Rozprawy doktorskie: „Cancer Cell Imaging”

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Kosmacek, Elizabeth Anne Ianzini Fiorenza Mackey Michael A. "Live cell imaging technology development for cancer research". [Iowa City, Iowa] : University of Iowa, 2009. http://ir.uiowa.edu/etd/388.

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Kosmacek, Elizabeth Anne. "Live cell imaging technology development for cancer research". Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/388.

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Live cell imaging is a unique tool for cellular research with a wide variety of applications. By streaming digital microscopic images an investigator can observe the dynamic morphology of a cell, track cell movement on a surface, and measure quantities or localization patterns of fluorescently labeled proteins or molecules. Digital image sequences contain a vast amount of information in the form of visually detectable morphological changes in the cell. We designed computer programs that allow the manual identification of visible events in live cell digital image sequences [Davis et al. 2007]. Once identified, the data are analyzed using algorithms to calculate the yield of individual events per cell over the time course of image acquisition. The sequence of event data is also constructed into directed acyclic graphs and through the use of a subgraph isomorphism algorithm we are able to detect specified patterns of events originating from a single cell. Two projects in the field of cancer research are here discussed that describe and validate the application of the event analysis programs. In the first project, mitotic catastrophe (MC) research [Ianzini and Mackey, 1997; Ianzini and Mackey, 1998; reviewed by Ianzini and Mackey, 2007] is enhanced with the addition of live cell imaging to traditional laboratory experiments. The event analysis program is used to describe the yield of normal or abnormal divisions, fusions, and cell death, and to detect patterns of reductive division and depolyploidization in cells undergoing radiation-induced MC. Additionally, the biochemical and molecular data used in conjunction with live cell imaging data are presented to illustrate the usefulness of combining biology and engineering techniques to elucidate pathways involved in cell survival under different detrimental cell conditions. The results show that the timing of depolyploidization in MC cells correlates with increased multipolar divisions, up-regulation of meiosis-specific genes, and the production of mononucleated cell progeny. It was confirmed that mononucleated cells are produced from multipolar divisions and these cells are capable of resuming normal divisions [Ianzini et al., 2009]. The implications for the induction of meiosis as a mechanism of survival after radiation treatment are discussed. In the second project, the effects of long-term fluorescence excitation light exposure are examined through measurements of cell division and cell death. In the field of live cell imaging, probably the most modern and most widely utilized technique is fluorescence detection for intracellular organelles, proteins, and molecules. While the technologies required to label and detect fluorescent molecules in a cell are well developed, they are not idealized for long term measurements as both the probes and excitation light are toxic to the cells [Wang and Nixon, 1978; Bradley and Sharkey, 1977]. From the event analysis data it was determined that fluorescence excitation light is toxic to multiple cell lines observed as the reduction of normal cell division, induction of cell death, and apparent morphological aberrations.

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Agrawal, Vishesh. "Quantitative Imaging Analysis of Non-Small Cell Lung Cancer". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27007763.

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Quantitative imaging is a rapidly growing area of interest within the field of bioinformatics and biomarker discovery. Due to the routine nature of medical imaging, there is an abundance of high-quality imaging linked to clinical and genetic data. This data is particularly relevant for cancer patients who receive routine CT imaging for staging and treatment purposes. However, current analysis of tumor imaging is generally limited to two-dimensional diameter measurements and assessment of anatomic disease spread. This conventional tumor-node-metastasis (TNM) staging system stratifies patients to treatment protocols including decisions regarding adjuvant therapy. Recently there have been several studies suggesting that these images contain additional unique information regarding tumor phenotype that can further aid clinical decision-making. In this study I aimed to develop the predictive capability of medical imaging. I employed the principles of quantitative imaging and applied them to patients with non-small cell lung cancer (NSCLC). Quantitative imaging, also termed radiomics, seeks to extract thousands of imaging data points related to tumor shape, size and texture. These data points can potentially be consolidated to develop a tumor signature in the same way that a tumor might contain a genetic signature corresponding to mutational burden. To accomplish this I applied radiomics analyses to patients with early and late stage NSCLC and tested these for correlation with both histopathological data as well as clinical outcomes. Patients with both early and late stage NSCLC were assessed. For locally advanced NSCLC (LA-NSCLC), I analyzed patients treated with preoperative chemoradiation followed by surgical resection. To assess early stage NSCLC, I analyzed patients treated with stereotactic body radiation therapy (SBRT). Quantitative imaging features were extracted from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. For patients who underwent SBRT, quantitative features were extracted from cone-beam CTs (CBCT) at multiple time points during therapy. Univariate and multivariate logistic regression were used to determine association with pathologic response. Concordance-index and Kaplan-Meier analyses were applied to time dependent endpoints of overall survival, locoregional recurrence-free and distant metastasis. In this study, 127 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. 99 SBRT patients were identified in a separate aim of this study. Reduction of CT-defined tumor volume (OR 1.06 [1.02-1.09], p=0.002) as continuous variables per percentage point was associated with pathologic complete response (pCR) and locoregional recurrence (LRR). Conventional response assessment determined by diameter (p=0.213) was not associated with pCR or any survival endpoints. Seven texture features on pre-treatment tumor imaging were associated with worse pathologic outcome (AUC 0.61-0.66). Quantitative assessment of lymph node burden demonstrated that pre-treatment and post-treatment volumes are significantly associated with both OS and LRR (CI 0.62-0.72). Textural analyses of these lymph nodes further identified 3 unique pre-treatment and 7 unique post-treatment features significantly associated with either LRR, DM or OS. Finally early volume change showed associated with overall survival in CBCT scans of early NSCLC. Quantitative assessment of NSCLC is thus strongly associated with pathologic response and survival endpoints. In contrast, conventional imaging response assessment was not predictive of pathologic response or survival endpoints. This study demonstrates the novel application of radiomics to lymph node texture, CBCT volume and patients undergoing neoadjuvant therapy for NSCLC. These examples highlight the potential within the rapidly growing field of quantitative imaging to better describe tumor phenotype. These results provide evidence to the growing radioimics literature that there is significant association between imaging, pathology and clinical outcomes. Further exploration will allow for more complete models describing tumor imaging phoentype with clinical outcomes.

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Kharin, Alexander. "Group IV nanoparticles for cell imaging and therapy". Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1032/document.

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La biomédecine et la biophotonique sont des champs de recherches en plein expansion qui grandissent à vive allure, constituant un secteur entier d'activités novatrices. Ce secteur, vraiment interdisciplinaire, comprend le développement de nouveaux nanomatériaux, de sources lumineuses et l'élaboration de nouveaux concepts, de dispositifs/équipements pour quantifier la conversion de photons et leurs interactions. L'importance décisive du diagnostic précoce et du traitement individuel des patients exige des thérapies soigneusement ciblées et la capacité de provoquer sélectivement la mort cellulaire des cellules malades. Malgré les progrès spectaculaires réalisés en utilisant les points quantiques ou des molécules biologiques organiques pour l'imagerie biologique et la libération ciblée de médicaments, plusieurs problèmes restent à résoudre : obtenir une sélectivité accrue pour une accumulation spécifique dans les tumeurs et une amélioration de l'efficacité des traitements. D'autres problèmes incluent la cytotoxicité et la génotoxicité, l'élimination lente et la stabilité chimique imparfaite. Des espérances nouvelles sont portées par de nouvelles classes de matériaux inorganiques comme les nanoparticules à base de silicium ou à base de carbone, qui pourraient faire preuves de caractéristiques de stabilité plus prometteuses tant pour le diagnostic médical que pour la thérapie. Pour cette raison, la découverte de nouveaux agents de marquage et de transport de médicaments représente un champ important de la recherche avec un potentiel de croissance renforcé
Biomedicine and biophotonics related businesses are currently growing at a breathtaking pace, thereby comprising one of the fastest growing sectors of innovative economy. This sector is truly interdisciplinary, including, very prominently, the development of novel nanomaterials, light sources, or novel device/equipment concepts to carry out photon conversion or interaction. The great importance of disease diagnosis at a very early stage and of the individual treatment of patients requires a carefully targeted therapy and the ability to induce cell death selectively in diseased cells. Despite the tremendous progress achieved by using quantum dots or organic molecules for bio-imaging and drug delivery, some problems still remain to be solved: increased selectivity for tumor accumulation, and enhancement of treatment efficiency. Other potential problems include cyto- and genotoxicity, slow clearance and low chemical stability. Significant expectations are now related to novel classes of inorganic materials, such as silicon-based or carbon-based nanoparticles, which could exhibit more stable and promising characteristics for both medical diagnostics and therapy. For this reason, new labeling and drug delivery agents for medical application is an important field of research with strongly-growing potential.The 5 types of group IV nanoparticles had been synthesized by various methods. First one is the porous silicon, produced by the electrochemical etching of bulk silicon wafer. That well-known technique gives the material with remarkably bright photoluminescence and the complicated porous structure. The porous silicon particles are the agglomerates of the small silicon crystallites with 3nm size. Second type is 20 nm crystalline silicon particles, produced by the laser ablation of the bulk silicon in water. Those particles have lack of PL under UV excitation, but they can luminesce under 2photon excitation conditions. 3rd type of the particles is the 8 nm nanodiamonds

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PHADNGAM, SURATCHANEE. "In Cell Imaging Techniques to Monitor Glucose Uptake, Cell Migration, and Vesicular Traffic: A Functional Study in Cancer Cells". Doctoral thesis, Università del Piemonte Orientale, 2016. http://hdl.handle.net/11579/115172.

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Mickler, Frauke Martina. "Live-cell imaging elucidates cellular interactions of gene nanocarriers for cancer therapy". Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-165829.

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Youniss, Fatma. "MULTI – MODALITY MOLECULAR IMAGING OF ADOPTIVE IMMUNE CELL THERAPY IN BREAST CANCER". VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3323.

