant which limits treatment options to patients. Understanding the molecular mechanisms involved in these two events is of crucial significance. Deregulation of Rho/ROCK signaling is common in HCC and regulates different cellular events including cell invasion and survival. In this study, we aimed to further investigate how members of the Rho/ROCK pathway regulate HCC cell invasion and chemoresistance.
By screening 71 pairs of human HCC samples using real-time qPCR, we identified that RhoE was frequently downregulated in human HCC. RhoE serves as an antagonist of the Rho/ROCK pathway. Clinicopathologically, downregulation of RhoE associated with shorter patient disease-free survival. In virto assays showed that stable knockdown of RhoE enhanced both HCC cell migration and invasion. In vivo mouse models also demonstrated that knockdown of RhoE promoted HCC invasiveness and intra-hepatic metastasis. Mechanically, knockdown of RhoE increased ROCK activity
By screening 71 pairs of human HCC samples using real-time qPCR, we identified that RhoE was frequently downregulated in human HCC. RhoE serves as an antagonist of the Rho/ROCK pathway. Clinicopathologically, downregulation of RhoE associated with shorter patient disease-free survival. In virto assays showed that stable knockdown of RhoE enhanced both HCC cell migration and invasion. In vivo mouse models also demonstrated that knockdown of RhoE promoted HCC invasiveness and intra-hepatic metastasis. Mechanically, knockdown of RhoE increased ROCK activity and inhibition of ROCK reversed the effect of RhoE knockdown on cell migration. RhoE overexpression induced disassembly of stress fibers while knockdown of RhoE enhanced formation of plasma membrane blebs. These findings suggested that RhoE acts as a metastatic suppressor in HCC via inhibiting Rho/ROCK signaling.
Downregulation of RhoE can increase ROCK activity which is reported to regulate cell survival. Therefore we investigated if the frequent downregulation of RhoE contributes to the high chemoresistance in HCC cells. Stable knockdown of RhoE suppressed cell death/apoptosis induced by chemotherapeutic agents such as cisplatin and doxorubicin. This effect could be reversed by addition of ROCK inhibitor. In vivo mouse model also confirmed that RhoE knockdown augmented HCC chemoresistance. We also observed that combined treatment of cisplatin and ROCK inhibitor profoundly inhibited tumor growth in nude mice. This part of our findings indicated that RhoE/ROCK played an important role in regulating chemoresistance in HCC.
We further identified two downstream molecular pathways which were involved in Rho/ROCK-induced chemoresistance. We found that STAT3 and JAK2 were activated by RhoE knockdown but inhibited by addition of ROCK inhibitor. Upon ROCK inhibition, expression of IL-6 and IL-6 receptor were suppressed and the transcription activating activity of STAT3 was also repressed. Finally, ROCK inhibition attenuated Erk1/2 activation. Literature searching suggested nuclear PTEN as a potential candidate for inactivating Erk1/2. We demonstrated that inhibition of ROCK increased the population of nuclear PTEN while overexpressing ROCK2 decreased it. Overexpression of nuclear PTEN alone could already reduce Erk activation in HCC cells. Our findings indicated that RhoE/ROCK may exert their effects on chemoresistance in HCC via regulating the IL-6/JAK2/STAT3 and PTEN/Erk pathways.
In conclusion, our study demonstrated the important role of RhoE in HCC. First, aberrant underexpression of RhoE promoted HCC invasion and intra-hepatic metastasis through upregulating the Rho/ROCK signaling. Second, downregulation of RhoE increased activity of the pro-survival IL-6/JAK2/STAT3 and Erk signalings to enhance chemoresistance in HCC cells. Our findings also suggested the Rho/ROCK signaling to be potential therapeutic target in anti-metastatic and chemo-sensitizing therapy.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
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Castven, Darko [Verfasser]. "Patient-derived cancer cells to dissect the molecular basis of treatment response in primary liver cancer: a mechanistic and functional approach / Darko Castven." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1198442395/34.
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LEE, EUNSUK. "RELATIONSHIPS AMONG DEPRESSIVE SYMPTOMS, SPIRITUAL WELL-BEING, AND QUALITY OF LIFE IN PRIMARY LIVER CANCER PATIENTS IN KOREA." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1333599857.
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Mastrogiovanni, Gianmarco. "Establishment of new human and mouse liver cancer models and their use to uncover the role of RNF43 and ZNRF3 in liver homeostasis and repair." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273341.
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Primary liver cancer (PLC) is the second most common cause of cancer death worldwide, preceded only by lung cancer. Current models for PLC either fail to fully recapitulate tumour histology and architecture or are expensive, time consuming and do not allow for personalised drug testing. During the first part of my PhD, I have collaborated with Dr. Laura Broutier in order to established a new 3D in vitro model system for liver cancer. Based on the current knowledge on organoid cultures, we have managed to establish a system to grow primary human liver cancer cells long-term (Broutier et al., in press). Interestingly, the tumour-derived organoids (tumoroids) recapitulate the original tumour histology and genetic alterations and are also able to generate tumours in an in vivo xenograft mouse model after long-term expansion. Furthermore, we have shown that tumoroids can also be successfully used for drug testing, suggesting their use to devise new targeted therapy as well as personalised treatment strategies. Current models to investigate the role of genes in cancer rely mostly on animal studies, which can be very time consuming and cost demanding, especially if resulting in negative outcomes. To overcome this issue, I have set up a protocol for introducing mutations in healthy human liver organoids using the CRISPR-Cas9 technology. Interestingly, after mutating TP53, RNF43 and ZNRF3 either alone or in combination, human organoids undergo genetic alterations and phenotypic changes that partially resemble the ones observed in tumoroids. This data suggests that this system could be used as a screening platform to study gene function before using animal models. In the last part, I have further explored the role of RNF43 and ZNRF3 (R&Z) - two newly identified WNT pathway negative regulators mutated in many cancer types - in the liver using an in vivo mouse model. Interestingly, conditional deletion of R&Z specifically in adult mouse hepatocytes results metabolic changes that eventually lead to extensive liver damage. However, when the liver is challenged to regenerate in a chronic damage model, R&Z mutated livers fail to fully repair and show presence of multiple regenerative nodules. Later, livers develop either focal nodular hyperplasia and/or early hepatocellular carcinoma. These data suggest that R&Z have an important role in both liver metabolic homeostasis and liver regeneration and that their alteration can eventually lead to cancer formation.
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Coles, Christopher. "Loss of heterozygosity on chromosome 17 and p53 mutation in primary human breast cancer." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/19636.
