Opposite prognostic roles of HIF1β and HIF2β expressions in bone metastatic clear cell renal cell cancer

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Szendroi, Attila; Szász, A. Marcell; Kardos, Magdolna

2016-01-01

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1β/HIF2β and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2β was lower in mRCC both at m...

Stratification of clear cell renal cell carcinoma (ccRCC) genomes by gene-directed copy number alteration (CNA) analysis.

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Thiesen, H-J; Steinbeck, F; Maruschke, M; Koczan, D; Ziems, B; Hakenberg, O W

2017-01-01

Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.

EphA2 Is a Potential Player of Malignant Cellular Behavior in Non-Metastatic Renal Cell Carcinoma Cells but Not in Metastatic Renal Cell Carcinoma Cells.

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Cho, Min Chul; Cho, Sung Yong; Yoon, Cheol Yong; Lee, Seung Bae; Kwak, Cheol; Kim, Hyeon Hoe; Jeong, Hyeon

2015-01-01

To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells. Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively. In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation. Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of

Expression of minichromosome maintenance genes in renal cell carcinoma

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Zhong HB

2017-11-01

Full Text Available Hongbin Zhong,1,* Bin Chen,1,* Henrique Neves,2 Jinchun Xing,1 Youxin Ye,1 Ying Lin,1 Guohong Zhuang,3 Shu-Dong Zhang,4 Jiyi Huang,1,5 Hang Fai Kwok2 1Xiang’an Branch, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China; 2Faculty of Health Sciences, University of Macau, Taipa, Macau SAR; 3Medical College of Xiamen University, Xiamen, Fujian, People’s Republic of China; 4Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, Londonderry, UK; 5The First Clinical School of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China *These authors contributed equally to this work Abstract: Minichromosome maintenance (MCM proteins play an essential role in DNA replication. They have been shown to be overexpressed in various types of cancer. However, the role of this family in renal cell carcinoma (RCC is widely unknown. In this study, we have identified a number of RCC datasets in the Gene Expression Omnibus database and also investigated the correlation between the expression levels of MCM genes and clinicopathological parameters. We found that the expression levels of MCM genes are positively correlated with one another. Expression levels of MCM2, MCM5, MCM6, and MCM7, but not of MCM3 and MCM4, were higher in RCC compared to paired adjacent normal tissue. Only the expression level of MCM4, but not of other MCMs, was positively correlated with tumor grade. In addition, a high-level expression of MCM2 in either primary tumor or metastases of RCC predicted a shorter disease-free survival time, while a high-level expression of MCM4 or MCM6 in primary tumor was also associated with poorer disease-free survival. Interestingly, we also demonstrated that patients with their primary RCC overexpressing 2 or more MCM genes had a shorter disease-free survival time, while those with RCC metastases overexpressing 3 or more MCM genes had a shorter

Expression of methionine adenosyltransferase 2A in renal cell carcinomas and potential mechanism for kidney carcinogenesis

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Wang, Xuliang; Guo, Xiaoqiang; Yu, Wenshui; Li, Cailing; Gui, Yaoting; Cai, Zhiming

2014-01-01

Methionine adenosyltransferase 2A (MAT2A) is an enzyme that catalyzes the formation of S-adenosylmethionine (SAMe) by joining methionine and ATP. SAMe is a methyl donor for transmethylation and has an important role for DNA and/or protein methylation. MAT2A is expressed widely in many tissues especially in kidney. Several studies have demonstrated that there are abnormal expressions of MAT2A in several kinds of cancers such as liver and colon cancers. But the relationship of MAT2A between renal cell carcinomas (RCC) is less understood. The mRNA expression level of the MAT2A gene was determined in 24 RCC patients and 4 RCC cell lines, using real-time quantitative-polymerase chain reaction (RT-PCR). The MAT2A protein content was measured by western blotting and immunohistochemical analysis in 55 RCC patients. The mRNA levels of heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) were also analysized in patients using RT-PCR. The correlations between the MAT2A and HO-1 as well as COX-2 were analyzed with nonparametric Spearman method. MAT2A transcript was significantly downregulated in cancer tissues compared to normal tissues (P < 0.05). Immunohistochemical analysis and western blotting indicated that level of MAT2A protein was decreased in cancer tissues. The statistical analysis reveals a negative correlation between MAT2A and HO-1 expression in RCC patients and cell lines (P < 0.01). This study demonstrated that MAT2A was lower expression in cancer tissues, suggesting that it may be involved in the development of RCC. MAT2A is a transcriptional corepressor for HO-1 expression by supplying SAM for methyltransferases, which may be one of potential mechanism of MAT2A as tumor suppressor in kidney carcinogenesis

Comparisons of ratchetting analysis methods using RCC-M, RCC-MR and ASME codes

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Yang Yu; Cabrillat, M.T.

2005-01-01

The present paper compares the simplified ratcheting analysis methods used in RCC-M, RCC-MR and ASME with some examples. Firstly, comparisons of the methods in RCC-M and efficiency diagram in RCC-MR are investigated. A special method is used to describe these two methods with curves in one coordinate, and the different conservation is demonstrated. RCC-M method is also be interpreted by SR (second ratio) and v (efficiency index) which is used in RCC-MR. Hence, we can easily compare the previous two methods by defining SR as abscissa and v as ordinate and plotting two curves of them. Secondly, comparisons of the efficiency curve in RCC-MR and methods in ASME-NH APPENDIX T are investigated, with significant creep. At last, two practical evaluations are performed to show the comparisons of aforementioned methods. (authors)

Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality in vitro.

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Calkoen, F G J; Vervat, C; van Pel, M; de Haas, V; Vijfhuizen, L S; Eising, E; Kroes, W G M; 't Hoen, P A C; van den Heuvel-Eibrink, M M; Egeler, R M; van Tol, M J D; Ball, L M

2015-03-01

Pediatric myelodysplastic syndrome (MDS) is a heterogeneous disease covering a spectrum ranging from aplasia (RCC) to myeloproliferation (RAEB(t)). In adult-type MDS there is increasing evidence for abnormal function of the bone-marrow microenvironment. Here, we extensively studied the mesenchymal stromal cells (MSCs) derived from children with MDS. MSCs were expanded from the bone-marrow of 17 MDS patients (RCC: n=10 and advanced MDS: n=7) and pediatric controls (n=10). No differences were observed with respect to phenotype, differentiation capacity, immunomodulatory capacity or hematopoietic support. mRNA expression analysis by Deep-SAGE revealed increased IL-6 expression in RCC- and RAEB(t)-MDS. RCC-MDS MSC expressed increased levels of DKK3, a protein associated with decreased apoptosis. RAEB(t)-MDS revealed increased CRLF1 and decreased DAPK1 expressions. This pattern has been associated with transformation in hematopoietic malignancies. Genes reported to be differentially expressed in adult MDS-MSC did not differ between MSC of pediatric MDS and controls. An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets. Copyright © 2015. Published by Elsevier B.V.

Integrative genome-wide gene expression profiling of clear cell renal cell carcinoma in Czech Republic and in the United States.

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Magdalena B Wozniak

Full Text Available Gene expression microarray and next generation sequencing efforts on conventional, clear cell renal cell carcinoma (ccRCC have been mostly performed in North American and Western European populations, while the highest incidence rates are found in Central/Eastern Europe. We conducted whole-genome expression profiling on 101 pairs of ccRCC tumours and adjacent non-tumour renal tissue from Czech patients recruited within the "K2 Study", using the Illumina HumanHT-12 v4 Expression BeadChips to explore the molecular variations underlying the biological and clinical heterogeneity of this cancer. Differential expression analysis identified 1650 significant probes (fold change ≥2 and false discovery rate <0.05 mapping to 630 up- and 720 down-regulated unique genes. We performed similar statistical analysis on the RNA sequencing data of 65 ccRCC cases from the Cancer Genome Atlas (TCGA project and identified 60% (402 of the downregulated and 74% (469 of the upregulated genes found in the K2 series. The biological characterization of the significantly deregulated genes demonstrated involvement of downregulated genes in metabolic and catabolic processes, excretion, oxidation reduction, ion transport and response to chemical stimulus, while simultaneously upregulated genes were associated with immune and inflammatory responses, response to hypoxia, stress, wounding, vasculature development and cell activation. Furthermore, genome-wide DNA methylation analysis of 317 TCGA ccRCC/adjacent non-tumour renal tissue pairs indicated that deregulation of approximately 7% of genes could be explained by epigenetic changes. Finally, survival analysis conducted on 89 K2 and 464 TCGA cases identified 8 genes associated with differential prognostic outcomes. In conclusion, a large proportion of ccRCC molecular characteristics were common to the two populations and several may have clinical implications when validated further through large clinical cohorts.

A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma

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Geiger, Christiane; Regn, Sybille; Weinzierl, Andreas; Noessner, Elfriede; Schendel, Dolores J

2005-01-01

We present a generic dendritic cell (DC) vaccine strategy for patients with renal cell carcinoma (RCC) based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs). Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells) as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs. Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs) specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP)-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease. PMID:16045799

A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma

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Noessner Elfriede

2005-07-01

Full Text Available Abstract We present a generic dendritic cell (DC vaccine strategy for patients with renal cell carcinoma (RCC based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs. Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs. Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease.

High Expression of Colony-Stimulating Factor 1 Receptor Associates with Unfavorable Cancer-Specific Survival of Patients with Clear Cell Renal Cell Carcinoma.

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Yang, Liu; Liu, Yidong; An, Huimin; Chang, Yuan; Zhang, Weijuan; Zhu, Yu; Xu, Le; Xu, Jiejie

2016-03-01

Colony-stimulating factor 1 receptor (CSF-1R), a single-pass type III transmembrane tyrosine-protein kinase, is mainly involved in inflammation and immune regulation to facilitate the progression of solid tumors. This study aimed to evaluate the impact of CSF-1R expression on clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) after surgery. We retrospectively enrolled 268 patients with ccRCC undergoing nephrectomy between 2001 and 2004. Clinicopathologic features and cancer-specific survival (CSS) were collected. Western blot analysis was performed in the pairwise comparisons of CSF-1R expression in peritumor and tumor tissues of patients with ccRCC. Immunohistochemistry was conducted to determine CSF-1R expression level in tumor specimens. Survival analysis was performed by the Kaplan-Meier method. Cox regression models were used to evaluate the impact of prognostic factors on CSS. A concordance index was calculated to measure prognostic accuracy. A prognostic nomogram was constructed on the basis of the identified independent prognostic factors. CSF-1R expression in tumor tissues was higher than in peritumor tissues in 71.4% (5 of 7) patients. CSF-1R expression of tumor tissues was positively associated with metastasis, tumor, node, metastasis classification system (TNM) stage, Eastern Cooperative Oncology Group performance status score and poor CSS. CSF-1R expression was determined as an independent prognostic factor for CSS in patients with ccRCC. Furthermore, extension of the well-established prognostic models with CSF-1R expression presented significantly improved prognostic accuracy. An efficient prognostic nomogram was constructed on the basis of the independent prognostic factors. High CSF-1R expression is a potential independent adverse prognostic factor for CSS in patients with ccRCC.

Identification of Molecular Tumor Markers in Renal Cell Carcinomas with TFE3 Protein Expression by RNA Sequencing

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Dorothee Pflueger

2013-11-01

Full Text Available TFE3 translocation renal cell carcinoma (tRCC is defined by chromosomal translocations involving the TFE3 transcription factor at chromosome Xp11.2. Genetically proven TFE3 tRCCs have a broad histologic spectrum with overlapping features to other renal tumor subtypes. In this study,we aimed for characterizing RCC with TFE3 protein expression. Using next-generation whole transcriptome sequencing (RNA-Seq as a discovery tool, we analyzed fusion transcripts, gene expression profile, and somatic mutations in frozen tissue of one TFE3 tRCC. By applying a computational analysis developed to call chimeric RNA molecules from paired-end RNA-Seq data, we confirmed the known TFE3 translocation. Its fusion partner SFPQ has already been described as fusion partner in tRCCs. In addition, an RNAread-through chimera between TMED6 and COG8 as well as MET and KDR (VEGFR2 point mutations were identified. An EGFR mutation, but no chromosomal rearrangements, was identified in a control group of five clear cell RCCs (ccRCCs. The TFE3 tRCC could be clearly distinguished from the ccRCCs by RNA-Seq gene expression measurements using a previously reported tRCC gene signature. In validation experiments using reverse transcription-PCR, TMED6-COG8 chimera expression was significantly higher in nine TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in 24 ccRCCs (P<.001 and 22 papillaryRCCs (P<.05-.07. Immunohistochemical analysis of selected genes from the tRCC gene signature showed significantly higher eukaryotic translation elongation factor 1 alpha 2 (EEF1A2 and Contactin 3 (CNTN3 expression in 16 TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in over 200 ccRCCs (P < .0001, both.

The role of apoptosis repressor with a CARD domain (ARC) in the therapeutic resistance of renal cell carcinoma (RCC): the crucial role of ARC in the inhibition of extrinsic and intrinsic apoptotic signalling.

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Toth, Csaba; Funke, Sarah; Nitsche, Vanessa; Liverts, Anna; Zlachevska, Viktoriya; Gasis, Marcia; Wiek, Constanze; Hanenberg, Helmut; Mahotka, Csaba; Schirmacher, Peter; Heikaus, Sebastian

2017-05-02

Renal cell carcinomas (RCCs) display broad resistance against conventional radio- and chemotherapies, which is due at least in part to impairments in both extrinsic and intrinsic apoptotic pathways. One important anti-apoptotic factor that is strongly overexpressed in RCCs and known to inhibit both apoptotic pathways is ARC (apoptosis repressor with a CARD domain). Expression and subcellular distribution of ARC in RCC tissue samples and RCC cell lines were determined by immunohistochemistry and fluorescent immunohistochemistry, respectively. Extrinsic and intrinsic apoptosis signalling were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT-263 or topotecan. ARC knock-down was performed in clearCa-12 cells using lentiviral transduction of pGIPZ. shRNAmir constructs. Extrinsic respectively intrinsic apoptosis were induced by TRAIL (TNF-related apoptosis-inducing ligand), ABT263 or topotecan. Potential synergistic effects were tested by pre-treatment with topotecan and subsequent treatment with ABT263. Activation of different caspases and mitochondrial depolarisation (JC-1 staining) were analysed by flow cytometry. Protein expression of Bcl-2 family members and ARC in RCC cell lines was measured by Western blotting. Statistical analysis was performed by Student's t-test. Regarding the extrinsic pathway, ARC knockdown strongly enhanced TRAIL-induced apoptosis by increasing the activation level of caspase-8. Regarding the intrinsic pathway, ARC, which was only weakly expressed in the nuclei of RCCs in vivo, exerted its anti-apoptotic effect by impairing mitochondrial activation rather than inhibiting p53. Topotecan- and ABT-263-induced apoptosis was strongly enhanced following ARC knockdown in RCC cell lines. In addition, topotecan pre-treatment enhanced ABT-263-induced apoptosis and this effect was amplified in ARC-knockdown cells. Taken together, our results are the first to demonstrate the importance of ARC protein in the inhibition of both the extrinsic

Regression of established renal cell carcinoma in nude mice using lentivirus-transduced human T cells expressing a human anti-CAIX chimeric antigen receptor

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Agnes Shuk-Yee Lo

2014-01-01

Full Text Available Carbonic anhydrase IX (CAIX is a tumor-associated antigen and marker of hypoxia that is overexpressed on > 90% of clear-cell type renal cell carcinoma (RCC but not on neighboring normal kidney tissue. Here, we report on the construction of two chimeric antigen receptors (CARs that utilize a carbonic anhydrase (CA domain mapped, human single chain antibody (scFv G36 as a targeting moiety but differ in their capacity to provide costimulatory signaling for optimal T cell proliferation and tumor cell killing. The resulting anti-CAIX CARs were expressed on human primary T cells via lentivirus transduction. CAR-transduced T cells (CART cells expressing second-generation G36-CD28-TCRζ exhibited more potent in vitro antitumor effects on CAIX+ RCC cells than first-generation G36-CD8-TCRζ including cytotoxicity, cytokine secretion, proliferation, and clonal expansion. Adoptive G36-CD28-TCRζ CART cell therapy combined with high-dose interleukin (IL-2 injection also lead to superior regression of established RCC in nude mice with evidence of tumor cell apoptosis and tissue necrosis. These results suggest that the fully human G36-CD28-TCRζ CARs should provide substantial improvements over first-generation mouse anti-CAIX CARs in clinical use through reduced human anti-mouse antibody responses against the targeting scFv and administration of lower doses of T cells during CART cell therapy of CAIX+ RCC.

Knockdown of MAGEA6 Activates AMP-Activated Protein Kinase (AMPK) Signaling to Inhibit Human Renal Cell Carcinoma Cells.

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Ye, Xueting; Xie, Jing; Huang, Hang; Deng, Zhexian

2018-01-01

Melanoma antigen A6 (MAGEA6) is a cancer-specific ubiquitin ligase of AMP-activated protein kinase (AMPK). The current study tested MAGEA6 expression and potential function in renal cell carcinoma (RCC). MAGEA6 and AMPK expression in human RCC tissues and RCC cells were tested by Western blotting assay and qRT-PCR assay. shRNA method was applied to knockdown MAGEA6 in human RCC cells. Cell survival and proliferation were tested by MTT assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by the TUNEL assay and single strand DNA ELISA assay. The 786-O xenograft in nude mouse model was established to test RCC cell growth in vivo. MAGEA6 is specifically expressed in RCC tissues as well as in the established (786-O and A498) and primary human RCC cells. MAGEA6 expression is correlated with AMPKα1 downregulation in RCC tissues and cells. It is not detected in normal renal tissues nor in the HK-2 renal epithelial cells. MAGEA6 knockdown by targeted-shRNA induced AMPK stabilization and activation, which led to mTOR complex 1 (mTORC1) in-activation and RCC cell death/apoptosis. AMPK inhibition, by AMPKα1 shRNA or the dominant negative AMPKα1 (T172A), almost reversed MAGEA6 knockdown-induced RCC cell apoptosis. Conversely, expression of the constitutive-active AMPKα1 (T172D) mimicked the actions by MAGEA6 shRNA. In vivo, MAGEA6 shRNA-bearing 786-O tumors grew significantly slower in nude mice than the control tumors. AMPKα1 stabilization and activation as well as mTORC1 in-activation were detected in MAGEA6 shRNA tumor tissues. MAGEA6 knockdown inhibits human RCC cells via activating AMPK signaling. © 2018 The Author(s). Published by S. Karger AG, Basel.

pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma

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Struckmann, K; Mertz, Kd; Steu, S

2008-01-01

Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to...

Somatostatin receptor scintigraphy in advanced renal cell carcinoma. Results of a phase II-trial of somatostatine analogue therapy in patients with advanced RCC

International Nuclear Information System (INIS)

Freudenberg, L.S.; Goerges, R.; Stergar, H.; Bockisch, A.; Gauler, T.; Bauer, S.; Antoch, G.; Schuette, J.

2008-01-01

Aims: objective of this prospective study was to evaluate the role of somatostatin receptor scintigraphy (SRS) in advanced renal cell carcinoma (RCC) with respect to potential therapy with somatostatin analogue (SST-A) and to assess the response rate under therapy with SST-A. Patients, methods: 16 patients with documented progression of histologically confirmed advanced RCC were included. Planar whole-body SRS was performed 4, 24 and 48h post i.v. injection of 175-200 MBq 111 In-pentetreoide. 5 and 25 h p.i. SPECT of thorax and abdomen were performed. Documentation of somatostatin receptor expression via SRS in > 50% of known tumour lesions was the criteria for treatment start with SST-A (Sandostatin LAR registered -Depot 30mg i.m. every four weeks). Results: in 9/16 of the patients SRS showed at least one metastasis with moderate (n = 5) or intense (n = 4) tracer uptake. Lesion-based SRS evaluation showed only 12.1% (20/165) of all metastases. Most false-negative lesions were located in the lungs. In too patients, the majority of the known metastases was SRS positive and these patients received SST-A therapy. The first radiographic evaluation after a two-month interval showed progressive disease in both patients. Conclusions: we conclude that SRS is of limited value in staging of advanced RCC. In our patients SST-A did not result in a growth control of RCC. Consequently, the use of SST-A in advanced RCC seems to be no relevant therapeutic option. (orig.)

Mouse RC/BTB2, a Member of the RCC1 Superfamily, Localizes to Spermatid Acrosomal Vesicles

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Shen, Xuening; Nagarkatti-Gude, David R.; Hess, Rex A.; Henderson, Scott C.; Strauss, Jerome F.; Zhang, Zhibing

2012-01-01

Mouse RC/BTB2 is an unstudied protein of the RCC1 (Regulator of Chromosome Condensation) superfamily. Because of the significant remodeling of chromatin that occurs during spermiogenesis, we characterized the expression and localization of mouse RC/BTB2 in the testis and male germ cells. The Rc/btb2 gene yields two major transcripts: 2.3 kb Rc/btb2-s, present in most somatic tissues examined; and 2.5 kb Rc/btb2-t, which contains a unique non-translated exon in its 5′-UTR that is only detected in the testis. During the first wave of spermatogenesis, Rc/btb2-t mRNA is expressed from day 8 after birth, reaching highest levels of expression at day 30 after birth. The full-length protein contains three RCC1 domains in the N-terminus, and a BTB domain in the C-terminus. In the testis, the protein is detectable from day 12, but is progressively up-regulated to day 30 and day 42 after birth. In spermatids, some of the protein co-localizes with acrosomal markers sp56 and peanut lectin, indicating that it is an acrosomal protein. A GFP-tagged RCC1 domain is present throughout the cytoplasm of transfected CHO cells. However, both GFP-tagged, full-length RC/BTB2 and a GFP-tagged BTB domain localize to vesicles in close proximity to the nuclear membrane, suggesting that the BTB domain might play a role in mediating full-length RC/BTB2 localization. Since RCC1 domains associate with Ran, a small GTPase that regulates molecular trafficking, it is possible that RC/BTB2 plays a role in transporting proteins during acrosome formation. PMID:22768142

Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma

International Nuclear Information System (INIS)

Tan, Min-Han; Furge, Kyle A; Kort, Eric; Giraud, Sophie; Ferlicot, Sophie; Vielh, Philippe; Amsellem-Ouazana, Delphine; Debré, Bernard; Flam, Thierry; Thiounn, Nicolas; Zerbib, Marc; Wong, Chin Fong; Benoît, Gérard; Droupy, Stéphane; Molinié, Vincent; Vieillefond, Annick; Tan, Puay Hoon; Richard, Stéphane; Teh, Bin Tean; Tan, Hwei Ling; Yang, Ximing J; Ditlev, Jonathon; Matsuda, Daisuke; Khoo, Sok Kean; Sugimura, Jun; Fujioka, Tomoaki

2010-01-01

Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC. Gene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15) and oncocytoma specimens (n = 15). Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP) genotyping was performed on independent samples (n = 14) using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors. A novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR) signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel immunohistochemical markers effectively discriminating

Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma

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Thiounn Nicolas

2010-05-01

Full Text Available Abstract Background Chromophobe renal cell carcinoma (chRCC and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC. Methods Gene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15 and oncocytoma specimens (n = 15. Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP genotyping was performed on independent samples (n = 14 using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors. Results A novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel

Efficient generation of patient-matched malignant and normal primary cell cultures from clear cell renal cell carcinoma patients: clinically relevant models for research and personalized medicine

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Lobo, Nazleen C.; Gedye, Craig; Apostoli, Anthony J.; Brown, Kevin R.; Paterson, Joshua; Stickle, Natalie; Robinette, Michael; Fleshner, Neil; Hamilton, Robert J.; Kulkarni, Girish; Zlotta, Alexandre; Evans, Andrew; Finelli, Antonio; Moffat, Jason; Jewett, Michael A. S.; Ailles, Laurie

2016-01-01

Patients with clear cell renal cell carcinoma (ccRCC) have few therapeutic options, as ccRCC is unresponsive to chemotherapy and is highly resistant to radiation. Recently targeted therapies have extended progression-free survival, but responses are variable and no significant overall survival benefit has been achieved. Commercial ccRCC cell lines are often used as model systems to develop novel therapeutic approaches, but these do not accurately recapitulate primary ccRCC tumors at the genomic and transcriptional levels. Furthermore, ccRCC exhibits significant intertumor genetic heterogeneity, and the limited cell lines available fail to represent this aspect of ccRCC. Our objective was to generate accurate preclinical in vitro models of ccRCC using tumor tissues from ccRCC patients. ccRCC primary single cell suspensions were cultured in fetal bovine serum (FBS)-containing media or defined serum-free media. Established cultures were characterized by genomic verification of mutations present in the primary tumors, expression of renal epithelial markers, and transcriptional profiling. The apparent efficiency of primary cell culture establishment was high in both culture conditions, but genotyping revealed that the majority of cultures contained normal, not cancer cells. ccRCC characteristically shows biallelic loss of the von Hippel Lindau (VHL) gene, leading to accumulation of hypoxia-inducible factor (HIF) and expression of HIF target genes. Purification of cells based on expression of carbonic anhydrase IX (CA9), a cell surface HIF target, followed by culture in FBS enabled establishment of ccRCC cell cultures with an efficiency of >80 %. Culture in serum-free conditions selected for growth of normal renal proximal tubule epithelial cells. Transcriptional profiling of ccRCC and matched normal cell cultures identified up- and down-regulated networks in ccRCC and comparison to The Cancer Genome Atlas confirmed the clinical validity of our cell cultures. The ability

HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma

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Ramakrishnan, Swathi; Ku, ShengYu; Ciamporcero, Eric; Miles, Kiersten Marie; Attwood, Kris; Chintala, Sreenivasulu; Shen, Li; Ellis, Leigh; Sotomayor, Paula; Swetzig, Wendy; Huang, Ray; Conroy, Dylan; Orillion, Ashley; Das, Gokul; Pili, Roberto

2016-01-01

Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student’s T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. Taking together, these results

Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

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Pooja Ghatalia

Full Text Available Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR and mammalian target of rapamycin (mTOR improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC, but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T, matched normal kidney (N and metastatic tumor tissue (M may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79 compared to those that did not develop metastasis for at least 2 years (n = 187. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001. The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3

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Zhao, Jun [Foshan Maternal and Child Health Care Hospital, Foshan (China); Lei, Ting [Zhongshan People’s Hospital, Zhongshan (China); Xu, Congjie [Department of Urology, Pepole’s Hospital of Hainan Province, Haikou (China); Li, Huan; Ma, Wenmin; Yang, Yunxia; Fan, Shuming [Foshan Maternal and Child Health Care Hospital, Foshan (China); Liu, Yuchen, E-mail: s_ycliu1@stu.edu.cn [Anhui Medical University, Hefei (China)

2013-08-23

Highlights: •miR-187 is down-regulated in clear cell renal cell carcinoma (ccRCC). •Down-regulation of miR-187 is associated with poor outcomes in patients with ccRCC. •miR-187 inhibits cell growth and migration though targeting B7-H3 in ccRCC. -- Abstract: Aberrantly expressed microRNAs (miRNAs) are frequently associated with the aggressive malignant behavior of human cancers, including clear cell renal cell carcinoma (ccRCC). Based on the preliminary deep sequencing data, we hypothesized that miR-187 may play an important role in ccRCC development. In this study, we found that miR-187 was down-regulated in both tumor tissue and plasma of ccRCC patients. Lower miR-187 expression levels were associated with higher tumor grade and stage. All patients with high miR-187 expression survived 5 years, while with low miR-187 expression, only 42% survived. Suppressed in vitro proliferation, inhibited in vivo tumor growth, and decreased motility were observed in cells treated with the miR-187 expression vector. Further studies showed that B7 homolog 3 (B7-H3) is a direct target of miR-187. Over-expression of miR-187 decreased B7-H3 mRNA level and repressed B7-H3-3′-UTR reporter activity. Knockdown of B7-H3 using siRNA resulted in similar phenotype changes as that observed for overexpression of miR-187. Our data suggest that miR-187 is emerging as a novel player in the disease state of ccRCC. miR-187 plays a tumor suppressor role in ccRCC.

MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3

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Zhao, Jun; Lei, Ting; Xu, Congjie; Li, Huan; Ma, Wenmin; Yang, Yunxia; Fan, Shuming; Liu, Yuchen

2013-01-01

Highlights: •miR-187 is down-regulated in clear cell renal cell carcinoma (ccRCC). •Down-regulation of miR-187 is associated with poor outcomes in patients with ccRCC. •miR-187 inhibits cell growth and migration though targeting B7-H3 in ccRCC. -- Abstract: Aberrantly expressed microRNAs (miRNAs) are frequently associated with the aggressive malignant behavior of human cancers, including clear cell renal cell carcinoma (ccRCC). Based on the preliminary deep sequencing data, we hypothesized that miR-187 may play an important role in ccRCC development. In this study, we found that miR-187 was down-regulated in both tumor tissue and plasma of ccRCC patients. Lower miR-187 expression levels were associated with higher tumor grade and stage. All patients with high miR-187 expression survived 5 years, while with low miR-187 expression, only 42% survived. Suppressed in vitro proliferation, inhibited in vivo tumor growth, and decreased motility were observed in cells treated with the miR-187 expression vector. Further studies showed that B7 homolog 3 (B7-H3) is a direct target of miR-187. Over-expression of miR-187 decreased B7-H3 mRNA level and repressed B7-H3-3′-UTR reporter activity. Knockdown of B7-H3 using siRNA resulted in similar phenotype changes as that observed for overexpression of miR-187. Our data suggest that miR-187 is emerging as a novel player in the disease state of ccRCC. miR-187 plays a tumor suppressor role in ccRCC

Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma

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Choi, Jieun; Koh, Eunjin; Lee, Yu Shin; Lee, Hyun-Woo; Kang, Hyeok Gu; Yoon, Young Eun; Han, Woong Kyu; Choi, Kyung Hwa; Kim, Kyung-Sup

2016-01-01

Clear cell renal carcinoma (RCC), the most common malignancy arising in the adult kidney, exhibits increased aerobic glycolysis and low mitochondrial respiration due to von Hippel-Lindau gene defects and constitutive hypoxia-inducible factor-α expression. Sirt3 is a major mitochondrial deacetylase that mediates various types of energy metabolism. However, the role of Sirt3 as a tumor suppressor or oncogene in cancer depends on cell types. We show increased Sirt3 expression in the mitochondrial fraction of human RCC tissues. Sirt3 depletion by lentiviral short-hairpin RNA, as well as the stable expression of the inactive mutant of Sirt3, inhibited cell proliferation and tumor growth in xenograft nude mice, respectively. Furthermore, mitochondrial pyruvate, which was used for oxidation in RCC, might be derived from glutamine, but not from glucose and cytosolic pyruvate, due to depletion of mitochondrial pyruvate carrier and the relatively high expression of malic enzyme 2. Depletion of Sirt3 suppressed glutamate dehydrogenase activity, leading to impaired mitochondrial oxygen consumption. Our findings suggest that Sirt3 plays a tumor-progressive role in human RCC by regulating glutamine-derived mitochondrial respiration, particularly in cells where mitochondrial usage of cytosolic pyruvate is severely compromised. -- Highlights: •Sirt3 is required for the maintenance of RCC cell proliferation. •Mitochondrial usage of cytosolic pyruvate is severely compromised in RCC. •Sirt3 supports glutamine-dependent oxidation in RCC.

Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma

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Choi, Jieun; Koh, Eunjin; Lee, Yu Shin; Lee, Hyun-Woo; Kang, Hyeok Gu [Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Yoon, Young Eun; Han, Woong Kyu [Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Choi, Kyung Hwa [Department of Urology, CHA Bundang Medical Center, CHA University, Seongnam 463-712 (Korea, Republic of); Kim, Kyung-Sup, E-mail: KYUNGSUP59@yuhs.ac [Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)

2016-06-03

Clear cell renal carcinoma (RCC), the most common malignancy arising in the adult kidney, exhibits increased aerobic glycolysis and low mitochondrial respiration due to von Hippel-Lindau gene defects and constitutive hypoxia-inducible factor-α expression. Sirt3 is a major mitochondrial deacetylase that mediates various types of energy metabolism. However, the role of Sirt3 as a tumor suppressor or oncogene in cancer depends on cell types. We show increased Sirt3 expression in the mitochondrial fraction of human RCC tissues. Sirt3 depletion by lentiviral short-hairpin RNA, as well as the stable expression of the inactive mutant of Sirt3, inhibited cell proliferation and tumor growth in xenograft nude mice, respectively. Furthermore, mitochondrial pyruvate, which was used for oxidation in RCC, might be derived from glutamine, but not from glucose and cytosolic pyruvate, due to depletion of mitochondrial pyruvate carrier and the relatively high expression of malic enzyme 2. Depletion of Sirt3 suppressed glutamate dehydrogenase activity, leading to impaired mitochondrial oxygen consumption. Our findings suggest that Sirt3 plays a tumor-progressive role in human RCC by regulating glutamine-derived mitochondrial respiration, particularly in cells where mitochondrial usage of cytosolic pyruvate is severely compromised. -- Highlights: •Sirt3 is required for the maintenance of RCC cell proliferation. •Mitochondrial usage of cytosolic pyruvate is severely compromised in RCC. •Sirt3 supports glutamine-dependent oxidation in RCC.

Accelerated pavement testing of thin RCC over soil cement pavements

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Zhong Wu

2016-05-01

Full Text Available Three full-scale roller compacted concrete (RCC pavement sections built over a soil cement base were tested under accelerated pavement testing (APT. The RCC thicknesses varied from 102 mm (4 in. to 152 mm (6 in. and to 203 mm (8 in., respectively. A bi-directional loading device with a dual-tire load assembly was used for this experiment. Each test section was instrumented with multiple pressure cells and strain gages. The objective was to evaluate the structural performance and load carrying capacity of thin RCC-surfaced pavements under accelerated loading. The APT results generally indicated that all three RCC pavement sections tested in this study possessed very high load carrying capacity; an estimated pavement life in terms of equivalent single axle load (ESAL for the thinnest RCC section (i.e., RCC thickness of 102 mm evaluated was approximately 19.2 million. It was observed that a fatigue failure would be the primary pavement distress type for a thin RCC pavement under trafficking. Specifically, the development of fatigue cracking was found to originate from a longitudinal crack at the edge or in the center of a tire print, then extended and propagated, and eventually merged with cracks of other directions. Instrumentation results were used to characterize the fatigue damage under different load magnitudes. Finally, based on the APT performance of this experiment, two fatigue models for predicting the fatigue life of thin RCC pavements were developed. Keywords: Roller compacted concrete, APT, Pavement performance, Non-destructive testing, Fatigue analysis

Downregulation of the long noncoding RNA TUG1 inhibits the proliferation, migration, invasion and promotes apoptosis of renal cell carcinoma.

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Zhang, Meng; Lu, Wei; Huang, Yiqiang; Shi, Jizhou; Wu, Xun; Zhang, Xiaolong; Jiang, Runze; Cai, Zhiming; Wu, Song

2016-08-01

Long non-coding RNAs, a newly discovered category of noncoding genes, play a leading role in various biological processes, including tumorigenesis. In our study, we aimed to examine the TUG1 expression, and explore the influence of TUG1 silencing on cell proliferation and apoptosis in renal cell carcinoma (RCC) cell lines. The TUG1 expression level was detected using quantitative real-time PCR reverse transcription-polymerase chain reaction in 40 paired clear cell renal cell carcinoma (ccRCC) and adjacent paired normal tissues, as well as four RCC cell lines and one normal human proximal tubule epithelial cell line HK-2. Small interfering RNA was applied to suppress the TUG1 expression in RCC cell lines (A489 and A704). In vitro assays were conducted to further deliberate its potential functions in RCC progression. The relative TUG1 expression was significantly higher in ccRCC tissues compared to the adjacent normal renal tissues. In addition, higher TUG1 expression was equally detected in RCC cell lines (particularly in A498 and A704) compared to HK-2. The ccRCC specimens with higher TUG1 expression had a higher Fuhrman grade and larger tumor size than those with lower TUG1 expression. In vitro assays results suggested that knockdown of TUG1 suppressed RCC cells migration, invasion and proliferation, while the apoptosis process was activated. Our results indicate that TUG1 is identified as a novel oncogene in the morbid state of RCC, which potentially acts as a therapeutic target/biomarker in RCC. The graphic abstract of the present work.

The IGF-I/JAK2-STAT3/miR-21 signaling pathway may be associated with human renal cell carcinoma cell growth.

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Su, Ying; Zhao, An; Cheng, Guoping; Xu, Jingjing; Ji, Enming; Sun, Wenyong

2017-07-04

Renal cell carcinoma (RCC) is the highest mortality rate of the genitourinary cancers, and the treatment options are very limited. Thus, identification of molecular mechanisms underlying RCC tumorigenesis, is critical for identifying biomarkers for RCC diagnosis and prognosis. To validate whether the IGF-I/JAK2-STAT3/miR-21 signaling pathway is associated with human RCC cell growth. qRT-PCR and Western blotting were used to detect the mRNA and protein expression levels, respectively. The MTT assay was performed to determine cell survival rate. The Annexin V-FITC/PI apoptosis detection kit was used to detect cell apoptosis. We employed RCC tissues and cell lines (A498; ACHN; Caki-1; Caki-2 and 786-O) in the study. IGF-I, and its inhibitor (NT-157) were administrated to detect the effects of IGF-I on the expression of miR-21 and p-JAK2. JAK2 inhibitor (AG490), and si-STAT3 were used to detect the effects of JAK2/STAT3 signaling pathway on the expression of miR-21. In our study, we firstly showed that the expression levels of IGF-I and miR-21 were up-regulated in RCC tissues and cell lines. After exogenous IGF-I treatment, the expression levels of miR-21, p-IGF-IR and p-JAK2 were significantly increased, whereas NT-157 treatment showed the reversed results. Further study indicated that JAK2 inhibitor or si-STAT3 significantly reversed the IGF-I-induced miR-21 expression level. Finally, we found that IGF-I treatment significantly prompted human RCC cell survival and inhibited cell apoptosis, and NT-157 treatment showed the reversed results. The IGF-I/JAK2-STAT3/miR-21 signaling pathway may be associated with human RCC cell growth.

Expression of CD44 and P53 in renal cell carcinoma: Association with tumor subtypes

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Farahnaz Noroozinia

2014-01-01

Full Text Available Renal cell carcinoma (RCC is a common malignancy of the kidney and accurate prediction of prognosis is valuable for the design of adjuvant therapy and counseling and effective scheduling of follow-up visits. Molecular genetic investigations of CD44 and P53 in RCC may be helpful in this regard. We studied the CD44 and P53 expressions semi-quantitatively on paraffin-embedded specimens of 64 RCC patients (37 male/27 female who underwent surgery from 2003 to 2008 by immunohistochemistry and analyzed the correlation of P53 and CD44 expression in RCC and outcome. Thirteen of 64 (20.3% specimens were P53 positive, 30/64 (46.9% were CD44 positive and five tumors with positive P53 expressed CD44 protein (P = 0.5. A statistically significant correlation was not found between CD44 and P53 expression (P = 0.5 and age (P = 0.07, sex (P= 0.3, tumor size (P = 0.7, grade (P = 0.23, vascular invasion (P = 1.00 and ureteral invasion (P = 1.00. Furthermore, a significant correlation was not found between P53 expression with age (P = 0.3, sex (P = 0.7, tumor size (P = 0.7, grade (P = 0.1, vascular inva-sion (P = 1.00 and ureteral invasion (P = 1.00. According to our findings, only P53 expression is generally accompanied by non-conventional subtype tumor.

