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1
White, S. D. M. "Flattening of the Galactic Spheroid." Steward Observatory, The University of Arizona (Tucson, Arizona), 1988. http://hdl.handle.net/10150/623909.
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2
Digby, Andrew. "Galactic spheroid structure from subluminous stars." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/27910.
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Galactic halo subdwarfs and white dwarfs are locally very scarce and are hence poorly understood. As the most common members of the spheroid, however, they are crucial to the understanding of our own and other galaxies, able to yield key information about the shape, formation, chemical history and dark matter of the spheroid, as well as providing, clues about the processes of stellar evolution. Wide-field photographic data spanning observations taken over long time baselines, such as those available from the SuperCOSMOS Sky Survey (SSS), are unparalleled in their ability to identify large numbers of these dwarf spheroid stars through their large space motions. This is illustrated here by a recent survey of SSS data which, with my involvement, discovered a potential population of cool halo white dwarfs that may constitute a significant proportion of Galactic baryonic dark matter. However, the “Achilles Heel” of photographic astronomy in studies such as this is poor photometry: a problem which can now be circumvented - whilst retaining the astrometric information of the photographic data - with the advent of large-scale, deep CCD surveys with accurate photometry such as the Sloan Digital Sky Survey (SDSS). In this thesis I show that the combination of these two types of dataset brings vast numbers of locally-rare dwarf spheroid stars into the observation reach of astronomers, yielding reliable samples many times larger than have previously been available solely from photographic data. Using SSS data coupled with the SDSS archive I identify a sample of ~2600 candidate subdwarfs through strict selection criteria. This forms one of the largest and most reliable samples of subdwarfs known, and enables accurate determination of luminosity functions along many different lines of sight. I derive the subdwarf luminosity function with unprecedented accuracy to MV 13, finding good agreement with recent local estimates but discrepancy with results for the more distant spheroid. This provides further evidence that the inner and outer parts of the stellar halo cannot be described by a single density distribution. It also use the data to show that the form of the inner spheroid density profile within distances of 2.5 kpc is closely matched by a power law with an index of α = -3.15 ± 0.3.
3
Berahim, Zurairah. "The potential of periodontal spheroid for periodontal regeneration." Thesis, University of Sheffield, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522565.
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Wetzel, Todd G. "Unsteady flow over a 6:1 prolate spheroid." Diss., This resource online, 1996. http://scholar.lib.vt.edu/theses/available/etd-08032007-102246/.
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Chaudhary, Priyanka. "SPHEROID DETECTION IN 2D IMAGES USING CIRCULAR HOUGH TRANSFORM." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_theses/9.
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Three-dimensional endothelial cell sprouting assay (3D-ECSA) exhibits differentiation of endothelial cells into sprouting structures inside a 3D matrix of collagen I. It is a screening tool to study endothelial cell behavior and identification of angiogenesis inhibitors. The shape and size of an EC spheroid (aggregation of ~ 750 cells) is important with respect to its growth performance in presence of angiogenic stimulators. Apparently, tubules formed on malformed spheroids lack homogeneity in terms of density and length. This requires segregation of well formed spheroids from malformed ones to obtain better performance metrics. We aim to develop and validate an automated imaging software analysis tool, as a part of a High-content High throughput screening (HC-HTS) assay platform, to exploit 3D-ECSA as a differential HTS assay. We present a solution using Circular Hough Transform to detect a nearly perfect spheroid as per its circular shape in a 2D image. This successfully enables us to differentiate and separate good spheroids from the malformed ones using automated test bench.
6
Westlake, P. C. "Interfacial and internal waves generated by a submerged prolate spheroid." Thesis, University of Southampton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242629.
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McMillan, Kay Seonaid. "Development of a microfluidic platform for multicellular tumour spheroid assays." Thesis, University of Strathclyde, 2016. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27926.
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Microfluidics is a valuable technology for a variety of different biomedical applications. In particular, within cancer research, it can be used to improve upon currently used in vitro screening assays by facilitating the use of 3D cell culture models. One of these models is the multicellular tumour spheroid (MCTS), which provides a more accurate reflection of the tumour microenvironment in vivo by reproducing the cell to cell contact, the development of a nutritional gradient and the formation of a heterogeneous population of cells. Therefore, the MCTS provides a more physiologically relevant in vitro model for testing the efficacy of treatments at the preclinical level. Currently, methods for the formation and culture of spheroids have several limitations, including being labour intensive, being low throughput, producing shear stress towards cells and the hanging drop system being unstable to physical shocks. Recently, microfluidics (especially droplet microfluidics) has been employed for the culture and screening of spheroids, providing a high-throughput methodology which only requires small volumes of fluids and small numbers of cells. However, current issues with droplet microfluidics include complicated droplet gelation procedures and short cell culture times. In this thesis, the use of microfluidic technologies as an approach for spheroid formation and culture are investigated with the aim to create a platform for radiotherapeutic and chemotherapeutic treatment of spheroids using cell lines. Initially, the use of emulsion technology at the macro scale was evaluated to determine the best conditions for spheroid culture. Once this was achieved the spheroids were compared to spheroids using a traditional method and radiotherapeutic treatment was conducted. Subsequently, avenues for miniaturising the developed emulsion-based methods were studied to provide a microfluidic technology. Finally, along with identifying the optimal culture conditions using hydrogels, a microfluidic system that integrated both droplet and single phase microfluidics features was developed for the formation and culture of spheroids. Using the latter, proof of principle experiments were conducted to demonstrate the suitability of the platform for both chemotherapeutic and radiotherapeutic assays within the same device.
8
Guerra, Joel Tynan. "Investigating the Effect of an Upstream Spheroid on Tandem Hydrofoils." DigitalCommons@CalPoly, 2018. https://digitalcommons.calpoly.edu/theses/1959.
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This thesis documents a series of three dimensional unsteady Reynolds Averaged Navier-Stokes CFD simulations used to investigate the influence of an upstream prolate spheroid body on tandem pitching hydrofoils. The model is validated by performing separate CFD simulations on the body and pitching hydrofoils and comparing results to existing experimental data. The simulations were run for a range of Strouhal numbers (0.2-0.5) and phase differences (0-π). Results were compared to identical simulations without an upstream body to determine how the body affects thrust generation and the unsteady flow field.
The combined time-averaged thrust increases with Strouhal number, and is highest when the foils pitch out of phase with each other. At intermediate phase differences between φ = 0 and φ = π the leading foil produces significantly more thrust than the trailing foil, peaking at φ = π/2. For St = 0.5 this difference is 21.7%.
Results indicate that adding an upstream prolate spheroid body does not significantly alter thrust results, though it does provide a small (nearly negligible) boost. Vorticity from the body is pulled downstream from the pitching foils, which interacts with the vortex generation when the vortex being generated is of the same sign as the body vorticity. This body vorticity does not affect the vorticity magnitude of the downstream vortex pairs.
9
Silva, Santisteban Tomas [Verfasser], and Matthias [Akademischer Betreuer] Meier. "Spheroid manipulation on a microfluidic chip platform for biomolecular analysis." Freiburg : Universität, 2017. http://d-nb.info/1144829658/34.
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Jones, Jane Elizabeth Davenport. "Neurotoxic mechanisms underlying ischaemia-reperfusion injury using rat brain spheroid cultures." Thesis, University of Hertfordshire, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302425.
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Song, Min. "THREE-DIMENSIONAL ENDOTHELIAL SPHEROID-BASED INVESTIGATION OF PRESSURE-SENSITIVE SPROUT FORMATION." UKnowledge, 2016. http://uknowledge.uky.edu/cbme_etds/39.
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This study explored hydrostatic pressure as a mechanobiological parameter to control in vitro endothelial cell tubulogenesis in 3-D hydrogels as a model microvascular tissue engineering approach. For this purpose, the present investigation used an endothelial spheroid model, which we believe is an adaptable microvascularization strategy for many tissue engineering construct designs. We also aimed to identify the operating magnitudes and exposure times for hydrostatic pressure-sensitive sprout formation as well as verify the involvement of VEGFR-3 signaling. For this purpose, we used a custom-designed pressure system and a 3-D endothelial cell spheroid model of sprouting tubulogenesis. We report that an exposure time of 3 days is the minimum duration required to increase endothelial sprout formation in response to 20 mmHg. Notably, exposure to 5 mmHg for 3 days was inhibitory for endothelial spheroid lengths without affecting sprout numbers. Moreover, endothelial spheroids exposed to 40 mmHg also inhibited sprouting activity by reducing sprout numbers without affecting sprout lengths. Finally, blockade of VEGFR-3 signaling abolished the effects of the 20-mmHg stimuli on sprout formation. Based on these results, VEGFR-3 dependent endothelial sprouting appears to exhibit a complex pressure dependence that one may exploit to control microvessel formation.
