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Oguejiofor, Kenneth Kenechukwu. "Prognostic markers in oropharyngeal cancers." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/prognostic-markers-in-oropharyngeal-cancers(fda96224-657d-4049-ae6c-50db33a5388a).html.
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Introduction: Human papillomavirus (HPV) is changing the prevalence, survival and treatment paradigms in oropharyngeal squamous cell carcinoma (OPSCC). Improved survival of patients with HPV positive compared to HPV negative OPSCC has led to trials of treatment de-escalation. Current HPV detection methods are imprecise, therefore standardised assessment of transcriptionally active HPV in OPSCC is required. Furthermore, the differences in immune characteristics and/or the hypoxia response/effects could explain observed differences in prognosis between HPV positive and negative OPSCC. Rigorous HPV detection and subsequent biomarker evaluation should provide additional information required before introduction of treatment de-escalation in broad patient groupings. Methods: The study cohort was 218 patients with OPSCC who received radiotherapy with curative intent. HPV status was determined on pre-treatment, formalin-fixed paraffin-embedded blocks using: 1) polymerase chain reaction (PCR); 2) in-situ hybridisation (ISH) and 3) immuno-histochemistry (IHC). QuantiGene multiplex assay was designed to detect mRNA of reference sequences of the common high-risk HPV types (16, 18, 33, 35, 45, 52 and 58). HPV detection methods were compared with mRNA quantification. Multimarker IHC of immune cell markers using chromogenic and fluorescent staining was performed, analysed and compared with single marker IHC using automated multispectral image analysis. A validated multiplex IHC method was used for a) chromogenic (CD3, CD4, CD8, and FoxP3) and b) fluorescent (CD8, CD68 and PD1/PD-L1) evaluation in tumour and stroma compartments. Single marker IHC was used to investigate tumour hypoxia markers (HIF-1α and CA-IX) in HPV positive and negative OPSCC. Results: p16 IHC and ISH were the most sensitive and specific, respectively, for classifying HPV status. The combination of the three tests had the highest positive/negative predictive values compared with QuantiGene mRNA detection. Multiplex validation showed that, for serial sections up to 6 μm apart, there were highly significant correlations (P<0.0001) between single and multiplex counts for both chromogenic and fluorescent IHC. Overall there was less variation in cell counts with fluorescent staining when compared to chromogenic staining. Multiplex IHC of TILs in HPV positive and negative OPSCC showed higher infiltration in both tumour and stromal areas of CD3+CD4+ and CD3+CD8+ T cells but not CD4+FoxP3 Tregs in HPV positive compared with HPV negative OPSCC. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). PD-L1 expression was higher in HPV negative OPSCC and this was related to macrophage (CD68) expression of PD-L1. In HPV negative tumours infiltration with CD68+PD-L1 was associated with a good prognosis. HPV negative patients had higher expression of HIF-1α but not CA-IX. High expression of both markers was associated with a poor prognosis irrespective of HPV status. Conclusions: There are other prognostic factors operating in the larger subdivision of HPV positive and negative OPSCC. Precise HPV detection and inclusion of other prognostic factors is required before treatment de-escalation is used. Expression of immune inhibitory factors (PD1/PD-L1) alone without contextualisation with immune cell density is insufficient for patient prognostication and potential selection for therapy using immune checkpoint inhibitors. Hypoxia modification of radiotherapy should be explored in both HPV positive and negative OPSCC.
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Blonski, Katharina. "Glycoconjugates as prognostic markers in ovarian cancer." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975965115.
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Salih, Tamir. "Prognostic and predictive markers in oesophageal cancer." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/15196/.
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Douglas, Catriona Mairi. "Prognostic markers in head and neck cancer." Thesis, University of Manchester, 2011. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:130436.
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Purpose: The management of head and neck squamous cell carcinoma (HNSCC) is complex and often involves multimodality treatment. Currently, most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumour biology. The identification of biomarkers that predict response to radiotherapy would be clinically useful in determining optimal management. The purpose of the thesis was to investigate potential biomarkers that might predict radiotherapy outcome in patients with HNSCC. Aims: 1) To investigate the hypoxia-associated biomarkers carbonic anhydrase 9 (CA9) and hypoxia-inducible factor -1α (HIF-1α) in patients with early glottis cancer who underwent radiotherapy as their primary mode of treatment, furthermore to investigate the role of accelerated hypofractionated radiotherapy in the management of T2 glottic cancer. 2) To investigate markers of hypoxia (CA9 and HIF-1α) and viral infection in oropharyngeal cancer, and in particular to test for an association between hypoxia markers and viral infection. 3) To investigate HIF-1 and CA9 in a series of patients undergoing surgery as their primary mode of treatment to explore whether they are associated specifically with radioresponsiveness or a general poor prognosis. Results: 1) Adverse prognostic factors for locoregional control were low pre-treatment haemoglobin (Hb; p = 0.010), advancing T stage (p = 0.001) and high CA9 expression (p = 0.032). Low Hb and high CA9 expression were independent factors on multivariate analysis; and combined predicted locoregional recurrence with an odds ratio of 8.0 (95% CI: 2.7-23.9), or either/or with an odds ratio of 3.3 (95% CI 1.5-7.1). In the subset of T2 patients, five-year locoregional control following radiotherapy was 82% and cancer specific survival was 90%. Serious morbidity occurred in 1.8% of patients. T stage subdivided by vocal cord movement was significant for local control. 2) Features associated with a poor locoregional control were older age (p=0.002), tongue base subsite (p=0.002), heavy alcohol use (p=0.004), heavy smoker (p=0.0002), low Hb level (p=0.001), advancing T (p=<0.0001), N (p=0.001) and AJC (p=0.001) stage, high CA9 expression (p=0.020) and high HIF-1α expression (p<0.0001). In multivariate analysis T stage (p=0.003) and high HIF-1α expression (p=0.001) remained significant. 3) Extracapsular spread was significantly associated with poor cancer specific survival (p=0.022). No other patient variables were associated with outcome. HIF-1α expression was significantly associated with poorly differentiated tumour (p=0.019) and the tumour having a cohesive front (p=0.026). Conclusion: 1) Hb and CA9 have potential to be used together as a biomarker to identify glottis cancer patients with a high probability of a poor outcome following radiotherapy, furthermore, vocal cord movement should be taken into consideration when managing glottis cancer. 2) As it does not appear to be influenced by HPV status, HIF-1α warrants further investigation as a biomarker in oropharyngeal patients treated with primary radiotherapy. 3) As HIF-1α and CA9 had no prognostic significance in patients undergoing surgery, they should be explored further as markers to help guide management decisions in patients with HNSCC.
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Laird, Alexander. "Molecular prognostic markers in renal cell carcinoma." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17873.
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Renal cell carcinoma (RCC) is the most deadly of urological malignancies. While metastatic disease affects one third of patients at diagnosis, a further third of patients who undergo extirpative surgery with curative intent subsequently develop metastatic disease. Inconsistency in the clinical course ensures predicting subsequent metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been proposed to be of prognostic significance; however there are currently no molecular prognostic markers in clinical use. Genetic intra-tumoural heterogeneity (genetic ITH) has been described in clear cell RCC (ccRCC) and may limit the clinical translation of biomarkers. There has been no assessment of ITH at other molecular levels. The aim of this work was to define and compare proteomic, transcriptomic and DNA methylation ITH in ccRCC, and identify potential prognostic biomarkers. Using reverse phase protein arrays to study protein expression in multiple spatially separate regions of primary and metastatic ccRCC, proteomic ITH was demonstrated for the first time. Interestingly there was no significant difference in proteomic ITH in metastatic ccRCC tumour deposits compared to primary tumours. However, on analysis of differential protein expression between primary and metastatic ccRCC tissue using a tissue microarray and automated analysis of immunofluorescence, there was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared to the primary tumours. Subsequent profiling of gene expression and DNA methylation in multiple areas of the same primary tumours confirmed transcriptomic and methylomic ITH. On comparison of this multimolecular ITH, significantly greater proteomic ITH was seen compared to gene expression and DNA promoter methylation heterogeneity. Recent evidence suggests DNA methylation may be prognostically important in RCC and given the lower methylomic ITH in ccRCC, the identification of prognostic DNA methylation changes in ccRCC were pursued using the Infinium HumanMethylation450K Beadchip. Following development of an analysis pipeline, identification and validation of prognostic differentially methylated regions (DMR) was performed on an experimental cohort and published dataset respectively. Five DMRs, which were associated with disease recurrence in ccRCC, were identified. NEFM gene promoter methylation was the only DMR associated with cancer specific survival, independent of TNM stage and nuclear grade on multivariate analysis, which was confirmed on a third independent published dataset. This thesis therefore demonstrates multi-molecular ITH in ccRCC for the first time. Despite this, NEFM promoter methylation may be a useful independent prognostic marker of cancer specific survival.
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Sevov, Marie. "RNA-based Prognostic Markers in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-133250.
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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease where a significant proportion of patients will develop an aggressive disease. Today, the mutational status of the immunoglobulin heavy variable (IGHV) genes is one of the strongest prognostic markers in CLL, where unmutated IGHV genes correlate with poor outcome. In addition, IGHV3-21 gene usage is associated with poor prognosis independent of mutational status. Recently, several genes were shown to be differently expressed between IGHV mutated and unmutated CLL and were suggested as prognostic markers. The aim of this thesis was to examine the applicability of these RNA-based prognostic markers in CLL. In papers I and II, the prognostic significance of LPL and TCL1A mRNA expression in CLL was investigated in 140 and 144 patients, respectively. High expression was found to be associated with inferior clinical outcome for both markers. However, CLL cases with mutated IGHV3-21 genes displayed low levels of LPL expression, indicating that LPL cannot identify this poor-risk patient group. In contrast, high TCL1A expression was detected in all IGHV3-21 cases. To elucidate the functionality of LPL in CLL, LPL lipase activity was measured in 33 cases. The lipase activity was found to be invariably low, implying an alternative function for LPL in CLL. In paper III, a comprehensive analysis of five RNA-based markers (LPL, TCL1A, ZAP70, CLLU1 and MCL1) was performed in 252 CLL patients. All RNA-based markers except MCL1 predicted clinical outcome, with LPL being the strongest. Moreover, LPL expression independently predicted overall survival when adjusted for established markers. All of the RNA-based markers added additional prognostic information to established markers, e.g. high LPL expression predicted an inferior outcome in patients with mutated IGHV genes or good-risk cytogenetics. For clinical application, over time stability of prognostic markers is crucial. In paper IV, the expression of LPL, TCL1A, ZAP70 and MCL1 was investigated in samples taken at diagnosis and at a follow-up of seven years in 104 CLL patients. LPL was found to be the most stable marker, displaying high correlation between the sequential samples, whereas ZAP70 and MCL1 varied significantly. TCL1A expression increased at follow-up, which may indicate disease progression as TCL1A promotes cell survival. In summary, this thesis highlights the applicability of RNA-based markers in CLL prognostication, both as single markers or in combination with established markers. In particular, LPL was shown to be the strongest RNA-based marker in terms of prognostic strength and stability.
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Whiteside, Michael C. R. "Genetic markers for prognostic prediction in colorectal cancer." Thesis, Queen's University Belfast, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387972.
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Kawesha, Anthony. "Prognostic molecular markers in resected ductal pancreatic carcinoma." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7596/.