Study on the correlation between SCT features and pathology, MVD, expressions of VEGF in renal cell carcinoma

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Chen Xuejun; Gao Jianbo; Yang Xuehua; Zhou Zhigang; Guo Hua; Yue Songwei

2005-01-01

Objective: To evaluate the correlation between spiral CT (SCT) features and pathology, MVD, and expressions of VEGF in renal cell carcinoma (RCC). Methods: Thirty-four patients with RCC diagnosed by pathology underwent SCT examinations. MVD and expressions of VEGF were examined immunohistochemically using SABC techniques. Results: (1) The detection and characterization as well as accuracy of staging in 34 RCC on two-phase enhanced SCT scans were 100%, 100%, and 94%, respectively. (2) Tumors with low density ring on SCT scans mostly had pseudocapsules at pathological examination. The nuclear grade was higher in groups of tumor without low density ring, with central necrosis, and the diameter larger than 3.0 cm than in those of tumor with low density ring, without central necrosis, and the diameter less than 3.0 cm (P<0.01, P<0.01, P<0.01, respectively). (3) In 34 cases of RCC, the mean MVD was 89.5 ± 56.0. The positive expression of VEGF was 70.6% (24/34). (4) The MVD and positive expressions of VEGF in groups of tumor without a low density ring, with central necrosis on SCT scans were higher than in those tumor with a low density ring, without central necrosis (P<0.05 respectively in each of the groups). On early enhanced scans, MVD was closely correlated with tumor enhancement (P<0.05). MVD was higher in tumors with intravenous tumor emboli than in tumors without emboli (P<0.01). Conclusion: (1) Two-phase enhanced SCT scan was a reliable technique in the detection, characterization and staging of RCC. (2) Some SCT features were closely correlated with MVD and expressions of VEGF in RCC, which could be a noninvasive method in predicting aggressiveness and metastasis. (authors)

The frequency of tumor-infiltrating Tie-2-expressing monocytes in renal cell carcinoma: its relationship to angiogenesis and progression.

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Ji, Jindong; Zhang, Guangbo; Sun, Bo; Yuan, Hexing; Huang, Yuhua; Zhang, Jianglei; Wei, Xuedong; Zhang, Xuefeng; Hou, Jianquan

2013-10-01

To examine the frequency of tumor-infiltrating Tie-2-expressing monocytes (TEMs) in renal cell carcinoma (RCC) and its association with microvessel density (MVD) and other clinical-pathologic features. This study enrolled 65 consecutive patients with RCC treated with radical nephrectomy. The frequency of tumor-infiltrating TEMs, which was defined as CD14(+) Tie-2(+) cells, was assessed using flow cytometry. MVD was measured by immunohistochemistry using anti-CD34 antibody. The association between clinicopathologic parameters, MVD, and the frequency of tumor-infiltrating TEMs in RCC was assessed. High frequency of tumor-infiltrating TEMs was significantly associated with advanced stage (P = .018), positive lymph nodes (P = .013), high grade (P = .019), and metastases (P = .006). Correlation analysis revealed that the frequency of TEMs was positively correlated with MVD. Our findings revealed a significant association between prognostic tumor features, MVD, and the frequency of tumor-infiltrating TEMs in RCC and indicated that TEMs may play an important role in angiogenesis and progression of RCC. Copyright © 2013 Elsevier Inc. All rights reserved.

Insulin-like growth factor-1 signaling in renal cell carcinoma

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Tracz, Adam F.; Szczylik, Cezary; Porta, Camillo; Czarnecka, Anna M.

2016-01-01

Renal cell carcinoma (RCC) incidence is highest in highly developed countries and it is the seventh most common neoplasm diagnosed. RCC management include nephrectomy and targeted therapies. Type 1 insulin-like growth factor (IGF-1) pathway plays an important role in cell proliferation and apoptosis resistance. IGF-1 and insulin share overlapping downstream signaling pathways in normal and cancer cells. IGF-1 receptor (IGF1R) stimulation may promote malignant transformation promoting cell proliferation, dedifferentiation and inhibiting apoptosis. Clear cell renal cell carcinoma (ccRCC) patients with IGF1R overexpression have 70 % increased risk of death compared to patients who had tumors without IGF1R expression. IGF1R signaling deregulation may results in p53, WT, BRCA1, VHL loss of function. RCC cells with high expression of IGF1R are more resistant to chemotherapy than cells with low expression. Silencing of IGF1R increase the chemosensitivity of ccRCC cells and the effect is greater in VHL mutated cells. Understanding the role of IGF-1 signaling pathway in RCC may result in development of new targeted therapeutic interventions. First preclinical attempts with anti-IGF-1R monoclonal antibodies or fragment antigen-binding (Fab) fragments alone or in combination with an mTOR inhibitor were shown to inhibit in vitro growth and reduced the number of colonies formed by of RCC cells

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome.

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Sato, Mototaka; Nakai, Yasutomo; Nakata, Wataru; Yoshida, Takahiro; Hatano, Koji; Kawashima, Atsunari; Fujita, Kazutoshi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio

2013-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC. EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined. EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib. Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome.

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Mototaka Sato

Full Text Available Extracellular matrix metalloproteinase inducer (EMMPRIN has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC.EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined.EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni. EMMPRIN-overexpressing RCC cells were resistant to sunitinib.Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

Progression of Human Renal Cell Carcinoma via Inhibition of RhoA-ROCK Axis by PARG1

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Junichiro Miyazaki

2017-04-01

Full Text Available Renal cell carcinoma (RCC is the most lethal urological malignancy with high risk of recurrence; thus, new prognostic biomarkers are needed. In this study, a new RCC antigen, PTPL1 associated RhoGAP1 (PARG1, was identified by using serological identification of recombinant cDNA expression cloning with sera from RCC patients. PARG1 protein was found to be differentially expressed in RCC cells among patients. High PARG1 expression is significantly correlated with various clinicopathological factors relating to cancer cell proliferation and invasion, including G3 percentage (P = .0046, Ki-67 score (p expression is also correlated with high recurrence of N0M0 patients (P = .0084 and poor prognosis in RCC patients (P = .0345. Multivariate analysis has revealed that high PARG1 expression is an independent factor for recurrence (P = .0149 of N0M0 RCC patients. In in vitro studies, depletion of PARG1by siRNA in human RCC cell lines inhibited their proliferation through inducing G1 cell cycle arrest via upregulation of p53 and subsequent p21Cip1/Waf1, which are mediated by increased RhoA-ROCK activities. Similarly, PARG1 depletion cells inhibited invasion ability via increasing RhoA-ROCK activities in the RCC cell lines. Conversely, overexpression of PARG1 on human embryonic kidney cell line HEK293T promotes its cell proliferation and invasion. These results indicate that PARG1 plays crucial roles in progression of human RCC in increasing cell proliferation and invasion ability via inhibition of the RhoA-ROCK axis, and PARG1 is a poor prognostic marker, particularly for high recurrence of N0M0 RCC patients.

Human Renal Normal, Tumoral, and Cancer Stem Cells Express Membrane-Bound Interleukin-15 Isoforms Displaying Different Functions

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Sandy Azzi

2015-06-01

Full Text Available Intrarenal interleukin-15 (IL-15 participates to renal pathophysiology, but the role of its different membrane-bound isoforms remains to be elucidated. In this study, we reassess the biology of membrane-bound IL-15 (mb-IL-15 isoforms by comparing primary cultures of human renal proximal tubular epithelial cells (RPTEC to peritumoral (ptumTEC, tumoral (RCC, and cancer stem cells (CSC/CD105+. RPTEC express a 14 to 16 kDa mb-IL-15, whose existence has been assumed but never formally demonstrated and likely represents the isoform anchored at the cell membrane through the IL-15 receptor α (IL-15Rα chain, because it is sensitive to acidic treatment and is not competent to deliver a reverse signal. By contrast, ptumTEC, RCC, and CSC express a novel N-hyperglycosylated, short-lived transmembrane mb-IL-15 (tmb-IL-15 isoform around 27 kDa, resistant to acidic shock, delivering a reverse signal in response to its soluble receptor (sIL-15Rα. This reverse signal triggers the down-regulation of the tumor suppressor gene E-cadherin in ptumTEC and RCC but not in CSC/CD105+, where it promotes survival. Indeed, through the AKT pathway, tmb-IL-15 protects CSC/CD105+ from non-programmed cell death induced by serum starvation. Finally, both mb-IL-15 and tmb-IL-15 are sensitive to metalloproteases, and the cleaved tmb-IL-15 (25 kDa displays a powerful anti-apoptotic effect on human hematopoietic cells. Overall, our data indicate that both mb-IL-15 and tmb-IL-15 isoforms play a complex role in renal pathophysiology downregulating E-cadherin and favoring cell survival. Moreover, “apparently normal” ptumTEC cells, sharing different properties with RCC, could contribute to organize an enlarged peritumoral “preneoplastic” environment committed to favor tumor progression.

Potential biological process of X-linked inhibitor of apoptosis protein in renal cell carcinoma based upon differential protein expression analysis.

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Chen, Chao; Zhao, Si Cong; Yang, Wen Zheng; Chen, Zong Ping; Yan, Yong

2018-01-01

The X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the IAP family and is a potent inhibitor of the caspase/apoptosis pathway. It has also been revealed that XIAP has additional biological functions that rely on its direct inhibition of apoptosis. In the present study, stably transfected Caki-1 cells with XIAP-knockdown were generated, and an isobaric tag for relative and absolute quantitation-based proteomics approach was employed to investigate the regulatory mechanism of XIAP in renal cell carcinoma (RCC). The results demonstrate that the sensitivity of the RCC cell line to apoptotic stimulation increased markedly with XIAP-knockdown. A number of differentially expressed proteins were detected between the original Caki-1 cell line and the XIAP-knockdown Caki-1 cell line; 87 at 0 h (prior to etoposide treatment), 178 at 0.5 h and 169 at 3 h, while no differentially expressed proteins were detected (ratio >1.5 or <0.5; P<0.05) at 12 h after etoposide treatment. Through analysis of the differentially expressed proteins, it was revealed that XIAP may participate in the tumor protein p53 pathway, the Wnt signaling pathway, glucose metabolism, endoplasmic reticulum stress, cytoskeletal regulation and DNA repair. These results indicate that XIAP may have a number of biological functions and may provide an insight into the biomedical significance of XIAP overexpression in RCC.

Nuclear localization of the CK2α-subunit correlates with poor prognosis in Clear Cell Renal Cell Carcinoma

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Rabjerg, Maj; Guerra, Barbara; Oliván-Viguera, Aida

2017-01-01

Protein kinase CK2a, one of the two catalytic isoforms of the protein kinase CK2 has been shown to contribute to tumor development, tumor proliferation and suppression of apoptosis in various malignancies. We conducted this study to investigate CK2 expression in different subtypes of Renal Cell...... Carcinoma (RCC) and in the benign oncocytoma. qRT-PCR, immunohistochemistry and Western blot analyses revealed that CK2a expression was significantly increased at the mRNA and protein levels in clear cell RCC (ccRCC). Also the kinase activity of CK2 was significantly increased in ccRCC compared to normal...... renal cortex. Nuclear protein expression of CK2a correlated in univariate analysis with poor Progression Free Survival (HR = 8.11, p = 0.016). Functional analyses (cell proliferation assay) revealed an inhibitory effect of Caki-2 cell growth following CK2 inhibition with CX-4945. Our results suggest...

Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo.

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Xiao-Dong Pan

Full Text Available Mammalian target of rapamycin (mTORin renal cell carcinoma (RCC represents a valuable oncotarget for treatment. We here tested the potential anti-RCC activity by a novel mTOR kinase inhibitor WYE-687in vitro and in vivo.WYE-687 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498 and primary human RCC cells. Yet, it was non-cytotoxic toHK-2 tubular epithelial cells.WYE-687 provoked caspase-dependent apoptosis in the RCC cells. At the molecular level, WYE-687 almost completely blocked mTORC1 (p-S6K1 and p-S6 and mTORC2 (p-Akt Ser 473 activation in both 786-Ocells and primary human RCC cells, where it downregulated both hypoxia-inducible factor (HIF-1α and HIF-2α expression. Significantly, oral administration of WYE-687 potently suppressed786-O tumor xenograft growth in nude mice. mTORC1/2 activation and HIF-1α/2α expression were also remarkably downregulated in WYE-687-treated tumor tissues. Thus, our preclinical results imply that WYE-687 may have important translational value for the treatment of RCC.

The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells.

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Koochekpour, S; Jeffers, M; Wang, P H; Gong, C; Taylor, G A; Roessler, L M; Stearman, R; Vasselli, J R; Stetler-Stevenson, W G; Kaelin, W G; Linehan, W M; Klausner, R D; Gnarra, J R; Vande Woude, G F

1999-09-01

Loss of function in the von Hippel-Lindau (VHL) tumor suppressor gene occurs in familial and most sporadic renal cell carcinomas (RCCs). VHL has been linked to the regulation of cell cycle cessation (G(0)) and to control of expression of various mRNAs such as for vascular endothelial growth factor. RCC cells express the Met receptor tyrosine kinase, and Met mediates invasion and branching morphogenesis in many cell types in response to hepatocyte growth factor/scatter factor (HGF/SF). We examined the HGF/SF responsiveness of RCC cells containing endogenous mutated (mut) forms of the VHL protein (VHL-negative RCC) with that of isogenic cells expressing exogenous wild-type (wt) VHL (VHL-positive RCC). We found that VHL-negative 786-0 and UOK-101 RCC cells were highly invasive through growth factor-reduced (GFR) Matrigel-coated filters and exhibited an extensive branching morphogenesis phenotype in response to HGF/SF in the three-dimensional (3D) GFR Matrigel cultures. In contrast, the phenotypes of A498 VHL-negative RCC cells were weaker, and isogenic RCC cells ectopically expressing wt VHL did not respond at all. We found that all VHL-negative RCC cells expressed reduced levels of tissue inhibitor of metalloproteinase 2 (TIMP-2) relative to the wt VHL-positive cells, implicating VHL in the regulation of this molecule. However, consistent with the more invasive phenotype of the 786-0 and UOK-101 VHL-negative RCC cells, the levels of TIMP-1 and TIMP-2 were reduced and levels of the matrix metalloproteinases 2 and 9 were elevated compared to the noninvasive VHL-positive RCC cells. Moreover, recombinant TIMPs completely blocked HGF/SF-mediated branching morphogenesis, while neutralizing antibodies to the TIMPs stimulated HGF/SF-mediated invasion in vitro. Thus, the loss of the VHL tumor suppressor gene is central to changes that control tissue invasiveness, and a more invasive phenotype requires additional genetic changes seen in some but not all RCC lines. These

Type-I interferon receptor expression: its circadian rhythm and downregulation after interferon-alpha administration in peripheral blood cells from renal cancer patients.

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Shiba, Masahiro; Nonomura, Norio; Nakai, Yasutomo; Nakayama, Masashi; Takayama, Hitoshi; Inoue, Hitoshi; Tsujimura, Akira; Nishimura, Kazuo; Okuyama, Akihiko

2009-04-01

To investigate the regulation of interferon-alpha (IFN-alpha) receptor expression in metastatic renal cell carcinoma (RCC) after IFN-alpha administration. Blood sampling was carried out in eight patients with metastatic RCC and six healthy volunteers. Flow-cytometric analysis using a monoclonal antibody against the active subunit of the type-I IFN-alpha receptor (IFNAR2) was carried out to examine the circadian rhythm of IFNAR2 expression in peripheral blood mononuclear cells (PBMC) as well as its downregulation after IFN-alpha administration. According to its circadian rhythm IFNAR2 in PBMC had a peak expression at night. Once IFN-alpha is administered, IFNAR2 levels in PBMC showed downregulation within 48 h and recovered within another 48 h. Our findings might support the establishment of an optimal schedule for IFN-alpha administration.

A PHASE II STUDY OF GEMCITABINE AND CAPECITABINE IN PATIENTS WITH ADVANCED RENAL CELL CANCER (RCC): SOUTHWEST ONCOLOGY GROUP STUDY S0312

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Van Veldhuizen, Peter J.; Hussey, Michael; Lara, Primo N.; Mack, Philip C.; Gandour-Edwards, Regina; Clark, Joseph I.; Lange, Marianne K.; Crawford, E. David

2010-01-01

Background Gemcitabine plus capecitabine has modest efficacy in patients with advanced RCC but has considerable toxicity. We evaluated the efficacy and toxicity of a modified dose-schedule of this doublet in patients with advanced unresectable or metastatic RCC. Methods Chemotherapy-naïve patients were treated with gemcitabine at 900mg/m2 on days 1,8,15 and capecitabine at 625mg/m2 twice daily on days 1 through 21, every 28 days. Eligible patients must have adequate performance status and end-organ function. The primary endpoint was tumor response rate (RR). No further evaluation of this regimen would be pursued if the RR was ≤ 5%. In an exploratory manner using archival specimens, we also evaluated potential markers of prognosis and treatment response including thymidylate synthase (TS) gene polymorphisms and tumor expression of p53, PTEN, pAKT, pmTOR, and ERCC1. Results Of 43 patients registered, 1 was ineligible and 2 were not analyzable. There was 1 confirmed complete response (CR) and three unconfirmed partial responses (PR), for an overall response rate of 10% (95% CI: 3, 24). Nineteen patients (48%) had stable disease (SD). The six-month freedom-from-treatment-failure and overall survival rates were 20% (95% CI: 8, 32) and 75% (95% CI: 62, 88), respectively. Median survival time was 23 months (95% CI: 10, 37). One patient each experienced Grade 4 neutropenia, fatigue, thrombocytopenia and hemolysis with renal failure. The most common Grade 3 toxicities were neutropenia (12 patients), fatigue (5), and leucopenia (4). Patients with a best response of stable disease or better were more likely to have a decrease in expression of PTEN and an increased expression of pmTOR. Conclusions Gemcitabine plus capecitabine at this reduced dose-schedule benefits a small percentage of patients with RCC with an acceptable toxicity profile. The combination of gemcitabine and capecitabine may serve as a base regimen for combination therapy with targeted agents in select RCC

Screening disrupted molecular functions and pathways associated with clear cell renal cell carcinoma using Gibbs sampling.

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Nan, Ning; Chen, Qi; Wang, Yu; Zhai, Xu; Yang, Chuan-Ce; Cao, Bin; Chong, Tie

2017-10-01

To explore the disturbed molecular functions and pathways in clear cell renal cell carcinoma (ccRCC) using Gibbs sampling. Gene expression data of ccRCC samples and adjacent non-tumor renal tissues were recruited from public available database. Then, molecular functions of expression changed genes in ccRCC were classed to Gene Ontology (GO) project, and these molecular functions were converted into Markov chains. Markov chain Monte Carlo (MCMC) algorithm was implemented to perform posterior inference and identify probability distributions of molecular functions in Gibbs sampling. Differentially expressed molecular functions were selected under posterior value more than 0.95, and genes with the appeared times in differentially expressed molecular functions ≥5 were defined as pivotal genes. Functional analysis was employed to explore the pathways of pivotal genes and their strongly co-regulated genes. In this work, we obtained 396 molecular functions, and 13 of them were differentially expressed. Oxidoreductase activity showed the highest posterior value. Gene composition analysis identified 79 pivotal genes, and survival analysis indicated that these pivotal genes could be used as a strong independent predictor of poor prognosis in patients with ccRCC. Pathway analysis identified one pivotal pathway - oxidative phosphorylation. We identified the differentially expressed molecular functions and pivotal pathway in ccRCC using Gibbs sampling. The results could be considered as potential signatures for early detection and therapy of ccRCC. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prognostic significance of overexpressed long non-coding RNA TUG1 in patients with clear cell renal cell carcinoma.

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Wang, P-Q; Wu, Y-X; Zhong, X-D; Liu, B; Qiao, G

2017-01-01

The long non-coding RNAs (lncRNAs) study has gradually become one of the hot topics in the field of RNA biology. However, little is known about the pathological role of lncRNA TUG1 in clear cell renal cell carcinoma (ccRCC) patients. This study attempted to investigate the association of lncRNA TUG1 expression with progression and prognosis in ccRCC patients. Using qRT-PCR, the expression of TUG1 was measured in 203 ccRCC tissues and 45 adjacent non-cancerous tissues. Then, the relationships between TUG1 level and the clinicopathological factors of patients with ccRCC were analyzed. The prognostic significance was evaluated using Kaplan-Meier and Cox regression analyses. The relative level of TUG1was significantly higher in ccRCC tissues compared to the adjacent non-tumor tissues (p TUG1 was associated significantly with histological grade, tumor stage, lymph node metastasis and distant metastasis (all p TUG1 expression levels were associated with a shorter overall survival (p TUG1 expression was an independent prognostic marker of poor outcome. These findings suggested that TUG1 may act as a tumor promoter in ccRCC and could serve as a potential therapeutic target for this tumor.

Triiodothyronine regulates cell growth and survival in renal cell cancer.

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Czarnecka, Anna M; Matak, Damian; Szymanski, Lukasz; Czarnecka, Karolina H; Lewicki, Slawomir; Zdanowski, Robert; Brzezianska-Lasota, Ewa; Szczylik, Cezary

2016-10-01

Triiodothyronine plays an important role in the regulation of kidney cell growth, differentiation and metabolism. Patients with renal cell cancer who develop hypothyreosis during tyrosine kinase inhibitor (TKI) treatment have statistically longer survival. In this study, we developed cell based model of triiodothyronine (T3) analysis in RCC and we show the different effects of T3 on renal cell cancer (RCC) cell growth response and expression of the thyroid hormone receptor in human renal cell cancer cell lines from primary and metastatic tumors along with human kidney cancer stem cells. Wild-type thyroid hormone receptor is ubiquitously expressed in human renal cancer cell lines, but normalized against healthy renal proximal tube cell expression its level is upregulated in Caki-2, RCC6, SKRC-42, SKRC-45 cell lines. On the contrary the mRNA level in the 769-P, ACHN, HKCSC, and HEK293 cells is significantly decreased. The TRβ protein was abundant in the cytoplasm of the 786-O, Caki-2, RCC6, and SKRC-45 cells and in the nucleus of SKRC-42, ACHN, 769-P and cancer stem cells. T3 has promoting effect on the cell proliferation of HKCSC, Caki-2, ASE, ACHN, SK-RC-42, SMKT-R2, Caki-1, 786-0, and SK-RC-45 cells. Tyrosine kinase inhibitor, sunitinib, directly inhibits proliferation of RCC cells, while thyroid hormone receptor antagonist 1-850 (CAS 251310‑57-3) has less significant inhibitory impact. T3 stimulation does not abrogate inhibitory effect of sunitinib. Renal cancer tumor cells hypostimulated with T3 may be more responsive to tyrosine kinase inhibition. Moreover, some tumors may be considered as T3-independent and present aggressive phenotype with thyroid hormone receptor activated independently from the ligand. On the contrary proliferation induced by deregulated VHL and or c-Met pathways may transgress normal T3 mediated regulation of the cell cycle.

Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma.

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Griffith, Thomas S; Fialkov, Jonathan M; Scott, David L; Azuhata, Takeo; Williams, Richard D; Wall, Nathan R; Altieri, Dario C; Sandler, Anthony D

2002-06-01

The lack of effective therapy for disseminated renal cell carcinoma (RCC) has stimulated the search for novel treatments including immunotherapeutic strategies. However, poor therapeutic responses and marked toxicity associated with immunological agents has limited their use. The tumor necrosis factor family member tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2 ligand induces apoptosis in a variety of tumor cell types, while having little cytotoxic activity against normal cells. In this study the activation and regulation of TRAIL-induced apoptosis and TRAIL receptor expression in human RCC cell lines and pathologic specimens was examined. TRAIL induced caspase-mediated apoptotic death of RCC cells with variable sensitivities among the cell lines tested. Compared with TRAIL-sensitive RCC cell lines (A-498, ACHN, and 769-P), the TRAIL-resistant RCC cell line (786-O) expressed lesser amounts of the death-inducing TRAIL receptors, and greater amounts of survivin, an inhibitor of apoptosis. Incubation of 786-O with actinomycin D increased the expression of the death-inducing TRAIL receptors and, concomitantly, decreased the intracellular levels of survivin, resulting in TRAIL-induced apoptotic death. The link between survivin and TRAIL regulation was confirmed when an increase in TRAIL resistance was observed after overexpression of survivin in the TRAIL-sensitive, survivin-negative RCC line A-498. These findings, along with our observation that TRAIL receptors are expressed in RCC tumor tissue, suggest that TRAIL may be useful as a therapeutic agent for RCC and that survivin may partially regulate TRAIL-induced cell death.

Aqueous Extract of Paeonia suffruticosa Inhibits Migration and Metastasis of Renal Cell Carcinoma Cells via Suppressing VEGFR-3 Pathway

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Shih-Chin Wang

2012-01-01

Full Text Available Renal cell carcinoma (RCC cells are characterized by strong drug resistance and high metastatic incidence. In this study, the effects of ten kinds of Chinese herbs on RCC cell migration and proliferation were examined. Aqueous extract of Paeonia suffruticosa (PS-A exerted strong inhibitory effects on cancer cell migration, mobility, and invasion. The results of mouse xenograft experiments showed that the treatment of PS-A significantly suppressed tumor growth and pulmonary metastasis. We further found that PS-A markedly decreased expression of VEGF receptor-3 (VEGFR-3 and phosphorylation of FAK in RCC cells. Moreover, the activation of Rac-1, a modulator of cytoskeletal dynamics, was remarkably reduced by PS-A. Additionally, PS-A suppressed polymerization of actin filament as demonstrated by confocal microscopy analysis and decreased the ratio of F-actin to G-actin in RCC cells, suggesting that PS-A inhibits RCC cell migration through modulating VEGFR-3/FAK/Rac-1 pathway to disrupt actin filament polymerization. In conclusion, this research elucidates the effects and molecular mechanism for antimigration of PS-A on RCC cells and suggests PS-A to be a therapeutic or adjuvant strategy for the patients with aggressive RCC.

Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer.

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Bouquerel, P; Gstalder, C; Müller, D; Laurent, J; Brizuela, L; Sabbadini, R A; Malavaud, B; Pyronnet, S; Martineau, Y; Ader, I; Cuvillier, O

2016-03-14

The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (VHL) gene and expressing high levels of HIF-2α, SphK1 activity controls HIF-2α expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2α loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2α accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P1) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2α in diverse cancer cell lineages notably ccRCC, where HIF-2α has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2α expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC.

Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma

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Meyer Werner

2010-10-01

Full Text Available Abstract Background Renal cell carcinoma (RCC represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. Methods We characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated. Results The highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3α-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3β and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters. Conclusion Increased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3α favours recruitment of immature DCs to the tumour bed, whereas de novo local expression of SLC and MIP-3β induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response.

Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma

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Middel, Peter; Brauneck, Sven; Meyer, Werner; Radzun, Heinz-Joachim

2010-01-01

Renal cell carcinoma (RCC) represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. We characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated. The highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3α-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3β and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters. Increased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3α favours recruitment of immature DCs to the tumour bed, whereas de novo local expression of SLC and MIP-3β induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response

HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients.

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Wang, Jiajun; Liu, Li; Qu, Yang; Xi, Wei; Xia, Yu; Bai, Qi; Xiong, Ying; Long, Qilai; Xu, Jiejie; Guo, Jianming

2018-01-01

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort. In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

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Christopher J. Ricketts

2018-04-01

Full Text Available Summary: Renal cell carcinoma (RCC is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD ChRCC that associated with extremely poor survival. : Ricketts et al. find distinctive features of each RCC subtype, providing the foundation for development of subtype-specific therapeutic and management strategies. Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes. Keywords: clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, CDKN2A, DNA hypermethylation, immune signature, chromatin remodeling, TCGA, PanCanAtlas

Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo.

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Chang, De-Kuan; Moniz, Raymond J; Xu, Zhongyao; Sun, Jiusong; Signoretti, Sabina; Zhu, Quan; Marasco, Wayne A

2015-06-11

Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). Therapeutic approaches targeting CAIX have focused on the development of CAIX inhibitors and specific immunotherapies including monoclonal antibodies (mAbs). However, current in vivo mouse models used to characterize the anti-tumor properties of fully human anti-CAIX mAbs have significant limitations since the role of human effector cells in tumor cell killing in vivo is not directly evaluated. The role of human anti-CAIX mAbs on CAIX(+) RCC tumor cell killing by immunocytes or complement was tested in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) as well as on CAIX(+) RCC cellular motility, wound healing, migration and proliferation. The in vivo therapeutic activity mediated by anti-CAIX mAbs was determined by using a novel orthotopic RCC xenograft humanized animal model and analyzed by histology and FACS staining. Our studies demonstrate the capacity of human anti-CAIX mAbs that inhibit CA enzymatic activity to result in immune-mediated killing of RCC, including nature killer (NK) cell-mediated ADCC, CDC, and macrophage-mediated ADCP. The killing activity correlated positively with the level of CAIX expression on RCC tumor cell lines. In addition, Fc engineering of anti-CAIX mAbs was shown to enhance the ADCC activity against RCC. We also demonstrate that these anti-CAIX mAbs inhibit migration of RCC cells in vitro. Finally, through the implementation of a novel orthotopic RCC model utilizing allogeneic human peripheral blood mononuclear cells in NOD/SCID/IL2Rγ(-/-) mice, we show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in

Intracellular lipid in papillary renal cell carcinoma (pRCC): T2 weighted (T2W) MRI and pathologic correlation

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Schieda, Nicola; Van der Pol, Christian B.; Moosavi, Bardia; McInnes, Matthew D.F. [The Ottawa Hospital, The University of Ottawa, Department of Medical Imaging, Ottawa, Ontario (Canada); Mai, Kien T.; Flood, Trevor A. [The Ottawa Hospital, The University of Ottawa, Department of Anatomical Pathology, Ottawa, Ontario (Canada)

2015-07-15

To evaluate if pRCCs demonstrate intracellular lipid (i-lipid) at chemical-shift (CS) MRI, and assess T2W-MRI and pathologic characteristics. Sixty-two patients with a pRCC diagnosis underwent MRI over 11 years (IRB-approved). Two radiologists independently assessed for presence of i-lipid on CS-MRI and homogeneity on T2W-MRI. Inter-observer agreement was assessed via an intraclass correlation and results were compared using the Chi-square test. Discordant cases were reviewed to establish consensus. T2W SI-ratios (SI.tumor/SI.kidney) and CS-SI index were compared using independent t-tests and Spearman correlation. Two pathologists re-evaluated the histopathology. Nine of the 62 pRCCs (14.5 %) demonstrated i-lipid; agreement was moderate (ICC = 0.63). Pathology review depicted clear cells in four tumours and foamy histiocytes in five tumours. 25.8-35.4 % (ICC = 0.65) of tumours were homogeneous on T2W-MRI. No pRCC with i-lipid was considered homogeneous (p = 0.01-0.04). Overall, T2W SI-ratio and CS-SI index were 0.89 (±0.29) and -3.63 % (-7.27 to 11.42). pRCC with i-lipid had significantly higher T2W SI-ratio (p = 0.003). There was a correlation between the CS-SI index and T2W SI-ratio, (r = 0.44, p < 0.001). Intracellular lipid is uncommonly detected in pRCCs due to clear cell changes and foamy histiocytes. These tumours are associated with heterogeneously-increased SI in T2W-MRI. (orig.)

Tumor signatures of PTHLH overexpression, high serum calcium, and poor prognosis were observed exclusively in clear cell but not non clear cell renal carcinomas

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Yao, Masahiro; Murakami, Takayuki; Shioi, Koichi; Mizuno, Nobuhiko; Ito, Hiroki; Kondo, Keiichi; Hasumi, Hisashi; Sano, Futoshi; Makiyama, Kazuhide; Nakaigawa, Noboru; Kishida, Takeshi; Nagashima, Yoji; Yamanaka, Shoji; Kubota, Yoshinobu

2014-01-01

High serum calcium (Ca) due to aberrant secretion of tumor parathyroid hormone-like hormone (PTHLH) is a well-known paraneoplastic sign and is associated with poor prognosis in patients with renal cell carcinoma (RCC). However, the status of serum Ca and tumor PTHLH expression have not been verified using the 2004 World Health Organization (WHO) renal tumor classification. We retrospectively reviewed corrected serum Ca levels at initial onset (n = 683) and/or as of recurrence (n = 71) in patients with RCC. We also examined a total of 623 renal parenchymal tumor samples for PTHLH mRNA expressions by quantitative real-time PCR. High serum Ca concomitant with PTHLH overexpression in tumors was observed exclusively in clear cell RCC but not in other non clear cell subtype tumors, including papillary, chromophobe, collecting-duct, unclassified, and other rare subtype RCCs or in benign oncocytomas and angiomyolipomas. In clear cell RCC, PTHLH expression was significantly high in male patients, and was associated with a symptomatic presentation, higher grade, and higher stage cases, whereas it was not associated with VHL gene status. Univariate analyses demonstrated that high PTHLH expression was strongly associated with poor outcome both in overall survival (OS) and disease-free survival (DFS) for patients who underwent standard nephrectomy. Further multivariate Cox analyses revealed that the PTHLH expressions remained as independent prognostic parameters for OS but not for DFS. These data suggest that the previously characterized tumor signatures of high serum Ca due to high PTHLH expression and poor prognosis are clear cell RCC-specific features, whereas these characteristics are rare in non clear cell RCCs

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients.

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Roseweir, Antonia K; Qayyum, Tahir; Lim, Zhi; Hammond, Rachel; MacDonald, Alasdair I; Fraser, Sioban; Oades, Grenville M; Aitchison, Michael; Jones, Robert J; Edwards, Joanne

2016-03-16

8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.

RCC1 regulates inner centromeric composition in a Ran-independent fashion.

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Zhang, Michael Shaofei; Furuta, Maiko; Arnaoutov, Alexei; Dasso, Mary

2018-01-01

RCC1 associates to chromatin dynamically within mitosis and catalyzes Ran-GTP production. Exogenous RCC1 disrupts kinetochore structure in Xenopus egg extracts (XEEs), but the molecular basis of this disruption remains unknown. We have investigated this question, utilizing replicated chromosomes that possess paired sister kinetochores. We find that exogenous RCC1 evicts a specific subset of inner KT proteins including Shugoshin-1 (Sgo1) and the chromosome passenger complex (CPC). We generated RCC1 mutants that separate its enzymatic activity and chromatin binding. Strikingly, Sgo1 and CPC eviction depended only on RCC1's chromatin affinity but not its capacity to produce Ran-GTP. RCC1 similarly released Sgo1 and CPC from synthetic kinetochores assembled on CENP-A nucleosome arrays. Together, our findings indicate RCC1 regulates kinetochores at the metaphase-anaphase transition through Ran-GTP-independent displacement of Sgo1 and CPC.

Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma

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Qing Zhang

2017-01-01

Full Text Available The chimeric antigen receptor-modified immune effector cell (CAR-T and CAR-NK therapies are newly developed adoptive treatments of cancers. However, their therapeutic efficacy against solid tumors is limited. Combining CAR-T or CAR-NK cells with chemotherapeutic drugs to treat solid tumor may be a promising strategy. We developed an epidermal growth factor- (EGFR- specific third-generation CAR. NK-92 cells were modified with the CAR by lentivirus infection. The specific killing ability of the CAR-modified NK-92 cells (CAR-NK-92 against renal cell carcinoma (RCC cell lines was confirmed in vitro. The synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells were investigated in vitro and in vivo. Our results showed that the CAR-NK-92 cells lyse RCC cells in an EGFR-specific manner. Treatment with cabozantinib could increase EGFR and decrease PD-L1 membrane surface expression in RCC cells and enhance the killing ability of CAR-NK-92 cells against the RCC cells in vitro. Furthermore, the CAR-NK-92 cells show synergistic therapeutic efficacy with cabozantinib against human RCC xenograft models. Our results provided the basis for combination with chemotherapy as a novel strategy for enhancing the therapeutic efficacy of CAR-modified immune effector cells for solid tumors.

Harnessing the p53-PUMA Axis to Overcome DNA Damage Resistance in Renal Cell Carcinoma

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Xiaoguang Zhou

2014-12-01

Full Text Available Resistance to DNA damage–induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC. This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage–induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA. We demonstrate that this disconnect is not caused by gene-specific repression through CCCTC-binding factor (CTCF but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage–induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients.

Comparison of clinicopathological parameters with FoxM1 expression in renal cell carcinoma

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Sezen Kocarslan

2014-01-01

Conclusion: This study showed that FoxM1 have a progressive oncogenic role in ccRRC. Our results suggested that higher expression of FoxM1 in tumor tissues predicts a locally aggressive behavior and poor outcome of patients with ccRCC, but not in patient with non-ccRCC.

Coronin-1C and RCC2 guide mesenchymal migration by trafficking Rac1 and controlling GEF exposure

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Williamson, Rosalind C.; Cowell, Christopher A. M.; Hammond, Christina L.; Bergen, Dylan J. M.; Roper, James A.; Feng, Yi; Rendall, Thomas C. S.; Race, Paul R.; Bass, Mark D.

2014-01-01

ABSTRACT Sustained forward migration through a fibrillar extracellular matrix requires localization of protrusive signals. Contact with fibronectin at the tip of a cell protrusion activates Rac1, and for linear migration it is necessary to dampen Rac1 activity in off-axial positions and redistribute Rac1 from non-protrusive membrane to the leading edge. Here, we identify interactions between coronin-1C (Coro1C), RCC2 and Rac1 that focus active Rac1 to a single protrusion. Coro1C mediates release of inactive Rac1 from non-protrusive membrane and is necessary for Rac1 redistribution to a protrusive tip and fibronectin-dependent Rac1 activation. The second component, RCC2, attenuates Rac1 activation outside the protrusive tip by binding to the Rac1 switch regions and competitively inhibiting GEF action, thus preventing off-axial protrusion. Depletion of Coro1C or RCC2 by RNA interference causes loss of cell polarity that results in shunting migration in 1D or 3D culture systems. Furthermore, morpholinos against Coro1C or RCC2, or mutation of any of the binding sites in the Rac1–RCC2–Coro1C complex delays the arrival of neural crest derivatives at the correct location in developing zebrafish, demonstrating the crucial role in migration guidance in vivo. PMID:25074804

Identification and validation of novel prognostic markers in Renal Cell Carcinoma.

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Rabjerg, Maj

2017-10-01

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

Estramustine-binding protein (EMBP) in renal cell carcinoma immunohistochemistry, immunoscintigraphy and in vitro estramustine effects

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Edgren, M.; Westlin, J.E.; Letocha, H.; Nordgren, H.; Kaelkner, K.M.; Nilsson, S.

1996-01-01

The present report shows that the human renal cell carcinoma (RCC) cell lines, A498 and CAKI-2, express the estramustine-binding protein (EMBP). The RCC cell lines investigated were highly sensitive for estramustine, with cell arrest in atypical metaphase. In vitro experiments using a fluorimetric cytotoxicity assay (FMCA) showed a pronounced cytotoxic effect mediate by estramustine. Immunohistochemical analysis of tumoru specimens from patients with RCC showed positive staining for EMBP in 12/16 cases. Immunoscintigraphy was performed in an experimental system in nude mice, heterotransplanted with the CAKI-2 cell line. A radiolabelled monoclonal anti-EMBP antibody was used. The results show a specific uptake of the antibody in the RCC tumour, expressed as a percentage of the injected dose per gram tissue, which ranged from 4.03 to 6.9. The results obtained from the basis for clinical studies on the feasibility of utilizing estramustine in the management of RCC. Immunoscintigraphy using the monoclonal anti-EMBP antibody is of potential use for in vivo characterization of the malignancy and in the selection patients suitable for treatment with estramustine. (orig.)

Overexpression of SATB1 is associated with biologic behavior in human renal cell carcinoma.

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Chao Cheng

Full Text Available Special AT-rich sequence-binding protein-1 (SATB1 has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of SATB1 in RCC remains unclear. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of SATB1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both, and upregulation of SATB1 was significantly associated with depth of invasion (P<0.001, lymph node status (P = 0.001 and TNM stage (P = 0.009. SATB1 knockdown inhibited the proliferation, migration and invasion of 786-O cells, whereas SATB1 overexpression promoted the growth and aggressive phenotype of ACHN cells in vitro. Furthermore, SATB1 expression was positively correlated with ZEB2 expression (P = 0.013, and inversely linked to levels of SATB2 and E-cadherin (P = 0.005 and P<0.001, respectively in ccRCC tissues. Our data provide a basis for the concept that overexpression of SATB1 may play a critical role in the acquisition of an aggressive phenotype for RCC cells through EMT, providing new insights into the significance of SATB1 in invasion and metastasis of ccRCC, which may contribute to fully elucidating the exact mechanism of development and progression of RCC.