12
Gaskell, H. "Development of a spheroid model to investigate drug-induced liver injury." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3004330/.
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Drug induced liver injury is a major problem for the pharmaceutical industry and health services. Yet 30-40 % of human hepatotoxins go undetected during in vitro studies. Hence, more predictive in vitro liver models are a critical requirement for preclinical screening of compounds demonstrating hepatotoxic liability. 3D liver spheroids show promise as a novel model to investigate drug-induced liver injury with preliminary studies indicating the ability of spheroids to detect hepatotoxins as well as displaying an enhanced functional lifespan compared to 2D monocultures. The aim of this thesis was to develop an improved in vitro model to investigate drug-induced liver injury. A viable C3A spheroid model with a lifespan of 32 days was successfully optimised. A characterisation of the spheroid model was performed, revealing direct cell-cell contacts, 3D morphology and cellular polarisation, hence recapitulating corresponding features of human liver tissue. Subsequently, liver-specific functions were investigated in the C3A spheroids and were found to display zonation, functional transporters, CYP enzyme activity, albumin production, urea synthesis and functional mitochondria. After validating the biology of the model, the ability of the spheroids to detect hepatotoxins was examined. The C3A spheroid model correctly identified 66.6 % of hepatotoxins to have a risk of liver injury, a higher predictive value than a 2D model. As hepatocytes only represent 60 % of the cells in the liver it was predicted that including non-parenchymal cells in the C3A spheroid model would cause increased sensitivity to hepatotoxins. Indeed when C3A spheroids were co-cultured with endothelial cells or immune cells they correctly predicted more compounds to have a risk of human hepatotoxicity, improving their predictivity to 91.6 % and 83.3 % respectively. It has been established that novel biomarkers of liver injury HMGB1, keratin 18 and miR-122 have enhanced sensitivity when compared to current clinical diagnostic markers, however they have not been extensively analysed in vitro. It was determined that keratin 18 could be quantified from the C3A spheroid model and provides important mechanistic insight into the mechanism of cell injury occurring. Mitochondrial damage is implicated in up to 50 % of human hepatotoxins. It was hypothesised that by analysing mitochondrial function in more detail one could reveal the mechanism of action by which a compound might be causing toxicity. Mitochondrial dysfunction could be successfully analysed in the C3A spheroids, which were found to be more sensitive to mitochondrial toxins than 2D cells. To conclude; C3A spheroids act as a human-relevant in vitro model with the potential to be incorporated into an initial drug safety screen, replacing 2D models with poor sensitivity and specificity. Results suggest that the inclusion of non-parenchymal cells may be advantageous to liver models. Furthermore the analysis of endpoints including clinical biomarkers and mitochondrial function may improve the sensitivity of the drug screen.
13
Lam, Hoyin. "3D co-culture spheroid drug screening platform for pancreatic cancer invasion." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/3d-coculture-spheroid-drug-screening-platform-for-pancreatic-cancer-invasion(5fb01f64-2526-46c7-b171-933a4ec066d2).html.
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Pancreatic ductal adenocarcinoma (PDAC) is the 5th most common cause of death by cancer in the UK, accounting for 5% of all cancer deaths in the UK. Only 8% of the PDAC patients from all stages combined, survives for 5 years or longer. Late stage diagnosis combined with early cancer cell dissemination and poor response to current available treatments highlights the need for novel therapeutics tackling tumour growth and invasion. Previously, it has been shown that cellular plasticity during disease progression and the tumour stroma could contribute to cancer metastasis and resistance to therapy. Furthermore, progression in genetic sub-type classification of PDAC has shown differences in patient survival and response to treatment. However, PDAC cell plasticity and morphology in the presence of matrix has not been extensively addressed nor linked with sub-types thus far. Moreover, while 3D models are increasingly applied in order to mimic in vivo conditions more closely, the majority of current screening assays do not include components of the stroma and are based mainly on cell viability. In addition, well established genetic engineered mouse models (GEMM) and patient derived xenograft (PDX) are not cost effective or widely accessible for screening purposes. Understanding the behavioural characteristics and drug responses of PDAC cells with models mimicking the in vivo microenvironment is pivotal in developing novel therapies. To address the need for invasion models that can be used for screening, I have first investigated PDAC cell behaviour with the 2.5D model in vitro and selected a representative cell line for screening. Subsequently, I have developed and optimised a 3D co-culture spheroid screening platform to assess compounds for inhibition of PDAC invasion in the presence of pancreatic stellate cells. A select drug library with 99 FDA approved compounds was probed for potential drug repurposing for PDAC invasion and selected for further validation. Together these experiments will provide us novel insight into the invasive behaviour of pancreatic cancer cells and identify potential novel molecular targets against PDAC cell invasion.
14
Bobyliov, Konstantin. "Casting voids influence on spheroid graphite cast iron high-cycle fatigue strength." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2008. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2008~D_20081128_120950-42235.
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The influence of casting voids on spheroid cast iron cracking threshold is investigated. The experimental results and their analytical and numerical analysis basing on linear fracture mechanics is presented.Nagrinėjamas liejimo tuštumų poveikis stipriojo ketaus pleišėjimo slenksčiui. Pateikiami eksperimentiniai rezultatai ir jų analitinė bei skaitinė analizė, remiantis tiesine irimo mechanika.
Исследуется влияние литейных пустот на порог трещиностойкости чугуна с шаровидным графитом. Представлены результаты экспериментального исследования и их аналитический и численный анализ, опираясь на линейную механику разрушения.
15
Tchoryk, Aleksandra. "3D spheroid models for in vitro evaluation of nanoparticles for cancer therapy." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/51750/.
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Many different nanoparticle delivery systems have been reported as potential cancer therapeutics, however, the tumour penetration and uptake characteristics have been determined for very few systems. Animal models are effective for assessing tumour localisation of nanosystems, but difficult to use for studying penetration beyond the vasculature. In this work, defined HCT 116 colorectal cancer spheroids were used to study the effect of nanoparticle size and surface modifications on their penetration and uptake. Incubation of spheroids with Hoechst 33342 resulted in a dye gradient which facilitated discrimination between the populations of cells in the core and at the periphery of spheroids by flow cytometry based on the degree of Hoechst staining. This model was used to compare doxorubicin and Doxil, a range of model polystyrene nanoparticles in different sizes (30 nm, 50 nm, 100 nm) and with different surface chemistry (50 nm unmodified, carboxylated, aminated) and polyethylene glycol modified NPs prepared from a promising new functionalized biodegradable polymer (poly(glycerol-adipate), PGA). Unmodified polystyrene nanoparticles (30 nm/50 nm) were able to penetrate to the core of HCT 116 spheroids more efficiently than larger polystyrene nanoparticles (100 nm). Penetration was also dependent on surface charge. PGA NPs of 100 nm showed similar penetration into spheroids as 50 nm polystyrene nanoparticles, and PEG surface modification significantly improved penetration into the spheroid core. The new spheroid model with Hoechst staining is shown to be a useful model for assessing NPs penetration and demonstrates the importance of controlling physical properties when designing nanomedicine.
16
Barber, Kevin Michael. "Mean velocity and turbulence measurements of flow around a 6:1 prolate spheroid." Thesis, This resource online, 1990. http://scholar.lib.vt.edu/theses/available/etd-03122009-040424/.
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Miyazaki, Yumiko. "Versican V1 in human endometrial epithelial cells promotes BeWo spheroid adhesion in vitro." Kyoto University, 2019. http://hdl.handle.net/2433/242394.
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18
Ahn, Seungki. "An experimental study of flow over a 6 to 1 prolate spheroid at incidence." Diss., This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-06062008-165846/.
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Madden, Michael Mark Jr. "Octant Analysis of the Reynolds Stresses in the Three Dimensional Turbulent Boundary Layer of a Prolate Spheroid." Thesis, Virginia Tech, 1997. http://hdl.handle.net/10919/35556.