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Previous studies of molecular prognostic markers following resection for exocrine pancreatic cancer have produced conflicting results. The aim of this study was to undertake a comprehensive analysis of potentially useful markers in a large multicentre patient population and compare these markers with standard pathological prognostic variables. Formalin fixed, paraffin-embedded specimens of pancreatic ductal adenocarcinoma were analysed from 157 patients (100 men and 57 women with a median [range] age of 60 [33-77] years) who had undergone pancreatectomy. Immunhistochemistry was used to detect expression of p16\(^{INK4}\), p53, p21\(^{WAF1}\), cyclin D1, c-erbB-2 and c-erbB-3. In a selected number of p53 positive and negative staining cases, mutational analysis was undertaken using DNA obtained from microdissected specimens. Mutations in codons 12 and 13 of the K-ras oncogene were detected by SSCP and sequencing following DNA extraction and amplification by PCR. The median [range] survival post-resection was 12.5 [3-83] months. Abnormalities of p16\(^{INK4}\), p53, p21\(^{WAF1}\), cyclin D1, c-erbB-2 and c-erbB-3 expression were found in 87%, 41%, 75%, 72%, 33% and 57% of cases, respectively. There was no significant correlation between expression of any of these markers and patient survival. K-ras mutations were found in 73 (75%) out of 97% cases with amplifiable DNA. The presence of K-ras mutation alone did not correlate with survival, but there were significant differences in survival according to the type of K-ras mutation (p=0.0007). Reduced survival was found in patients with GaT, cGT and GcT K-ras mutations compared to GtT, aGT and GaC mutations. In conclusion survival was associated with the type of K-ras mutation but not the expression of p16\(^{INK4}\), p53, p21\(^{WAF1}\), cyclinD1, c-erbB-2 and c-erbB3.
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Martins, Ana Teresa Pinto Teixeira. ""Prognostic Value Of Methilation Markers In Breast Cancer"." Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/20022.
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Bur, H. (Hamid). "Biological prognostic and predictive markers in Hodgkin lymphoma." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526219455.
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Abstract Hodgkin lymphoma (HL) is among a heterogeneous group of lymphomas. Over 80% of all patients can be cured with chemo- and radiotherapy. HL has become a model to study long-term effects of radio- and chemotherapy, because of the excellent prognosis. There are a significant number of patients who suffer or die because of the treatment-related long-term toxicity. The aim of this work was to discover new possible biological factors to predict poor prognosis and offer new aspects to individualize patient treatment in a convenient manner in HL. The retrospective study involved HL patients uniformly treated in 1997–2015. Immunohistochemistry was used to determine the expression of various biological markers, including oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and the antioxidant enzymes manganese superoxide dismutase (MnSOD) as well as peroxiredoxins (Prx II, Prx III, Prx V, Prx VI) in HL patient samples. Using immunohistochemistry, we also evaluated expression of hypoxia-inducible factors (HIF-1α, HIF-2α), prolyl hydroxylase domain enzymes (PHD1, PHD2, PHD3), the epigenetic regulator lysine (K)-specific demethylase 4 (KDM4A, KDM4B, KDM4D) as well as sirtuins (SIRT1, SIRT4, SIRT6), the DNA-repair proteins Human Rap1 interacting factor 1 (Rif1) and O6-alkylguanine DNA alkyltransferase (MGMT) from representative classical Hodgkin lymphoma (cHL) patient samples. Low-level expression of 8-OHdG was associated with poorer relapse-free survival (RFS) in advanced-stage HL and a high extent of MnSOD predicted early relapse in the whole HL cohort. Strong expression of PHD1, KDM4B and KDM4D predicted dismal RFS in radiotherapy-treated cHL patients. The results also showed that strong expression of HIF-1α, SIRT6 and Rif1, and SIRT6 together with Rif1, were associated with prolonged RFS, especially in advanced-stage radiotherapy-treated cHL patients. In multivariate analysis, PHD1, MnSOD, 8-OHdG and Rif1 separately and together with SIRT6 were statistically significant predictors of RFS. The results reflect the significance of the studied biomarkers in HL, especially in radiotherapy-treated patients. This might be beneficial when individualizing treatment strategies, avoiding overtreatment and controlling long-term treatment-related toxicity. Further research, however, is needed to confirm these preliminary findingsTiivistelmä Hodgkinin lymfooma (engl. HL) kuuluu heterogeeniseen imukudossyöpien eli lymfoomen ryhmään. Yli 80 % lymfoomapotilaista voidaan parantaa solunsalpaaja- ja sädehoidon avulla. Hyvän ennusteen takia HL- tutkimuksen tärkeä painopiste on säde- ja solunsalpaajahoidon pitkän ajan haittavaikutukset. Huomattava määrä potilaista kärsii tai jopa kuolee hoitoon liittyvistä pitkäaikaishaitoista johtuen. Tämän tutkimuksen tarkoituksena oli löytää uusia mahdollisia biologisia tekijöitä, jotka ennakoisivat taudin huonoa ennustetta ja samalla antaa uusia näkökulmia HL potilaiden hoidon yksilöllistämiseen. Tämä retrospektiivinen tutkimus käsitti vuosina 1997-2015 samanlaisesti hoidettuja Hodgkinin lymfooma -potilaita. Immunohistokemiallisilla värjäyksillä määritettiin biologisten merkkiaineiden, mukaan lukien oksidatiivisen stressin markkereiden 8- hydroksideoksiguanosiinin (8-OHdG) ja nitrotyrosiinin, sekä antioksidanttientsyymien mangaanisuperoksidi-dismutaasin (MnSOD) sekä peroksiredoksiinien (Prx II, Prx III, Prx V, Prx VI) ilmentymistä HL -potilasnäytteissä. Määrittelimme myös immunohistokemiallisilla värjäyksillä epigeneettisten säätelijöiden lysiinin spesifisen demetylaasientsyymin 4 (KDM4A, KDM4B, KDM4D) sekä sirtuiinien (SIRT1, SIRT4, SIRT6), hypoksiaa indusoivien tekijöiden (HIF-1α, HIF-2α), prolyylihydroksylaasientsyymien (PHD1, PHD2, PHD3) ja DNA:ta korjaavien proteiinien Rap1 vaikuttuvan tekijä 1 (Rif1) ja O6-metyyliguaniini-DNA metyylitransferaasin (MGMT) ilmentymistä edustavissa klassista Hodgkinin lymfoomaa sairastavien potilaiden (engl. cHL) näytteissä. Heikko 8-OHdG värjäytyminen ennusti ennenaikaista taudin uusiutumaa levinneessä HL:ssa ja korkea MnSOD ilmaantuvuus ennusti ennenaikaista taudin uusiutumaa koko HL -ryhmässä. Sädehoidetuilla cHL potilailla voimakas PHD1, KDM4B ja KDM4D värjäytyminen ennusti ennenaikaista taudin uusiutumaa. Tulokset osoittivat myös, että erityisesti sädehoidetuilla levinneen taudin cHL potilailla voimakas HIF-1α, SIRT6, Rif1 ja SIRT6 yhdessä Rif1:n kanssa oli yhteydessä pidentyneeseen uusiutumavapaaseen aikaan. Monimuuttuja-analyysissä PHD1, MnSOD, 8-OHdG ja Rif1 itsenäisenä ja yhdessä SIRT6 kanssa ennustivat tilastollisesti merkitsevästi taudin ennenaikaista uusiutumaa. Tulokset osoittavat näiden eri biomarkkereiden merkittävyyden HL:ssä, erityisesti sädehoitoa saaneilla potilailla. Tuloksista voi olla hyötyä, kun hoitokäytäntöjä yksilöidään, mikä voisi helpottaa välttämään liiallista hoitoa ja hallitsemaan pitkäaikaisiin hoitoihin liittyviä haittoja. Näiden alustavien havaintojen vahvistamiseksi tarvitaan kuitenkin lisätutkimuksia
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Isohookana, J. (Joel). "Emerging novel prognostic markers in pancreatic ductal adenocarcinoma." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220352.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, the 5-year survival rate being less than 5%. At the time of diagnosis, 90% of PDACs extend beyond the pancreas and distant metastases are often present. Due to aggressive growth, local expansion and early appearance of metastasis, primary PDAC tumours are local enough for curative surgical resection in only 10–20% of the cases. Adjuvant chemotherapy is indicated in these curative-treated cases, with slight improvement in survival. PDAC is considered to represent a heterogeneous group of biologically and prognostically different malignancies. Characterization of these subgroups is essential and there is an urgent need for more accurate biomarkers and targeted treatments in PDAC. In the current work, we immunohistochemically investigated the expression levels and prognostic values of oxidative stress markers (8-OHdG, Keap1, Prx I, II, III, V and VI), epigenetic histone modifiers (KDM4A, KDM4B, KDM4D and SIRT1–4), and cell-cycle regulators (p16, Rb, CDK4) and DNA-repair enzymes (FEN1 and MGMT) in the cohort of surgically treated PDAC patients. We found that Keap1 expression was associated with better pancreatic cancer-specific survival. Expression of antioxidative peroxiredoxins I, III, V and VI was also connected with a more favourable tumour characteristics and Prx I and VI showed prognostic value. When considering the biology of PDAC, we noticed that pivotal epigenetic regulation also occurred in exocrine pancreatic tissue adjacent to resection margins. Overexpression of the cell-cycle regulator CDK4 and the DNA-repair enzyme FEN1 in the whole population, and elevated expression level of MGMT in the most high-risk patients were connected with worse prognosis. The results of the study can be utilized in the future when individualized therapies are being designed for PDAC patients. Due to occurrence of the epigenetic regulation also in exocrine pancreatic tissue adjacent to resection margins, it could be evaluated in future for routine diagnostics and treatment optimization. The potential role of MGMT in the development of PDAC chemoresistance should be studied in the futureTiivistelmä Haiman duktaalinen adenokarsinooma (PDAC) on yksi aggressiivisimmista syöpäsairauksista. Viiden vuoden elossaoloennuste on vain lähellä 5 prosenttia. Diagnoosihetkellä 90% haiman adenokarsinoomista yltää haiman ulkopuolelle ja usein kasvain on jo lähettänyt etäpesäkkeitä. Kasvutaipumuksen sekä metastasoinnin takia kuratiivinen kirurginen hoito on mahdollista vain 10–20% tapauksista. Liitännäissolunsalpaajahoito on aiheellista näissä kuratiivistavoitteisesti hoidetuissa tapauksissa. Kuitenkin vaikutus kokonaiselossaoloaikaan on melko vähäinen. Uusimman tutkimustiedon valossa PDAC:aa pidetäänkin heterogeenisenä ryhmänä biologisesti ja ennusteellisesti erilaisia tautiryhmiä. Näiden tautiryhmien tunteminen ja tunnistaminen riittävän tarkkojen merkkiaineiden avulla olisi ensiarvoisen tärkeää, jotta hoitoja voitaisiin kohdentaa niistä hyötyville potilaille. Väitöskirjatutkimuksessa selvitimme immunohistokemiallisin menetelmin oksidatiivisen stressin merkkiaineiden (8-OHdG, Keap1, Prx I, II, III, V ja VI), epigeneettisten histonimodifikaattorien (KDM4A, KDM4B, KDM4D ja SIRT1–4) sekä solusyklin säätelijöiden (p16, Rb, CDK4) ja DNA-korjausentsyymien (FEN1 ja MGMT) ilmentymistä ja ennusteellista arvoa kirurgisesti hoidetuilla PDAC-potilailla. Tutkimuksessamme totesimme, että kasvainkudoksen Keap1-ilmentymä yhdistyi parempiennusteiseen taudinkuvaan. Antioksidatiivisten peroksiredoksiinien I, III, V ja VI ilmentyminen yhdistyi niin ikään suotuisampaan kasvaimen fenotyyppiin ja Prx I ja VI osoittivat ennusteellista arvoa. Havaitsimme lisäksi, että PDAC:n biologiaan keskeistesti vaikuttavaa epigeneettistä säätelyä tapahtuu myös malignin haimakudoksen viereisessä eksokriinisessä haimakudoksessa. Solusyklin säätelijä CDK4:n ja DNA-korjausentsyymi FEN1:n voimakas ilmentyminen koko tutkimuspopulaatiossa sekä kohonnut MGMT:n ilmentyminen korkeimman riskin potilailla yhdistyivät huonompaan taudin ennusteeseen. Väitöskirjatyön tutkimustuloksia voidaan tulevaisuudessa hyödyntää, kun tutkitaan yksilöllisiä hoitomuotoja PDAC-potilailla. Koska epigeneettistä säätelyä tapahtuu myös syövän viereisessä eksokriinisessa haimakudoksessa, voidaan tulevaisuudessa tämän kudoksen arviointia mahdollisesti käyttää rutiinisti diagnostiikassa sekä hoidon optimoinnissa. MGMT:n mahdollinen rooli PDAC:n kemoresistenssin kehittymisessä tulisi tulevaisuudessa selvittää
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Varghese, Robin. "Novel Prognostic Markers and Therapeutic Targets for Glioblastoma." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/71420.