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A high frequency of LOH (61%) has been detected in a series of breast tumours at a site at a 17p13.3 suggesting the presence of a tumour suppressor gene involved in breast cancer on chromosome 17p (Mackay et al., 1988a). Following on from this work the incidence of LOH in primary breast tumours was determined at other loci on chromosome 17p and served a two fold purpose. First, the pattern of LOH at different loci on chromosome 17 in individual breast tumours was determined in order to define a shortest region of overlap (SRO). Identification of such a region, commonly lost in all tumours showing LOH, could be used to pinpoint the position of the putative tumour suppressor gene. Secondly, as two of the probes used to investigate LOH detect loci close to the known tumour suppressor gene p53, a potential role of the p53 gene in breast cancer development could be investigated. Two tumour samples showed LOH at the p53 locus and not at the more distal 17p13.3 site, suggesting the involvement of the p53 gene in breast tumorigenesis. Furthermore LOH at the p53 gene locus was detected in 49% of primary breast tumour samples. Exons 5-9 of the p53 gene, which contain known mutation hotspots, were examined for mutation in 78 primary breast tumours using the HOT (amplification and mismatch detection) technique. Twenty four (31%) of the breast tumours were found to possess a somatically acquired p52 mutation, mostly single base substitutions resulting in missense mutations. In tumours with data on both LOH and p53 mutation, the majority of p53 mutations were found to be accompanied by LOH, indicating the importance of the removal of the tumour suppressive function of the gene.
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Lu, Wenjing, and 鲁文静. "The interaction of mortalin and p53 in human hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46330069.
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Schuster, Susanne, and Antje Garten. "Resveratrol Differentially Regulates NAMPT and SIRT1 in Hepatocarcinoma Cells and Primary Human Hepatocytes." Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142581.
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Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate
the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on
NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells)
and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in
hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in
hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and
apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol
treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol
induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was
absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by
EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53
hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that
NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that
resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells.
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Cockbain, Andrew James. "The effect of eicosapentaenoic acid on biomarkers of growth and vascularity of human colorectal cancer liver metastases." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/5903/.
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Background: The omega-3 fatty acid eicosapentaenoic acid (EPA) has been demonstrated to be incorporated into tumours and inhibit tumour growth in pre-clinical models of colorectal cancer liver metastases (CRCLM). Aims: To test the safety, tolerability and effect on tumour biomarkers of growth and vascularity of orally administered EPA in patients awaiting liver resection surgery for CRCLM. Methods: In a Phase II randomised, double-blind, placebo-controlled trial, patients with CRCLM received EPA 2g daily (n=43) or placebo (n=45) prior to surgery. CRCLM tissue was analysed for fatty acid content, PGE2 content, proliferation index (Ki-67), apoptosis index and vascularity. Blood was collected for platelet function and monocyte NFkB binding studies, and urine for measurement of PGE-M. Supplementary in vitro endothelial cell studies investigated the effects of EPA on angiogenesis. Results: The two treatment groups were well matched for burden of disease and previous chemotherapy exposure. Mean duration of EPA treatment was 30 days (range 12-65 days). EPA was safe and well tolerated, with a small excess of diarrhoea (p=0.09), and no excess of post-operative complications. Tumours from the EPA group had a 40% higher EPA content (p<0.01), no difference in proliferation or apoptosis, and a trend to reduced vascularity. EPA treatment was associated with a 36% reduction in urinary PGE-M (p=0.03) compared to placebo, and reduced monocyte NFкB DNA binding compared to baseline (p=0.03). EPA inhibited angiogenesis in vitro. Conclusions: EPA 2g daily is safe and well-tolerated in patients with CRCLM before liver resection. EPA incorporates into CRCLMs, exhibits systemic anti-inflammatory effects, and may have anti-angiogenic activity. Phase III clinical evaluation of prolonged EPA treatment is warranted in patients with, or at risk of, CRCLM.
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Jor, Wing-yan Irene, and 左穎欣. "Proteomic analysis of the effects of omega-3 fatty acids on human hepatocarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40204042.
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Bénay, Cassandre E. "Abnormal expression of proprotein convertases PC56 but not NARC-1 in human colorectal cancer and their liver metastases." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100766.
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The generation of bioactive proteins is key to the cell's homeostasis. Proprotein convertases (PCs) are the enzymes responsible for this spatio-temporal regulated processing of inactive protein precursors into their active form. Until recently, PCs had been implicated in tumorigenesis in vitro and in animal models but not in human colorectal cancer. Our group showed that the expression of PC1/3, PC2 and 7B2 are aberrant in colorectal liver carcinoma. In this study, we have shown that the expression of PC5 but not NARC-1 was aberrant in colorectal cancer and their metastases. NARC-1's expression was not altered in either primary colorectal cancer or their metastases. Nevertheless, we found that its expression was greater in the liver than in the colon. PCS was overexpression in the primary tumor but downregulated in the metastases. We do not know if this altered protein expression profile is a cause or a consequence of tumorigenesis. Nonetheless, this aberrant expression may result in an alteration of the secretory pathway and consequently of the cellular microenvironment and thus favour tumor growth and/or metastasis.
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Tung, Kwok-kwan, and 董國焜. "Epigenetic inactivation and tumor suppressive roles of hepatocyte growth factor activator inhibitors(HAIs) in human hepatocellularcarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B3979376X.
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Varandas, Edna Soraia Gregório Ribeiro Varandas. "Low-dose effects of Bisphenol A on human primary vascular endothelial cells and colon cancer cells." Doctoral thesis, ISA/UL, 2014. http://hdl.handle.net/10400.5/7338.
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Doutoramento em Biologia - Instituto Superior de AgronomiaBisphenol A (BPA) is an extensively utilized endocrine disruptor for which human exposure is considered generalized through ingestion. Information regarding BPA effects on vascular and digestive tract tissues is scarce. Therefore, in this work primary Human Umbilical Vein Endothelial Cells (HUVEC) and human colon adenocarcinona cell line HT29 were used to evaluate BPA effects at two distinct low-dose concentrations relevant in terms of human health risk assessment. BPA differentially affects the cell types studied, with more pronounced aneugenic effects, nucleolar disruption and transcriptional deregulation observed in HUVEC. Prolonged BPA exposure affects aging processes in senescent HUVEC. Interaction experiments involving expression of key cancer related genes shows that BPA antagonizes transcriptional effects of the chemotherapeutic agent doxorubicin in HT29. Additionally BPA aneugenic effects are enhanced by co-exposure with Eupatorium cannabinum L. ethanolic extract, a medicinal plant, for which a potent cytotoxic activity against HT29 cells is also demonstrated here. Altogether these results support increasing concerns regarding harmful effects of BPA at low-dose on human health and draw attention to the importance of a deeper understanding of BPA potential interactions with other chemicals.
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Qin, Lanfang, and 秦蘭芳. "Signficance of cell cycle regulators in human hepatocellular carcinomaand gene expression induced by cisplatin in hepatoma cell lines." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31242248.
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Zhu, Meifen, and 朱玫芬. "Mir-23a involves in the anti-cancer effect of CRAE and berberine in human hepatocellular carcinoma cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46944771.