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The Reynolds stresses in a three-dimensional turbulent
boundary layer were examined using octant analysis. The
representative flow was a pressure driven, three-dimensional
turbulent boundary layer on the leeside
(x/L=0.76-0.78, f=105°-130°) of a 6:1 prolate spheroid at
10° angle of attack. The Reynolds number for the flow was
Re=4.2x10E+6. The LDV data of Chesnakas, Simpson, and Madden
(1994) were the basis of examination. This data set employed
a post-processing technique for refining the radial location
of the measurments. A least-squares fit of the Spalding wall
law was used to both correct the measurement locations and
estimate the wall shear stress. This paper presents a
previously unpublished assesment of the techinque. Octant
analysis was performed on the corrected data under
free-stream and wall-collateral coordinates. (The wall-collateral
coordinate system is aligned with the mean tangential
velocity in the buffer-layer.) The octant analysis led to
the development of a structural model that extends the
sweep/ejection process to three dimensions. Ejections and
sweeps produce w' through the same mechanism that produces
u'; they transport fluid across a spanwise velocity
gradient. The model's results remain consistent with
coordinate rotation. The model also describes the
asymmetries that evolve between ejections and sweeps with
spanwise fluctuations (w') of opposite sign. These
asymmetries cause non-zero u'w' and v'w' in the buffer
layer. Comparison of the two coordinate systems reveals
that wall-collateral coordinates provides a simpler
foundation for octant analysis. The sweep and ejection
octants maintain a nearly equal distribution of velocity
events throughout the buffer and lower log layers. Also, the
spanwise velocity profile monotonically decreases to a
constant value at the boundary layer edge, simplifying
application of the sweep/ejection model to spanwise
fluctuations. Comparison with other 3DTBL experiments
suggests that the wall-collateral coordinates are more
closely aligned with the quasi-streamwise vortex structures
than free-stream coordinates. The octant analysis also
reveals structural behavior consistent with the four
mechanisms revealed by the direct numerical simulation of
Sendstad and Moin (1992).Master of Science
20
Norman, Julia. "Investigating Peptide Conjugation for the Selective Activation of Metal Complexes in Tumours." Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/9506.
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There are various strategies in the treatment of cancer including surgical excision, radiotherapy, chemotherapy and immunotherapy. Chemotherapy offers the distinct advantage of systemic distribution, with the potential to reach primary tumours as well as metastases. A significant drawback of the vast majority of chemotherapeutic agents is their lack of specificity for cancer cells as well as poor tumour penetration, meaning that cells distal to blood vessels receive an inadequate dose and remain viable. There is an imperative need for the development of anti-tumour drugs which exhibit good tumour penetration and distribution with minimal systemic toxicity. Tumour activated prodrugs (TAPs) are one of the main strategies now employed in antitumour drug development, and involve administering an inert, less toxic form of a particular drug which is then selectively transformed into its toxic version by the body in the vicinity of the tumour.1 In this study, TAPs which contain a matrix-metalloproteinase II (MMP-2) specific peptide cleavage sequence were synthesised. There is significant evidence that there is increased expression of MMP-1, -2, -3, -7, -9, -13, -14 in both primary tumours and metastases, and that there is a positive correlation between high levels of MMP expression and poor patient prognosis.2 In this work, recombinant DNA techniques were used to visualise the expression of MMP-2 and MMP-9 in vitro. Plasmid constructs in which MMP-2 and MMP-9 were fused to the AmCyan fluorescent protein gene were generated for insertion into a mammalian transfection vector. Transfection into three cell lines that exhibited different levels of MMP-2 and MMP-9 expression was evaluated by measuring the fluorescence emission in the 480 – 550 nm range. The results demonstrated potential for monitoring MMP expression and secretion in monolayer and 3D cell culture by transfection with MMP-fluorescent protein plasmid vectors. However, employing AmCyan as the fluorescent protein resulted in an unexpected interaction with the riboflavin component of cell culture media whereby fluorescence emission could not be observed in the 500 - 550 nm range as expected. The use of other fluorescent proteins should also be pursued, as well as the use of cell-culture media which is riboflavin-free. In order to evaluate the potential of targeting MMP-2 overexpression in solid tumours for selective activation of a TAP, a series of model fluorophore-peptide substrates were investigated in cell monolayers and 3D multicellular tumour spheroids. The target compound DDDDK(FITC)DIPVSLRSK(RhB) (4.8) contained a tetra-aspartate (DDDD) uptake-blocking group designed to prevent influx of the compound into the cell prior to activation by MMP-2 cleavage. Additionally the fluorescein isothiocyanate and rhodamine B fluorophores we attached to the peptide on opposing sites of the MMP-2 cleavage site, facilitating visualisation of the intact peptide as well as the post-cleavage fragments. LC-MS studies showed that in the absence of the uptake-blocking group K(FITC)DIPVSLRSK(RhB) (4.5) is almost entirely cleaved into its respective fragments K(FITC)DIPVS (4.6) and LRKS(RhB) (4.7) after 24 hours. LC-MS results also showed that the uptake-blocking group slows cleavage of the peptide, a trait which was also observed in fluorescence confocal microscopy. K(FITC)DIPVSLRSK(RhB) (4.5) and DDDDK(FITC)DIPVSLRSK(RhB) (4.8) were tested in DLD-1 cell monolayers in the absence of MMP-2 activity. After 4 hours K(FITC)DIPVSLRSK(RhB) (4.5) was found to have entered the cells intact and undergone a small degree of cleavage, while DDDDK(FITC)DIPVSLRSK(RhB) (4.8) did not enter cells intact, and instead only a very minor amount of intracellular fluorescence in the red channel was visible, indicative of non-specific cleavage. In the presence of MMP-2, less uptake of the intact K(FITC)DIPVSLRSK(RhB) (4.5) peptide was observed and instead discreet localised fluorescence was observed in the red and green channels, suggesting that cleavage was occurring in the extracellular space. This result was also observed, but to a lesser degree, for DDDDK(FITC)DIPVSLRSK(RhB) (4.8). These compounds were then also tested in multicellular tumour spheroid models, where the intact peptide K(FITC)DIPVSLRSK(RhB) (4.5) underwent cleavage in the surrounding media, resulting in sequestration of the LRSK(RhB) (4.7) fragment by the outermost cells, preventing it from penetrating further into the spheroid. Contrastingly, the slower cleavage of DDDDK(FITC)DIPVSLRSK(RhB) (4.8) improved the distribution of fluorescence in the red channel, having allowed the intact peptide to diffuse further into the spheroid before cleavage and cellular uptake of the LRSK(RhB) (4.7) fragment. These results confirmed the importance of the uptake-blocking group for ensuring delivery of the payload to the less accessible regions of solid tumour. Overall, this work demonstrated the potential of using an MMP-2 specific cleavage sequence for the selective delivery of chemotherapeutic agents to solid tumours, and as such a series of cytotoxin-peptide substrates containing the MMP-2 specific cleavage sequence were synthesised. The cytotoxic compounds investigated were the platinum(IV) complex cis, cis, trans-acetato[(1R,2R)-cyclohexane-1,2-diamine-N,N’]succinatooxalatoplatinum(IV) and ruthenium(II) complex [(4-methyl-4'-carboxy-2,2'-bipyridine)bis(4,4'-di-tert-butyl-2,2'-bipyridine)]ruthenium(II) hexafluorophosphate. The cytotoxic properties of library of platinum(IV)-peptide conjugates were tested, with none of the peptide-Pt(IV) conjugates possessing IC50 values similar to the free platinum(II) precursor. The intact DIPVSLRSK(Pt) (5.8) peptide is slightly less toxic than its post-cleavage fragment LRSK(Pt) (5.7) in the absence of MMP-2, but the IC50 of DIPVSLRSK(Pt) (5.8) is almost identical to LRSK(Pt) (5.7) in the presence of MMP-2, suggesting that MMP-2 is contributing to the activation and subsequent cytotoxicity of the compound. In both cell lines, the conjugate which contains the uptake-blocking group DDDDGDIPVSLRSK(Pt) (5.9) is not cytotoxic, proving that incorporation of the tetra-aspartate moiety can modify the activity of these compounds. Platinum accumulation studies in cell monolayers did not show a significant difference between the levels of intracellular platinum following incubation with LRSK(Pt) (5.7), DIPVSLRSK(Pt) (5.8), and DDDDGDIPVSLRSK(Pt) (5.9). However, no platinum was detected in the hypoxic/necrotic regions or periphery of spheroids treated with LRSK(Pt) (5.7) and DDDDGDIPVSLRSK(Pt) (5.9) when analysed by SRIXE mapping. After observing the poor spheroid penetration of the hydrophilic platinum(IV)-peptide compounds, the substitution of the cytotoxic platinum(IV) complex for a ruthenium(II)-bipyridyl complex saw an improvement in spheroid penetration. Peptide conjugation of the ruthenium(II) complex improved the cellular uptake of the ruthenium(II) and fluorescence confocal microscopy of LRSK(Ru) (5.10) showed that the compound was localised in the cytoplasm, while little of the free complex [Ru(tBu2bpy)2(HOOC-4’-CH3bpy)]2PF6 (5.6) was observed inside cells. This increase in uptake is likely to have contributed to the increased cytotoxicity of the compound, reducing the IC50 value by a factor of 2.
