Global ETD Search

1	Caractérisation de la SERPINA1, une antiprotéase différentiellement exprimée dans le cancer épithélial de l’ovaire Normandin, Karine 12 1900 (has links) Le cancer épithélial de l’ovaire est le cancer gynécologique le plus létal. La survie à 5 ans est de 30-40% chez les patientes atteintes d’une tumeur invasive (TOV), comparativement à 95% chez les patientes diagnostiquées pour une tumeur à faible potentiel de malignité ou borderline (LMP). Au laboratoire, l’analyse de l’expression des gènes de la micropuce à ADN U133 d’Affymetrix a révélé que la SERPINA1 est un gène dont l’expression varie entre les tumeurs LMP et TOV. La validation par Q-PCR nous a confirmé que cette antiprotéase est majoritairement surexprimée dans les tumeurs LMP, par rapport aux tumeurs bénignes (BOV) et aux tumeurs TOV. Nous avons donc surexprimé la SERPINA1 dans les lignées cellulaires invasives TOV 112D et TOV 1946 du cancer de l’ovaire et dérivé des clones stables. Les résultats obtenus nous indiquent que la surexpression de la SERPINA1 a un effet sur la capacité d’invasion et de migration cellulaire et non au niveau de la croissance cellulaire et la formation de structures tridimensionnelles. Les résultats issus de l’étude in vivo dans les souris SCID nous permettront de déterminer si la surexpression de la SERPINA1 a un effet sur la tumorigénèse ovarienne. Ainsi, la SERPINA1 demeure à notre avis un candidat d’intérêt pour tenter de mieux comprendre les différences biologiques entre les tumeurs LMP et TOV, ainsi que le rôle des protéases et de leurs inhibiteurs dans la progression tumorale du cancer de l’ovaire. / Epithelial ovarian cancer is the most lethal gynecologic cancer with a five-year survival rate of 30-40% in patients diagnosed with high-grade invasive disease (TOV). This is in stark contrast to the 95% five-year survival in patients diagnosed with low malignant potential (LMP) disease. It is therefore important to understand the biological differences between LMP and TOV. We have previously identified differential expression of SERPINA1 between serous LMP and TOV tumors through gene expression analysis using Affymetrix U133 DNA microarrays. Expression of this protease inhibitor in the majority of LMP tumors was confirmed and validated by Q-PCR. To study the effects of its overexpression on the invasive potential of ovarian cancer cell lines, SERPINA1 was cloned in the pcDNA3.1+ plasmid and stable clones were derived from two invasive ovarian cancer cell lines, TOV 112D and TOV 1946. Comparisons between clones and controls have shown no SERPINA1-dependent difference in cellular growth or spheroid formation. However, effects on cellular migration and invasion are observed in cells overexpressing SERPINA1. Results from an in vivo xenograft study in SCID mice will allow us to determine if SERPINA1 overexpression affects ovarian tumorigenesis. SERPINA1 remains an interesting candidate gene whose further characterization may lead to insights into its role, and the role of proteases and their inhibitors, in ovarian cancer disease progression. Cancer épithélial de l’ovaire Expression différentielle Tumeur invasive SERPINA1 Inhibiteur de protéase Epithelial ovarian cancer Differential expression Invasive tumor SERPINA1 Protease inhibitor
2	Caractérisation de la SERPINA1, une antiprotéase différentiellement exprimée dans le cancer épithélial de l’ovaire Normandin, Karine 12 1900 (has links) Le cancer épithélial de l’ovaire est le cancer gynécologique le plus létal. La survie à 5 ans est de 30-40% chez les patientes atteintes d’une tumeur invasive (TOV), comparativement à 95% chez les patientes diagnostiquées pour une tumeur à faible potentiel de malignité ou borderline (LMP). Au laboratoire, l’analyse de l’expression des gènes de la micropuce à ADN U133 d’Affymetrix a révélé que la SERPINA1 est un gène dont l’expression varie entre les tumeurs LMP et TOV. La validation par Q-PCR nous a confirmé que cette antiprotéase est majoritairement surexprimée dans les tumeurs LMP, par rapport aux tumeurs bénignes (BOV) et aux tumeurs TOV. Nous avons donc surexprimé la SERPINA1 dans les lignées cellulaires invasives TOV 112D et TOV 1946 du cancer de l’ovaire et dérivé des clones stables. Les