Tesis sobre el tema "Preclinical oncology"
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Loskog, Angelica. "Immunogene Therapy of Bladder Carcinoma : A Preclinical Study". Doctoral thesis, Uppsala universitet, Enheten för onkologi, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2637.
Texto completoChaffee, Beth K. "Preclinical Modeling of Musculoskeletal Cancer". The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376844544.
Texto completoVenugopal, Balaji. "Preclinical evaluation of a novel drug delivery system for cisplatin". Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/4198/.
Texto completoMartín, Liberal Juan Jesús. "Combination of cytotoxic agents and targeted therapy for the treatment of advanced sarcomas: preclinical background and early clinical development". Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/401753.
Texto completoLos sarcomas son un grupo de tumores caracterizados por su mal pronóstico y la ausencia de tratamientos efectivos. La mediana de supervivencia de los pacientes afectos de sarcoma avanzado es de tan solo 1 año a pesar de recibir tratamiento. Por lo tanto, es necesario encontrar nuevas estrategias terapéuticas efectivas. Nuestra hipótesis es que la inhibición de la angiogénesis y de la vía de mTOR en sarcomas en combinación con agentes citotóxicos activos potencia la actividad anti tumoral de cada una de las estrategias terapéuticas por separado sin toxicidad significativa. Para confirmar dicha hipótesis realizamos dos ensayos clínicos fase I con experimentos preclínicos asociados que han sido publicados en revistas científicas internacionales. Artículo 1: Ensayo clínico fase I de sorafenib en combinación con ifosfamida en pacientes con sarcoma avanzado: un estudio del Grupo Español de Investigación en Sarcomas (GEIS). Este ensayo clínico fase I evaluó la seguridad, la farmacocinética, la toxicidad limitante de dosis, la dosis máxima tolerada y la dosis recomendada de la combinación de sorafenib más ifosfamida en pacientes con sarcoma avanzado. La dosis recomendada fue sorafenib 400 mg bid más ifosfamida 6 g/m2, un esquema que permite la administración de dosis activas de ambos fármacos. También se observaron signos preliminares de actividad antitumoral. Artículo 2: Ensayo clínico fase I y evaluación de la eficacia preclínica del inhibidor de mTOR sirolimus más gemcitabina en pacientes con tumores sólidos avanzados Llevamos a cabo un ensayo clínico fase I en pacientes con tumores sólidos avanzados para identificar la dosis recomendada, evaluar la PK, la actividad farmacodinámica y la eficacia antitumoral preclínica de la combinación de sirolimus y gemcitabina. La dosis recomendada fue sirolimus 5 mg al día más gemcitabina 800 mg/m2. Además, se observó actividad antitumoral en los modelos preclínicos de sarcoma, así como inhibición de la vía de mTOR.
Sambandam, Vaishnavi. "The Role of Hedgehog signaling in Hepatitis B virus X protein mediated hepatocellular carcinoma". Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/292349.
Texto completoPh.D.
Hepatitis B virus encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to cancer. Thus, experiments were designed to test the hypothesis that HBx contributes to HCC via activation of Hh signaling. HBx expression correlated with up-regulation of Hh markers in human liver cancer cell lines, in HBx transgenic mice that developed HCC and in liver samples from HBV infected patients with HCC. The findings in human samples provide clinical validation of those in the HBx transgenic mice (HBxTg), and underscore the relevance of these transgenic mice to disease pathogenesis. Further, blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage independent growth, HCC tumorigenesis in HBx transgenic mice and tumor growth in xenograft model. These results suggest that the ability of HBx to promote cancer is at least partially dependent upon Hh activation and that activation of Hh signaling appears to be important for the development of HBx associated HCC. HBx also activates pathways that stimulate downstream Hh signaling, such as PI3K/AKT and Ras/Raf/MEK, also referred as non-canonical Hh signaling. Upon canonical Hh inhibition, compensatory activation of these pathways was seen in the presence of HBx in liver cancer cell lines and in HBxTg mice. Individual inhibition of these pathways also down-regulated Gli2 expression in HBx positive cell lines. These data suggests that in addition to canonical Hh signaling, activation of PI3K/AKT and ERK pathways by HBx leads to up-regulation of Gli2 expression in HBV-mediated HCC. This work identifies Hh pathway inhibition as a therapeutic strategy to slow tumor development and this work could lead to combination therapies that target Hh, AKT and ERK pathways, which may prevent or delay the appearance/progression of HCC.