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Volkmann, Tina. "The effects of silver nanoparticles on the expression of protein biomarkers of cell stress, apoptosis and inflammation by the human liver cancer cell line, HepG2." University of Western Cape, 2021. http://hdl.handle.net/11394/8429.
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>Magister Scientiae - MScNanoscience is the study of phenomena and objects at the nanoscale (around 1-100 nm), socalled nanomaterials. These nanomaterials exhibit novel properties that are often very different to those of the bulk materials used for their synthesis. Hence, nanoparticles are widely commercialised, especially silver nanoparticles (AgNPs) due to their antimicrobial properties and some other useful phenomena. This commercialisation leads to inevitable exposure to the environment and humans, which leads to inhalation, ingestion or dermal uptake of AgNPs by the human body culminating in distribution to several major organs, including the liver. Both chronic and acute exposure to AgNPs have been linked to detrimental effects in both in vitro and in vivo studies. These include oxidative stress, induction of inflammation, DNA damage, cell death and many others.
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Chalmers, Claire Ritchie. "The effects of the selective cyclooxygenase-2 inhibitor rofecoxib & hypoxia on human colorectal cancer liver metastases : angiogenesis and prostaglandin metabolism." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522921.
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Lechler, Christian [Verfasser], Fabian [Akademischer Betreuer] Geisler, Gabriele [Gutachter] Multhoff, and Fabian [Gutachter] Geisler. "Characterization of tumor initiation and development in a mouse model of primary liver cancer / Christian Lechler ; Gutachter: Gabriele Multhoff, Fabian Geisler ; Betreuer: Fabian Geisler." München : Universitätsbibliothek der TU München, 2020. http://d-nb.info/1226287417/34.
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Okoli, Arinze Stanley Medical Sciences Faculty of Medicine UNSW. "Molecular studies of the response of Helicobacter hepaticus to bile, and the effect of Helicobacter bilis on human hepatoma cells." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43379.
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Enterohepatic Helicobacter species (EHS) are emerging infectious disease agents. Infection of the enterohepatobiliary tract of several mammals by this group of bacteria results in various pathological disorders. The availability of the Helicobacter hepaticus sequenced and annotated genome, allowed molecular characterisation of the responses of H. hepaticus to host factors such as bile. The adaptation/responses of the bacterium to bovine, porcine and human bile were investigated using proteomics and transcriptomics. Ninety-one different proteins were identified in the responses of H. hepaticus response to the three types of bile. These proteins participate in several key cellular processes including DNA replication; protein transcription, translation and folding; oxidative stress response; motility; virulence; and metabolism. In particular, the bacteria deployed several strategies such as inhibition of the TCA cycle and the electron transport chain as well as iron sequestration to ensure control of the levels of hydroxyl radicals. The results of this study revealed also the modulation by bile of the expression of H. hepaticus genes involved in response to oxidative stress and virulence. The responses of human HEp-2 and Huh7-derived cell-lines to H. hepaticus and Helicobacter bilis, respectively, were investigated employing proteomics and transcriptomics. One-hundred and twenty different proteins were differentially expressed in the responses of the human cells to the presence of Helicobacter spp. in the cell cultures. These proteins are involved in regulation of cell proliferation and structure; metabolism; protein transcription, translation and modification; stress response; and tumour induction. For example, in co-cultures of Huh7-derived cells and H. bilis, the activation of several mitochondrial and endoplasmic reticulum stress-related proteins and the dysregulation of several apoptosis effectors were suggested as mechanisms that could result in the death of the liver cells. Importantly, the differential expression of several tumour-related proteins by the Huh7 cells supported a possible role for Helicobacter spp. in liver cancer.
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Karnosky, Julia [Verfasser], and Christian [Akademischer Betreuer] Schulz. "Association between human papillomavirus and primary lung cancer – a systematic review and pilot study / Julia Karnosky ; Betreuer: Christian Schulz." Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1216703590/34.
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Laryea, D., A. Isaksson, Colin W. Wright, R. Larsson, and P. Nygren. "Characterization of the cytotoxic activity of the indoloquinoline alkaloid cryptolepine in human tumour cell lines and primary cultures of tumour cells from patients." Springer, 2009. http://hdl.handle.net/10454/4533.
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noThe plant derived indoloquinoline alkaloid cryptolepine was investigated for its cytotoxic properties in 12 human tumour cell lines and in primary cultures of tumour cells from patients. The fluorometric microculture cytotoxicity assay was used to assess cytotoxicity and DNA mocro-array analysis to evaluate gene expression. Cryptolepine mean IC50 in the cell line panel was 0.9 microM compared with 1.0 and 2.8 microM in haemaotological and solid tumour malignancies respectively. Among patient solid tumour samples, those from breast cancer were the most sensitive and essentially as sensitive as haematological malignancies, respectively. Among patient solid tumour samples, those from breast cancer were the most sensitive and essentially as senstive as haematological malignancies. Cryptolepine activity showed highest correlations to topoisomerase II and microtubule targetting drugs. In the cell lines cryptolepine activity was essentially unaffected by established mechanisms of drug resistance. A number of genes were identified as associated with cryptolepine activity. In conclusion, cryptolepine shows interesting in vitro cytotoxic properties and its further evaluation as an anticancer drug seems warranted.
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Christie, Leane Michelle. "Factors influencing the impact of primary and secondary prevention strategies for cervical cancer among Queensland women." Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/64067/1/Leane_Christie_Thesis.pdf.
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Since the introduction of the National Human Papillomavirus Vaccine Program (NHPVP) in 2007, few studies have assessed women's knowledge, beliefs and attitudes towards cervical screening and human papillomavirus (HPV) vaccination in Australia. It is imperative to ascertain this, as substantial changes are anticipated to the National Cervical Screening Program (NCSP) through a process called 'the Renewal', to ensure any changes that are introduced will be acceptable and well understood by women.
The objectives of this study were to describe Queensland women's current knowledge of cervical cancer/screening and HPV, their beliefs and attitudes towards Pap smears and the HPV vaccine and seek their advice on effective methods for communicating changes to the NCSP in their communities. This research was a descriptive-exploratory study that incorporated a combination of qualitative and quantitative methods within the context of the Health Belief Model (HBM). A computer-assisted telephone interview (CATI) survey of 1002 Queensland women was conducted in Phase 1 of the study. During Phase 2 of the study, 23 focus groups were conducted throughout Queensland to gather in-depth information about women's knowledge, awareness and acceptance about cervical cancer prevention strategies.