résultats obtenus nous indiquent que la surexpression de la SERPINA1 a un effet sur la capacité d’invasion et de migration cellulaire et non au niveau de la croissance cellulaire et la formation de structures tridimensionnelles. Les résultats issus de l’étude in vivo dans les souris SCID nous permettront de déterminer si la surexpression de la SERPINA1 a un effet sur la tumorigénèse ovarienne. Ainsi, la SERPINA1 demeure à notre avis un candidat d’intérêt pour tenter de mieux comprendre les différences biologiques entre les tumeurs LMP et TOV, ainsi que le rôle des protéases et de leurs inhibiteurs dans la progression tumorale du cancer de l’ovaire. / Epithelial ovarian cancer is the most lethal gynecologic cancer with a five-year survival rate of 30-40% in patients diagnosed with high-grade invasive disease (TOV). This is in stark contrast to the 95% five-year survival in patients diagnosed with low malignant potential (LMP) disease. It is therefore important to understand the biological differences between LMP and TOV. We have previously identified differential expression of SERPINA1 between serous LMP and TOV tumors through gene expression analysis using Affymetrix U133 DNA microarrays. Expression of this protease inhibitor in the majority of LMP tumors was confirmed and validated by Q-PCR. To study the effects of its overexpression on the invasive potential of ovarian cancer cell lines, SERPINA1 was cloned in the pcDNA3.1+ plasmid and stable clones were derived from two invasive ovarian cancer cell lines, TOV 112D and TOV 1946. Comparisons between clones and controls have shown no SERPINA1-dependent difference in cellular growth or spheroid formation. However, effects on cellular migration and invasion are observed in cells overexpressing SERPINA1. Results from an in vivo xenograft study in SCID mice will allow us to determine if SERPINA1 overexpression affects ovarian tumorigenesis. SERPINA1 remains an interesting candidate gene whose further characterization may lead to insights into its role, and the role of proteases and their inhibitors, in ovarian cancer disease progression. Cancer épithélial de l’ovaire Expression différentielle Tumeur invasive SERPINA1 Inhibiteur de protéase Epithelial ovarian cancer Differential expression Invasive tumor SERPINA1 Protease inhibitor
3	Proteomic Analysis of Urinary Bladder Cancer : Aiming for Novel Biomarkers Lindén, Mårten January 2013 (has links) Urinary bladder cancer is a heterogeneous disease appearing in different forms, e.g. non-muscle invasive and muscle invasive. For all variants, the expression of proteins is interesting to analyze for diagnostic, predictive, prognostic and drug targeting purposes, since it reflects the altered gene expression causing the cancer. Since urothelial cells of the bladder are in direct contact with urine it is likely that this body fluid contains cancer-related proteins. In Paper I, unbiased analysis of proteins in urine from urinary bladder cancer patients and controls, using label-free quantification by mass spectrometry, was applied and four interesting proteins APOE, FGB, LRG and SERPINA1 were selected and further analyzed with western and dot blot. In Paper II, two more proteins, POLR1E and TOP2A, were validated as relevant proteins in bladder cancer urine. In Paper III and IV, the proteins GAL1 and STMN1 were investigated for their prognostic and therapeutic target potential in bladder cancer. In Paper II, III and IV, the expression of seven of the proteins were analyzed on tissue microarrays representing tumour tissue from 360 patients with different tumour stages. For the proteins identified by the urine screening approach, their protein expressions were confirmed in bladder cancer tissue. The expression level in tissue of five of the proteins, APOE, FGB, POLR1E (Paper II), GAL1 (Paper III) and STMN1 (Paper IV), increased with tumour stage, showing diagnostic relevance and three of the proteins, SERPINA1 (Paper II), STMN1 (Paper IV) and GAL1 (Paper III) had prognostic potential in urinary bladder cancer. In addition, GAL1 and STMN1 were demonstrated to be highly expressed in metastatic disease and inhibition of STMN1 reduced cell growth (Paper III and IV), indicating that these proteins are promising drug targets in urinary bladder cancer. In conclusion, the approach of this thesis has generated several candidate protein biomarkers in urine and tissue, validated with independent methods, which have the potential to improve the care for bladder cancer patients. urine APOE FGB GAL1 LRG1 POLR1E SERPINA1 STMN1 TOP2A biomarker diagnostic biomarker prognostic biomarker predictive biomarker mass spectrometry western blot dot blot immunohistochemistry IHC tissue microarray TMA urothelium antibody antibody-based urinblåsecancer biomarkör diagnos prognos urin proteomik masspektrometri immunohistokemi antikroppar