Temple University--Theses
Gullbo, Joachim. "Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3785.
Texto completoJeon, Jae Yoon. "Preclinical and clinical development of kinase inhibitors in acute myeloid leukemia". The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu158699311567933.
Texto completoKarlsson, Henning. "New preclinical strategies for characterization and development of anticancer drugs". Doctoral thesis, Uppsala universitet, Cancerfarmakologi och beräkningsmedicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330999.
Texto completoRecasens, Zorzo Clara. "Preclinical evaluation of the antitumor activity of a new CXCR4 inhibitor: a novel therapeutic approach in diffuse large B-cell lymphoma". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663897.
Texto completoLa activación constitutiva del receptor de quemocinas CXCR4 está asociada a la progresión tumoral, invasión y resistencia al tratamiento. En el linfoma difuso de células grandes (LDCG) la sobreexpresión de CXCR4 concede un peor pronóstico, pero la relevancia biológica de este receptor no se ha estudiado en profundidad. En esta tesis se ha evaluado un nuevo inhibidor de CXCR4 (IQS-01.01) en modelos preclínicos de LDCG. Usando tanto modelos in vitro como in vivo de LDCG se ha concluido 1) que la inhibición de CXCR4 en LDCG tiene un efecto antitumoral, 2) que IQS-01.01RS tiene mayores propiedades farmacológicas que el inhibidor de referencia, AMD3100 3) que el tratamiento con IQS-01.01RS reduce los niveles del oncogén MYC y 4) que la combinación de IQS-01.01 RS con el inhibido de BET, CPI203, confiere un efecto antitumoral sinérgico. Los resultados de esta tesis doctoral ponen en evidencia una cooperación entre MYC y CXCR4 en LDCG e indican que la inhibición de CXCR4 en combinación con un inhibidor de MYC es una terapia prometedora contra el LDCG.
Chakupurakal, Geothy. "Preclinical studies of adenovirus-specific T-cells for adoptive transfer to haemopoietic stem cell transplant recipients". Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/2883/.
Texto completoHöglund, Johanna. "On the Use of 76Br-labelled Monoclonal Antibodies for PET : Preclinical Evaluation of Halogenated Antibodies for Diagnosis and Treatment of Cancer". Doctoral thesis, Uppsala universitet, Institutionen för onkologi, radiologi och klinisk immunologi, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1908.
Texto completoDereure, Erwan. "Quantitative analysis of bioluminescent signals in preclinical imaging". Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS090.
Texto completoBioluminescence imaging (BLI) is an optical imaging technology in which a living organism or cell emits light through a biological substrate/enzyme reaction without any light excitation.This technology, used in preclinical oncology in order to quantify the tumor status in a non-invasive way, is still quite recent and for now biologists lack automated processing tools to improve the quantification of images. In addition, some experimental protocols require to extract the photon flux of multiple tumors on the same side of the animal. This can be difficult and can introduce errors and biases as BLI suffers from a lack of robustness because of a variability in vascularization, or hypoxic and necrotic zones within the tumors. In this work, we propose the use of Non-Negative Matrix Factorization to separate the photon flux of different tumors within the same bioluminescence image by leveraging the different pixel-wise temporal patterns. Such spatio-temporal unmixing yields several important challenges that we have tackled. In a first contribution, we use prior knowledge on the appearance of the tumors and show the importance of penalizing the norm of the wavelet coefficients corresponding to the sources estimated during the optimization process to obtain a high spatial consistency of unmixed tumors. In a second contribution we deal with strong heterogeneities within tumors corrupting the separation by presenting a dedicated pipeline for pre-aligning the photon flux of the different pixels. We show that the resulting method is capable of accurately extracting the photon flux of different tumors present within a single bioluminescence image. These algorithms were tested and validated on two real BLI datasets and on one synthetic dataset generated with a bioluminescence image simulator we designed and developed. In a third contribution, we propose a pharmacokinetics model to calibrate the tumor photon flux based on the bioluminescence signal emitted by a muscle. This allows us to extract meaningful physiological parameters from the image like substrate exchange rates. We show that these parameters represent significant features of the tumor state and can be used to improve the quantification of bioluminescence images
Mitchell, Shaneice Renee. "Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1546527486477125.