This study found high levels of awareness of HPV (over 60%) and the HPV vaccine (over 86%) amongst Queensland women. However, it also identified considerable uncertainty amongst participants about perceived susceptibility to cervical cancer, especially, the link between cervical cancer, HPV and sexual activity. Women also had limited understanding of the benefit of the Pap smear as a preventative strategy, with many women thinking the main purpose of the Pap smear was for the early detection of cancer. Despite high awareness of HPV, women participating in this study also had significant knowledge deficits about their susceptibility to HPV and the severity of HPV infection. Queensland women had high levels of awareness of the HPV vaccine, which was most commonly via the media. High acceptance of the HPV vaccine was found amongst participants although awareness of the full benefits of vaccination was not evident with little acknowledgement that the quadrivalent vaccine used in the NHPVP would also prevent genital warts.
Extensive barriers to having Pap smears, including physical and psychological discomfort, were identified and the most common barriers to vaccination were concerns about side effects and a lack of information upon which to make a decision about consent. Women described enablers for screening participation, such as reminder systems and practitioner characteristics, and expressed positive views towards self collected testing as an enabler, particularly for women who did not attend screening.
As this study was conducted with Queensland women it may therefore not be representative of women from other parts of Australia and as participants were more likely to report they were regular screeners than Queensland women overall, these results may not be representative of women least likely to participate in cervical screening. The use of self-reported cervical screening history may also have led to over-reporting of screening status and previous abnormalities by participants. This study reveals significant gaps in Queensland women's knowledge that require effective communication strategies to address. Recommendations from this study highlight the need for increased community education to raise awareness about primary and secondary cervical cancer prevention strategies, training of cervical screening providers in sensitive examination techniques, a reduction in costs associated with screening, the exploration of alternative service models and communication plans that incorporate methods women trust and recommend for disseminating information about changes to the NCSP.
This study is the first large study to explore women's perceptions of the Pap smear and barriers to screening, their knowledge about HPV and their attitudes towards the HPV vaccine in Queensland, since the introduction of the NHPVP. It highlights considerable uncertainty about many aspects of cervical cancer and primary and secondary prevention strategies available in Australia and identified many barriers to cervical screening and concerns about HPV vaccination. These knowledge gaps and barriers need to be taken into account and addressed within the context of anticipated changes to the NCSP to ensure benefits are maximised for women in future primary and secondary cervical cancer prevention strategies in the Australian context.
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Al-Qahtani, Khalid Hussain. "Detection of human papillomavirus in primary site of oraloropharyngeal cancer and in cervical lymph nodes : correlation with clinico-pathological parameters and prognostic significance." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=83960.
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Objectives. (1) To Determine the presence of HPV 6, 11, 16, 18, 31, 33, 35, 52b, 58 subtypes in resected oral/oropharyngeal SCCA cancer and associated lymph nodes. (2) To Determine if a relationship exists between koilocytosis, tumor grade, stage, or prognosis.Methods. Retrospective analysis and pathology review of patients with SCCA of the oral cavity at McGill in the last 5 years was performed. Age at diagnosis, risk factors, tumor stage, grade, koilocytosis, treatment, outcome, and presence of HPV by PCR were analysed.
Results. 199 patients included were included in the analyses; 5 years mortality was 18.5%. 146 cases reviewed by pathology revealed 67% koilocytosis. One sample was positive for HPV subtype 35 as determined by PCR. Radiotherapy (p<0,5) and complications from radiotherapy (p<0.5) significantly affected survival.
Conclusions. Many oral SCCA's do not contain HPV 6, 11, 16, 18, 31, 33, 35, 52b, 58 subtypes. Given the high prevelence of koilocytosis, probe for other subtypes should be utilized. Mortality rates and survival are similar to those published in the literature. The presence of koilocytosis, it is not related grade, stage or prognosis. Only radiotherapy and its complications affect survival.
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Aarab-Terrisse, Safae. "Impact de l'axe microbiome-thymus sur l'efficacité de la déprivation androgénique et sur le renforcement de l’immuno-surveillance dans le cancer de la prostate Immunodynamics of Explanted Human Tumors for Precision and Personalized Immuno-Oncology Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL025.
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La déprivation androgénique est la pierre angulaire du traitement du cancer de la prostate (CaP), mais la plupart des patients deviendront réfractaires à la castration (CRPC). En outre, les immunothérapies par inhibiteurs de points de contrôle immunitaire ne sont pour l’instant pas un standard dans la prise en charge de ce cancer en raison de son environnement immunosuppresseur. Notre hypothèse est que pour accroître la sensibilité des patients aux traitements immuno-modulateurs (déprivation androgénique, inhibiteurs des points de contrôle immunitaire et autres), il faudrait restaurer l’environnement immunitaire systémique de l’hôte, et rétablir ainsi un microenvironnement intra-tumoral immuno-reactif de manière plus précoce dans la prise en charge de la maladie.Étant donné que les patients atteints d'un cancer avancé peuvent présenter une dysbiose intestinale, qu’on sait que la composition du microbiote intestinal joue un rôle essentiel dans le succès de tout traitement immuno-modulateur, nous avons donc analysé l'impact du système immunitaire, de la composition du microbiote intestinal et la relation entre les deux composants sur la durée de l’hormono-sensibilité chez les patients atteints de CaP et dans un modèle murin de cancer de la prostate (Lignées Myc-CaP).Tout d'abord, en utilisant des anticorps depletant les lymphocytes CD4 ou CD8 et des souris nudes- athymiques, nous avons démontré le rôle clé des lymphocytes T dans le temps jusqu’à résistance à la castration. Ensuite, à l'aide d'expériences d'antibiotiques à large spectre, de « cohousing », de transplantation microbienne fécale (FMT) et d’utilisation de probiotiques immunogènes nous avons dévoilé le rôle fondamental du microbiote intestinal de l’hôte dans le contrôle de la croissance des tumeurs pendant la suppression androgénique. Troisièmement, la métagénomique des fèces couplées aux analyses métabolomiques sanguines ont mis en évidence des changements significatifs associés à la castration et aux manipulations du microbiote. Enfin, l’intégrité du thymus semble être compromise par la présence du cancer de la prostate, que la castration ne restaure pas. Néanmoins, un microbiote sain restaurerait la thymopoïèse et l'émigration des lymphocytes matures associés à une immunosurveillance anticancéreuse efficace. Dans l'ensemble, nous démontrons que la déprivation androgénique permet d'obtenir une efficacité anti-cancéreuse optimale et de longue durée, de manière dépendante des lymphocytes T lorsque la dysbiose intestinale est compensée par la FMT d’individus sains ou par des probiotiques immunogènes. Par ailleurs ce renforcement du tonus immunitaire de l’hôte permettrait de sensibiliser le cancer de la prostate aux traitements ultérieurs par immunothérapieAndrogen deprivation therapy (ADT) is the backbone treatment for Prostate cancer (PCa), but most patients will become refractory to castration (CRPC). In addition, immune checkpoint blockade may not be an option for CRPC. Given that advanced cancer patients may exhibit a gut dysbiosis and the pivotal role of the intestinal microbiota composition in dictating the success of chemo-and immuno-therapy, we analyzed the role of the immune system, the impact of the gut microbiota and the inter-relationship between both components in the time to CRPC in PCa patients and in a mouse model of prostate cancer (MyC-CaP cell line). First, using CD4 or CD8 depleting antibodies and athymic nude mice, we demonstrated the key role of T lymphocytes in the time to progression during ADT. Secondly, using cohousing experiments, fecal microbial transplantation and broad spectrum antibiotics, we unveiled the seminal role of the host microbiota in governing tumor growth control during ADT. Third, metagenomics coupled with metabolomics analyses highlighted significant changes associated with ADT, their physiological relevance being currently investigated. Finally, while the development of PCa compromises the thymus integrity despite ADT; healthy microbiota restores thymopoiesis and the emigration of mature lymphocytes associated with effective anticancer immunosurveillance. Altogether, ADT mediates a full blown T cell-dependent anti-PCa cancer efficacy when intestinal dysbiosis is compensated by FMT or immunogenic probiotics
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Cox, Julie. "Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39340.