21
Phelan, Michael. "THE DESIGN, CONSTRUCTION, AND VALIDATION OF NOVEL ROTATING WALL VESSEL BIOREACTORS." Master's thesis, Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/488702.
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BioengineeringM.S.
The rotating wall vessel (RWV) bioreactor is a well-established cell culture device for the simulation of microgravity for suspension cells and the generation of spheroids and organoids. The key to the success of these systems is the generation of a delicately maintained fluid dynamics system which induces a solid body rotation capable of suspending cells and other particles in a gentle, low-shear environment. Despite the unique capabilities of these systems, the inherently delicate nature of their fluid dynamics makes the RWV prone to multiple failure modes. One of the most frequently occurring, difficult to avoid, and deleterious modes of failure is the formation of bubbles. The appearance of even a small bubble in an RWV disrupts the crucial laminar flow shells present in the RWV, inducing a high-shear environment incapable of maintaining microgravity or producing true spheroids. The difficulty of eliminating bubbles from the RWV substantially increases the learning curve and subsequent barrier-to-entry for the use of this technology. The objective of this study is to create a novel RWV design capable of eliminating the bubble formation failure mode and to demonstrate the design’s efficacy. The tested hypothesis is: “The addition of a channel capable of segregating bubbles from the fluid body of the RWV will protect its crucial fluid dynamics system while enabling the growth of consistently sized and properly formed cell spheroids, improving ease of use of the RWV and decreasing experimental failure.”
Temple University--Theses
22
Thoenes, Lilja. "A proteomic and genomic approach to in vivo chemoresistance using spheroid and xenograft cancer models." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-125700.
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Karamikamkar, Solmaz. "Development and evaluation of a novel approach to producing uniform 3-D tumor spheroid constructs." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/56296.
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In vitro tumor spheroid models have been developed using microfluidic systems to generate 3-D hydrogel beads containing components of alginate and ECM protein, such as collagen, with high uniformity and throughput. During bead gelation, alginate acts as a fast gelling component helping to maintain the spherical shape of beads and to prevent adjacent or underlying beads from coalescing when working with the slower gelling temperature and pH-sensitivity of collagen components. There are also well-known limitations in using microfluidic systems when working with temperature-sensitive components of collagen type I, and it is determined that to produce uniform hydrogel droplets through a microfluidic system, the mixtures must be homogeneous. However, the issue of collagen’s sensitivity to temperature causes concern for chunks of collagen gel inside of the mixture before bead encapsulation; therefore causing the mixture to become non-uniform and risking chip clogging. In order to overcome this limitation, previous approaches have used a cooling system during bead encapsulation while tumor cells were also present in the mixture, but this procedure assisted in postponing collagen gelation prior to bead production and potentially contributing to a delay in cell proliferation.
Here a novel yet simple method is developed to prepare homogeneous pre-bead-encapsulation-mixtures containing collagen through ultrasonication, while extending cell viability and proliferation. This method allows the cultivation of homogenous TS cultures with high uniformity and compact structure, and not only maintains cell viability but also stimulates the proliferation of cells in alginate/collagen hydrogel bead cultures. Depending on the sonication parameters, time and temperature, gelation of collagen is controlled by small sized fibrils to thick fibers. Human-source-Michigan-Cancer-Foundation-7 (MCF-7) cells isolated from a breast cancer cell line are successfully incorporated into alginate/collagen mixtures, followed by sonication, and then bead production. After bead gelation, the encapsulated MCF-7 cells remained viable and proliferated to form uniform TSs when the beads contained alginate and collagen. Results indicate that ultrasound treatment provides a powerful technique to change the structure of collagen from fiber to fibril, and to disperse collagen fibers in the mixture homogeneously for an application to generate uniform hydrogel beads and spheroids while not disturbing cell proliferation.Applied Science, Faculty of
Graduate
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Cheung, Hoi-yan, and 張凱恩. "The study of Chinese herbal medicinal compound on implantation : in vitro spheroid-endometrium co-culture." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196547.
Full textAbstract:
Traditional Chinese medicine (TCM) plays an important role in the Chinese healthcare system for over five thousand years. It includes the use of herbal medicine, acupuncture, Tui Na (推拿), and diet therapy. TCM helps to maintain a balance of Yin-Yang (阴阳), Five Phases (五行), Meridians (经络) and Qi (气) inside the body. In practise, pregnant women take tocolytic drugs to tonify the blood and qi to provide a continuous supply of nutrients for baby.
Traditional Chinese herbal medicines usually prescribed as a complex formula to produce synergistic or agonistic effect to maintain a well balance of the above components in human bodies. Moreover, TCM usually cannot produce immediate effect on patients, therefore, the efficacy of individual component remains largely unknown. This study aims to investigate whether Chinese tocolytic drug components could modulate fertility by affecting the in vitro spheroid (blastocyte surrogate) attachment process by using trophoblastic (JEG-3) and endometrial epithelial (Ishikawa) cells to mimic the embryo-endometrial implantation process.
Nine Chinese herbal medicinal compounds (Atractylenolide I(白术内酯), Atractylenolide II(白术内酯II), Atractylenolide III(白术内酯III), Paeoniflorin(芍药苷), Albiflorin(芍药内酯苷), Nuzhenide(女贞子甙), Ecliptasaponin A(旱莲甙A), Wedelolactone(蟛蜞菊内酯) and Columbianadin(二氢欧山芹醇当归酸酯)) which are commonly found in traditional Chinese tocolytic drug formula were selected to study (1) the toxicity of the drugs on trophoblastic (JEG-3) and endometrial epithelial (Ishikawa) cells growth, (2) the effect of three tocolytic drugs (Atractylenolide I, Atractylenolide II and Atractylenolide III) on spheroid attachment, and (3) their effect of the expression of Wingless (Wnt) signaling molecules (Active-β-Catenin, Axin-2, β-catenin, E-cadherin, GSK-3β, and Mucin-1).
It was found that the nine compounds, Atractylenolide I, Atractylenolide II, Atractylenolide III, Paeoniflorin, Albiflorin, Nuzhenide, Ecliptasaponin A, Wedelolactone and Columbianadin did not affect cell viability at 25μM, 25μM, 5μM, 0.2μM, 125μM, 125μM, 125μM, 5μM and 25μM, respectively, by cell proliferation assay. However, at these concentrations, the spheroid attachment was not significantly increased by Atractylenolide I, Atractylenolide II and Atractylenolide III. Interestingly, the protein expression of GSK-3β and Active-β-catenin were up-regulated by the three compounds in both cells and JEG-3 cells respectively. The expressions of Axin-2 and E-cadherin were up-regulated by Atractylenolide III in Ishikawa cells and Atractylenolide II in JEG-3 cells. Atractylenolide I and Atractylenolide III increase the Ishikawa cells expression of Active-β-catenin and β-catenin respectively and together suppress the JEG-3 cells Mucin-1 and β-catenin expression.
In conclusion, the nine tocolytic compounds have different effect on cell proliferation. Atractylenolide I, Atractylenolide II and Atractylenolide III did not enhance the attachment rate of JEG-3 spheroid onto Ishikawa monolayer. However, they affected Wnt-signaling molecules expression, suggesting that they may modulate endometrial receptivity. Further experiments are needed to study their combined effect on co-culture and expression of Wnt-signaling molecules.published_or_final_version
Obstetrics and Gynaecology
Master
Master of Medical Sciences
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Bell, Helen Susan. "The pathogenesis and regulation of cell death in glioblastoma : experimental studies using glioma spheroid cultures." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/25064.