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Glioblastoma is the most common and lethal malignant brain tumor with a survival rate of 14.6 months and a tumor recurrence rate of ninety percent. Two key causes for glioblastomas grim outcome derive from the lack of applicable prognostic markers and effective therapeutic targets. By employing a loss of function RNAi screen in glioblastoma cells we found a list of 20 kinases that can be considered glioblastoma survival kinases. These survival kinases which we term as survival kinase genes, (SKGs) were investigated to find prognostic markers as well as therapeutic targets for glioblastoma. Analyzing these survival kinases in The Cancer Genome Atlas patient database, we found that CDCP1, CDKL5, CSNK1𝜀, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 genes could be used as prognostic markers for glioblastoma with or without temozolomide chemotherapeutic treatment as a covariate. For the first time, we found that patients with increased levels of NEK9 and PIK3CB mRNA expression had a higher probability of recurrent tumors. We also discovered that expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary glioblastoma tumors was associated with tumor recurrence prognosis. To note, of these recurrent prognostic candidates, PIK3CB expression in recurrent tumor tissue had much higher expression compared to primary tissue. Further investigation in the PI3K pathway showed a strong correlation with recurrence rate, days to recurrence and survival emphasizing the role of PIK3CB in tumor recurrence in glioblastoma. In efforts to find effective therapeutic targets for glioblastoma we used SKGs as potential candidates. We chose the serine/threonine kinase, Casein Kinase 1 Epsilon (CSNK1𝜀) as a target for glioblastoma because multiple shRNAs targeted this gene in our loss of function screen and multiple commercially available inhibitors of this gene are available. Casein kinase 1 epsilon protein and mRNA expression were investigated using computational tools. It was revealed that CSNK1𝜀 expression has higher expression in glioblastoma than normal tissue. To further examine this gene we knocked down (KD) or inhibited CSNK1𝜀 in glioblastoma cells lines and noticed a significant increase in cell death without any significant effect on normal cell lines. KD and inhibition of CSNK1𝜀 in cancer stem cells, a culprit of tumor recurrence, also revealed limited self-renewal and proliferation in cancer stem cells and a significant decrease in cell survival without affecting normal stem cells. Further analysis of downstream effects of CSNK1𝜀 knockdown and inhibition indicate a significant increase in the protein expression of β-catenin (CTNNB1). We found that CSNK1𝜀 KD activated β-catenin, which increased GBM cell death, but can be rescued using CTNNB1 shRNA. Our survival kinase screen, computational analyses, patient database analyses and experimental methods contributed to the discovery of novel prognostic markers and therapeutic targets for glioblastoma.Ph. D.
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Martins, Ana Teresa Pinto Teixeira. ""Prognostic Value Of Methilation Markers In Breast Cancer"." Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2008. http://hdl.handle.net/10216/20022.
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Bueno, Marinas Maria. "MicroRNA profiling in Arrhythmogenic Cardiomyopathy and prognostic markers." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3427265.
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Background: Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease, characterised by a progressive myocardial dystrophy with fibro-fatty replacement, and represents one of the major causes of sudden cardiac death in the young and athletes. Although half of AC patients harbour private desmosomal gene mutations, their low and age-dependent penetrance suggests the involvement of other regulatory molecules. MicroRNAs (miRNAs) are a group of endogenous short noncoding RNAs that regulate gene expression by sequence-specific recognition of their target transcripts. They have been associated with numerous pathophysiological conditions, including cardiovascular diseases; however, their role as key regulatory molecules in AC as well as their impact on the onset and progression of the disease is largely unknown.
Purpose: miRNA profiling in genotype-positive AC-patients with different gene mutations in order to identify their potential as AC biomarkers.
Methods: The study involved 59 subjects with a definite AC diagnosis, previously genotyped, and 14 healthy controls. 84-miRNA array was applied on 8 frozen right-ventricle (RV) myocardial tissue samples, from heart transplanted AC patients; 9 whole blood samples, from patients with definite AC diagnosis, and 6 healthy controls (HC). In the validation study, seven miRNAs were analysed on 42-AC and 8-HC blood samples. miRNA analysis was performed by qPCR, relative quantification ΔΔCt method and in silico target prediction. All data were expressed in fold-change values. Receiver operating characteristic (ROC) analysis was performed on validated miRNAs.
Results: miRNA profiling on AC-tissue samples displayed a genotype-related profile, 19 miRNAs were differentially expressed in PKP2 carriers, 15 in DSP carriers and 14 in DSG2 carriers, when compared to healthy controls. A common signature between PKP2 and DSP carriers was identified with 14 miRNAs in common (PKP2/DSP profile). None of these miRNAs were shown within DSG2 profile. In silico target prediction identified Hippo Signaling Pathway as a common target for both profiles. Analysis of AC-tissue samples as a unique group confirmed 26 differentially expressed miRNAs (AC-tissue profile) with predicted targets in the AC pathway. AC-blood miRNA profiling demonstrated a 14-miRNA signature, with 10 miRNAs differentially expressed in common with AC-tissue profile. Hsa-miR-144-3p, -122-5p, -208a-3p and -494-3p as well as hsa-miR-21-5p, -155-5p and -320a were analysed on a larger cohort of 42-AC and 8-HC. Only hsa-mir-122-5p was significantly overexpressed (p-value<0,05). ROC analysis showed hsa-miR-122-5p to be a potential AC biomarker (area under the curve: 0.83).
Conclusions: A genotype-related miRNA profile was observed in AC-tissue samples, as to reflect clinical variability. In addition, 10 miRNAs in common were identified between AC-tissue and AC-blood profiles, proving a specific miRNA signature for AC. These miRNA profiles targeted pathways involved in AC pathogenesis demonstrating their key roles in the onset and progression of the disease. Circulating level of hsa-miR-122-5p was significantly elevated in AC subjects, demonstrating its potential as a prognostic marker for heart failure in AC.Introduzione. La Cardiomiopatia Aritmogena (AC) è una malattia clinicamente e geneticamente eterogenea del miocardio, caratterizzata da una progressiva distrofia miocardica con sostituzione fibro-adiposa, e rappresenta una delle principali cause di morte improvvisa nei giovani e negli atleti. Nonostante circa la metà dei pazienti affetti da AC presentino mutazioni nei geni desmosomiali, la bassa penetranza e dipendenza dall’età della patologia suggeriscono il coinvolgimento di altre molecole regolatrici. I microRNA (miRNA) sono un gruppo di molecole endogene, di RNA non codificante, che regolano l'espressione genica mediante lo specifico riconoscimento di sequenze target dei trascritti. Sono stati associati a numerose condizioni patofisiologiche, tra cui malattie cardiovascolari; tuttavia, il loro ruolo come molecole regolatrici nella AC e il loro impatto sull'insorgenza e sulla progressione della malattia è in gran parte sconosciuto. Scopo dello studio. Analizzare il profilo di espressione dei miRNA in pazienti affetti da AC genotipicamente positivi allo scopo di studiare il loro potenziale come biomarcatori prognostici. Materiali e metodi. Lo studio ha coinvolto 59 soggetti con una diagnosi clinica di AC, precedentemente genotipizzati, e 14 controlli sani (HC). Un array composto da 84-miRNA è stato testato su: 8 campioni di tessuto miocardico congelato del ventricolo destro, proveniente da pazienti trapiantati affetti da AC; 9 campioni di sangue intero congelato, da pazienti con diagnosi clinica di AC e 6 controlli sani. Nella fase di validazione sono stati analizzati sette miRNA su campioni di sangue provenienti da 42-AC e 8-HC. L'analisi è stata eseguita mediante qPCR seguita da quantificazione relativa con il metodo ΔΔCt e predizione in silico dei geni target. I risultati sono stati espressi in valori di “fold-change” e le curve ROC (Receiver Operating Characteristic) analizzate sui miRNA validati. Risultati. L’analisi dei miRNA su 8 campioni di tessuto di pazienti affetti da AC mostrava un profilo correlato al genotipo rispetto ai controlli sani, in particolare: 19 miRNA erano differenzialmente espressi nei portatori di una mutazione in PKP2, 15 nei portatori di una mutazioni in DSP e 14 nei portatori di una mutazione in DSG2. E’ stato identificato un profilo d’espressione in comune tra i portatori della mutazione in PKP2 e i portatori della mutazione in DSP, con 14 miRNA alterati (profilo PKP2/DSP). Nessuno di questi miRNA è stato trovato nel profilo DSG2. Lo studio in silico dei possibili geni target ha identificato la via di segnale “Hippo Signaling Pathway” come target comune per entrambi i profili (PKP2/DSP- DSG2). Considerando i campioni di tessuto AC come un unico gruppo indipendentemente dal gene mutato sono emersi 26 miRNA differenzialmente espressi (profilo AC-tessuto) che hanno come target geni coinvolti nel pathway AC. Lo studio dei miRNA nei 9 campioni di sangue dei pazienti affetti da AC ha dimostrato un profilo costituito 14-miRNA alterati, dei quali 10 alterati anche nel profilo AC-tessuto. Hsa-miR-144-3p, -122-5p, -208a-3p e -494-3p così come hsa-miR-21-5p, -155-5p e -320a sono stati infine validati su una coorte più ampia di 42-AC e 8-HC. Solo hsa-mir-122-5p è stato riscontrato come significativamente sovraespresso (valore p <0,05). L'analisi di curve ROC ha mostrato che hsa-miR-122-5p è un potenziale biomarcatore di AC (AUC: 0.83). Conclusione. Nei campioni AC di tessuto è stato osservato un profilo di miRNA correlato al genotipo, tale da rispecchiare la variabilità clinica della patologia. Inoltre, sono stati identificati 10 miRNA in comune tra i profili dei campioni AC di tessuto e sangue, evidenziando un profilo di espressione di miRNA specifico per AC. Entrambi i profili infatti (tessuto e sangue) hanno come target vie di segnale coinvolte nella patogenesi della AC, dimostrando un ruolo chiave nella insorgenza e la progressione della malattia. In particolare il livello di hsa-miR-122-5p in circolo era significativamente elevato nei soggetti affetti da AC, dimostrando il suo potenziale come marcatore prognostico della malattia.
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Sabnis, Durgagauri. "An investigation of druggable prognostic markers in paediatric ependymoma." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33243/.
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Background: Paediatric ependymomas are the second most common malignant brain tumours in children. Tumour recurrence, chemoresistance and invasion of surrounding critical structures are the hallmarks of ependymomas. These features are consistent with the cancer stem cell (CSC) hypothesis which states that tumours harbour a sub-population of stem-like cells which underlie therapeutic resistance. This study investigates the role of the radial glial stem cell marker BLBP, the multidrug transporter ABCB1, and the DNA repair enzyme MGMT in therapy failure in ependymomas with particular emphasis on the role of CSCs. Material and Methods: Database analyses were performed to assess the expression of the aforementioned markers in patients from 3 publicly available gene expression datasets. Furthermore, samples from 2 European paediatric ependymoma trial cohorts were screened for ABCB1, BLBP and MGMT expression by immunohistochemistry to elucidate their prognostic value. The expression of these markers was also determined in a panel of 5 ependymoma derived cell lines by QRT-PCR or western blotting analysis. Roles in chemoresistance (clonogenic & cytotoxicity assays) and tumour invasion (wound healing & 3D invasion assay) were then investigated. Results: Poor survival in the chemotherapy-led paediatric ependymoma CNS9204 trial was significantly associated with ABCB1 (P=0.007) and BLBP (P=0.03) expression whilst MGMT (P<0.001) and BLBP (P=0.002) expression predicted poor survival in the radiotherapy-led CNS9904 trial cohort. ABCB1 and BLBP expression was consistent with the CSC hypothesis whilst MGMT was expressed in both CSCs as well as the tumour bulk. Inhibition of ABCB1 and BLBP, with the phosphodiesterase-5 inhibitor vardenafil and PPAR-ϒ antagonist GW9662 respectively, potentiated response to chemotherapy and also inhibited the ability of ependymoma cell lines to migrate and invade. Finally, whilst each of the tested cell lines were resistant to the alkylating agent temozolomide, they were sensitive to the novel N3-propargyl analogue of temozolomide. Conclusion: ABCB1, BLBP and MGMT were not only markers of robust prognostic value but they also contributed functionally to the aggressive behaviour of ependymoma. Inhibition of ABCB1 and BLBP by vardenafil and GW9662 may represent effective approaches to overcome chemoresistance and invasion in ependymoma patients. The N3-propargyl analogue of temozolomide could also represent a novel treatment option for MGMT expressing ependymoma patients.