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In vitro genetic toxicity tests using cultured bacterial or mammalian cells provide a cost- and time-effective alternative to animal tests. Unfortunately, existing in vitro assays are not always reliable. This is in part due to the limited metabolic capacity of the cells used, which is often critical to accurately assess chemical genotoxicity. This limited metabolic capacity necessitates the use of exogenous sources of mammalian metabolic enzymes that can simulate in vivo mammalian metabolic activation reactions. In response to this, and other limitations, alongside the worldwide trend to reduce animal testing, there is an acute need to consider various strategies to improve in vitro mutagenicity assessment. This thesis first examined the utility of exogenous metabolic activation systems based on human hepatic S9, relative to conventional induced rat liver S9, for routine genetic toxicity assessment. This was accomplished by critically evaluating existing literature, as well as new experimental data. The results revealed the limitations of human liver S9 for assessment of chemical mutagenicity. More specifically, the analyses concluded that, due to the increased risk of false negative results, human liver S9 should not be used as a replacement for induced rat liver S9. To address the limitations of conventional mammalian cell genetic toxicity assays that require exogenous hepatic S9, the thesis next evaluated the utility of an in vitro mutagenicity assay based on metabolically-competent primary hepatocytes (PHs) derived from the transgenic MutaMouse. Cultured MutaMouse PHs were thoroughly characterized, and found to temporarily retain the phenotypic attributes of hepatocytes in vivo; they express hepatocyte-specific proteins, exhibit the karyotype of typical hepatocytes, and maintain metabolic activity for at least the first 24 hours after isolation. Preliminary validation of the in vitro MutaMouse PH gene mutation assay, using a panel of thirteen mutagenic and non-mutagenic chemicals, demonstrated excellent sensitivity and specificity. Moreover, inclusion of substances requiring a diverse array of metabolic activation pathways revealed comprehensive metabolic competence. Finally, the thesis further investigated the applicability domain of the in vitro MutaMouse PH assay by challenging the assay with selected azo compounds. Comparison of these results with those obtained using the in vivo MutaMouse TGR (transgenic rodent) assay revealed that MutaMouse PHs can carry out some forms of reductive metabolism. Overall, this thesis demonstrated that a gene mutation assay based on MutaMouse PHs holds great promise for routine assessments of chemical mutagenicity.
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Pedersen, Jenny M. "ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-205355.
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Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions. In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.
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L'Hermitte, Antoine. "Rôle de LECT2 dans le microenvironnement immunitaire au cours de la cancérogènese hépatique." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS360/document.
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Le carcinome hépatocellulaire (CHC) est la deuxième cause de mortalité par cancer dans le monde. Plusieurs études attestent du rôle du microenvironnement tumoral (MET) comme acteur fondamental de la carcinogenèse. A l’aide de modèles murins mimant un sous groupe de CHC fréquent, notre équipe avait identifié la molécule LECT2 comme un effecteur moléculaire important du MET dans le contrôle de l’agressivité tumorale.L'objectif de ma thèse a été d’adresser le rôle fonctionnel de LECT2 dans le microenvironnement immunitaire au cours du CHC.A l’aide de modèles murins, nous observons que l’absence de LECT2 entraine une accumulation importante de cellules myéloïdes dans le MET. Nous montrons que ces cellules myéloïdes sont immatures, arborent des capacités immunosuppressives puissantes vis-à-vis des lymphocytes T et ont un programme transcriptionnel permettant une action promotrice de tumeurs. De façon intéressante, l’accumulation de ces acteurs dans le microenvironnement est associée à l’émergence de nodules tumoraux indifférenciés exprimant des marqueurs de transition épithélio-mésenchymateuse/cellules progénitrices/métastases.D’un point de vue mécanistique, nous avons démontré une perte de différenciation plus importante des hépatocytes en absence de LECT2 dans des conditions d’activation de la signalisation β-caténine. Nous montrons également par des expériences de co-culture que les cellules myéloïdes infiltrant les tumeurs en absence de LECT2 ont une forte capacité à induire une perte de différenciation des hépatocytes.Enfin, nous avons analysé l'expression de LECT2 dans une vaste cohorte d’échantillons humains de CHC. Nous montrons que la diminution d’expression de LECT2 corrèle fortement avec 1)- la présence d’invasion vasculaire, 2)- la perte de différenciation des hépatocytes tumoraux et 3)- la présence d’infiltrats inflammatoires.L’ensemble de ces données démontre que LECT2 agit comme un régulateur essentiel dans la cancérogénèse hépatique à travers son action double sur les hépatocytes et sur la fonction des cellules myéloïdes infiltrant les tumeurs. Ainsi, ces travaux identifient LECT2 comme un biomarqueur potentiel ouvrant de nouvelles perspectives de traitement du CHCHepatocellular carcinoma (HCC) is the second cause of cancer-rel ated death worldwide. Several studies highlighted the tumor microenvironment (TEM) as a key player in cancer from initiation to progression steps of tumorigenesis. Using relevant HCC mouse models, our team identified the chemokine-like LECT2 as a critical actor of liver TEM in the control of tumor aggressiveness.The aim of my thesis was to address functionally the role of LECT2 in the immune microenvironment during HCC.Using mouse models, we observed that the absence of LECT2 induces a significant accumulation of myeloid cells in the TEM. We showed that these myeloid cells were immature, harbored strong immunosuppressive capabilities on T cells and expressed a transcriptional program sustaining tumor progression. Interestingly, the accumulation of these actors in the microenvironment is associated with the emergence of poorly differentiated tumor nodules expressing epithelial-to-mesenchymal transition / progenitor / metastasis markers.Mechanistically, we demonstrated that LECT2-deficient hepatocytes in the context of β-catenin activation were able to perform EMT like WT hepatocytes do after TGF-β1 challenge. In co-culture experiments, we demonstrated that tumor-infiltrating myeloid cells in the absence of LECT2 have a strong ability to induce hepatocyte EMT.Finally, we analyzed the expression of LECT2 in a vast cohort of HCC liver samples and found that downregulation of LECT2 expression strongly correlates with 1) - the presence of vascular invasion, 2) – histological grade and 3) - the presence of inflammatory infiltrates.Altogether, our data demonstrate that LECT2 acts as a strong regulator of liver tumor aggressiveness through its dual action on hepatocytes and impact on the function of tumor infiltrating myeloid cells. This work identifies LECT2 as a new biomarker for HCC and pave the way to new therapeutic strategies
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Essid, Ebtisam [Verfasser]. "Apoptosis induction by Ochratoxin A, LPS, TNF-alpha, H2O2, and uv light in cultured primary rat hepatocytes, in immortalized rat liver cells and in human hepatoma cells and the prevention by Silibinin / Ebtisam Essid." Gießen : Universitätsbibliothek, 2013. http://d-nb.info/1065320140/34.