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Cancer treatment by adoptive immune cell therapy (AIT) is a form of immunotherapy that relies on the in vitro activation and/or expansion of immune cells. In this approach, immune cells, particularly CD8+ T lymphocytes, can potentially be harvested from a tumor-bearing patient, then activated and/or expanded in vitro in the presence of cytokines and other growth factors, and then transferred back into the same patient to induce tumor regression. AIT allows the in vitro generation and activation of T-lymphocytes away from the immunosuppressive tumor microenvironment, thereby providing optimum conditions for potent anti-tumor activity. The overall objective of this study is to: a) develop multi-modality (optical- and radionuclide-based) molecular imaging approaches to study the overall kinetics of labeled adoptively transferred T- lymphocytes in vivo, b) to non-invasively image and assess in-vivo, targeting and retention of adoptively transferred labeled T-lymphocytes at the tumor site. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in vitro with Bryostatin/ Ionomycin for 18 hours, and were grown in either Interleukin-2 (IL-2) or combination of Interleukin-7 and Interleukin-15 (IL-7/IL-15) for 13 days, (cells grown in IL-2 called IL2 cells, and cells grown in IL7/15 called IL7/15 cells). In order to validate the methodology and to offer future clinical translation, both direct and indirect cell labeling methods were expanded and employed. The first method was based on direct in vitro cell labeling by lipophilic near-infrared (NIR) fluorescent probe, 1,1- dioctadecyltetramethyl indotricarbocyanine iodide, (DiR), followed by intravenous (i.v.) injection into BALB/C mice for multi-spectral fluorescence imaging (MSFI). The second method was based on indirect labeling of T- lymphocytes through transduction of a reporter gene (cell cytoplasm labeling Herpes Simplex Virus type 1- thymidine kinase (HSV-1 tk). The product of this reporter gene is an enzyme (HSV-1TK) which phosphorylates a radio labeled substrate 2-fluoro-2-deoxy-1 β- D- arabinofuranosyl-5-iodouracil ([124I]-FIAU) for Positron Emission tomography (PET) imaging. ATP based cell viability assay, flow cytometry and interferon-γ (IFN-γ) ELISA were used to investigate if there are any changes in cell viability, proliferation and function respectively, before and after direct and indirect labeling. The results showed that cell viability, proliferation, and function of labeled 4T1 specific T-lymphocytes were not affected by labeling for direct labeling methods at DiR concentration of 320µg/ml. For the indirect labeling method, the viability and proliferation results showed that cell viability decreases as multiplicity of infectious (MOI) increases. In particular, at MOI of 10 almost all cells die 3 days post transduction. At MOI of 5, cells viability was ≤ 30% and at MOI of 2 was ≤ 60%. Cell viability was 80% at MOI of 1. The results of optical imaging were as follows: when the recipient mice with established 4T1 tumors were injected with DiR labeled 4T1 specific T-lymphocytes, the 4T1 specific T-lymphocytes (IL2 cells) infused into tumor-bearing mice showed high tumor retention, which peaked 3 or 6 days post infusion depending on the tumor size and persisted at the tumor site for 3 weeks. In contrast, IL7/15 cells showed lower signal at the tumor site and this peaked on day 8. On the other case when 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes. IL2 T-lymphocytes moved out of lymphoid compartments to the site of subsequent 4T1 inoculation within two hours and peaked on day 3 and the signal persisted for 2 more weeks. In contrast with infusion of IL7/15 cells, the signal was barely detected and did not show a similar trafficking pattern as with IL2 cells. The results of the indirect labeling method, PET reporter gene (PRG) system (HSV-1tk / [124I ] FIAU ) showed that both IL2 and IL7/15 cells were successfully transduced as verified ex vivo by real time PCR and western blot. T Cells transduction efficiency was assessed from cell uptake study in comparison to stable transduced Jurkat cells which have transduction efficiency of 100 %. Both IL2 and IL7/15 cells showed lower transduction efficiency (≤ 30%) compared to Jurkat cells. Consequently, PET imaging did not show a detectable signal of transduced T cells in vivo. Biodistribution study was carried out on day 3 post [124I]-FIAU injections. Results were consistent with the optical imaging results, except for IL7/15 cells. Transduced and untransduced IL2 and IL7/15 cells were labeled with DiR and injected ( i.v.) into Balb / C mice and then imaged by both imaging modalities (MSFI and PET) at the same time. MSFI images of transduced IL2 cell showed detectable signal starting from 2 hours, peaked at 72 hours and persisted up to 2 weeks, while IL7/15 cells were detectable at the tumor site starting at 24 hours, peaked at 72 hours and persisted up to 2 weeks. By the end of this study animals were dissected and tissue activities were counted using gamma counting and expressed as % Injected dose/gram of tissue (%ID/gm). Transduced IL2 and IL7/15 cells showed higher %ID/gm than other organs at lungs, liver, spleen, tumor, lymph nodes and bone/bone marrow. IL7/15 cells compared to IL2 cells showed higher %ID/gm at same organs. Neither IL2 nor IL7/15 untransduced DiR labeled cells showed any activity at tumor site, and their activities at other organs was very low compared to transduced cells. To investigate whether labeled T-lymphocytes will localize at tumor metastases or not, and to study the difference in their migration patterns to the tumor site versus tumor metastases, 4T1 tumor cells were successfully transduced with HSV-1tk as confirmed by RT-PCR , western blot and cell uptake study. Transduced 4T1 cells were implanted in the right flank or in the mammary fat pad of the mouse. Serial PET imaging was carried out in the third and fourth week post tumor implantation to know when the tumor will metastasizes. PET imaging showed only signal at the tumor site and no metastasis were detected.

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Soldà, Alice <1986&gt. "Electrochemical imaging of living cell metabolism: investigation on Warburg effect in cancer". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/7072/1/Solda_Alice_tesi.pdf.

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Cancer is one of the principal causes of death in the world; almost 8.2 million of deaths were counted in 2012. Emerging evidences indicate that most of the tumors have an increased glycolytic rate and a detriment of oxidative phosphorylation to support abnormal cell proliferation; this phenomenon is known as aerobic glycolysis or Warburg effect. This switching toward glycolysis implies that cancer tissues metabolize approximately tenfold more glucose to lactate in a given time and the amount of lactate released from cancer tissues is much greater than from normal ones. In view of these fundamental discoveries alterations of the cellular metabolism should be considered a crucial hallmark of cancer. Therefore, the investigation of the metabolic differences between normal and transformed cells is important in cancer research and it might find clinical applications. The aim of the project was to investigate the cellular metabolic alterations at single cell level, by monitoring glucose and lactate, in order to provide a better insight in cancer research. For this purpose, electrochemical techniques have been applied. Enzyme-based electrode biosensors for lactate and glucose were –ad hoc- optimized within the project and used as probes for Scanning Electrochemical Microscopy (SECM). The UME biosensor manufacturing and optimization represented a consistent part of the work and a full description of the sensor preparation protocols and of the characterization methods employed is reported. This set-up (SECM used with microbiosensor probes) enabled the non-invasive study of cellular metabolism at single cell level. The knowledge of cancer cell metabolism is required to design more efficient treatment strategies.

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Soldà, Alice <1986&gt. "Electrochemical imaging of living cell metabolism: investigation on Warburg effect in cancer". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/7072/.

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Cancer is one of the principal causes of death in the world; almost 8.2 million of deaths were counted in 2012. Emerging evidences indicate that most of the tumors have an increased glycolytic rate and a detriment of oxidative phosphorylation to support abnormal cell proliferation; this phenomenon is known as aerobic glycolysis or Warburg effect. This switching toward glycolysis implies that cancer tissues metabolize approximately tenfold more glucose to lactate in a given time and the amount of lactate released from cancer tissues is much greater than from normal ones. In view of these fundamental discoveries alterations of the cellular metabolism should be considered a crucial hallmark of cancer. Therefore, the investigation of the metabolic differences between normal and transformed cells is important in cancer research and it might find clinical applications. The aim of the project was to investigate the cellular metabolic alterations at single cell level, by monitoring glucose and lactate, in order to provide a better insight in cancer research. For this purpose, electrochemical techniques have been applied. Enzyme-based electrode biosensors for lactate and glucose were –ad hoc- optimized within the project and used as probes for Scanning Electrochemical Microscopy (SECM). The UME biosensor manufacturing and optimization represented a consistent part of the work and a full description of the sensor preparation protocols and of the characterization methods employed is reported. This set-up (SECM used with microbiosensor probes) enabled the non-invasive study of cellular metabolism at single cell level. The knowledge of cancer cell metabolism is required to design more efficient treatment strategies.

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Ronteix, Gustave. "Inferring cell-cell interactions from quantitative analysis of microscopy images". Thesis, Institut polytechnique de Paris, 2021. http://www.theses.fr/2021IPPAX111.

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Les systèmes biologiques sont bien plus que la somme de leurs constituants. En effet, ils sont souvent caractérisés par des comportements macroscopiques complexes résultant de boucles d'interactions et de rétroactions. Par exemple, la régulation et le rejet éventuel des tumeurs par le système immunitaire est le résultat de multiples réseaux de régulation, influençant à la fois le comportement des cellules cancéreuses et immunitaires. Pour simuler ces effets complexes in-vitro, j'ai conçu une puce microfluidique permettant de confronter des sphéroïdes de mélanome à de multiples cellules T et d'observer les interactions qui en résultent avec une haute résolution spatio-temporelle et sur de longues périodes de temps. En utilisant de l'analyse d'images avancée, combinée à des modèles mathématiques, je démontre qu'une boucle de rétroaction positive conduit l'accumulation de cellules T sur la tumeur, ayant pour conséquence une fragmentation accrue des sphéroïdes. Cette étude met en lumière l'initiation de la réponse immunitaire à l'échelle de la cellule unique : elle montre que même le tout premier contact entre une cellule T et un sphéroïde tumoral augmente la probabilité que la cellule T suivante arrive sur la tumeur. Elle montre également qu'il est possible de récapituler des comportements antagonistes complexes in-vitro, ce qui ouvre la voie à l'élaboration de protocoles plus sophistiqués, impliquant par exemple un micro-environnement tumoral plus complexe.De nombreux processus biologiques sont le résultat d'interactions entre de multiples types de cellules, en particulier au cours du développement. Le foie fœtal est le lieu de la maturation et de l'expansion du système hématopoïétique, mais on sait peu de choses sur sa structure et son organisation. De nouveaux protocoles expérimentaux ont été récemment mis au point pour imager cet organe et j'ai développé des outils pour interpréter et quantifier ces données, permettant la construction d'un "réseau jumeau" de chaque foie fœtal. Cette méthode permet de combiner les échelles unicellulaire et de l'organe dans une seule analyse, révélant l'accumulation de cellules myéloïdes autour des vaisseaux sanguins irriguant le foie fœtal aux derniers stades du développement de l'organe. À l'avenir, cette technique permettra d'analyser précisément les environnements de cellules d'intérêt de manière quantitative. Ceci pourrait à son tour nous aider à comprendre les étapes du développement de types cellulaires cruciaux tels que les cellules souches hématopoïétiques.Les interactions entre les bactéries et leur environnement sont essentielles pour comprendre l'émergence de comportements collectifs complexes tels que la formation de biofilms. Un mécanisme d'intérêt est celui de la rhéotaxie, par lequel le mouvement bactérien est entraîné par les gradients de la contrainte de cisaillement du fluide dans lequel les cellules se déplacent. J'ai développé une méthode pour calculer les équations semi-analytiques guidant le mouvement des bactéries dans la contrainte de cisaillement. Ces équations prédisent des comportements qui ne sont pas observés expérimentalement, mais la divergence est résolue une fois que la diffusion rotationnelle est prise en compte. Les résultats expérimentaux correspondent bien à la prédiction théorique : les bactéries dans les gouttelettes se séparent de manière asymétrique lorsqu'un cisaillement est généré dans le milieu
In his prescient article “More is different”, P. W. Anderson counters the reductionist argument by highlighting the crucial role of emergent properties in science. This is particularly true in biology, where complex macroscopic behaviours stem from communication and interaction loops between much simpler elements. As an illustration, I hereby present three different instances in which I developed and used quantitative methods in order to learn new biological processes.For instance, the regulation and eventual rejection of tumours by the immune system is the result of multiple positive and negative regulation networks, influencing both the behaviour of the cancerous and immune cells. To mimic these complex effects in-vitro, I designed a microfluidic assay to challenge melanoma tumour spheroids with multiple T cells and observe the resulting interactions with high spatiotemporal resolution over long (>24h) periods of time. Using advanced image analysis combined with mathematical modelling I demonstrate that a positive feedback loop drives T cell accumulation to the tumour site, leading to enhanced spheroid fragmentation. This study sheds light on the initiation if the immune response at the single cell scale: showing that even the very first contact between T cell and tumour spheroid increases the probability of the next T cell to come to the tumour. It also shows that it is possible to recapitulate complex antagonistic behaviours in-vitro, which paves the way for the elaboration of more sophisticated protocols, involving for example a more complex tumour micro-environment.Many biological processes are the result of complex interactions between cell types, particularly so during development. The foetal liver is the locus of the maturation and expansion of the hematopoietic system, yet little is known about its structure and organisation. New experimental protocols have been recently developed to image this organ and I developed tools to interpret and quantify these data, enabling the construction of a “network twin” of each foetal liver. This method makes it possible to combine the single-cell scale and the organ scale in the analysis, revealing the accumulation of myeloid cells around the blood vessels irrigating the foetal liver at the final stages of organ development. In the future, this technique will make it possible to analyse precisely the environmental niches of cell types of interest in a quantitative manner. This in turn could help us understand the developmental steps of crucial cell types such as hematopoietic stem cells.The interactions between bacteria and their environment is key to understanding the emergence of complex collective behaviours such a biofilm formation. One mechanism of interest is that of rheotaxis, whereby bacterial motion is driven by gradients in the shear stress of the fluid the cells are moving in. I developed a framework to calculate the semi-analytical equations guiding bacteria movement in shear stress. These equations predict behaviours that aren’t observed experimentally, but the discrepancy is solved once rotational diffusion is taken into account. Experimental results are well-fitted by the theoretical prediction: bacteria in droplets segregate asymmetrically when a shear is generated in the media.Although relating to very different topics, these three studies highlight the pertinence of quantitative approaches for understanding complex biological phenomena: biological systems are more than the sum of their constituents.a

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Szucs, Zoltan. "An orthotopic mammary epithelial cell transplantation model and prognostic molecular imaging of early breast cancer formation". Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709323.

