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Mathematical modelling of acetaminophen induced hepatotoxicityReddyhoff, Dennis January 2016 (has links)
Acetaminophen, known as paracetamol in the UK and Tylenol in the United States, is a widespread and commonly used painkiller all over the world. Taken in large enough doses, however, it can cause fatal liver damage. In the U.S., 56000 people are admitted to hospital each year due to acetaminophen overdose and its related effects, at great cost to healthcare services. In this thesis we present a number of different models of acetaminophen metabolism and toxicity. Previously, models of acetaminophen toxicity have been complex and due to this complexity, do not lend themselves well to more advanced mathematical analysis such as the perturbation analysis presented later in this thesis. We begin with a simple model of acetaminophen metabolism, studying a single liver cell and performing numerical and sensitivity analysis to further understand the most important mechanisms and pathways of the model. Through this we identify key parameters that affect the total toxicity in our model. We then proceed to perform singular perturbation analysis, studying the behaviour of the model over different timescales, finding a number of key timescales for the depletion and subsequent recovery of various cofactors as well as critical dose above which we see toxicity occurring. Later in the thesis, this model is used to model metabolism in a spheroid cell culture, examining the difference spatial effects have on metabolism across a 3D cell culture. We then present a more complex model, examining the difference the addition of an adaptive response to acetaminophen overdose from the Nrf2 signalling pathway, has on our results. We aim to reproduce an unexplained result in the experimental data of our colleagues, and so analyse the steady states of our model when subjected to an infused dose, rather than a bolus one. We identify another critical dose which leads to GSH depletion in the infused dose case and find that Nrf2 adaptation decreases toxicity and model sensitivity. This model is then used as part of a whole-body PBPK model, exploring the effects that the distribution of the drug across the bloodstream and different organs has. We explore the affects of that a delay in up-regulation from the Nrf2 pathway has on the model, and find that with rescaled parameters we can qualitatively reproduce the results of our collaborators. Finally, we present the results of in vitro work that we have undertaken, the aim of which was to find new parameters for the model in human hepatocytes, rather than from rodent models, and find a new value for a parameter in our model from human cell lines.
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Characterization of HCT 116 Spheroid Layers by Flow Cytometry and Mass SpectrometryLindhorst, Philip H. January 2021 (has links)
No description available.
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L2pB1 cells are essential for the inhibition of 3D tumor spheroids by syngeneic peritoneal immune cellsBootwala, Ali Habib 21 February 2019 (has links)
INTRODUCTION: Programmed Death Ligand 2 positive B1 cells (L2pB1) cells have a unique immunoglobulin repertoire that is poly-reactive to self-antigens and have previously been shown to have an essential role in autoimmunity. The active accumulation of L2pB1 cells inside tumors grown in vivo led us to hypothesize that this subpopulation of B1a cells may play a role in the immunosurveillance of cancer. Here, we report our investigation of the role of L2pB1 cells in the antitumor response using a three dimensional (3D) murine melanoma and colon cancer models. Our results showed that the depletion of L2pB1 cells rendered the loss of tumor inhibition effects of the syngeneic peritoneal immune cells.
METHODS: Lymphocytes were collected from L2pB1 cell depleted and non-depleted peritoneal cavity washout (PCW) from an inducible knockout mouse model. Then tumor spheroids were incubated with PCW cells. Spheroid cross-sectional area (CSA) and volume were measured using a Celigo plate imager and Keyence fluorescence microscope.
RESULTS: Tumor spheroid growth was significantly inhibited following incubation with syngeneic PCW but not with splenocytes. Depletion of L2pB1 significantly attenuated the tumor-inhibition effect and showed a negligible difference from the untreated control. This loss of tumor inhibition indicated that L2pB1 cells are essential for the tumor-inhibition effects of autologous peritoneal immune cells.
CONCLUSIONS: These findings demonstrate the robust anti-tumor function of L2pB1 cells. In particular, peritoneal L2pB1 cells play an essential role in cancer inhibition. Future studies into the activation and antigen presentation pathways of L2pB1 cells could lead to novel immunotherapy of cancer.
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Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3 / ナルディライジンはSTAT3の活性化を介して肝細胞がんの進展に寄与するKasai, Yosuke 24 July 2017 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20607号 / 医博第4256号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 泰広, 教授 松田 道行, 教授 長船 健二 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor Initiating Cells / 患者由来癌幹細胞から樹立した異種移植マウスモデルを用いた抗癌剤感受性試験Maekawa, Hisatsugu 26 November 2018 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21419号 / 医博第4409号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 小川 誠司, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDSShahi Thakuri, Pradip January 2019 (has links)
No description available.
