Abstract:
:Kidney cancer (Renal Cell Carcinoma (RCC)) is one of the most deadly malignancies due to frequent late diagnosis and poor treatment options. Histologically, RCC embraces a wide variety of different subtypes with the clear cell variant (ccRCC) being the most common, accounting for 75-90% of all RCCs. At present, the surveillance protocols for follow-up of RCC patients after radical nephrectomy are based on the American Joint Committee on Cancers (AJCC) pathological tumor-node-metastasis (TNM) classification system. Other comprehensive staging modalities have emerged and have been implemented in an attempt to improve prognostication by combining other pathological and clinical variables, including Fuhrman nuclear grade and Leibovich score. However, even early stage tumors remain at risk of metastatic progression after surgical resection and 20-40% of patients undergoing nephrectomy for clinically localized RCC will develop a recurrence. Identifying this high-risk group of RCC patients remains a challenge. Hence, novel molecular prognostic biomarkers are needed to better predict clinical outcomes. An intensive search within this field has been ongoing in the past few years, and the three main predictive and prognostic markers validated in RCC are Von Hippel Lindau (VHL), vascular endothelial growth factor (VEGF) and carbonic anhydrase IX (CAIX). Nonetheless, the use of these is still debated and none of them have yet been implemented in clinical routine. RCC is resistant to conventional oncological therapies, such as chemotherapy and radiation. The availability of novel targeted therapies directed against tumorigenic and angiogenic pathways have increased over the last years, and the outcome of patients with advanced RCC has significantly improved as a consequence. Unfortunately, all patients eventually become resistant. Thus, the development of novel targeted therapies is of great importance. The aim of this thesis was therefore to contribute in the search for novel prognostic molecular markers in RCC and to identify novel targeted therapies by in-vitro studies. This was specifically conducted by investigating; 1) The impact of symptom presentation of RCC on prognosis, 2) The expression of Calcium-activated potassium channels in RCC, the correlation of KCa3.1 to prognosis in ccRCC and the ability of TRAM-34, RA-2 and Paxilline to inhibit the proliferation of ccRCC cell lines in-vitro, 3) The gene expression and prognostic value of 19 selected genes in ccRCC and 4) The expression of the protein kinase CK subunits in subtypes of RCC, the prognostic impact of high protein expression of the CK2α subunit in ccRCC and the ability of CX-4945 and E9 to inhibit ccRCC growth in-vitro. Our molecular study cohort consisted of 155 patients with different subtypes of RCC and the benign renal neoplasm, oncocytoma. They were diagnosed in Region of Southern Denmark in 2001-2013. Frozen tissue from tumor and normal renal cortex parenchyma, together with paraffin-embedded tissue was available for every patient. We performed gene expression analysis by qRT-PCR, immunohistochemical staining of Tissue Micro Arrays, protein kinase activity analysis and functional studies. Study I was performed as a descriptive observational study focusing on the prognostic impact of symptom presentation in RCC. We included 204 patients with renal neoplasms diagnosed in 2011-2012. Incidentally discovered RCC without symptomatic presentation had overall a better prognosis, and presented with smaller tumors, a lower T-stage, lower Fuhrman grade and lower Leibovich score. In addition, the non-symptomatic patient group experienced metastatic disease less frequently. In study II we focused on the expression of two calcium-activated potassium channels in ccRCC and oncocytoma. Both KCa3.1 and KCa1.1 were higher expressed in ccRCC compared to oncocytoma. High expression of KCa3.1 was moreover correlated with poor progression free survival of ccRCC. Functional studies provided new insights since we could detect currents compatible with KCa3.1 and KCa1.1 in the cell membrane of primary and commercial ccRCC cell lines. Nonetheless, we were not able to show any significant inhibition of cell growth by the selective inhibitors of KCa3.1 and KCa1.1, TRAM-34, RA-2 and Paxilline. In study III our aim was to investigate the prognostic role of 19 genes selected on the basis of an earlier study done by the group. We used Taqman® Low Density Array to perform a quantitative real-time PCR analysis. By selecting an optimal cut-point and correct for overestimation of the p-value, we could identify three genes with impact on prognosis of ccRCC in both univariate and multivariate analysis. High expression of the genes SPP1 and CSNK2A1 (encoding Osteopontin and CK2α respectively) correlated with poor prognosis while high expression of DEFB1 (encoding β-Defensin) correlated with better prognosis. Study IV focused on validating the results obtained in Paper III by investigating the protein expression of CK2α (Protein kinase 2, alpha subunit) in the different subtypes of RCC and oncocytoma. Furthermore, we investigated whether protein expression of CK2α in ccRCC correlated with prognosis. Here we could show, that a positive nuclear staining was a marker of poor prognosis in high-stage ccRCC. Moreover, enzyme activity analysis revealed a higher activity of the protein kinase in tumor tissue of ccRCC than in normal renal cortex. Novel insights were provided in a proliferation study where we investigated the selective inhibitors of CK2α, CX-4945 and E9. CX-4945 was able to inhibit ccRCC cell growth by nearly 50%. All together the studies presented in this thesis add additional information to the ongoing research within identification of novel prognostic markers in ccRCC. We have discovered four new molecular markers, which reliably can predict prognosis at the time of diagnosis. Additionally, we identified CK2α as a novel therapeutic target of ccRCC. The studies suggest further research to validate the findings on larger cohorts and thereby obtain more insight into the involved pathways. Future research initiatives based on the results presented in this thesis could clarify the potential role of CX-4945 as a novel targeted treatment of ccRCC patients.
