No description available.

Compared to radical nephrectomy (RN), partial nephrectomy (PN) leads to improved renal function preservation. However, PN may be infrequently utilized, particularly in patients susceptible to chronic kidney disease. We conducted a population-based, retrospective, observational study using the Canadian Institute for Health Information Discharge Abstract Database. All patients treated for a renal mass with either RN or PN from April 1, 1998 to March 31, 2008 were included in the analysis. Using descriptive statistics and multivariable regression modelling, we demonstrated low uptake of PN (17.5% overall); year, age, geographic region, Charlson score, hospital volume, and physician volume were independently associated with PN use, whereas DM, HTN and income quintile were not. In this contemporary analysis PN continues to be underutilized, and the rate of PN in DM, HTN and the elderly was less than expected given their known relationship to chronic renal failure.

Compared to radical nephrectomy (RN), partial nephrectomy (PN) leads to improved renal function preservation. However, PN may be infrequently utilized, particularly in patients susceptible to chronic kidney disease. We conducted a population-based, retrospective, observational study using the Canadian Institute for Health Information Discharge Abstract Database. All patients treated for a renal mass with either RN or PN from April 1, 1998 to March 31, 2008 were included in the analysis. Using descriptive statistics and multivariable regression modelling, we demonstrated low uptake of PN (17.5% overall); year, age, geographic region, Charlson score, hospital volume, and physician volume were independently associated with PN use, whereas DM, HTN and income quintile were not. In this contemporary analysis PN continues to be underutilized, and the rate of PN in DM, HTN and the elderly was less than expected given their known relationship to chronic renal failure.

Renal cell carcinoma (RCC), following prostate and bladder tumours, is the third most prevalent genitourinary malignancy. Clear cell renal cell carcinoma makes up the bulk of RCC cases (ccRCC). Despite the fact that ccRCC is the most aggressive type of RCC, our understanding of its pathophysiology is limited. Previous research in our laboratory revealed important oncogenic roles of contactin 1 (CNTN1), a neuronal cell adhesion protein, in prostate cancer. CNTN1 is involved in a number of signalling pathways that are often changed in cancer, including the VEGFC-VEGF receptor 3 (VEFGR3)/fms-related tyrosine kinase 4 (Flt4) axis, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axis, and the Notch signalling system. Collectively, evidence suggests that CNTN1 facilitates ccRCC. To examine this possibility, I have established stable ccRCC 786-O and A498 cell lines expressing either empty vector (EV) or CNTN1. In comparison to the respective EV lines, ectopic expression of CNTN1 enhances colony formation and cell proliferation. In comparison to A498 EV cells, A498 CNTN1 cells seems to possess enhanced migration ability based on wound healing assay. Taken together, my research provides in vitro evidence supporting CNTN1 in facilitating ccRCC pathogenesis. Future research will be required to investigate this concept using in vivo systems and primary ccRCC tumor tissues. / Thesis / Master of Science (MSc)

No description available.

Cellular adaptation to conditions of stress is critical to the survival of all organisms. In mammalian cells, reduced oxygen availability, or hypoxia, triggers a myriad of alterations within molecular pathways aimed at ensuring sustained viability and functionality of vital organs. The master regulator of the hypoxic response is the heterodimeric HIF transcription factor, composed of an oxygen-labile HIFalpha subunit and a constitutively expressed and stable HIFbeta(ARNT) subunit. While experiments in mice have demonstrated the indispensability of HIF1alpha/HIF2alpha, unchecked hyperactivation of HIF is associated with pathological complications, such as the development of clear-cell renal cell carcinoma (ccRCC), the most common form of kidney cancer. In particular, overexpression of HIF2alpha has been intimately linked to ccRCC molecular pathogenesis. Here, we report that HIF2alpha overexpression leads to Akt-mediated hyperactivation of Hdm2, resulting in decreased activity of p53 and increased resistance to apoptosis. Significantly, we show that restoration of p53 activity via inhibition of Hdm2 reverses chemoresistance of otherwise refractory ccRCC cells. We also demonstrate that the picornavirus EMCV (Encephalomyocarditis virus) efficiently destroys ccRCC tumour cells in an NF-kappaB- and HIFalpha-dependent manner both in vitro and in a mouse xenograft model. This work provides pre-clinical evidence for the potential use of EMCV in an oncolytic virus-based approach to the treatment of advanced ccRCC. In addition, using a cell biology-based approach we reveal that inhibition of the DNA methyltransferase DNMT1 leads to enhanced HIF promoter-binding affinity and transactivation activity in a manner that is independent of changes in HIFalpha protein levels. This study uncovers a novel HIF regulatory mechanism in mammalian cells. In summary, the work presented here provides insight into the molecular mechanisms governing HIF activity and the effects of HIF on the molecular pathogenesis of ccRCC. Our findings have the potential to provide new therapeutic avenues for the treatment of kidney cancer.