Full textAbstract:
Understanding the pathways by which endogenous cell death occurs in tumours may be of considerable value when identifying potential therapies. In glioblastoma, two main types of cell death are observed, apoptosis and necrosis. Although the regulatory mechanisms leading to necrotic and apoptotic morphologies are thought to vary widely, their close association in glioblastoma suggests they may share some regulatory function. High levels of Fas (APO-1), HIF-la and PARP found within perinecrotic tissue in vivo suggests regulatory factors do exist. The presence of these regulatory factors, sub-lethal stress and a high apoptotic index suggests the p53 pathway may be involved in the cell death response around these areas. In order to investigate cell death regulatory factors in vitro, particularly those relating to the p53 pathway, the glioma spheroid system was utilised. Glioma spheroids are known reproduce some of the regional heterogeneity found in vivo and they form areas of necrosis as the spheroids become larger and the central core of cells becomes metabolically compromised. Using spheroids derived from four glioma cell lines, the aims of this project were (i) to fully characterise the glioma spheroid system for the four glioma cell lines, U87, U373, MOG-GCCM and A172 and to establish that the system adequately reflects many of the features found in glioblastoma cell populations in vivo; (ii) to define the exact time point in spheroid growth when central cell death occurs and to identify the modes of cell death present (iii) to establish which p53-related proteins are associated with areas of cell death within stressed glioblastoma cell populations and to determine any correlations between this distribution and the genetic status of the cell lines; and finally, (iv) to ascertain whether modulation of the P53 status of the cells has an effect on the development of cell death and the expression of p53-related proteins within glioma spheroid cultures. Regions of proliferation, death and differentiation were first assessed using a variety of immunohistochemical and microscopical techniques. Spheroid growth and apoptotic index were also quantitatively recorded. Onset of central cell death was seen to occur over week 3 and these spheroids were examined using electron microscopy to establish the primary mode of cell death (apoptosis or necrosis). HIF-la expression was used as a marker to determine the metabolic status of spheroid central regions at this time point. The P53 genotype of the cell lines was then determined and the reactivity of p53, Bax, p21 and MDM2 in monolayer cultures of the 4 lines was assessed following exposure to hypoxia and free radical stress. Perinecrotic expression of p53, Bax, p21 and MDM2 was recorded in both week 3 spheroid cultures and in glioblastoma biopsy material. The cell lines were transfected with wild-type and dominant negative P53 transcripts to investigate the effect of increasing and decreasing levels of endogenous p53 on cell death susceptibility within 3-dimensional spheroid cultures. Cross-sections of large glioma spheroids appeared highly representative of GBM tissue, modeling the span from blood vessels to nutritionally compromised, necrotic tissue distinct from the vasculature. The primary cell death morphology observed was necrosis, followed by increases in perinecrotic apoptotic index. Increases in HIF-la expression coincided with the onset of necrosis. HIF-la, p53 and p21 accumulation were associated with U87 and A172 monolayer cultures (p53 wild-type), but not U373 and MOG-G-CCM monolayer cultures (.P53 mutant), following exposure to oxidative stress. No increases in p53, Bax and p21 expression were found within perinecrotic tissue in spheroid cultures derived from any of the cell lines. A 60kDa MDM2 isoform was found to be upregulated within perinecrotic tissue in both spheroids and in 80% of biopsy cases irrespective of P53 status. The addition of a wildtype P53 transcript to U87 cells did not effect cell death susceptibility within U87 spheroids. U373 cells transfected with wild-type P53 died 3 days post transfection. Cell death susceptibility was not altered in either U87 and U373 spheroids following transfection with dominant negative P53. In conclusion, in large 3-dimensional glioma spheroid cultures, necrosis is the primary cell death event, followed by increases in perinecrotic apoptotic index. Although increases in p53-related expression are observed in P53 wild-type lines in response to oxidative stresses, p53, Bax and p21 accumulation do not appear to be important for the regulation of cell death in spheroid cultures, irrespective of the P53 status of the cell lines. Although the TGdgene appears to be essentially redundant within perinecrotic tissue, high levels of 60kDa MDM2 may associate with other cell death regulatory factors thus significantly influencing cell death susceptibility in both P53 wild-type and mutant cell populations.
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Kim, Kihwan. "MULTICEULLULAR TUMOR HEMI-SPHEROID: A NOVEL IN VITRO 3D MODEL PLATFORM FOR ACCELERATED DRUG DEVELOPMENT." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481900120946458.
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Inamdar, Sharvari Satish. "THE EFFECT OF CHEMOTHERAPY DRUGS ON GLOBAL OXYGEN UPTAKE IN A MULTICELLULAR TUMOR HEMI-SPHEROID." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1595958820583196.
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Paullin, Trillitye. "Gene Expression Profiling and the Role of HSF1 in Ovarian Cancer in 3D Spheroid Models." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6563.
Full textAbstract:
Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. These poor statistics are related to a lack of early symptoms and inadequate screening techniques. This results in the cancer going undetected until later stages when the tumor has metastasized through a process that requires the epithelial to mesenchymal transition (EMT). In lieu of traditional monolayer cell culture, EMT and cancer progression in general is best characterized through the use of 3D spheroid models. In this study, we examine gene expression changes through microarray analysis in spheroid versus monolayer ovarian cancer cells treated with TGFβ to induce EMT. Transcripts that included Coiled-Coil Domain Containing 80 (CCDC80), Solute Carrier Family 6 (Neutral Amino Acid Transporter), Member 15 (SLC6A15), Semaphorin 3E (SEMA3E) and PIF1 5'-To-3' DNA Helicase (PIF1) were downregulated more than 10-fold in the 3D cells while Inhibitor Of DNA Binding 2, HLH Protein (ID2), Regulator Of Cell Cycle (RGCC), Protease, Serine 35 (PRSS35), and Aldo-Keto Reductase Family 1, Member C1 (AKR1C1) were increased more than 50-fold.
Interestingly, stress responses and epigenetic processes were significantly affected by 3D growth. The heat shock response and the oxidative stress response were also identified as transcriptome responses that showed significant changes upon 3D growth. Subnetwork enrichment analysis revealed that DNA integrity (e.g. DNA damage, genetic instability, nucleotide excision repair, and the DNA damage checkpoint pathway) were altered in the 3D spheroid model. In addition, two epigenetic processes, DNA methylation and histone acetylation, were increased with 3D growth. These findings support the hypothesis that three dimensional ovarian cell culturing is physiologically different from its monolayer counterpart.
The proteotoxic stress-responsive transcription factor HSF1 is frequently overexpressed in a variety of cancers and is vital to cellular proliferation and invasion in some cancers. Upon analysis of various patient data sets, we find that HSF1 is frequently overexpressed in ovarian tumor samples. In order to determine the role of HSF1 in ovarian cancer, inducible HSF1 knockdown cell lines were created. Knockdown of HSF1 in SKOV3 and HEY ovarian cancer cell lines attenuates the epithelial-tomesenchymal transition (EMT) in cells treated with TGFβ, as determined by western blot and quantitative RT-PCR analysis of multiple EMT markers.
To further explore the role of HSF1 in ovarian cancer EMT, we cultured multicellular spheroids in a non-adherent environment to simulate early avascular tumors. In the spheroid model, cells more readily undergo EMT; however, EMT inhibition by HSF1 knockdown becomes more pronounced in the spheroid model. These findings suggest that HSF1 is important in the ovarian cancer TGFβ response and in EMT.
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Lama, Rati. "Preclinical evaluation and identification of potent tubulin and Hsp27 inhibitors as anticancer agents." Cleveland State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=csu1430232901.
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Kong, Dali. "Analytical and numerical studies of several fluid mechanical problems." Thesis, University of Exeter, 2012. http://hdl.handle.net/10036/3651.
Full textAbstract:
In this thesis, three parts, each with several chapters, are respectively devoted to hydrostatic, viscous and inertial fluids theories and applications. In the hydrostatics part, the classical Maclaurin spheroids theory is generalized, for the first time, to a more realistic multi-layer model, which enables the studies of some gravity problems and direct numerical simulations of flows in fast rotating spheroidal cavities. As an application of the figure theory, the zonal flow in the deep atmosphere of Jupiter is investigated for a better understanding of the Jovian gravity field. High viscosity flows, for example Stokes flows, occur in a lot of processes involving low-speed motions in fluids. Microorganism swimming is such typical a case. A fully three dimensional analytic solution of incompressible Stokes equation is derived in the exterior domain of an arbitrarily translating and rotating prolate spheroid, which models a large family of microorganisms such as cocci bacteria. The solution is then applied to the magnetotactic bacteria swimming problem and good consistency has been found between theoretical predictions and laboratory observations of the moving patterns of such bacteria under magnetic fields. In the analysis of dynamics of planetary fluid systems, which are featured by fast rotation and very small viscosity effects, three dimensional fully nonlinear numerical simulations of Navier-Stokes equations play important roles. A precession driven flow in a rotating channel is studied by the combination of asymptotic analyses and fully numerical simulations. Various results of laminar and turbulent flows are thereby presented. Computational fluid dynamics requires massive computing capability. To make full use of the power of modern high performance computing facilities, a C++ finite-element analysis code is under development based on PETSc platform. The code and data structures will be elaborated, along with the presentations of some preliminary results.