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Al-Khalili, Faris. "Coronary heart disease in women : diagnostic and prognostic markers /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4092-4/.
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Chiu, Kam-hung, and 趙錦鴻. "Genetic aberrations in chronic lymphocytic leukaemia as prognostic markers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290781.
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Chen, Dong. "Identification of new prognostic markers in renal cell carcinoma." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168397.
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The clinical course of renal cell carcinoma (RCC) shows a high variability. Prognostic markers are essential to enable an individualized therapeutic strategy. The objective of this study was the identification of novel independent prognostic markers and potential therapeutic targets in RCC. The focus was on genes involved in epithelial-mesenchymal transition (EMT) and cancer stem cell biology.
EMT enhances tumor cell motility and hence plays a critical role in invasion and metastasis in various carcinomas. A set of transcription factors acts as master regulators of EMT. Whether EMT is important for tumor progression in clear cell renal cell carcinoma (RCC) is unknown. Therefore, EMT-related genes were selected from the literature, and their role and prognostic relevance in RCC were analyzed. The known cancer stem cell marker CXCR4 and the associated TPBG gene were also analyzed in this project. Additionally, a novel filter strategy was used to analyze RCC oligonucleotide microarray data for identification of potential prognostic markers: genes with increasing expression during tumor progression (normal kidney < primary tumor < metastases) were selected for outcome analysis because they could be crucial for RCC biology.
Expression of 46 EMT-related genes was analyzed using oligonucleotide microarrays and gene set enrichment analysis (GSEA) in tissue samples from normal kidney and G1 and G3 primary RCC, 14 samples each. Expression of selected EMT genes was validated by real-time polymerase chain reaction (PCR) in normal kidney, primary RCC and metastases in an independent cohort of 112 patients and then combined with follow-up data for survival analysis. Immunohistochemistry, Western blot and flow cytometry were performed to further examine the expression of CXCR4 and co-expression of CXCR4 and TPBG on the surface of RCC cells. GSEA and dChip software were used for microarray data analysis.
The EMT gene set was preferentially expressed in primary tumors compared to normal tissue (false discovery rate FDR=0.01), but no difference between G1 and G3 tumors was found. Quantitative RT-PCR showed down-regulation of critical EMT genes like CDH2 and ZEB1 in metastases which suggests reversal of EMT during metastasis. Kaplan-Meier analysis demonstrated a significant better outcome for patients with low CXCR4, vimentin, fibronectin and TWIST1 mRNA levels. Multivariate analysis revealed that CXCR4 and vimentin up-regulation represent independent prognostic markers for poor cancer-specific survival of RCC patients. The microarray approach using filtering and further RT-PCR validation of progression-associated genes revealed that ATAD2, TET3, HELLS and TOP2A are independent and previously unknown predictors of poor outcome in RCC patients.
Taken together, this study provides strong evidence that EMT occurs in RCC. Modulation of EMT in RCC, therefore, might represent a future therapeutic option. Expression levels of a number of EMT-related genes (like the genes encoding the cancer stem cell marker CXCR4 and vimentin) could be identified as independent prognostic markers. Using a novel filtering approach on array data, additional novel prognostic markers could be identified. These findings contribute to a better risk stratification of RCC patients that can support an individualized and optimized therapeutic strategy.Der klinische Verlauf des Nierenzellkarzinoms (RCC) zeigt eine hohe Variabilität. Prognostische Marker sind unerlässlich, um eine individuelle Therapiestrategie zu ermöglichen. Das Ziel dieser Studie war die Identifizierung neuer unabhängiger prognostischer Marker und potentieller therapeutischer Targets beim RCC. Der Schwerpunkt lag auf Genen, die bei der Epithelial-Mesenchymalen Transition (EMT) und Tumorstammzellenbiologie beteiligt sind. EMT steigert die Beweglichkeit von Tumorzellen und spielt eine entscheidende Rolle bei der Invasion und Metastasierung bei verschiedenen Karzinomen. Eine Reihe von Transkriptionsfaktoren fungiert als die Hauptregulatoren von EMT. Ob EMT wichtig ist für die Tumorprogression beim klarzelligen Nierenzellkarzinom (RCC), ist unbekannt. Daher wurden EMT-Gene aus der Literatur ausgewählt und ihre Rolle und prognostische Relevanz bei RCC wurden analysiert. Der bekannte Tumorstammzellmarker CXCR4 und das damit assoziierte TPBG-Gen wurden auch in diesem Projekt analysiert. Zusätzlich wurde eine neuartige Filter-Strategie bei RCC-Microarray-Daten verwendet, um mögliche prognostische Marker zu identifizieren: Gene mit zunehmender Expression während der Tumorprogression (normale Niere < Primärtumor < Metastasen) wurden für die Outcome-Analyse ausgewählt, weil sie entscheidend für die RCC-Biologie sein könnten. Die Expression von 46 EMT-Genen wurde mit Oligonukleotid-Microarrays und Gene Set Enrichment Analysis (GSEA) an Gewebeproben von normaler Niere und G1 und G3 Primärtumoren (jeweils 14 Proben) analysiert. Die Expression von ausgewählten EMT-Genen wurde mittels RT-PCR in normaler Niere, primärem RCC und Metastasen an einer unabhängigen Kohorte von 112 Patienten validiert und dann mit Follow-up-Daten für die Survivalanalyse kombiniert. Immunhistochemie, Western Blot und Durchflusszytometrie wurden durchgeführt, um die Expression von CXCR4 und die Co-Expression von CXCR4 und TPBG auf der Oberfläche von RCC-Zellen weiter zu untersuchen. Die Software GSEA und dChip wurde für die Analyse der Microarray-Daten verwendet. Das EMT-gene set wurde bevorzugt in Primärtumoren exprimiert, verglichen mit dem Normalgewebe (false discovery rate FDR = 0,01), es wurde aber kein Unterschied zwischen G1- und G3-Tumoren gefunden. Quantitative RT-PCR zeigte Herunterregulation von kritischen EMT-Genen wie CDH2 und ZEB1 in Metastasen, was eine Umkehrung der EMT während der Metastasierung vermuten lässt. Die Kaplan-Meier-Analyse zeigte signifikant bessere Ergebnisse für die Patienten mit niedriger CXCR4, Vimentin, Fibronectin und TWIST1 mRNA Expression. Die multivariate Analyse zeigte, dass eine Hochregulierung von CXCR4 und Vimentin unabhängige prognostischer Marker darstellen für ein schlechtes tumorspezifisches Überleben von RCC-Patienten. Der Microarray-Ansatz mit Filtern und weiterer RT-PCR-Validierung der Progressions-assoziierten Gene ergab, dass ATAD2, TET3, HELLS und TOP2A unabhängige und bisher unbekannte Prädiktoren für schlechtes Outcome bei RCC-Patienten sind. Insgesamt liefert diese Studie deutliche Hinweise, dass EMT bei RCC vorkommt. Die Modulation von EMT bei RCC könnte daher eine zukünftige therapeutische Option darstellen. Die Expressionsstärke einiger EMT-Gene (z.B. die Gene für den Tumorstammzellmarker CXCR4 und Vimentin) konnten als unabhängige prognostische Marker identifiziert werden. Mit Hilfe eines neuartigen Filter-Ansatzes bei Array-Daten konnten zusätzliche neue prognostische Marker identifiziert werden. Diese Ergebnisse tragen bei zu einer besseren Risikostratifizierung von RCC-Patienten, was eine individualisierte und optimierte Therapiestrategie unterstützen kann.
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Chiu, Kam-hung. "Genetic aberrations in chronic lymphocytic leukaemia as prognostic markers." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290781.
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Bhoi, Sujata. "Prognostic markers and DNA methylation profiling in lymphoid malignancies." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328616.
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In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We validated the signature as an independent marker in multivariate analysis and further reported that subset #2 cases were predominantly classified as i-CLL, although displaying a similar outcome as n-CLL. In paper III, we investigated the methylation status and expression level of miR26A1 in both CLL (n=70) and MCL (n=65) cohorts. High miR26A1 methylation was associated with IGHV-unmutated (U-CLL) and shorter overall survival (OS) in CLL, while it was uniformly hypermethylated in MCL. Furthermore, overexpression of miR26A1 resulted in significant downregulation of EZH2 that in turn led to increased apoptosis. In paper IV, we performed DNA methylation profiling in 176 CLL cases assigned to one of 8 major stereotyped subsets (#1-8) in relation to non-subset CLL (n=325) and different normal B-cell subpopulations. Principal component analysis of subset vs. non-subset CLL revealed that U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL, respectively, indicating common cellular origins. In contrast, subset #2 emerged as the first defined member of the i-CLL subgroup, which in turn alludes to a distinct cellular origin for subset #2 and i-CLL patients. Altogether, this thesis confirms the prognostic significance of RNA and epigenetic-based markers in CLL, provides insight into the mechanism of miRNA deregulation in lymphoid malignancies and further unravels the DNA methylation landscape in stereotyped subsets of CLL.
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Ambrosini, Spaltro Andrea <1978>. "Immunohistochemical and Molecular Prognostic/Predictive Markers in Neoplastic Diseases." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4309/1/ambrosinispaltro_andrea_tesi.pdf.
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Traditional morphological examinations are not anymore sufficient for a complete evaluation of tumoral tissue and the use of neoplastic markers is of utmost importance. Neoplastic markers can be classified in: diagnostic, prognostic and predictive markers. Three markers were analyzed.
1) Insulin-like growth factor binding protein 2 (IGFBP2) was immunohistochemically examined in prostatic tissues: 40 radical prostatectomies from hormonally untreated patients with their preoperative biopsies, 10 radical prostatectomies from patients under complete androgen ablation before surgery and 10 simple prostatectomies from patients with bladder outlet obstruction. Results were compared with α-methylacyl-CoA racemase (AMACR). IGFBP2 was expressed in the cytoplasm of untreated adenocarcinomas and, to a lesser extent, in HG-PIN; the expression was markedly lower in patients after complete androgen ablation. AMACR was similarly expressed in both adenocarcinoma and HG-PIN, the level being similar in both lesions; the expression was slightly lower in patients after complete androgen ablation.
IGFBP2 may be used a diagnostic marker of prostatic adenocarcinomas.
2) Heparan surface proteoglycan immunohistochemical expression was examined in 150 oral squamous cell carcinomas. Follow up information was available in 93 patients (range: 6-34 months, mean: 19±7). After surgery, chemotherapy was performed in 8 patients and radiotherapy in 61 patients. Multivariate and univariate overall survival analyses showed that high expression of syndecan-1 (SYN-1) was associated with a poor prognosis. In patients treated with radiotherapy, such association was higher.
SYN-1 is a prognostic marker in oral squamous cell carcinomas; it may also represent a predictive factor for responsiveness to radiotherapy.
3) EGFR was studied in 33 pulmonary adenocarcinomas with traditional DNA sequencing methods and with two mutation-specific antibodies. Overall, the two antibodies had 61.1% sensitivity and 100% specificity in detecting EGFR mutations.
EGFR mutation-specific antibodies may represent a predictive marker to identify patients candidate to tyrosine kinase inhibitors therapy.
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Ambrosini, Spaltro Andrea <1978>. "Immunohistochemical and Molecular Prognostic/Predictive Markers in Neoplastic Diseases." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4309/.
Full textAbstract:
Traditional morphological examinations are not anymore sufficient for a complete evaluation of tumoral tissue and the use of neoplastic markers is of utmost importance. Neoplastic markers can be classified in: diagnostic, prognostic and predictive markers. Three markers were analyzed.