Cellular adaptation to conditions of stress is critical to the survival of all organisms. In mammalian cells, reduced oxygen availability, or hypoxia, triggers a myriad of alterations within molecular pathways aimed at ensuring sustained viability and functionality of vital organs. The master regulator of the hypoxic response is the heterodimeric HIF transcription factor, composed of an oxygen-labile HIFalpha subunit and a constitutively expressed and stable HIFbeta(ARNT) subunit. While experiments in mice have demonstrated the indispensability of HIF1alpha/HIF2alpha, unchecked hyperactivation of HIF is associated with pathological complications, such as the development of clear-cell renal cell carcinoma (ccRCC), the most common form of kidney cancer. In particular, overexpression of HIF2alpha has been intimately linked to ccRCC molecular pathogenesis. Here, we report that HIF2alpha overexpression leads to Akt-mediated hyperactivation of Hdm2, resulting in decreased activity of p53 and increased resistance to apoptosis. Significantly, we show that restoration of p53 activity via inhibition of Hdm2 reverses chemoresistance of otherwise refractory ccRCC cells. We also demonstrate that the picornavirus EMCV (Encephalomyocarditis virus) efficiently destroys ccRCC tumour cells in an NF-kappaB- and HIFalpha-dependent manner both in vitro and in a mouse xenograft model. This work provides pre-clinical evidence for the potential use of EMCV in an oncolytic virus-based approach to the treatment of advanced ccRCC. In addition, using a cell biology-based approach we reveal that inhibition of the DNA methyltransferase DNMT1 leads to enhanced HIF promoter-binding affinity and transactivation activity in a manner that is independent of changes in HIFalpha protein levels. This study uncovers a novel HIF regulatory mechanism in mammalian cells. In summary, the work presented here provides insight into the molecular mechanisms governing HIF activity and the effects of HIF on the molecular pathogenesis of ccRCC. Our findings have the potential to provide new therapeutic avenues for the treatment of kidney cancer.

Renal cell carcinoma is a high risk and high mortality cancer. While the VHL pathway is frequently altered in renal cell carcinoma, emerging evidences points towards involvement of multiple complex pathways in the progression of renal cell carcinoma. In this present work, we aimed to investigate the role of newly identified protein, Major Intrinsically disordered NOTCH2-Associated Receptor 1 (MINAR1), in renal cell carcinoma. We used immunohistochemistry and demonstrated that MINAR1 is highly expressed in normal kidney epithelium. Furthermore, MINAR1 was expressed at variable levels in human renal cell carcinoma cell lines. More importantly, we found that MINAR1 was significantly downregulated in human samples of renal cell carcinoma. Although further studies are needed, our data suggests a potential role for MINAR1 in renal biology. Given that MINAR1 expression appears to be downregulated in renal cancer patients, it is suggestive that MINAR1 could function as a tumor suppressor. / 2020-06-17T00:00:00Z

Renal cell carcinoma (RCC) is the commonest urogenital tumor, characterized by increased expression of hypoxia inducible factors (HIFs). During normoxia, HIFα subunits are targeted for proteasomal degradation by the product of the von Hippel Lindau gene (pVHL). In RCC, mutations in the VHL gene allow the HIFα subunits to escape degradation and translocate to the nucleus where they activate transcription of their target genes. Although both HIF1α and HIF2α are upregulated in RCC, it has been suggested that HIF2α plays the dominant role. To further elucidate the function of HIF2α in RCC, we generated a transgenic mouse model that permits temporal stabilization of HIF2α in renal tubular cells. Induction of HIF2α results in the rapid development of renal cysts - a feature observed in RCC. Taken together, these results suggest that HIF2α is a key player in development of RCC and an excellent candidate target for therapy in this disorder.

Das Nierenzellkarzinom ist in Europa die 10. häufigste Tumorerkrankung [1]. Da das Prädi- lektionsalter bei 62 Jahren liegt [2] und die Inzidenz mit steigendem Alter zunimmt, geht die Erkrankung häufig mit einer Vielzahl an Komorbiditäten einher. Dies fordert eine Auseinan- dersetzung mit der Anwendung minimal invasiver Methoden, die das operative Risiko mini- mieren. Immernoch wird die Therapie durch radikale Nephrektomie favorisiert. Ziel der Stu- die war es deshalb Entscheidungshilfen für die Anwendung der Radiofrequenzablation (RFA) zu liefern. Daher untersuchten wir an Hausschweinen technische Einflussgrößen auf Behandlungszeit, Ablationsvolumen und Läsionsform bei bipolarer und multipolarer RFA im Vergleich. Dabei ergaben sich nach 3-D-Rekonstruktion größere Ablationsvolumina im mul- tipolaren Modus, wobei sich signifikante Formunterschiede in beiden Anwendungen heraus- kristallisierten. Bei multipolarer RFA ergaben sich größere Inhomogenitäten. Die Ablation kleinerer Tumorgrößen unter 2 cm erscheint mit bipolarer RFA sicher. Patienten mit Tumo- ren bis zu 3 cm profitieren von mutipolarer Radiofrequenzablation. Die Anwendung multi- polarer RFA bei Tumoren größer 3 cm gestaltet sich durch die inhomogene Ablation schwie- rig und bietet ein schwer kalkulierbares Risiko für die Patienten. Es konnte kein Vorteil durch Steigerung des Energietransfers innerhalb eines Modus nachgewiesen werden, da dies mit einer längeren Behandlungszeit einherging, jedoch nicht mit einer Zunahme der Läsiongröße korrelierte. Bei Patienten mit Niereninsuffizienz, Einzelnieren oder bilateralen Tumoren liegt ein Hauptaugenmerk der Therapie auf dem Erhalt der Nierenfunktion. Um eine mögliche Schädigung von gesundem Nierengewebe durch die RFA zu detektieren, färbten wir die Mar- kerproteine aktivierte Caspase3 und HSP70 immunohistochemisch an. Bei Ablation nahe des Nierenbeckenkelchsystems konnten beide Proteine sowohl im System des distalen Sammel- rohrs, als auch im Nierenmark gefunden werden. Hauptsächlich war das Auftreten jedoch auf die Randgebiete der zentralen Koagulationszone begrenzt. Die Radiofrequenzablation scheint daher ein sicheres Verfahren für die Therapie von Tumoren ≤ 3 cm zu sein.