A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases

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Jhaveri, Pavan M. [Dept. of Radiology, Section of Radiation Oncology, Baylor College of Medicine, Houston (United States); Teh, Bin S.; Paulino, Arnold C.; Blanco, Angel I.; Butler, E. Brian [Dept. of Radiation Oncology, The Methodist Hospital/The Methodist Hospital Research Inst., Houston (United States)], email: bteh@tmhs.org; Lo, Simon S. [Dept. of Radiation Oncology, Univ. Hospitals Seidman Cancer Center, Case Western Reserve Univ., Cleveland (United States); Amato, Robert J. [Dept. of Internal Medicine, Div. of Oncology, Univ. of Texas Health Sciences Center, Houston (United States)

2012-05-15

Background. To investigate the utility of stereotactic body radiotherapy (SBRT) in the treatment of painful renal cell carcinoma (RCC) bone metastases, and for a possible dose effect on time to symptom relief. Material and methods. Eighteen patients with 24 painful osseous lesions from metastatic RCC were treated with SBRT. The most common treatment regimens were 24 Gy in 3 fractions and 40 Gy in 5 fractions. The times from treatment to first reported pain relief and time to symptom recurrence were evaluated. Median follow-up was 38 weeks (1-156 weeks). Results. Seventy-eight percent of all patients had pain relief. Patients treated with a BED > 85 Gy achieved faster and more durable pain relief compared to those treated with a BED < 85 Gy. There was decrease in time to pain relief after a change in treatment regimen to 8 Gy x 5 fractions (BED = 86). There was only one patient with grade 1 skin toxicity. No neurological or other toxicity was observed. Conclusions. SBRT can safely and effectively treat painful RCC bony metastases. There appears to be a relationship between radiation dose and time to stable pain relief.

Immunohistochemical expression of CD44s in renal cell carcinoma lacks independent prognostic significance

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Walter Henriques da Costa

2012-08-01

Full Text Available PURPOSE: To analyze the immunohistochemical expression of the standard isoform of CD44 (CD44s adhesion molecule in clear cell renal cell carcinoma (CCRCC and its impact on clinical outcomes. MATERIALS AND METHODS: Ninety-nine consecutive patients treated surgically for RCC between 1992 and 2009 were selected. A single pathologist reviewed all cases to effect a uniform reclassification and determine the most representative tumor areas for construction of a tissue microarray. The same pathologist, who was blinded to the outcome of the cases, semi-quantitatively scored the staining intensity of CD44s in all specimens. The counting was done using the H-Score algorithm. RESULTS: Of the 99 immunostained RCC specimens, 57(57.7% showed low expression, and 42(42.4% showed high expression levels of CD44s. The expression of CD44s was directly associated with tumor size (p = 0.03, clinical stage (p = 0.02 and Fuhrman grade (p = 0.02. Disease specific survival (DSS rates for patients whose specimens expressed low and high levels of CD44s was 88.1% and 67.5%, respectively (p = 0.009. Progression free survival (PFS rates in patients with low and high expression of CD44s were 78.8% and 61.7%, respectively (p = 0.05. Classical features such as the presence of metastasis and clinical stage remained isolated predictors of survival. CONCLUSIONS: Immunohistochemical expression of CD44s was associated with important clinical variables such as stage and Fuhrman grade. However, it was not an independent predictor of survival. Therefore, we believe it has a limited role as a prognostic marker in patients with CCRCC.

A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).

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Atchison, Elizabeth; Eklund, John; Martone, Brenda; Wang, Lili; Gidron, Adi; Macvicar, Gary; Rademaker, Alfred; Goolsby, Charles; Marszalek, Laura; Kozlowski, James; Smith, Norm; Kuzel, Timothy M

2010-09-01

High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness

NARCIS (Netherlands)

C.H.J. Lamers (Cor); S. van Steenbergen-Langeveld (Sabine); M. van Brakel (Mandy); C.M. Groot-van Ruijven (Corrien); P.M.M.L. van Elzakker (Pascal); B.A. van Krimpen (Brigitte); S. Sleijfer (Stefan); J.E.M.A. Debets (Reno)

2014-01-01

textabstractTherapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T

Sequential Ground Motion Effects on the Behavior of a Base-Isolated RCC Building

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Zhi Zheng

2017-01-01

Full Text Available The sequential ground motion effects on the dynamic responses of reinforced concrete containment (RCC buildings with typical isolators are studied in this paper. Although the base isolation technique is developed to guarantee the security and integrity of RCC buildings under single earthquakes, seismic behavior of base-isolated RCC buildings under sequential ground motions is deficient. Hence, an ensemble of as-recorded sequential ground motions is employed to study the effect of including aftershocks on the seismic evaluation of base-isolated RCC buildings. The results indicate that base isolation can significantly attenuate the earthquake shaking of the RCC building under not only single earthquakes but also seismic sequences. It is also found that the adverse aftershock effect on the RCC can be reduced due to the base isolation applied to the RCC. More importantly, the study indicates that disregarding aftershocks can induce significant underestimation of the isolator displacement for base-isolated RCC buildings.

Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells.

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Chintalapudi, Mastan R; Markiewicz, Margaret; Kose, Nurgun; Dammai, Vincent; Champion, Kristen J; Hoda, Rana S; Trojanowska, Maria; Hsu, Tien

2008-04-01

The von Hippel-Lindau (VHL) protein serves as a negative regulator of hypoxia-inducible factor (HIF)-alpha subunits. Since HIF regulates critical angiogenic factors such as vascular endothelial growth factor (VEGF) and lesions in VHL gene are present in a majority of the highly vascularized renal cell carcinoma (RCC), it is believed that deregulation of the VHL-HIF pathway is crucial for the proangiogenic activity of RCC. Although VEGF has been confirmed as a critical angiogenic factor upregulated in VHL-mutant cells, the efficacy of antiangiogenic therapy specifically targeting VEGF signaling remains modest. In this study, we developed a three-dimensional in vitro assay to evaluate the ability of RCC cells to promote cord formation by the primary human dermal microvascular endothelial cells (HDMECs). Compared with VHL wild-type cells, VHL-mutant RCC cells demonstrated a significantly increased proangiogenic activity, which correlated with increased secretion of cysteine-rich 61 (Cyr61)/cysteine-rich 61-connective tissue growth factor-nephroblastoma overexpressed (CCN) 1, connective tissue growth factor (CTGF)/CCN2 and VEGF in conditioned culture medium. Both CCN proteins are required for HDMEC cord formation as shown by RNA interference knockdown experiments. Importantly, the proangiogenic activities conferred by the CCN proteins and VEGF are additive, suggesting non-overlapping functions. Expression of the CCN proteins is at least partly dependent on the HIF-2alpha function, the dominant HIF-alpha isoform expressed in RCC. Finally, immunohistochemical staining of Cyr61/CCN1 and CTGF/CCN2 in RCC tissue samples showed that increased expression of these proteins correlates with the loss of VHL protein expression. These findings strengthened the notion that the hypervascularized phenotype of RCC is afforded by multiple proangiogenic factors that function in parallel pathways.

Cyr61/CCN1 and CTGF/CCN2 mediate the pro-angiogenic activity of VHL mutant renal carcinoma cells

Science.gov (United States)

Chintalapudi, Mastan R.; Markiewicz, Margaret; Kose, Nurgun; Dammai, Vincent; Champion, Kristen J.; Hoda, Rana S.; Trojanowska, Maria; Hsu, Tien

2008-01-01

The von Hippel-Lindau (VHL) protein serves as a negative regulator of hypoxia inducible factor-alpha subunit (HIF-α). Since HIF regulates critical angiogenic factors such as vascular endothelial growth factor (VEGF) and lesions in VHL gene are present in a majority of the highly vascularized renal cell carcinoma (RCC), it is believed that deregulation of the VHL-HIF pathway is crucial for the pro-angiogenic activity of RCC. Although VEGF has been confirmed as a critical angiogenic factor up-regulated in VHL mutant cells, the efficacy of anti-angiogenic therapy specifically targeting VEGF signaling remains modest. In this study we developed a three-dimensional in vitro assay to evaluate the ability of RCC cells to promote cord formation by the primary human dermal microvascular endothelial cells (HDMECs). Compared to VHL wild-type cells, VHL mutant RCC cells demonstrated a significantly increased pro-angiogenic activity, which correlated with increased secretion of Cyr61/CCN1, CTGF/CCN2 and VEGF in conditioned culture medium. Both CCN proteins are required for HDMEC cord formation as shown by RNAi knock-down experiments. Importantly, the pro-angiogenic activities conferred by the CCN proteins and VEGF are additive, suggesting non-overlapping functions. Expression of the CCN proteins is at least partly dependent on the HIF-2α function, the dominant HIF-α isoform expressed in RCC. Finally, immunohistochemical staining of Cyr61/CCN1 and CTGF/CCN2 in renal cell carcinoma tissue samples showed that increased expression of these proteins correlates with loss of VHL protein expression. These findings strengthened the notion that the hypervascularized phenotype of RCC is afforded by multiple pro-angiogenic factors that function in parallel pathways. PMID:18212329

Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF-κB signaling pathway.

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Li, Gang; Wang, Ziming; Chong, Tie; Yang, Jie; Li, Hongliang; Chen, Haiwen

2017-10-01

The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. Copyright © 2017. Published by Elsevier Masson SAS.

Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma

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Grosso, Ana R; Leite, Ana P; Carvalho, Sílvia; Matos, Mafalda R; Martins, Filipa B; Vítor, Alexandra C; Desterro, Joana MP; Carmo-Fonseca, Maria; de Almeida, Sérgio F

2015-01-01

Aberrant expression of cancer genes and non-canonical RNA species is a hallmark of cancer. However, the mechanisms driving such atypical gene expression programs are incompletely understood. Here, our transcriptional profiling of a cohort of 50 primary clear cell renal cell carcinoma (ccRCC) samples from The Cancer Genome Atlas (TCGA) reveals that transcription read-through beyond the termination site is a source of transcriptome diversity in cancer cells. Amongst the genes most frequently mutated in ccRCC, we identified SETD2 inactivation as a potent enhancer of transcription read-through. We further show that invasion of neighbouring genes and generation of RNA chimeras are functional outcomes of transcription read-through. We identified the BCL2 oncogene as one of such invaded genes and detected a novel chimera, the CTSC-RAB38, in 20% of ccRCC samples. Collectively, our data highlight a novel link between transcription read-through and aberrant expression of oncogenes and chimeric transcripts that is prevalent in cancer. DOI: http://dx.doi.org/10.7554/eLife.09214.001 PMID:26575290

Dynamic contrast-enhanced CT (DCE-CT) as a potential biomarker in patients with metastatic renal cell carcinoma (mRCC)

DEFF Research Database (Denmark)

Mains, Jill Rachel; Donskov, Frede; Pedersen, Erik Morre

Purpose To explore the impact of DCE-CT as a biomarker in mRCC.  Methods and Materials 12 patients with mRCC participating in a phase II trial with immunotherapy and bevacizumab and with a follow-up time of at least 2 years were included in this preliminary analysis. DCE-CT interpretation (max s...

Chemosensitization of Human Renal Cell Cancer Using Antisense Oligonucleotides Targeting the Antiapoptotic Gene Clusterin

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Tobias Zellweger

2001-01-01

Full Text Available BACKGROUND: Renal cell cancer (RCC is a chemoresistant disease with no active chemotherapeutic agent achieving objective response rates higher than 15%. Clusterin is a cell survival gene that increases in human renal tubular epithelial cells after various states of injury and disease. Downregulation of clusterin, using antisense oligonucleotides (ASO, has recently been shown to increase chemosensitivity in several prostate cancer models. The objectives in this study were to evaluate clusterin expression levels in human RCC and normal kidney tissue, and to test whether clusterin ASO could also enhance chemosensitivity in human RCC Caki-2 cells both in vitro and in vivo. METHODS: Immunohistochemical staining was used to characterize clusterin expression in 67 RCC and normal kidney tissues obtained from radical nephrectomy specimens. Northern blot analysis was used to assess changes in clusterin mRNA expression after ASO and paclitaxel treatment. The effects of combined clusterin ASO and paclitaxel treatment on Caki-2 cell growth was examined using an MTT assay. Athymic mice bearing Caki-2 tumors were treated with clusterin ASO alone, clusterin ASO plus paclitaxel, and mismatch control oligonucleotides plus paclitaxel, over a period of 28 days with measurement of tumor volumes once weekly over 8 weeks. RESULTS: Immunohistochemistry of normal and malignant kidney tissue sections of 67 patients demonstrated positive clusterin staining for almost all RCC (98% and an overexpression, compared to normal tissue, in a majority of RCC (69%. Clusterin ASO, but not mismatch control oligonucleotides, decreased clusterin mRNA expression in Caki-2 cells in a dosedependent and sequence-specific manner. Pretreatment of Caki-2 cells with clusterin ASO significantly enhanced chemosensitivity to paclitaxel in vitro. Characteristic apoptotic DNA laddering was observed after combined treatment with ASO plus paclitaxel, but not with either agent alone. In vivo

An overview of Pazopanib in metastatic renal cell carcinoma (mRCC in Ministry of Health (MOH, Malaysia: A multicentre experience

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May Feng Chen

2017-12-01

Full Text Available Background: Pazopanib was listed in MOH, Malaysia’s drug formulary on July 2013 for the treatment of mRCC. Two landmark trials were used to support the listing i.e. VEG105192 and COMPARZ which showed a median progression free survival (PFS of 9.2 and 8.4 months respectively. The efficacy and tolerability of Pazopanib in patients with mRCC have been found to differ in Western and Asian populations. Due to the difference in tolerability, dose adjustment in Asian patients is required. In most MOH hospitals in Malaysia, we tend to start mRCC patients with a lower dose as most patients can’t tolerate 800 mg of Pazopanib. We aim to prognosticate and evaluate PFS in patients with mRCC treated in MOH, Malaysia. We also aim to correlate PFS of patients on different doses of Pazopanib. Methods: The largest referral centre in central and southern Malaysia was selected namely Hospital Kuala Lumpur and Hospital Sultan Ismail. A retrospective analysis was done for patients using hospital supply of Pazopanib from 2010 to 2016. PFS is defined as the time of Pazopanib initiation till 1st documented disease progression. Prognostic variables such as age, sex, race, histology, common sites of metastasis, number of organs involved, ECOG, modified MSKCC risk category, prior history of nephrectomy or systemic treatment and initial dose of Pazopanib was analysed. Results: There was a total of 87 patients with mRCC registered. Median time since diagnosis to initiation of Pazopanib was 5 months. PFS for the overall study population was 8.0 months (95%CI, 5.6–10.4 months. PFS based on dose showed 400 mg vs. 800 mg of Pazopanib was 9.0 months (95%CI 4.5–13.4 months vs. 6.0 months (95%CI 1.9–10.1 months respectively (p = 0.209. Modified MSKCC risk category was a significant prognostic variable (p = 0.045. Conclusion: This retrospective review shows no significant difference in PFS between 400 mg vs. 800 mg of Pazopanib. MOH hospitals in Malaysia have similar PFS

Amplification of epidermal growth factor receptor gene in renal cell carcinoma

DEFF Research Database (Denmark)

El-Hariry, Iman; Powles, Thomas; Lau, Mike R

2010-01-01

Expression of epidermal growth factor receptor (EGFR) may be of prognostic value in renal cell cancer (RCC). Gene amplification of EGFR was investigated in a cohort of 315 patients with advanced RCC from a previously reported randomised study. Using fluorescent in situ hybridisation, only 2...

RNA interference-mediated silencing of speckle-type POZ protein promotes apoptosis of renal cell cancer cells.

Science.gov (United States)

Liu, Xiaoxia; Sun, Guiling; Sun, Xiuju

2016-01-01

This study aimed to investigate the effects of silencing the speckle-type POZ protein (SPOP) gene on renal cell cancer (RCC) cells and to explore its possible mechanism. The A498 and ACHN RCC cells were transfected with small interference RNA (siRNA)-SPOP by lipofection methods. The silencing efficiency was monitored by quantitative real-time polymerase chain reaction and Western blot. The effects of SPOP silencing on cell apoptosis, cell viability, colony formation ability, cell migration ability, and chemosensitivity to Sorafenib were assessed by flow cytometry, an MTT assay, a colony formation assay, a trans-well migration assay, and a CCK-8 assay, respectively. Its effects on the expression of several cytokines were determined by a protein microarray. Relevant signaling pathways were also analyzed. Compared with the control group, the cell apoptosis rate was significantly higher; the cell viability, the colony formation, and migration ability were significantly decreased in the siRNA-SPOP group. The protein microarray screening showed that the expression of vascular endothelial growth factor receptor, matrix metallopeptidase-9, vascular cell adhesion molecule-1, and stromal cell-derived factor-1 in the siRNA group was significantly decreased and that the expression of granulocyte-macrophage colony-stimulating factor and E-cadherin was significantly increased (Pmatrix organization signal pathway. SPOP gene silencing induced cell apoptosis, decreased cell viability, colony formation, and migration ability, and elevated the drug sensitivity in the RCC cells. A possible mechanism is that silencing SPOP induces the differential expression of E-cadherin, vascular endothelial growth factor receptor, matrix metallopeptidase-9, and vascular cell adhesion molecule, which are related to the integrin-mediated cell surface interactions and extracellular matrix organization signaling pathway.

The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the "obesity paradox".

Science.gov (United States)

Ito, Ryuichi; Narita, Shintaro; Huang, Mingguo; Nara, Taketoshi; Numakura, Kazuyuki; Takayama, Koichiro; Tsuruta, Hiroshi; Maeno, Atsushi; Saito, Mitsuru; Inoue, Takamitsu; Tsuchiya, Norihiko; Satoh, Shigeru; Habuchi, Tomonori

2017-01-01

Although obesity increases the risk of renal cell carcinoma (RCC), obese patients with RCC experience longer survival than non-obese patients. However, the mechanism of this "obesity paradox" is unknown. We examined the impact of preoperative BMI, serum total adiponectin (sAd) level, total adiponectin secretion from perinephric adipose tissue, and intratumoral expression of adiponectin receptors on RCC aggressiveness and survival. We also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells stimulated with exogenous adiponectin. Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003 and p = 0.027, respectively). Cancer-specific survival was significantly longer in overweight and obese patients than in normal patients in all patients (p = 0.035). There was a weak inverse correlation between sAd level and BMI in RCC patients (r = -0.344, p = 0.002). Tumor size was slightly correlated with sAd level, and high sAd was significantly associated with poor overall survival rates in patients with non-metastatic RCC (p = 0.035). Adiponectin levels in perinephric adipose tissue and intratumoral AdipoR1/R2 expression were not correlated with RCC aggressiveness or survival. Proliferation significantly increased in 786-O and Caki-2 cells exposed to exogenous adiponectin, whereas cell invasion and migration were unaffected. In addition, exogenous adiponectin significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL levels. In summary, low BMI and high adiponectin levels are associated with aggressive cell behaviors and poor survival in surgically-treated RCC patients. The effects of adiponectin on proliferation and apoptosis might underlie the "obesity paradox" of RCC.

Identification of miR-508-3p and miR-509-3p that are associated with cell invasion and migration and involved in the apoptosis of renal cell carcinoma

International Nuclear Information System (INIS)

Zhai, Qingna; Zhou, Liang; Zhao, Chunjuan; Wan, Jun; Yu, Zhendong; Guo, Xin; Qin, Jie; Chen, Jing; Lu, Ruijing

2012-01-01

Highlights: ► Previous method was the second-generation sequencing technology. ► miR-508-3p and miR-509-3p were significantly down-regulated in RCC tissues. ► They can inhibit cell proliferation and migration and promote cell apoptosis. ► The expression of miR-508-3p was significantly decreased in RCC patients plasma. ► miR-508-3p may be a novel diagnostic marker of RCC. -- Abstract: MicroRNAs (miRNAs) have emerged as powerful regulators of multiple processes linked to human cancer, including cell apoptosis, proliferation and migration, suggesting that the regulation of miRNA function could play a critical role in cancer progression. Recent studies have found that human serum/plasma contains stably expressed miRNAs. If they prove indicative of disease states, miRNAs measured from peripheral blood samples may be a source for routine clinical detection of cancer. Our studies showed that both miR-508-3p and miR-509-3p were down-regulated in renal cancer tissues. The level of miR-508-3p but not miR-509-3p in renal cell carcinoma (RCC) patient plasma demonstrated significant differences from that in control plasma. In addition, the overexpression of miR-508-3p and miR-509-3p suppressed the proliferation of RCC cells (786-0), induced cell apoptosis and inhibited cell migration in vitro. Our data demonstrated that miR-508-3p and miR-509-3p played an important role as tumor suppressor genes during tumor formation and that they may serve as novel diagnostic markers for RCC.

Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status.

Science.gov (United States)

Messai, Yosra; Gad, Sophie; Noman, Muhammad Zaeem; Le Teuff, Gwenael; Couve, Sophie; Janji, Bassam; Kammerer, Solenne Florence; Rioux-Leclerc, Nathalie; Hasmim, Meriem; Ferlicot, Sophie; Baud, Véronique; Mejean, Arnaud; Mole, David Robert; Richard, Stéphane; Eggermont, Alexander M M; Albiges, Laurence; Mami-Chouaib, Fathia; Escudier, Bernard; Chouaib, Salem

2016-10-01

Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene. To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression. A series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation. Fisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions. We demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells. Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy. We investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We

Radiometer Calibration and Characterization (RCC) User's Manual: Windows Version 4.0

Energy Technology Data Exchange (ETDEWEB)

Andreas, Afshin M. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Wilcox, Stephen M. [National Renewable Energy Lab. (NREL), Golden, CO (United States)

2016-02-29

The Radiometer Calibration and Characterization (RCC) software is a data acquisition and data archival system for performing Broadband Outdoor Radiometer Calibrations (BORCAL). RCC provides a unique method of calibrating broadband atmospheric longwave and solar shortwave radiometers using techniques that reduce measurement uncertainty and better characterize a radiometer's response profile. The RCC software automatically monitors and controls many of the components that contribute to uncertainty in an instrument's responsivity. This is a user's manual and guide to the RCC software.

Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma.

Science.gov (United States)

Asma, Gati; Amal, Gorrab; Raja, Marrakchi; Amine, Derouiche; Mohammed, Chebil; Amel, Ben Ammar Elgaaied

2015-05-01

The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4(+)CD25(high) regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4(+) T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4(+)CD25(-) T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients.

RCC-MX (2008 edition)

International Nuclear Information System (INIS)

Bravo, X.; Drubay, B.

2008-10-01

The RCC-MX books is a compilation of design and construction rules for the mechanical materials of experimental reactors, for their auxiliaries and irradiation devices. This second edition includes the updates of references to NF, EN and ISO standards, the compliance with the regulations for nuclear pressure equipments, and the feedback since the 2005 edition. It comprises 9 books and a CD-Rom and includes a presentation document. The RCC-MX has been developed for the Jules Horowitz reactor but can be used for the design and construction of new projects of new experimental reactors or new equipments and devices for existing facilities. Content: - Book 1: general dispositions, materials for experimental reactors and their auxiliaries, for irradiation devices and for control or handling mechanisms, complementary requirements and particular dispositions; - Book 2: materials for the reactor and for its level 1 auxiliaries; - Book 3: materials for the reactor and for its level 2 and level 3 auxiliaries, control and handling mechanisms, materials for irradiation devices; - Book 4: technical appendixes - materials characteristics (steels and alloys); - Book 5: technical appendixes (design rules); - Book 6: technical specifications of materials; - Book 7: tests and control methods; - Book 8: welding; - Book 9: fabrication. (J.S.)

The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the "obesity paradox".

Directory of Open Access Journals (Sweden)

Ryuichi Ito

Full Text Available Although obesity increases the risk of renal cell carcinoma (RCC, obese patients with RCC experience longer survival than non-obese patients. However, the mechanism of this "obesity paradox" is unknown. We examined the impact of preoperative BMI, serum total adiponectin (sAd level, total adiponectin secretion from perinephric adipose tissue, and intratumoral expression of adiponectin receptors on RCC aggressiveness and survival. We also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells stimulated with exogenous adiponectin. Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003 and p = 0.027, respectively. Cancer-specific survival was significantly longer in overweight and obese patients than in normal patients in all patients (p = 0.035. There was a weak inverse correlation between sAd level and BMI in RCC patients (r = -0.344, p = 0.002. Tumor size was slightly correlated with sAd level, and high sAd was significantly associated with poor overall survival rates in patients with non-metastatic RCC (p = 0.035. Adiponectin levels in perinephric adipose tissue and intratumoral AdipoR1/R2 expression were not correlated with RCC aggressiveness or survival. Proliferation significantly increased in 786-O and Caki-2 cells exposed to exogenous adiponectin, whereas cell invasion and migration were unaffected. In addition, exogenous adiponectin significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL levels. In summary, low BMI and high adiponectin levels are associated with aggressive cell behaviors and poor survival in surgically-treated RCC patients. The effects of adiponectin on proliferation and apoptosis might underlie the "obesity paradox" of RCC.

Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results.

Science.gov (United States)

Amin, Asim; Dudek, Arkadiusz Z; Logan, Theodore F; Lance, Raymond S; Holzbeierlein, Jeffrey M; Knox, Jennifer J; Master, Viraj A; Pal, Sumanta K; Miller, Wilson H; Karsh, Lawrence I; Tcherepanova, Irina Y; DeBenedette, Mark A; Williams, W Lee; Plessinger, Douglas C; Nicolette, Charles A; Figlin, Robert A

2015-01-01

AGS-003 is an autologous immunotherapy prepared from fully matured and optimized monocyte-derived dendritic cells, which are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. AGS-003 was evaluated in combination with sunitinib in an open label phase 2 study in intermediate and poor risk, treatment naïve patients with metastatic clear cell renal cell carcinoma (mRCC). Twenty-one intermediate and poor risk patients were treated continuously with sunitinib (4 weeks on, 2 weeks off per 6 week cycle). After completion of the first cycle of sunitinib, patients were treated with AGS-003 every 3 weeks for 5 doses, then every 12 weeks until progression or end of study. The primary endpoint was to determine the complete response rate. Secondary endpoints included clinical benefit, safety, progression free survival (PFS) and overall survival (OS). Immunologic response was also monitored. Thirteen patients (62%) experienced clinical benefit (9 partial responses, 4 with stable disease); however there were no complete responses in this group of intermediate and poor risk mRCC patients and enrollment was terminated early. Median PFS from registration was 11.2 months (95% CI 6.0, 19.4) and the median OS from registration was 30.2 months (95% CI 9.4, 57.1) for all patients. Seven (33%) patients survived for at least 4.5 years, while five (24%) survived for more than 5 years, including 2 patients who remain progression-free with durable responses for more than 5 years at the time of this report. AGS-003 was well tolerated with only mild injection-site reactions. The most common adverse events were related to expected toxicity from sunitinib therapy. In patients who had sequential samples available for immune monitoring, the magnitude of the increase in the absolute number of CD8(+) CD28(+) CD45RA(-) effector/memory T cells (CTLs) after 5 doses of AGS-003 relative to baseline, correlated with overall survival. AGS-003 in combination with sunitinib was

Application of a polycarboxylate ether admixture in RCC dam construction[ACI SP-239

Energy Technology Data Exchange (ETDEWEB)

Asmus, S.M.F.; Christensen, B.J.; Varley, N.J. [BASF Construction Chemicals Asia Pacific, Shanghai (China)

2006-07-01

Chemical admixtures are used in dam construction to improve plasticity of the dry materials mixture over time. Roller compacted concrete (RCC) has been used on many dam projects in China. However, the use of RCC has frequently resulted in water reduction problems. This paper provided details of an admixture based on polycarboxylate ether (PCE) which was developed to improve the quality of RCC constructions at the JinHong dam in China. Use of the polymer at the JinHong dam resulted in a vibration sensitive concrete that was sustained over time. Under identical mix-design and compaction conditions in the laboratory, specific gravity of the RCC was increased from 2417 kg/m{sup 3} to 2463 kg/m{sup 3}. The high specific gravity of the material resulted in satisfactory strength data from the dam project. The key-ratio of the splitting tensile strength versus compressive strength was higher than 8 per cent in all cases. A key advantage of the tailored PCE-RCC was the short Vebe times sustained over elapsed time in the RCC. Without additional compaction or vibration efforts, the specific density of RCC was better than conventional admixture technologies. The reduced viscosity provided cement paste films which formed on the surface of each layer of the RCC, which resulted in better bonding between the layers. It was concluded that the new PCE polymer is compatible with alternative retarder systems, which contributes to more extensive setting times under strict hydration regimes. 7 refs., 4 tabs., 4 figs.

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

NARCIS (Netherlands)

Lamers, C.H.; Sleijfer, S.; Steenbergen, S. van; Elzakker, P. van; Krimpen, B. van; Groot, C. de; Vulto, A.; Bakker, M. den; Oosterwijk, E.; Debets, R.; Gratama, J.W.

2013-01-01

Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of

MicroRNA-34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

Science.gov (United States)

Hussein, Mohammad H.; Al-Qahtani, Saeed Awad M.; Shaalan, Aly A. M.

2017-01-01

Renal cell carcinoma (RCC) incidence has increased over the past two decades. Recent studies reported microRNAs as promising biomarkers for early cancer detection, accurate prognosis, and molecular targets for future treatment. This study aimed to evaluate the expression levels of miR-34a and 11 of its bioinformatically selected target genes and proteins to test their potential dysregulation in RCC. Quantitative real-time PCR for miR-34a and its targets; MET oncogene; gene-regulating apoptosis (TP53INP2 and DFFA); cell proliferation (E2F3); and cell differentiation (SOX2 and TGFB3) as well as immunohistochemical assay for VEGFA, TP53, Bcl2, TGFB1, and Ki67 protein expression have been performed in 85 FFPE RCC tumor specimens. Clinicopathological parameter correlation and in silico network analysis have also implicated. We found RCC tissues displayed significantly higher miR-34a expression level than their corresponding noncancerous tissues, particularly in chromophobic subtype. MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 were downregulated. ROC analysis showed high diagnostic performance of miR-34a (AUC = 0.854), MET (AUC = 0.765), and E2F3 (AUC = 0.761). The advanced pathological grade was associated with strong TGFB1, VEGFA, and Ki67 protein expression and absent Tp53 staining. These findings indicate miR-34a along with its putative target genes could play a role in RCC tumorigenesis and progression. PMID:29104726

MicroRNA-34a: A Key Regulator in the Hallmarks of Renal Cell Carcinoma

Directory of Open Access Journals (Sweden)

Eman A. Toraih

2017-01-01

Full Text Available Renal cell carcinoma (RCC incidence has increased over the past two decades. Recent studies reported microRNAs as promising biomarkers for early cancer detection, accurate prognosis, and molecular targets for future treatment. This study aimed to evaluate the expression levels of miR-34a and 11 of its bioinformatically selected target genes and proteins to test their potential dysregulation in RCC. Quantitative real-time PCR for miR-34a and its targets; MET oncogene; gene-regulating apoptosis (TP53INP2 and DFFA; cell proliferation (E2F3; and cell differentiation (SOX2 and TGFB3 as well as immunohistochemical assay for VEGFA, TP53, Bcl2, TGFB1, and Ki67 protein expression have been performed in 85 FFPE RCC tumor specimens. Clinicopathological parameter correlation and in silico network analysis have also implicated. We found RCC tissues displayed significantly higher miR-34a expression level than their corresponding noncancerous tissues, particularly in chromophobic subtype. MET and E2F3 were significantly upregulated, while TP53INP2 and SOX2 were downregulated. ROC analysis showed high diagnostic performance of miR-34a (AUC = 0.854, MET (AUC = 0.765, and E2F3 (AUC = 0.761. The advanced pathological grade was associated with strong TGFB1, VEGFA, and Ki67 protein expression and absent Tp53 staining. These findings indicate miR-34a along with its putative target genes could play a role in RCC tumorigenesis and progression.

Retrofitting Of RCC Piles By Using Basalt Fiber Reinforced Polymer BFRP Composite Part 1 Review Papers On RCC Structures And Piles Retrofitting Works.

OpenAIRE

R. Ananda Kumar; Dr. C. Selvamony; A. Seeni; Dr. T. R. Sethuraman

2015-01-01

Abstract Retrofitting works are immensely essential for deteriorated and damaged structures in Engineering and Medical fields in order to keep or return to the originality for safe guarding the structures and consumers. In this paper different types of methods of retrofitting review notes are given based on the experimental numerical and analytical methods results on strengthening the Reinforced cement concrete RCC structures including RCC piles. Soil-pile interaction on axial load lateral lo...

β-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma

Directory of Open Access Journals (Sweden)

Yang CM

2017-02-01

Full Text Available Chun-ming Yang,1 Shan Ji,2 Yan Li,3 Li-ye Fu,3 Tao Jiang,3 Fan-dong Meng31Department of Urology, The First Affiliated Hospital, China Medical University, 2Department of Endocrinology, The Fifth People’s Hospital of Shenyang, 3Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital, China Medical University, Shenyang, ChinaAbstract: β-Catenin (CTNNB1 gene coding protein is a component of the Wnt signaling pathway that has been shown to play an important role in the formation of certain cancers. Abnormal accumulation of CTNNB1 contributes to most cancers. This research studied the involvement of β-catenin in renal cell carcinoma (RCC cell proliferation, apoptosis, migration, and invasion. Proliferation, cell cycle, and apoptosis were analyzed by using Cell Counting Kit-8 and by flow cytometry. Migration and invasion assays were measured by transwell analysis. Real-time polymerase chain reaction and Western blot analysis were used to detect the expression of CTNNB1, ICAM-1, VCAM-1, CXCR4, and CCL18 in RCC cell lines. It was found that CTNNB1 knockdown inhibited cell proliferation, migration, and invasion and induced apoptosis of A-498 cells. CTNNB1 overexpression promoted cell proliferation, migration, and invasion and inhibited apoptosis of 786-O cells. Moreover, knockdown of CTNNB1 decreased the levels of ICAM-1, VCAM-1, CXCR4, and CCL18 expression, but CTNNB1 overexpression increased the expression of ICAM-1, VCAM-1, CXCR4, and CCL18. Further in vivo tumor formation study in nude mice indicated that inhibition of CTNNB1 delayed the progress of tumor formation through inhibiting PCNA and Ki67 expression. These results indicate that CTNNB1 could act as an oncogene and may serve as a promising therapeutic strategy for RCC.Keywords: kidney cancer, oncogene, β-catenin, survival time, tumor migration-related protein

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma.

Science.gov (United States)

Fisel, Pascale; Stühler, Viktoria; Bedke, Jens; Winter, Stefan; Rausch, Steffen; Hennenlotter, Jörg; Nies, Anne T; Stenzl, Arnulf; Scharpf, Marcus; Fend, Falko; Kruck, Stephan; Schwab, Matthias; Schaeffeler, Elke

2015-10-13

Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation. CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics. CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780,Harrell's c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrell's c-index = 80.0%). Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC.

The entire miR-200 seed family is strongly deregulated in clear cell renal cell cancer compared to the proximal tubular epithelial cells of the kidney

NARCIS (Netherlands)

Duns, Gerben; van den Berg, Anke; van Dijk, Marcory C. R. F.; van Duivenbode, Inge; Giezen, Cor; Kluiver, Joost; van Goor, Harry; Hofstra, Robert M. W.; van den Berg, Eva; Kok, Klaas

Despite numerous studies reporting deregulated microRNA (miRNA) and gene expression patterns in clear cell renal cell carcinoma (ccRCC), no direct comparisons have been made to its presumed normal counterpart: the renal proximal tubular epithelial cells (PTECs). The aim of this study was to

Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines.

Directory of Open Access Journals (Sweden)

Matthew A Bill

Full Text Available The Janus kinase-2 (Jak2-signal transducer and activator of transcription-3 (STAT3 pathway is critical for promoting an oncogenic and metastatic phenotype in several types of cancer including renal cell carcinoma (RCC and melanoma. This study describes two small molecule inhibitors of the Jak2-STAT3 pathway, FLLL32 and its more soluble analog, FLLL62. These compounds are structurally distinct curcumin analogs that bind selectively to the SH2 domain of STAT3 to inhibit its phosphorylation and dimerization. We hypothesized that FLLL32 and FLLL62 would induce apoptosis in RCC and melanoma cells and display specificity for the Jak2-STAT3 pathway. FLLL32 and FLLL62 could inhibit STAT3 dimerization in vitro. These compounds reduced basal STAT3 phosphorylation (pSTAT3, and induced apoptosis in four separate human RCC cell lines and in human melanoma cell lines as determined by Annexin V/PI staining. Apoptosis was also confirmed by immunoblot analysis of caspase-3 processing and PARP cleavage. Pre-treatment of RCC and melanoma cell lines with FLLL32/62 did not inhibit IFN-γ-induced pSTAT1. In contrast to FLLL32, curcumin and FLLL62 reduced downstream STAT1-mediated gene expression of IRF1 as determined by Real Time PCR. FLLL32 and FLLL62 significantly reduced secretion of VEGF from RCC cell lines in a dose-dependent manner as determined by ELISA. Finally, each of these compounds inhibited in vitro generation of myeloid-derived suppressor cells. These data support further investigation of FLLL32 and FLLL62 as lead compounds for STAT3 inhibition in RCC and melanoma.

High volume fly ash RCC for dams - I : mixture optimization and mechanical properties

Energy Technology Data Exchange (ETDEWEB)

Jacobsen, S. [PEAB Construction Co., Oslo (Norway); Lahus, O. [Norwegian Building Research Inst., Oslo (Norway)

2001-07-01

Roller compacted concretes (RCC) were developed for the Norwegian Skjerka hydropower project. RCCs were developed to have a high-volume fly ash content to address environmental issues, including the reduction of carbon dioxide emissions associated with dam construction. They also makes good use of waste product and conserve natural resources. This study examined a series of mixtures to determine the appropriateness of using RCC as a competing alternative to the traditional rock fill dam proposed for the Skjerka hydropower project. The main advantage of RCC is speed, allowing a relatively large dam to be constructed in just one summer season, saving financial costs and providing early return on the investment. In addition, fly ash can be used in the structure, using clean and renewable energy. Several procedures to proportion RCC mixtures were proposed, including the optimal paste volume method which is based on the assumption that an optimal RCC should have just enough paste to fill the space between particles when the granular skeleton has reached its maximum density under compaction. With this assumption, RCC tests began in 1998 in the laboratories of the Norwegian Building Research Institute. An ordinary portland cement was used and combined with ordinary low lime fly ash. Both coarse and fine aggregate were used. The tests determined the optimum paste-mortar ratio, the content of coarse aggregates and the production of specimens for test on hardened and fresh concrete. The study showed that the compressive strength of RCC increased with increasing cement/(cement + fly ash) ratio. The permeability coefficient decreased with increasing cement-content and increasing cement/(cement + fly ash) ratio due to the slow pozzolanic reaction of fly ash making a more open pore structure. It was concluded that an optimized mixture can result in a high performance RCC in terms of fresh and hardened concrete properties. 15 refs., 5 tabs., 11 figs.

Angiogenesis and expression of vascular endothelial growth factor, tumour necrosis factor-α and hypoxia inducible factor-1α in canine renal cell carcinoma.