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Hill, Esme. "Perfusion imaging and tissue biomarkers for colorectal cancer". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:4a309265-6f27-4839-9259-f19cf9648c2d.

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Background: Systemic chemotherapy and radiotherapy play an important role in the treatment of colorectal cancer. Tumour perfusion and oxygenation is known to influence radiosensitivity and chemosensitivity. In this thesis, I propose that the evaluation of changes in tumour perfusion using perfusion CT (pCT) and dynamic contrast-enhanced (Dce) MRI can guide the rational sequencing of drugs and radiation. Methods: Dce-MRI and pCT scans were incorporated into a clinical trial of hypofractionated pelvic radiotherapy and nelfinavir in 10 patients with rectal cancer. Toxicity and tissue biomarkers (tumour cell density, microvessel density, CAIX, HIF1-alpha, phospho-Akt and phospho-PRAS40) were evaluated. pCT liver scans were incorporated into an imaging study in patients with colorectal liver metastases randomised to receive either oxaliplatin/ 5FU chemotherapy or oxaliplatin/ 5FU chemotherapy plus selective internal radiotherapy. Results: After 7 days of nelfinavir concurrent with hypo-fractionated pelvic radiotherapy, there was a mean 42% increase in median K^trans (P=0.03, paired t test) on Dce-MRI and a median 30% increase in mean blood flow on pCT (P=0.028, Wilcoxon Rank Sum), although no statistically significant changes in perfusion parameters were demonstrated after 7 days of nelfinavir prior to radiotherapy. The feasibility of evaluating tumour cell density in rectal biopsies before and after radiotherapy and a radiosensitising drug as an early endpoint of response was demonstrated. In patients with colorectal liver metastases who received oxaliplatin and modified de Gramont chemotherapy alone, after 4 cycles of chemotherapy, a 28% decrease in the mean hepatic arterial fraction was observed (P=0.018, paired t test). Between pCT scans 2 days before SIRT and 39-47 days following SIRT and continued 2-weekly chemotherapy, there was a mean 62% (P=0.009) reduction in Blood Flow and 61% (P=0.006) reduction in Blood Volume (paired t test). Conclusions This research does not support the hypothesis that nelfinavir before radiotherapy improves blood flow to human rectal cancer. Increases in rectal tumour perfusion during radiotherapy and concurrent nelfinavir are likely to be primarily explained by the acute biological effects of radiation. Four or more cycles of oxaliplatin and modified de Gramont chemotherapy may result in changes in tumour perfusion of colorectal liver metastases which would be detrimental to subsequent radiotherapy. Selective internal radiotherapy resulted in substantial reductions in tumour perfusion 39-47 days after the treatment. Perfusion imaging can be used to detect changes in tumour perfusion in response to radiotherapy and systemic therapy which have implications for the sequencing of therapies.

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Hoppe, Andreas. "Adaptive spline method for the assessment of cell motility and its application to lesions". Thesis, University of South Wales, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341937.

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Chaudry, Qaiser Mahmood. "Improving cancer subtype diagnosis and grading using clinical decision support system based on computer-aided tissue image analysis". Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/47745.

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This research focuses towards the development of a clinical decision support system (CDSS) based on cellular and tissue image analysis and classification system that improves consistency and facilitates the clinical decision making process. In a typical cancer examination, pathologists make diagnosis by manually reading morphological features in patient biopsy images, in which cancer biomarkers are highlighted by using different staining techniques. This process is subjected to pathologist's training and experience, especially when the same cancer has several subtypes (i.e. benign tumor subtype vs. malignant subtype) and the same cancer tissue biopsy contains heterogeneous morphologies in different locations. The variability in pathologist's manual reading may result in varying cancer diagnosis and treatment. This Ph.D. research aims to reduce the subjectivity and variation existing in traditional histo-pathological reading of patient tissue biopsy slides through Computer-Aided Diagnosis (CAD). Using the CAD, quantitative molecular profiling of cancer biomarkers of stained biopsy images are obtained by extracting and analyzing texture and cellular structure features. In addition, cancer sub-type classification and a semi-automatic grade scoring (i.e. clinical decision making) for improved consistency over a large number of cancer subtype images can be performed. The CAD tools do have their own limitations and in certain cases the clinicians, however, prefer systems which are flexible and take into account their individuality when necessary by providing some control rather than fully automated system. Therefore, to be able to introduce CDSS in health care, we need to understand users' perspectives and preferences on the new information technology. This forms as the basis for this research where we target to present the quantitative information acquired through the image analysis, annotate the images and provide suitable visualization which can facilitate the process of decision making in a clinical setting.

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Bolin, Celeste, Caleb Sutherland, Ken Tawara, Jim Moselhy i Cheryl Jorcyk. "Novel mouse mammary cell lines for in vivo bioluminescence imaging (BLI) of bone metastasis". BioMed Central, 2012. http://hdl.handle.net/10150/610032.

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BACKGROUND:Tumor cell lines that can be tracked in vivo during tumorigenesis and metastasis provide vital tools for studying the specific cellular mechanisms that mediate these processes as well as investigating therapeutic targets to inhibit them. The goal of this study was to engineer imageable mouse mammary tumor cell lines with discrete propensities to metastasize to bone in vivo. Two novel luciferase expressing cell lines were developed and characterized for use in the study of breast cancer metastasis to bone in a syngeneic mouse model.RESULTS:The 4 T1.2 luc3 and 66c14 luc2 cell lines were shown to have high levels of bioluminescence intensity in vitro and in vivo after orthotopic injection into mouse mammary fat pads. The 4 T1.2 luc3 cell line was found to closely model the sites of metastases seen in human patients including lung, liver, and bone. Specifically, 4 T1.2 luc3 cells demonstrated a high incidence of metastasis to spine, with an ex-vivo BLI intensity three orders of magnitude above the commercially available 4 T1 luc2 cells. 66c14 luc2 cells also demonstrated metastasis to spine, which was lower than that of 4 T1.2 luc3 cells but higher than 4 T1 luc2 cells, in addition to previously unreported metastases in the liver. High osteolytic activity of the 4 T1.2 luc3 cells in vivo in the bone microenvironment was also detected.CONCLUSIONS:The engineered 4 T1.2 luc3 and 66c14 luc2 cell lines described in this study are valuable tools for studying the cellular events moderating the metastasis of breast tumor cells to bone.

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16

Martelli, C. "Experimental strategies for the in vivo imaging of cell-mediated therapies in cancer and myopathies". Doctoral thesis, Università degli Studi di Milano, 2009. http://hdl.handle.net/2434/167674.

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Introduction. Cell-mediated therapies have acquired great importance in the last years and numerous protocols based on the use of dendritic cells in anti-neoplastic immunotherapies and of stem cells in regenerative medicine were described. However, important parameters such as the distribution and survival of the injected cells, the target organ localisation and the cell proliferation and differentiation deserve being deeply evaluated in order to improve the efficacy of cell-mediated treatments. Here we propose some experimental strategies for in vivo imaging by MRI and SPET of dendritic cell-mediated immunotherapy treatments, in a transgenic murine model of breast cancer (MMTV-v-Ha-Ras) and labelling protocols for in vivo visualisation by MRI of human mesoangioblasts to be used in the treatment of inflammatory myopathies. Materials and Methods. Total bone marrow cells were extracted from wt mice. DC differentiation was studied by flow cytometry; on the 6 day of culture DCs were labelled with commercial MNPs. Dose-response and kinetic of labelling studies were performed (100-200-400 μg of iron/ml, for 6-16-24-48 hours). Labelling efficiency was evaluated by optical microscopy after Perl’s staining and relaxometric analysis. Tumour lysates from breast cancer lesions of transgenic mice were used to load immature DCs (iDCs) and maturation was monitored by flow cytometry. Stimulatory activity of antigen-loaded DCs was evaluated by T-cell proliferation and IFN-γ production by T cells; their migratory ability was evaluated in the presence of 6Ckine, MIP-3, MIP-1 and MIP-1. Two millions of MNP-labelled DCs loaded with tumour antigens were then injected into the footpad of a transgenic tumour bearing mouse. Then, imaging was performed by use of a 7T MR scanner (Bruker) after 4, 24 and 48 hours from cell administration by use of MSME and FLASH sequences. After 48 hours, Perl’s staining was carried out on the section of the collected draining lymph node to evaluate DC migration. DCs were also labelled with different amounts of 111In-oxine, and labelling efficiency and viability analyses were performed. Two millions of labelled and antigen-loaded DCs were injected in the murine model, and SPET imaging with a new prototype of γ-camera (DRAGO, in collaboration with the Politecnico of Milan) was performed after 4, 24 and 48 hours from cell injection. Ex vivo analysis of the collected lymph nodes was then carried out to evaluate the presence of radioactivity due to migrating DCs. Human mesoangioblasts were cultured in collaboration with a team from the Catholic University of Rome, and labelled for 24 and 48h with different amounts of MNPs (Endorem®, 0-100-200-400 μg of iron/ml) in the presence or absence of transfection agents (Poly-L-Lysine or Polybrene). Cells were washed with PBS and analysed for viability, iron content (Perl’s staining) and morphology or plated for further analysis of multipotency or differentiation capability. One million of mesoangioblasts labelled with 200 μg of iron/mL in presence of PLL for 48h were washed twice and injected intramuscularly or in the femoral artery into SCID mice after N2 damage of the tibial posterior muscle. MRI imaging was performed 1h and 3 days after injection using a 7T MR scanner (Bruker). Mice were acquired prone: multislice Spin-Echo (MSME) and 3D gradient Echo (FLASH 3D) sequences were performed. Results. The cytofluorimetric analyses identified the best time point to perform labelling of DCs with MNPs (maximum iDCs:mDCs ratio) on day 6 of culture. Results showed that the labelling efficiency was proportional to the iron content in the medium and to the incubation time. The ideal labelling condition (85% efficiency) was identified as being 200ug Fe/ml for 16h. Viability was not deeply affected by the MNP internalisation. Relassometric assay showed that the T2 reduction is proportional to the iron content. Labelling with MNPs did affect neither DC immune-phenotype nor functionality as demonstrated by the expression levels of CD86 and CD83 and by the observation that LPS stimulation induced maturation of the labelled DCs. Antigen-loaded DCs induced T-cell proliferation and INF-γ production; the 1:5 and 1:10 (DCs-tumour cells) ratio resulted in the highest efficiency of DC maturation as demonstrated by the MHCII expression levels. Migration assays showed that antigen-loaded DCs, also in presence of MNPs, were able to migrate in the presence of stimulatory chemokines (6Ckine and MIP3). Imaging through Magnetic Resonance and SPET evidenced the presence of MNPs- or 111In-labelled and antigen-loaded DCs in the draining lymph nodes. Perl’s staining of lymph node sections confirmed these data, indicating that mature and labelled DCs migrate in vivo from the site of injection to the draining lymph node; moreover ex vivo analysis of colleted lymph nodes showed the presence of radioactivity in the nodes omolateral to the injection site. After thawing, human mesoangioblasts were cultured and incubated for 24 or 48 hours with 0-50-100-200 μg of iron/ml in presence of transfection agents (PLL and PB), and no difference in terms of viability was observed between labelled and non-labelled cells in the presence or absence of PLL or PB, except for the case of 200 μg of iron/ml for 24 hours in the presence of PLL. On the contrary, the percentage of Iron-positive cells increased in proportion to the iron content in the medium and in the presence of PLL. In particular we obtained 99,6%+1 iron-positive cells in the samples incubated with 200 μg of iron/ml for 48 hours with PLL present. The labelling procedures determined a reduction in T2 time in all the conditions, revealing that the signal was stronger at 24 hours than at 48 hours: the signal was proportional to the iron content. Iron-labelled cells, cultured for a further 5 passages, maintained the phenotypic characteristics of non labelled human mesoangioblasts, as revealed by cytofluorimetric analysis. Growth of labelled cells was comparable to control cells and they maintained their ability to differentiate and form myotubes. As no differences between controls and cells incubated with 200 μg of iron/ml for 48 hours in presence of PLL were present, this condition was deemed ideal for cell labelling and in vivo visualisation by MRI. Imaging evidenced the presence of MNPs-labelled mesoangioblasts in the site of intramuscular injections and in the damaged muscles. Perl’s staining of muscle sections confirmed these data, indicating that labelled MBs migrate in vivo from the site of injection to the muscle injury. Conclusions. The isolation of the murine dendritic cell population proved efficient while the labelling protocols with MNPs did not affect DC physiology and functionality. Cultured DCs maintained their ability to migrate in response to specific chemokines and to activate T cells. Moreover, the protocol for 111In-oxine permitted labelling cells with high efficiency and without influencing the cell viability. Dynamic in vivo MRI and SPET monitoring of these cells permitted to follow the migration and localization of DCs in the animal model. The labelling of human mesoangioblasts with MNPs for visualisation by MRI was as efficient as DCs protocols and no alterations in cell phenotype and morphology was observed. MRI allowed to study the fate of these cells once injected into the recipient SCID mice after muscle injury. The possibility of tracking injected cells will shed light on the fundamental parameters responsible for the cell-mediated therapy efficacy (such as the administration route, the amount of cells, the adjuvant treatment, etc.), while the use of clinically approved MNPs will speed up the transfer from pre-clinical investigations to clinical applications.