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Degli, Esposti Davide. "Les mécanismes de réponse à l'inflammation chronique dans le foie stéatosique et les conséquences sur l'homéostasie cellulaire et la cancérogénèse." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00652594.
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Le foie est un organe essentiel à la vie chez tous les mammifères. C'est un organe central du métabolisme énergétique et de la détoxification des substances xénobiotiques auxquelles l'individu est exposé. Le foie est la cible d'agressions diverses, telles que les virus, l'alcool, les substances chimiques présentes dans l'alimentation ou l'environnement. Il peut également subir destransformations pathologiques profondes, lors du diabète ou de l'obésité par exemple.La stéatose hépatique, caractérisée par une accumulation de triglycérides sous forme de vésiculesgénérant une réponse inflammatoire, est connue depuis de nombreuses années. Son étude a permisde définir un modèle en deux étapes (" two hits ") indispensables à la genèse d'une stéatohépatite ou NASH. La première est l'accumulation de lipides, la seconde consiste en la genèse d'un stress oxydant et la libération de cytokines. La NASH est une des conséquences pathologiques du syndrome métabolique au cours duquel une résistance des tissus à l'insuline se développe.Récemment, la composition des lipides accumulés dans la NASH a été décrite et montre la présence de cholestérol libre et de différents métabolites des acides gras dont la toxicité est grande mais variable. De façon surprenante, une nouvelle hypothèse tend à émerger quant aux rôles protecteurs de certaines catégories de lipides. En effet, le stockage des triglycérides sous forme de vésicules pourrait être un mécanisme de survie cellulaire (Neuschwander-Tetri, 2010). Il s'agirait principalement d'une tolérance à la mort cellulaire par nécrose ou apoptose. Dans ce contexte,l'activation de l'autophagie serait capitale et la nécrose ne serait plus un mécanisme non contrôlé,mais au contraire un système finement régulé.Des données expérimentales récentes suggèrent l'existence d'un réseau complexe d'interactions moléculaires qui lient, dans la NASH comme dans le cas de la cancérogenèse, le métabolisme énergétique, la réponse inflammatoire systémique et tissulaire et des altérations subcellulaires, telles que les lésions des mitochondries et du réticulum endoplasmique.Nous avons utilisé le cas particulier du préconditionnement ischémique, une technique chirurgicale qui consiste, grâce à de courtes périodes d'occlusion vasculaire avant l'ischémie, à conférer au tissu une protection contre les lésions d'ischémie/reperfusion (I/R), pour étudier les mécanismes de survie mis en place par les hépatocytes stéatosiques au cours d'un stress d'I/R. Dans deux contextes différents, celui d'une ischémie chaude au cours d'une hépatectomie partielle et celui d'une ischémie froide au cours de la transplantation hépatique, nous avons montré que l'autophagie peut jouer un rôle central dans la protection des hépatocytes stéatosiques. Cependant, il est envisageable qu'un dysfonctionnement de l'autophagie pourrait conduire à la genèse d'altérations cellulaires comme une instabilité génomique, caractéristique de la transformation cancéreuse. L'équilibre entre la survie et la mort cellulaire dépend donc de l'intégration de cette signalisation complexe, qui concerne l'état énergétique de la cellule, la réponse aux stress transitoires et l'adaptation aux stress chroniques. Dans ce contexte, l'autophagie semble jouer un rôle central dans l'intégration de la réponse aux stress (Kroemer et al 2010), ce qui pourrait favoriser directement ou indirectement la transformation cancéreuse d'une cellule.L'amélioration de la compréhension des mécanismes impliqués dans la tolérance et la survie des hépatocytes chargés de lipides en réponse à un stress inflammatoire, ischémique ou du réticulum endoplasmique semble donc essentielle. Elle permettrait en effet la mise en place de nouvelles stratégies thérapeutiques qui pourraient améliorer la prise en charge des patients, augmenter le nombre de greffons disponibles pour les greffes, et la prévention des risques cancérogènes pour le foie.
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Hermetet, Francois. "La dualité de l'apoptose des cellules du cancer du col de l'utérus ou la face de Janus de l'apoptose : un objectif thérapeutique et une implication dans le transfert horizontal d'oncogènes viraux." Thesis, Besançon, 2015. http://www.theses.fr/2015BESA3009/document.