Texto completoFrumento, Guido. "Preclinical development of adoptive T-cell immunotherapy for EBV-associated diseases using third-party donors". Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8364/.
Texto completoHöglund, Johanna. "On the Use of 76Br-labelled Monoclonal Antibodies for PET : Preclinical Evaluation of Halogenated Antibodies for Diagnosis and Treatment of Cancer". Doctoral thesis, Uppsala University, Department of Oncology, Radiology and Clinical Immunology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1908.
Texto completoRadioactive substances are used in vivo to localize and characterize malignant tumours, generally by scintigraphic methods. In this context positron emission tomography (PET) in combination with radiolabelled monoclonal antibodies (mAbs) may provide a sensitive and specific method for detection of cancer. Individual dose calculations, based on such PET measurements, may be carried out to predict the possible use of mAbs labelled with therapeutic nuclides. The positron emitter 76Br, with a half-life of 16 h, is a well-suited candidate for radiolabelling and PET imaging. One drawback of radiobromine is that bromide, the ultimate catabolite after degradation of brominated mAb, is only tardily excreted from the body and is evenly distributed throughout the extracellular space, thereby increasing the background radioactivity. The aim of this work was to produce 76Br-mAb preparations with high accumulation and retention in tumour tissue together with a quick clearance of 76Br-labelled catabolites. Furthermore, the possibility to use brominated or iodinated mAbs in combination with PET to predict 211At-mAb dosimetry was evaluated.
Monoclonal Abs directed against colorectal cancer were labelled with 76Br using the direct Chloramine-T-method or indirectly by labelling the precursor molecule N-succinimidyl para-(tri-methylstannyl) benzoate with 76Br, which was subsequently conjugated to the mAbs. Monoclonal Ab A33 labelled with 76Br using the two labelling protocols was characterized in vitro and in vivo in a rat tumour xenograft model. The mAb A33 was also labelled with 125I for comparison. In addition, mAb A33 was labelled with 211At, 125I and 76Br using the indirect labelling protocol and the mAb pharmacokinetics was studied in normal rats in order to estimate if data from brominated or iodinated mAb could be used for dosimetry of 211At in healthy organs and tissue.
In conclusion, both direct and indirect labelling resulted in high yields and mAbs with preserved immunoreactivity. In vivo characterization of 76Br-brominated mAb A33 showed that the indirect labelling method makes 76Br-brominated mAb A33 a promising candidate for tumour imaging with PET due to the faster excretion of radiolabelled catabolites compared with direct bromination. Finally, mAb A33 labelled with 76Br and 124/125I can be used to predict the 211At dose of astatinated mAb A33 in most organs given that a correction factor is applied for organs with varying uptake.
Hovstadius, Peter. "Preclinical and Clinical Development of the Novel Cyanoguanidine CHS 828 for Cancer Treatment". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6178.
Texto completoPiggott, Luke. "Investigating the therapeutic potential of cellular FLICE-like inhibitory protein and TRAIL in preclinical models of breast cancer". Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/44561/.
Texto completoRaes, Florian. "Imagerie photoacoustique couplée à l’échographie haute résolution et à la fluorescence infrarouge en oncologie préclinique translationnelle". Thesis, Orléans, 2016. http://www.theses.fr/2016ORLE2082/document.