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Akpe, Victor. "Breast Cancer Cell Detection and Profiling Using Nanomaterial-Derived Scaffolds". Thesis, Griffith University, 2021. http://hdl.handle.net/10072/407561.

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Background: The concentration of circulating tumour cells (CTCs) or cancer cell per mL in clinical blood sample is estimated to contain 106 white blood cells and 109 red bloods, suggesting CTCs are very rare. Other characteristics of cancer cells such as vulnerability in vitro, their minuscule sizes and variability (4-10 μm) in cluster, and the cancer cell subtypes and phenotypes etc. have been areas of intense research. Technological innovations have therefore focused on platforms for cancer cell detection, selective cancer cell capture, cancer cell separation/analysis platforms etc. Additionally, there has been increasing interest in biological and synthetic materials as cell-based scaffolds for preclinical screening. Methods: Breast cancer cells (BC) derived from a human adenocarcinoma were profiled using nanomaterial-derived scaffolds. This thesis utilises the following techniques to study the properties of BCs: cell culture preparation, electrochemical biosensor development, assay screening, fluorescence imaging, batch-assay studies, and estimation of the chemotherapeutic dose uptake of cancer cells in various assay systems (as outlined in detail in the relevant chapters). Results: Chapter 2 reviews the current literature and covers a broad spectrum related to the etiology of cancer cells and the mode of cellular invasion. Various nanotechnology platforms of selective CTC capture, separation, and detection of CTC encumbrance in patients’ whole blood samples, as well as the significance of CTC as biological markers for tumour detection were extensively reviewed in that chapter. Chapter 3 utilises various cellular biological markers to characterise BC cell surface using an amperometry detection method. The positive assay produced six-fold current output compared to the negative controls. The nanozyme which contained iron oxide loaded with gold particles produced a wide capturing range (10-105 cells/ml) in phosphate-buffered saline (pH = 7.4). The limit of detection (LOD) was calculated at 0.4 U/ml. The cancer cells captured were later used in the post-expansion of BC cells in vitro, suggesting the potential expansion of BC phenotypes in cell-based scaffolds of 2D, 3D or 3D coculture platforms. Chapter 4 used substrate casts developed to potentiate growth inhibition of MCF-7 cells prior to cisplatin addition to the cells (Chapters 4 and 5). The results from Chapter 4 suggests that cisplatin exposed to MCF-7 cells on SNP: PEG substrate casts was more effective by 26-fold than in the control sample; 32 times more effective than SNP: PEG: fruit ethyl acetate extract of Terminalia ferdinandiana cast, and 8-fold more effective than SNP: PEG: leaf methanolic extract of the Terminalia ferdinandiana cast. Chapter 5 focuses on a table algorithm to reduce systematic errors from sample preparations, which otherwise can make the data incomprehensible, especially for cross-prediction performance as assay models. Lastly, Chapter 6 comments and summarises some of the cancer models in the 3D study and highlights future directions for the development and integration of 3D co-culture cell models on biosensor platforms for the detection and profiling cancer cells. Conclusions: Overall, the following objectives have been addressed in this thesis : (1) development of assay cascade methods for the efficient capture of BC cells and in the post-expansion of captured cells in vitro; (2) the development of an electrochemical based amplification method for BC detection and profiling the biomarker expression levels on BC cells; (3) development of an assay cascade method for differentiating BC cells and as synergistic platforms for effective drug dosing; and (4) the development of a simple algorithm for screening irrelevant cell-based scaffolds.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
Full Text

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Maruno, Takahisa. "Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging". Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265166.

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京都大学
新制・論文博士
博士(医学)
乙第13427号
論医博第2231号
新制||医||1053(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授松田道行, 教授渡邊直樹, 教授川口義弥
学位規則第4条第2項該当
Doctor of Medical Science
Kyoto University
DFAM

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Zahir, Sheba Adam. "Evaluating the efficacy of DNA repair biomarkers to assess human cell response to chemotherapy using imaging flow cytometry". Thesis, Brunel University, 2013. http://bura.brunel.ac.uk/handle/2438/7768.

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Chemotherapy and radiotherapy are widely accepted as common forms of treatment for cancers. The majority of cancer patients receive chemotherapy alone or in combination with radiotherapy. Most chemotherapeutic drugs cause DNA damage to the rapidly dividing cancer cells but normal cells are also damaged in the process. Therefore DNA repair levels in tumour and normal cells may determine the success of the treatment. The aim of this work was to evaluate the use of DNA repair biomarkers for assessing responses to chemotherapeutic drugs. The novel technique of imaging flow cytometry was employed to analyse the induction and resolution of γ-H2AX and RAD51 DNA repair biomarkers in DNA repair normal cell lines MRC5-SV1 and NB1-HTERT, an ATM-deficient cell line AT5BIVA (derived from an Ataxia Telangiectasia patient) and an XPF-deficient cell line GM08437B. Two cell lines were also developed, MRC5-SV1R and NB1-HTERTR which had been made resistant to HN2. A range of chemotherapeutic drugs, Adriamycin, Cisplatin and Nitrogen Mustard which have different modes of action were examined in this work. We have demonstrated distinct differences in γ-H2AX and RAD51 foci induction and resolution between the two DNA repair normal cell lines following exposure to different chemotherapeutic drugs. Additionally, it was demonstrated that both the resistant and sensitive cell lines have elevated γ-H2AX and RAD51 expression profiles in comparison to the parental cell lines over a 48 hour period post treatment with the cross-linking agent HN2. It is concluded that while both the γ-H2AX and Rad51 biomarkers may be useful for determining chemotherapeutic response, a larger cohort of cell lines and tumour samples is required for further analysis.

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Tavassoly, Iman. "Dynamics of Cell Fate Decisions Mediated by the Interplay of Autophagy and Apoptosis in Cancer Cells: Mathematical Modeling and Experimental Observations". Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/79557.

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Autophagy is a conserved biological stress response in mammalian cells that is responsible for clearing damaged proteins and organelles from the cytoplasm and recycling their contents via the lysosomal pathway. In cases where the stress is not too severe, autophagy acts as a survival mechanism. In cases of severe stress, it may lead to programmed cell death. Autophagy is abnormally regulated in a wide-range of diseases, including cancer. To integrate the existing knowledge about this decision process into a rigorous, analytical framework, we built a mathematical model of cell fate decision mediated by autophagy. The model treats autophagy as a gradual response to stress that delays the initiation of apoptosis to give the cell an opportunity to survive. We show that our dynamical model is consistent with existing quantitative measurements of time courses of autophagic responses to cisplatin treatment. To understand the function of this response in cancer cells we have provided a systems
biology experimental framework to study dynamical aspects of autophagy in single cancer cells using live-cell imaging and quantitative uorescence microscopy. This framework can provide new insights on function of autophagic response in cancer cells.
Ph. D.

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Phyu, Su Myat. "Targeting of the PI3K/AKT/mTOR signalling pathway and associated kinases in breast and colon cancer cells and response evaluation by molecular imaging techniques". Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=238576.

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The phosphatidylinositol-3-kinase/AKT (Protein Kinase B)/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway, downstream of tyrosine kinase receptors, is upregulated in human cancers including breast and colon cancers. Glycogen synthase kinase 3 (GSK 3) is a serine/threonine protein kinase plays important role in various cellular processes including glycogen synthesis mediated by insulin signalling pathway. Moreover, 5' adenosine monophosphate activated protein kinase (AMPK), a crucial cellular energy sensor, has regulatory role in cell growth and proliferation through mTOR pathway. Phosphatidylcholine (PtdCho) is the major phospholipid in the mammalian cell membranes and is mainly synthesized by the CDP-choline pathway. Malignant transformation has been reported to be associated with altered choline metabolism. Hyperactivation of the PI3K/AKT signalling pathway upregulates the key enzymes of phospholipid metabolism. The first line antidiabetic drug, metformin, modulates glucose and concomitant lipid metabolism through AMPK activation. Studies suggest phosphatidylcholine biosynthesis and breakdown through CDP-choline pathway are modulated by glucose metabolism and de novo fatty acid synthesis. Cancer cell growth inhibitory effect of PI3K/AKT/mTOR/GSK3 pathway inhibitors and metformin were investigated by cytotoxic assay, western blot and cell cycle analysis in breast and colon cancer cells. IC50 values of anticancer drugs and combination indices between drug combinations were determined. 31P-NMR was carried out on cell extracts after drug treatments. [14C (U)] glucose and [3H] choline incorporation into lipids were also determined. All inhibitors targeting PI3K/AKT/mTOR signaling pathway, GSK3 and metformin have cancer cell growth inhibition. By 31P-NMR, PI3K/AKT/mTOR pathway inhibition induced agent-specific changes in PCho intensity. Increased UDP-sugars observed in breast and colon cancer cell extracts treated with LY294002 and AZD8055, an effect abrogated by inclusion of a GSK3 inhibitor. A link between glycolytic intermediates and phosphatidylcholine biosynthesis was investigated by metformin and GSK3 inhibitor in breast and colon cancer cells.

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Gustafsson, Linnéa. "Internalisation of antigen-adjuvant conjugate in human dendritic cells : An assay development for using live cell imaging". Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434224.