1) Insulin-like growth factor binding protein 2 (IGFBP2) was immunohistochemically examined in prostatic tissues: 40 radical prostatectomies from hormonally untreated patients with their preoperative biopsies, 10 radical prostatectomies from patients under complete androgen ablation before surgery and 10 simple prostatectomies from patients with bladder outlet obstruction. Results were compared with α-methylacyl-CoA racemase (AMACR). IGFBP2 was expressed in the cytoplasm of untreated adenocarcinomas and, to a lesser extent, in HG-PIN; the expression was markedly lower in patients after complete androgen ablation. AMACR was similarly expressed in both adenocarcinoma and HG-PIN, the level being similar in both lesions; the expression was slightly lower in patients after complete androgen ablation.
IGFBP2 may be used a diagnostic marker of prostatic adenocarcinomas.
2) Heparan surface proteoglycan immunohistochemical expression was examined in 150 oral squamous cell carcinomas. Follow up information was available in 93 patients (range: 6-34 months, mean: 19±7). After surgery, chemotherapy was performed in 8 patients and radiotherapy in 61 patients. Multivariate and univariate overall survival analyses showed that high expression of syndecan-1 (SYN-1) was associated with a poor prognosis. In patients treated with radiotherapy, such association was higher.
SYN-1 is a prognostic marker in oral squamous cell carcinomas; it may also represent a predictive factor for responsiveness to radiotherapy.
3) EGFR was studied in 33 pulmonary adenocarcinomas with traditional DNA sequencing methods and with two mutation-specific antibodies. Overall, the two antibodies had 61.1% sensitivity and 100% specificity in detecting EGFR mutations.
EGFR mutation-specific antibodies may represent a predictive marker to identify patients candidate to tyrosine kinase inhibitors therapy.
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Bartrolí, Comellas Mariona. "Prognostic markers and therapeutic targets for metastatic renal cell carcinoma." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664198.
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Targeting cancer metastasis has gained considerable importance in the recent years when aiming to increase patients’ overall survival. In Renal Cell Carcinoma (RCC), the discovery of metastatic biomarkers and targets is still required, as most patients present metastatic disease at the time of diagnosis.
Therefore, the aim of this thesis is the discovery of new biomarkers and targets of metastatic RCC using two variants of a patient-derived orthoxenograft (PDOX) animal model of clear cell RCC (ccRCC). Indeed, PDOX models have recently gained significant relevance for studying the progression of cancer and metastasis, due to their better mimicking of the histology, the metastatic capacity and treatment responses of human cancers. To this purpose, previous results had sequenced the two variants of this PDOX model, both at DNA and at RNA level, and had performed a FISH analysis.
Firstly, Carboxypeptidase E (CPE), which was one of the highest expressed genes in the metastatic variant, has demonstrated to play a role in invasion when it is secreted to the medium, even though its overexpression alone is not sufficient to generate metastasis in vivo. In addition, it has showed a clear association to ccRCC and an inverse correlation with the overall survival of these patients. Secondly, we have studied two molecules of the coagulation pathway due to its relevance as one of the most upregulated pathways at RNA level. On the one hand, Factor XIII (FXIII or F13) has shown to be related to CPE in vivo, despite the overexpression of both molecules is not sufficient to develop all the metastatic cascade. However, it also affects the overall survival of ccRCC patients, highlighting these two molecules as possible biomarkers for this type of cancer. On the other hand, Coagulation Factor II Thrombin Receptor (F2R or PAR1) has demonstrated to play a role in metastasis, since its inhibition reduces both the early and late phases of this process. With the use of F2R inhibitors and the clinical association of the coagulation pathway to worse prognosis, this thesis opens new opportunities for the treatment of metastasis and cancer malignization.
In summary, we have discovered new metastatic biomarkers and targets which, together with further validations, especially in the clinical setting, are proposed to be useful for RCC patients in the future.Recentment, l’estudi de la metàstasi ha guanyat importància amb l’objectiu d’augmentar la supervivència dels pacients amb càncer. En el càncer renal (RCC), el descobriment de biomarcadors metastàtics i dianes terapèutiques és necessari degut a que la majoria de pacients presenten metàstasi en el moment del diagnòstic. L’objectiu d’aquesta tesi ha estat el descobriment de nous biomarcadors i dianes terapèutiques pel càncer renal metastàtic a través de dues variants d’un model animal orthoxenograft (PDOX) de RCC de cèl·lula clara (ccRCC). Els models PDOX han guanyat molta importància en l’estudi de la progressió del càncer i la metàstasi, ja que mimetitzen la histologia, la capacitat metastàtica i la resposta als tractaments. Prèviament, s’havien seqüenciat les dues variants d’aquest model PDOX tant a nivell de DNA com de RNA, juntament amb un anàlisi FISH. En primer lloc, la Carbxoxipeptidasa E (CPE), un dels gens més expressats en la variant metastàtica, ha demostrat ser important en la invasió quan és secretada al medi, tot i no ser suficient per generar metàstasi in vivo. A més, s’ha associat amb el ccRCC i anti-correlacionat amb la supervivència d’aquests pacients. En segon lloc, hem estudiat dues molècules de la cascada de coagulació, una de les més alterades en nivells de RNA. Hem demostrat que el Factor XIII (FXIII o F13) està relacionat amb CPE in vivo, malgrat que l’expressió de les dues molècules no és suficient per a que es desenvolupi la metàstasi. Tot i així, el F13 afecta la supervivència de pacients amb ccRCC, suggerint aquestes dues molècules com a possibles biomarcadors d’aquest tipus de càncer. A més, la inhibició del Receptor del Factor de Coagulació II (F2R) ha demostrat reduir les fases inicials i finals del procés metastàtic. Així doncs, l’ús d’inhibidors de F2R, juntament amb el fet que la cascada de coagulació es relaciona amb el pronòstic dels pacients, fa que aquesta tesi obri noves oportunitats per al tractament de la metàstasi i la malignització del càncer. En resum, hem descobert nous biomarcadors i dianes terapèutiques que, juntament amb futures validacions, sobretot en clínica, poden ser útils per als pacients metastàtics de ccRCC.
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Bin, Kaderi Mohamed Arifin. "Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Hematologi och immunologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110371.
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The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
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Laatio, L. (Liisa). "In search of new prognostic molecular markers in ovarian cancer." Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514298349.
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Abstract Ovarian cancer is the leading cause of death from gynaecological cancers in the Western world. Ovarian cancer comprises of tumours with distinct behaviour and individually different responses to chemotherapy, even within the same histology. Unfortunately, there are no molecular markers in clinical use to either distinguish between patients with better and worse prognosis or to predict individual chemosensitivity. The comprehension of the molecular effects of chemotherapeutic drugs is a prerequisite for finding predictive molecular factors for chemoresponse and prognosis. Some proteins in molecular pathways contributing to DNA damage response, angiogenesis and oxidative stress have been implicated in ovarian cancer prognosis. In this study, the responses in p53 pathway and among angiogenesis-related factors to chemotherapeutic drugs were analysed in ovarian cancer cell lines. In OVCAR-3 cells with mutated p53, cisplatin but not docetaxel induced p14ARF, an important regulator of p53, at mRNA and protein level. Cisplatin also significantly increased the mRNA expression of angiogenesis-related factors TSP-1, BMP-4, ET-1 and PlGF-2 while an equivalent dose of docetaxel had only minor effects. In clinical ovarian carcinomas, the expression of BMP-4, TSP-1 and CD105 as well as the marker of oxidative stress derived DNA damage, 8-OHdG, and peroxiredoxin antioxidants were analysed by immunohistochemistry. High expression of BMP-4 and cytoplasmic peroxiredoxin IV were associated with better prognosis, while high 8-OHdG expression associated with shorter survival. Explant cultures of fresh ovarian tumour tissue were used for the evaluation of individual responses of p53 and Hdm2 after in vitro treatments of the explant cultures by carboplatin or docetaxel. Major differences between the individual tumours were found, especially in the responses of p53 to carboplatin. The results of this study suggest, that BMP-4, 8-OHdG and peroxiredoxin IV may serve as prognostic markers in ovarian cancer. The differences shown in the molecular responses to platinum and taxane drugs may have value in tailoring individual chemotherapy. Also, fresh ovarian cancer tissue explant culture is worth further studies as a predictive method for analysing individual tumour responses for chemotherapeutic agentsTiivistelmä Munasarjasyöpä on suurinta kuolleisuutta aiheuttava gynekologinen syöpä läntisessä maailmassa. Munasarjakasvaimet eroavat toisistaan niin käyttäytymiseltään kuin yksilölliseltä sytostaattihoitovasteeltaan, jopa sama histologisen tyypin sisällä. Kliinisessä käytössä ei valitettavasti ole sellaisia molekulaarisia merkkiaineita, jotka erottaisivat toisistaan paremman ja huonomman ennusteen kasvaimet tai ennustaisivat yksilöllistä solunsalpaajaherkkyyttä. Hoitovastetta ja potilaan prognoosia ennustavien merkkiaineiden löytämisen edellytys on kemoterapian molekyylitason vaikutusten ymmärtäminen. DNA vaurion tunnistamiseen, angiogeneesiin ja oksidatiiviseen stressiin liittyvien vaikutusreittien joillakin proteiineilla on ehdotettu olevan ennusteellista merkitystä munasarjasyövässä. Tässä väitöskirjatyössä analysoitiin munasarjasyöpäsoluja käyttäen p53 vaikutusreitin ja eräiden angiogeneesiin liittyvien tekijöiden vasteita sytostaateille. Mutatoitunutta p53 proteiinia kantavissa OVCAR-3 soluissa sisplatiini, toisin kuin dosetakseli, indusoi p53 proteiinin tärkeää säätelijää, p14ARF:a sekä mRNA- että proteiinitasolla. Sisplatiini lisäsi merkittävästi myös usean angiogeneesiin liittyvän tekijän (TSP-1, BMP-4, ET-1 ja PlGF-2) mRNA:ta. Dosetakselin vaikutukset vastaavalla annoksella olivat vähäiset. Kliinisissä munasarjasyövissä BMP-4, TSP-1 ja CD105 sekä oksidatiivisen stressin aiheuttaman DNA-vaurion merkkiaineen, 8-OHdG:n sekä peroksiredoksiiniantioksidanttien ilmeneminen analysoitiin immunohistokemiallisesti. BMP-4:n ja sytoplasmisen peroksiredoksiini IV:n vahva ilmentyminen liittyivät parempaan ennusteeseen, kun taas 8-OHdG:n vahva ilmentyminen liittyi huonompaan elinajan ennusteeseen. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn avulla selvitettiin p53 ja Hdm2 proteiinien vasteita syöpäkudoksen karboplatiini- tai dosetakseli-käsittelyille. Selkeitä yksilökohtaisia eroja havaittiin erityisesti karboplatiinin aiheuttamissa p53 vasteissa niin eri potilaiden kuin eri histologisten kasvaintyyppien välillä. Tämän väitöskirjatutkimuksen tulokset antavat viitteitä BMP-4:n, 8-OHdG:n ja peroksiredoksiinin mahdollisesta ennusteellisesta merkityksestä munasarjasyövässä. Erot platinayhdisteiden ja taksaanien välillä saattavat osoittautua merkittäviksi yksilöllisiä syövän hoitoja räätälöitäessä. Tuoreen munasarjasyöpäkudoksen eksplanttiviljelyn mahdollisuuksia yksilöllisten kasvainten hoitovasteiden ennustamisessa kannattaa selvittää jatkotutkimuksin
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Davidson, Scott M. "Analysis of prognostic and drug resistance markers in lung cancer." Connect to e-thesis, 2007. http://theses.gla.ac.uk/101/.
Full textAbstract:
Thesis (M.D.) - University of Glasgow, 2007.M.D. thesis submitted to the Centre for Oncology and Applied Pharmacology, Cancer Research UK Beatson Laboratories, University of Glasgow, 2007. Includes bibliographical references. Print version also available.