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Morrone, Luigi. "The Influence of 3D Cell Organization in Tumor Spheroid on Natural Killer Cell Infiltration and Migration." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-286605.
Full textAbstract:
Natural Killer cells are a type of lymphocyte belonging to the innate immune system and they operate cell-mediated cytotoxicity and release of pro-inflammatory cytokines against cancerous cells. However, in vivo testings have shown a reduced activity of NK cells against solid tumors probably due to the negative influence of the immunosuppressive tumor microenvironment. Multicellular tumor spheroids may constitute an advantageous model in cancer biology for studying the mechanisms behind cancer immune editing since it more closely mimics the complexity of the human body compared with the 2D model counterpart. This study investigated the interaction between NK cells isolated from blood and tumor spheroids obtained from A498 renal carcinoma cells, using light-sheet microscopy imaging which allows satisfactory cell tracking in the inner layers of the spheroids. NK cells not only indeed interact with tumor spheroids, but many of them were able to penetrate the spheroids inducing some changes in the structure of the latter. NK cells were also tracked over time, displaying the migration path and calculating the speed. The fluorescence intensity of the NK cells was found reduced as soon as they penetrate the spheroid but, conversely, the speed seems to increase inside the spheroid, a possible sign of the fallibility of the tracking algorithm in this specific case. We propose solutions for more sophisticated future implementations, involving the use of marks during the experimental phase and drift corrections at the data analysis level.
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costa, aurora. "INHIBITION OF CYCLIN-DEPENDENT PROTEIN KINASES AS A POTENTIAL NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA." Doctoral thesis, Università di Siena, 2023. https://hdl.handle.net/11365/1227738.
Full textAbstract:
Direct or indirect exposure to asbestos fibers can cause various respiratory pathologies such as asbestosis
or pleural effusion, up to more serious pathologies, even tumors such as malignant pleural mesothelioma
(MPM).
MPM is a highly aggressive tumor for which there is still no effective therapeutic strategy today and, despite
the use of asbestos being banned in many western countries, unfortunately an increase in incidence is still
estimated. This is due both to the long clinical latency that characterizes the development of MPM (about
40 years), and to the environmental persistence of materials containing asbestos. To date, MPM still
represents a therapeutic challenge, and therefore, the identification of new and effective therapies is
urgently needed.
In recent years various approaches have been tested in the preclinical phase by the group where I carried
out my thesis activity, such as the inhibition of the oncogenic kinase SRC, or the reactivation of p53, both
capable of inducing cell death both in MPM lines than in in vivo experiments. More recently they observed
that reactivation of the RBL2/p130 tumor suppressor was also able to induce apoptosis in MPM cell lines.
These data suggested that acting by restoring the function of retinoblastoma family proteins could be an
effective strategy for this tumor.
The aim of my thesis project was to verify whether the inhibition of the cyclin-cycline kinase dependent
complexes, more specifically using the cyclin dependent kinase (CDK) inhibitor abemaciclib, was able to act on the pocket proteins, reactivating their tumor suppressor potential.First of all, we demonstrated that abemaciclib dose-dependently inhibits the cell proliferation in short- and long-term of MPM cell lines, however, it did not show the same cytotoxic effects on the mesothelium cell line used as a control. Subsequently, we tested and confirmed that abemaciclib is able to induce apoptosis in some MPM lines by cytofluorimetric assay of annexin. In Addition, we then evaluated the ability of abemaciclib on 3D cell cultures, drug showed the capacity inhibiting the formation of 1st and 2nd generation spheroids but also blocking the proliferation of fully formed spheroids. Again, to investigate the molecular mechanism through which the inhibitor acts, by western blotting, the phosphorylation levels of all three pocket proteins (RBL2/p130, RBL1/p107 and RB1/p105) were evaluated, as expected. The inhibitor induces a reduction in p130 (Ser952) and (Ser941), p107 (Ser975), and p105 (Ser780) phosphorylation with consequent restoration of protein functionality. Moreover, since previous studies demonstrate that reactivation of the RBL2/p130 tumor suppressor mediates apoptosis in MPM cell lines by counteracting the AKT-activated antiapoptotic pathway, we tested the levels of AKT protein and its phosphorylation, and how we expected this drug induces reduction of AKT phosphorylation (Ser473). Finally, we decided to evaluate the sensitivity to abemacilib on ciplatin-resistant cells, and the results show that the more aggressive mesotlioma cells remained sensitive to this drug even though resistant to cisplatin. The data obtained are certainly still preliminary, the subsequent studies are necessary above all to understand what happens to the progression of the cell cycle, but at the same time, they are promising, urging us to continue and making us hypothesize that this treatment could be effective for patients with MPM
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Grist, Samantha Marie. "A microfluidic platform to study real-time tumour cell and tumour spheroid response to chronic and transient hypoxia." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58212.
Full textAbstract:
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Applied Science, Faculty of
Electrical and Computer Engineering, Department of
Graduate
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Yamaura, Tadayoshi. "Accurate diagnosis of mismatch repair deficiency in colorectal cancer using high-quality DNA samples from cultured stem cells." Kyoto University, 2019. http://hdl.handle.net/2433/242418.
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Shahi, Thakuri Pradip. "MODELING ANTI-CANCER DRUG RESISTANCE USING TUMOR SPHEROIDS." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574725861735168.
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Monazzam, Azita. "Multicellular Tumour Spheroids in a Translational PET Imaging Strategy." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8196.
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Corrêa, de Sampaio Pedro Vaz de Almada. "Using a novel 3-dimensional in vitro spheroid model to investigate new roles for stromal metalloproteinases in tumour angiogenesis." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610640.
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Kim, Byung Juen. "Development of Multiple Fluorescent Tumour Spheroid Models To Investigate the use of Transition Metal Complexes as Hypoxia-Activated Prodrugs." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12494.
Full textAbstract:
The use of transition metal based tumour-activated prodrugs is a promising strategy to improve the selectivity of anticancer agents towards cancer over healthy tissues. The rational design of these agents is difficult, as knowledge and tools to understand their biological activities have been lacking to date. In this study, multiple fluorescent cellular models have been developed and characterised to study metal complexes [M(acac)3] and [M(dbm)3], as models of hypoxia-activated prodrugs, where M = Co, Fe, Ru. The biological activities of these metal complexes were evaluated in both the monolayer cultures as well as spheroids, an exemplary in vitro tumour model. As most anticancer agents have been developed with the purpose of damaging the nucleus and the DNA, the changes in the cell cycle progression caused by the prodrugs was investigated using the fluorescent ubiquitination cell cycle indicator (FUCCI) system. When the metal complexes chaperone the cytotoxin to the hypoxic region of the tumour, the metal complexes that have undergone ligand exchange are also found in the same region. To monitor the changes in spatial and temporal regulation of the intracellular labile iron pool, one copy of the iron responsive element from the human ferritin light gene was utilised to drive the translation of EosFP. Finally, the promoter region of hypoxia-related genes was manipulated to visualise hypoxia in a tumour microenvironment. Also, a robust method to select hypoxia responsive cells has been developed. The outcomes of this study provided insights into how metal complexes are taken up by cells, their cytotoxic effects, their impact on the cell cycle, their indirect involvement in iron metabolism and hypoxia selectivity in spheroids. These new findings will contribute to the design and development of effective prodrugs for treating cancer.
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Futrega, Katarzyna. "Device and application development for haematopoietic stem and progenitor cell (HSPC) and mesenchymal stromal cell (MSC) 3D spheroid cultures." Thesis, Queensland University of Technology, 2016. https://eprints.qut.edu.au/92605/1/Katarzyna_Futrega_Thesis.pdf.
Full textAbstract:
With an overall aim to improve haematopoietic stem/progenitor cell (HSPC) and mesesnchymal stromal cells (MSC) 3D culture systems, this PhD Thesis addressed the following four interlinked AIMs: (1) The development of a high throughput microwell platform that enabled evaluation of MSC spheroid potential to expand HSPC in vitro; (2) Utilization of the high throughput microwell platform to manufacture HSPC/MSC spheroids to improve the efficacy of direct bone marrow transplantation; (3) The development of an improved microwell platform that retains spheroids within discrete microwells throughout culture; and (4) Characterization of HSPC surface marker change in response to the microwell material.