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Introduction: Cancer vaccines are a therapeutic approach to initiate an antigen specific cytotoxic immune responses against tumors. Cancer vaccines are composed by an antigen (tumor peptide) and adjuvant. A peptide in combination with adjuvants effectively activate dendritic cells (DCs), the most efficient antigen presenting cells in our immune system. DCs prime and activate CD8+ cytotoxic T cells which generates an antigen specific response.Aim: Developing an assay to study the internalisation rout of an antigen-adjuvant conjugate in human dendritic cells by using live cell imaging. Method: Immobilisation of cells is necessary for the ability to perform live cell imaging for several hours. The immobilisation ability of three coatings, collagen type I, fibronectin and matrigel, at different concentrations were evaluated by using live cell imaging in a fluorescence microscope. The potential induction of activation of the cells were evaluated by using flow cytometry and ELISA. Results: Immature DCs internalise antigen-adjuvant conjugate more efficiently than mature and activated DCs. Therefore, it is important that the coating do not induce activation. Cells must also be immobilised for the possibility of long term detection. Collagen type I immobilised cells and induced activation in all investigated concentrations. Fibronectin and matrigel had concentration-dependent abilities to immobilise the cells. Matrigel did not activate the cells whilst fibronectin was concentration dependent. Conclusion: Matrigel immobilise the cells which enables long term single cell imaging without activation.

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Christakou, Athanasia. "Ultrasound-assisted Interactions of Natural Killer Cells with Cancer Cells and Solid Tumors". Doctoral thesis, KTH, Biomedicinsk fysik och röntgenfysik, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-158522.

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In this Thesis, we have developed a microtechnology-based method for culturing and visualizing high numbers of individual cells and cell-cell interactions over extended periods of time. The foundation of the device is a silicon-glass multiwell microplate (also referred as microchip) directly compatible with fluorescence microscopy. The initial microchip design involved thousands of square wells of sizes up to 80 µm, for screening large numbers of cell-cell interactions at the single cell level. Biocompatibility and confinement tests proved the feasibility of the idea, and further investigation showed the conservation of immune cellular processes within the wells. Although the system is very reliable for screening, limitations related to synchronization of the interaction events, and the inability to maintain conjugations for long time periods, led to the development of a novel ultrasonic manipulation multiwell microdevice. The main components of the ultrasonic device is a 100-well silicon-glass microchip and an ultrasonic transducer. The transducer is used for ultrasonic actuation on the chip with a frequency causing half-wave resonances in each of the wells (2.0-2.5 MHz for wells with sizes 300-350 µm). Therefore, cells in suspension are directed by acoustic radiation forces towards a pressure node formed in the center of each well. This method allows simultaneous aggregation of cells in all wells and sustains cells confined within a small area for long time periods (even up to several days). The biological target of investigation in this Thesis is the natural killer (NK) cells and their functional properties. NK cells belong to the lymphatic group and they are important factors for host defense and immune regulation. They are characterized by the ability to interact with virus infected cells and cancer cells upon contact, and under suitable conditions they can induce target cell death. We have utilized the ultrasonic microdevice to induce NK-target cell interactions at the single cell level. Our results confirm a heterogeneity within IL-2 activated NK cell populations, with some cells being inactive, while others are capable to kill quickly and in a consecutive manner. Furthermore, we have integrated the ultrasonic microdevice in a temperature regulation system that allows to actuate with high-voltage ultrasound, but still sustain the cell physiological temperature. Using this system we have been able to induce formation of up to 100 solid tumors (HepG2 cells) in parallel without using surface modification or hydrogels. Finally, we used the tumors as targets for investigating NK cells ability to infiltrate and kill solid tumors. To summarize, a method is presented for investigating individual NK cell behavior against target cells and solid tumors. Although we have utilized our technique to investigate NK cells, there is no limitation of the target of investigation. In the future, the device could be used for any type of cells where interactions at the single cell level can reveal critical information, but also to form solid tumors of primary cancer cells for toxicology studies.

QC 20150113

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Zhang, Jingxiang. "Series of porphyrin-ru conjugates as two-photon induced bifunctional therapeutic vectors : synthese, characterization, photophysis, cell imaging and photodynamic therapy". HKBU Institutional Repository, 2012. https://repository.hkbu.edu.hk/etd_ra/1447.

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Miller, Brandon Lee. "Quantitative, Multiparameter Analysis of Fluorescently Stained, Negatively Enriched, Peripheral Blood from Cancer Patients". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1386005404.

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Selvaraju, Ram kumar. "[68Ga]Exendin-4: Bench-to-Bedside : PET molecular imaging of the GLP-1 receptor for diabetes and cancer". Doctoral thesis, Uppsala universitet, Plattformen för preklinisk PET, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-261629.

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Diabetes epidemic is underway. Beta cell dysfunction (BCF) and loss of beta cell mass (BCM) are known to be key events in its progression. Currently, there are no reliable techniques to estimate or follow the loss of BCM, in vivo. Non-invasive imaging and quantification of the whole BCM in the pancreas, therefore, has a great potential for understanding the progression of diabetes and the scope for early diagnosis for Type 2 diabetes. Glucagon-like peptide-1 receptor (GLP-1R) is known to be selectively expressed on the pancreatic beta cells and overexpressed on the insulinoma, a pancreatic neuroendocrine tumor (PNET). Therefore, this receptor is considered to be a selective imaging biomarker for the beta cells and the insulinoma. Exendin-4 is a naturally occurring analog of GLP-1 peptide. It binds and activates GLP-1R with same the potency and engages in the insulin synthesis, with a longer biological half-life. In this thesis, Exendin-4 precursor, DO3A-VS-Cys40-Exendin-4 labeled with [68Ga], [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 ([68Ga]Exendin-4), was evaluated in different species models, namely, immune deficient nude mice, rats, pigs, non-human primate (NHP), and clinically in one insulinoma patient by positron emission tomography (PET), for its potential in beta cell imaging and its quantification as well as for visualizing the insulinoma. From internal dosimetry, the possible number of repetitive [68Ga]Exendin-4-PET/CT scans was estimated. Pancreatic uptake and insulinoma tumor uptake of [68Ga]Exendin-4 were confirmed to be mediated by the specific binding to the GLP-1R. Pancreatic GLP-1R could be visualized and semi-quantified, for diabetic studies, except in rats. Nonetheless, we found conflicting results regarding the GLP-1R being a selective imaging biomarker for the beta cells. PET/CT scan of the patient with [68Ga]Exendin-4 has proven to be more sensitive than the clinical neuroendocrine tracer, [11C]5-HTP, as it could reveal small metastatic tumors in liver. The kidney was the dose-limiting organ in the entire species model, from absorbed dose estimation. Before reaching a yearly kidney limiting dose of 150 mGy and a whole body effective dose of 10 mSv, 2–4 [68Ga]Exendin-4 PET/CT scans be performed in an adult human, which enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma, as well as in healthy volunteers enrolled in the early phase of anti-diabetic drug development studies.

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Mickler, Frauke Martina [Verfasser], i CHRISTOPH [Akademischer Betreuer] BRAEUCHLE. "Live-cell imaging elucidates cellular interactions of gene nanocarriers for cancer therapy / Frauke Martina Mickler. Betreuer: Christoph Bräuchle". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1047300516/34.

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Trigonis, Ioannis. "Imaging tumour proliferation with [F-18]fluorothymidine PET in patients with non-small cell lung cancer in response to radiotherapy". Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/imaging-tumour-proliferation-with-f18fluorothymidine-pet-in-patients-with-nonsmall-cell-lung-cancer-in-response-to-radiotherapy(8d342eac-55fb-4fc0-95e6-ebe11ffd319f).html.

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Improved radiotherapy (RT) outcomes may be facilitated through monitoring of physiological processes implicated in radio-resistance such as proliferation. To this end, we studied 16 patients with non-small cell lung cancer with dynamic 3'-deoxy-3'-fluorothymidine (FLT) PET-CT before and after a week of radical RT. In absence of changes in primary tumour volume manually delineated on CT, RT induced a significant, moderately variable decrease in maximum and mean standard uptake values (SUVmax and SUVmean) of the order of 25%. Metastatic nodes showed a larger relative decrease in uptake approximating 40% associated with volumetric regression and only partially accountable by partial volume effect. Implementation of different segmentation approaches including manual delineation by a second operator and PET-based semi-automatic algorithms [two fixed thresholds, 2/3-cluster Fuzzy C-means (FCM-2, FCM-3) and 2/3-cluster fuzzy locally adaptive Bayesian algorithm (FLAB-2, FLAB-3)] yielded substantially different volumes and SUVs but consistent SUV responses. Reproducibility comparison favoured manual delineation, while thresholding delivered poor volumetric robustness and no apparent SUV reproducibility advantage over SUVmax or SUVpeak. FCM-2/FLAB-2 demonstrated intermediate reproducibility. In contrast to anatomical volumes, metabolic volumes exhibited significant increases with treatment, which for FLAB-2 correlated with changes of intratumoural uptake heterogeneity quantified by the coefficient of variation. Normal tissue analysis revealed an anterior-posterior gradient of lung uptake and an association of baseline marrow SUV with type/timing of neo-adjuvant chemotherapy. RT induced a dramatic (≈-76%), sharply demarcated marrow SUV decline in response to a minimum of 5Gy and a small (≈-20%), consistent decline in normal lung SUV. Kinetic analysis revealed a significant increase in the tumour delivery constant K1 (+32%) and a decrease in Ki/K1, larger (-36%) and more variable than the Ki (-26%) and SUV responses. Furthermore, despite baseline independence, we found a strong negative correlation between Ki/K1 and K1 at the response level. Kinetic analysis of the most uptake-avid tumour cluster extracted with FCM-3 yielded similar results with attenuated changes in delivery and retention. Overall, we found that RT induces early measurable changes in lung tumour FLT uptake. Spatial analysis indicated a variable dissociation of anatomical and metabolic volumes, while temporal analysis showed a variable antagonistic effect on delivery and phosphorylation, indicating that SUV analysis may misrepresent the magnitude and variability of RT anti-proliferative effect.

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Yang, Jun. "Approaches to prostate cancer imaging and therapy the use of pharmacokinetics, metabolism and biodistribution to identify new drugs /". Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133362520.

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Mehnert, Andrew James Heinrich. "Image analysis for the study of chromatin distribution in cell nuclei with application to cervical cancer screening /". St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17876.pdf.

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Dazzoni, Régine. "Unravelling the role of Nuclear Membrane dynamics in the behaviour of cancer cells : A multidisciplinary approach using cell biology, advanced imaging and biophysics". Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0310.