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Davidson, Scott Mitchell. "Analysis of prognostic and drug resistance markers in lung cancer." Thesis, University of Glasgow, 2007. http://theses.gla.ac.uk/101/.
Full textAbstract:
It was shown that LS310 is 2.3 times more resistant to cisplatin and shows a 50% reduction in MLH1 expression when compared to LS274 (p < 0.001). It was demonstrated that the hMLH1 promoter region of LS310 exhibited methylation whereas the LS274 promoter region did not. Neither of these lines exhibited methylation of the p16, MINT 25 or DAPK loci suggesting that de novo methylation was not responsible for the methylation specific PCR results. Further work demonstrated that treatment of the LS310 cell line with the demethylating agent decitabine increased its cisplatin sensitivity as well as increasing the level of MLH1 expression of the cell line. No such changes were demonstrated in the LS274 cell line after treatment with decitabine. In summary, this research project was limited by the availability of samples. However it has demonstrated that collaborative multidisciplinary prospective planned translational research can be done and emphasises the need for a translational component to be an integral part of future lung cancer studies.
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Callagy, Grace Mary Barbara. "Identifying prognostic markers in breast cancer using array-based methodology." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616000.
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Coimbra, Carla Susana Meireles. "Prognostic Value of Inflammatory and Oxidative Stress Markers in Psoríasis." Doctoral thesis, Faculdade de Farmácia da Universidade do Porto, 2009. http://hdl.handle.net/10216/54007.
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Ferreira, Carla Susana Mendes. "Prognostic markers in 980 patients with ACS hospitalized in CHBV." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/12944.
Full textAbstract:
Mestrado em Biomedicina MolecularAcute coronary syndrome consists in a state of clinical symptoms compatible with acute myocardial ischaemia that may result from various thrombotic coronary artery diseases: unstable angina, non–ST-segment elevation acute myocardial infarction and STsegment elevation myocardial infarction. This disease normally occurs due to atherosclerosis, through the rupture of an unstable atherosclerotic plaque or through superficial endothelial erosion. Eventually the activation of the coagulation cascade and platelet adhesion, activation and aggregation ends up leading to acute thrombosis. Risk stratification in patients with acute coronary syndrome is very important in the determination of the proper treatment strategy. Various clinical features are known to be associated with an increased risk of a worse outcome in the event of an acute coronary syndrome and are taken into account in various risk scores. The main aim of this work is the determination of clinical characteristics that are associated with a worse outcome in a group of patients with acute coronary syndrome admitted to the Cardiac Intensive Care Unit of Hospital Infante D. Pedro, in Centro Hospitalar do Baixo Vouga, in order to identify potential prognostic markers in these patients, and the assessment of the association of these markers with other clinical characteristics, in order to determine their influence in the physiology of patients with acute coronary syndrome. A prospective observational study was conducted in 980 patients with acute coronary syndrome admitted to the cardiac intensive care unit of Hospital Infante D. Pedro, in Centro Hospitalar do Baixo Vouga, between January 2008 and June 2012. Data collected was analysed using Student's T-test, One-way Anova, Kruskal-Wallis test, Pearson’s X2 test, Fisher's Exact test, Cox Proportional Hazards Model e Kaplan-Meyer estimate, and included general clinical information and information regarding cardiac risk factors, general blood test, serum cardiac markers, left ventricular ejection fraction, provided revascularization therapy and previous and posterior cardiac events The results obtained indicate that female gender, advanced age, anemia, low left ventricular ejection fraction, the presence of a previous event, hypertension, dyslipidemia and obesity are associated with a poorer prognosis in patients with acute coronary syndrome.
O síndrome coronário agudo consiste num estado de sintomas físicos compatíveis com isquemia miocárdica aguda, podendo resultar de várias doenças arteriais coronárias: angina instável, enfarte agudo do miocárdio sem elevação do segmento-ST e enfarte agudo do miocárdio com elevação do segmento-ST. Esta doença ocorre normalmente devido a aterosclerose, através da rutura de uma placa aterosclerótica instável ou através de erosão endotelial. Eventualmente a ativação da cascata de coagulação e a adesão, ativação e agregação de plaquetas levam a trombose aguda. A estratificação do risco em pacientes com síndrome coronário agudo é muito importante na determinação da estratégia terapêutica adequada. Várias características clínicas estão associadas com um risco aumentado de um prognóstico adverso aquando de um síndrome coronário agudo, sendo tidos em conta em várias tabelas de previsão de risco. O principal objetivo deste trabalho é a determinação de características clínicas associadas com pior um prognóstico num grupo de doentes com síndrome coronário agudo internados na unidade de cuidados intensivos cardíacos do Hospital Infante D. Pedro, no Centro Hospitalar do Baixo Vouga, de forma a identificar potenciais marcadores de prognóstico nestes doentes, e a determinação da sua associação com outras características clínicas, de forma a determinar a sua influência na fisiologia de doentes com síndrome coronário agudo. Levou-se a cabo um estudo prospetivo observacional em 980 doentes com síndrome coronário agudo internados na unidade de cuidados intensivos cardíacos do Hospital Infante D. Pedro, no Centro Hospitalar do Baixo Vouga, entre Janeiro de 2008 e Junho de 2012. A informação recolhida foi analisada usando Student's T-test, One-way Anova, Kruskal-Wallis test, Pearson’s X2 test, Fisher's Exact test, Cox Proportional Hazards Model e Kaplan-Meyer estimate, e incluiu informação clínica geral e informação sobre fatores de risco cardíacos, análise sanguínea geral, marcadores cardíacos séricos, fração de ejeção ventricular esquerda, terapia de revascularização e eventos cardíacos prévios e posteriores. Os resultados obtidos indicam que sexo feminino, idade avançada, baixa fração de ejeção ventricular esquerda, a presença de um evento prévio, hipertensão, dislipidémia e obesidade estão associados com um prognóstico adverso em pacientes com síndrome coronário agudo.
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Ramsden, Alex. "New approaches to gene therapy and prognostic markers in melanoma." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445930/.
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The c-myc proto-oncogene plays a key role in cell proliferation, malignant transformation and apoptosis. Previous work at RAFT demonstrated that c-myc expression levels are an accurate prognostic marker in melanoma. Ribozymes are catalytic RNA molecules that cleave specific mRNA sequences to prevent gene expression. A ribozyme was constructed targeting the c-myc translation initiation site. A375M melanoma cells were transfected using liposomes and growth was assessed using a MTS growth assay, c-myc expression was measured with immuno-staining and flow-cytometry. Ribozyme treatment of A375M melanoma cells reduced c-myc expression when compared to non-specific controls (p < 0.001). Ribozyme treatment also significantly reduced growth of A375M cells in-vitro compared to untreated controls (p < 0.001). Ribozymes were investigated in combination with interferon and cis- platinum. A prospective investigation of c-myc expression in 117 melanomas was undertaken using immunostaining and flow cytometric analysis. Clinico-pathological details were also studied. Analysis revealed that high c-myc expression was associated with a worse prognosis (p=0.043). Multivariate analysis demonstrated c-myc as an independent prognostic marker when measured against other routine parameters including Breslow thickness. To facilitate rapid screening for molecular alterations in melanoma, a tissue micro-array was created using historical paraffin embedded specimens. 126 tumours were included in the array block representing all stages of disease progression. Analysis was performed on a variety of genes associated with c-myc examining prognostic significance. High expression of p27 and p53 were significantly associated with improved survival (p < 0.05). Cyclins A, E and D1 correlated with disease progression (p < 0.05). Conclusions. Ribozymes can effectively block c-myc gene expression in vitro and may have a role in the treatment of melanoma. Flow cytometric analysis of c-myc expression provides a new important independent prognostic marker for melanoma. Tissue array technology is a simple and powerful tool in the search for new prognostic markers in melanoma.
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Coimbra, Carla Susana Meireles. "Prognostic Value of Inflammatory and Oxidative Stress Markers in Psoríasis." Tese, Faculdade de Farmácia da Universidade do Porto, 2009. http://hdl.handle.net/10216/54007.
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NORDIO, LAURA. "COMPARATIVE EVALUATION OF PROGNOSTIC MARKERS IN CANINE AND FELINE MELANOMAS." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/625608.
Full textAbstract:
The present PhD project investigates animal spontaneous models of non-UV induced melanomas, namely canine oral melanoma and feline iris diffuse melanoma (FDIM), which shares unique similarities in biological behavior with human mucosal melanoma and human iris melanoma, respectively.
The project investigates selected markers related to the pathogenesis and prognosis of these tumors, i.e. gene and proteins that have been implicated in the progression and metastasis in human, canine and feline melanomas, such as Leukotriene A4 Hydrolase (LTA4H), Fragile X mental retardation-related protein 1 (FXR1) and matrix-metalloproteinases (MMPs). LTA4H is an enzyme of the arachidonic acid cascade, FXR1 is a RNA binding protein, MMPs a family of proteolytic enzymes of the extracellular matrix.
The specific aims of the project are:
1) the validation of anti-FXR1 antibodies in the canine species;
2) the investigation of the expression of LTA4H and FXR1 in canine oral melanoma;
3) the study of FXR1-induced modulation of MMPs in canine oral melanoma;
4) the study of MMPs and tumor-matrix interaction in feline diffuse iris melanoma.
1) Two different commercially available polyclonal anti-human FXR1 antibodies were validated for use in dogs. Western blot experiments highlighted the specificity of cross-reaction. Immunohistochemistry described for the first time the specific distribution of FXR1 protein in canine normal tissues, and then the expression of FXR1 in a pool of canine melanocytic tumors.
2) LTA4H and FXR1 genes and proteins expression was investigated in FFPE canine oral melanomas (histology and immunohistochemistry, n=36, from 32 dogs; RT-PCR, subset n=23; clinical follow-up, subset n=13). ΔCt expression values ranged 0.76-5.11 for LTA4H and 0.22-6.24 range for FXR1 (out of range in 3 cases). The immunohistochemical expression of the proteins was evaluated as IRS-score (percentage of positive cells combined with intensity of the staining). IRS-score of LTA4H and FXR1 proteins did not correlate with the expression of the codifying genes. LTA4H and FXR1 seemed not correlated with the known criteria of malignancy or with the clinical outcome, when available.
3) Since FXR1 belongs to a family of RNA binding protein able to modulate the mRNA coding for the proteolytic enzyme MMP-9, MMP-9 and its inhibitor TIMP-2 were investigated by immunohistochemistry in canine oral melanomas to assess the association of FXR1 with MMP-9 and the association of MMPs activity with the clinical outcome. MMP-9 expression seemed not associated with FXR1 in canine oral melanomas. Anyway, intense levels of MMP-9/TIMP-2 were observed in cases with high expression of FXR1 and with unfavorable clinical outcome in canine oral melanoma.
4) The expression of MMPs in FDIM was investigated. Immunohistochemical expression of MMP-9/TIMP-2 was investigated in 62 FDIM and results were compared with the histological grade and mitotic index. MMP-9 and TIMP-2 were expressed in 77.4% and 71.0% FDIM, respectively. Increasing MMP-9 and TIMP-2 paralleled with high histological grades and high mitotic index.
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Wallin, Ulrik. "Cancer of the Colon and Rectum : Prognostic Factors and Early Detection." Doctoral thesis, Uppsala universitet, Kolorektalkirurgi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-159142.
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Colorectal cancer (CRC) is one of the most common causes of death from malignant disease. Nevertheless, no ideal screening method exists and there is a lack of prognostic and predictive factors to support clinical decisions and to aid the development of a more individualized treatment for patients with CRC. The aim of this thesis was to investigate early detection, prognostic and predictive factors of CRC. In the first paper, a novel method to collect cells for DNA quantification from the rectal mucosa was investigated. The sensitivity and specificity of this test to detect CRC or any pathology in colon and rectum were ultimately too low to be acceptable. In the second paper, the prognostic value of growth differentiation factor 15 (GDF 15) was evaluated in patients curatively operated for colorectal cancer. GDF 15 expression was demonstrated to be associated with a negative prognosis in patients with stages I-III and III disease. In the third paper, the prognostic value of BRAF, PIK3CA KRAS and MSI was evaluated in a cohort of patients with CRC stratified by disease and recurrence. The results indicated that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence. In the fourth paper, histopathological predictors of pathologic complete response (pCR) as well as the association between pre-treatment carcinoembryonic antigen (CEA) levels and pCR in non-smoking and smoking patients receiving preoperative chemo-radiotherapy for rectal cancer were evaluated. Only in non-smokers was a low CEA level significantly associated with pCR, suggesting that the predictive value of CEA for pCR in rectal cancer in smokers can be limited. In sum, this research has investigated a new method for CRC detection and further evaluated the clinical use of prognostic and predictive markers in CRC.