Texto completoPreclinical imaging has become an unavoidable step for pathophysiological parameters assessments, for the follow up of tumor growth and for the anticancer therapies development. Technological improvements have emerged in recent years, allowing the emergence of new imaging modalities with a high potential for translation into clinical practice. This manuscript presents several approaches by ultrasound imaging, photoacoustics and near infrared fluorescence in order to monitor the cancer pathology. Initially, we focused on the characterization of hypoxia and its longitudinal assessment in various preclinical models of human cancers. Various multimodal imaging strategies were implemented to assess the efficacy of a new therapeutic prodrug allowing the release of an active molecule in the tumor microenvironment on human models of pancreatic, breast and lung tumors. Finally, in a context of translational research, we explored the potential of photoacoustic and near infrared fluorescence imaging to highlight the lymph node invasion by cancer cells implementing minimally invaded sentinel lymph node models. In this work, we have shown the interest in monitoring the tumor hypoxia in onco-pharmacology and highlighted the high potential of photoacoustic imaging for oncology translational approaches. The main limitation is the relatively shallow depth of regions that we can explore, but this point is currently subject to many technological developments. Feasibility studies performed and validation of proof of concept protocols will enable routine exploitation of these new imaging modalities
Ahlgren, Sara. "Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules : Preparation and Preclinical Evaluation". Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-122177.
Texto completoEriksson, Emma. "Preclinical evaluation of immunostimulatory gene therapy for pancreatic cancer". Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330189.
Texto completoBenay, Stephan. "Mise au point des outils analytiques et formels utilisés dans la recherche préclinique en oncologie". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5501.
Texto completoA nonlinear pharmacokinetic-pharmacodynamic model has been devised do simultaneously describe the loss of erlotinib and its effect on the cell growth over time, in order to analyze impedance-based data of erlotinib effect on A431 cells growth in vitro over time. The model non-linearity requiring the use of iterative methods for parameter estimation, several steps of the model identification were studied, and solutions proposed, with application examples to cancer drugs :Choice of the optimization criterion - superiotity of the geometric mean functionnal relationship for non-linear model identification. Real data application : calibration curve of a bevacizumab ELISA quantification experiment.Choice of the most appropriate algorithm for the pharmacokinetic process identification problem. The derivative algorithms perform better. Real data application : simultaneous identification of the 5-fluorouracil and of its main metabolite pharmacokinetic system.Transform of the differential initial continuous-time model in a recursive discrete time model. The transformed model becomes linear with respect to its parameters, allowing straightforward parameter estimation without using any optimization algorithm. It is then also possible to track the parameter variations over time. Real data application : pharmacokinetic model parameter estimation of fotemustine, mitoxantrone and 5-fluorouracil
Sargeant, Aaron Matthew. "Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876.
Texto completoShuang, Wu. "When oncology meets immunology: improving GL261 glioblastoma treatment through cancer-related immunity and MRSI-based non-invasive follow-up of response". Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670857.
Texto completoLos Glioblastomas (GB) son tumores cerebrales invasivos, con mal pronóstico y respuesta pobre a la terapia. Esta tesis pretende mejorar el tratamiento del GB preclínico utilizando la inmunidad relacionada con el cáncer y el seguimiento no invasivo de la respuesta mediante Imagen Espectroscópica de Resonancia Magnética (IERM). El modelo de GB GL261 fue escogido por ser inmunocompetente y adecuado para estudios de terapia. Se investigaron tres estrategias terapéuticas: a) quimioterapia (Temozolamida, TMZ), en protocolo metronómico respetuoso con el sistema inmune (Immune-Enhancing Metronomic Schedule, IMS-TMZ), b) un inhibidor de punto de control inmunológico (Programmed cell death protein 1, anticuerpo anti-PD-1), y c) combinación de TMZ+anti-PD-1 en IMS. Diferentes tipos de daño celular desencadenados por la terapia estimulan la respuesta inmune anti-cáncer. Nuestro objetivo fue, por un lado, inducir daño celular inmunogénico, preservando las células del sistema inmune (IMS-TMZ). Por otro lado, contrarrestar la