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Marrero, Bernadette. "Evaluation of Immunogene Therapy Using a Plasmid Encoding IL-15 Delivered by Electroporation in a 3D Tumor Model and a Mouse Melanoma Model." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3520.
Full textAbstract:
Melanoma is an aggressive disease with few effective treatment options. Non-toxic, anti-tumor therapies and prophylactic approaches are currently being investigated to identify treatment options that will control and remove late-stage melanoma.
The overall goal of this project was to establish an effective delivery method for a plasmid encoding human interleukin (phIL-15) into mouse melanoma cells (B16.F10) using the gene transfer technique electroporation (EP)1. The EP delivery phIL-15 was optimized using an in vitro 3D tumor model. The purpose was to translate these IL-15 delivery conditions into an in vivo mouse melanoma model to study IL-15 signal transduction and stimulate immune cells to destroy tumor antigens as well as promote an anti-tumor immune memory response.
The in vitro 3D tumor model and the mouse model demonstrated similar expression patterns when delivering phIL-15 with different EP conditions. Intra-tumoral delivery using 500V/cm 20ms enhanced gene delivery and increased IL-15 protein expression compared to 1300V/cm 100μs. There was also a visible increase in transfection efficacy between tumor cells compared to skin cells when delivering pmIL-12 and phIL-15 plasmid constructs in vivo. The plasmid+EP groups 1300V/cm and 500V/cm stimulated increased expression of cytokines IL-1β, IL-6, INFγ, MIP-1β and TNFα. These EP groups also promoted tumor regression by up-regulating CD8+ T cells and CD4+ T cells which targeted melanoma. Regression and survival studies demonstrated that 73.3% of mice cleared B16.F10 cells when treated with phIL-xi15+1300V/cm and pVax+500V/cm. In addition, 53% of the mice responded to the phIL-15+500V/cm treatment group. Furthermore, 75% of the mice from group phIL-15+500V/cm survived secondary inoculation and tumor challenge. In conclusion, plasmid with encoding gene insert phIL-15 delivered by EP has the potential to act as an anti-tumor therapy because it promotes melanoma regression and enhances mouse survival through innate and adaptive cell-mediated immune responses.
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CALZADA, MICHEL. "Influence de la non sphericite sur le comportement spectral d'un aerosol a partir d'une comparaison sphere-spheroide." Toulouse 3, 1989. http://www.theses.fr/1989TOU30026.
Full textAbstract:
Calcul des proprietes de diffusion des particules spheroidales a l'aide d'une methode approchee hybride entre le modele de rayleigh-gans et le modele de lorentz-mie. Evaluation de l'influence du parametre de forme sur un domaine spectral de 2 a 55 microns
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Maekawa, Hisatsugu. "A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor Initiating Cells." Kyoto University, 2018. http://hdl.handle.net/2433/235985.
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Reddyhoff, Dennis. "Mathematical modelling of acetaminophen induced hepatotoxicity." Thesis, Loughborough University, 2016. https://dspace.lboro.ac.uk/2134/23008.
Full textAbstract:
Acetaminophen, known as paracetamol in the UK and Tylenol in the United States, is a widespread and commonly used painkiller all over the world. Taken in large enough doses, however, it can cause fatal liver damage. In the U.S., 56000 people are admitted to hospital each year due to acetaminophen overdose and its related effects, at great cost to healthcare services. In this thesis we present a number of different models of acetaminophen metabolism and toxicity. Previously, models of acetaminophen toxicity have been complex and due to this complexity, do not lend themselves well to more advanced mathematical analysis such as the perturbation analysis presented later in this thesis. We begin with a simple model of acetaminophen metabolism, studying a single liver cell and performing numerical and sensitivity analysis to further understand the most important mechanisms and pathways of the model. Through this we identify key parameters that affect the total toxicity in our model. We then proceed to perform singular perturbation analysis, studying the behaviour of the model over different timescales, finding a number of key timescales for the depletion and subsequent recovery of various cofactors as well as critical dose above which we see toxicity occurring. Later in the thesis, this model is used to model metabolism in a spheroid cell culture, examining the difference spatial effects have on metabolism across a 3D cell culture. We then present a more complex model, examining the difference the addition of an adaptive response to acetaminophen overdose from the Nrf2 signalling pathway, has on our results. We aim to reproduce an unexplained result in the experimental data of our colleagues, and so analyse the steady states of our model when subjected to an infused dose, rather than a bolus one. We identify another critical dose which leads to GSH depletion in the infused dose case and find that Nrf2 adaptation decreases toxicity and model sensitivity. This model is then used as part of a whole-body PBPK model, exploring the effects that the distribution of the drug across the bloodstream and different organs has. We explore the affects of that a delay in up-regulation from the Nrf2 pathway has on the model, and find that with rescaled parameters we can qualitatively reproduce the results of our collaborators. Finally, we present the results of in vitro work that we have undertaken, the aim of which was to find new parameters for the model in human hepatocytes, rather than from rodent models, and find a new value for a parameter in our model from human cell lines.
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Burand, Jr Anthony John. "Consequences of in vitro and in vivo environmental cues on localized delivery of MSCs." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6919.
Full textAbstract:
Mesenchymal stromal cells (MSCs) are being explored for treatment of inflammatory, ischemic, autoimmune, and degenerative diseases. More and more of these diseases require MSCs to be delivered locally to the diseased site rather than systemically injected into patients. However, little is understood about whether cell cryopreservation or prelicensing will affect the efficacy of the locally injected product or how the local injection environment affects MSC expression of trophic factors and interactions with patient immune cells. Several groups have disagreed on whether cryopreservation hinders MSC potency and therefore it is important to understand the effects of cryopreservation on MSC function and in what contexts cryopreservation can be used. Therefore, a better understanding of MSC phenotype after local injection is needed so that cryopreservation and prelicensing can be optimized to modulate cell potency for more efficacious MSC products.
Currently, it has been shown that in vivo there are rapid drastic shifts in gene expression by MSCs which have been locally injected. One of the most prominent gene changes is in the enzyme COX-2 which leads to the production of bioactive lipids called prostaglandins, namely PGE2. PGE2 has several functions depending on the context in which other cells encounter it. In order to model the gene changes that occur in vivo, in vitro cell aggregates termed spheroids have been utilized to study the effects of local injection of MSCs. MSC spheroids have shown more potency than their 2D counterparts in shifting macrophage polarization and rescue of cells from ischemic damage.
This thesis examines how process variables like cryopreservation and prelicensing affect the efficacy of the MSC product in the context of local injection. Additionally, it shows how spheroid formation alters therapeutic factor expression and activity and how drug treatment and biomaterials can be utilized to modify potency of these cells. In Chapter 2, we demonstrate that cryopreservation in the context of an ischemia/reperfusion injury in the eye does not significantly decrease MSCs effectiveness in salvaging neuronal cells. However, IFN-γ, a commonly used prelicensing cytokine to increase MSC potency, led to a decrease in the effectiveness of MSCs in this model. Chapters 3 and 4 define the changes that occur to several of MSCs’ trophic factors including immunomodulatory and growth factors and how these alterations affect MSC interactions with macrophages and T cells. Because validation and tracking of locally injected products can be cost-prohibitive for many research groups, Chapter 5 lays out a low-cost method to track fluorescently labeled cells in local injections to skin to aid in minimization of variability in results obtained from animal wound healing models.
These findings demonstrate that initial preparation of MSC therapeutics is critical to their efficacy in local injection. Therefore, careful testing of potency for large-scale MSC production pipelines should be evaluated to ensure the efficacy of the resulting product. Additionally, spheroids exhibit differences in the mechanisms of action due to alterations in their secretome which can be partly overcome with co-administration of steroids such as budesonide. Therefore, steroid co-administration with MSCs being considered for local application should be further explored for use in local delivery of MSCs for the treatment of inflammatory conditions. Finally, this research demonstrates the need to further understand the mechanisms by which spheroids alter their gene and trophic factor production to better tailor MSC therapies for disease specific localized injection.
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Hoarau, Jessica. "Halfway Between 2D Models and Animal Models : a New Multicellular 3D Spheroid Model Organized to Study Tumor-Endothelium Interactions in Ovarian Cancer." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS111.