journal_name
Dan Med Jjournal_title
Danish medical journalauthors
Rabjerg Msubject
Has Abstractpub_date
2017-10-01 00:00:00issue
10issn
2245-1919pii
B5339journal_volume
64pub_type
杂志文章abstract:INTRODUCTION:The optimal treatment of acute, displaced midshaft clavicle fractures is controversial. Despite lack of compelling evidence towards superior results after primary surgery, it seems that more and more patients are treated surgically. The aim of this study was to investigate which treatment modality should b...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2012-07-01 00:00:00
abstract:INTRODUCTION:In Copenhagen, Denmark, patients in need of prehospital emergency assistance dial 112 and may then receive evaluation and treatment by physicians (from the Mobile Emergency Care Unit (MECU)). ST-elevation myocardial infarction (STEMI) is a severe condition leaving only a limited time frame to deliver optim...
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journal_title:Danish medical journal
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更新日期:2012-08-01 00:00:00
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更新日期:2015-10-01 00:00:00
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更新日期:2013-01-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2016-11-01 00:00:00
abstract::End-stage liver diseases represent major health problems that are currently treated by liver transplantation. However, given the world-wide shortage of donor livers novel strategies are needed for therapeutic treatment. Adult stem cells have the ability to self-renew and differentiate into the more specialized cell ty...
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更新日期:2013-05-01 00:00:00
abstract:INTRODUCTION:The aim of the study is to identify how disease management programmes for patients with a chronic disease work. This issue is explored from the patients' perspective. Specifically, we study how transition and coordination are related to the patient's perception of quality of care, with a particular focus o...
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更新日期:2016-03-01 00:00:00
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doi:
更新日期:2015-11-01 00:00:00
abstract:INTRODUCTION:(99m)Tc-pertechnetate scintigraphy is much used in the evaluation of patients with nodular goitre. We investigated the ability of experienced observers to estimate the thyroid 24-h (131)I uptake (RAIU) and the thyroid volume by visual evaluation of the scintigram. MATERIAL AND METHODS:Two endocrinologists...
journal_title:Danish medical journal
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doi:
更新日期:2014-02-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
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更新日期:2013-10-01 00:00:00
abstract::Heart failure is a complex clinical syndrome and one of the leading causes of morbidity and mortality with a prevalence of 1%-2% of the adult population. The prognosis is poor with a 5-year mortality rate of 50%, which partly can be attributed to the presence of concomitant comorbidity, including neurological and psyc...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2018-04-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2015-03-01 00:00:00
abstract:INTRODUCTION:Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assis...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2017-01-01 00:00:00
abstract::Both non-pathological psychological stress states and mental disorders are associated with molecular, cellular and epidemiological signs of accelerated aging. Oxidative stress on nucleic acids is a critical component of cellular and organismal aging, and a suggested pathogenic mechanism in several age-related somatic ...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2013-07-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-01-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2013-04-01 00:00:00
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pub_type: 临床试验,杂志文章
doi:
更新日期:2012-01-01 00:00:00
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pub_type: 杂志文章,评审
doi:
更新日期:2015-07-01 00:00:00
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doi:
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pub_type: 临床试验,杂志文章
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更新日期:2012-02-01 00:00:00
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更新日期:2017-03-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
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更新日期:2017-04-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2012-06-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-04-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2016-05-01 00:00:00
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journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2020-08-01 00:00:00