inmunosupresión en el tumor (anti-PD-1). El protocolo de IMS-TMZ ha mejorado la supervivencia de los ratones con GB GL261, sobrepasando resultados previos del grupo. La terapia con anti-PD-1 fue efectiva en doses elevadas (500/250 μg), aunque diferencias en el volumen tumoral al inicio de la inmunoterapia impactan en su eficacia. La terapia combinada anti-PD-1+TMZ en IMS ha resultado mejor que las terapias por separado. Estos resultados respaldan la participación del sistema inmune en la respuesta a la terapia en GB. Estudios de nuestro grupo con imágenes nosológicas basadas en IERM apuntan a que los cambios en el patrón metabolómico estarían relacionados con la acción del sistema inmune sobre los tumores, actuando como marcador subrogado de respuesta a la terapia. Nos hemos preguntado si los mismos cambios metabolómicos se apreciarían si este sistema fuese aplicado a estrategias de inmunoterapia. Se siguió con dicho sistema la evolución de ratones con tumores GL261 tratados con IMS-TMZ, IMS-anti-PD-1 e IMS-anti-PD-1/TMZ. El protocolo de IMS-TMZ produce oscilación de cambios en el patrón metabolómico, con una frecuencia de 6 días. Dicho comportamiento se ha confirmado en ratones tratados con inmunoterapia, sola o en combinación, sugiriendo que los cambios en el patrón metabolómico son comunes a distintas estrategias terapéuticas, siempre que haya estímulo y atracción del sistema inmune con ataque productivo a las células tumorales. Ello abre el camino para un uso traslacional del biomarcador basado en MRSI para terapia personalizada en pacientes de GB, incluyendo inmunoterapia, para la cual aún no se dispone de biomarcadores no invasivos fiables. La participación del sistema inmune también es respaldada por el porcentaje de animales curados observados en esta tesis (50-100% dependiendo de la terapia), los cuales presentaron memoria inmune contra subsecuentes intentos de generación del mismo tipo de tumor. La resistencia a TMZ es una de las causas del fracaso de la quimioterapia adyuvante en el tratamiento de GB. Hemos investigado el papel de la O6-methylguanine-DNA-methyltransferase (MGMT) y programmed death-ligand 1 (PD-L1) en la quimioresistencia, utilizando western-blot, en tumores que escapan a la terapia IMS-TMZ después de presentar respuesta transitoria. La expresión de PD-L1 se triplica en esos tumores en comparación con controles, indicando que dichos niveles podrían ser relevantes en la resistencia a la TMZ in vivo, teniendo la terapia anti-PD-1 potencial para ‘rescatar’ tumores escapando de la terapia con TMZ. La combinación de oncología e inmunología guiará el camino para una mejorar tanto la eficacia de la terapia como los resultados obtenidos con pacientes de GB.
Glioblastomas (GB) are invasive brain tumours associated with poor prognosis and limited response to therapy. This thesis focused in improving preclinical GB treatment through cancer-related immunity and Magnetic Resonance Spectroscopic Imaging (MRSI)-based non-invasive response follow-up. The GL261 GB was chosen since it is an immunocompetent preclinical model suitable for studying therapies. Three therapeutic strategies have been tested: a) chemotherapy (Temozolomide, TMZ), administered in an Immune-Enhancing Metronomic Schedule (IMS-TMZ), b) immune checkpoint inhibitor (Programmed cell death protein 1, PD-1 antibody) and c) IMS-anti-PD-1/TMZ combination therapy. Anti-tumour immune responses can be stimulated by therapies targeting different aspects of cell damage. We aimed, on one hand, to induce immunogenic tumour cell damage while sparing replicating immune system cells (with IMS-TMZ). On the other hand, we wanted to counteract the immune suppression within the tumour (anti-PD-1 immunotherapy). IMS-TMZ significantly improved survival in GL261 GB-bearing mice in comparison with standard TMZ treatment, confirming and surpassing results reported by our group. Anti-PD-1 monotherapy was effective when applied at high dose (500/250 μg), although care should be taken since results suggest that differences in tumour volume at immunotherapy starting time can have great impact in its efficacy. As expected, the IMS-anti-PD-1/TMZ combination therapy showed a great beneficial effect, with much better therapeutic outcome than monotherapies administration. These results support the fact that the host immune system is clearly involved in GB response processes. Previous studies from our group with MRSI-based nosological images pointed that the metabolomic pattern changes could be linked to host immune system local effects onto tumours, acting as a surrogate biomarker of therapy response. Accordingly, we wondered whether the application of this non-invasive MRSI approach in evaluating immunotherapeutic strategies would reflect the same type of metabolomics changes. Thus, the evolution of GL261-tumor bearing mice treated with IMS-TMZ, IMS-anti-PD-1 and IMS-anti-PD-1/TMZ was evaluated using the same