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Le cancer de l'ovaire (CO) est la cinquième cause de décès chez les femmes qui se caractérise par son diagnostic tardif (stades FIGO III et IV) et par l’importance de ses métastases abdominales souvent observées au moment du diagnostic. Le traitement repose sur une chirurgie cytoréductive complète associée à une chimiothérapie. Malheureusement, parmi les patientes ayant une rémission clinique complète après la fin du traitement initial, 60% des personnes atteintes d'un cancer épithélial de l'ovaire (CEO) à un stade avancé rechuteront dans les cinq ans.L'importance de la néo-angiogenèse dans le développement des tumeurs a poussé les chercheurs à étudier d'autres stratégies. Les thérapies anti-angiogéniques ciblant le système vasculaire tumoral sont désormais utilisées en association avec la thérapie cytotoxique standard dans le traitement des CEO. Malheureusement, les progrès réalisés grâce à cette approche offrent encore un succès limité, qui peut s'expliquer en partie par l'interaction hétérotypique entre les cellules endothéliales et la tumeur. Plusieurs études suggèrent un dialogue complexe entre les cellules cancéreuses de l'ovaire (OCC) et les cellules endothéliales (EC) pouvant entraîner une sensibilité différente à la chimiothérapie et aux traitements anti-angiogéniques conduisant à la progression tumorale.L’objectif de la présente étude est d’étudier le rôle des interactions entre EC et OCC dans la prolifération et la chimiorésistance des CEO. Pour modéliser l'endothélium de la tumeur, nous avons utilisé notre modèle de cellules endothéliales AKT activées (E4+EC). Nous avons démontré en utilisant un modèle de coculture 2D que l’endothélium activé induit une prolifération et une chimiorésistance accrues dans les CEO par l’activation de la signalisation de Notch. Nous avons montré que l’expression et l’activation des récepteurs Notch étaient augmentées dans les cultures en coculture et dans les OCC résistantes à la chimiothérapie.L’accumulation d’ascite dans l’abdomen des patientes atteintes de CO semble jouer un rôle clé dans le mécanisme de propagation des OCC. Les OCC isolées flottent généralement dans l'ascite et forment des sphéroïdes multicellulaires. Dans ce contexte, nous avons développé un nouveau modèle 3D de sphéroïde pour étudier les interactions tumeur-endothélium dans un modèle plus proche des conditions in vivo. Nous avons démontré que les E4+EC et OCC formaient des angiosphères organisées avec un noyau de cellules endothéliales entourées par des OCC qui prolifèrent rapidement. Nous avons établi que l'activation de l'AKT dans les EC était nécessaire pour la formation d'angiosphères organisées. Fait intéressant, dans les ascites de patientes CEO, nous avons pu trouver des structures très similaires à nos angiosphères. De plus, dans une cohorte rétrospective de 59 patientes, nous avons montré que les EC étaient AKT activé chez des patientes atteintes de CEO, ce qui confirme l'importance de l'activation d’AKT dans la CEO. De plus, nous avons démontré l'importance du FGF2, de la Pentraxine 3 (PTX3), du PD-ECGF et du TIMP-1 dans l'organisation de l'angiosphères. Enfin, nous avons confirmé le rôle de Notch3/Jag1 dans le cross-talk des OCC-EC dans la prolifération et l'invasion des OCC au péritoine.En conclusion, notre étude illustre l’importance des EC AKT activé dans les CEO. Au vu des résultats mitigés des traitements anti-angiogéniques, se concentrer sur la normalisation vasculaire dans l'angiogenèse pathologique pourrait être plus efficace. Bien que l'AKT soit difficilement ciblable, la caractérisation génétique des tumeurs pourrait potentiellement identifier un sous-ensemble de tumeurs avec une signalisation NOTCH aberrante qui constituerait une cible idéale pour des inhibiteurs spécifiques. Alors que nous nous dirigeons vers la médecine personnalisée et de précision, il pourrait y avoir une place pour l'inhibition de NOTCH dans les CO en combinaison avec d'autres stratégies thérapeutiquesOvarian cancer (OC) is the most lethal gynecologic malignancy in developed countries and the fifth cause of death among women. OC is a heterogeneous disease, which is characterized by its late diagnosis (FIGO III and IV stages) and the importance of abdominal metastases often observed at the time of diagnosis. The mainstay of treatment involves complete cytoreductive surgery associated with platinum and taxane-based chemotherapy. Unfortunately, among patients achieving complete clinical remission after completion of initial treatment, 60% with advanced epithelial ovarian cancer (EOC) will relapse within five years.The importance of neo-angiogenesis in tumor formation, growth and dissemination has driven researchers to investigate into alternative strategies. Anti-angiogenic therapies targeting tumor vasculature are now used in combination with standard cytotoxic therapy in the treatment of EOC. Unfortunately, the progress achieved by this approach still offers limited success which can partly be explained by the heterotypic interaction between the tumor and endothelial cells. Evidence suggests a complex cross-talk between ovarian cancer cells (OCCs) and endothelial cells (ECs) that can result in the emergence of a heterogeneous tumoral and endothelial population with different sensitivity to chemotherapy and anti-angiogenic therapies leading to an increase of OCC proliferation and dissemination.The objective of the present study is to investigate the role of ECs and OCCs interactions in the proliferation and chemoresistance of EOC. To model tumor endothelium, we used our model of Akt-activated endothelial cells (E4+ECs). We demonstrated using a 2D co-culture model that activated endothelium induces increased proliferation and chemoresistance in EOC through the activation of Notch signaling. We showed that Notch receptor expression and activation are increased in co-culture and in OCCs resistant to chemotherapy.The accumulation of ascites in the abdomen of an OC patient seems to play a key role in the mechanism of OCC spreading. Detached cancer cells usually float in ascites and form multicellular spheroids. In this context, we developed a new model of organized multicellular 3D spheroid to study tumor-endothelium interactions in a model closer to in vivo conditions. We demonstrated that when cocultured in 3D condition, E4+ECs and OCCs formed organized tumor angiospheres with a core of endothelial cells surrounded by highly proliferating OCCs. We established that AKT activation in ECs was mandatory for the formation of organized angiospheres. Interestingly, in EOC patient ascites, we were able to find structures that were very similar to our angiospheres. In addition, in a retrospective cohort of 59 patients, we showed that ECs were AKT activated in EOC patients which support the importance of AKT activation in EC in EOC. Besides, we demonstrated the importance of FGF2, Pentraxin 3 (PTX3), PD-ECGF and TIMP-1 in angiosphere organization. Finally, we confirmed the role of Notch3/Jagged1 in OCCs-ECs crosstalk for OCC proliferation but also during peritoneum invasion.Altogether, our study illustrates the importance of AKT activated ECs in EOC. In a context of poor results of anti-angiogenic therapies in clinical settings, focusing on vascular normalization in pathological angiogenesis could be more efficient. While AKT is hardly targetable, the genetic characterization of tumors could potentially identify a subset of tumors with aberrant NOTCH signaling that would constitute an ideal target for specific inhibitors. As we move toward personalized and precision medicine, there might be a place for notch inhibition in advanced ovarian cancer in combination with other therapeutic strategies
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Kasai, Yosuke. "Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3." Kyoto University, 2017. http://hdl.handle.net/2433/226761.
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Klicks, Julia [Verfasser], and Mathias [Akademischer Betreuer] Hafner. "Development and characterization of a novel, simple, spheroid-based tri-culture model composed of fibroblasts, keratinocytes, and melanoma cells / Julia Klicks ; Betreuer: Mathias Hafner." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1192373057/34.
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Häger, Jan-Dirk [Verfasser]. "Establishment of a bovine placental trophoblast cell line and a 3-dimensional spheroid culture model: biological effects of epidermal growth factor (EGF) / Jan-Dirk Häger." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2011. http://d-nb.info/1013334027/34.
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Klutzny, Saskia [Verfasser], Patrick [Akademischer Betreuer] Steigemann, Juri [Gutachter] Rappsilber, Roland [Gutachter] Lauster, and Patrick [Gutachter] Steigemann. "Identification of hypoxia-specific anti-cancer drugs using an in vitro spheroid model / Saskia Klutzny ; Gutachter: Juri Rappsilber, Roland Lauster, Patrick Steigemann ; Betreuer: Patrick Steigemann." Berlin : Technische Universität Berlin, 2018. http://d-nb.info/1164076345/34.
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Halfter, Kathrin [Verfasser], and Barbara [Akademischer Betreuer] Mayer. "Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy - The SpheroNEO Study / Kathrin Halfter ; Betreuer: Barbara Mayer." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1140435698/34.
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