Science.gov (United States)

Yhee, J Y; Yu, C H; Kim, J H; Im, K S; Kim, N H; Brodersen, B W; Doster, A R; Sur, J-H

2012-01-01

The aim of the present study was to determine the distribution and characteristics of microvessels in various histological types of canine renal cell carcinoma (RCC). The study compared microvessel density (MVD) and distribution of blood vessels according to histological type and evaluated the presence of angiogenesis-related proteins. Nine archival samples of canine RCC were studied. MVD was calculated as the mean number of blood vessels per mm(2). The diameter of blood vessels was calculated by determining either the length of the long axis of blood vessels (diameter(max)) or the mean distance from the centre of each blood vessel to the tunica adventia (diameter(mean)). A significant difference in MVD was evident between RCCs and normal kidneys (46.6 ± 28.0 versus 8.4 ± 2.2 microvessels/mm(2)). Diameter(max) in canine RCCs (34.1 ± 14.7 μm) was also significantly different from normal canine kidney (23.2 ± 3.4 μm). Vascular endothelial growth factor (VEGF) was expressed by tumour cells and vascular endothelial cells and tumour necrosis factor (TNF)-α expression was observed in vascular endothelial cells in both neoplastic and normal kidney. Although VEGF is involved in angiogenesis and correlates with tumour stage of development, no correlation was found between VEGF expression and MVD. Tumour-associated macrophages expressing TNF-α and hypoxia inducible factor 1α were identified in peritumoural tissue and may play an important role in angiogenesis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synchronous clear cell renal cell carcinoma and tubulocystic carcinoma: genetic evidence of independent ontogenesis and implications of chromosomal imbalances in tumor progression

Directory of Open Access Journals (Sweden)

Quiroga-Garza Gabriela

2012-02-01

Full Text Available Abstract Seven percent of renal cell carcinoma (RCC cases are diagnosed as "unclassified" RCC by morphology. Genetic profiling of RCCs helps define renal tumor subtypes, especially in cases where morphologic diagnosis is inconclusive. This report describes a patient with synchronous clear cell RCC (ccRCC and a tubulocystic renal carcinoma (TCRC in the same kidney, and discusses the pathologic features and genetic profile of both tumors. A 67 year-old male underwent CT scans for an unrelated medical event. Two incidental renal lesions were found and ultimately removed by radical nephrectomy. The smaller lesion had multiple small cystic spaces lined by hobnail cells with high nuclear grade separated by fibrous stroma. This morphology and the expression of proximal (CD10, AMACR and distal tubule cell (CK19 markers by immunohistochemistry supported the diagnosis of TCRC. The larger lesion was a typical ccRCC, with Fuhrman's nuclear grade 3 and confined to the kidney. Molecular characterization of both neoplasms using virtual karyotyping was performed to assess relatedness of these tumors. Low grade areas (Fuhrman grade 2 of the ccRCC showed loss of 3p and gains in chromosomes 5 and 7, whereas oncocytic areas displayed additional gain of 2p and loss of 10q; the high grade areas (Fuhrman grade 3 showed several additional imbalances. In contrast, the TCRC demonstrated a distinct profile with gains of chromosomes 8 and 17 and loss of 9. In conclusion, ccRCC and TCRC show distinct genomic copy number profiles and chromosomal imbalances in TCRC might be implicated in the pathogenesis of this tumor. Second, the presence of a ccRCC with varying degrees of differentiation exemplifies the sequence of chromosomal imbalances acquired during tumor progression. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1790525735655283

Differential transfection efficiency rates of the GM-CSF gene into human renal cell carcinoma lines by lipofection.

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Hernández, A; Zöller, K; Enczmann, J; Ebert, T; Schmitz-Draeger, B; Ackermann, R; Wernet, P

1997-01-01

One of the major questions in any gene therapy approach is the selection of the appropriate vector system. Here, the optimization of a gene transfer protocol for renal cell carcinoma using lipofection as a nonviral gene transduction system was evaluated. To select the promoter which gives the highest expression, different plasmids which are able to express Escherichia coli beta-galactosidase gene as a reporter gene under the control of different promoters were tested: human cytomegalovirus promoter (pCMVbeta), simian virus 40 promoter (pSVbeta), adenovirus promoter (ADbeta), and herpes simplex virus thymidine kinase promoter (TKbeta). The pCMVbeta revealed the highest expression of the beta-gal gene in the renal cell carcinoma (RCC) lines. Thus this CMV promoter was selected for the expression of the granulocyte-macrophage colony stimulator factor (GM-CSF) gene. Three different lipids (LipofectAmine, LipofectAce, and Lipofectin) were compared for their transduction efficiency, and the optimal conditions for quantitatively high lipofection rates were established. The consistently best results regarding gene expression as well as viability of the RCC lines were obtained when Lipofectin was used. Gene expression was monitored by a specific enzyme-linked immunosorbent assay and functionally validated by a cell proliferation test. The GM-CSF expression profile showed a peak at 48 hours after transfection and was still detectable after 5 days. Here the feasibility of efficient lipofection of the GM-CSF gene into RCC lines is demonstrated. Most importantly, considerable differences in the relative quantity of GM-CSF gene transfer into the different RCC lines was observed here. This may be of critical relevance for the design of any clinical gene transduction protocol in tumor cell vaccination attempts.

RNA interference-mediated silencing of speckle-type POZ protein promotes apoptosis of renal cell cancer cells

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Liu X

2016-04-01

Full Text Available Xiaoxia Liu, Guiling Sun, Xiuju Sun Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, People’s Republic of China Abstract: This study aimed to investigate the effects of silencing the speckle-type POZ protein (SPOP gene on renal cell cancer (RCC cells and to explore its possible mechanism. The A498 and ACHN RCC cells were transfected with small interference RNA (siRNA-SPOP by lipofection methods. The silencing efficiency was monitored by quantitative real-time polymerase chain reaction and Western blot. The effects of SPOP silencing on cell apoptosis, cell viability, colony formation ability, cell migration ability, and chemosensitivity to Sorafenib were assessed by flow cytometry, an MTT assay, a colony formation assay, a trans-well migration assay, and a CCK-8 assay, respectively. Its effects on the expression of several cytokines were determined by a protein microarray. Relevant signaling pathways were also analyzed. Compared with the control group, the cell apoptosis rate was significantly higher; the cell viability, the colony formation, and migration ability were significantly decreased in the siRNA-SPOP group. The protein microarray screening showed that the expression of vascular endothelial growth factor receptor, matrix metallopeptidase-9, vascular cell adhesion molecule-1, and stromal cell-derived factor-1 in the siRNA group was significantly decreased and that the expression of granulocyte–macrophage colony-stimulating factor and E-cadherin was significantly increased (P<0.05. The relevant signaling pathways were the integrin-mediated cell surface interactions pathway and extracellular matrix organization signal pathway. SPOP gene silencing induced cell apoptosis, decreased cell viability, colony formation, and migration ability, and elevated the drug sensitivity in the RCC cells. A possible mechanism is that silencing SPOP induces the differential expression of E-cadherin, vascular endothelial

Cell-Type-Specific Gene Programs of the Normal Human Nephron Define Kidney Cancer Subtypes.

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Lindgren, David; Eriksson, Pontus; Krawczyk, Krzysztof; Nilsson, Helén; Hansson, Jennifer; Veerla, Srinivas; Sjölund, Jonas; Höglund, Mattias; Johansson, Martin E; Axelson, Håkan

2017-08-08

Comprehensive transcriptome studies of cancers often rely on corresponding normal tissue samples to serve as a transcriptional reference. In this study, we performed in-depth analyses of normal kidney tissue transcriptomes from the TCGA and demonstrate that the histological variability in cellularity, inherent in the kidney architecture, lead to considerable transcriptional differences between samples. This should be considered when comparing expression profiles of normal and cancerous kidney tissues. We exploited these differences to define renal-cell-specific gene signatures and used these as a framework to analyze renal cell carcinoma (RCC) ontogeny. Chromophobe RCCs express FOXI1-driven genes that define collecting duct intercalated cells, whereas HNF-regulated genes, specific for proximal tubule cells, are an integral part of clear cell and papillary RCC transcriptomes. These networks may be used as a framework for understanding the interplay between genomic changes in RCC subtypes and the lineage-defining regulatory machinery of their non-neoplastic counterparts. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma

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Fengju Chen

2016-03-01

Full Text Available On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression, we classified 894 renal cell carcinomas (RCCs of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

Biphasic papillary renal cell carcinoma is a rare morphological variant with frequent multifocality: a study of 28 cases.

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Trpkov, Kiril; Athanazio, Daniel; Magi-Galluzzi, Cristina; Yilmaz, Helene; Clouston, David; Agaimy, Abbas; Williamson, Sean R; Brimo, Fadi; Lopez, Jose I; Ulamec, Monika; Rioux-Leclercq, Nathalie; Kassem, Maysoun; Gupta, Nilesh; Hartmann, Arndt; Leroy, Xavier; Bashir, Samir Al; Yilmaz, Asli; Hes, Ondřej

2018-04-01

To further characterise biphasic squamoid renal cell carcinoma (RCC), a recently proposed variant of papillary RCC. We identified 28 tumours from multiple institutions. They typically showed two cell populations-larger cells with eosinophilic cytoplasm and higher-grade nuclei, surrounded by smaller, amphophilic cells with scanty cytoplasm. The dual morphology was variable (median 72.5% of tumour, range 5-100%); emperipolesis was found in all cases. The male/female ratio was 2:1, and the median age was 55 years (range 39-86 years). The median tumour size was 20 mm (range 9-65 mm). Pathological stage pT1a was found in 21 cases, pT1b in three, and pT3a and pT3b in one each (two not available). Multifocality was found in 32%: multifocal biphasic RCC in one case, biphasic + papillary RCC in two cases, biphasic + clear cell RCC in three cases, biphasic + low-grade urothelial carcinoma of the renal pelvis in one case, and biphasic + Birt-Hogg-Dubé syndrome in one case. Positive immunostains included: PAX8, cytokeratin (CK) 7, α-methylacyl-CoA racemase, epithelial membrane antigen, and vimentin. Cyclin D1 was expressed only in the larger cells. The Ki67 index was higher in the larger cells (median 5% versus ≤1%). Negative stains included: carbonic anhydrase 9, CD117, GATA-3, WT1, CK5/6, and CK20; CD10 and 34βE12 were variably expressed. Gains of chromosomes 7 and 17 were found in two evaluated cases. Follow-up was available for 23 patients (median 24 months, range 1-244 months): 19 were alive without disease, one was alive with recurrence, and one had died of disease (two had died of other causes). Biphasic papillary RCC is a rare variant of papillary RCC, and is often multifocal. © 2017 John Wiley & Sons Ltd.

MicroRNAs Associated with Von Hippel-Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review.

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Schanza, Lisa-Maria; Seles, Maximilian; Stotz, Michael; Fosselteder, Johannes; Hutterer, Georg C; Pichler, Martin; Stiegelbauer, Verena

2017-11-22

Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel-Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.

MicroRNAs Associated with Von Hippel–Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review

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Lisa-Maria Schanza

2017-11-01

Full Text Available Renal cell carcinoma (RCC are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs, a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel–Lindau (VHL genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma.

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Giridhar, Karthik V; Sosa, Carlos P; Hillman, David W; Sanhueza, Cristobal; Dalpiaz, Candace L; Costello, Brian A; Quevedo, Fernando J; Pitot, Henry C; Dronca, Roxana S; Ertz, Donna; Cheville, John C; Donkena, Krishna Vanaja; Kohli, Manish

2017-11-03

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04-0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05-0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only ( p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

Cancers as wounds that do not heal: differences and similarities between renal regeneration/repair and renal cell carcinoma.

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Riss, Joseph; Khanna, Chand; Koo, Seongjoon; Chandramouli, Gadisetti V R; Yang, Howard H; Hu, Ying; Kleiner, David E; Rosenwald, Andreas; Schaefer, Carl F; Ben-Sasson, Shmuel A; Yang, Liming; Powell, John; Kane, David W; Star, Robert A; Aprelikova, Olga; Bauer, Kristin; Vasselli, James R; Maranchie, Jodi K; Kohn, Kurt W; Buetow, Ken H; Linehan, W Marston; Weinstein, John N; Lee, Maxwell P; Klausner, Richard D; Barrett, J Carl

2006-07-15

Cancers have been described as wounds that do not heal, suggesting that the two share common features. By comparing microarray data from a model of renal regeneration and repair (RRR) with reported gene expression in renal cell carcinoma (RCC), we asked whether those two processes do, in fact, share molecular features and regulatory mechanisms. The majority (77%) of the genes expressed in RRR and RCC were concordantly regulated, whereas only 23% were discordant (i.e., changed in opposite directions). The orchestrated processes of regeneration, involving cell proliferation and immune response, were reflected in the concordant genes. The discordant gene signature revealed processes (e.g., morphogenesis and glycolysis) and pathways (e.g., hypoxia-inducible factor and insulin-like growth factor-I) that reflect the intrinsic pathologic nature of RCC. This is the first study that compares gene expression patterns in RCC and RRR. It does so, in particular, with relation to the hypothesis that RCC resembles the wound healing processes seen in RRR. However, careful attention to the genes that are regulated in the discordant direction provides new insights into the critical differences between renal carcinogenesis and wound healing. The observations reported here provide a conceptual framework for further efforts to understand the biology and to develop more effective diagnostic biomarkers and therapeutic strategies for renal tumors and renal ischemia.

Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro

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Cardillo, Thomas M; Trisal, Preeti; Arrojo, Roberto; Goldenberg, David M; Chang, Chien-Hsing

2013-01-01

Advanced or metastatic renal cell carcinoma (RCC) has a poor prognosis, because it is relatively resistant to conventional chemotherapy or radiotherapy. Treatments with human interferon-α2b alone or in combination with mammalian target of rapamycin (mTOR) inhibitors have led to only a modest improvement in clinical outcome. One observation made with mTOR inhibitors is that carcinomas can overcome these inhibitory effects by activating the insulin-like growth factor-I (IGF-I) signaling pathway. Clinically, there is an association of IGF-I receptor (IGF-IR) expression in RCC and poor long-term patient survival. We have developed a humanized anti-IGF-IR monoclonal antibody, hR1, which binds to RCC, resulting in effective down-regulation of IGF-IR and moderate inhibition of cell proliferation in vitro. In this work, we evaluate the anti-tumor activity of two novel IGF-1R-targeting agents against renal cell carcinoma given alone or in combination with an mTOR inhibitor. hR1 was linked by the DOCK-AND-LOCK™ (DNL™) method to four Fabs of hR1, generating Hex-hR1, or to four molecules of interferon-α2b, generating 1R-2b. Eight human RCC cell lines were screened for IGF-1R expression and sensitivity to treatment with hR1 in vitro. Synergy with an mTOR inhibitor, temsirolimus, was tested in a cell line (ACHN) with low sensitivity to hR1. Hex-hR1 induced the down-regulation of IGF-IR at 10-fold lower concentrations compared to the parental hR1. Sensitivity to growth inhibition mediated by hR1 and Hex-hR1 treatments correlated with IGF-1R expression (higher expression was more sensitive). The potency of 1R-2b to inhibit the in vitro growth of RCC was also demonstrated in two human cell lines, ACHN and 786-O, with EC 50 –values of 63 and 48 pM, respectively. When combined with temsirolimus, a synergistic growth-inhibition with hR1, Hex-hR1, and 1R-2b was observed in ACHN cells at concentrations as low as 10 nM for hR1, 1 nM for Hex-hR1, and 2.6 nM for 1R-2b. Both Hex-hR1

Simulation analysis of temperature control on RCC arch dam of hydropower station

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XIA, Shi-fa

2017-12-01

The temperature analysis of roller compacted concrete (RCC) dam plays an important role in their design and construction. Based on three-dimensional finite element method, in the computation of temperature field, many cases are included, such as air temperature, elevated temperature by cement hydration heat, concrete temperature during placing, the influence of water in the reservoir, and boundary temperature. According to the corresponding parameters of RCC arch dam, the analysis of temperature field and stress field during the period of construction and operation is performed. The study demonstrates that detailed thermal stress analysis should be performed for RCC dams to provide a basis to minimize and control the occurrence of thermal cracking.

Harmonization of welding qualification provisions in RCC-M and European standards

International Nuclear Information System (INIS)

Lemoine, M.; Lainez, B.; Anastassiades, P.

2007-01-01

Since a long time, numerous precautions for welding have been integrated in the nuclear codes, in particular in the RCC-M applicable to pressurized water reactors, in order to guarantee a high quality level of permanent assemblies. In parallel, European and ISO standardization works have led to a harmonisation of practices on qualification of welding processes, welders and operators. In the context of the regulatory evolutions presented during this conference, it was judged appropriate to bring closer the RCC-M practices and those of EN and ISO standards, while taking the precaution of specifying, if necessary, the complementary provisions allowing maintaining guarantees of quality consistent with the prior experience feedback. This paper presents the amendments brought to the RCC-M Code by the 2005 and 2007 addenda, in order to respond to this objective, and develops their motivations. (authors) [fr

Maslinic acid inhibits proliferation of renal cell carcinoma cell lines and suppresses angiogenesis of endothelial cells

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Parth Thakor

2017-03-01

Full Text Available Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC remains a treatment-re-sistant cancer. As red and processed meat are considered risk factors for RCC, and a vegetable-rich diet is thought to reduce this risk, research into plant-based therapeutics may provide valuable complementary or alternative therapeutics for the management of RCC. Herein, we present the antiproliferative and antiangiogenic effects of maslinic acid, which occurs naturally in edible plants, particularly in olive fruits, and also in a variety of medicinal plants. Human RCC cell lines (ACHN, Caki-1, and SN12K1, endothelial cells (human umbilical vein endothelial cell line [HUVEC], and primary cultures of kidney proximal tubular epithelial cells (PTEC were treated with maslinic acid. Maslinic acid was relatively less toxic to PTEC when compared with RCC under similar experimental conditions. In RCC cell lines, maslinic acid induced a significant reduction in proliferation, proliferating cell nuclear antigen, and colony formation. In HUVEC, maslinic acid induced a significant reduction in capillary tube formation in vitro and vascular endothelial growth factor. This study provides a rationale for incorporating a maslinic acid–rich diet either to reduce the risk of developing kidney cancer or as an adjunct to existing antiangiogenic therapy to improve efficacy.

VHL-dependent regulation of a β-dystroglycan glycoform and glycogene expression in renal cancer.

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Aggelis, Vassilis; Craven, Rachel A; Peng, Jianhe; Harnden, Patricia; Schaffer, Lana; Hernandez, Gilberto E; Head, Steven R; Maher, Eamonn R; Tonge, Robert; Selby, Peter J; Banks, Rosamonde E

2013-11-01

Identification of novel biomarkers and targets in renal cell carcinoma (RCC) remains a priority and one cellular compartment that is a rich potential source of such molecules is the plasma membrane. A shotgun proteomic analysis of cell surface proteins enriched by cell surface biotinylation and avidin affinity chromatography was explored using the UMRC2- renal cancer cell line, which lacks von Hippel-Lindau (VHL) tumour suppressor gene function, to determine whether proteins of interest could be detected. Of the 814 proteins identified ~22% were plasma membrane or membrane-associated, including several with known associations with cancer. This included β-dystroglycan, the transmembrane subunit of the DAG1 gene product. VHL-dependent changes in the form of β-dystroglycan were detected in UMRC2-/+VHL transfectants. Deglycosylation experiments showed that this was due to differential sialylation. Analysis of normal kidney cortex and conventional RCC tissues showed that a similar change also occurred in vivo. Investigation of the expression of genes involved in glycosylation in UMRC2-/+VHL cells using a focussed microarray highlighted a number of enzymes involved in sialylation; upregulation of bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) was validated in UMRC2- cells compared with their +VHL counterparts and also found in conventional RCC tissue. These results implicate VHL in the regulation of glycosylation and raise interesting questions regarding the extent and importance of such changes in RCC.

A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR.

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Kelly Broen

Full Text Available Nonmyeloablative allogeneic stem cell transplantation (SCT can induce remission in patients with renal cell carcinoma (RCC, but this graft-versus-tumor (GVT effect is often accompanied by graft-versus-host disease (GVHD. Here, we evaluated minor histocompatibility antigen (MiHA-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI. One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.

Development and confirmation of potential gene classifiers of human clear cell renal cell carcinoma using next-generation RNA sequencing.

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Eikrem, Oystein S; Strauss, Philipp; Beisland, Christian; Scherer, Andreas; Landolt, Lea; Flatberg, Arnar; Leh, Sabine; Beisvag, Vidar; Skogstrand, Trude; Hjelle, Karin; Shresta, Anjana; Marti, Hans-Peter

2016-12-01

A previous study by this group demonstrated the feasibility of RNA sequencing (RNAseq) technology for capturing disease biology of clear cell renal cell carcinoma (ccRCC), and presented initial results for carbonic anhydrase-9 (CA9) and tumor necrosis factor-α-induced protein-6 (TNFAIP6) as possible biomarkers of ccRCC (discovery set) [Eikrem et al. PLoS One 2016;11:e0149743]. To confirm these results, the previous study is expanded, and RNAseq data from additional matched ccRCC and normal renal biopsies are analyzed (confirmation set). Two core biopsies from patients (n = 12) undergoing partial or full nephrectomy were obtained with a 16 g needle. RNA sequencing libraries were generated with the Illumina TruSeq ® Access library preparation protocol. Comparative analysis was done using linear modeling (voom/Limma; R Bioconductor). The formalin-fixed and paraffin-embedded discovery and confirmation data yielded 8957 and 11,047 detected transcripts, respectively. The two data sets shared 1193 of differentially expressed genes with each other. The average expression and the log 2 -fold changes of differentially expressed transcripts in both data sets correlated, with R²   =   .95 and R²   =   .94, respectively. Among transcripts with the highest fold changes were CA9, neuronal pentraxin-2 and uromodulin. Epithelial-mesenchymal transition was highlighted by differential expression of, for example, transforming growth factor-β 1 and delta-like ligand-4. The diagnostic accuracy of CA9 was 100% and 93.9% when using the discovery set as the training set and the confirmation data as the test set, and vice versa, respectively. These data further support TNFAIP6 as a novel biomarker of ccRCC. TNFAIP6 had combined accuracy of 98.5% in the two data sets. This study provides confirmatory data on the potential use of CA9 and TNFAIP6 as biomarkers of ccRCC. Thus, next-generation sequencing expands the clinical application of tissue analyses.

Von Hippel-Lindau tumor suppressor gene loss in renal cell carcinoma promotes oncogenic epidermal growth factor receptor signaling via Akt-1 and MEK-1.

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Lee, S Justin; Lattouf, Jean-Baptiste; Xanthopoulos, Julie; Linehan, W Marston; Bottaro, Donald P; Vasselli, James R

2008-10-01

Clear-cell renal cell carcinoma (RCC) is the most prevalent form of kidney cancer and is frequently associated with loss of von Hippel-Lindau (VHL) gene function, resulting in the aberrant transcriptional activation of genes that contribute to tumor growth and metastasis, including transforming growth factor-alpha (TGF-alpha), a ligand of the epidermal growth factor receptor (EGFR) tyrosine kinase. To determine the functional impact of EGFR activation on RCC, we suppressed critical components of this pathway: EGFR, Akt-1, and MEK-1. Stable transfection of RCC cells with plasmids bearing shRNA directed against each of these genes was used to individually suppress their expression. Transfectants were characterized for growth and invasiveness in vitro and tumorigenesis in vivo. RCC cell transfectants displayed significantly reduced growth rate and matrix invasion in vitro and RCC tumor xenograft growth rate in vivo. Analysis of tumor cells that emerged after extended periods in each model showed that significant EGFR suppression was sustained, whereas Akt-1 and MEK-1 knock-down cells had escaped shRNA suppression. EGFR, Akt-1, and MEK-1 are individually critical for RCC cell invasiveness in vitro and tumorigenicity in vivo, and even partial suppression of each can have a significant impact on tumor progression. The emergence of transfectants that had escaped Akt-1 and MEK-1 suppression during tumorigenicity experiments suggests that these effectors may each be more critical than EGFR for RCC tumorigenesis, consistent with results from clinical trials of EGFR inhibitors for RCC, where durable clinical responses have not been seen.

Von Hippel-Lindau Tumor Suppressor Gene Loss in Renal Cell Carcinoma Promotes Oncogenic Epidermal Growth Factor Receptor Signaling via Akt-1 and MEK1

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Lee, S. Justin; Lattouf, Jean-Baptiste; Xanthopoulos, Julie; Linehan, W. Marston; Bottaro, Donald P.; Vasselli, James R.

2008-01-01

Objectives Clear-cell renal cell carcinoma (RCC) is the most prevalent form of kidney cancer and is frequently associated with loss of von Hippel-Lindau (VHL) gene function, resulting in the aberrant transcriptional activation of genes that contribute to tumor growth and metastasis, including transforming growth factor-α (TGF-α), a ligand of the epidermal growth factor receptor (EGFR) tyrosine kinase. To determine the functional impact of EGFR activation on RCC, we suppressed critical components of this pathway: EGFR, Akt-1, and MEK-1. Methods Stable transfection of RCC cells with plasmids bearing shRNA directed against each of these genes was used to individually suppress their expression. Transfectants were characterized for growth and invasiveness in vitro and tumorigenesis in vivo. Results RCC cell transfectants displayed significantly reduced growth rate and matrix invasion in vitro and RCC tumor xenograft growth rate in vivo. Analysis of tumor cells that emerged after extended periods in each model showed that significant EGFR suppression was sustained, whereas Akt-1 and MEK-1 knockdown cells had escaped shRNA suppression. Conclusions EGFR, Akt-1, and MEK-1 are individually critical for RCC cell invasiveness in vitro and tumorigenicity in vivo, and even partial suppression of each can have a significant impact on tumor progression. The emergence of transfectants that had escaped Akt-1 and MEK-1 suppression during tumorigenicity experiments suggests that these effectors may each be more critical than EGFR for RCC tumorigenesis, consistent with results from clinical trials of EGFR inhibitors for RCC, where durable clinical responses have not been seen. PMID:18243508

Carbonic Anhydrase IX is Not a Predictor of Outcomes in Non-Metastatic Clear Cell Renal Cell Carcinoma - A Digital Analysis of Tissue Microarray

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Marcelo Zerati

2013-07-01

Full Text Available Introduction The knowledge about the molecular biology of clear cell renal cell carcinoma (ccRCC is evolving, and Carbonic Anhydrase type IX (CA-IX has emerged as a potential prognostic marker in this challenging disease. However, most of the literature about CA-IX on ccRCC comes from series on metastatic cancer, with a lack of series on non-metastatic cancer. The objective is to evaluate the expression of CA-IX in a cohort of non-metastatic ccRCC, correlating with 1 overall survival, and 2 with established prognostic parameters (T stage, tumor size, Fuhrman nuclear grade, microvascular invasion and peri-renal fat invasion. Materials and Methods This is a retrospective cohort study. We evaluated 95 patients with non-metastatic clear cell renal cell carcinoma, as to the expression of CA-IX. The analyzed parameters where: overall survival (OS, TNM stage, tumor size (TS, Fuhrman nuclear grade (FNG, microvascular invasion (MVI, peri-renal fat invasion (PFI. We utilized a custom built tissue microarray, and the immunoexpression was digitally quantified using the Photoshop® software. Results: Th e mean follow-up time was 7.9 years (range 1.9 to 19.5 years. The analysis of CA-IX expression against the selected prognostic parameters showed no correlation. The results are as follows: Overall survival (p = 0.790; T stage (p = 0.179; tumor size (p = 0.143; grouped Fuhrman nuclear grade (p = 0.598; microvascular invasion (p = 0.685, and peri-renal fat invasion (p = 0.104. Conclusion Carbonic anhydrase type IX expression does not correlate with overall survival and conventional prognostic parameters in non-metastatic clear cell renal cell carcinoma.

Retrofitting Of RCC Piles By Using Basalt Fiber Reinforced Polymer BFRP Composite Part 1 Review Papers On RCC Structures And Piles Retrofitting Works.

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R. Ananda Kumar

2015-01-01

Full Text Available Abstract Retrofitting works are immensely essential for deteriorated and damaged structures in Engineering and Medical fields in order to keep or return to the originality for safe guarding the structures and consumers. In this paper different types of methods of retrofitting review notes are given based on the experimental numerical and analytical methods results on strengthening the Reinforced cement concrete RCC structures including RCC piles. Soil-pile interaction on axial load lateral load reviews are also presented. This review paper is prepared to find out the performance of basalt fibre reinforced polymer BFRP composite retrofitted reinforced cement concrete single end bearing piles.

RCC-M - Design and Conception Rules for Mechanical Components of PWR Nuclear Islands

International Nuclear Information System (INIS)

2007-01-01

The design and construction rules applicable to mechanical components of PWR Nuclear Islands (RCC-M) are a part of the collection of design and construction rules for nuclear power plants. It covers the rules applicable to the design and manufacture of pressure boundaries of mechanical equipment of pressurized water reactors (PWR). The pressure components subject to the RCC-M are specified in A 4000. They include the reactor fluid systems (primary, secondary and auxiliary systems) and other components which are not subject to pressure: vessel internals, supports for pressure components subject to the RCC-M, nuclear island storage tanks. When a pressure equipment is subject to the RCC-M, all its elements subject to pressure are also, in accordance with the provisions of A 4000, and these elements are the same class as the component. In this case all the provisions of the RCC-M are applicable: design, procurement, manufacture, inspection and pressure testing. Elements which are not subject to pressure and which are subject to the RCC-M may be covered within the Code by limited specific provisions (procurement of materials for example). The other rules applicable to this equipment must be in contractual form. The assemblies comprising pressure equipment assembled by a manufacturer to constitute an integrated and functional whole, shall be subject to the rules indicated in this Code. Main objectives of Code Requirements are to ensure the integrity and mechanical stability over the equipment design life. Function ability and operability of equipment are not directly addressed in the Code. The RCC-M contributes to ensuring compliance with regulatory requirements. These requirements depend on the applicable regulatory context. The RCC-M is representative of the state of the art as concerns the design and manufacture of PWR components, ensuring an overall safety level tested through experience. The RCC-M consists of five sections, which provide rules for the design and

Percutaneous Cryoablation of Solitary, Sporadic Renal Cell Carcinoma: Outcome Analysis Based on Clear-Cell versus Papillary Subtypes.

Science.gov (United States)

Haddad, Mustafa M; Schmit, Grant D; Kurup, A Nicholas; Schmitz, John J; Boorjian, Stephen A; Geske, Jennifer; Thompson, R Houston; Callstrom, Matthew R; Atwell, Thomas D

2018-06-07

To evaluate treatment outcomes with percutaneous cryoablation (PCA) based on renal cell carcinoma (RCC) histology. Patients treated with PCA for a solitary, sporadic stage T1a RCC from 2003 to 2016 were identified from a single institution's renal ablation registry. Patients with multiple tumors, history of RCC, or genetic syndromes associated with RCC (n = 60); no specific RCC subtype determined from core biopsy (n = 66); RCC subtype other than clear-cell or papillary (n = 7); or less than 3 mo of follow-up imaging (n = 5) were excluded. In total, 173 patients met study inclusion criteria. Oncologic outcomes, clinical outcomes, and complications were evaluated based on tumor subtype. Of the 173 patients who underwent PCA for a stage T1a RCC, 130 (75%) had clear-cell RCC (ccRCC) and 43 (25%) had papillary RCC (pRCC). Median tumor size was 2.9 cm (range, 1.3-4.0 cm). Technically successful cryoablation was achieved in all 173 patients. Local tumor recurrence developed in 6 patients with ccRCC (4.6%), new renal tumors developed in 1 patient (0.8%), and metastatic RCC developed in 1 patient (0.8%) who also had local tumor recurrence. No patients with pRCC showed local tumor recurrence, new renal tumors, or metastatic disease. The 5-year disease-free survival rate in patients with ccRCC was 88%, compared with 100% in patients with pRCC (P = .48). Nine patients (5.2%), all with ccRCC, experienced major complications (P = .11). Percutaneous ablation is a viable treatment option for patients with clinical stage T1a pRCC and ccRCC. Percutaneous ablation may be a very favorable treatment strategy particularly for pRCC. Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.

RCC-C: Design and construction rules for fuel assemblies of PWR nuclear power plants

International Nuclear Information System (INIS)

2015-01-01

The RCC-C code contains all the requirements for the design, fabrication and inspection of nuclear fuel assemblies and the different types of core components (rod cluster control assemblies, burnable poison rod assemblies, primary and secondary source assemblies and thimble plug assemblies). The design, fabrication and inspection rules defined in RCC-C leverage the results of the research and development work pioneered in France, Europe and worldwide, and which have been successfully used by industry to design and build nuclear fuel assemblies and incorporate the resulting feedback. The code's scope covers: fuel system design, especially for assemblies, the fuel rod and associated core components, the characteristics to be checked for products and parts, fabrication methods and associated inspection methods. The RCC-C code is used by the operator of the PWR nuclear power plants in France as a reference when sourcing fuel from the world's top two suppliers in the PWR market, given that the French operator is the world's largest buyer of PWR fuel. Fuel for EPR projects is manufactured according to the provisions of the RCC-C code. The code is available in French and English. The 2005 edition has been translated into Chinese. Contents of the 2015 edition of the RCC-C code: Chapter 1 - General provisions: 1.1 Purpose of the RCC-C, 1.2 Definitions, 1.3 Applicable standards, 1.4 Equipment subject to the RCC-C, 1.5 Management system, 1.6 Processing of non-conformances; Chapter 2 - Description of the equipment subject to the RCC-C: 2.1 Fuel assembly, 2.2 Core components; Chapter 3 - Design: Safety functions, operating functions and environment of fuel assemblies and core components, design and safety principles; Chapter 4 - Manufacturing: 4.1 Materials and part characteristics, 4.2 Assembly requirements, 4.3 Manufacturing and inspection processes, 4.4 Inspection methods, 4.5 Certification of NDT inspectors, 4.6 Characteristics to be inspected for the

Endogenous biotin expression in renal and testicular tumours and literature review.

Science.gov (United States)

Fahmy, Nader; Woo, Mark; Alameldin, Mona; Lee, Joe King; MacDonald, Kyle; Goneau, Lee W; Cadieux, Peter; Burton, Jeremy; Pautler, Stephen

2014-07-01

The aim of this study was to examine endogenous biotin levels in tumour specimens collected from patients with renal and testicular tumours and compare them to the surrounding non-neoplastic surgical margin. Frozen samples were obtained from the Ontario Tumour Bank. Renal and testicular tumour tissue were included in this study. Normal tissue from the negative surgical margins of each tumour served as a control. Biotin detection in tissue specimens was determined using immunohistochemistry (IHC). Specimens collected from 56 patients (36 men and 20 women) were included in this study. Histopathology of the 52 renal tumours included 31 (60%) conventional type RCC, 5 (10%) chromophobe RCC, 5 (10%) papillary RCC, 1 (2%) oncocytoma and 10 (19%) upper tract urothelial carcinoma (UC). The 4 testicular tumours included 1 seminomatous (25%) germ cell tumour and 3 (75%) non seminomatous germ cell tumours. No biotin signal was perceived in all tested tumour samples. Endogenous biotin expression was detected in the matching non-neoplastic surgical margin of tested renal tissues. This lack of staining may prove to be a valuable tool in future studies.

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells

Directory of Open Access Journals (Sweden)

Giuseppe Fiume

2016-11-01

Full Text Available The IBTK gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after IBTK knock-down by shRNA transduction. In HeLa cells, 1285 (2.03% of 63,128 mapped transcripts were differentially expressed in IBTK-shRNA-transduced cells, as compared to cells treated with control-shRNA, with 587 upregulated (45.7% and 698 downregulated (54.3% RNAs. In K562 cells, 1959 (3.1% of 63128 mapped RNAs were differentially expressed in IBTK-shRNA-transduced cells, including 1053 upregulated (53.7% and 906 downregulated (46.3%. Only 137 transcripts (0.22% were commonly deregulated by IBTK silencing in both HeLa and K562 cells, indicating that most IBTKα effects on gene expression are cell type-specific. Based on gene ontology classification, the genes responsive to IBTK are involved in different biological processes, including in particular chromatin and nucleosomal organization, gene expression regulation, and cellular traffic and migration. In addition, IBTK RNA interference affected RNA maturation in both cell lines, as shown by the evidence of alternative 3′- and 5′-splicing, mutually exclusive exons, retained introns, and skipped exons. Altogether, these results indicate that IBTK differently modulates gene expression and RNA splicing in HeLa and K562 cells, demonstrating a novel biological role of this protein.

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells.

Science.gov (United States)

Fiume, Giuseppe; Scialdone, Annarita; Rizzo, Francesca; De Filippo, Maria Rosaria; Laudanna, Carmelo; Albano, Francesco; Golino, Gaetanina; Vecchio, Eleonora; Pontoriero, Marilena; Mimmi, Selena; Ceglia, Simona; Pisano, Antonio; Iaccino, Enrico; Palmieri, Camillo; Paduano, Sergio; Viglietto, Giuseppe; Weisz, Alessandro; Scala, Giuseppe; Quinto, Ileana

2016-11-07

The IBTK gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after IBTK knock-down by shRNA transduction. In HeLa cells, 1285 (2.03%) of 63,128 mapped transcripts were differentially expressed in IBTK -shRNA-transduced cells, as compared to cells treated with control-shRNA, with 587 upregulated (45.7%) and 698 downregulated (54.3%) RNAs. In K562 cells, 1959 (3.1%) of 63128 mapped RNAs were differentially expressed in IBTK -shRNA-transduced cells, including 1053 upregulated (53.7%) and 906 downregulated (46.3%). Only 137 transcripts (0.22%) were commonly deregulated by IBTK silencing in both HeLa and K562 cells, indicating that most IBTKα effects on gene expression are cell type-specific. Based on gene ontology classification, the genes responsive to IBTK are involved in different biological processes, including in particular chromatin and nucleosomal organization, gene expression regulation, and cellular traffic and migration. In addition, IBTK RNA interference affected RNA maturation in both cell lines, as shown by the evidence of alternative 3'- and 5'-splicing, mutually exclusive exons, retained introns, and skipped exons. Altogether, these results indicate that IBTK differently modulates gene expression and RNA splicing in HeLa and K562 cells, demonstrating a novel biological role of this protein.

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma

Directory of Open Access Journals (Sweden)

Karthik V. Giridhar

2017-11-01

Full Text Available The Memorial Sloan Kettering Cancer Center (MSKCC prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR of 0.14, p < 0.0001, 95% confidence interval (CI 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34 were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001. Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

Characterizing the outcomes of metastatic papillary renal cell carcinoma

DEFF Research Database (Denmark)

Connor Wells, John; Donskov, Frede; Fraccon, Anna P

2017-01-01

Outcomes of metastatic papillary renal cell carcinoma (pRCC) patients are poorly characterized in the era of targeted therapy. A total of 5474 patients with metastatic renal cell carcinoma (mRCC) in the International mRCC Database Consortium (IMDC) were retrospectively analyzed. Outcomes were...... compared between clear cell (ccRCC; n = 5008) and papillary patients (n = 466), and recorded type I and type II papillary patients (n = 30 and n = 165, respectively). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) favored ccRCC over pRCC. OS was 8 months longer...

Plutonium recycle concept for RCC - type PWRs

International Nuclear Information System (INIS)

Bonet, H.; Charlier, A.; Deramaix, P.; Vanderberg, C.

1975-01-01

Self-generated Pu recycling schemes in RCC-type PWRs have been defined. The main results of survey studies performed to compare the relative merits of various Pu recycle strategies and the merits of alternative solutions of the assembly design such as the Pu-island assembly or the all-Pu assembly are presented [fr

A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma

Science.gov (United States)

Wei, Jin-Huan; Haddad, Ahmed; Wu, Kai-Jie; Zhao, Hong-Wei; Kapur, Payal; Zhang, Zhi-Ling; Zhao, Liang-Yun; Chen, Zhen-Hua; Zhou, Yun-Yun; Zhou, Jian-Cheng; Wang, Bin; Yu, Yan-Hong; Cai, Mu-Yan; Xie, Dan; Liao, Bing; Li, Cai-Xia; Li, Pei-Xing; Wang, Zong-Ren; Zhou, Fang-Jian; Shi, Lei; Liu, Qing-Zuo; Gao, Zhen-Li; He, Da-Lin; Chen, Wei; Hsieh, Jer-Tsong; Li, Quan-Zhen; Margulis, Vitaly; Luo, Jun-Hang

2015-01-01

Clear cell renal cell carcinomas (ccRCCs) display divergent clinical behaviours. Molecular markers might improve risk stratification of ccRCC. Here we use, based on genome-wide CpG methylation profiling, a LASSO model to develop a five-CpG-based assay for ccRCC prognosis that can be used with formalin-fixed paraffin-embedded specimens. The five-CpG-based classifier was validated in three independent sets from China, United States and the Cancer Genome Atlas data set. The classifier predicts the overall survival of ccRCC patients (hazard ratio=2.96−4.82; P=3.9 × 10−6−2.2 × 10−9), independent of standard clinical prognostic factors. The five-CpG-based classifier successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome in respective clinical stages and individual ‘stage, size, grade and necrosis' scores. Moreover, methylation at the five CpGs correlates with expression of five genes: PITX1, FOXE3, TWF2, EHBP1L1 and RIN1. Our five-CpG-based classifier is a practical and reliable prognostic tool for ccRCC that can add prognostic value to the staging system. PMID:26515236

TFE3-positive renal cell carcinomas are not always Xp11 translocation carcinomas: Report of a case with a TPM3-ALK translocation.