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SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2 / SNAIL2はIGFBP2の制御によって膵癌の腫瘍形成と化学療法抵抗性に寄与するMasuo, Kenji 25 July 2022 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第24136号 / 医博第4876号 / 新制||医||1060(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 藤田 恭之, 教授 波多野 悦朗, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Focused Ultrasound Treatment of a Spheroid In Vitro Tumour ModelLandgraf, Lisa, Kozlowski, Adam, Zhang, Xinrui, Fournelle, Marc, Becker, Franz-Josef, Tretbar, Steffen, Melzer, Andreas 09 June 2023 (has links)
Focused ultrasound (FUS) is a non-invasive technique producing a variety of biological effects by either thermal or mechanical mechanisms of ultrasound interaction with the targeted tissue. FUS could bring benefits, e.g., tumour sensitisation, immune stimulation, and targeted drug delivery, but investigation of FUS effects at the cellular level is still missing. New techniques are commonly tested in vitro on two-dimensional (2D) monolayer cancer cell culture models. The 3D tumour model—spheroid—is mainly utilised to mimic solid tumours from an architectural standpoint. It is a promising method to simulate the characteristics of tumours in vitro and their various responses to therapeutic alternatives. This study aimed to evaluate the effects of FUS on human prostate and glioblastoma cancer tumour spheroids in vitro. The experimental follow-up enclosed the measurements of spheroid integrity and growth kinetics, DNA damage, and cellular metabolic activity by measuring intracellular ATP content in the spheroids. Our results showed that pulsed FUS treatment induced molecular effects in 3D tumour models. With the disruption of the spheroid integrity, we observed an increase in DNA double-strand breaks, leading to damage in the cancer cells depending on the cancer cell type.
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Targeting the formyl peptide receptor 1 for treatment of glioblastomaAhmet, Djevdet S. January 2021 (has links)
Background and Aims Gliomas account for over half of all primary brain
tumours and have a very poor prognosis, with a median survival of less than
two years. There is an urgent and unmet clinical need to develop new
therapies against glioma. Recent reports have indicated the overexpression of
FPR1 in gliomas particularly in high grade gliomas. The aim of this project was
to identify and synthesise small molecule FPR1 antagonists, and to
demonstrate a proof of principle in preclinical in vitro and in vivo models that
small molecule FPR1 antagonism can retard expansion of glioma.
Methods A number of small molecule FPR1 antagonists were identified by
in silico design, or from the literature and then were prepared using chemical
synthesis. FPR1 antagonists were evaluated in vitro for their ability to abrogate
FPR1-induced cellular responses in a range of models including calcium
mobilisation, cell migration, and invasion. The efficacy of FPR1 antagonist
ICT12035 in vivo was assessed in a U-87 MG subcutaneous xenograft model.
Results Virtual high throughput screening using a homology model of
FPR1 led to the identification of two small molecule FPR1 antagonists. At the
same time chemical synthesis of two other antagonists, ICT5100 and
ICT12035 as well as their analogues were carried out. The FPR1 antagonists
were assessed in calcium flux assay which gave an insight into their structure-activity
relationship. Further investigation of both ICT5100 and ICT12035
demonstrated that both small molecule FPR1 antagonists were effective at
abrogating FPR1-induced calcium mobilisation, migration, and invasion in U-
87 MG in vitro models in a dose-dependent manner. ICT12035 is a particularly
selective and potent inhibitor of FPR1 with an IC50 of 37.7 nM in calcium flux
assay. Additionally, it was shown that the FPR1 antagonist ICT12035 was able
to arrest the growth rate of U-87 MG xenografted tumours in mice.
Conclusion The results demonstrate that targeting FPR1 by a small
molecule antagonist such as ICT12035, could provide a potential new therapy
for the treatment of glioblastoma. / Yorkshire Cancer Research
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Migrating Myofibroblastic Iliotibial Band-Derived Fibroblasts Represent a Promising Cell Source for Ligament ReconstructionSchwarz, Silke, Gögele, Clemens, Ondruschka, Benjamin, Hammer, Niels, Kohl, Benjamin, Schulze-Tanzil, Gundula 10 January 2024 (has links)
The iliotibial band (ITB) is a suitable scaffold for anterior cruciate ligament (ACL)
reconstruction, providing a sufficient mechanical resistance to loading. Hence, ITB-derived fibroblasts
attract interest for ligament tissue engineering but have so far not been characterized. This present
study aimed at characterizing ITB fibroblasts before, during, and after emigration from cadaveric
ITB explants to decipher the emigration behavior and to utilize their migratory capacity for seeding
biomaterials. ITB and, for comparison, ACL tissues were assessed for the content of alpha smooth
muscle actin (αSMA) expressing fibroblasts and degeneration. The cell survival and αSMA expression
were monitored in explants used for cell isolation, monolayer, self-assembled ITB spheroids, and
spheroids seeded in polyglycolic acid (PGA) scaffolds. The protein expression profile of targets
typically expressed by ligamentocytes (collagen types I–III, elastin, lubricin, decorin, aggrecan,
fibronectin, tenascin C, CD44, β1-integrins, vimentin, F-actin, αSMA, and vascular endothelial growth
factor A [VEGFA]) was compared between ITB and ACL fibroblasts. A donor- and age-dependent
differing percentage of αSMA positive cells could be detected, which was similar in ITB and ACL
tissues despite the grade of degeneration being significantly higher in the ACL due to harvesting
them from OA knees. ITB fibroblasts survived for several months in an explant culture, continuously
forming monolayers with VEGFA and an increased αSMA expression. They shared their expression
profile with ACL fibroblasts. αSMA decreased during the monolayer to spheroid/scaffold transition.
Using self-assembled spheroids, the migratory capacity of reversible myofibroblastic ITB cells can be
utilized for colonizing biomaterials for ACL tissue engineering and to support ligament healing.
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