4	<b>CHARACTERIZATION OF SERPINA1 IN ADULT SPINAL HOMEOSTASIS TO INFORM TREATMENT STRATEGIES</b> Neharika Bhadouria (17266174) 07 December 2023 (has links) <p dir="ltr">People suffering from COPD are also known to suffer from other musculoskeletal issues like fracture risk, back pain, etc. Intervertebral disc degeneration (IVD) is a prominent cause of back pain and inflammation, influenced by factors such as aging, sudden loading, and genetics. <i>SERPINA1</i>, a common genetic variant in individuals with chronic obstructive pulmonary disease (COPD), encodes the alpha-antitrypsin protein (AAT). AAT deficiency is also associated with IVD degeneration, bone loss, and gait impairment. Currently, AAT-deficient individuals receive costly and short-lived weekly AAT injections, with no established guidelines for managing IVD degeneration and osteoporosis. Our primary research objective was to examine the effects of <i>serpinA1a/c</i> using a mouse model with global knockout (KO) of <i>serpinA1a/c</i>, generated through CRISPR technology, on intervertebral discs (IVD) and bone. We found that global deletion of <i>serpinA1a/c</i> was found to cause IVD elastin degradation, leading to a loss of mechanical properties. Moreover, <i>serpinA1</i> was associated with increased bone-resorbing cells (osteoclasts) and a reduction in bone-forming cells (osteoblasts). Notably, sexual dimorphism was observed, with female IVDs exhibiting less degeneration than male counterparts, and <i>serpinA1a/c</i> KO mice were protected from mechanically-induced tail compression. Even in human IVDs, males expressed more AAT-1 compared to female IVDs. There are no FDA-approved drugs currently existing for IVD degeneration. Since IVD degeneration frequently occurs in individuals with osteoporosis, it shows a probable cross-talk happening between IVD and bone. In our study, we found the association of <i>serpinA1 </i>with estrogen receptor alpha and osteoclasts. Hence, we investigated the potential of raloxifene, an FDA-approved selective estrogen receptor modulator (SERM) typically prescribed to post-menopausal women for osteoporosis treatment, in averting IVD degeneration and improving mechanical characteristics in IVD. Our findings suggest that raloxifene injection may retard IVD degeneration induced by AAT deficiency, particularly in male mice. Furthermore, the latter study touched upon a conditional <i>serpinA1a</i> mouse model crossed with aggrecan-cre, specifically targeting <i>serpinA1a</i>-expressing cells in the IVD while sparing bone. Conditional <i>serpinA1a</i> deletion induced mild IVD degeneration without affecting bone loss. In summary, this study serves as a foundation for testing potential treatments for AAT patients with IVD degeneration and osteoporosis. It also provides compelling evidence for considering raloxifene as a treatment option for IVD degeneration in AAT-deficient patients experiencing IVD-related pain.</p> Genetically modified animals Animal structure and function Respiratory diseases Orthopaedics Pain Surgery Biomedical imaging Biomechanics SERPINA1 gene Raloxifene/pharmacokinetic Intervertebraldisc bone intervertebral disc injury Human intervertebral disc discogenic pain genetically modified animals Sex dimorphism aging behavioral assays Magnetic resonance Imaging Chronic obstructive pulmonary disease Spine biomechanics AAT-1 alpha-antitrypsin emphysema crosstalk treatment EVISTA tail disc lumbar disc tail compression FTIR QPCR Gene expression SerpinA1 isoforms lung conditional KO mice Global KO mice

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