Science.gov (United States)

Thorner, Paul Scott; Shago, Mary; Marrano, Paula; Shaikh, Furqan; Somers, Gino R

2016-10-01

Translocation-associated renal cell carcinoma (RCC) is a distinct subtype of RCC with gene rearrangements of the TFE3 or TFEB loci. The TFE3 gene is located at Xp11 and can fuse to a number of translocation partners, resulting in high nuclear expression of TFE3 protein. TFE3 immunostaining is often used as a surrogate marker for a TFE3 translocation. We report a case of an RCC that expressed TFE3 but showed only gain of TFE3 rather than a translocation. Moreover, this case had a t(1;2) translocation fusing ALK and TMP3, identical to that seen in inflammatory myofibroblastic tumour. There was resulting overexpression of ALK protein in a cytoplasmic and membranous pattern. The patient was not treated with chemotherapy but following regional nodal recurrence, an ALK inhibitor was added and the patient remains alive one year later. There are only rare reports of RCC with an ALK-TMP3 fusion, and these tumours can express TFE3 on some unknown basis not related to a TFE3 translocation. Any RCC positive for TFE3 and lacking a translocation should be tested for ALK expression and translocation. Recognition of this subtype of RCC will allow ALK inhibitor therapy to be added, in the hope of improving patient outcome. Copyright © 2016 Elsevier GmbH. All rights reserved.

Material report in support to RCC-MRX code 2010 stainless steel parts and products

International Nuclear Information System (INIS)

Ancelet, Olivier; Lebarbe, Thierry; Dubiez-Le Goff, Sophie; Bonne, Dominique; Gelineau, Odile

2012-01-01

This paper presents the Material Report dedicated to stainless steels parts and products issued by AFCEN (Association Francaise pour les regles de Conception et de Construction des Materiels des Chaudieres Electro-Nucleaires) in support to RCC-MRx 2010 Code. The RCC-MRx Code is the result of the merger of the RCC-MX 2008, developed in the context of the research reactor Jules Horowitz Reactor project, in the RCC-MR 2007, which set up rules applicable to the design of components operating at high temperature and to the Vacuum Vessel of ITER (a presentation of RCC-MRx 2010 Code is the subject of another paper proposed in this Congress; it explains in particular the status of this Code). This Material Report is part of a set of Criteria of RCC-MRx (this set of Criteria is under construction). The Criteria aim at explaining the design and construction rules of the Code. They cover analyses rules as well as part procurement, welding, methods of tests and examination and fabrication rules. The Material Report particularly provides justifications and explanations on requirements and features dealing with parts and products proposed in the Code. The Material Report contains the following information: Introduction of the grade(s): codes and standards and Reference Procurement Specifications covering parts and products, applications and experience gained, - Physical properties, - Mechanical properties used for design calculations (base metal and welds): basic mechanical properties, creep mechanical properties, irradiated mechanical properties, - Fabrication: experience gained, metallurgy, - Welding: weldability, experience gained during welding and repair procedure qualifications, - Non-destructive examination, - In-service behaviour. In the article, examples of data supplied in the Material Report dedicated to stainless steels will be exposed. (authors)

Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer.

Science.gov (United States)

Santagata, Sara; Napolitano, Maria; D'Alterio, Crescenzo; Desicato, Sonia; Maro, Salvatore Di; Marinelli, Luciana; Fragale, Alessandra; Buoncervello, Maria; Persico, Francesco; Gabriele, Lucia; Novellino, Ettore; Longo, Nicola; Pignata, Sandro; Perdonà, Sisto; Scala, Stefania

2017-09-29

With the intent to identify biomarkers in renal cell carcinoma (RCC) the functional status of T-regulatory cells (Tregs) was investigated in primary RCC. Tregs were isolated from tumoral-(TT), peritumoral tissue-(PT) and peripheral blood-(PB) of 42 primary RCC patients and function evaluated through effector T cells (Teff) proliferation, cytokines release and demethylation of Treg Specific Region (TSDR). The highest value of Tregs was detected in TT with the uppermost amount of effector-Tregs-(CD4 + CD25 hi FOXP3 hi CD45RA - ). PB-RCC Tregs efficiently suppress Teff proliferation compared to healthy donor (HD)-Tregs and, at the intrapatient evaluation, TT-derived Tregs were the most suppressive. Higher demethylation TSDR was detected in TT- and PB-RCC Tregs vs HD-Tregs ( P <0,001). CXCR4 is highly expressed on Tregs, thus we wished to modulate Tregs function through CXCR4 inhibition. CXCR4 antagonism, elicited by a new peptidic antagonist, Peptide-R29, efficiently reversed Tregs suppression of Teff proliferation. Thus Tregs functional evaluation precisely reflects Tregs status and may be a reliable biomarker of tumoral immune response. In addition, treatment with CXCR4 antagonist, impairing Tregs function, could improve the anticancer immune response, in combination with conventional therapy and/or immunotherapy such as checkpoints inhibitors.

Enhanced expression of Stim, Orai, and TRPC transcripts and proteins in endothelial progenitor cells isolated from patients with primary myelofibrosis.

Directory of Open Access Journals (Sweden)

Silvia Dragoni

Full Text Available BACKGROUND: An increase in the frequency of circulating endothelial colony forming cells (ECFCs, the only subset of endothelial progenitor cells (EPCs truly belonging to the endothelial phenotype, occurs in patients affected by primary myelofibrosis (PMF. Herein, they might contribute to the enhanced neovascularisation of fibrotic bone marrow and spleen. Store-operated Ca2+ entry (SOCE activated by the depletion of the inositol-1,4,5-trisphosphate (InsP3-sensitive Ca2+ store drives proliferation in ECFCs isolated from both healthy donors (N-ECFCs and subjects suffering from renal cellular carcinoma (RCC-ECFCs. SOCE is up-regulated in RCC-ECFCs due to the over-expression of its underlying molecular components, namely Stim1, Orai1, and TRPC1. METHODOLOGY/PRINCIPAL FINDINGS: We utilized Ca2+ imaging, real-time polymerase chain reaction, western blot analysis and functional assays to evaluate molecular structure and the functional role of SOCE in ECFCs derived from PMF patients (PMF-ECFCs. SOCE, induced by either pharmacological (i.e. cyclopiazonic acid or CPA or physiological (i.e. ATP stimulation, was significantly higher in PMF-ECFCs. ATP-induced SOCE was inhibited upon blockade of the phospholipase C/InsP3 signalling pathway with U73111 and 2-APB. The higher amplitude of SOCE was associated to the over-expression of the transcripts encoding for Stim2, Orai2-3, and TRPC1. Conversely, immunoblotting revealed that Stim2 levels remained constant as compared to N-ECFCs, while Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in PMF-ECFCs. ATP-induced SOCE was inhibited by BTP-2 and low micromolar La3+ and Gd3+, while CPA-elicited SOCE was insensitive to Gd3+. Finally, BTP-2 and La3+ weakly blocked PMF-ECFC proliferation, while Gd3+ was ineffective. CONCLUSIONS: Two distinct signalling pathways mediate SOCE in PMF-ECFCs; one is activated by passive store depletion and is Gd3+-resistant, while the other one is regulated by the InsP3

Differentiation of low- and high-grade clear cell renal cell carcinoma: Tumor size versus CT perfusion parameters.

Science.gov (United States)

Chen, Chao; Kang, Qinqin; Xu, Bing; Guo, Hairuo; Wei, Qiang; Wang, Tiegong; Ye, Hui; Wu, Xinhuai

To compare the utility of tumor size and CT perfusion parameters for differentiation of low- and high-grade clear cell renal cell carcinoma (RCC). Tumor size, Equivalent blood volume (Equiv BV), permeability surface-area product (PS), blood flow (BF), and Fuhrman pathological grading of clear cell RCC were retrospectively analyzed. High-grade clear cell RCC had significantly higher tumor size and lower PS than low grade. Tumor size positively correlated with Fuhrman grade, but PS negatively did. Tumor size and PS were significantly independent indexes for differentiating high-grade from low-grade clear cell RCC. Copyright © 2017 Elsevier Inc. All rights reserved.

RCC-E: Design and construction rules for electrical equipment of PWR nuclear islands

International Nuclear Information System (INIS)

2016-01-01

RCC-E describes the rules for designing, building and installing electrical and I and C systems and equipment for pressurized water reactors. The code was drafted in partnership with industry, engineering firms, manufacturers, building control firms and operators, and represents a collection of best practices in accordance with IAEA requirements and IEC standards. The code's scope covers: architecture and the associated systems, materials engineering and the qualification procedure for normal and accidental environmental conditions, facility engineering and management of common cause failures (electrical and I and C) and electromagnetic interference, testing and inspecting electrical characteristics, quality assurance requirements supplementing ISO 9001 and activity monitoring. Use: RCC-E has been used to build the following power plants: France's last 12 nuclear units (1,300 MWe (8) and 1,450 MWe (4)), 2 M310 reactors in Korea (2), 44 M310 (4), CPR-1000 (28), CPR-600 (6), HPR-1000 (4) and EPR (2) reactors in service or undergoing construction in China, 1 EPR reactor in France. RCC-E is used for maintenance operations in French power plants (58 units) and Chinese M310 and CPR-1000 power plants. RCC-E has been chosen for the construction of the EPR plants in Hinkley Point, UK. Contents of the 2016 edition of the RCC-E code: Volume 1 - General requirements and quality assurance; Volume 2 - Specification of requirements; Volume 3 - I and C systems; Volume 4 - Electrical systems; Volume 5 - Materials engineering; Volume 6 - Installation of electrical and I and C systems; Volume 7 - Inspection and test methods

Bap1 and Pbrm1: Determinants of Tumor Grade and mTOR Activation in VHL-Deficient Mouse Models of Renal Cell Carcinoma.

Science.gov (United States)

Leung, Janet Y; Kim, William Y

2017-08-01

Large genome sequencing efforts have identified frequent mutations in the histone-modifying and chromatin-remodeling genes BAP1 and PBRM1 in clear cell renal cell carcinoma (ccRCC). In this issue of Cancer Discovery , Gu and colleagues model these genetic events in mice and report that dual inactivation of Vhl with either Bap1 or Pbrm1 results in faithful genetically engineered murine models of ccRCC. Moreover, their work establishes that Bap1 and Pbrm1 are determinants of tumor grade and mTORC1 activation and provocatively suggests that the cell of origin of ccRCC may lie in PAX8-expressing Bowman capsule cells. Cancer Discov; 7(8); 802-4. ©2017 AACR See related article by Gu et al., p. 900 . ©2017 American Association for Cancer Research.

Functional significance of erythropoietin in renal cell carcinoma

International Nuclear Information System (INIS)

Morais, Christudas; Johnson, David W; Vesey, David A; Gobe, Glenda C

2013-01-01

One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion

MicroRNA-200a-3p suppresses tumor proliferation and induces apoptosis by targeting SPAG9 in renal cell carcinoma

Energy Technology Data Exchange (ETDEWEB)

Wang, Xinsheng; Jiang, Fuquan; Song, Haitao; Li, Xu; Xian, Jiantao; Gu, Xinquan, E-mail: guxqprofessor@163.com

2016-02-12

Sperm-associated antigen 9(SPAG9), as a well-recognized oncogene protein, has a critical effect on renal cell carcinoma (RCC) progression. Our study tried to explore the mediator of miR-200a-3p, a tumor suppressing miRNA on SPAG9 expression and renal cell proliferation and apoptosis. We found the expression of miR-200a-3p was significantly lower in RCC specimens. Based on in vitro assays, we found miR-200a-3p significantly inhibit cancer cell proliferation by inducing apoptosis. In addition, our study uncovered that miR-200a-3p directly regulates oncogenic SPAG9 in 786-O and ACHN cells. Silencing of SPAG9 resulted in significantly decreased in the growth and the cell cycle of the renal cancer cell lines. Understanding of oncogenic SPAG9 regulated by miR-200a-3p might be beneficial to reveal new therapeutic targets for RCC. - Highlights: • MiR-200a-3p is downregulated in renal cell carcinoma. • MiR-200a-3p regulates cell proliferation through inducing apoptosis. • MiR-200a-3p is involved in cell cycle regulation. • SPAG9 is a potential target of miR-200a-3p.

Creep-fatigue rules in the RCC-MR code

International Nuclear Information System (INIS)

Drubay, B.

1988-01-01

In 1978, CEA, Electricite de France (EDF) and NOVATOME decided to draw up a complete set of design and construction rules for LMFBR components. This RCC-MR code issued in June 1985 and completed in November 1987 was chosen as a sound basis for the next European Fast Reactor (EFR). The purpose of this paper is to describe the present RCC-MR creep-fatigue design rules to be applied with elastic analysis including the modifications adopted in the first addenda. This method is based on a separate evaluation of a fatigue usage fraction V and creep rupture usage fraction W with the common linear summation rule. The fatigue usage fraction is obtained from continuous fatigue curves (without hold times) and from total strain ranges (elastic + plastic + creep). The creep rupture usage fraction W is obtained from stress to rupture curves and a stress σk evaluating the stress generated during the cycle. (author)

Test and Analysis Correlation of Form Impact onto Space Shuttle Wing Leading Edge RCC Panel 8

Science.gov (United States)

Fasanella, Edwin L.; Lyle, Karen H.; Gabrys, Jonathan; Melis, Matthew; Carney, Kelly

2004-01-01

Soon after the Columbia Accident Investigation Board (CAIB) began their study of the space shuttle Columbia accident, "physics-based" analyses using LS-DYNA were applied to characterize the expected damage to the Reinforced Carbon-Carbon (RCC) leading edge from high-speed foam impacts. Forensic evidence quickly led CAIB investigators to concentrate on the left wing leading edge RCC panels. This paper will concentrate on the test of the left-wing RCC panel 8 conducted at Southwest Research Institute (SwRI) and the correlation with an LS-DYNA analysis. The successful correlation of the LS-DYNA model has resulted in the use of LS-DYNA as a predictive tool for characterizing the threshold of damage for impacts of various debris such as foam, ice, and ablators onto the RCC leading edge for shuttle return-to-flight.

Consideration of creep in design rules of AFCEN RCC-MRx 2012 code

International Nuclear Information System (INIS)

Lebarbe, T.; Petesch, C.; Lejeail, Y.; Lamagnere, P.; Dubiez-Le Goff, S.

2014-01-01

The 2012 edition of the RCC-MRx Code has been issued in French and English versions by AFCEN (Association Francaise pour les regles de Conception et de Construction des Materiels des Chaudieres Electro-nucleaires). This Code is the result of the merger of the RCC-MX 2008 developed in the context of the research reactor Jules Horowitz Reactor project, in the RCC-MR 2007 which set up rules applicable to the design of components operating at high temperature and to the Vacuum Vessel of ITER. This new edition is the opportunity to publish also the background of the rules. This paper is one illustration of what may be such a document, on a dedicated example, the creep rules. It contains an overview of the design rules associated to the creep damage and explains the purpose and the origins of these rules. This type of exercise is going to be generalized to all the parts of the code in AFCEN technical publications, the criteria. (authors)

Local Control Rates of Metastatic Renal Cell Carcinoma (RCC) to Thoracic, Abdominal, and Soft Tissue Lesions Using Stereotactic Body Radiotherapy (SBRT)

International Nuclear Information System (INIS)

Altoos, Basel; Amini, Arya; Yacoub, Muthanna; Bourlon, Maria T.; Kessler, Elizabeth E.; Flaig, Thomas W.; Fisher, Christine M.; Kavanagh, Brian D.; Lam, Elaine T.; Karam, Sana D.

2015-01-01

We report the radiographic response rate of SBRT compared to conventional fractionated radiotherapy (CF-EBRT) for thoracic, abdominal, skin and soft tissue RCC lesions treated at our institution. Fifty three lesions where included in the study (36 SBRT, 17 CF-EBRT), treated from 2004 to 2014 at our institution. We included patients that had thoracic, skin & soft tissue (SST), and abdominal metastases of histologically confirmed RCC. The most common SBRT fractionation was 50 Gy in 5 fractions. The median time of follow-up was 16 months (range 3–97 months). Median BED was 216.67 (range 66.67–460.0) for SBRT, and 60 (range 46.67–100.83) for CF-EBRT. Median radiographic local control rates at 12, 24, and 36 months were 100, 93.41, and 93.41 % for lesions treated with SBRT versus 62.02, 35.27 and 35.27 % for those treated with CF-EBRT (p < 0.001). Predictive factors for radiographic local control under univariate analysis included BED ≥ 100 Gy (HR, 0.048; 95 % CI, 0.006–0.382; p = 0.005), dose per fraction ≥ 9 Gy (HR, 0.631; 95 % CI, 0.429–0.931; p = 0.021), and gender (HR, 0.254; 95 % CI, 0.066–0.978; p = 0.048). Under multivariate analysis, there were no significant predictors for local control. Toxicity rates were low and equivalent in both groups, with no grade 4 or 5 side effects reported. SBRT is safe and effective for the treatment of RCC metastases to thoracic, abdominal and integumentary soft tissues. Radiographic response rates were greater and more durable using SBRT compared to CF-EBRT. Further prospective trials are needed to evaluate efficacy and safety of SBRT for RCC metastases

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

NARCIS (Netherlands)

Ricketts, Christopher J.; De Cubas, Aguirre A.; Fan, Huihui; Smith, Christof C.; Lang, Martin; Reznik, Ed; Bowlby, Reanne; Gibb, Ewan A.; Akbani, Rehan; Beroukhim, Rameen; Bottaro, Donald P.; Choueiri, Toni K.; Gibbs, Richard A.; Godwin, Andrew K.; Haake, Scott; Hakimi, A. Ari; Henske, Elizabeth P.; Hsieh, James J.; Ho, Thai H.; Kanchi, Rupa S.; Krishnan, Bhavani; Kwaitkowski, David J.; Lui, Wembin; Merino, Maria J.; Mills, Gordon B.; Myers, Jerome; Nickerson, Michael L.; Reuter, Victor E.; Schmidt, Laura S.; Shelley, Carl Simon; Shen, Hui; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George; Vincent, Benjamin G.; Vocke, Cathy D.; Wheeler, David A.; Yang, Lixing; Kim, William T.; Robertson, A. Gordon; Caesar-Johnson, Samantha J.; Demchok, John A.; Felau, Ina; Kasapi, Melpomeni; Ferguson, Martin L.; Hutter, Carolyn M.; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean C.; Zhang, Jiashan (Julia); Chudamani, Sudha; Liu, Jia; Lolla, Laxmi; Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu; Wu, Ye; Cho, Juok; DeFreitas, Timothy; Frazer, Scott; Gehlenborg, Nils; Getz, Gad; Heiman, David I.; Kim, Jaegil; Lawrence, Michael S.; Lin, Pei; Meier, Sam; Noble, Michael S.; Saksena, Gordon; Voet, Doug; Zhang, Hailei; Bernard, Brady; Chambwe, Nyasha; Dhankani, Varsha; Knijnenburg, Theo; Kramer, Roger; Leinonen, Kalle; Liu, Yuexin; Miller, Michael; Reynolds, Sheila; Shmulevich, Ilya; Thorsson, Vesteinn; Zhang, Wei; Akbani, Rehan; Broom, Bradley M.; Hegde, Apurva M.; Ju, Zhenlin; Kanchi, Rupa S.; Korkut, Anil; Li, Jun; Liang, Han; Ling, Shiyun; Liu, Wenbin; Lu, Yiling; Mills, Gordon B.; Ng, Kwok Shing; Rao, Arvind; Ryan, Michael; Wang, Jing; Weinstein, John N.; Zhang, Jiexin; Abeshouse, Adam; Armenia, Joshua; Chakravarty, Debyani; Chatila, Walid K.; de Bruijn, Ino; Gao, Jianjiong; Gross, Benjamin E.; Heins, Zachary J.; Kundra, Ritika; La, Konnor; Ladanyi, Marc; Luna, Augustin; Nissan, Moriah G.; Ochoa, Angelica; Phillips, Sarah M.; Reznik, Ed; Sanchez-Vega, Francisco; Sander, Chris; Schultz, Nikolaus; Sheridan, Robert; Sumer, S. Onur; Sun, Yichao; Taylor, Barry S.; Wang, Jioajiao; Zhang, Hongxin; Anur, Pavana; Peto, Myron; Spellman, Paul; Benz, Christopher; Stuart, Joshua M.; Wong, Christopher K.; Yau, Christina; Hayes, D. Neil; Parker, Joel S.; Wilkerson, Matthew D.; Ally, Adrian; Balasundaram, Miruna; Bowlby, Reanne; Brooks, Denise; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert; Jones, Steven J.M.; Kasaian, Katayoon; Lee, Darlene; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Mungall, Karen; Robertson, A. Gordon; Sadeghi, Sara; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Tse, Kane; Wong, Tina; Berger, Ashton C.; Beroukhim, Rameen; Cherniack, Andrew D.; Cibulskis, Carrie; Gabriel, Stacey B.; Gao, Galen F.; Ha, Gavin; Meyerson, Matthew; Schumacher, Steven E.; Shih, Juliann; Kucherlapati, Melanie H.; Kucherlapati, Raju S.; Baylin, Stephen; Cope, Leslie; Danilova, Ludmila; Bootwalla, Moiz S.; Lai, Phillip H.; Maglinte, Dennis T.; Van Den Berg, David J.; Weisenberger, Daniel J.; Auman, J. Todd; Balu, Saianand; Bodenheimer, Tom; Fan, Cheng; Hoadley, Katherine A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Corbin D.; Meng, Shaowu; Mieczkowski, Piotr A.; Mose, Lisle E.; Perou, Amy H.; Perou, Charles M.; Roach, Jeffrey; Shi, Yan; Simons, Janae V.; Skelly, Tara; Soloway, Matthew G.; Tan, Donghui; Veluvolu, Umadevi; Fan, Huihui; Hinoue, Toshinori; Laird, Peter W.; Shen, Hui; Zhou, Wanding; Bellair, Michelle; Chang, Kyle; Covington, Kyle; Creighton, Chad J.; Dinh, Huyen; Doddapaneni, Harsha Vardhan; Donehower, Lawrence A.; Drummond, Jennifer; Gibbs, Richard A.; Glenn, Robert; Hale, Walker; Han, Yi; Hu, Jianhong; Korchina, Viktoriya; Lee, Sandra; Lewis, Lora; Li, Wei; Liu, Xiuping; Morgan, Margaret; Morton, Donna; Muzny, Donna; Santibanez, Jireh; Sheth, Margi; Shinbrot, Eve; Wang, Linghua; Wang, Min; Wheeler, David A.; Xi, Liu; Zhao, Fengmei; Hess, Julian; Appelbaum, Elizabeth L.; Bailey, Matthew; Cordes, Matthew G.; Ding, Li; Fronick, Catrina C.; Fulton, Lucinda A.; Fulton, Robert S.; Kandoth, Cyriac; Mardis, Elaine R.; McLellan, Michael D.; Miller, Christopher A.; Schmidt, Heather K.; Wilson, Richard K.; Crain, Daniel; Curley, Erin; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Candace; Shelton, Troy; Sherman, Mark; Thompson, Eric; Yena, Peggy; Bowen, Jay; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik; Corcoran, Niall; Costello, Tony; Hovens, Christopher; Carvalho, Andre L.; de Carvalho, Ana C.; Fregnani, José H.; Longatto-Filho, Adhemar; Reis, Rui M.; Scapulatempo-Neto, Cristovam; Silveira, Henrique C.S.; Vidal, Daniel O.; Burnette, Andrew; Eschbacher, Jennifer; Hermes, Beth; Noss, Ardene; Singh, Rosy; Anderson, Matthew L.; Castro, Patricia D.; Ittmann, Michael; Huntsman, David; Kohl, Bernard; Le, Xuan; Thorp, Richard; Andry, Chris; Duffy, Elizabeth R.; Lyadov, Vladimir; Paklina, Oxana; Setdikova, Galiya; Shabunin, Alexey; Tavobilov, Mikhail; McPherson, Christopher; Warnick, Ronald; Berkowitz, Ross; Cramer, Daniel; Feltmate, Colleen; Horowitz, Neil; Kibel, Adam; Muto, Michael; Raut, Chandrajit P.; Malykh, Andrei; Barnholtz-Sloan, Jill S.; Barrett, Wendi; Devine, Karen; Fulop, Jordonna; Ostrom, Quinn T.; Shimmel, Kristen; Wolinsky, Yingli; Sloan, Andrew E.; De Rose, Agostino; Giuliante, Felice; Goodman, Marc; Karlan, Beth Y.; Hagedorn, Curt H.; Eckman, John; Harr, Jodi; Myers, Jerome; Tucker, Kelinda; Zach, Leigh Anne; Deyarmin, Brenda; Hu, Hai; Kvecher, Leonid; Larson, Caroline; Mural, Richard J.; Somiari, Stella; Vicha, Ales; Zelinka, Tomas; Bennett, Joseph; Iacocca, Mary; Rabeno, Brenda; Swanson, Patricia; Latour, Mathieu; Lacombe, Louis; Têtu, Bernard; Bergeron, Alain; McGraw, Mary; Staugaitis, Susan M.; Chabot, John; Hibshoosh, Hanina; Sepulveda, Antonia; Su, Tao; Wang, Timothy; Potapova, Olga; Voronina, Olga; Desjardins, Laurence; Mariani, Odette; Roman-Roman, Sergio; Sastre, Xavier; Stern, Marc Henri; Cheng, Feixiong; Signoretti, Sabina; Berchuck, Andrew; Bigner, Darell; Lipp, Eric; Marks, Jeffrey; McCall, Shannon; McLendon, Roger; Secord, Angeles; Sharp, Alexis; Behera, Madhusmita; Brat, Daniel J.; Chen, Amy; Delman, Keith; Force, Seth; Khuri, Fadlo; Magliocca, Kelly; Maithel, Shishir; Olson, Jeffrey J.; Owonikoko, Taofeek; Pickens, Alan; Ramalingam, Suresh; Shin, Dong M.; Sica, Gabriel; Van Meir, Erwin G.; Zhang, Hongzheng; Eijckenboom, Wil; Gillis, Ad; Korpershoek, Esther; Looijenga, Leendert; Oosterhuis, Wolter; Stoop, Hans; van Kessel, Kim E.; Zwarthoff, Ellen C.; Calatozzolo, Chiara; Cuppini, Lucia; Cuzzubbo, Stefania; DiMeco, Francesco; Finocchiaro, Gaetano; Mattei, Luca; Perin, Alessandro; Pollo, Bianca; Chen, Chu; Houck, John; Lohavanichbutr, Pawadee; Hartmann, Arndt; Stoehr, Christine; Stoehr, Robert; Taubert, Helge; Wach, Sven; Wullich, Bernd; Kycler, Witold; Murawa, Dawid; Wiznerowicz, Maciej; Chung, Ki; Edenfield, W. Jeffrey; Martin, Julie; Baudin, Eric; Bubley, Glenn; Bueno, Raphael; De Rienzo, Assunta; Richards, William G.; Kalkanis, Steven; Mikkelsen, Tom; Noushmehr, Houtan; Scarpace, Lisa; Girard, Nicolas; Aymerich, Marta; Campo, Elias; Giné, Eva; Guillermo, Armando López; Van Bang, Nguyen; Hanh, Phan Thi; Phu, Bui Duc; Tang, Yufang; Colman, Howard; Evason, Kimberley; Dottino, Peter R.; Martignetti, John A.; Gabra, Hani; Juhl, Hartmut; Akeredolu, Teniola; Stepa, Serghei; Hoon, Dave; Ahn, Keunsoo; Kang, Koo Jeong; Beuschlein, Felix; Breggia, Anne; Birrer, Michael; Bell, Debra; Borad, Mitesh; Bryce, Alan H.; Castle, Erik; Chandan, Vishal; Cheville, John; Copland, John A.; Farnell, Michael; Flotte, Thomas; Giama, Nasra; Ho, Thai; Kendrick, Michael; Kocher, Jean Pierre; Kopp, Karla; Moser, Catherine; Nagorney, David; O'Brien, Daniel; O'Neill, Brian Patrick; Patel, Tushar; Petersen, Gloria; Que, Florencia; Rivera, Michael; Roberts, Lewis; Smallridge, Robert; Smyrk, Thomas; Stanton, Melissa; Thompson, R. Houston; Torbenson, Michael; Yang, Ju Dong; Zhang, Lizhi; Brimo, Fadi; Ajani, Jaffer A.; Gonzalez, Ana Maria Angulo; Behrens, Carmen; Bondaruk, Jolanta; Broaddus, Russell; Czerniak, Bogdan; Esmaeli, Bita; Fujimoto, Junya; Gershenwald, Jeffrey; Guo, Charles; Lazar, Alexander J.; Logothetis, Christopher; Meric-Bernstam, Funda; Moran, Cesar; Ramondetta, Lois; Rice, David; Sood, Anil; Tamboli, Pheroze; Thompson, Timothy; Troncoso, Patricia; Tsao, Anne; Wistuba, Ignacio; Carter, Candace; Haydu, Lauren; Hersey, Peter; Jakrot, Valerie; Kakavand, Hojabr; Kefford, Richard; Lee, Kenneth; Long, Georgina; Mann, Graham; Quinn, Michael; Saw, Robyn; Scolyer, Richard; Shannon, Kerwin; Spillane, Andrew; Stretch, onathan; Synott, Maria; Thompson, John; Wilmott, James; Al-Ahmadie, Hikmat; Chan, Timothy A.; Ghossein, Ronald; Gopalan, Anuradha; Levine, Douglas A.; Reuter, Victor; Singer, Samuel; Singh, Bhuvanesh; Tien, Nguyen Viet; Broudy, Thomas; Mirsaidi, Cyrus; Nair, Praveen; Drwiega, Paul; Miller, Judy; Smith, Jennifer; Zaren, Howard; Park, Joong Won; Hung, Nguyen Phi; Kebebew, Electron; Linehan, W. Marston; Metwalli, Adam R.; Pacak, Karel; Pinto, Peter A.; Schiffman, Mark; Schmidt, Laura S.; Vocke, Cathy D.; Wentzensen, Nicolas; Worrell, Robert; Yang, Hannah; Moncrieff, Marc; Goparaju, Chandra; Melamed, Jonathan; Pass, Harvey; Botnariuc, Natalia; Caraman, Irina; Cernat, Mircea; Chemencedji, Inga; Clipca, Adrian; Doruc, Serghei; Gorincioi, Ghenadie; Mura, Sergiu; Pirtac, Maria; Stancul, Irina; Tcaciuc, Diana; Albert, Monique; Alexopoulou, Iakovina; Arnaout, Angel; Bartlett, John; Engel, Jay; Gilbert, Sebastien; Parfitt, Jeremy; Sekhon, Harman; Thomas, George; Rassl, Doris M.; Rintoul, Robert C.; Bifulco, Carlo; Tamakawa, Raina; Urba, Walter; Hayward, Nicholas; Timmers, Henri; Antenucci, Anna; Facciolo, Francesco; Grazi, Gianluca; Marino, Mirella; Merola, Roberta; de Krijger, Ronald; Gimenez-Roqueplo, Anne Paule; Piché, Alain; Chevalier, Simone; McKercher, Ginette; Birsoy, Kivanc; Barnett, Gene; Brewer, Cathy; Farver, Carol; Naska, Theresa; Pennell, Nathan A.; Raymond, Daniel; Schilero, Cathy; Smolenski, Kathy; Williams, Felicia; Morrison, Carl; Borgia, Jeffrey A.; Liptay, Michael J.; Pool, Mark; Seder, Christopher W.; Junker, Kerstin; Omberg, Larsson; Dinkin, Mikhail; Manikhas, George; Alvaro, Domenico; Bragazzi, Maria Consiglia; Cardinale, Vincenzo; Carpino, Guido; Gaudio, Eugenio; Chesla, David; Cottingham, Sandra; Dubina, Michael; Moiseenko, Fedor; Dhanasekaran, Renumathy; Becker, Karl Friedrich; Janssen, Klaus Peter; Slotta-Huspenina, Julia; Abdel-Rahman, Mohamed H.; Aziz, Dina; Bell, Sue; Cebulla, Colleen M.; Davis, Amy; Duell, Rebecca; Elder, J. Bradley; Hilty, Joe; Kumar, Bahavna; Lang, James; Lehman, Norman L.; Mandt, Randy; Nguyen, Phuong; Pilarski, Robert; Rai, Karan; Schoenfield, Lynn; Senecal, Kelly; Wakely, Paul; Hansen, Paul; Lechan, Ronald; Powers, James; Tischler, Arthur; Grizzle, William E.; Sexton, Katherine C.; Kastl, Alison; Henderson, Joel; Porten, Sima; Waldmann, Jens; Fassnacht, Martin; Asa, Sylvia L.; Schadendorf, Dirk; Couce, Marta; Graefen, Markus; Huland, Hartwig; Sauter, Guido; Schlomm, Thorsten; Simon, Ronald; Tennstedt, Pierre; Olabode, Oluwole; Nelson, Mark; Bathe, Oliver; Carroll, Peter R.; Chan, June M.; Disaia, Philip; Glenn, Pat; Kelley, Robin K.; Landen, Charles N.; Phillips, Joanna; Prados, Michael; Simko, Jeffry; Smith-McCune, Karen; VandenBerg, Scott; Roggin, Kevin; Fehrenbach, Ashley; Kendler, Ady; Sifri, Suzanne; Steele, Ruth; Jimeno, Antonio; Carey, Francis; Forgie, Ian; Mannelli, Massimo; Carney, Michael; Hernandez, Brenda; Campos, Benito; Herold-Mende, Christel; Jungk, Christin; Unterberg, Andreas; von Deimling, Andreas; Bossler, Aaron; Galbraith, Joseph; Jacobus, Laura; Knudson, Michael; Knutson, Tina; Ma, Deqin; Milhem, Mohammed; Sigmund, Rita; Godwin, Andrew K.; Madan, Rashna; Rosenthal, Howard G.; Adebamowo, Clement; Adebamowo, Sally N.; Boussioutas, Alex; Beer, David; Giordano, Thomas; Mes-Masson, Anne Marie; Saad, Fred; Bocklage, Therese; Landrum, Lisa; Mannel, Robert; Moore, Kathleen; Moxley, Katherine; Postier, Russel; Walker, Joan; Zuna, Rosemary; Feldman, Michael; Valdivieso, Federico; Dhir, Rajiv; Luketich, James; Pinero, Edna M.Mora; Quintero-Aguilo, Mario; Carlotti, Carlos Gilberto; Dos Santos, Jose Sebastião; Kemp, Rafael; Sankarankuty, Ajith; Tirapelli, Daniela; Catto, James; Agnew, Kathy; Swisher, Elizabeth; Creaney, Jenette; Robinson, Bruce; Shelley, Carl Simon; Godwin, Eryn M.; Kendall, Sara; Shipman, Cassaundra; Bradford, Carol; Carey, Thomas; Haddad, Andrea; Moyer, Jeffey; Peterson, Lisa; Prince, Mark; Rozek, Laura; Wolf, Gregory; Bowman, Rayleen; Fong, Kwun M.; Yang, Ian; Korst, Robert; Rathmell, W. Kimryn; Fantacone-Campbell, J. Leigh; Hooke, Jeffrey A.; Kovatich, Albert J.; Shriver, Craig D.; DiPersio, John; Drake, Bettina; Govindan, Ramaswamy; Heath, Sharon; Ley, Timothy; Van Tine, Brian; Westervelt, Peter; Rubin, Mark A.; Lee, Jung Il; Aredes, Natália D.; Mariamidze, Armaz; Spellman, Paul T.; Rathmell, W. Kimryn; Linehan, W. Marston

2018-01-01

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC,

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

OpenAIRE

Christopher J. Ricketts; Aguirre A. De Cubas; Huihui Fan; Christof C. Smith; Martin Lang; Ed Reznik; Reanne Bowlby; Ewan A. Gibb; Rehan Akbani; Rameen Beroukhim; Donald P. Bottaro; Toni K. Choueiri; Richard A. Gibbs; Andrew K. Godwin; Scott Haake

2018-01-01

Summary: Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of sub...

Design and Construction Rules for Mechanical components of FBR nuclear islands: RCC-MR. Tome 1, Volume A: generalities

International Nuclear Information System (INIS)

1985-06-01

The French Rules of Mechanical equipments of Fast Neutron nuclear Reactors (RCC-MR) aims at equipments included in a safety classification. The equipments concerned are those of the nuclear boiler and its auxiliaries: tanks, vessels, internal equipments of the reactor, exchangers, pumps, fittings, pipes, and supports. The present edition of the RCC-MR comprises 12 books presented in the present one in the volume A. The chapter RA 3000 defines the documents to be established in application of the RCC-MR rules. The chapter RA 5000 defines the requirements to take into account to establish and carry out quality Assurance programs according to the RCC-MR rules [fr

Discretization of Gene Expression Data Unmasks Molecular Subgroups Recurring in Different Human Cancer Types.

Directory of Open Access Journals (Sweden)

Manfred Beleut

Full Text Available Despite the individually different molecular alterations in tumors, the malignancy associated biological traits are strikingly similar. Results of a previous study using renal cell carcinoma (RCC as a model pointed towards cancer-related features, which could be visualized as three groups by microarray based gene expression analysis. In this study, we used a mathematic model to verify the presence of these groups in RCC as well as in other cancer types. We developed an algorithm for gene-expression deviation profiling for analyzing gene expression data of a total of 8397 patients with 13 different cancer types and normal tissues. We revealed three common Cancer Transcriptomic Profiles (CTPs which recurred in all investigated tumors. Additionally, CTPs remained robust regardless of the functions or numbers of genes analyzed. CTPs may represent common genetic fingerprints, which potentially reflect the closely related biological traits of human cancers.

MiT family translocation renal cell carcinoma.

Science.gov (United States)

Argani, Pedram

2015-03-01

The MiT subfamily of transcription factors includes TFE3, TFEB, TFC, and MiTF. Gene fusions involving two of these transcription factors have been identified in renal cell carcinoma (RCC). The Xp11 translocation RCCs were first officially recognized in the 2004 WHO renal tumor classification, and harbor gene fusions involving TFE3. The t(6;11) RCCs harbor a specific Alpha-TFEB gene fusion and were first officially recognized in the 2013 International Society of Urologic Pathology (ISUP) Vancouver classification of renal neoplasia. These two subtypes of translocation RCC have many similarities. Both were initially described in and disproportionately involve young patients, though adult translocation RCC may overall outnumber pediatric cases. Both often have unusual and distinctive morphologies; the Xp11 translocation RCCs frequently have clear cells with papillary architecture and abundant psammomatous bodies, while the t(6;11) RCCs frequently have a biphasic appearance with both large and small epithelioid cells and nodules of basement membrane material. However, the morphology of these two neoplasms can overlap, with one mimicking the other. Both of these RCCs underexpress epithelial immunohistochemical markers like cytokeratin and epithelial membrane antigen (EMA) relative to most other RCCs. Unlike other RCCs, both frequently express the cysteine protease cathepsin k and often express melanocytic markers like HMB45 and Melan A. Finally, TFE3 and TFEB have overlapping functional activity as these two transcription factors frequently heterodimerize and bind to the same targets. Therefore, on the basis of clinical, morphologic, immunohistochemical, and genetic similarities, the 2013 ISUP Vancouver classification of renal neoplasia grouped these two neoplasms together under the heading of "MiT family translocation RCC." This review summarizes our current knowledge of these recently described RCCs. Copyright © 2015 Elsevier Inc. All rights reserved.

ASME and RCC-MR comparison for the prevention of fatigue analysis

International Nuclear Information System (INIS)

Autrusson, B.; Acker, D.