MRSI-based nosological images approach. Results confirmed that the IMS-TMZ protocol consistently produced the expected oscillatory changes in the MRSI metabolomics pattern, with a frequency of ca. 6 days. This oscillatory behaviour was also confirmed in mice treated with immunotherapy both in combination with TMZ and as monotherapy, hinting that the observed spectral pattern changes observed during therapy response are shared by different therapeutic strategies, provided the host immune system is elicited and is able to productively attack tumour cells. This opens the way for a translational use of the MRSI-based biomarker for patient-tailored GB therapy, including immunotherapy, for which reliable non-invasive biomarkers are still missing. The participation of immune system is also supported by the rate of cured animals observed in this thesis (range 50 - 100 % depending on the treatment), which also held long-term immune memory against tumour cell re-challenge. Resistance to TMZ treatment is one of the main reasons for the chemotherapy failure in adjuvant treatment of GB. We investigated the relevance of O6-methylguanine-DNA-methyltransferase (MGMT) and programmed death-ligand 1 (PD-L1) content in chemoresistance, by western-blot (WB) analysis, with special focus on tumours escaping therapy after transient response. Result showed a 3-fold increase in PD-L1 expression in IMS-TMZ relapsing tumours in comparison with control tumours, indicating that PD-L1 can be involved in TMZ resistance for GL261 GB in vivo. Accordingly, anti-PD1 therapy may have potential to ‘rescue’ tumours escaping from TMZ therapy. Appropriate combination of oncology and immunology will pave the way for improving GB treatment and patient outcome.
Desmonts, Cedric. "Apport des technologies TEMP et TEP numériques en médecine nucléaire dans le domaine de l’oncologie clinique et préclinique". Electronic Thesis or Diss., Normandie, 2023. http://www.theses.fr/2023NORMC429.
Texto completoIn recent years, nuclear medicine has undergone significant technological advances with the introduction of digital cameras based on the use of semiconductor detectors. In single-photon emission computed tomography (SPECT), this technology was first introduced on dedicated cardiac CzT cameras. More recently, 360° CzT cameras with extended field-of-view have been developed to enable whole-body tomographic explorations. Similarly, the cameras used in positron emission tomography (PET) have undergone a transition to digital technologies thanks to the use of new SiPM-based detectors. This work has allowed for the evaluation of the performance of these digital SPECT and PET cameras in nuclear medicine, within the field of clinical and preclinical oncology. We have thus demonstrated the improvements in sensitivity, energy resolution, and image contrast achieved through the use of 360° CzT cameras compared to conventional Anger cameras. Additionally, we demonstrated the feasibility of using this type of camera developed for humans, to perform preclinical imaging in small animals. Furthermore, we have evaluated SiPM-based PET cameras using phantoms for potential preclinical applications. We have thus measured performance approaching that obtained with dedicated microPET cameras, enabling simultaneous imaging of four animals, and demonstrated the ability to perform accurate quantification in preclinical oncology
Sensi, Francesca. "Recellularized colorectal patient-derived scaffold as in vitro pre-clinical 3D model for drug screening". Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3423320.
Texto completoLópez, Fauqued Marta. "Preclinical Study of PI3K and BRAF Inhibitors in Malignant Melanoma / Estudio preclínico de inhibidores de PI3K y BRAF en melanoma maligno". Doctoral thesis, Universitat de Barcelona, 2010. http://hdl.handle.net/10803/1040.
Texto completoAlthough PI-103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway was more effective. The combination of the two drugs showed a synergistic effect inhibiting RAS and PI3K pathways and in vitro melanoma cell proliferation in a cell line dependent manner. However, the combined treatment of orthotopic xenographs in immunocompetent FVB mice did not cooperate blocking tumor growth. Surprisingly, the in vivo treatment with PI-103 enhanced tumor growth. Our results also revealed that PI-103 caused immunosuppression inducing thymus atrophy and upregulating the intratumoral transcriptional levels of inmunosuppressors. In addition, PI-103 induced the antiapoptotic BH3 family proteins Mcl-1, Bcl-2 and BclXL, which correlated with the lower apoptotic rate observed within the PI-103 treated tumors.
These data indicates that due to melanoma heterogeneity, some precautions should be taken when using these inhibitors for treatment. Moreover, these results certainly make an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models before conducting clinical studies.