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Des malformations de l’enveloppe nucléaire sont observées dans des maladies de dystrophie musculaire ainsi que dans certains types de cancer tels que le cancer du sein ou du rein. Les mécanismes impliqués dans le maintien de la morphologie de l’enveloppe nucléaire sont basés sur des interactions protéo-lipidiques. Il a été démontré récemment que les propriétés physiques de lipides spécifiques jouent un rôle dans le processus de formation de l’enveloppe nucléaire chez le modèle de l’oursin. Afin de comprendre l’implication des lipides dans la régulation de l’architecture de l’enveloppe nucléaire nous avons utilisé les méthodes quantitatives de spectrométrie de masse et de résonance magnétique nucléaire (RMN) afin d’étudier la composition lipidique et les propriétés dynamiques de l’enveloppe nucléaire. L’extraction de noyaux a été effectuée à partir de cellules humaines de rein, les HEK 293T. Une extraction physique basée sur un traitement de pression et un gradient de sucrose a été optimisée afin d’obtenir une large quantité de noyaux intacts (lipides de l’enveloppe nucléaire) requis pour nos expériences. Ces noyaux purifiés comprennent un minimum de débris cellulaires, de réticulum endoplasmique et de l’appareil de golgi. Les lipides nucléaires sont ensuite extraits en utilisant une méthode Folch modifiée. Des expériences de RMN des liquides ont montré que l’enveloppe nucléaire était composée de nombreux types de phospholipides et dont la phosphatidylcholine était le lipide majoritaire. Par ailleurs, nous avons observé une grande quantité de phosphatidilinositol en comparaison avec d’autres types de membranes. Les expériences de spectrométrie de masse ont permis de mettre en évidence que la membrane nucléaire était composée majoritairement de lipides très insaturés et de chaines comportant en moyenne 34 atomes de carbone. Les analyses de RMN du solide effectuées sur des membranes reconstituées à partir des lipides nucléaires ont permis de mettre en évidence des propriétés physiques atypiques. La température de transition de phase fluide-gel est particulièrement faible et large à -10°C ±15°C. Ce phénomène est certainement dû à la présence de nombreuses espèces de lipides et de nombreuse insaturations. Par ailleurs, à 25°C, les membranes reconstituées de lipides nucléaires sont plus rigides que des membranes modèles classiques ce qui implique une plus large épaisseur de membrane. Enfin, les liposomes de membranes reconstituées ont montré une très importante déformation en ellipsoide de type prolate, dans les champs magnétiques, ce qui est particulièrement rare pour des membranes biologiques et ce qui suggère une importante élasticité de courbure de la membrane
Muscular dystrophy diseases, breast and kidney cancers are linked to malformation of the nuclear envelope (NE). Mechanisms involved in the maintenance of NE morphology are based on proteo-lipid interactions. Recently, the physical properties of specific lipids has highlighted their essential role in NE assembly process of a sea urchin model. To provide molecular insight in how the nuclear architecture is regulated, we used Mass spectrometry and Nuclear Magnetic Resonance (NMR) as quantitative methods to investigate the lipid composition and the dynamics of the NE. Nuclei extraction were performed from HEK 293T human kidney cells. A physical extraction based on a pressure treatment and a sucrose gradient was used and improved considerably the nuclei yield, and afforded obtaining a high quantity of intact nuclei (NE lipids) required for experiments, with a minimum of cell debris, or the ER and Golgi compartments. The nuclear lipids were then extracted from the pure nuclei using a modified Folch method. Liquid-state NMR experiments showed that the NE is composed of a complex mixture of phospholipids and with phosphatitylcholine present in a higher proportion compared to other membrane organelles. Furthermore, an unusual proportion of phosphatidylinositol has been found at the NE. Mass spectrometry experiments have shown that the composition of phospholipids is dominated by species with greatky unsaturated chains with an average length of 34 carbons. Reconstructed nuclear lipid extract membranes were analysed by solid-state NMR and exhibit atypical physical properties. The lamellar gel-fluid phase transition temperature was found very low and broad at -10  15°C, possibly due to the presence of numerous lipid species and unsaturated acyl chains. Furthermore, at 25°C, reconstructed nuclear lipid membrane was found to be more rigid than classical model membranes suggesting a larger bilayer thickness. Finally, reconstructed nuclear lipid liposomes have shown a very important prolate deformation in a magnetic field, which is unusual for biological membranes and suggests an important curvature elasticity for the membrane

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32

Grah, Joana Sarah. "Mathematical imaging tools in cancer research : from mitosis analysis to sparse regularisation". Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/273243.

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This dissertation deals with customised image analysis tools in cancer research. In the field of biomedical sciences, mathematical imaging has become crucial in order to account for advancements in technical equipment and data storage by sound mathematical methods that can process and analyse imaging data in an automated way. This thesis contributes to the development of such mathematically sound imaging models in four ways: (i) automated cell segmentation and tracking. In cancer drug development, time-lapse light microscopy experiments are conducted for performance validation. The aim is to monitor behaviour of cells in cultures that have previously been treated with chemotherapy drugs, since atypical duration and outcome of mitosis, the process of cell division, can be an indicator of successfully working drugs. As an imaging modality we focus on phase contrast microscopy, hence avoiding phototoxicity and influence on cell behaviour. As a drawback, the common halo- and shade-off effect impede image analysis. We present a novel workflow uniting both automated mitotic cell detection with the Hough transform and subsequent cell tracking by a tailor-made level-set method in order to obtain statistics on length of mitosis and cell fates. The proposed image analysis pipeline is deployed in a MATLAB software package called MitosisAnalyser. For the detection of mitotic cells we use the circular Hough transform. This concept is investigated further in the framework of image regularisation in the general context of imaging inverse problems, in which circular objects should be enhanced, (ii) exploiting sparsity of first-order derivatives in combination with the linear circular Hough transform operation. Furthermore, (iii) we present a new unified higher-order derivative-type regularisation functional enforcing sparsity of a vector field related to an image to be reconstructed using curl, divergence and shear operators. The model is able to interpolate between well-known regularisers such as total generalised variation and infimal convolution total variation. Finally, (iv) we demonstrate how we can learn sparsity promoting parametrised regularisers via quotient minimisation, which can be motivated by generalised Eigenproblems. Learning approaches have recently become very popular in the field of inverse problems. However, the majority aims at fitting models to favourable training data, whereas we incorporate knowledge about both fit and misfit data. We present results resembling behaviour of well-established derivative-based sparse regularisers, introduce novel families of non-derivative-based regularisers and extend this framework to classification problems.

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33

Huang, Xiaohua. "Gold Nanoparticles Used in Cancer Cell Diagnostics, Selective Photothermal Therapy and Catalysis of NADH Oxidation Reaction". Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/10565.

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Gold nanoparticles strongly absorb and scatter visible and near infrared light because of the strongly enhanced electric fields at the surface. This provides the potential of designing novel optically active reagents for simultaneous molecular imaging and photothermal cancer therapy. In this thesis, gold nanospheres and nanorods conjugated with anti-epidermal growth factor receptor (anti-EGFR) antibodies that specifically target EGFR on the cell surface are shown to be used for dual diagnostics and therapy. Using micro-absorption spectroscopy and light scattering imaging, cancerous (HOC 313 and HSC 3) and noncancerous cells (HaCat) can be differentiated due to the overexpression of EGFR on the surface of cancer cells. By irradiating the cells with a CW laser, selective photothermal cancer therapy is realized in visible region by using gold nanospheres and in near infrared region by using gold nanorods. The use of nanorods allow for in vivo therapy due to the fact that their absorption is in the near infrared region at which the laser light meets less interference from the tissue absorption. In addition, the catalytic effect of gold nanoparticles on the oxidization of NADH to NAD+ is investigated. The addition of gold nanoparticles is found to quench the NADH fluorescence intensities but has no effect on the fluorescence lifetime. This suggests that the fluorescence quenching is not due to coupling with the excited state, but due to changing the ground state of NADH. The intensity of the 340 nm absorption band of NADH is found to decrease while that of the 260 nm band of NAD+ is found to increase as the concentration of gold nanoparticles increase. This conversion reaction is further supported by nuclear magnetic resonance and mass spectroscopy. The linear relationship between the initial reaction rate of NADH and the concentration of gold nanoparticles strongly supports that NADH is surface catalyzed by the gold nanoparticles. The catalytic property of this important reaction might have important future applications in biological and medical fields.

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Cho, Hoon-Sung. "Design and Development of a multifunctional nano carrier system for imaging, drug delivery, and cell targeting in cancer research". University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275936260.

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35

Alzubaidi, Laith. "Deep learning for medical imaging applications". Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/227812/1/Laith_Alzubaidi_Thesis.pdf.

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This thesis investigated novel deep learning techniques for advanced medical imaging applications. It addressed three major research issues of employing deep learning for medical imaging applications including network architecture, lack of training data, and generalisation. It proposed three new frameworks for CNN network architecture and three novel transfer learning methods. The proposed solutions have been tested on four different medical imaging applications demonstrating their effectiveness and generalisation. These solutions have already been employed by the scientific community showing excellent performance in medical imaging applications and other domains.

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36

Lindström, Sara. "Microwell devices for single-cell analyses". Doctoral thesis, KTH, Nanobioteknologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-11665.

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Powerful tools for detailed cellular studies are emerging, increasing the knowledge ofthe ultimate target of all drugs: the living cell. Today, cells are commonly analyzed inensembles, i.e. thousands of cells per sample, yielding results on the average responseof the cells. However, cellular heterogeneity implies the importance of studying howindividual cells respond, one by one, in order to learn more about drug targeting andcellular behavior. In vitro assays offering low volume sampling and rapid analysis in ahigh-throughput manner are of great interest in a wide range of single-cellapplications. This work presents a microwell device in silicon and glass, developed using standardmicrofabrication techniques. The chip was designed to allow flow-cytometric cellsorting, a controlled way of analyzing and sorting individual cells for dynamic cultureand clone formation, previously shown in larger multiwell plates only. Dependent onthe application, minor modifications to the original device were made resulting in agroup of microwell devices suitable for various applications. Leukemic cancer cellswere analyzed with regard to their clonogenic properties and a method forinvestigation of drug response of critical importance to predict long-term clinicaloutcome, is presented. Stem cells from human and mouse were maintainedpluripotent in a screening assay, also shown useful in studies on neural differentiation.For integrated liquid handling, a fluidic system was integrated onto the chip fordirected and controlled addition of reagents in various cell-based assays. The chip wasproduced in a slide format and used as an imaging tool for low-volume sampling withthe ability to run many samples in parallel, demonstrated in a protein-binding assay fora novel bispecific affinity protein. Moving from cells and proteins into geneticanalysis, a method for screening genes from clones in a rapid manner was shown bygene amplification and mutation analysis in individual wells. In summary, a microwelldevice with associated methods were developed and applied in a range of biologicalinvestigations, particularly interesting from a cell-heterogeneity perspective.
QC 20100728

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Xiaoqian, Chen. "Liposome and drug-targeted molecular probes for detecting lipid droplets and tracking cancer cells". Магістерська робота, Kyiv National University of Technology and Design, 2021. https://er.knutd.edu.ua/handle/123456789/19264.

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LDs are considered to be organelles with extremely low water content and high viscosity. Related to diseases such as diabetes, diabetes, cancer, etc., when the disease is abnormal, lipid droplets in cells will appear, so we have developed four types of lipid droplets. We designed and constructed a simple coumarin-absorbed p-nitrophenbutylethyl compound as a potential new organic biocatalyst for imaging groups. The internal projection belt shifts to the solar wavelength region. In addition, it is produced by the framework of the donor structure of the Fox also bridge. Stokes camera (100 nm, more than good LD, low biological toxicity and low biological toxicity and introduction. In addition, the biological probe Cou-LDs can also mark the emission of LDs in live zebras. We synthesized two new probes, LDP-1 and LDP-2, which showed a resolution of 4758 cm-1 and 3986 cm-1, respectively. In addition, the biological probes LDP1 and LDP show low biological toxicity and good specificity. These two probes are also suitable for life cycle monitoring of cell LD release in HeLa. At the same time, we have developed a new type of luminescent chemical sensor that can effectively mark the inside of the cell. In addition, the anti-interference, pH stability, and low biological toxicity of decoys have been deeply rooted in cell imaging and zebra fish imaging.
Ліпідні краплі (LD) вважаються органелами з надзвичайно низьким вмістом води та високою в’язкістю. Пов’язані з такими захворюваннями, як цукровий діабет, рак, тобто, коли хвороба є аномальною, у клітинах з’являться ліпідні краплі, тому ми розробили чотири типи ліпідних крапель. Розроблено просту п-нітрофенбутилетилову сполуку, що поглинає кумарин, як потенційний новий органічний біокаталізатор для груп візуалізації. Внутрішній проекційний спектр зміщується в видимій області світла. Крім того, сполуку виготовляють на основі донорського матеріалу. Камера Стокса (100 нм, більш ніж хороший LD, низька біологічна токсичність і низька біологічна токсичність і введення). Синтезовано два нових зонди, LDP-1 і LDP-2, які показали роздільну здатність 4758 см-1 і 3986 см-1 відповідно. Крім того, біологічні зонди LDP-1 і LDP-2 демонструють низьку біологічну токсичність і хорошу специфічність. Ці два зонди також підходять для моніторингу життєвого циклу вивільнення клітинної LD в HeLa. Розроблено новий тип люмінесцентного хімічного датчика, який може ефективно позначати внутрішню частину клітини.