1989-01-01

The purpose of this survey is to compare the simplified methods, without reference to the safety factor allowed for the mechanical properties. An application of both codes, RCC-MR and ASME, on the design of the wall mock-up of the NET project is made and also an estimation with an elastoplastic analysis. In the case of fatigue analysis according to ASME in the plastic field, the elastic stress is magnified by a K e factor derived from stress variation, S n , disregarding geometrical discontinuities. According to RCC-MR, the elastic maximum strain will magnified by two coefficients accounting for plasticity and variation of Poisson ratio

Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation.

Science.gov (United States)

Jang, Yunseon; Han, Jeongsu; Kim, Soo Jeong; Kim, Jungim; Lee, Min Joung; Jeong, Soyeon; Ryu, Min Jeong; Seo, Kang-Sik; Choi, Song-Yi; Shong, Minho; Lim, Kyu; Heo, Jun Young; Kweon, Gi Ryang

2015-11-10

Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel-Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.

Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model.

Science.gov (United States)

Suarez, Eloah Rabello; Chang, De Kuan; Sun, Jiusong; Sui, Jianhua; Freeman, Gordon J; Signoretti, Sabina; Zhu, Quan; Marasco, Wayne A

2016-06-07

Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50-80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.

Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma

International Nuclear Information System (INIS)

Li, Siming; Kong, Yan; Si, Lu; Chi, Zhihong; Cui, Chuanliang; Sheng, Xinan; Guo, Jun

2014-01-01

The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment. Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules. In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of

Urinary collecting system invasion is associated with poor survival in patients with clear-cell renal cell carcinoma.

Science.gov (United States)

Bailey, George C; Boorjian, Stephen A; Ziegelmann, Matthew J; Westerman, Mary E; Lohse, Christine M; Leibovich, Bradley C; Cheville, John C; Thompson, R Houston

2017-04-01

To evaluate the prognostic significance of urinary collecting system invasion (UCSI) in a large series of patients with clear-cell renal cell carcinoma (RCC). Patients with clear-cell RCC treated with nephrectomy between 2001 and 2010 were reviewed from a prospectively maintained registry. One urological pathologist re-reviewed all slides. Cancer-specific survival was estimated using the Kaplan-Meier method, and associations of UCSI with death from RCC were evaluated using Cox models. Of the 859 patients with clear-cell RCC, 58 (6.8%) had UCSI. At last follow-up, 310 patients had died from RCC at a median of 1.8 years after surgery. The median follow-up for patients alive at last follow-up was 8.2 years. The estimated cancer-specific survival at 10 years after surgery for patients with UCSI was 17%, compared with 60% for patients without UCSI (P system invasion is associated with poor prognosis among patients with clear-cell RCC. If validated, consideration should be given to including UCSI in future staging systems. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

RCC-CW - Rules for design and construction of PWR nuclear civil works

International Nuclear Information System (INIS)

2016-01-01

RCC-CW describes the rules for designing, building and testing civil engineering works in PWR reactors. It explains the principles and requirements for the safety, serviceability and durability of concrete and metal frame structures, based on Eurocode design principles (European standards for the structural design of construction works) combined with specific measures for safety-class buildings. The code is produced as part of the RCC-CW Subcommittee, which includes all the parties involved in civil engineering works in the nuclear sector: clients, contractors, general and specialized firms, consultancies and inspection offices. The code covers the following areas relating to the design and construction of civil engineering works that play an important safety role: geotechnical aspects, reinforced concrete structures and galleries, pre-stressed containments with metal liner, metal containment and pool liners, metal frames, anchors, concrete cylinder pipes, containment leak tests. The RCC-CW code is available as an ETC-C version specific to EPR projects (European pressurized reactor). Contents of the 2016 edition of the RCC-CW Code: Part G - General: scope, standards, notations, quality management, general principles; Part D - Design: actions and combinations of actions, geotechnical aspects, pre-stressed or reinforced concrete structures, metal containment liners, metal pool liners, metal frames, anchors; Part C - Construction: geotechnical aspects, concrete, surface finish and formwork, reinforcement for reinforced concrete, pre-stressing processes, prefabricated concrete elements, metal containment liners, metal pool liners, metal frames, anchors, embedded pipelines, joint sealing, survey networks and tolerances; Part M - Maintenance and monitoring: containment integrity and rate tests

Commentary on: "An integrated metabolic atlas of clear cell renal cell carcinoma." Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, Aksoy BA, Liu EM, Shen R, Lee W, Chen Y, Stirdivant SM, Russo P, Chen YB, Tickoo SK, Reuter VE, Cheng EH, Sander C, Hsieh JJ.: Cancer Cell. 2016 Jan 11;29(1):104-16.

Science.gov (United States)

Lee, Byron H

2017-09-01

Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort. Copyright © 2017 Elsevier Inc. All rights reserved.

Role of Mitochondrial DNA Copy Number Alteration in Human Renal Cell Carcinoma

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Chen-Sung Lin

2016-05-01

Full Text Available We investigated the role of mitochondrial DNA (mtDNA copy number alteration in human renal cell carcinoma (RCC. The mtDNA copy numbers of paired cancer and non-cancer parts from five resected RCC kidneys after radical nephrectomy were determined by quantitative polymerase chain reaction (Q-PCR. An RCC cell line, 786-O, was infected by lentiviral particles to knock down mitochondrial transcriptional factor A (TFAM. Null target (NT and TFAM-knockdown (TFAM-KD represented the control and knockdown 786-O clones, respectively. Protein or mRNA expression levels of TFAM; mtDNA-encoded NADH dehydrogenase subunit 1 (ND1, ND6 and cytochrome c oxidase subunit 2 (COX-2; nuclear DNA (nDNA-encoded succinate dehydrogenase subunit A (SDHA; v-akt murine thymoma viral oncogene homolog 1 gene (AKT-encoded AKT and v-myc myelocytomatosis viral oncogene homolog gene (c-MYC-encoded MYC; glycolytic enzymes including hexokinase II (HK-II, glucose 6-phosphate isomerase (GPI, phosphofructokinase (PFK, and lactate dehydrogenase subunit A (LDHA; and hypoxia-inducible factors the HIF-1α and HIF-2α, pyruvate dehydrogenase kinase 1 (PDK1, and pyruvate dehydrogenase E1 component α subunit (PDHA1 were analyzed by Western blot or Q-PCR. Bioenergetic parameters of cellular metabolism, basal mitochondrial oxygen consumption rate (mOCRB and basal extracellular acidification rate (ECARB, were measured by a Seahorse XFe-24 analyzer. Cell invasiveness was evaluated by a trans-well migration assay and vimentin expression. Doxorubicin was used as a chemotherapeutic agent. The results showed a decrease of mtDNA copy numbers in resected RCC tissues (p = 0.043. The TFAM-KD clone expressed lower mtDNA copy number (p = 0.034, lower mRNA levels of TFAM (p = 0.008, ND1 (p = 0.007, and ND6 (p = 0.017, and lower protein levels of TFAM and COX-2 than did the NT clone. By contrast, the protein levels of HIF-2α, HK-II, PFK, LDHA, AKT, MYC and vimentin; trans-well migration activity (p = 0

First Delayed Resection Findings After Irreversible Electroporation (IRE) of Human Localised Renal Cell Carcinoma (RCC) in the IRENE Pilot Phase 2a Trial

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Wendler, Johann Jakob, E-mail: johann.wendler@med.ovgu.de [Otto von Guericke University of Magdeburg, Department of Urology, University Hospital (Germany); Ricke, Jens, E-mail: jens.Ricke@med.ovgu.de; Pech, Maciej, E-mail: macej.pech@med.ovgu.de; Fischbach, Frank, E-mail: frank.fischbach@med.ovgu.de; Jürgens, Julian, E-mail: julian.juergens@med.ovgu.de [University of Magdeburg, Department of Radiology (Germany); Siedentopf, Sandra, E-mail: sandra.siedentopf@med.ovgu.de; Roessner, Albert, E-mail: albert.roessner@med.ovgu.de [University of Magdeburg, Institute of Pathology (Germany); Porsch, Markus, E-mail: markus.porsch@med.ovgu.de; Baumunk, Daniel, E-mail: daniel.baumunk@med.ovgu.de; Schostak, Martin, E-mail: martin.schostak@med.ovgu.de [Otto von Guericke University of Magdeburg, Department of Urology, University Hospital (Germany); Köllermann, Jens, E-mail: jens.koellermann@sana.de [Sana Klinikum Offenbach Am Main, Institute of Pathology (Germany); Liehr, Uwe-Bernd, E-mail: uwe-bernd.liehr@med.ovgu.de [Otto von Guericke University of Magdeburg, Department of Urology, University Hospital (Germany)

2016-02-15

IntroductionIt is postulated that focal IRE affords complete ablation of soft-tissue tumours while protecting the healthy peritumoral tissue. Therefore, IRE may be an interesting option for minimally invasive, kidney-tissue-sparing, non-thermal ablation of renal tumours.AimWith this current pilot study (“IRENE trial”), we present the first detailed histopathological data of IRE of human RCC followed by delayed tumour resection. The aim of this interim analysis of the first three patients was to investigate the ablation efficiency of percutaneous image-guided focal IRE in RCC, to assess whether a complete ablation of T1a RCC and tissue preservation with the NanoKnife system is possible and to decide whether the ablation parameters need to be altered.MethodsFollowing resection 4 weeks after percutaneous IRE, the success of ablation and detailed histopathological description were used to check the ablation parameters.ResultsThe IRE led to a high degree of damage to the renal tumours (1 central, 2 peripheral; size range 15–17 mm). The postulated homogeneous, isomorphic damage was only partly confirmed. We found a zonal structuring of the ablation zone, negative margins and, enclosed within the ablation zone, very small tumour residues of unclear malignancy.ConclusionAccording to these initial, preliminary study results of the first three renal cases, a new zonal distribution of IRE damage was described and the curative intended, renal saving focal ablation of localised RCC below <3 cm by percutaneous IRE by the NanoKnife system appears to be possible, but needs further, systematic evaluation for this treatment method and treatment protocol.

Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins.

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Stoyanoff, Tania Romina; Rodríguez, Juan Pablo; Todaro, Juan Santiago; Espada, Joaquín Diego; Colavita, Juan Pablo Melana; Brandan, Nora Cristina; Torres, Adriana Mónica; Aguirre, María Victoria

2016-10-01

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC. Tissue samples were obtained at the Urology Unit of the J.R. Vidal Hospital (Corrientes, Argentina), from patients who underwent radical nephrectomy for renal cancer between 2011 and 2014. Four experimental groups according to pathological stage and nuclear grade were organized: T1G1 (n = 6), T2G1 (n = 4), T1G2 (n = 7), and T2G2 (n = 7). The expression of HIF-1α, EPO, EPO-R, VEGF, VEGFR-2, Bcl-x L , and SCD-1 were evaluated by immunohistochemistry, Western blotting, and/or RT-PCR. Apoptosis was assessed by the TUNEL in situ assay, and tumor proliferation was determined by Ki-67 immunohistochemistry. Data revealed that HIF-1α, EPO, EPO-R, VEGF, and VEGF-R2 were overexpressed in most samples. The T1G1 group showed the highest EPO levels, approximately 200 % compared with distal renal tissue. Bcl-x L overexpression was concomitant with the enhancement of proliferative indexes. SCD-1 expression increased with the tumor size and nuclear grade. Moreover, the direct correlations observed between SCD-1/HIF-1α and SCD-1/Ki-67 increments suggest a link among these molecules, which would determine tumor progression in early stages of ccRCC. Our results demonstrate the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (HIF-1α, EPO, VEGF), their

Cutaneous metastasis of bilateral renal cell carcinoma.

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Abbasi, Fariba; Alizadeh, Mansur; Noroozinia, Farahnaz; Moradi, Amin

2013-01-01

Renal cell carcinoma (RCC) is a malignant lethal tumour with high potential of metastasis. However, metastasis from RCC to the skin is much less common. It is virtually a sign of poor prognosis. We represent a 42 years old man with bilateral RCC of clear cell type followed by metastasis to the scalp one month later. In this case the relatively young age of the patient, bilaterality of RCC and occurance of skin metastasis in the absence of recurrent kidney tumour are interesting.

Creep design rules in french ''RCC-MR'' code

International Nuclear Information System (INIS)

Roche, H.

1986-04-01

In this paper, four points enlightening the originality of the ''RCC-MR'' analysis rules in the creep range will be discussed. The three first points will concern elastic analysis, the fourth one materials data. The rules given in this paper are applicable for class 1 components and level A conditions. They are given by way of illustration in a simplified form

Creep-fatigue damage evaluation for SS-316LN (ORNL PLATES): - RCC-MR vs. ASME SEC III - NH

International Nuclear Information System (INIS)

Sati, Bhuwan Chandra; Jalaldeen, S.; Velusamy, K.; Selvaraj, P.

2016-01-01

Investigations of high temperature tests done on ORNL plate with deformation control loading, under creep-fatigue damage have been presented. The test results with methodology of RCC-MR and ASME-NH life prediction under creep-fatigue loading have been assessed. The stress relaxation effect in calculating the life using RCC-MR under creep-fatigue damage is found to be significant in presence of secondary stress. RCC-MR: 2007 is more realistic number of cycles (predicts 51 number of cycles) as compared to ASME-NH (predicts 312 number of cycles) which is demonstrated by the experimental work (observed 86 numbers of cycles). Between RCC-MR and experimental work, design code seems to be more conservative for life prediction due to creep-fatigue damage. For fatigue damage, the approaches are same and the difference comes from material properties and the starting stress for applying Neuber's rule. ASME approach has the limitation of stress range magnitude. ASME approach predicts lower elastic plus plastic strain for the cases having S* above the linear stress limit. For creep strain and creep damage evaluation, ASME and RCC-MR have different approaches for calculating the stress at the beginning and during the hold period. The RCC-MR takes account of cyclic hardening or softening effects (hardening in the present case of 316 LN) by means of the cyclic stress-strain curve and the benefit of symmetrization effects which are significant for this material. The ASME code neglects these effects and instead relies on an approach based on the isochronous stress-strain curves. (author)

Surgical treatment of Renal Cell Carcinoma (RCC with level III–IV tumor venous thrombosis

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M. I. Davydov

2016-01-01

Full Text Available Objective: to assess the results of nephrectomy, thrombectomy in RCC patients with level III–IV tumor venous thrombosis with and without cardiopulmonary bypass.Materials and methods. Medical data of 167 consecutive RCC patients with level III–IV tumor venous thrombosis underwent nephrectomy thrombectomy in N.N. Blokhin Russian Cancer Research Center between 1998 and 2012 were collected. Right side tumor was in 122 (73.1 %, left side – in 42 (25.1 %, bilateral – in 3 (1.8 % cases. The extent of thrombus was defined as intrahepatic in 82 (49.1 %, supradiaphragmatic – in 85 (50.9 % (intrapericardial – in 44 (26.3 %, intraatrial – in 39 (23.4 %, intraventricular – in 2 (1.2 % cases. Nephrectomy, thrombectomy with cardiopulmonary bypass was used in 9 (5.4 %, 158 (94.6 % patients underwent radical nephrectomy with thrombectomy without CPBP and sternotomy. Intrapericardial IVC and right atrium were exposed through transdiaphragmatic approach and providing vascular control over infradiaphragmatic IVC and renal veins.Results. Median blood loss was 6000 (600–27 000 ml. Complications rate was 62.8 %, 90-day mortality – 13.2 %. Intraoperative complications were registered in 80 (47.9 %, postoperative – in 66 (40.5 % (grade II – 16 (9.8 %, grade IIIb – 1 (0.6 %, grade IVа – 28 (17.2 %, grade IVb – 3 (1.8 %, grade V – 18 (11.1 % patients. Modified thrombectomy technique insignificantly decreased blood loss compared to thrombectomy with CPB, did nоt increase complications rate including pulmonary vein thromboembolism, or mortality. Five-year overall, cancer-specific and recurrence-free survival was 46.2, 58.3 and 47.1 %, respectively. Thrombectomy technique did nоt affect survival.Conclusion. In selected patients with mobile thrombi transdiaphragmatic approach allows to avoid the use of CPBP and decrease surgical morbidity without survival compromising.

The RCC-MR design code for LMFBR components. A useful basis for fusion reactor design tools development

International Nuclear Information System (INIS)

Acker, D.; Chevereau, G.

1986-01-01

LMFBR and fusion reactors exhibit common features with regard to structural materials, temperature service level, loading types. So, design and construction rules used in France for LMFBR, that is to say RCC-MR Code, can constitute a good basis for fusion reactors design. Some original aspects of RCC-MR design rules are described, relating to unsignificant creep, ratchetting effect, fatigue and creep damage limits, creep damage evaluation, fatigue damage evaluation, buckling. The main originality of RCC-MR consists to propose comprehensive simplified rules based on elastic calculations and extended from classical cold temperatures to the elevated temperature domain. (author)

GSK-3 directly regulates phospho-4EBP1 in renal cell carcinoma cell-line: an intrinsic subcellular mechanism for resistance to mTORC1 inhibition

International Nuclear Information System (INIS)

Ito, Hiromi; Ichiyanagi, Osamu; Naito, Sei; Bilim, Vladimir N.; Tomita, Yoshihiko; Kato, Tomoyuki; Nagaoka, Akira; Tsuchiya, Norihiko

2016-01-01

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin 1 (mTORC1) signaling pathway is aberrantly activated in renal cell carcinoma (RCC). We previously demonstrated glycogen synthase kinase-3β (GSK-3β) positively regulated RCC proliferation. The aim of this study was to evaluate the role of GSK-3 in the PI3K/Akt/mTORC1 pathway and regulation of the downstream substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), ribosomal protein S6 kinase (S6K), and ribosomal protein S6 (S6RP). We used human RCC cell lines (ACHN, Caki1, and A498) and, as normal controls, human renal proximal tubular epithelial cell (HRPTEpC) and non-tumorous kidney tissues that were obtained surgically for treatment of RCC patients. Rapamycin-resistant ACHN (ACHN/RR) cells were generated with chronic exposure of ACHN to rapamycin ranging from 1nM finally to 1 μM. Cell viability, cell cycling and direct interaction between GSK-3β and 4EBP1 were evaluated with MTS assay, flowcytometry and in vitro kinase assay with recombinant GSK-3β and 4EBP1products, respectively. Protein expression and phosphorylation of molecules associated with the PI3K/Akt/mTORC1 pathway were examined by immunoblotting. Effects of drug combination were determined as the combination index with CompuSyn software. Overexpression and phosphorylation of 4EBP1 and S6RP together with GSK-3 activation were observed in RCC cell lines, but not in human normal kidney cells and tissues. Cell proliferation, p4EBP1 and pS6RP were strongly suppressed by GSK-3 inhibition. Rapamycin and LY294002 sufficiently decreased pS6RP, but only moderately p4EBP1. In vitro kinase assays showed that recombinant GSK-3β phosphorylated recombinant 4EBP1, and the effect was blocked by GSK-3 inhibitors. Different from rapamycin, AR- A014418 remarkably inhibited cell proliferation, and rapidly suppressed p4EBP1 and pS6RP in ACHN and ACHN/RR (in 30 min to 1 h). AR- A014418 and rapamycin combination showed

The effect of increased centrifugation temperature on the quality of red-blood-cell concentrates of automated whole blood processing.

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Weinigel, C; Rummler, S; Barz, D

2013-10-01

There are manual and automated methods to separate whole blood (WB) available. The Atreus whole blood processing system is an automated method, which combines centrifugation and expression of components into a single device. A major difference to conventional methods is that centrifugation temperature is not controlled at 22°C. The aim of this study was to examine the influence of increased centrifugation temperatures on the quality of red-blood-cell concentrates (RCC) after active cooling of WB prior to processing. A total of 28 WB were processed: 16 at centrifugation temperatures of up to 28°C (1st protocol) and 12 at 34°C (2nd protocol). RCC quality parameters were tested weekly for 42 days. Red-blood-cell concentrates (RCC) quality complied with the European and German guidelines. Haemolysis was not significantly different throughout storage. Significant statistical differences were detected between both protocols in potassium concentration at the end of storage and in ATP levels at the day of processing. Centrifugation temperatures of up to 34°C are well tolerated by the red blood cells with minimal interference with the RCC quality parameters. © 2013 International Society of Blood Transfusion.

Longterm results in the therapy of 100 cases of metastatic renal cell carcinoma (RCC)

International Nuclear Information System (INIS)

Falk, W.; Halama, J.M.; Halama, J.

1990-01-01

The success of renal cell carcinoma (RCC)-nephrectomy with radical lymph node dissection in stage I and II disease is undisputed. Through these measures 23% of metastases are controlled. The five-year survival time in stage III disease, however, stagnates at 35%±14% despite radical surgery. Also, the additional tumor-vaccine-therapy of the Mainz-Joint-Study-Group was successful only in stage I and II disease, whereas stage III disease did not benefit from this therapy. As 50% of all radically operated patients developed metastases within three years after surgery, the call by radiooncologists for supplementary radiotherapy beginning with stage III disease must be put foreward. The problems of therapy and chances of survival in generalized disease are demonstrated in 100 of our cases treated by surgery, radiotherapy and with MPA (medroxyprogesteroneacetate). Whereas Schmiedt et al. show a total survival time of 10.3 months after diagnosis of metastatic disease, the Offenbach patients achieved 16.5 months with a median survival time of 11.75 months. The necessity of therapeutic intervention is confirmed by the fact that the most favorable median survival time, 15.75 months, was achieved in metastatic disease involving three organs. We present here the special features of the individual organ manifestations and point out that not only the mean and median survival time, but also the very widely varying survival times in individual cases, make conscientious oncological post-treatment follow up and management a requirement. (orig.) [de

Pathological significance and prognostic roles of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios in clear cell renal cell carcinoma.

Science.gov (United States)

Nakanishi, Hiromi; Miyata, Yasuyoshi; Mochizuki, Yasushi; Yasuda, Takuji; Nakamura, Yuichiro; Araki, Kyohei; Sagara, Yuji; Matsuo, Tomohiro; Ohba, Kojiro; Sakai, Hideki

2018-05-19

The immune system is closely associated with malignant behavior in renal cell carcinoma (RCC). Therefore, understanding the pathological roles of immune cells in tumor stroma is essential to discuss the pathological characteristics of RCC. In this study, the clinical significance of densities of CD57+ cells, CD68+ cells, and mast cells, and their ratios were investigated in patients with clear cell RCC. The densities of CD57+, CD68+, and mast cells were evaluated by immunohistochemical techniques in 179 patients. Proliferation index (PI), apoptotic index (AI), and microvessel density (MVD) were evaluated by using anti-Ki-67, anti-cleaved caspase-3, and anti-CD31 antibodies, respectively. The density of CD57+ cell was negatively correlated with grade, pT stage, and metastasis, although densities of CD68+ cell and mast cell were positively correlated. Ratios of CD68+ cell/CD57+ cell and mast cell/CD57+ cell were significantly correlated with grade, pT stage, and metastasis. Survival analyses showed that the CD68+ cell/CD57+ cell ratio was a significant predictor for cause-specific survival by multi-variate analyses (hazard ratio=1.41, 95% confidential interval=1.03-1.93, P=.031), and was significantly correlated with PI, AI, and MVD (r=.47; P <. 001, r=-.31, P<.001, and r=.40, P<.001, respectively). In conclusion, CD57+ cell, CD68+ cell, and mast cell played important roles in malignancy in clear cell RCC. The CD68+ cell/CD57+ cell ratio was strongly correlated with pathological features and prognosis in these patients because this ratio reflected the status of cancer cell proliferation, apoptosis, and angiogenesis. Copyright © 2018. Published by Elsevier Inc.

Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma.

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Chapman-Fredricks, Jennifer R; Herrera, Loren; Bracho, Jorge; Gomez-Fernandez, Carmen; Leveillee, Raymond; Rey, Luis; Jorda, Merce

2011-10-01

Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable-type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component

The RCC-MR design code for LMFBR components. A useful basic for fusion reactor design tools development

International Nuclear Information System (INIS)

Acker, D.; Chevereau, G.

1985-11-01

LMFBR and fusion reactors exhibit common features with regard to structural materials (Stainless steels), temperature service level (550-600 0 C), loading types. So, design and construction rules used in France for LMFBR, that is to say RCC-MR Code, can constitute a good basis for fusion reactors design. Some original aspects of RCC-MR design rules are described, relating to unsignificant creep, ratchetting effect, fatigue and creep damage limits, creep damage evaluation, fatigue damage evaluation, buckling. The main originality of RCC-MR consists to propose comprehensive simplified rules based on elastic calculations and extended from classical cold temperatures to the elevated temperature domain

Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma.

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Nouhaud, François-Xavier; Blanchard, France; Sesboue, Richard; Flaman, Jean-Michel; Sabourin, Jean-Christophe; Pfister, Christian; Di Fiore, Frédéric

2018-02-23

Gene copy number variations (CNVs) have been reported to be frequent in renal cell carcinoma (RCC), with potential prognostic value for some. However, their clinical utility, especially to guide treatment of metastatic disease remains to be established. Our objectives were to assess CNVs on a panel of selected genes and determine their clinical relevance in patients who underwent treatment of metastatic RCC. The genetic assessment was performed on frozen tissue samples of clear cell metastatic RCC using quantitative multiplex polymerase chain reaction of short fluorescent fragment method to detect CNVs on a panel of 14 genes of interest. The comparison of the electropherogram obtained from both tumor and normal renal adjacent tissue allowed for CNV identification. The clinical, biologic, and survival characteristics were assessed for their associations with the most frequent CNVs. Fifty patients with clear cell metastatic RCC were included. The CNV rate was 21.4%. The loss of CDKN2A and PLG was associated with a higher tumor stage (P relevance, especially those located on CDKN2A, PLG, and ALDOB, in a homogeneous cohort of patients with clear cell metastatic RCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Ovatodiolide Targets β-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

Directory of Open Access Journals (Sweden)

Jar-Yi Ho

2013-01-01

Full Text Available Dysregulated β-catenin signaling is intricately involved in renal cell carcinoma (RCC carcinogenesis and progression. Determining potential β-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β-catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β-catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β-catenin (S552 that inhibited β-catenin nuclear translocation. Moreover, ovatodiolide decreased β-catenin stability and impaired the association of β-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

Culture in embryonic kidney serum and xeno-free media as renal cell carcinoma and renal cell carcinoma cancer stem cells research model.

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Krawczyk, Krzysztof M; Matak, Damian; Szymanski, Lukasz; Szczylik, Cezary; Porta, Camillo; Czarnecka, Anna M

2018-04-01

The use of fetal bovine serum hinders obtaining reproducible experimental results and should also be removed in hormone and growth factor studies. In particular hormones found in FBS act globally on cancer cell physiology and influence transcriptome and metabolome. The aim of our study was to develop a renal carcinoma serum free culture model optimized for (embryonal) renal cells in order to select the best study model for downstream auto-, para- or endocrine research. Secondary aim was to verify renal carcinoma stem cell culture for this application. In the study, we have cultured renal cell carcinoma primary tumour cell line (786-0) as well as human kidney cancer stem cells in standard 2D monolayer cultures in Roswell Park Memorial Institute Medium or Dulbecco's Modified Eagle's Medium and Complete Human Kidney Cancer Stem Cell Medium, respectively. Serum-free, animal-component free Human Embryonic Kidney 293 media were tested. Our results revealed that xeno-free embryonal renal cells optimized culture media provide a useful tool in RCC cancer biology research and at the same time enable effective growth of RCC. We propose bio-mimic RCC cell culture model with specific serum-free and xeno-free medium that promote RCC cell viability.

Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types.

Science.gov (United States)

Syring, Isabella; Klümper, Niklas; Offermann, Anne; Braun, Martin; Deng, Mario; Boehm, Diana; Queisser, Angela; von Mässenhausen, Anne; Brägelmann, Johannes; Vogel, Wenzel; Schmidt, Doris; Majores, Michael; Schindler, Anne; Kristiansen, Glen; Müller, Stefan C; Ellinger, Jörg; Shaikhibrahim, Zaki; Perner, Sven

2016-04-26

The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking.We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.

Store-operated Ca2+ entry is remodelled and controls in vitro angiogenesis in endothelial progenitor cells isolated from tumoral patients.

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Francesco Lodola

Full Text Available Endothelial progenitor cells (EPCs may be recruited from bone marrow to sustain tumor vascularisation and promote the metastatic switch. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca(2+ entry (SOCE, which is activated by a depletion of the intracellular Ca(2+ pool, regulates the growth of human EPCs, where is mediated by the interaction between the endoplasmic reticulum Ca(2+-sensor, Stim1, and the plasmalemmal Ca(2+ channel, Orai1. As oncogenesis may be associated to the capability of tumor cells to grow independently on Ca(2+ influx, it is important to assess whether SOCE regulates EPC-dependent angiogenesis also in tumor patients.The present study employed Ca(2+ imaging, recombinant sub-membranal and mitochondrial aequorin, real-time polymerase chain reaction, gene silencing techniques and western blot analysis to investigate the expression and the role of SOCE in EPCs isolated from peripheral blood of patients affected by renal cellular carcinoma (RCC; RCC-EPCs as compared to control EPCs (N-EPCs. SOCE, activated by either pharmacological (i.e. cyclopiazonic acid or physiological (i.e. ATP stimulation, was significantly higher in RCC-EPCs and was selectively sensitive to BTP-2, and to the trivalent cations, La(3+ and Gd(3+. Furthermore, 2-APB enhanced thapsigargin-evoked SOCE at low concentrations, whereas higher doses caused SOCE inhibition. Conversely, the anti-angiogenic drug, carboxyamidotriazole (CAI, blocked both SOCE and the intracellular Ca(2+ release. SOCE was associated to the over-expression of Orai1, Stim1, and transient receptor potential channel 1 (TRPC1 at both mRNA and protein level The intracellular Ca(2+ buffer, BAPTA, BTP-2, and CAI inhibited RCC-EPC proliferation and tubulogenesis. The genetic suppression of Stim1, Orai1, and TRPC1 blocked CPA-evoked SOCE in RCC-EPCs.SOCE is remodelled in EPCs

TREM-1 expression in craniopharyngioma and Rathke's cleft cyst: its possible implication for controversial pathology.

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Liu, Yi; Wang, Chao-Hu; Li, Dan-Ling; Zhang, Shi-Chao; Peng, Yu-Ping; Peng, Jun-Xiang; Song, Ye; Qi, Song-Tao; Pan, Jun

2016-08-02

Whether a mixed type of craniopharyngioma (CP) exists and whether papillary craniopharyngioma (pCP) is on a histopathological continuum with Rathke's cleft cyst (RCC) remain controversial. Herein, we examined the expression and localization of β-catenin, BRAF p.V600E (V600E), and triggering receptor expressed on myeloid cells-1 (TREM-1) in 58 samples including 20 pCPs, 26 adamantinomatous craniopharyngiomas (aCP), and 12 RCCs. Five aCPs were diagnosed with mixed type CPs and the remaining 21 cases were pure aCPs. Four of the 12 RCCs presented with significant squamous epithelium (SE). V600E immunoreactivity was observed in all pCPs in the cytoplasm, but not in the nuclei. aCPs and RCCs, including mixed type CP, did not express V600E. Nuclear β-catenin translocation was detected exclusively in aCPs. TREM-1 was expressed in pCPs. Additionally, TREM-1 expression was detected in the SE of 5 "mixed type" CPs, while it was absent in pure aCPs. TREM-1 was expressed in 4 RCCs with SE, but not in the remaining 8 RCCs. TREM-1 mRNA levels were compared in cultured pCP and aCP cells. TREM-1 mRNA level was significantly (p < 0.001; up to 4.045 fold) higher in pCPs than in aCPs. Western blotting revealed a significantly (p < 0.001; up to 7.19 fold) lower level of TREM-1 expression in aCP cells compared to that in pCP cells. Our findings further supported that RCC and pCP may represent two ends of a morphological spectrum. A variant showing overlapping histological features of aCP and pCP should not be considered as a mixed type.

T-cell receptor Vβ skewing frequently occurs in refractory cytopenia of childhood and is associated with an expansion of effector cytotoxic T cells: a prospective study by EWOG-MDS

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Aalbers, A M; Heuvel-Eibrink, M M van den; Baumann, I; Beverloo, H B; Driessen, G J; Dworzak, M; Fischer, A; Göhring, G; Hasle, H; Locatelli, F; De Moerloose, B; Noellke, P; Schmugge, M; Stary, J; Yoshimi, A; Zecca, M; Zwaan, C M; Dongen, J J M van; Pieters, R; Niemeyer, C M; Velden, V H J van der; Langerak, A W

2014-01-01

Immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A, is effective in refractory cytopenia of childhood (RCC), suggesting that, similar to low-grade myelodysplastic syndromes in adult patients, T lymphocytes are involved in suppressing hematopoiesis in a subset of RCC patients. However, the potential role of a T-cell-mediated pathophysiology in RCC remains poorly explored. In a cohort of 92 RCC patients, we prospectively assessed the frequency of T-cell receptor (TCR) β-chain variable (Vβ) domain skewing in bone marrow and peripheral blood by heteroduplex PCR, and analyzed T-cell subsets in peripheral blood by flow cytometry. TCRVβ skewing was present in 40% of RCC patients. TCRVβ skewing did not correlate with bone marrow cellularity, karyotype, transfusion history, HLA-DR15 or the presence of a PNH clone. In 28 patients treated with IST, TCRVβ skewing was not clearly related with treatment response. However, TCRVβ skewing did correlate with a disturbed CD4 + /CD8 + T-cell ratio, a reduction in naive CD8 + T cells, an expansion of effector CD8 + T cells and an increase in activated CD8 + T cells (defined as HLA-DR + , CD57 + or CD56 + ). These data suggest that T lymphocytes contribute to RCC pathogenesis in a proportion of patients, and provide a rationale for treatment with IST in selected patients with RCC

Prognostic significance of multidrug-resistance protein (MDR-1 in renal clear cell carcinomas: A five year follow-up analysis

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Strazzullo Viviana

2006-12-01

Full Text Available Abstract Background A large number of renal cancer patients shows poor or partial response to chemotherapy and the mechanisms have not been still understood. Multi-drug resistance is the principal mechanism by which many cancers develop resistance to chemotherapic drugs. The role of the multi-drug resistant transporter (MDR-1/P-glycoprotein, the gene product of MDR-1, and that one of the so-called multi-drug resistance associated protein (MRP, two energy-dependent efflux pumps, are commonly known to confer drug resistance. We studied MDR-1 expression in selected cases of renal cell carcinoma (RCC, clear cell type, with long-term follow-up, in order to establish its prognostic role and its possible contribution in the choice of post-surgical therapy. Methods MDR-1 has been studied by standard LSAB-HRP immunohistochemical technique, in paraffin embedded RCC samples. Protein expression has been compared to clinical and histopathological data and to disease specific survival of RCC patients, by Kaplan-Meier curve and Cox multivariate regression analyses. Results Two groups of RCCs were obtained by esteeming MDR-1 expression and disease specific survival (obtained with Kaplan-Meier curve and Cox multivariate regression analyses: the first one presents low or absent MDR-1 expression and good survival; the second one is characterized by high MDR-1 expression and significant poor outcome (p p p p Conclusion In our opinion, the results of this study well prove the relationship between MDR-1 expression and worse clinical prognosis in RCC, because MDR-1 over-expressing RCCs can be considered a group of tumours with a more aggressive behavior. This finding outlines a possible role of MDR-1 as prognostic factor, dependent and independent of multidrug resistance. These results could be useful to predict cancer evolution and to choose the appropriate treatment: this is another step that can stimulate further promising and interesting investigations on broader

Coffee consumption and risk of renal cell carcinoma.

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Antwi, Samuel O; Eckel-Passow, Jeanette E; Diehl, Nancy D; Serie, Daniel J; Custer, Kaitlynn M; Arnold, Michelle L; Wu, Kevin J; Cheville, John C; Thiel, David D; Leibovich, Bradley C; Parker, Alexander S

2017-08-01

Studies have suggested an inverse association between coffee consumption and risk of renal cell carcinoma (RCC); however, data regarding decaffeinated coffee are limited. We conducted a case-control study of 669 incident RCC cases and 1,001 frequency-matched controls. Participants completed identical risk factor questionnaires that solicited information about usual coffee consumption habits. The study participants were categorized as non-coffee, caffeinated coffee, decaffeinated coffee, or both caffeinated and decaffeinated coffee drinkers. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusting for multiple risk factors for RCC. Compared with no coffee consumption, we found an inverse association between caffeinated coffee consumption and RCC risk (OR 0.74; 95% CI 0.57-0.99), whereas we observed a trend toward increased risk of RCC for consumption of decaffeinated coffee (OR 1.47; 95% CI 0.98-2.19). Decaffeinated coffee consumption was associated also with increased risk of the clear cell RCC (ccRCC) subtype, particularly the aggressive form of ccRCC (OR 1.80; 95% CI 1.01-3.22). Consumption of caffeinated coffee is associated with reduced risk of RCC, while decaffeinated coffee consumption is associated with an increase in risk of aggressive ccRCC. Further inquiry is warranted in large prospective studies and should include assessment of dose-response associations.

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.

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Naito, Sei; Makhov, Peter; Astsaturov, Igor; Golovine, Konstantin; Tulin, Alexei; Kutikov, Alexander; Uzzo, Robert G; Kolenko, Vladimir M

2017-04-25

Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

RCC Plug Repair Thermal Tools for Shuttle Mission Support

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Rodriguez, Alvaro C.; Anderson, Brian P.

2010-01-01

A thermal math model for the Space Shuttle Reinforced Carbon-Carbon (RCC) Plug Repair was developed to increase the confidence in the repair entry performance and provide a real-time mission support tool. The thermal response of the plug cover plate, local RCC, and metallic attach hardware can be assessed with this model for any location on the wing leading edge. The geometry and spatial location of the thermal mesh also matches the structural mesh which allows for the direct mapping of temperature loads and computation of the thermoelastic stresses. The thermal model was correlated to a full scale plug repair radiant test. To utilize the thermal model for flight analyses, accurate predictions of protuberance heating were required. Wind tunnel testing was performed at CUBRC to characterize the heat flux in both the radial and angular directions. Due to the complexity of the implementation of the protuberance heating, an intermediate program was developed to output the heating per nodal location for all OML surfaces in SINDA format. Three Design Reference Cases (DRC) were evaluated with the correlated plug thermal math model to bound the environments which the plug repair would potentially be used.

Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma

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Clara E. Jäkel

2012-01-01

Full Text Available Metastatic renal cell carcinoma (RCC seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.

Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-Bromopyruvate.

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Nilsson, H; Lindgren, D; Mandahl Forsberg, A; Mulder, H; Axelson, H; Johansson, M E

2015-01-08

Changes of cellular metabolism are an integral property of the malignant potential of most cancer cells. Already in the 1930s, Otto Warburg observed that tumor cells preferably utilize glycolysis and lactate fermentation for energy production, rather than the mitochondrial oxidative phosphorylation dominating in normal cells, a phenomenon today known as the Warburg effect. Even though many tumor types display a high degree of aerobic glycolysis, they still retain the activity of other energy-producing metabolic pathways. One exception seems to be the clear cell variant of renal cell carcinoma, ccRCC, where the activity of most other pathways than that of glycolysis has been shown to be reduced. This makes ccRCC a promising candidate for the use of glycolytic inhibitors in treatment of the disease. However, few studies have so far addressed this issue. In this report, we show a strikingly reduced mitochondrial respiratory capacity of primary human ccRCC cells, resulting in enhanced sensitivity to glycolytic inhibition by 3-Bromopyruvate (3BrPA). This effect was largely absent in established ccRCC cell lines, a finding that highlights the importance of using biologically relevant models in the search for new candidate cancer therapies. 3BrPA markedly reduced ATP production in primary ccRCC cells, followed by cell death. Our data suggest that glycolytic inhibitors such as 3BrPA, that has been shown to be well tolerated in vivo, should be further analyzed for the possible development of selective treatment strategies for patients with ccRCC.

Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

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Zantl Niko

2010-06-01

Full Text Available Abstract Background Human renal cell carcinoma (RCC is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

Repression of hTERT transcription by the introduction of chromosome 3 into human oral squamous cell carcinoma

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Nishio, Sachiyo [Division of Oral and Maxillofacial Biopathological Surgery, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503 (Japan); Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, 683-8503 (Japan); Ohira, Takahito; Sunamura, Naohiro [Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, 683-8503 (Japan); Oshimura, Mitsuo [Chromosome Engineering Research Center, Tottori University, Yonago, Tottori, 683-8503 (Japan); Ryoke, Kazuo [Division of Oral and Maxillofacial Biopathological Surgery, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503 (Japan); Kugoh, Hiroyuki, E-mail: kugoh@med.tottori-u.ac.jp [Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, 683-8503 (Japan); Chromosome Engineering Research Center, Tottori University, Yonago, Tottori, 683-8503 (Japan)

2015-10-30

Telomerase is a ribonucleoprotein enzyme that maintains telomere length. Telomerase activity is primarily attributed to the expression of telomerase reverse transcriptase (TERT). It has been reported that introduction of an intact human chromosome 3 into the human oral squamous cell carcinoma cell line HSC3 suppresses the tumorigenicity of these cells. However, the mechanisms that regulate tumorigenicity have not been elucidated. To determine whether this reduction in tumorigenicity was accompanied by a reduction in telomerase activity, we investigated the transcriptional activation of TERT in HSC3 microcell hybrid clones with an introduced human chromosome 3 (HSC3#3). HSC#3 cells showed inhibition of hTERT transcription compared to that of the parental HSC3 cells. Furthermore, cell fusion experiments showed that hybrids of HSC3 cells and cells of the RCC23 renal carcinoma cell line, which also exhibits suppression of TERT transcription by the introduction of human chromosome 3, also displayed suppressed TERT transcription. These results suggested that human chromosome 3 may carry functionally distinct, additional TERT repressor genes. - Highlights: • hTERT mRNA expression level decreased in the chromosome 3 introduced HSC3 clones. • hTERT mRNA expression level was tend to suppressed in HSC3 and RCC23 hybrid cells. • We provide evidence that human chromosome 3 carries at least two distinct hTERT regulatory factors.

Repression of hTERT transcription by the introduction of chromosome 3 into human oral squamous cell carcinoma

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Nishio, Sachiyo; Ohira, Takahito; Sunamura, Naohiro; Oshimura, Mitsuo; Ryoke, Kazuo; Kugoh, Hiroyuki

2015-01-01

Telomerase is a ribonucleoprotein enzyme that maintains telomere length. Telomerase activity is primarily attributed to the expression of telomerase reverse transcriptase (TERT). It has been reported that introduction of an intact human chromosome 3 into the human oral squamous cell carcinoma cell line HSC3 suppresses the tumorigenicity of these cells. However, the mechanisms that regulate tumorigenicity have not been elucidated. To determine whether this reduction in tumorigenicity was accompanied by a reduction in telomerase activity, we investigated the transcriptional activation of TERT in HSC3 microcell hybrid clones with an introduced human chromosome 3 (HSC3#3). HSC#3 cells showed inhibition of hTERT transcription compared to that of the parental HSC3 cells. Furthermore, cell fusion experiments showed that hybrids of HSC3 cells and cells of the RCC23 renal carcinoma cell line, which also exhibits suppression of TERT transcription by the introduction of human chromosome 3, also displayed suppressed TERT transcription. These results suggested that human chromosome 3 may carry functionally distinct, additional TERT repressor genes. - Highlights: • hTERT mRNA expression level decreased in the chromosome 3 introduced HSC3 clones. • hTERT mRNA expression level was tend to suppressed in HSC3 and RCC23 hybrid cells. • We provide evidence that human chromosome 3 carries at least two distinct hTERT regulatory factors.

Racial difference in histologic subtype of renal cell carcinoma

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Olshan, Andrew F; Kuo, Tzy-Mey; Meyer, Anne-Marie; Nielsen, Matthew E; Purdue, Mark P; Rathmell, W Kimryn

2013-01-01

In the United States, renal cell carcinoma (RCC) has rapidly increased in incidence for over two decades. The most common histologic subtypes of RCC, clear cell, papillary, and chromophobe have distinct genetic and clinical characteristics; however, epidemiologic features of these subtypes have not been well characterized, particularly regarding any associations between race, disease subtypes, and recent incidence trends. Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, we examined differences in the age-adjusted incidence rates and trends of RCC subtypes, including analysis focusing on racial differences. Incidence rates increased over time (2001–2009) for all three subtypes. However, the proportion of white cases with clear cell histology was higher than among blacks (50% vs. 31%, respectively), whereas black cases were more likely than white cases to have papillary RCC (23% vs. 9%, respectively). Moreover, papillary RCC incidence increased more rapidly for blacks than whites (P < 0.01) over this period. We also observed that increased incidence of papillary histology among blacks is not limited to the smallest size strata. We observed racial differences in proportionate incidence of RCC subtypes, which appear to be increasing over time; this novel finding motivates further etiologic, clinical, molecular, and genetic studies. Using national data, we observed a higher proportion of black renal cell carcinoma (RCC) cases with papillary histology compared to Caucasian cases. We also observed time trends in black-white incidence differences in histologic RCC subtypes, with rapid increases in the disproportionate share of black cases with papillary histology

Comparison of Utility of Histogram Apparent Diffusion Coefficient and R2* for Differentiation of Low-Grade From High-Grade Clear Cell Renal Cell Carcinoma.

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Zhang, Yu-Dong; Wu, Chen-Jiang; Wang, Qing; Zhang, Jing; Wang, Xiao-Ning; Liu, Xi-Sheng; Shi, Hai-Bin

2015-08-01

The purpose of this study was to compare histogram analysis of apparent diffusion coefficient (ADC) and R2* for differentiating low-grade from high-grade clear cell renal cell carcinoma (RCC). Forty-six patients with pathologically confirmed clear cell RCC underwent preoperative BOLD and DWI MRI of the kidneys. ADCs based on the entire tumor volume were calculated with b value combinations of 0 and 800 s/mm(2). ROI-based R2* was calculated with eight TE combinations of 6.7-22.8 milliseconds. Histogram analysis of tumor ADCs and R2* values was performed to obtain mean; median; width; and fifth, 10th, 90th, and 95th percentiles and histogram inhomogeneity, kurtosis, and skewness for all lesions. Thirty-three low-grade and 13 high-grade clear cell RCCs were found at pathologic examination. The TNM classification and tumor volume of clear cell RCC significantly correlated with histogram ADC and R2* (ρ = -0.317 to 0.506; p histogram ADC and R2* indexes, 10th percentile ADC had the highest accuracy (91.3%) in discriminating low- from high-grade clear cell RCC. R2* in discriminating hemorrhage was achieved with a threshold of 68.95 Hz. At this threshold, high-grade clear cell RCC had a significantly higher prevalence of intratumor hemorrhage (high-grade, 76.9%; low-grade, 45.4%; p Histogram analysis of ADC and R2* allows differentiation of low- from high-grade clear cell RCC with high accuracy.

Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy

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Anbalagan, Selvakumar; Pires, Isabel M.; Blick, Christopher; Hill, Mark A.; Ferguson, David J.P.; Chan, Denise A.; Hammond, Ester M.

2012-01-01

Background and purpose: For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation. Materials and methods: Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels. Results: STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions. Conclusions: This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.

The value of blood oxygenation level-dependent (BOLD MR imaging in differentiation of renal solid mass and grading of renal cell carcinoma (RCC: analysis based on the largest cross-sectional area versus the entire whole tumour.

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Guang-Yu Wu

Full Text Available To study the value of assessing renal masses using different methods in parameter approaches and to determine whether BOLD MRI is helpful in differentiating RCC from benign renal masses, differentiating clear-cell RCC from renal masses other than clear-cell RCC and determining the tumour grade.Ninety-five patients with 139 renal masses (93 malignant and 46 benign who underwent abdominal BOLD MRI were enrolled. R2* values were derived from the largest cross-section (R2*largest and from the whole tumour (R2*whole. Intra-observer and inter-observer agreements were analysed based on two measurements by the same observer and the first measurement from each observer, respectively, and these agreements are reported with intra-class correlation coefficients and 95% confidence intervals. The diagnostic value of the R2* value in the evaluation was assessed with receiver-operating characteristic analysis.The intra-observer agreement was very good for R2*largest and R2*whole (all > 0.8. The inter-observer agreement of R2*whole (0.75, 95% confidence interval: 0.69~0.79 was good and was significantly improved compared with the R2*largest (0.61, 95% confidence interval: 0.52~0.68, as there was no overlap in the 95% confidence interval of the intra-class correlation coefficients. The diagnostic value in differentiating renal cell carcinoma from benign lesions with R2*whole (AUC=0.79/0.78[observer1/observer2] and R2*largest (AUC=0.75[observer1] was good and significantly higher (p=0.01 for R2*largest[observer2] vs R2*whole[observer2], p 0.7 and were not significantly different (p=0.89/0.93 for R2*largest vs R2*whole[observer1/observer2], 0.96 for R2*whole[observer1] vs R2*largest[observer2] and 0.96 for R2*whole [observer2] vs R2*largest[observer1].BOLD MRI could provide a feasible parameter for differentiating renal cell carcinoma from benign renal masses and for predicting clear-cell renal cell carcinoma grading. Compared with the largest cross

Stage-dependent prognostic impact of molecular signatures in clear cell renal cell carcinoma

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Weber T

2014-05-01

0.75 to 0.78. In patients with "organ-confined" ccRCC, no disease-related deaths occurred in the group with p21-expression below the threshold of 32.5% p21-positive cells (log rank test: P=0.002.Conclusion: The prognostic information of the studied protein biomarkers depended on anatomic tumor stages, which displayed different acquired biological tumor characteristics. Analysis of prognostic factors within different clinical ccRCC groups could help to enhance their prognostic power. The p21-staining was an independent prognostic factor and increased prognostic accuracy in a predictive model in "organ-confined" ccRCC.Keywords: survival, prognostic groups, localized, p21, advanced

Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

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Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

2017-11-18

Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Prognostic implication of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma: a tissue microarray study

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Wang Facheng

2008-10-01

Full Text Available Abstract Background p27Kip1 plays a major role as a negative regulator of the cell cycle. The regulation of p27Kip1 degradation is mediated by its specific ubiquitin ligase subunits S-phase kinase protein (Skp 2 and cyclin-dependent kinase subunit (Cks 1. However, little is known regarding the prognostic utility of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma. Methods Immunohistochemistry was performed for p27Kip1, Skp2 and Cks1 in tissue microarrays of 482 renal cell carcinomas with follow-up. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. Results Immunoreactivity of p27Kip1, Skp2 and Cks1 was noted in 357, 71 and 82 patients, respectively. Skp2 and Cks1 expression were not noted in chromophobe cancers. A strong correlation was found between Skp2 and Cks1 expression (P Kip1 levels (P = 0.006 and P Kip1 expression and Skp2 expression were correlated with larger tumor size and higher stage, as well as tumor necrosis. Cks1 expression was only correlated with tumor size. In univariate analysis, low p27Kip1 expression, Skp2 and Cks1 expression were all associated with a poor prognosis, while in multivariate analysis, only low p27Kip1 expression were independent prognostic factors for both cancer specific survival and recurrence-free survival in patients with RCC. Conclusion Our results suggest that immunohistochemical expression levels of p27Kip1, Skp2 and Cks1 may serve as markers with prognostic value in renal cell carcinoma.

Colony, hanging drop, and methylcellulose three dimensional hypoxic growth optimization of renal cell carcinoma cell lines.

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Matak, Damian; Brodaczewska, Klaudia K; Lipiec, Monika; Szymanski, Łukasz; Szczylik, Cezary; Czarnecka, Anna M

2017-08-01

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, comprising 3% of all human neoplasms, and the incidence of kidney cancer is rising annually. We need new approaches to target tumor cells that are resistant to current therapies and that give rise to recurrence and treatment failure. In this study, we focused on low oxygen tension and three-dimensional (3D) cell culture incorporation to develop a new RCC growth model. We used the hanging drop and colony formation methods, which are common in 3D culture, as well as a unique methylcellulose (MC) method. For the experiments, we used human primary RCC cell lines, metastatic RCC cell lines, human kidney cancer stem cells, and human healthy epithelial cells. In the hanging drop assay, we verified the potential of various cell lines to create solid aggregates in hypoxic and normoxic conditions. With the semi-soft agar method, we also determined the ability of various cell lines to create colonies under different oxygen conditions. Different cell behavior observed in the MC method versus the hanging drop and colony formation assays suggests that these three assays may be useful to test various cell properties. However, MC seems to be a particularly valuable alternative for 3D cell culture, as its higher efficiency of aggregate formation and serum independency are of interest in different areas of cancer biology.

Rate of renal cell carcinoma subtypes in different races

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Alexander Sankin

2011-02-01

Full Text Available PURPOSE: We sought to identify racial differences among histological subtypes of renal cell carcinoma (RCC between black and non-black patients in an equal-access health care system. MATERIALS AND METHODS: We established a multi-institutional, prospective database of patients undergoing partial or radical nephrectomy between January 1, 2000 and Sept 31, 2009. For the purposes of this study, data captured included age at diagnosis, race, tumor size, presence of lymphovascular invasion, presence of capsular invasion, margin status, and tumor histology. RESULTS: 204 kidney tumors were identified (Table-1. Of these, 117 (57.4% were in black patients and 87 (42.6% were in non-black patients. Age at surgery ranged from 37 to 87 with a median of 62. Tumor size ranged from 1.0 to 22.0 cm with a median of 5.0 cm. Overall, tumors were composed of clear cell RCC in 97 cases (47.5%, papillary RCC in 65 cases (31.9%, chromophobe RCC in 13 cases (6.4%, collecting duct/medullary RCC in 2 cases (1.0%, RCC with multiple histological subtypes in 8 cases (3.9%, malignant tumors of other origin in 6 cases (2.9%, and benign histology in 13 cases (6.4%. Among black patients, papillary RCC was seen in 56 cases (47.9%, compared to 9 cases (10.3% among non-black patients (p < 0.001 (Table-2. Clear cell RCC was present in 38 (32.5% of black patients and in 59 (67.8% of non-blacks (p < 0.001. CONCLUSIONS: In our study, papillary RCC had a much higher occurrence among black patients compared to non-black patients. This is the first study to document such a great racial disparity among RCC subtypes.

Wnt Signaling in Renal Cell Carcinoma

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Qi Xu

2016-06-01

Full Text Available Renal cell carcinoma (RCC accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers.

Nano-Phase Powder Based Exothermic Braze Repair Technology For RCC Materials, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The Phase II project will advance innovative, cost effective and reliable nano-phase exothermic RCC joining processes (ExoBrazeTM) in order to be able to reinforce...

Large prospective investigation of meat intake, related mutagens, and risk of renal cell carcinoma.

Science.gov (United States)

Daniel, Carrie R; Cross, Amanda J; Graubard, Barry I; Park, Yikyung; Ward, Mary H; Rothman, Nathaniel; Hollenbeck, Albert R; Chow, Wong-Ho; Sinha, Rashmi

2012-01-01

The evidence for meat intake and renal cell carcinoma (RCC) risk is inconsistent. Mutagens related to meat cooking and processing, and variation by RCC subtype may be important to consider. In a large US cohort, we prospectively investigated intake of meat and meat-related compounds in relation to risk of RCC, as well as clear cell and papillary RCC histologic subtypes. Study participants (492,186) completed a detailed dietary assessment linked to a database of heme iron, heterocyclic amines (HCA), polycyclic aromatic hydrocarbons (PAHs), nitrate, and nitrite concentrations in cooked and processed meats. Over 9 (mean) y of follow-up, we identified 1814 cases of RCC (498 clear cell and 115 papillary adenocarcinomas). HRs and 95% CIs were estimated within quintiles by using multivariable Cox proportional hazards regression. Red meat intake [62.7 g (quintile 5) compared with 9.8 g (quintile 1) per 1000 kcal (median)] was associated with a tendency toward an increased risk of RCC [HR: 1.19; 95% CI: 1.01, 1.40; P-trend = 0.06] and a 2-fold increased risk of papillary RCC [P-trend = 0.002]. Intakes of benzo(a)pyrene (BaP), a marker of PAHs, and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), an HCA, were associated with a significant 20-30% elevated risk of RCC and a 2-fold increased risk of papillary RCC. No associations were observed for the clear cell subtype. Red meat intake may increase the risk of RCC through mechanisms related to the cooking compounds BaP and PhIP. Our findings for RCC appeared to be driven by strong associations with the rarer papillary histologic variant. This study is registered at clinicaltrials.gov as NCT00340015.

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma.

Science.gov (United States)

Batra, U; Parikh, P M; Prabhash, K; Tongaonkar, H B; Chibber, P; Dabkara, D; Deshmukh, C; Ghadyalpatil, N; Hingmire, S; Joshi, A; Raghunath, S K; Rajappa, S; Rajendranath, R; Rawal, S K; Singh, Manisha; Singh, R; Somashekhar, S P; Sood, R

2016-01-01

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of "Take Home Messages" at the end is a convenient tool for busy practitioners.

Nano-Phase Powder Based Exothermic Braze Repair Technology For RCC Materials, Phase I

Data.gov (United States)

National Aeronautics and Space Administration — MRi is proposing, with its partner, Exotherm Corp (Camden, NJ) to demonstrate the feasibility of using exothermic brazing to join RCC (or C:SiC) composites to itself...

Metastatic Renal Cell Carcinoma versus Pancreatic Neuroendocrine Tumor in von Hippel-Lindau Disease: Treatment with Interleukin-2

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Christopher Williams

2005-01-01

Full Text Available Differentiating between clear cell neuroendocrine tumor (NET of the pancreas and renal cell carcinoma (RCC metastatic to the pancreas can be challenging in patients with von Hippel-Lindau disease (VHL. The clear cell features of both NET and RCC in VHL patients may lead to misdiagnosis, inaccurate staging, and alternative treatment. We present a patient in which this occurred. As clear cell NETs closely resembling metastatic RCC are distinctive neoplasms of VHL and metastatic RCC to the pancreas in the VHL population is rare, careful pathologic examination should be performed prior to subjecting patients to definitive surgical or medical therapies.

Reference genes for gene expression analysis by real-time reverse transcription polymerase chain reaction of renal cell carcinoma.

Science.gov (United States)

Bjerregaard, Henriette; Pedersen, Shona; Kristensen, Søren Risom; Marcussen, Niels

2011-12-01

Differentiation between malignant renal cell carcinoma and benign oncocytoma is of great importance to choose the optimal treatment. Accurate preoperative diagnosis of renal tumor is therefore crucial; however, existing imaging techniques and histologic examinations are incapable of providing an optimal differentiation profile. Analysis of gene expression of molecular markers is a new possibility but relies on appropriate standardization to compare different samples. The aim of this study was to identify stably expressed reference genes suitable for the normalization of results extracted from gene expression analysis of renal tumors. Expression levels of 8 potential reference genes (ATP5J, HMBS, HPRT1, PPIA, TBP, 18S, GAPDH, and POLR2A) were examined by real-time reverse transcription polymerase chain reaction in tumor and normal tissue from removed kidneys from 13 patients with renal cell carcinoma and 5 patients with oncocytoma. The expression levels of genes were compared by gene stability value M, average gene stability M, pairwise variation V, and coefficient of variation CV. More candidates were not suitable for the purpose, but a combination of HMBS, PPIA, ATP5J, and TBP was found to be the best combination with an average gene stability value M of 0.9 and a CV of 0.4 in the 18 tumors and normal tissues. A combination of 4 genes, HMBS, PPIA, ATP5J, and TBP, is a possible reference in renal tumor gene expression analysis by reverse transcription polymerase chain reaction. A combination of four genes, HMBS, PPIA, ATP5J and TBP, being stably expressed in tissues from RCC is possible reference genes for gene expression analysis.

A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in Renal Cell Carcinoma

OpenAIRE

Suwaki, Natsuko; Vanhecke, Elsa; Atkins, Katelyn M.; Graf, Manuela; Swabey, Katherine; Huang, Paul; Schraml, Peter; Moch, Holger; Cassidy, Amy; Brewer, Daniel; Al-Lazikani, Bissan; Workman, Paul; De-Bono, Johann; Kaye, Stan B.; Larkin, James

2011-01-01

Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. While VEGF and mTOR targeted therapies have shown clinical activity, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens to determine that Src kinase signaling is elevated in RCC cells that retain ...

CT prediction of the Fuhrman grade of clear cell renal cell carcinoma (RCC): towards the development of computer-assisted diagnostic method.

Science.gov (United States)

Huhdanpaa, Hannu; Hwang, Darryl; Cen, Steven; Quinn, Brian; Nayyar, Megha; Zhang, Xuejun; Chen, Frank; Desai, Bhushan; Liang, Gangning; Gill, Inderbir; Duddalwar, Vinay

2015-10-01

There are distinct quantifiable features characterizing renal cell carcinomas on contrast-enhanced CT examinations, such as peak tumor enhancement, tumor heterogeneity, and percent contrast washout. While qualitative visual impressions often suffice for diagnosis, quantitative metrics if developed and validated can add to the information available from standard of care diagnostic imaging. The purpose of this study is to assess the use of quantitative enhancement metrics in predicting the Fuhrman grade of clear cell RCC. 65 multiphase CT examinations with clear cell RCCs were utilized, 44 tumors with Fuhrman grades 1 or 2 and 21 tumors with grades 3 or 4. After tumor segmentation, the following data were extracted: histogram analysis of voxel-based whole lesion attenuation in each phase, enhancement and washout using mean, median, skewness, kurtosis, standard deviation, and interquartile range. Statistically significant difference was observed in 4 measured parameters between grades 1-2 and grades 3-4: interquartile range of nephrographic attenuation values, standard deviation of absolute enhancement, as well as interquartile range and standard deviation of residual nephrographic enhancement. Interquartile range of nephrographic attenuation values was 292.86 HU for grades 1-2 and 241.19 HU for grades 3-4 (p value 0.02). Standard deviation of absolute enhancement was 41.26 HU for grades 1-2 and 34.66 HU for grades 3-4 (p value 0.03). Interquartile range was 297.12 HU for residual nephrographic enhancement for grades 1-2 and 235.57 HU for grades 3-4 (p value 0.02), and standard deviation of the same was 42.45 HU for grades 1-2 and 37.11 for grades 3-4 (p value 0.04). Our results indicate that absolute enhancement is more heterogeneous for lower grade tumors and that attenuation and residual enhancement in nephrographic phase is more heterogeneous for lower grade tumors. This represents an important step in devising a predictive non-invasive model to predict the

Methylation of 10 miRNA genes in clear cell renal cell carcinoma and their diagnostic value

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V. I. Loginov

2017-01-01

Full Text Available Introduction. Clear cell renal cell carcinoma (ccRCC is characterized by the high (30–40 % of cases frequency of lethal outcomes which at metastasis reaches 90 %. Lack of efficient diagnostics at early stages of a disease indicates the need of searching on new ccRCC markers.Objective: for definition of methylation role of some tumor suppressor microRNA (miRNA genes in ccRCC pathogenesis and progression and marker identification for ccRCC diagnostics and metastasis predictions.Materials and methods. The alterations of methylation status of 10 miRNA genes were determined by methylation specific polymerase chain reaction in tumor DNA samples and matched histologically unchanged tissues from 70 patients with ccRCC, as well as in DNA samples of kidney tissues from 19 post-mortal individuals without cancer history. Methylation of MIR MIR-107, -130b and -148a genes in ccRCC was studied for the first time.Results. It was shown that 8 miRNA genes (MIR-9-1/3, -34b/c, -124a-1/2/3, -129-2, -130b were methylated in ccRCC tumors with significantly higher frequency than in the matched histologically unchanged kidney tissues. It was established the association of methylation of 4 miRNA genes (MIR-107, -124a-3, -129-2, -130b with ccRCC progression (stage, tumor size, differentiation grade, including metastasis in the lymph nodes or distant organs, revealed for MIR-107 and -129-2. The association of MIR-107 and -130b methylation with progression of ccRCC is shown for the first time. Potential marker systems are made for ccRCC diagnostics using tumor biopsy; according to the ROC analysis, systems from 4 and 5 genes (MIR-9-1, -4b/c, -124a-3, -129-2/with addition of MIR-130b are characterized by high clinical sensitivity of 90 % and specificity of 94 % (area under ROC curve 0.93 and 0.94. Conclusion. The received results will form the basis of noninvasive ccRCC diagnostics further development. To conclude, it is shown the association of methylation of 9

RCC-F: Design and construction rules for PWR fire protection systems

International Nuclear Information System (INIS)

2013-01-01

The RCC-F code defines the rules for designing, building and installing the fire protection systems used to manage the nuclear hazards inherent in the outbreak of a fire inside the facility and thereby control the fundamental nuclear functions. The code provides fire protection recommendations in terms of: the industrial risk (loss of assets and/or operation), personnel safety, the environment. The code is divided into five main sections: generalities, design safety principles, fire protection design bases, construction provisions, rules for installing the fire protection components and equipment. The RCC-F code is available as an ETC-F version specifically for EPR projects (European pressurized reactor). Contents of the 2013 edition of the ETC-F code: Volume A - Generalities: Structure of ETC-F general points, documentation (in progress), chapter (provision) quality assurance; Volume B - Design safety principles: design nuclear safety principles; Volume C - Fire protection design bases: fire protection design bases; Volume D - Construction provisions: construction provisions; Volume E - Installation rules for fire protection: rules for installing the fire protection, components and equipment

Metastasis in renal cell carcinoma: Biology and implications for therapy

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Jun Gong

2016-10-01

Full Text Available Although multiple advances have been made in systemic therapy for renal cell carcinoma (RCC, metastatic RCC remains incurable. In the current review, we focus on the underlying biology of RCC and plausible mechanisms of metastasis. We further outline evolving strategies to combat metastasis through adjuvant therapy. Finally, we discuss clinical patterns of metastasis in RCC and how distinct systemic therapy approaches may be considered based on the anatomic location of metastasis.

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma

Directory of Open Access Journals (Sweden)

U Batra

2016-01-01

Full Text Available The Oncology Gold Standard (OGS Expert Group on renal cell carcinoma (RCC developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of "Take Home Messages" at the end is a convenient tool for busy practitioners.

Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal.

Science.gov (United States)

Wei, Muyun; Mao, Shaowei; Lu, Guoliang; Li, Liang; Lan, Xiaopeng; Huang, Zhongxian; Chen, Yougen; Zhao, Miaoqing; Zhao, Yueran; Xia, Qinghua

2018-04-17

Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-β, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-β /pSMAD3 and AMPK/AKT pathways. 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-β/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. VPA not only exhibits

Renal cell carcinoma presenting as mandibular metastasis

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Hassan Ahmadnia

2013-01-01

Full Text Available Renal clear cell carcinoma (RCC has different manifestations, including uncommon metastasis and paraneoplastic syndromes. Here we report a rare case of RCC presenting as metastasis to the mandible. A 57-year-old patient with mandibular swelling was referred to the dentist. After necessary evaluations, an incisional biopsy of mandible showed metastatic RCC. The patient was referred to the urologist. The patient underwent right radical nephrectomy. Pathological examination showed clear renal cell carcinoma. Every abnormal bone lesion in the oral cavity should be evaluated carefully and the possibility of a malignant lesion should always be considered.

Renal cell carcinoma: new insights and challenges for a clinician scientist.

Science.gov (United States)

Shingarev, Roman; Jaimes, Edgar A

2017-08-01

There is a growing recognition of the complex interplay between renal cell cancer (RCC), kidney function, mechanical reduction of nephron mass, and systemic agents targeting the cancer. Earlier detection of RCC and rising life expectancy of cancer survivors places a greater emphasis on preservation of renal function after cancer resection and during systemic therapy. Unique adverse effects associated with RCC drugs not only help reveal cancer pathophysiology but also expand our knowledge of normal cell signaling and metabolism. In this review, we outline our current understanding of RCC biology and treatment, their bidirectional relationship with kidney function, and unmet research needs in this field. Copyright © 2017 the American Physiological Society.

Evaluation of renal cell carcinoma histological subtype and fuhrman grade using {sup 18}F-fluorodeoxyglucose-positron emission tomography/computed tomography

Energy Technology Data Exchange (ETDEWEB)

Nakajima, Reiko; Nozaki, Sayumi; Abe, Koichiro; Sakai, Shuji [Tokyo Women' s Medical University, Department of Diagnostic Imaging and Nuclear Medicine, Tokyo (Japan); Kondo, Tsunenori [Tokyo Women' s Medical University, Department of Urology, Tokyo (Japan); Nagashima, Yoji [Tokyo Women' s Medical University, Department of Surgical Pathology, Tokyo (Japan)

2017-11-15

We evaluated {sup 18}F-fluorodeoxyglucose (FDG) uptake by renal cell carcinomas (RCCs) to determine whether different histological subtypes and Fuhrman grades can be distinguished. We retrospectively reviewed the records and maximum standardised uptake value (SUVmax) of 147 patients with 154 RCCs who underwent FDG-positron emission tomography (PET)/computed tomography (CT) prior to tumour resection. The SUVmax was significantly lower in chromophobe RCC (chRCC) tumours than in clear cell RCC (ccRCC; p = 0.003) and papillary RCC (pRCC; p = 0.034) tumours. The mean tumour SUVmax was 4.58 ± 4.1 (range, 1.29-30.4) for ccRCC, 3.98 ± 1.9 (range, 0.49-6.72) for pRCC, and 1.93 ± 0.9 (range, 0.89-3.41) for chRCC. The SUVmax was not significantly different between the ccRCC and pRCC groups. In ccRCC and pRCC tumours, high-grade tumours had a significantly greater SUVmax (p < 0.001 and p < 0.05) than low-grade tumours by analysis of variance (ANOVA) and the Mann-Whitney U test. In ccRCC, multivariate regression analysis indicated that the SUVmax was a significant indicator of Fuhrman grade. No significant differences in uptake were observed between high- and low-grade chRCC tumours. The SUVmax obtained using FDG-PET/CT may be an important indicator for predicting tumour grade in ccRCC and pRCC. (orig.)

Generation of chimeric bispecific G250/anti-CD3 monoclonal antibody, a tool to combat renal cell carcinoma

NARCIS (Netherlands)

Luiten, R. M.; Coney, L. R.; Fleuren, G. J.; Warnaar, S. O.; Litvinov, S. V.

1996-01-01

The monoclonal antibody (MAb) G250 binds to a tumour-associated antigen, expressed in renal cell carcinoma (RCC), which has been demonstrated to be a suitable target for antibody-mediated immunotherapy. A bispecific antibody having both G250 and anti-CD3 specificity can cross-link G250

RCC-MRx: Design and construction rules for mechanical components in high-temperature structures, experimental reactors and fusion reactors

International Nuclear Information System (INIS)

2015-01-01

The RCC-MRx code was developed for sodium-cooled fast reactors (SFR), research reactors (RR) and fusion reactors (FR-ITER). It provides the rules for designing and building mechanical components involved in areas subject to significant creep and/or significant irradiation. In particular, it incorporates an extensive range of materials (aluminum and zirconium alloys in response to the need for transparency to neutrons), sizing rules for thin shells and box structures, and new modern welding processes: electron beam, laser beam, diffusion and brazing. The RCC-MR code was used to design and build the prototype Fast Breeder Reactor (PFBR) developed by IGCAR in India and the ITER Vacuum Vessel. The RCC-Mx code is being used in the current construction of the RJH experimental reactor (Jules Horowitz reactor). The RCC-MRx code is serving as a reference for the design of the ASTRID project (Advanced Sodium Technological Reactor for Industrial Demonstration), for the design of the primary circuit in MYRRHA (Multi-purpose hybrid Research Reactor for High-tech Applications) and the design of the target station of the ESS project (European Spallation Source). Contents of the 2015 edition of the RCC-MRx code: Section I General provisions; Section II Additional requirements and special provisions; Section III Rules for nuclear installation mechanical components: Volume I: Design and construction rules: Volume A (RA): General provisions and entrance keys, Volume B (RB): Class 1 components and supports, Volume C (RC): Class 2 components and supports, Volume D (RD): Class 3 components and supports, Volume K (RK): Examination, handling or drive mechanisms, Volume L (RL): Irradiation devices, Volume Z (Ai): Technical appendices; Volume II: Materials; Volume III: Examinations methods; Volume IV: Welding; Volume V: Manufacturing operations; Volume VI: Probationary phase rules

Trichloroethylene exposure and somatic mutations of the VHL gene in patients with Renal Cell Carcinoma

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Fevotte Joelle

2007-11-01

Full Text Available Abstract Background We investigated the association between exposure to trichloroethylene (TCE and mutations in the von Hippel-Lindau (VHL gene and the subsequent risk for renal cell carcinoma (RCC. Methods Cases were recruited from a case-control study previously carried out in France that suggested an association between exposures to high levels of TCE and increased risk of RCC. From 87 cases of RCC recruited for the epidemiological study, 69 were included in the present study. All samples were evaluated by a pathologist in order to identify the histological subtype and then be able to focus on clear cell RCC. The majority of the tumour samples were fixed either in formalin or Bouin's solutions. The majority of the tumours were of the clear cell RCC subtype (48 including 2 cystic RCC. Mutation screening of the 3 VHL coding exons was carried out. A descriptive analysis was performed to compare exposed and non exposed cases of clear cell RCC in terms of prevalence of mutations in both groups. Results In the 48 cases of RCC, four VHL mutations were detected: within exon 1 (c.332G>A, p.Ser111Asn, at the exon 2 splice site (c.463+1G>C and c.463+2T>C and within exon 3 (c.506T>C, p.Leu169Pro. No difference was observed regarding the frequency of mutations in exposed versus unexposed groups: among the clear cell RCC, 25 had been exposed to TCE and 23 had no history of occupational exposure to TCE. Two patients with a mutation were identified in each group. Conclusion This study does not confirm the association between the number and type of VHL gene mutations and exposure to TCE previously described.

Evaluation of morphologically unclassified renal cell carcinoma with electron microscopy and novel renal markers: implications for tumor reclassification.

Science.gov (United States)

Talento, Romualdo; Hewan-Lowe, Karlene; Yin, Ming

2013-02-01

Despite progress in the classification of renal cell carcinomas (RCC), a subset of these carcinomas remains unclassified (RCC-U). Patients with RCC-U usually present at a late stage and have a poor prognosis. Several studies have attempted to extract new classifications of newly recognized renal carcinomas from the group of RCC-U. However, to date, no studies in the literature have attempted to characterize the RCC-U with unrecognizable cell types beyond the morphologic evaluation on H&E-stained sections. The purpose of this study was to evaluate this group of RCC-U using electron microscopy and novel renal markers. Ten cases of such RCC-U were identified for this study. At the ultrastructural level, they did not show typical morphology that resembled any of the well-studied, recognizable subtypes of RCC. However, they did reveal features of renal tubular epithelial differentiation. The histologic, ultrastructural, and immunophenotypic features indicated that these tumors are poorly differentiated renal epithelial tumors, possibly derived from the proximal nephron, with an immunohistochemical profile similar to high-grade clear cell RCC. It is, therefore, proposed that this group of renal carcinomas be renamed "poorly differentiated renal cell carcinoma, not otherwise specified." The current study showed that PAX-8 and carbonic anhydrase IX are reliable markers for this novel group of renal carcinoma, and that electron microscopy is an important adjunct in the evaluation of new and unusual renal entities.

Unusual Spread of Renal Cell Carcinoma to the Clivus with Cranial Nerve Deficit

OpenAIRE

Okudo, Jerome; Anusim, Nwabundo

2016-01-01

Renal cell carcinoma (RCC) has unusual presentation affecting elderly males with a smoking history. The incidence of RCC varies while the incidence of spread of RCC to the clivus is rare. The typicality of RCC presentation includes hematuria, flank pain, and a palpable flank mass; however, RCC can also present with clival metastasis. The unique path of the abducens nerve in the clivus makes it susceptible to damage in metastasis. We report a case of a 54-year-old African American female that ...

Application of the active flexible fixture with passive RCC function to peg-in-hole task

International Nuclear Information System (INIS)

Yamaguchi, Tomomi; Higuchi, Masahiro

2005-01-01

This paper describes the application of the active flexible fixture (AFLEF) with passive RCC to the peg-in-hole task on the disk in the X-band accelerator. The AFLEF can fix any work and position the fixed work at short range. In this paper, the 2-dimensional AFLEF is proposed as the simplified type and is provided with passive RCC function to be equipped with dexterity for a peg-in-hole task. As results of the experiment on the peg-in-hole task on the X-band accelerator disks with the AFLEF, we make the ability of the AFLEF for the task clear and also the boundary conditions to the complete task clear. (author)

Phase II trial of Modified Vaccinia Ankara (MVA virus expressing 5T4 and high dose Interleukin-2 (IL-2 in patients with metastatic renal cell carcinoma

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Mitcham Josephine

2009-01-01

Full Text Available Abstract Background Interleukin-2 (IL-2 induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC but the antigen(s responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity. Methods 25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses. Results There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12% were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48% had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261. All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs. Conclusion Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients. Trial registration number ISRCTN83977250

A Gene Module-Based eQTL Analysis Prioritizing Disease Genes and Pathways in Kidney Cancer

Directory of Open Access Journals (Sweden)

Mary Qu Yang

Full Text Available Clear cell renal cell carcinoma (ccRCC is the most common and most aggressive form of renal cell cancer (RCC. The incidence of RCC has increased steadily in recent years. The pathogenesis of renal cell cancer remains poorly understood. Many of the tumor suppressor genes, oncogenes, and dysregulated pathways in ccRCC need to be revealed for improvement of the overall clinical outlook of the disease. Here, we developed a systems biology approach to prioritize the somatic mutated genes that lead to dysregulation of pathways in ccRCC. The method integrated multi-layer information to infer causative mutations and disease genes. First, we identified differential gene modules in ccRCC by coupling transcriptome and protein-protein interactions. Each of these modules consisted of interacting genes that were involved in similar biological processes and their combined expression alterations were significantly associated with disease type. Then, subsequent gene module-based eQTL analysis revealed somatic mutated genes that had driven the expression alterations of differential gene modules. Our study yielded a list of candidate disease genes, including several known ccRCC causative genes such as BAP1 and PBRM1, as well as novel genes such as NOD2, RRM1, CSRNP1, SLC4A2, TTLL1 and CNTN1. The differential gene modules and their driver genes revealed by our study provided a new perspective for understanding the molecular mechanisms underlying the disease. Moreover, we validated the results in independent ccRCC patient datasets. Our study provided a new method for prioritizing disease genes and pathways. Keywords: ccRCC, Causative mutation, Pathways, Protein-protein interaction, Gene module, eQTL

A case–control study of occupation/industry and renal cell carcinoma risk

International Nuclear Information System (INIS)

Karami, Sara; Rothman, Nathanial; Chow, Wong-Ho; Purdue, Mark P; Colt, Joanne S; Schwartz, Kendra; Davis, Faith G; Ruterbusch, Julie J; Munuo, Stella S; Wacholder, Sholom; Stewart, Patricia A; Graubard, Barry I

2012-01-01

The role of occupation in the etiology of renal cell carcinoma (RCC) is unclear. Here, we investigated associations between employment in specific occupations and industries and RCC, and its most common histologic subtype, clear cell RCC (ccRCC). Between 2002 and 2007, a population-based case–control study of Caucasians and African Americans (1,217 cases; 1,235 controls) was conducted within the Detroit and Chicago metropolitan areas to investigate risk factors for RCC. As part of this study, occupational histories were ascertained through in-person interviews. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating occupation and industry to RCC risk using adjusted unconditional logistic regression models. Employment in the agricultural crop production industry for five years or more was associated with RCC (OR = 3.3 [95% CI = 1.0-11.5]) and ccRCC in particular (OR = 6.3 [95% CI = 1.7-23.3], P for trend with duration of employment = 0.0050). Similarly, RCC risk was elevated for employment of five years or longer in non-managerial agricultural and related occupations (OR RCC = 2.1 [95% CI = 1.0-4.5]; OR ccRCC = 3.1 [95% CI = 1.4-6.8]). Employment in the dry-cleaning industry was also associated with elevated risk (OR RCC = 2.0 [95% CI = 0.9-4.4], P for trend = 0.093; OR ccRCC = 3.0 [95% CI = 1.2-7.4], P for trend = 0.031). Suggestive elevated associations were observed for police/public safety workers, health care workers and technicians, and employment in the electronics, auto repair, and cleaning/janitorial services industries; protective associations were suggested for many white-collar jobs including computer science and administrative occupations as well employment in the business, legislative, and education industries. Our findings provide support for an elevated risk of RCC in the agricultural and dry-cleaning industries and suggest that these associations may be stronger for the ccRCC subtype. Additional studies are needed to confirm

Activation of Stat3 in renal tumors.