Eberle-Singh, Jaime. "Delineating the function, efficacy, and mechanism of a novel preclinical agent for the treatment of pancreatic ductal adenocarcinoma". Thesis, 2018. https://doi.org/10.7916/D8XK9Z08.
Texto completoBrodeur, Melica. "Predictive carboplatin treatment response models for epithelial ovarian cancer : comparison of 2D, 3D and in-vivo models". Thesis, 2021. http://hdl.handle.net/1866/25659.
Texto completoEpithelial ovarian adenocarcinoma (EOC) is the most lethal gynecological cancer. The drug discovery pipeline is heavily based on preclinical models. Typically, 2D cell line (CL)-based models are used to screen compounds followed by validation in animal models to generate the evidence needed to design clinical trials. This process incurs a high cost to the research pipeline and still results in high drug attrition rates. This may in part reflect the poor translation of preclinical to clinical results and points to deficiencies in modeling. Previous work from our laboratory shows that the sensitivity of our EOC CLs to carboplatin therapy varies between 2D and 3D in vitro models, however it is unclear how these differences align with the in vivo response. We hypothesize that 3D models will more closely reflect therapeutic in vivo response. The objective of this study was to characterize the carboplatin sensitivity of EOC CLs in 2D and 3D-spheroids and compare them to in vivo response using mouse xenografts. We injected mice with 6 different EOC CLs that were treated with 3 different carboplatin concentrations. Tumor volume measurements and immunofluorescence viability stains were used to categorize CLs by their sensitivity. The same CLs were seeded in low attachment plates to form, and thereafter treat, spheroids. Flow cytometry analysis was used to classify CLs by their 50% inhibitory response (IC50). The 2D response (IC50) for these CLs has previously been published. Our results show that therapeutic response changes significantly for a single CL between different systems, and the 3D model was most concordant with the in vivo model. Our ultra-resistant CL in 2D became more sensitive in 3D/mouse models. In contrast, the highly 2D sensitive CL became more resistant in our xenograft/spheroid models. The results are important to consider when investing time/funds in drug screening and therapeutic response prediction studies.
Tsoi, Mayra. "Anti-VEGFA therapy reduces tumor growth and extends survival in a murine model of ovarian granulosa cell tumor". Thèse, 2012. http://hdl.handle.net/1866/9608.
Texto completoOvarian granulosa cell tumors (GCTs) are potentially malignant tumors that have a tendency for late recurrence and cause death in 80% of women with advanced GCT due to recurrent disease. Although GCTs represent 5% of ovarian tumors in women, few studies have evaluated adjuvant treatment protocols for advanced or recurrent disease. Our goal was to determine the potential of targeting the vascular endothelial growth factor A (VEGFA) signaling pathway for the treatment of GCT. We used a genetically engineered mouse model, Ptentm1Hwu/tm1Hwu; Ctnnb1tm1Mmt/+; Amhr2tm3(cre)Bhr/+ (PCA), which imitates the advanced human disease. A monoclonal anti-VEGFA antibody was administered by intra-peritoneal injection once a week beginning at 3 weeks of age. Anti-VEGFA therapy significantly decreased tumor weights by 6 weeks of age (p<0.05) and increased survival in treated animals in comparison to controls. Significant decreases in tumor cell proliferation (p<0.05) and microvessel density (p<0.01), but no significant difference in apoptosis was found in PCA tumors. p44/p42 MAPK, a VEGFA receptor 2 (VEGFR2) signaling effector associated with cell proliferation, was significantly less activated in anti-VEGFA-treated tumors (p<0.05). In contrast, AKT activation, a VEGFR2 signaling effector associated with cell survival was similar among all groups. These results suggest that anti-VEGFA therapy effectively reduces cell proliferation and microvessel density in PCA mice by inhibition of the VEGFR2-MAPK pathway, resulting in inhibition of GCT growth. We conclude that anti-VEGFA therapy merits further investigation in the form of controlled randomized trials for the treatment of human GCT.
GRASSI, LUDOVICA. "Development of preclinical models for Renal Cell Carcinoma". Doctoral thesis, 2018. http://hdl.handle.net/11573/1086689.
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