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38

Smolina, Margarita. "Breast cancer cell lines grown in a three-dimensional culture model: a step towards tissue-like phenotypes as assessed by FTIR imaging". Doctoral thesis, Universite Libre de Bruxelles, 2018. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/267686.

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Despite the possible common histopathological features at diagnosis, cancer cells present within breast carcinomas are highly heterogeneous in their molecular signatures. This heterogeneity is responsible for disparate clinical behaviors, treatment responses and long-term outcomes in breast cancer patients. Although the few histopathological markers can partially describe the diversity of cells found in tumor tissue sections, the full molecular characterization of individual cancer cells is currently impossible in routine clinical practice. In this respect, Fourier transform infrared (FTIR) microspectroscopic imaging of histological sections allows obtaining, for each pixel of tissue images, hundreds of independent potential markers, which makes this technique a particularly powerful tool to distinguish cell types and subtypes. As a complement to the conventional clinicopathological evaluation, this spectroscopic approach has the potential to directly reveal molecular descriptors that should allow identifying different clonal lineages found within a single tumor and therefore provide knowledge relevant to diagnosis, prognosis and treatment personalization. Yet, interpretation of infrared (IR) spectra acquired on tissue sections requires a well-established calibration, which is currently missing. Conventionally, mammary epithelial cells are studied in vitro as adherent two-dimensional (2D) monolayers, which lead to the alteration of cell-microenvironmental interplay and consequently to the loss of tissue structure and function. A number of key in vivo-like interactions may be re-established with the use of three-dimensional (3D) laminin-rich extracellular matrix (lrECM)-based culture systems. The aim of this thesis is to investigate by FTIR imaging the influence of the in vitro growth environment (2D culture versus 3D lrECM culture and 3D monoculture versus 3D co-culture with fibroblasts) on a series of thirteen well-characterized human breast cancer cell lines and to determine culture conditions generating spectral phenotypes that are closer to the ones observed in malignant breast tissues. The reference cell lines cultured in a physiologically relevant basement membrane model and having undergone formalin fixation, paraffin embedding (FFPE), a routine treatment used to preserve clinical tissue specimens, could contribute to the construction of a spectral database. The latter could be ultimately employed as a valuable tool to interpret IR spectra of cells present in tumor tissue sections, particularly through the recognition of unique spectral markers.To achieve the goal, we developed and optimized, in a first step, the preparation of samples derived from traditional 2D and 3D lrECM cell cultures in order to preserve their morphological and molecular relevance for FTIR microspectroscopic analysis. We then highlighted the importance of the influence of the growth environment on the cellular phenotype by comparing spectra of 2D- and 3D-cultured breast cancer cell lines between them. A particular focus was placed to establish a correlation between FTIR spectral data and publicly available microarray-based gene expression patterns of the whole series of breast cancer cell lines grown in 2D and 3D lrECM cultures. Our results revealed that, although based on completely different principles, gene expression profiling and FTIR spectroscopy are similarly sensitive to both the cell line identity and the phenotypes induced by cell culture conditions. We also identified by FTIR imaging changes in the chemical content occurring in the microenvironment surrounding cell spheroids grown in 3D lrECM culture model. Finally, we illustrated the impact of the in vivo-like microenvironment on the IR spectra of breast cancer cell lines grown in 3D lrECM co-culture with fibroblasts and compared them with spectra of cell lines grown in 3D lrECM monoculture. Unsupervised statistical data analyses reported that cells grown in 3D co-cultures produce spectral phenotypes similar to the ones observed in FFPE tumor tissue sections from breast carcinoma patients. Altogether, our results suggest that FFPE samples prepared from 3D lrECM cultures of breast cancer cell lines and studied by FTIR microspectroscopic imaging provide reliable information that could be integrated in the setting up of a recognition model aiming to identify and interpret specific spectral signatures of cells present in breast tumor tissue sections.
Le cancer du sein est une maladie très hétérogène, tant au niveau clinique que biologique. Cette hétérogénéité rend impossible la caractérisation moléculaire complète des cellules cancéreuses individuelles dans la pratique clinique courante. Dans ce contexte, l’imagerie infrarouge à transformée de Fourier (FTIR) des coupes tissulaires permet d'obtenir pour chaque pixel d'une image de tissu des centaines de marqueurs potentiels indépendants, ce qui pourrait faire de cette technique un outil particulièrement puissant pour identifier des différents types et sous-types cellulaires. L'interprétation des spectres infrarouges (IR) enregistrés à partir des coupes histologiques nécessite cependant une calibration qui fait actuellement défaut. Cette calibration pourrait être obtenue à partir de lignées cellulaires tumorales bien caractérisées. Traditionnellement, les cellules épithéliales mammaires sont étudiées in vitro sous forme de monocouches adhérentes bidimensionnelles (2D), ce qui conduit à l'altération de la communication entre les cellules et leur environnement et, par conséquent, à la perte de l’architecture et de la fonction du tissu épithélial. Un certain nombre d'interactions physiologiques clés peuvent être rétablies en utilisant des systèmes de culture tridimensionnelle (3D) dans une matrice extracellulaire riche en laminine (lrECM). L'objectif de cette thèse consiste à étudier par imagerie FTIR l'influence du microenvironnement (via une comparaison entre les cultures 2D et 3D lrECM ou les cultures 3D lrECM en présence ou en l’absence de fibroblastes) sur une série de treize lignées de cellules tumorales mammaires humaines bien caractérisées et à déterminer les conditions de culture générant des phénotypes spectraux qui se rapprochent le plus de ceux observés dans les tissus tumoraux. Au cours de ce travail, nous avons mis au point la culture des lignées cellulaires dans un modèle 3D lrECM ainsi qu’une méthodologie de préparation des échantillons offrant la possibilité de les comparer de manière pertinente avec les cellules cancéreuses présentes dans les coupes histologiques. De même, nous avons étudié par imagerie FTIR les effets du microenvironnement sur les lignées de cellules tumorales et inversement. Pour les lignées investiguées, le passage d’une culture 2D à une culture 3D lrECM s’accompagne, en effet, de modifications du spectre IR étroitement corrélées aux modifications du transcriptome. Les marqueurs spectraux indiquent également que l’environnement 3D génère un phénotype cellulaire proche de celui trouvé dans les coupes histologiques. De manière intéressante, cette proximité est d’autant plus renforcée en présence de fibroblastes dans le milieu de culture.
Doctorat en Sciences agronomiques et ingénierie biologique
info:eu-repo/semantics/nonPublished

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39

Spaeth-Cook, Douglas M. Jr. "Identification of Thioredoxin-Interacting Protein as a Potential Mediator of Anoikis-Resistance in Ovarian Cancer". The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1494314758133333.

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40

Nakao, Kyoko. "Frequency and risk factors of thoracic metastases and optimization of the use of cross-sectional chest imaging in follow-up patients with cervical cancer". Kyoto University, 2019. http://hdl.handle.net/2433/242361.

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41

Besson, Florent. "Integrating PET-MR data for a multiparametric approach of tumour heterogeneity in non-small-cell lung cancer (NSCLC)". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS081.

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L'hétérogénéité tumorale est un facteur important de progression et de résistance au traitement. L'imagerie multiparamétrique TEP-IRM offre des opportunités uniques de caractérisation biologique cellulaire, mais n’a jamais été évalué à l’échelle régionale intra-tumorale dans le cancer du poumon non à petites cellules (CBNPC), première cause de décès oncologique. Une approche multiparamétrique dynamique simultanée TEP-IRM au 18F-FDG a été développée en ce sens. Cette approche a nécessité l’implémentation « maison » de la méthode de référence de quantification TEP du métabolisme glucidique (modèle tri-compartimental de Sokoloff); le développement d’une méthode de correction inédite des distorsions géométriques en imagerie de diffusion, validée sur fantôme et testée cliniquement ; la validation sur fantôme de méthodes d’IRM quantitative (relaxométrie T1/T2), également testées cliniquement; et l’implémentation « maison » du modèle compartimental de Tofts (version étendue) pour l’évaluation de la vascularisation tumorale en IRM dynamique de perfusion. Les résultats de nos travaux expérimentaux effectués à l’échelle intra-tumorale régionale illustrent l’hétérogénéité des rapports entre métabolisme glucidique et vascularisation dans le CBNPC, deux caractéristiques biologiques fondamentales de progression tumorale, et montrent qu’un partitionnement tumoral non supervisé par modèle de mélange gaussien, intégrant l’ensemble des biomarqueurs TEP-IRM de ce projet, individualise 3 types de supervoxels, dont la signature biologique peut être prédite avec une exactitude de 97% par 4 biomarqueurs TEP-IRM dominants, révélés par méthodes métaheuristiques d'apprentissage machine
Tumor heterogeneity is an important factor of progression and resistance to treatment. Multiparametric PET-MRI imaging offers unique opportunities to characterize biological cellular processes, but has never been evaluated at the regional level in Non-Small Cell Lung Cancer (NSCLC), the leading cause of oncological death. A simultaneous dynamic multiparametric 18F-FDG PET-MRI approach has been developed to this end. This approach required the “in-house” implementation of the reference absolute PET quantitative method of glucose metabolism (Sokoloff's tri-compartmental model); the development of a method for correcting geometric distortions in diffusion weighted imaging, validated on phantom and clinically tested; the phantom validation of quantitative MRI methods (T1/T2 relaxometry), also clinically tested; and the "in-house" implementation of the Tofts compartmental model (extended version) for the evaluation of tumor vascularization by dynamic perfusion MRI. The results of our work, performed at the regional intra-tumor level, illustrate the heterogeneity of the regional interlinks between glucose metabolism and vascularization in NSCLC, two fundamental biological hallmarks of tumor progression, and show that an unsupervised tumor partitioning by Gaussian mixture model, integrating all the PET-MRI biomarkers of this project, individualizes 3 types of supervoxels, whose biological signature can be predicted with 97% accuracy by 4 dominant PET-MRI biomarkers, revealed by metaheuristic machine learning methods

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42

Hoque, Apu E. (Ehsanul). "Migration and invasion pattern analysis of oral cancer cells in vitro". Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220239.