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À l'heure actuelle, une large proportion des recherches vouées à l'identification et au développement de nouvelles thérapies anticancéreuses est basée sur l'apoptose. Dans les dernières décennies, divers composés phytochimiques ont été caractérisés comme des agents pharmacologiques susceptibles d'éliminer les cellules cancéreuses via l'induction de l'apoptose. Parmi ceux-ci, l'isoliquiritigénine (ILG), un flavonoïde naturellement présent dans les racines de réglisse, se distingue des autres par ses nombreuses propriétés thérapeutiques incluant une activité antitumorale. Chez les mammifères, les cellules apoptotiques (CA) peuvent être complètement dégradées via leur capture par des cellules phagocytaires spécialisées ou servir de vecteurs d'ADN dans un processus appelé transfert horizontal de gènes (THG). Ainsi, il a été mis en évidence que des CA dérivées de cancer du col de l'utérus peuvent induire le transfert de séquences d'oncogènes de papillomavirus humains (HPV) à des fibroblastes primaires humains (HPFs) qui acquièrent des propriétés de cellules transformées. Cependant, les mécanismes cellulaires et moléculaires impliqués dans l'internalisation de CA par les fibroblastes, un modèle de phagocyte non-professionnel, n'ont pas encore été clairement identifiés et la caractérisation de ces événements qui précèdent le THG est essentielle à la compréhension de ce processus et de la transformation des cellules receveuses qui peut en découler.Dans ce contexte, les objectifs de cette thèse étaient, (i) d'analyser les effets anticancéreux de l'ILG sur des cellules dérivées de cancer du col de l'utérus, (ii) de caractériser les mécanismes cellulaires et moléculaires impliqués dans la capture des CA par les HPFs, (iii) d'étudier les événements cellulaires qui font suite à ce processus comme la maturation des phagosomes, le THG et l'acquisition de propriétés de transformation et enfin, (iv) de démontrer la preuve de la conservation de la capacité tumorigénique des CA in vivo.Un premier travail a permis de mettre en lumière les propriétés antitumorales de l'ILG via une multiplicité d'actions sur des modèles cellulaires de cancer du col de l'utérus in vitro, incluant des activités anti-proliférative, pro-apoptotique, anti-migratoire. Concernant la lignée cellulaire Ca Ski, p53 sauvage et représentative du carcinome du col utérin le plus fréquent, associé à une infection transformante par HPV16, l'apoptose induite par l'ILG semble dépendante de p53 et de la mitochondrie, mais aussi de la voie des récepteurs de mort, comme attesté par l'augmentation des niveaux de protéines p53 et p21, la dissipation du potentiel membranaire mitochondrial, la libération du cytochrome c et le clivage des caspases-9, -8 et -3. Ces effets pourraient être la conséquence de la diminution de l'expression de l'oncoprotéine virale E6 d'HPV16 induite par l'ILG entraînant la restauration de l'expression de p53. Nos travaux révèlent un fort potentiel de l'ILG contre différents types de cellules malignes et ouvrent le champ à de nouvelles modalités de traitement des cancers associés à HPVMost of the research strategies aiming at improving anticancer therapies currently target apoptosis. Over the last decades, several natural products derived from herbal medicine or food have been identified as pharmacological agents for cancer cell elimination through apoptosis induction. Among them, isoliquiritigenin (ILG) is a chalcone derivative isolated from liquorice and shallots which exhibits a wide variety of biological functions including antitumor properties.In mammals, apoptotic cells (AC) can either be eliminated after their capture by specialized phagocytes or act as vectors of DNA in a process named horizontal gene transfer (HGT). For instance, AC derived from cervical cancer cells can transfer human papillomavirus (HPV) oncogene sequences to human primary fibroblasts (HPFs) which subsequently acquire transformed cell properties. The molecular mechanisms underlying AC uptake by HPFs, a model of non-professional phagocytes, have not been clearly identified. Characterizing these upstream events appears critical to broaden our understanding of HGT and the ultimate transformation of recipient cells which may subsequently occur.The aims of this work were to (i) study the antitumor effects of ILG on cervical cancer cell lines,(ii) characterize the cellular and molecular mechanisms underlying AC uptake by HPF, (iii) study the cellular events which occur in HPFs following AC engulfment such as phagosome maturation, HGT and acquisition of transformed properties, and (iv) evaluate the tumorigenic properties of AC in vivo.In a first part of this PhD project, we found that ILG exhibits multiple antitumor actions on cervical cancer cells in vitro including anti-proliferative, pro-apoptotic and anti-migration properties. Further studies on apoptosis-related events were conducted in Ca Ski cells (p53wt, HPV16 DNA positive), which are representative of the most frequent cervical carcinoma. The treatment of Ca Ski cells with ILG is associated with increased levels of p53 and p21 proteins, loss of mitochondrial membrane potential, cytochrome c release and caspase-9, -8 and -3 cleavage. These features suggest that ILG-induced apoptosis is dependent on p53 and involve both mitochondrial and death receptor- mediated pathways. The effect of ILG in Ca Ski cells may be partly explained by the decrease of HPV16 E6 oncoprotein expression and the associated raise of p53 levels observed after cell treatment. Our work highlights the potential of ILG as an antitumor agent and provides the opportunity of new treatment. ln the second part of this work, we set up a method based on flow cytometry to quantitatively analyze AC uptake. This original method and microscopy analysis allowed us to show that HPFs act as non-professional phagocytes and are able to engulf subcellular fragments rather than dying whole cells, with lower efficiency and rapidity compared to professional phagocytes as macrophages. Uptake of AC by HPFs depends on time, temperature and the presence of bivalent ions. Morphological analysis and fonctional assays using endocytosis inhibitors revealed a mechanism related to phagocytosis and/or macropinocytosis. The recognition of phosphatidylserine exposed on the surface of AC by their receptor BAIl has emerged as a required event for AC uptake by HPFs
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Bellamri, Medjda. "Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B033/document.
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Les amines hétérocycliques aromatiques (AHA) sont des contaminants de l'environnement et de l'alimentation, majoritairement formés lors de la cuisson de viande et poisson ainsi que dans la fumée de cigarette et les gaz d'échappements. Les AHA sont mutagènes chez la bactérie, cancérogènes multi-sites chez le rongeur et sont classées comme cancérogènes possibles ou probables chez l'Homme par l'IARC. Il est aujourd'hui indispensable de caractériser des biomarqueurs d'exposition dérivés des AHA (adduits à l'ADN et métabolites) pour améliorer l'estimation du risque chez l'Homme. Des résultats de l'équipe ont démontré que le 2-amino-9H-pyrido[2,3-b]indole (AαC) forme des niveaux d'adduits à l'ADN élevés dans les hépatocytes humains. Ces niveaux sont plus élevés que ceux formés par les autres AHA. L'objectif de cette thèse est de mieux comprendre le potentiel génotoxique d'AαC chez l'Homme. Nos travaux ont démontré que les adduits à l'ADN dérivés d'AαC sont persistants dans les hépatocytes humains et formés à des doses aussi faibles que 1nM. De plus, le CYP1A2 a été confirmé comme enzyme majoritaire dans la bioactivation d'AαC dans le foie humain. Nous avons également caractérisé les métabolites majeurs dérivés d'AαC dans les hépatocytes humains. Cette étude a permis d'établir pour la première fois une corrélation entre l'activité catalytique du CYP1A2, la formation d'AαC-HN2-O-Gl et la formation des adduits à l'ADN dérivés d'AαC. Le métabolite AαC-HN2-O-Gl étant réactif vis-à-vis de l'ADN in vitro, nos travaux confortent l'hypothèse que la voie des UDP-Glucuronosyltransférases (UGTs) est une nouvelle voie de bioactivation d'AαC dans le foie humain. De plus, nous avons montré que les adduits à l'ADN dérivés des AHA sont formés dans les lymphocytes T humains activés et en particulier les adduits en position C8 de la guanine dérivés d'AαC. Au total, ces travaux ont permis l'identification de métabolites stables et des adduits à l'ADN, potentiels biomarqueurs d'exposition à AαC, qui sont indispensables pour une meilleure estimation du risque génotoxique d'AαC chez l'HommeHeterocyclic aromatic amines (HAA) are environmental and food contaminants, mainly formed during meat and fish cooking, but also in cigarette smoke and exhaust gaz. HAA are mutagenic in bacteria, carcinogenic in rodents and are classified as possible or probable human carcinogens by IARC. Today it is essential to characterize exposure biomarkers i.e. DNA adducts and metabolites, to assess the human risk associated with HAA. The research team has previously demonstrated that 2-amino-9H-pyrido[2,3-b]indole (AαC) form high levels of DNA adducts in human hepatocytes. These levels are greater that those derived from other HAAs. Thus, the aim of this thesis was to better understand the genotoxic potential of AαC in human. We demonstrated that in human hepatocytes, DNA adducts derived from AαC are persistent and formed at doses as low as 1nM. Moreover, we confirmed that CYP1A2 is the major enzyme implicated in the bioactivation of AαC in human liver. We have also characterized the major metabolites derived from AαC formed in human hepatocytes. This study allows, for the first time, the establishment of a correlation between the catalytic activity of CYP1A2, AαC-HN2-O-Gl formation and AαC derived DNA adducts formation. AαC-HN2-O-Gl being reactive toward DNA in vitro, our work reinforces the hypothesis that the UDP-glucuronosyltransferase (UGTs) pathway is a new bioactivation pathway for AαC in human liver. Moreover, we demonstrated the formation of HAA derived DNA adducts, especially those derived from AαC at position C8 of guanine, in activated human T lymphocytes. Taken together, our data lead to the identification of stable metabolites as well as DNA adducts which are potentials AαC exposure biomarkers in human. These biomarkers are essential for a better assessment of the genotoxic risk of AαC in human
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Lorz, Axel. "Der Leptinrezeptor im Modell primärer humaner Hepatozyten." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-150410.