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Jham, Seema Hari. "Prognostic immune markers for chronic allograft injury in renal transplant recipients." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7535/.
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Introduction: Alloimmunity is a major contributor to chronic allograft injury. There are currently no routine clinical cell-based assays that allow quantification of the recipients' alloimmune response towards a graft. Previous work from our group identified indirect alloimmune responses to non-polymorphic regions of HLA Class 1. The aim of this thesis was to assess the alloimmune response in renal transplant recipients (RTRs) by using synthetic peptides to nonpolymorphic regions ofHLA Class 2. Methods: Responses to newly synthesized HLA Class 2 peptides were tested in RTRs via any interferon ELISPOT assay. Cell surface staining techniques and Luminex technology were used to identify the T-cell subsets driving the immune responses and subsequent cytokine production respectively. Results: Increased responses to HLA Class 2 derived peptides were detected in renal transplant recipients compared to healthy controls. The activated effector memory subset ofT-cells was expanded in RTRs compared to healthy controls and generated these responses. T effector memory cell dependent TNF-a and IL-2 and T regulatory dependent IL-10 synthesis in the presence of specific peptide antigen was detected. Conclusion: A potential reproducible assay ofT cell alloreactivity has been identified to help stratify RTRs at risk of an ongoing alloimmune response but needs further testing in a larger multicentre study.
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McKnight, C. Jason. "Clinical testing and prognostic markers for the development of leprosy neuropathy." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536801.
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Selvarajah, Johann Rajinder. "Plasma and genetic inflammatory markers as prognostic indicators innon-disabling cerebrovascular disease." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504721.
Full textAbstract:
TIA and minor stroke confer increased risk of further vascular events, with resulting morbidity and mortality. Inflammation is implicated in the pathogenesis and outcome of vascular disease and cerebral ischaemia. Circulating inflammatory markers or inflammatory gene polymorphisms may indicate those at greatest risk of major vascular events. The primary hypothesis of this work is that plasma concentrations of interleukin-1 receptor antagonist (IL-1 RA), IL-6 and C-reactive protein (CRP), and/or inflammatory genotypes, measured after a recent TIA or minor stroke predict the short-term risk of recurrent vascular events (the primary outcome). In a prospective study of 711 patients recruited at a median of 15 days after TIA or minor stroke, baseline plasma IL-1RA, IL-6 and CRP concentrations were not associated with the primary outcome. However, in a secondary analysis, ESR was significantly associated with outcome (OR 1.39, 95% CI=1.03-1.85, p=O.03). An exploratory analysis of single nucleotide polymorphisms (SNP) in six inflammatory genes indicated that IL-1A, IL-6 and {3-fibrinogen genotypes were significantly associated with primary outcome. This large cohort is representative of the patient population attending a range of regional UK secondary prevention services. Most markers of the acute inflammatory response are not of prognostic value in this group. Several reasons for this, including late clinical presentation, are discussed. However, delayed or chronic inflammation and its genetic determinants may yet have prognostic importance and are worthy of further study.
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Phillips, Patrick Peter John. "Prognostic and surrogate markers for outcome in the treatment of pulmonary tuberculosis." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2009. http://researchonline.lshtm.ac.uk/1544172/.
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Phase III trials for new tuberculosis treatment regimens require large numbers of participants and can take over five years to complete. A surrogate marker for poor outcome (failure at end of treatment or recurrence following successful treatment), the established endpoint in such trials, could shorten trial duration and reduce trial size. Culture results after two months of treatment have shown the most promise but, prior to this research, no formal evaluation had been performed. In this thesis, culture results during treatment are evaluated as prognostic and surrogate markers for poor outcome using data on 6974 patients from twelve tuberculosis treatment randomised controlled multi-arm trials conducted in East Africa and East Asia. A strong association was found between culture results during treatment and poor outcome. Nevertheless, culture results were not good patient-specific predictors of poor outcome with low sensitivities and specificities. Existing meta-analytic methods for evaluating surrogate markers are not wholly suited to this setting of multi-arm trials with binary true and surrogate endpoints. Extending these methods, the two month culture was found to be a good surrogate marker using data from Hong Kong trials and the three month culture was found to be a good surrogate marker using data from East African trials. These results are an indication that cultures during treatment do capture some of the treatment effect. Further work is needed in understanding the differences between the Hong Kong and East African trials. The meta-analytic methods for evaluating surrogate markers in this thesis included a graphical representation that permitted a clear visual evaluation of the surrogate. Methods developed in this thesis for modelling the relationship between the treatment effects on the true and surrogate endpoints were not satisfactory. The deficiencies were not overcome with the two extensions proposed. Further work is needed in developing a more appropriate model.
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Maksymyuk, V. V. "Genetic prognostic markers of severe acute pancreatitis and development of its complications." Thesis, БДМУ, 2017. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/16912.
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Keegan, Philip Edward. "Prognostic markers in human bladder cancer : P53, MDM2 and MDM2 splice variants." Thesis, University of Newcastle upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394723.
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Schneider, Brigitte. "Prognostic value of tumour endothelial markers (TEMs) in patients with endometrial cancer /." [S.l.] : [s.n.], 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000277058.
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Cheang, Maggie Chon U. "Biological classification of clinical breast cancer using tissue microarrays." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/2430.
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Gene expression profiles have identified five major molecular breast cancer subtypes (Luminal A, Luminal B, Basal-like, HER2+/estrogen receptor− , and Normal Breast-like) that show significant differences in survival. The cost and complexity of gene expression technology has impeded its clinical implementation. By comparison, immunohistochemistry is an economical technique applicable to the standard formalin-fixed, paraffin-embedded material commonly used in hospital labs, and has the advantage of simultaneously interpretation with histomorphology.
In this thesis, I hypothesize that a surrogate panel of immunohistochemical biomarkers can be developed to discriminate the breast cancer biological subtypes. The main study cohort consists of over 4000 primary invasive breast tumors, assembled into tissue microarrays. These patients were referred to the British Columbia Cancer Agency between 1986-1992 and have staging, pathology, treatment and follow-up information. In summary, our results demonstrate that (1) the rabbit monoclonal antibody, SP1, is an improved standard for immunohistochemiscal estrogen receptor assessment in breast cancer; (2) the transcription factor, GATA-3, is almost exclusively expressed among estrogen receptor positive tumors but does not seem to predict for tamoxifen response among estrogen receptor positive patients; (3) the proliferation marker, Ki-67, together with HER2 can segregate Luminal A from Luminal B subtypes, which carry distinct risks for breast cancer relapse and death; and (4) the inclusion of the basal markers EGFR and ck5/6 to “triple negative” breast cancers provides a more specific definition of basal-like breast cancer that better predicts patient survival.
These results consistently demonstrate that an immunopanel of six biomarkers (estrogen receptor, progesterone receptor, HER2, Ki-67, epidermal growth factor receptor and cytokeratin 5/6) can be readily applied to standard pathology specimens to subtype breast cancer samples based on their underlying molecular biology. These findings have been considered sufficient to justify application of this panel onto NCIC (MA5, MA12) and CALGB (9341 and 9741) clinical trials specimens. This followup work which is underway and will determine if the six marker immunopanel can guide decisions about which patients need aggressive systemic drug treatment, and thereby ensure patients get the most effective, individualized adjuvant systemic therapy for their breast tumor.
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LOIACONO, LUISA. "Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer." Doctoral thesis, Università di Foggia, 2017. http://hdl.handle.net/11369/363287.
Full textAbstract:
Background:
Nel complesso scenario di disregolazione dei pathway coinvolti nella cancerogenesi del tumore al colonretto
(CRC), quelli attivati da EphA2 ed EphB2 sembrano rivestire un ruolo fondamentale. In particolare,
durante la progressione tumorale, l’espressione di EphA2 risulta significativamente aumentata ed è stata
correlata all’aggressività e alle proprietà simil-staminali delle cellule tumorali. Il recettore EphA2 è coinvolto
in cross-talk multipli con altri network cellulari tra cui quelli di EGFR, FAK e VEGF, con i quali coopera
nell’attivazione della migrazione cellulare, invasione e metastasi.
Obiettivo:
Scopo della tesi è stato quello di isolare e caratterizzare sottopopolazioni omogenee EphA2high e EphB2high a
partire dall’eterogeneo contesto del cancro al colon-retto, per valutarne il ruolo nella cancerogenesi e nella
progressione tumorale.
Disegno sperimentale:
A partire dal modello murino AOM/DSS, che rappresenta un’affidabile piattaforma per lo studio del CRC,
abbiamo isolato tramite FACS (Fluorescence-activated cell sorting) sottopopolazioni cellulari EphA2high ed
EphB2high, la cui identità molecolare è stata confermata tramite Real Time PCR. Abbiamo così identificato
una signature EphA2/EGFR validata in sei coorti indipendenti di pazienti stratificati in base all’espressione di
EphA2, per verificarne il ruolo prognostico e predittivo di risposta alla targeted therapy.
Risultati:
Abbiamo sviluppato un metodo di separazione cellulare basato sull’espressione di membrana di recettori
EphA2 ed EphB2, che ci ha permesso di isolare sottopopolazioni cellulari con differente grado di staminalità
e differenziamento.
Nelle cellule EphA2high isolate da tumori murini abbiamo identificato un pattern di espressione genica
(EphA2, Efna1, EGFR, Ptpn12, Atf2) che riflette l’attivazione dei pathway di EphA2 ed EGFR, associato ad
una coerente disregolazione dei miRNAs mir-26b e mir-200a. In analisi uni- e multivariate tale pattern si è
rivelato un fattore prognostico significativo per pazienti allo stadio I-III del cancro al colon-retto. È stato
inoltre possibile associare con significatività i livelli di espressione del pattern EphA2/Efna1/EGFR alla
risposta al cetuximab in pazienti allo stadio IV con KRAS wild type. Infine, l’overespressione di EphA2 ed
EGFR ha dimostrato un effetto combinato nella resistenza al cetuximab indipendentemente dallo stato
mutazionale di KRAS.
Conclusioni:
Alla luce di questi risultati, i geni EphA2/Efna1/EGFR, sotto la regolazione dei miRNAs mir-200a e mir-26b,
possono essere proposti come nuovi marcatori prognostici nel CRC. Inoltre, EphA2 può essere correlato a
un meccanismo di resistenza alla terapia con cetuximab alternativo alle mutazioni di KRAS.In the complex hierarchical scenario of the altered pathways in colorectal carcinogenesis, the ones activated by EphA2 and EphB2 seem to have fundamental roles. Particularly, EphA2 expression is significantly increased in CRC progression and has been correlated to stem-like properties of cells and tumor malignancy. EphA2 receptor is involved in multiple cross-talks with other cellular networks including EGFR, FAK and VEGF pathways, with which it collaborates to stimulate cell migration, invasion and metastasis. Purpose: The aim of this study was to isolate and characterize homogeneous EphA2high and EphB2high cell subpopulations from the heterogeneous landscape of colorectal cancer to investigate their role in carcinogenesis and tumor progression. Experimental Design: From the highly reliable platform of the AOM/DSS murine model of carcinogenesis we isolated EphA2high and EphB2highcell subpopulations by FACS (Fluorescence-activated cell sorting)-assisted procedures and we assessed their molecular identity with Real Time PCR. We identified an EphA2/EGFR gene signature that was validated in six independent cohorts of patients stratified by EphA2 expression to determine its potential prognostic role and its effect on response to targeted therapies. Results: We developed a cell isolation method based on surface expression of EphA2 and EphB2 receptors, which allowed us to isolate cell subpopulations with different levels of differentiation and stemness properties. In murine CRC EphA2high cells we identified a gene expression pattern (EphA2, Efna1, EGFR, Ptpn12, Atf2) that reflects the activation of EphA2 and EGFR pathways accompanied by a coherent dysregulation of mir-26b and mir-200a. Such pattern showed prognostic significance in stage I-III CRC patients, in both univariate and multivariate analysis. In stage IV patients with wild type KRAS EphA2/Efna1/EGFR gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect in cetuximab resistance, independently from KRAS mutation status. Conclusions: These results suggest that EphA2/Efna1/EGFR genes, controlled by mir-200a and mir-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.