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Abstract Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but relatively little is known about its role in cancer. In this study, the function of Dsg3 was investigated in oral squamous cell carcinoma (SCC) cell lines in vitro using locally established human leiomyoma tumor microenvironment (TME) matrices. Since Dsg3 has been identified as a key regulator in cell adhesion, we hypothesized that it may play a role in oral SCC cells adhesion and motility. Thus, one aim of the study was to explore this hypothesis by both gain and loss of function methods in four human buccal mucosa SCC SqCC/Y1 cell lines: transduction of vector control (Ct), full-length (FL) or two different C-terminally truncated Dsg3 mutants (Δ238 and Δ560). Live cell imaging was performed for 2D migration and 3D sandwich, alongside other assays. In 3D sandwich, we tested the effects of the monoclonal antibody, AK23, targeting the extracellular domain of Dsg3 in SqCC/Y1 cells. Our results showed that loss of Dsg3 disrupted cell adhesion and protein expression. In 2D assays, FL and Dsg3 mutants migrated faster with higher accumulated distances than Ct. In contrast with 2D, mutants showed accelerated invasion over the Ct in 3D models. The AK23 antibody inhibited only the invasion of FL cells. The TME in vivo consists of cellular and matrix elements playing a leading role in carcinoma progression. To study carcinoma cells invasion in vitro, mouse Matrigel® and rat type 1 collagen are the most commonly used matrices in 3D models. Since they are non-human in origin, they do not perfectly mimic human TME. To address this, we have developed a solid organotypic myoma disc model derived from human uterus leiomyoma tumor. Here, we introduce a novel Myogel, prepared from leiomyoma similar to Matrigel®. We validated Myogel for cell-TME interactions in 3D models, using SqCC/Y1 and HSC-3 cell lines. Compared with Matrigel® and type I collagen, oral SCC cell lines invaded more efficiently in Myogel containing matrices. This study describes promising 3D models using human TME mimicking Myogel which is suitable to analyze oral SCC cells both in carcinoma monocultures and in co-cultures, such as with TME fibroblasts. We also introduce a possible novel therapeutic target against Dsg3 to suppress cancer cell invasion
Tiivistelmä Desmogleiini 3 (Dsg3) on desmosomien adheesioreseptori, jonka merkityksestä syövässä tiedetään vähän. Koska Dsg3 on tärkeä epiteelisolujen välisissä liitoksissa, oletimme sillä olevan vaikutusta myös suun karsinoomasolujen tarttumisessa ja niiden liikkuvuudessa. Testasimme hypoteesiamme muuttamalla Dsg3:n toimintaa ihmisen posken karsinoomasolulinjassa SqCC/Y1, josta oli aiemmin valmistettu neljä erilaista muunnosta: tyhjän vektorin sisältävä kontrollisolulinja (Ct), kokopitkää Dsg3 tuottava solulinja (FL), sekä kaksi Dsg3 C-päästä lyhennettyä mutanttisolulinjaa (Δ238 ja Δ560). Immunofluoresenssi-menetelmää käyttäen analysoimme solulinjoissamme solujen välisiä liitoksia. Lisäksi mittasimme solujen liikkeitä 2D-migraatio- ja 3D-sandwich-kokeissa. Testasimme myös Dsg3:n solunulkoista osaa tunnistavan monoklonaalisen vasta-aineen (AK23) vaikutusta solujen invaasioon. Osoitimme, että Dsg3:n rakenteen muuttaminen ja toiminnan estyminen häiritsi solujen tarttumista. 2D-kokeissa sekä FL että mutanttilinjat (Δ238 ja Δ560) migroivat kontrollisoluja nopeammin ja pidemmälle, mutta 3D-kokeissa vain mutanttilinjat invasoituivat kontrollisoluja tehokkaammin. AK23-vasta-aine esti vain FL-solujen invaasiota. Syöpäsolujen 3D-invaasiota mittaavissa kokeissa käytetään yleensä hiiren kasvaimesta valmistettua kaupallista Matrigeeliä® tai rotan kudoksista eristettyä tyypin I kollageenia. Tutkimusryhmämme on jo aiemmin kehittänyt organotyyppisen myoomamallin, jossa valmistamme myoomakudosnapit ihmisen kohdun leiomyoomakasvaimista. Tässä työssä valmistimme leiomyoomasta Myogeelia, vertasimme sitä Matrigeeliin®, sekä tutkimme tarkemmin Myogeeli-valmisteen soveltuvuutta 3D-tutkimuksiin. Totesimme, että kielen (HSC-3) ja posken (SqCC/Y1) karsinoomasolut invasoituivat tehokkaimmin Myogeeli-pitoisissa matrikseissa kuin Matrigeeliä® tai kollageeniä sisältävissä kasvatusalustoissa. Tutkimustulostemme perusteella Myogeeli-pohjaiset 3D-mallit soveltuvat hyvin sekä syöpäsolulinjojen invaasiotutkimuksiin että yhteisviljelmiin, joissa syöpäsoluja viljellään yhdessä syöpäkasvaimen ympärillä olevien solujen, kuten fibroblastien, kanssa

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Oscanoa1, Julio, Marcelo Mena i Guillermo Kemper. "A Detection Method of Ectocervical Cell Nuclei for Pap test Images, Based on Adaptive Thresholds and Local Derivatives". Science and Engineering Research Support Society, 2015. http://hdl.handle.net/10757/624843.

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Cervical cancer is one of the main causes of death by disease worldwide. In Peru, it holds the first place in frequency and represents 8% of deaths caused by sickness. To detect the disease in the early stages, one of the most used screening tests is the cervix Papanicolaou test. Currently, digital images are increasingly being used to improve Pap test efficiency. This work develops an algorithm based on adaptive thresholds, which will be used in Pap smear assisted quality control software. The first stage of the method is a pre-processing step, in which noise and background removal is done. Next, a block is segmented for each one of the points selected as not background, and a local threshold per block is calculated to search for cell nuclei. If a nucleus is detected, an artifact rejection follows, where only cell nuclei and inflammatory cells are left for the doctors to interpret. The method was validated with a set of 55 images containing 2317 cells. The algorithm successfully recognized 92.3% of the total nuclei in all images collected.
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O'Farrell, Alice C. "Development of in vivo tumour models for non-invasive proof-of-principle investigation of novel therapeutic agents. Engineering and characterisation of bioluminescent cell reporter systems for in vivo analysis of anti-cancer therapy pharmacodynamics". Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5391.

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

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Hanna, G. G. "An evaluation of the role of Positron Emission Tomography/Computed Tomography Imaging in Radiotherapy Target Volume Definition for the treatment of Non-Small Cell Lung Cancer". Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.527810.

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Rollakanti, Kishore Reddy. "Protoporphyrin IX Fluorescence for Enhanced Photodynamic Diagnosis and Photodynamic Therapy in Murine Models of Skin and Breast Cancer". Cleveland State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=csu1431466604.

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Niinimäki, R. (Riitta). "Osteonecrosis in children, adolescents and young adults treated for cancer". Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526203348.

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Abstract Treatment-related late effects have increasingly become important, since the majority of children, adolescents and young adults with cancer become long-term survivors. Osteonecrosis (ON) is recognized as a potential debilitating sequel in patients with cancer. The aims of this work were to define the incidence of and clinical risk factors for ON identified with end-of-therapy magnetic resonance imaging (MRI) screening among patients with childhood cancer and to investigate the incidence of and risk factors for ON requiring total joint arthroplasty (TJA) in patients treated for cancer in childhood, adolescence or young adulthood in a register-based study. MRI of the lower extremities revealed ON in 23 (24%) of the 97 patients with acute lymphoblastic leukemia (ALL) at the end of treatment. High body mass index, female gender, older age at diagnosis, and higher cumulative dexamethasone dose were independent risk factors for ON. Six of the 32 patients (19%) treated for lymphoma or solid tumor had ON in MRI scans at the end of the treatment. All of these patients with ON had non-Hodgkin lymphoma or Hodgkin lymphoma. In a register-based study, patients diagnosed with cancer before 31 years of age were identified from the Finnish and Danish Cancer registries. These data were combined with data from the National Hospital Discharge and the Finnish Arthroplasty registers. The cohort consisted of 6,358 patients diagnosed with hematologic malignancy and 18,542 patients diagnosed with solid tumor from 1975 to 2000 in Finland and from 1975 to 2006 in Denmark. The estimated cumulative incidence of TJA was 4.5% at 20 years for patients treated for chronic myeloid leukemia, followed by 2.1% for patients treated for acute myeloid leukemia and 0.4% for patients treated for ALL. Allogeneic stem cell transplantation increased the risk of TJA. In conclusion, ON as determined with MRI is a common complication in children after treatment for ALL. High BMI was identified as a new significant risk factor for ON in patients with pediatric ALL. The incidence of ON requiring TJA was highest among children, adolescents and young adults treated for myeloid leukemias
Tiivistelmä Syöpähoitojen aiheuttamien myöhäisvaikutusten merkitys on viime vuosina kasvanut, koska suuri osa lapsena tai nuorena aikuisena syöpään sairastuneista paranee. Syöpähoitojen seurauksena voi syntyä luukuolioita, jotka heikentävät merkittävästi elämänlaatua ja liikuntakykyä. Tämän väitöskirjatyön tarkoituksena oli selvittää magneettitutkimuksella luukuolioiden ilmaantuvuus ja riskitekijät syöpähoitojen lopetusvaiheessa lapsuusiän syövän sairastaneilla sekä selvittää rekisteritutkimuksella tekonivelleikkausta vaativan luukuolion ilmaantuvuus ja riskitekijät lapsena tai nuorena aikuisena hoidetuilla syöpäpotilailla. Akuutin lymfaattisen leukemian (ALL) sairastaneista 23/97:lla (24 %) todettiin alaraajojen magneettitutkimuksessa luukuolioita. Korkea painoindeksi, naissukupuoli, vanhempi ikä diagnoosihetkellä ja suurempi kumulatiivinen deksametasoniannos lisäsivät luukuolion todennäköisyyttä. Lymfooman tai kiinteän kasvaimen sairastaneista 6/32:lla (19 %) todettiin luukuolioita. Tutkimme tekonivelleikkausta vaativan luukuolion ilmaantuvuutta Suomen ja Tanskan väestöpohjaisten rekistereiden avulla. Tutkimuskohorttimme muodostui 6 358 leukemiaan ja lymfooman sekä 18 542 kiinteään kasvaimeen Suomessa ja Tanskassa alle 31-vuotiaana sairastuneesta potilaasta. Tekonivelleikkausta vaativan luukuolion kumulatiivinen ilmaantuvuus 20 vuoden seurannan aikana oli kroonisen myelooisen leukemian sairastaneilla 4,5 %, akuutin myelooisen leukemian sairastaneilla 2,1 % ja ALL:n sairastaneilla 0,4 %. Allogeeninen kantasolujen siirto lisäsi luukuolioiden todennäköisyyttä. Tässä väitöskirjatyössä osoitettiin, että ALL:n sairastaneilla lapsilla magneettitutkimuksella todetut luukuoliot ovat yleinen haittavaikutus. Korkea painoindeksi on luukuolioiden uusi merkittävä riskitekijä. Tutkimus antoi myös uutta tietoa tekonivelleikkausta vaativan luukuolion ilmaantuvuudesta ja riskitekijöistä lapsuusiällä tai nuorella aikuisiällä syövän sairastaneilla

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O'Farrell, Alice Claire. "Development of in vivo tumour models for non-invasive proof-of-principle investigation of novel therapeutic agents : engineering and characterisation of bioluminescent cell reporter systems for in vivo analysis of anti-cancer therapy pharmacodynamics". Thesis, University of Bradford, 2011. http://hdl.handle.net/10454/5391.

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

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Hübner, Doreen, Christiane Rieger, Ralf Bergmann, Martin Ullrich, Sebastian Meister, Marieta Toma, Ralf Wiedemuth i in. "An orthotopic xenograft model for high-risk non-muscle invasive bladder cancer in mice: influence of mouse strain, tumor cell count, dwell time and bladder pretreatment". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2018. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-231536.

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Background Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging. Methods Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET). Results Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder. Conclusions With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.

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Hübner, Doreen, Christiane Rieger, Ralf Bergmann, Martin Ullrich, Sebastian Meister, Marieta Toma, Ralf Wiedemuth i in. "An orthotopic xenograft model for high-risk non-muscle invasive bladder cancer in mice: influence of mouse strain, tumor cell count, dwell time and bladder pretreatment". BioMed Central, 2017. https://tud.qucosa.de/id/qucosa%3A30688.

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Background Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging. Methods Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET). Results Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder. Conclusions With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.

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