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Diese Arbeit beinhaltet Untersuchungen zu den unterschiedlichen Isoformen des Leptinrezeptors und dessen Regulation in primären humanen Hepatozyten. Leptin und der Leptinrezeptor nehmen in der Physiologie des menschlichen Energiehaushaltes eine wesentliche Funktion ein und sind an der Pathogenese der Adipositas mit Folgeerkrankungen wie der Entwicklung einer Fettleber beteiligt. Es wird erstmalig geprüft inwieweit das Modellsystem primärer humaner Hepatozyten für Analysen der Leptinrezeptor-Expression und der Abspaltung von löslichem Leptinrezeptor geeignet ist. Weiterhin werden untersucht, welchen Einfluss endokrine Regulatoren wie Dexamethason, Leptin und Glucagon auf die isoformspezifischen Rezeptormengen in primären Hepatozyten haben und wie der Rezeptor unter Apoptose reguliert ist, welche durch die lipotoxischen Effekte der freien Fettsäure Palmitat und den Apoptoseinduktor Staurosporin induziert wird. Hierdurch können Rückschlüsse auf eine möglicherweise veränderte Wirksamkeit des Leptins in der Leber gezogen werden.
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"Effects of gambogic acid on human hepatoma cells." 2008. http://library.cuhk.edu.hk/record=b5893597.
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Lee, Ngan Hon.Thesis (M.Phil.)--Chinese University of Hong Kong, 2008.
Includes bibliographical references (leaves 120-133).
Abstracts in English and Chinese.
Acknowledgements --- p.IV
Abstract --- p.V
論文摘要 --- p.VII
Table of Contents --- p.IX
List of Figures --- p.XI
List of Abbreviations --- p.XIII
Chapter 1 Introduction --- p.1
Chapter 1.1 --- Hepatocellular carcinoma (HCC) --- p.1
Chapter 1.1.1 --- Risk factors --- p.1
Chapter 1.1.2 --- Molecular mechanism of HCC --- p.4
Chapter 1.1.3 --- Treatment of HCC --- p.7
Chapter 1.2 --- Gambogic acid (GA) - a compound derived from Tradition Chinese Medicine (TCM) --- p.9
Chapter 1.2.1 --- Traditional Chinese Medicine (TCM) --- p.9
Chapter 1.2.2 --- Gambogic acid --- p.13
Chapter 1.3 --- Molecular mechanism of apoptosis --- p.18
Chapter 1.3.1 --- Overview of apoptosis --- p.18
Chapter 1.3.2 --- Caspases cascade --- p.18
Chapter 1.3.3 --- Bcl-2 family --- p.20
Chapter 1.3.4 --- Mitochondria in apoptosis --- p.23
Chapter 1.4 --- Apoptosis as a strategy for cancer therapies --- p.26
Chapter 1.5 --- Aims of study --- p.29
Chapter Chapter 2 --- Materials and Methods --- p.30
Chapter 2.1 --- Cell culture and treatment --- p.30
Chapter 2.1.1 --- Cell lines used --- p.30
Chapter 2.1.2 --- Gambogic acid (GA) --- p.31
Chapter 2.1.3 --- Chemicals and reagents --- p.31
Chapter 2.1.4 --- Preparation of solutions --- p.32
Chapter 2.1.5 --- Procedures --- p.33
Chapter 2.2 --- Apoptotic detection --- p.35
Chapter 2.2.1 --- Chemicals and reagents --- p.35
Chapter 2.2.2 --- Preparation of solutions --- p.35
Chapter 2.2.3 --- Procedures --- p.37
Chapter 2.3 --- Effects of GA on gene expression in HepG2 --- p.41
Chapter 2.3.1 --- Chemicals and Reagents --- p.41
Chapter 2.3.2 --- Preparation of solutions --- p.41
Chapter 2.3.3 --- Procedures --- p.43
Chapter 2.4 --- Protein expression in GA-induced apoptotic cells --- p.51
Chapter 2.4.1 --- Chemicals and Reagents --- p.51
Chapter 2.4.2 --- Preparation of solution --- p.51
Chapter 2.4.3 --- Procedures --- p.54
Chapter 2.5 --- Caspase cascade study in GA-induced apoptosis --- p.60
Chapter 2.5.1 --- Chemicals and reagents --- p.60
Chapter 2.5.2 --- Procedures --- p.60
Chapter 2.6 --- Downregulation of mRNA using siRNA vector --- p.62
Chapter 2.6.1 --- siRNA expression vector --- p.62
Chapter 2.6.2 --- Chemicals and Reagents --- p.63
Chapter 2.6.3 --- Preparation of solution --- p.63
Chapter 2.6.4 --- Procedures --- p.64
Chapter Chapter 3 --- Results --- p.71
Chapter 3.1 --- GA induces apoptosis in hepatocellular cells --- p.71
Chapter 3.2 --- Effects of gene expression in HCC --- p.80
Chapter 3.3 --- Caspase cascade studies in GA-induced apoptosis --- p.83
Chapter 3.4 --- Caspase 8 activation in GA-treated cells lead to Bid cleavage --- p.89
Chapter 3.5 --- GA induces Bax conformational changes and cytochrome c release --- p.95
Chapter 3.6 --- Levels of protein players involved in apoptosis and cell cycle --- p.101
Chapter Chapter 4 --- Discussion --- p.106
References --- p.120