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Lindahl, Thomas. "Prognostic markers in breast cancer associated with cell cycle control, proliferation and angiogenesis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-860-2/.
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Pacifico, Marc Dominic. "Improving outcome in melanoma by early detection and identification of novel prognostic markers." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445091/.
Full textAbstract:
The incidence of cutaneous melanoma continues to rise rapidly. Problems are faced throughout its management and this thesis addresses them as follows: secondary prevention, prediction of prognosis and early detection of metastatic disease. Secondary prevention has been shown to be an effective strategy for improving survival in other cancers. A study of the rapid access, early detection, pigmented lesion clinic at Mount Vernon Hospital demonstrates for the first time that such an approach improves outcome in melanoma. Refining current prognostic capability in melanoma is essential for improving disease management. Tissue microarray was used to investigate 480 specimens from 120 primary melanomas for novel prognostic markers. Several markers were identified, including MCAM, CD44v3, Nm23 and P-cadherin, which showed a significant bearing on melanoma patient outcome. Their identification reveals valuable markers for predicting outcome and potential targets for therapeutic manipulation. Immunoscintigraphy is the use of radiolabeled tumour-specific antibodies to detect disease. Previously the whole monoclonal antibody LHM2, directed against the high molecular weight melanoma-associated antigen was studied. Whilst being highly melanoma-specific, its use in melanoma detection is limited. Its large size (150 kDa) results in background accumulation in normal organs, reducing image quality and hindering metastasis detection. The single chain Fv fragment (scFv) is the smallest part of the whole monoclonal antibody that maintains full antigen- binding capability. Its potential superiority over whole monoclonal antibodies has been demonstrated however it requires further refinement before routine use in patients. Two methods of improving tumour targeting with scFvs were investigated: use of a cocktail of scFvs binding different epitopes and use of scFv multimers. The use of a scFv cocktail improved tumour targeting in the spleen and muscle. Dimeric scFvs were shown to improve tumour retention whilst maintaining rapid blood clearance, leading to overall improved tumour targeting compared with monomers.
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Hedström, Gustaf. "Prognostic Markers in Diffuse Large B-cell Lymphoma : How Bad can it be." Doctoral thesis, Uppsala universitet, Enheten för onkologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-220010.
Full textAbstract:
Diffuse large B-cell lymphoma (DLBCL), which is the most common type of lymphoma, is characterised by its aggressiveness and poor outcome without adequate treatment and also for its biological and clinical heterogeneity. It is therefore highly desirable to gain a more profound understanding of the underlying biology of the disease, as well as predictive factors for the guidance of treatment. The studies presented here attempt to gain an overall grasp on DLBCL, from the epidemiological level down to the genomic level. The tumour microenvironment consists of both tumour cells and normal infiltrating cells in a delicate interplay. By assessing the number of infiltrating mast cells (MCs) in the microenvironment, a correlation between low numbers of MCs and poorer prognosis of DLBCL was found. However, malignant cells are not only affected by environmental conditions but also by intrinsic factors, such as small non-coding microRNAs. A low expression level of microRNA-129 was found to correlate with poor survival of DLBCL and the finding remained significant even for rituximab-treated patients. An even smaller intracellular genomic unit is one single nucleotide. The single nucleotide polymorphism 309 (SNP309) is a T to G change in the promotor region of MDM2, a regulatory protein in the p53 pathway, which results in increased transcription of MDM2 and thus decreased levels of p53. It was found that homozygous T allele patients had longer overall survival, as well as disease-specific survival and disease-free survival. However, treatment with rituximab eliminated the predictive value of the SNP309 polymorphism. In the last project presented in this thesis we used epidemiological methods to analyse all DLBCL cases diagnosed 2000-2013 in Sweden. Here it was possible to categorically show that higher age is an adverse prognostic factor, and most importantly, this starts from a young age. In conclusion, within this thesis I have applied different laboratory and analysis techniques to examine DLBCL biology in relation to the clinic. I have identified potential new prognostic markers, contributed to an enhanced understanding of DLBCL biology and described epidemiological data from one of the largest DLBCL cohorts ever presented. All of these aspects provide important information for a deeper understanding of the disease DLBCL.
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Ong, Chee Wee. "Clinical and molecular characterisation of prognostic markers and therapeutic targets in prostate cancer." Thesis, Queen's University Belfast, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709689.
Full textAbstract:
The increasing advances in genomic technologies in the last decade have allowed us to understand the molecular mutational landscape of prostate cancer. However, validation of genomic profiles generated by high-throughput efforts is laborious and expensive. Therefore, there is a need for a systematic and streamlined assessment of high-throughput genomic data to prioritise genes for further detailed biological validation studies for which this thesis entailed. Through cluster analysis of a panel of carefully selected markers, such as AR, ERG, MYC, RB1, PTEN and TP53, we were able to align patients into individual subgroups based on their PTEN status. Subsequently, through an objective computer learning elastic net modelling, we identified a cluster of 35 genes that was defining the clusters in our cohort. The prognostic effect of this signature was conserved in three independent datasets, with prominent statistical power, in Gleason 7 prostate cancer. Notably, our study is the first to report a signature with prognostic value in Gleason 7 cases. Additionally, we were able to identify a putative actionable target, S1PR2, by overlapping PTEN-low expressing clinical cases with gene expression data available from a Pten-knockout mouse model. From our analysis, we have observed that the combined inhibition of S1PR2 and the S1P kinases, SPHK1/2 were able to reduce cell migration and viability. Through a series of molecular validation, we postulated that the inhibition of both S1PR2 and SPHK1/2 could decrease cell viability and migration essential for cancer cell survival. Collectively, our findings contributed to the better understanding of the genomic changes associated with the heterogeneity of prostate cancer. Furthermore, we have uncovered several possible avenues for novel therapeutic interventions for untreated Gleason 7 prostate cancer.
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Krogerus, Leena. "Prognostic markers in breast cancer analysed by lectin stainings, immunocytochemistry and flow cytometry." Helsinki : University of Helsinki, 2001. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/krogerus/.
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El, Hajj Petra. "New prognosis markers and new targets for therapy in high risk melanoma: evaluation of TYRP1 as a melanoma prognostic marker and its regulation by miRNA(s)." Doctoral thesis, Universite Libre de Bruxelles, 2015. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209064.
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L’espérance de vie des patients atteints de mélanome à haut risque ne peut être prédite d’une façonfiable en se basant sur les analyses d’histopathologies de la lésion primitive et est souvent ajustée
durant la progression de la maladie. Notre étude vise à élargir nos observations initiales au niveau
des métastases cutanées et d’évaluer la valeur pronostique de tyrosinase related protein 1 (TYRP1)
dans les métastases ganglionnaires des patients atteints de mélanome de stades III et IV. TYRP1 est
une enzyme mélanosomale qui partage des similitudes structurelles avec la tyrosinase, l'enzyme clé
de la mélanogenèse.
L’expression de l'ARNm de TYRP1 a été quantifiée dans 104 métastases ganglionnaires par PCR
en temps réel et normalisée par rapport à l’expression de l’ARNm de S100B (marqueur reconnu du
mélanome) pour corriger l’expression de TYRP1 suivant la charge tumorale de l’échantillon. Le
rapport TYRP1/S100B a été calculé et la médiane a été utilisée en tant que valeur seuil. Ensuite
nous avons étudié la relation entre les valeurs de TYRP1/S100B, le suivi clinique et les
caractéristiques histopathologiques de la tumeur primitive.
Un rapport élevé de l’ARNm TYRP1/S100B corrélait significativement avec une survie sans
récidive et une survie globale plus courtes, avec une épaisseur de Breslow plus élevée et avec la
présence d'une ulcération au niveau de la tumeur primitive. En outre, une expression élevée de
TYRP1/S100B était de meilleure valeur pronostique pour la survie globale que l'épaisseur de
Breslow et l'ulcération des primitifs. De plus, cette expression est bien conservée au cours de la
progression de la maladie par rapport aux groupes de TYRP1 bas/élevé.
Nous avons constaté qu’une expression élevée de TYRP1/S100B dans les métastases de patients
atteints de mélanome est associée à un résultat clinique défavorable et une survie courte. Menée sur
des patients atteints d'un mélanome à haut risque de récidive, cette première étude a suggéré que
l'ARNm de TYRP1 dans les métastases pourrait servir de biomarqueur pour affiner le pronostic
initial des patients surtout ceux ayant des lésions primitives de localisation inconnues ou non
évaluables et peut permettre une gestion différente des deux groupes de patients. Son expression
conservée au cours de la progression de la maladie est en faveur de son utilisation comme cible
thérapeutique.
En second lieu, en évaluant l’expression de la protéine TYRP1 par immunohistochimie dans les
métastases cutanées et ganglionnaires, nous avons observé qu’elle n'était pas détectée dans la moitié
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des tissus exprimant bel et bien l'ARNm correspondant et qu’elle, contrairement à l'ARNm, n’était
pas associée à la survie.
Des données récentes ont indiqué que le 3'-UTR de l’ARNm de TYRP1 contient trois sites de
liaison putatifs de miR-155 dont deux présentant un polymorphisme d'un seul nucléotide (SNPs:
rs683 et rs910) qui favorisent la dégradation en cas d’hybridation miARN-ARNm parfaite de
l’ARNm ou non en cas d’hybridation imparfaite. Nous avons cherché à examiner si miR-155 peut
affecter l’expression de l’ARNm et de la protéine TYRP1 en fonction de ces SNPs. Tout d'abord,
nous avons transfecté deux lignées de mélanome ayant chacune l’une ou l’autre de l’allèle (au
niveau rs683 et rs910) avec différentes concentrations de pré-miR-155 et nous avons évalué
l’expression du miR-155 et l’ARNm TYRP1 par PCR en temps réel ainsi que l’expression de la
protéine TYRP1 par western blot. Nous avons constaté qu’une surexpression de miR-155 a induit
une dégradation importante des ARNm TYRP1 et a perturbé sa traduction en protéine dans la lignée
avec le génotype “hybridation parfaite”. Ensuite, nous avons examiné l'expression des ARNm et
protéines de TYRP1, le niveau de miR-155 et les SNPs rs683 et rs910 dans 192 échantillons de
métastases cutanées et ganglionnaires de mélanome. Nous avons trouvé que le groupe d'échantillons
avec le génotype “hybridation parfaite” était significativement associé à un niveau de protéine de
TYRP1 plus bas alors qu'aucune différence de niveau d’expression n'a été trouvée pour l’ARNm de
TYRP1 ou miR-155 entre les deux groupes de génotype, confirmant que les SNPs au niveau de 3’-
UTR de TYRP1 peuvent spécifiquement affecter l'expression de la protéine TYRP1. En outre, nous
avons montré que l’ARNm de TYRP1 est inversement corrélé avec l’expression miR-155, mais pas
avec la protéine TYRP1 dans le groupe " hybridation parfaite", alors qu'il corrèle positivement avec
la protéine mais pas avec miR-155 dans le groupe "hybridation imparfaite" où la protéine corrélait
inversement à la survie. Cela montre que les SNPs dans le 3'-UTR de l'ARNm TYRP1 affectent la
régulation de l’ARNm par miR-155 et la traduction en protéine. Ces SNPs rendent la régulation de
l’ARNm et la protéine de TYRP1 indépendante de miR-155 et confèrent une valeur pronostique à
la protéine TYRP1
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Hellman, Kristina. "Vaginal carcinoma : studies on etiology and prognostic factors /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-519-4/.
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