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Guo, Charles; Yang, Guanyu; Khun, Kyle; Kong, Xiantian; Levy, David; Lee, Peng; Melamed, Jonathan

2009-02-28

Signal transducer and activator of transcription 3 (Stat3) plays a vital role in signal transduction pathways that mediate transformation and inhibit apoptosis. Oncogenic Stat3 is persistently activated in several human cancers and transformed cell lines. Previous studies indicate activation of Stat3 in renal cell carcinoma (RCC). However, the detailed characterization of the Stat3 expression pattern in different histologic types of RCC is lacking. We have analyzed the immunoprofile of activated or phosphorylated Stat3 (pStat3) in a tissue microarray of renal tumors of different histologic types, including 42 cases of conventional clear cell type, 24 chromophobe, and 7 papillary, 15 oncocytoma, 7 urothelial carcinoma and 21 normal kidney tissues using an anti-pStat3 antibody (recognizes only activated STAT3). pStat3 nuclear staining was observed in 25 of 42 conventional clear cell RCC (59.5 %), 8 of 24 chromophobe RCC (33.3%), 4 of 7 papillary RCC (57.1%). In the other tumor groups, 4 of 15 oncocytomas (26.7%) and 6 of 7 urothelial carcinomas (85.7%) showed positive nuclear staining. Weak nuclear immunoreactivity for pStat3 was seen in 4 of 21 cases of non-neoplastic kidney tissue (19.0%). The extent of Stat3 activation as determined by nuclear expression of its phosphorylated form is increased in histologic types of renal tumors with greater malignant potential, specifically conventional clear cell RCC, papillary RCC and urothelial carcinoma, only slightly increased in chromophobe RCC, and not increased in oncocytoma. These results suggest a role of Stat3 activation in different types of renal neoplasia, possibly serving as a prognostic marker or therapeutic target.

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

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Yang, Shu-Mei [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Huang, Chao-Yuan [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Shiue, Horng-Sheng [Department of Chinese Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan (China); Pu, Yeong-Shiau [Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China); Hsieh, Yi-Hsun; Chen, Wei-Jen [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Lin, Ying-Chin [Department of Family Medicine, Shung Ho Hospital, Taipei Medical University, Taipei, Taiwan (China); Department of Health Examination, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan (China); Division of Family Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan (China); Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw [School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China); Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

2016-08-15

Our previous study showed that high urinary total arsenic levels were associated with higher odds ratio (OR) for renal cell carcinoma (RCC). Single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) might influence DNMT enzyme activity associated with tumorigenesis. In this study, we investigated the association of five SNPs from DNMT1 (rs8101626 and rs2228611), DNMT3A (rs34048824 and rs1550117), and DNMT3B (rs1569686) with the risk of clear cell renal cell carcinoma (ccRCC). We also examined the combined effects of DNMT genotypes and urinary arsenic levels on ccRCC risk. We conducted a hospital-based case-control study, which included 293 subjects with ccRCC and 293 age- and gender-matched controls. The urinary arsenic species were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Genotypes were investigated using polymerase chain reaction and restriction fragment length polymorphism analyses. We observed that the DNMT1 rs8101626 G/G genotype was significantly associated with reduced odds ratio (OR) of ccRCC [OR = 0.38, 95% confidence interval (CI) 0.14–0.99]. Subjects with concurrent DNMT1 rs8101626 A/A + A/G and DNMT3A rs34048824 T/T + T/C genotypes had significantly higher OR for ccRCC [OR = 2.88, 95% CI 1.44–5.77]. Participants with the high-risk genotype of DNMT1 rs8101626 and DNMT3A rs34048824 with concurrently high urinary total arsenic levels had even higher OR of ccRCC in a dose-response manner. This is the first study to evaluate variant DNMT1 rs8101626 and DNMT3A rs34048824 genotypes that modify the arsenic-related ccRCC risk in a geographic area without significant arsenic exposure in Taiwan. - Highlights: • High urinary total arsenic level or polymorphism of DNMT1 increased the OR of ccRCC. • High risk genotypes of combination of DNMT1 and DNMT3A increased the OR of ccRCC. • A joint effect of urinary total arsenic level and DNMTs genotypes may affect ccRCC.

Iodine quantification to distinguish clear cell from papillary renal cell carcinoma at dual-energy multidetector CT: a multireader diagnostic performance study.

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Mileto, Achille; Marin, Daniele; Alfaro-Cordoba, Marcela; Ramirez-Giraldo, Juan Carlos; Eusemann, Christian D; Scribano, Emanuele; Blandino, Alfredo; Mazziotti, Silvio; Ascenti, Giorgio

2014-12-01

To investigate whether dual-energy multidetector row computed tomographic (CT) imaging with iodine quantification is able to distinguish between clear cell and papillary renal cell carcinoma ( RCC renal cell carcinoma ) subtypes. In this retrospective, HIPAA-compliant, institutional review board-approved study, 88 patients (57 men, 31 women) with diagnosis of either clear cell or papillary RCC renal cell carcinoma at pathologic analysis, who underwent contrast material-enhanced dual-energy nephrographic phase study between December 2007 and June 2013, were included. Five readers, blinded to pathologic diagnosis, independently evaluated all cases by determining the lesion iodine concentration on color-coded iodine maps. The receiving operating characteristic curve analysis was adopted to estimate the optimal threshold for discriminating between clear cell and papillary RCC renal cell carcinoma , and results were validated by using a leave-one-out cross-validation. Interobserver agreement was assessed by using an intraclass correlation coefficient. The correlation between tumor iodine concentration and tumor grade was investigated. A tumor iodine concentration of 0.9 mg/mL represented the optimal threshold to discriminate between clear cell and papillary RCC renal cell carcinoma , and it yielded the following: sensitivity, 98.2% (987 of 1005 [95% confidence interval: 97.7%, 98.7%]); specificity, 86.3% (272 of 315 [95% confidence interval: 85.0%, 87.7%]); positive predictive value, 95.8% (987 of 1030 [95% confidence interval: 95.0%, 96.6%]); negative predictive value, 93.7% (272 of 290 [95% confidence interval: 92.8%, 94.7%]); overall accuracy of 95.3% (1259 of 1320 [95% confidence interval: 94.6%, 96.2%]), with an area under the curve of 0.923 (95% confidence interval: 0.913, 0.933). An excellent agreement was found among the five readers in measured tumor iodine concentration (intraclass correlation coefficient, 0.9990 [95% confidence interval: 0. 9987, 0.9993). A

Understanding familial and non-familial renal cell cancer.

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Bodmer, Daniëlle; van den Hurk, Wilhelmina; van Groningen, Jan J M; Eleveld, Marc J; Martens, Gerard J M; Weterman, Marian A J; van Kessel, Ad Geurts

2002-10-01

Molecular genetic analysis of familial and non-familial cases of conventional renal cell carcinoma (RCC) revealed a critical role(s) for multiple genes on human chromosome 3. For some of these genes, e.g. VHL, such a role has been firmly established, whereas for others, definite confirmation is still pending. Additionally, a novel role for constitutional chromosome 3 translocations as risk factors for conventional RCC development is rapidly emerging. Also, several candidate loci have been mapped to other chromosomes in both familial and non-familial RCCs of distinct histologic subtypes. The MET gene on chromosome 7, for example, was found to be involved in both forms of papillary RCC. A PRCC-TFE3 fusion gene is typically encountered in t(X;1)-positive non-familial papillary RCCs and results in abrogation of the cell cycle mitotic spindle checkpoint in a dominant-negative fashion, thus leading to RCC. Together, these data turn human RCC into a model system in which different aspects of both familial and non-familial syndromes may act as novel paradigms for cancer development.

A comparative study of physical and chemical properties of different pozzolanic materials used for roller compacted concrete RCC dams

OpenAIRE

Husein Malkawi Abdallah I.; Shatnawi Ehab; Husein Malkawi Dima A.

2017-01-01

This paper addresses the feasibility and the efficiency of using Natural Pozzolan and/or Rock flour in Roller Compacted Concrete (RCC) gravity dams. For this purpose, five identical mortar trial mixes were prepared using five different supplementary materials, i.e., fly ash produced in South Africa (proven to be effective in RCC construction), fly ash produced in Turkey, Jordanian natural pozzolan, Saudi natural pozzolan, and rock flour from Mujib Dam basalt quarry. The physical and chemical ...

Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells.

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Zhang, Xiao-Fei; Weng, De-Sheng; Pan, Ke; Zhou, Zi-Qi; Pan, Qiu-Zhong; Zhao, Jing-Jing; Tang, Yan; Jiang, Shan-Shan; Chen, Chang-Long; Li, Yong-Qiang; Zhang, Hong-Xia; Chang, Alfred E; Wicha, Max S; Zeng, Yi-Xin; Li, Qiao; Xia, Jian-Chuan

2017-11-01

Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and resistance to therapeutic agents; they are usually less sensitive to conventional cancer therapies, and could cause tumor relapse. An ideal therapeutic strategy would therefore be to selectively target and destroy CSCs, thereby preventing tumor relapse. The aim of the present study was to evaluate the effectiveness of dendritic cells (DCs) pulsed with antigen derived from CD105+ human renal cell carcinoma (RCC) CSCs against renal cancer cells in vitro and in vivo. We identified "stem-like" characteristics of CD105+ cells in two human RCC cell lines: A498 and SK-RC-39. Loading with cell lysates did not change the characteristics of the DCs. However, DCs loaded with lysates derived from CD105+ CSCs induced more functionally specific active T cells and specific antibodies against CSCs, and clearly depressed the tumor growth in mice. Our results could form the basis for a novel strategy to improve the efficacy of DC-based immunotherapy for human RCC. © 2017 Wiley Periodicals, Inc.

Telemetry Standards, RCC Standard 106-17, Chapter 4, Pulse Code Modulation Standards

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2017-07-01

A-4 Appendix 4-B. Citations ...investigation can be found in a paper by J. L. Maury, Jr. and J. Styles , “Development of Optimum Frame Synchronization Codes for Goddard Space Flight Center...Standards, RCC Standard 106-17 Chapter 4, July 2017 B-1 APPENDIX 4-B Citations Aeronautical Radio, Inc. Mark 33 Digital Information Transfer

The occult nature of intramedullary spinal cord metastases from renal cell carcinoma.

LENUS (Irish Health Repository)

Zakaria, Zaitun

2012-01-01

Renal cell carcinomas (RCC) are characterised by a tendency to metastasise widely, often while remaining occult. Intramedullary spinal cord metastases (ISCM) from RCC may be the presenting feature of the disease or present at any time in the disease course. This case report discusses an ISCM from RCC which became manifested at the time of resection of the primary tumour. We review the literature published on ISCM from RCC from 1990 to date comparing disease characteristics and presentations.

The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling*

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Tringali, Cristina; Lupo, Barbara; Silvestri, Ilaria; Papini, Nadia; Anastasia, Luigi; Tettamanti, Guido; Venerando, Bruno

2012-01-01

The human plasma membrane sialidase NEU3 is a key enzyme in the catabolism of membrane gangliosides, is crucial in the regulation of cell surface processes, and has been demonstrated to be significantly up-regulated in renal cell carcinomas (RCCs). In this report, we show that NEU3 regulates β1 integrin trafficking in RCC cells by controlling β1 integrin recycling to the plasma membrane and controlling activation of the epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK)/protein kinase B (AKT) signaling. NEU3 silencing in RCC cells increased the membrane ganglioside content, in particular the GD1a content, and changed the expression of key regulators of the integrin recycling pathway. In addition, NEU3 silencing up-regulated the Ras-related protein RAB25, which directs internalized integrins to lysosomes, and down-regulated the chloride intracellular channel protein 3 (CLIC3), which induces the recycling of internalized integrins to the plasma membrane. In this manner, NEU3 silencing enhanced the caveolar endocytosis of β1 integrin, blocked its recycling and reduced its levels at the plasma membrane, and, consequently, inhibited EGFR and FAK/AKT. These events had the following effects on the behavior of RCC cells: they (a) decreased drug resistance mediated by the block of autophagy and the induction of apoptosis; (b) decreased metastatic potential mediated by down-regulation of the metalloproteinases MMP1 and MMP7; and (c) decreased adhesion to collagen and fibronectin. Therefore, our data identify NEU3 as a key regulator of the β1 integrin-recycling pathway and FAK/AKT signaling and demonstrate its crucial role in RCC malignancy. PMID:23139422

A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8

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McCooke John K

2012-08-01

Full Text Available Abstract Background Nephronophthisis (NPHP as a cause of cystic kidney disease is the most common genetic cause of progressive renal failure in children and young adults. NPHP is characterized by abnormal and/or loss of function of proteins associated with primary cilia. Previously, we characterized an autosomal recessive phenotype of cystic kidney disease in the Lewis Polycystic Kidney (LPK rat. Results In this study, quantitative trait locus analysis was used to define a ~1.6Mbp region on rat chromosome 10q25 harbouring the lpk mutation. Targeted genome capture and next-generation sequencing of this region identified a non-synonymous mutation R650C in the NIMA (never in mitosis gene a- related kinase 8 ( Nek8 gene. This is a novel Nek8 mutation that occurs within the regulator of chromosome condensation 1 (RCC1-like region of the protein. Specifically, the R650C substitution is located within a G[QRC]LG repeat motif of the predicted seven bladed beta-propeller structure of the RCC1 domain. The rat Nek8 gene is located in a region syntenic to portions of human chromosome 17 and mouse 11. Scanning electron microscopy confirmed abnormally long cilia on LPK kidney epithelial cells, and fluorescence immunohistochemistry for Nek8 protein revealed altered cilia localisation. Conclusions When assessed relative to other Nek8 NPHP mutations, our results indicate the whole propeller structure of the RCC1 domain is important, as the different mutations cause comparable phenotypes. This study establishes the LPK rat as a novel model system for NPHP and further consolidates the link between cystic kidney disease and cilia proteins.

77 FR 17569 - United States-Canada Regulatory Cooperation Council (RCC)-Transportation-Dangerous Goods Working...

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2012-03-26

... identified in the Joint Action Plan, the Transportation--Dangerous Goods Working Group led by senior...)-- Transportation--Dangerous Goods Working Group AGENCY: Pipeline and Hazardous Materials Safety Administration...--Dangerous Goods Working Group, of the United States-Canada Regulatory Cooperation Council (RCC). Comments...

Clinicopathologic Characteristics and Prognosis of Xp11.2 Translocation Renal Cell Carcinoma: Multicenter, Propensity Score Matching Analysis.

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Choo, Min Soo; Jeong, Chang Wook; Song, Cheryn; Jeon, Hwang Gyun; Seo, Seong Il; Hong, Sung Kyu; Byun, Seok-Soo; Chung, Jin Soo; Hong, Sung-Hoo; Hwang, Eu Chang; Kim, Hyeon Hoe; Kwak, Cheol

2017-10-01

We evaluated the clinicopathologic characteristics and prognosis of Xp11.2 translocation (Xp11.2t) renal cell carcinoma (RCC) from a multicenter study and compare them with clear-cell RCC using a propensity score matching analysis. Between 2004 and 2013, 8384 consecutive patients from 7 institutions who were diagnosed with RCC were reviewed, and the pathologically confirmed Xp11.2t cases were enrolled. The oncological outcomes of Xp11.2t were compared with those of clear-cell RCC by selecting matched cases using 1:3 propensity score matching methods in a precollected clear-cell RCC data set from our hospital. The patients were divided into 2 subgroups on the basis of age of onset, either before (early) or after (late) 45 years old. Xp11.2t was found in 61 cases, corresponding to 0.72% of RCC cases for the 10 years. The mean age was 38.2 ± 19.4 years, and the mean tumor size was 6.2 ± 3.9 cm. The Xp11.2t cases were at more advanced stages and showed tendencies to involve lymph nodes at diagnosis. After the matching, there were no significant differences in recurrence-free and overall survival compared with clear-cell RCC. The age of incidence for Xp11.2t had a bimodal distribution, which was most common in the 30s and smaller peak in the 60s. Xp11.2t corresponded to a significantly worse prognosis for overall survival in late onset (after 45 years) subgroup (P = .038; hazard ratio, 3.199; 95% confidence interval, 1.065-9.609). This neoplasm has more aggressive clinicopathologic features at diagnosis. In older patients with onset age > 45 years, Xp11.2t showed a significantly worse prognosis than clear-cell RCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of Pumphouse RCC Frame Structure for Soil Structure Interaction

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Mr A.S. Thombare; Prof. V.P. Kumbhar; Prof. A.H. Kumbhar

2016-01-01

When structure is built on ground some elements of structure are direct contact with soil. When loads are applied on structure internal forces are developed in both the structure as well as in soil. It results in deformation of both the components which are independent to each other. This are called soil structure interaction. The analysis is done by using (Bentley STAAD.Pro V8i Version 2007) software. The analysis carried out been pump house structure R.C.C. frame structure find ...

Colonic metastasis from renal cell carcinoma: helical-CT demonstration

International Nuclear Information System (INIS)

Diaz-Candamio, M.J.; Pombo, S.; Pombo, F.

2000-01-01

Clinically evident colonic metastasis from renal cell carcinoma (RCC) is rare. In the present study a hypervascular sigmoid mass was demonstrated on arterial-phase helical CT using a water enema in a patient who had suffered left nephrectomy 8 years previously for RCC. The intense and early enhancement of the lesion suggested the possibility of a solitary colonic metastasis from RCC, a diagnosis which was pathologically confirmed. (orig.)

Renal cell carcinoma: evolving approaches to advanced non-clear cell carcinoma

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Daniel Y.C. Heng

2011-12-01

Full Text Available The treatment of metastatic renal cell carcinoma (RCC has changed dramatically with the introduction of targeted therapies including sunitinib, sorafenib, and temsirolimus. Because patients with conventional clear cell histology account for 75- 80% of all patients with RCC, there has been little accumulated evidence on the treatment of patients with non-clear cell histologies. Most clinical trials have excluded them from enrolment, except for randomized studies investigating temsirolimus. Many retrospective studies on the use of all three of these targeted therapies in patients with non-clear cell histology have demonstrated response rates ranging from 3.7%–16%. Although response rates may not be as high compared to patients with clear cell histologies, targeted therapy does provide a clinically meaningful response.

A 3D Human Renal Cell Carcinoma-on-a-Chip for the Study of Tumor Angiogenesis.

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Miller, Chris P; Tsuchida, Connor; Zheng, Ying; Himmelfarb, Jonathan; Akilesh, Shreeram

2018-06-01

Tractable human tissue-engineered 3D models of cancer that enable fine control of tumor growth, metabolism, and reciprocal interactions between different cell types in the tumor microenvironment promise to accelerate cancer research and pharmacologic testing. Progress to date mostly reflects the use of immortalized cancer cell lines, and progression to primary patient-derived tumor cells is needed to realize the full potential of these platforms. For the first time, we report endothelial sprouting induced by primary patient tumor cells in a 3D microfluidic system. Specifically, we have combined primary human clear cell renal cell carcinoma (ccRCC) cells from six independent donors with human endothelial cells in a vascularized, flow-directed, 3D culture system ("ccRCC-on-a-chip"). The upregulation of key angiogenic factors in primary human ccRCC cells, which exhibited unique patterns of donor variation, was further enhanced when they were cultured in 3D clusters. When embedded in the matrix surrounding engineered human vessels, these ccRCC tumor clusters drove potent endothelial cell sprouting under continuous flow, thus recapitulating the critical angiogenic signaling axis between human ccRCC cells and endothelial cells. Importantly, this phenotype was driven by a primary tumor cell-derived biochemical gradient of angiogenic growth factor accumulation that was subject to pharmacological blockade. Our novel 3D system represents a vascularized tumor model that is easy to image and quantify and is fully tunable in terms of input cells, perfusate, and matrices. We envision that this ccRCC-on-a-chip will be valuable for mechanistic studies, for studying tumor-vascular cell interactions, and for developing novel and personalized antitumor therapies. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

A comparative study of physical and chemical properties of different pozzolanic materials used for roller compacted concrete RCC dams

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Husein Malkawi Abdallah I.

2017-01-01

Full Text Available This paper addresses the feasibility and the efficiency of using Natural Pozzolan and/or Rock flour in Roller Compacted Concrete (RCC gravity dams. For this purpose, five identical mortar trial mixes were prepared using five different supplementary materials, i.e., fly ash produced in South Africa (proven to be effective in RCC construction, fly ash produced in Turkey, Jordanian natural pozzolan, Saudi natural pozzolan, and rock flour from Mujib Dam basalt quarry. The physical and chemical properties of these pozzolanic materials were determined. The effectiveness of each one of these mineral admixtures used as a cement replacement material in controlling alkali silica reaction are studied and analyzed. Correlations were made between the mechanical properties for the five proposed mixes and a control mix using the Jordanian Portland Cement. The results demonstrate that the performance of Natural Pozzolana and/or rock flour as compared with that of fly ash and other pozzolanic material is very satisfactory and can be effectively used in RCC construction.

Tubulocystic renal cell carcinoma: a new radiological entity

Energy Technology Data Exchange (ETDEWEB)

Cornelis, F.; Grenier, N. [Pellegrin Hospital, Department of Radiology, Bordeaux (France); Helenon, O.; Correas, J.M. [Necker Hospital, Department of Radiology, Paris (France); Lemaitre, L. [Claude Huriez Hospital, Department of Radiology, Lille (France); Andre, M. [La-Conception Hospital, Department of Radiology, Marseille (France); Meuwly, J.Y. [Centre Hospitalier Universitaire Vaudois, Department of Radiology, Lausanne (Switzerland); Sengel, C. [Grenoble Hospital, Department of Radiology, Grenoble (France); Derchi, L. [Universita di Genova, Radiologia - DICMI, Genova (Italy); Yacoub, M. [Pellegrin Hospital, Department of Pathology, Bordeaux (France); Verkarre, V. [Necker Hospital, Department of Pathology, Paris (France)

2016-04-15

Tubulocystic renal cell carcinoma (TC-RCC) is a recently identified renal malignancy. While approximately 100 cases of TC-RCC have been reported in the pathology literature, imaging features have not yet been clearly described. The purpose of this review is to describe the main radiologic features of this rare sub-type of RCC on ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), based jointly on the literature and findings from a multi-institutional retrospective HIPAA-compliant review of pathology and imaging databases. Using a combination of sonographic and CT/MRI features, diagnosis of TC-RCC appeared to be strongly suggested in many cases. (orig.)

Evaluation of KALIMER IHTS piping using French RCC-MR code

International Nuclear Information System (INIS)

Lee, Hyeong Yeon; Kim, J. B.; Lee, J. H.

2001-12-01

In the present report, the evaluation of design integrity for the liquid metal reactor(LMR) of KALIMER IHTS(intermediate heat transport system) piping according to the French design guideline of RCC-MR RC3600 developed for secondary piping of LMR and the evaluation procedure was presented. The evaluation results showed that the results by the simple RC-3600 procedure of design by formula were more conservative than those of ASME section III subsection NH of the design by analysis for the class I structural components

The role of glutathione transferases in renal cell carcinoma

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Ćorić Vesna

2016-01-01

Full Text Available Mounting evidence suggest that members of the subfamily of cytosolic glutathione S-transferases (GSTs possess roles far beyond the classical glutathione-dependent enzymatic conjugation of electrophilic metabolites and xenobiotics. Namely, monomeric forms of certain GSTs are capable of forming protein: protein interactions with protein kinases and regulate cell apoptotic pathways. Due to this dual functionality of cytosolic GSTs, they might be implicated in both the development and the progression of renal cell carcinoma (RCC. Prominent genetic heterogeneity, resulting from the gene deletions, as well as from SNPs in the coding and non-coding regions of GST genes, might affect GST isoenzyme profiles in renal parenchyma and therefore serve as a valuable indicator for predicting the risk of cancer development. Namely, GSTs are involved in the biotransformation of several compounds recognized as risk factors for RCC. The most potent carcinogen of polycyclic aromatic hydrocarbon diol epoxides, present in cigarette smoke, is of benzo(apyrene (BPDE, detoxified by GSTs. So far, the relationship between GST genotype and BPDE-DNA adduct formation, in determining the risk for RCC, has not been evaluated in patients with RCC. Although the association between certain individual and combined GST genotypes and RCC risk has been debated in a the literature, the data on the prognostic value of GST polymorphism in patients with RCC are scarce, probably due to the fact that the molecular mechanism supporting the role of GSTs in RCC progression has not been clarified as yet.

Identification and Characterization of Renal Cell Carcinoma Gene Markers

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Louis S. Liou

2007-01-01

Full Text Available Microarray gene expression profiling has been used to distinguish histological subtypes of renal cell carcinoma (RCC, and consequently to identify specific tumor markers. The analytical procedures currently in use find sets of genes whose average differential expression across the two categories differ significantly. In general each of the markers thus identifi ed does not distinguish tumor from normal with 100% accuracy, although the group as a whole might be able to do so. For the purpose of developing a widely used economically viable diagnostic signature, however, large groups of genes are not likely to be useful. Here we use two different methods, one a support vector machine variant, and the other an exhaustive search, to reanalyze data previously generated in our Lab (Lenburg et al. 2003. We identify 158 genes, each having an expression level that is higher (lower in every tumor sample than in any normal sample, and each having a minimum differential expression across the two categorie at a signifi cance of 0.01. The set is highly enriched in cancer related genes (p = 1.6 × 10 – 12, containing 43 genes previously associated with either RCC or other types of cancer. Many of the biomarkers appear to be associated with the central alterations known to be required for cancer transformation. These include the oncogenes JAZF1, AXL, ABL2; tumor suppressors RASD1, PTPRO, TFAP2A, CDKN1C; and genes involved in proteolysis or cell-adhesion such as WASF2, and PAPPA.

The Effect of Anatomical Location of Lymph Node Metastases on Cancer Specific Survival in Patients with Clear Cell Renal Cell Carcinoma.

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Nini, Alessandro; Larcher, Alessandro; Cianflone, Francesco; Trevisani, Francesco; Terrone, Carlo; Volpe, Alessandro; Regis, Federica; Briganti, Alberto; Salonia, Andrea; Montorsi, Francesco; Bertini, Roberto; Capitanio, Umberto

2018-01-01

Positive nodal status (pN1) is an independent predictor of survival in renal cell carcinoma (RCC) patients. However, no study to date has tested whether the location of lymph node (LN) metastases does affect oncologic outcomes in a population submitted to radical nephrectomy (RN) and extended lymph node dissection (eLND). To describe nodal disease dissemination in clear cell RCC (ccRCC) patients and to assess the effect of the anatomical sites and the number of nodal areas affected on cancer specific mortality (CSM). The study included 415 patients who underwent RN and eLND, defined as the removal of hilar, side-specific (pre/paraaortic or pre/paracaval) and interaortocaval LNs for ccRCC, at two institutions. Descriptive statistics were used to depict nodal dissemination in pN1 patients, stratified according to nodal site and number of involved areas. Multivariable Cox regression analyses and Kaplan-Meier curves were used to explore the relationship between pN1 disease features and survival outcomes. Median number of removed LN was 14 (IQR 9-19); 23% of patients were pN1. Among patients with one involved nodal site, 54 and 26% of patients were positive only in side-specific and interaortocaval station, respectively. The most frequent nodal site was the interaortocaval and side-specific one, for right and left ccRCC, respectively. Interaortocaval nodal positivity (HR 2.3, CI 95%: 1.3-3.9, p < 0.01) represented an independent predictor of CSM. When ccRCC patient harbour nodal disease, its spreading can occur at any nodal station without involving the others. The presence of interoartocaval positive nodes does affect oncologic outcomes. Lymph node invasion in patients with clear cell renal cell carcinoma is not following a fixed anatomical pattern. An extended lymph node dissection, during treatment for primary kidney tumour, would aid patient risk stratification and multimodality upfront treatment.

RCC-M: Design and construction rules for mechanical components of PWR nuclear islands

International Nuclear Information System (INIS)

2017-01-01

AFCEN's RCC-M code concerns the mechanical components designed and manufactured for pressurized water reactors (PWR). It applies to pressure equipment in nuclear islands in safety classes 1, 2 and 3, and certain non-pressure components, such as vessel internals, supporting structures for safety class components, storage tanks and containment penetrations. RCC-M covers the following technical subjects: sizing and design, choice of materials and procurement. Fabrication and control, including: associated qualification requirements (procedures, welders and operators, etc.), control methods to be implemented, acceptance criteria for detected defects, documentation associated with the different activities covered, and quality assurance. The design, manufacture and inspection rules defined in RCC-M leverage the results of the research and development work pioneered in France, Europe and worldwide, and which have been successfully used by industry to design and build PWR nuclear islands. AFCEN's rules incorporate the resulting feedback. Use: France's last 16 nuclear units (P'4 and N4); 4 CP1 reactors in South Africa (2) and Korea (2); 44 M310 (4), CPR-1000 (28), CPR-600 (6), HPR-1000 (4) and EPR (2) reactors in service or undergoing construction in China; 4 EPR reactors in Europe: Finland (1), France (1) and UK (2). Content: Section I - nuclear island components, subsection 'A': general rules, subsection 'B': class 1 components, subsection 'C': class 2 components, subsection 'D': class 3 components, subsection 'E': small components, subsection 'G': core support structures, subsection 'H': supports, subsection 'J': low pressure or atmospheric storage tanks, subsection 'P': containment penetration, subsection 'Q': qualification of active mechanical components, subsection 'Z': technical appendices; section II - materials; section III - examination

Breast Cancer with Synchronous Renal Cell Carcinoma: A Rare Presentation.

Science.gov (United States)

Arjunan, Ravi; Kumar, Durgesh; Kumar, K V Veerendra; Premlatha, C S

2016-10-01

Primary cancer arising from multiple organs is a well known fact. Synchronous tumours have been most commonly associated with kidney cancer. Bladder, prostate, colorectal and lung cancer are the most common synchronous primaries with Renal Cell Carcinoma (RCC) identified till date. We found metachronous tumours of breast with RCC in literature search which included both metastatic tumours as well second primaries. Overall, 25 cases of metastatic breast tumours and eight cases of second primary in previously treated RCC have been reported in the literature. Here, we are reporting a case of synchronous presentation of carcinoma breast with RCC which is very rare because most of the multiple malignancies reported in the literature are metastatic tumours or metachronous breast malignancy with RCC.

The option value of innovative treatments for non-small cell lung cancer and renal cell carcinoma.

Science.gov (United States)

Thornton Snider, Julia; Batt, Katharine; Wu, Yanyu; Tebeka, Mahlet Gizaw; Seabury, Seth

2017-10-01

To develop a model of the option value a therapy provides by enabling patients to live to see subsequent innovations and to apply the model to the case of nivolumab in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). A model of the option value of nivolumab in RCC and NSCLC was developed and estimated. Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and published clinical trial results were used to estimate survival curves for metastatic cancer patients with RCC, squamous NSCLC, or nonsquamous NSCLC. To estimate the conventional value of nivolumab, survival with the pre-nivolumab standard of care was compared with survival with nivolumab assuming no future innovation. To estimate the option value of nivolumab, long-term survival trends in RCC and squamous and nonsquamous NSCLC were measured in SEER to forecast mortality improvements that nivolumab patients may live to see. Compared with the previous standard of care, nivolumab extended life expectancy by 6.3 months in RCC, 7.5 months in squamous NSCLC, and 4.5 months in nonsquamous NSCLC, according to conventional methods. Accounting for expected future mortality trends, nivolumab patients are likely to gain an additional 1.2 months in RCC, 0.4 months in squamous NSCLC, and 0.5 months in nonsquamous NSCLC. These option values correspond to 18%, 5%, and 10% of the conventional value of nivolumab, respectively. Option value is important when valuing therapies like nivolumab that extend life in a rapidly evolving area of care.

CT differentiation of renal tumor invading parenchyma and pelvis: renal cell carcinoma vs transitional cell carcinoma

International Nuclear Information System (INIS)

Lee, Chang Hee; Cho, Seong Beum; Park, Cheol Min; Cha, In Ho; Chung, Kyoo Byung

1994-01-01

The differentiation between renal cell carcinoma(RCC) and transitional cell carcinoma(TCC) is important due to the different methods of treatment and prognosis. But occasionally it is difficult to draw a distinction between the two diseases when renal parenchyma and renal collecting systems are invaded simultaneously. We reviewed CT scans of 37 cases of renal cell carcinoma and 12 cases of transitional cell carcinoma which showed involvement of renal parenchyma and renal sinus fat on CT. Retrospective analysis was performed by 3 abdominal radiologists. Check points were renal contour bulging or reinform shape, location of mass center, intact parenchyma overlying the tumor, cystic change, calcification, LN metastasis, vessel invasion, and perirenal extention. There were renal contour bulging due to the tumor mass in 33 out of 37 cases of renal cell carcinoma, where a and nine of 12 cases of transitional cell carcinoma maintained the reinform appearance. This is significant statiscal difference between the two(P<0.005). Center of all TCCs were located in the renal sinus, and 24 out of 35 cases of RCC were located in the cortex(P<0.005). Thirty-six out of 37 cases of RCC lost the overlying parenchyma, where as 4 out of 9 cases of well enhanced TCC had intact overlying parenchyma(P<0.005) RCC showed uptic change within the tumor mags in 31 cases which was significanity higher than the 4 cases in TCC(P<0.05). CT findings of renal cell carcinoma are contour bulging, peripheral location, obliteration of parenchyma, and cystic change. Findings of transitional cell carcinoma are reinform appearance, central location within the kidney, intact overlying parenchyma, and rare cystic change

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target.

Science.gov (United States)

Chen, C-H; Fong, L W R; Yu, E; Wu, R; Trott, J F; Weiss, R H

2017-06-22

Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS (MARCKS phosphorylation site domain) peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

Hsa-let-7a functions as a tumor suppressor in renal cell carcinoma cell lines by targeting c-myc

Energy Technology Data Exchange (ETDEWEB)

Liu, Yongchao; Yin, Bingde; Zhang, Changcun; Zhou, Libin [Department of Urology, Shanghai First People' s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080 (China); Fan, Jie, E-mail: jief67@sina.com [Department of Urology, Shanghai First People' s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080 (China)

2012-01-06

Highlights: Black-Right-Pointing-Pointer This study is the first to test the let-7a/c-myc loop in renal cell carcinoma cell lines. Black-Right-Pointing-Pointer Let-7a down-regulated c-myc in three renal cell carcinoma cell lines. Black-Right-Pointing-Pointer c-myc target genes were down-regulated because of the let-7a-mediated down-regulation of c-myc. Black-Right-Pointing-Pointer The let-7a/c-myc loop has a significant function in renal cell carcinoma cell lines. -- Abstract: Widespread functions of the c-myc pathway play a crucial role in renal cell carcinoma (RCC) carcinogenesis. Thus, we evaluated the connection between proto-oncogenic c-myc and anti-neoplastic hsa-let-7a (let-7a) in RCC cell lines. The levels of c-myc and let-7a in 3 RCC cell lines (769P, Caki-1 and 786O) were measured after transfecting the cells with let-7a mimics or a negative control. The change in c-myc protein level was confirmed by Western blot. The anti-neoplastic function of let-7a was evaluated using cell counting kit-8 (CCK-8) for proliferation analysis and cell flow cytometry for cell cycle analysis. The changes of downstream targets of c-myc were measured using reverse transcription quantitative real-time PCR (qRT-PCR). Our results suggest for the first time that let-7a acts as a tumor suppressor in RCC cell lines by down-regulating c-myc and c-myc target genes such as proliferating cell nuclear antigen (PCNA), cyclin D1 (CCND1) and the miR17-92 cluster, which is accompanied by proliferation inhibition and cell cycle arrest.

Telemetry Standards, RCC Standard 106-17. Chapter 3. Frequency Division Multiplexing Telemetry Standards

Science.gov (United States)

2017-07-01

Standard 106-17 Chapter 3, July 2017 3-5 Table 3-4. Constant-Bandwidth FM Subcarrier Channels Frequency Criteria\\Channels: A B C D E F G H Deviation ...Telemetry Standards , RCC Standard 106-17 Chapter 3, July 2017 3-i CHAPTER 3 Frequency Division Multiplexing Telemetry Standards Acronyms...Frequency Division Multiplexing Telemetry Standards ................................ 3-1 3.1 General

More than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma: a case report

Energy Technology Data Exchange (ETDEWEB)

Yuan, J.L.; Wang, F.L.; Yi, X.M.; Qin, W.J.; Wu, G.J. [Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi (China); Huan, Y. [Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi (China); Yang, L.J.; Zhang, G.; Yu, L.; Zhang, Y.T.; Qin, R.L.; Tian, C.J. [Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi (China)

2014-10-31

Although radical nephrectomy alone is widely accepted as the standard of care in localized treatment for renal cell carcinoma (RCC), it is not sufficient for the treatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome despite the use of multiple therapies. Currently, sequential targeted agents are recommended for the management of mRCC, but the optimal drug sequence is still debated. This case was a 57-year-old man with clear-cell mRCC who received multiple therapies following his first operation in 2003 and has survived for over 10 years with a satisfactory quality of life. The treatments given included several surgeries, immunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus regimens. In the course of mRCC treatment, well-planned surgeries, effective sequential targeted therapies and close follow-up are all of great importance for optimal management and a satisfactory outcome.

Renal cell carcinoma in long-term survivors of advanced stage neuroblastoma in early childhood

International Nuclear Information System (INIS)

Fleitz, Julie M.; Wootton-Gorges, Sandra L.; Kurzrock, Eric A.; Wyatt-Ashmead, Josephine; McGavran, Loris; Koyle, Martin; Odom, Lorrie F.; West, Daniel C.; Martin, Kenneth W.

2003-01-01

Renal cell carcinoma (RCC) is rare in children and comprises only 1-3% of all pediatric primary renal tumors. Recently, several case reports have described RCC developing in patients previously treated for advanced stage neuroblastoma (NB). Our experience with four patients treated for advanced stage NB during early childhood who developed RCC later in life are added to 14 others in the literature. These patients and our review of the literature suggest an association between RCC and NB that warrants further study. (orig.)

Tensin3 is a negative regulator of cell migration and all four Tensin family members are downregulated in human kidney cancer.

Directory of Open Access Journals (Sweden)

Danuta Martuszewska

Full Text Available The Tensin family of intracellular proteins (Tensin1, -2, -3 and -4 are thought to act as links between the extracellular matrix and the cytoskeleton, and thereby mediate signaling for cell shape and motility. Dysregulation of Tensin expression has previously been implicated in human cancer. Here, we have for the first time evaluated the significance of all four Tensins in a study of human renal cell carcinoma (RCC, as well as probed the biological function of Tensin3.Expression of Tensin2 and Tensin3 at mRNA and protein levels was largely absent in a panel of diverse human cancer cell lines. Quantitative RT-PCR analysis revealed mRNA expression of all four Tensin genes to be significantly downregulated in human kidney tumors (50-100% reduction versus normal kidney cortex; P<0.001. Furthermore, the mRNA expressions of Tensins mostly correlated positively with each other and negatively with tumor grade, but not tumor size. Immunohistochemical analysis revealed Tensin3 to be present in the cytoplasm of tubular epithelium in normal human kidney sections, whilst expression was weaker or absent in 41% of kidney tumors. A subset of tumor sections showed a preferential plasma membrane expression of Tensin3, which in clear cell RCC patients was correlated with longer survival. Stable expression of Tensin3 in HEK 293 cells markedly inhibited both cell migration and matrix invasion, a function independent of putative phosphatase activity in Tensin3. Conversely, siRNA knockdown of endogenous Tensin3 in human cancer cells significantly increased their migration.Our findings indicate that the Tensins may represent a novel group of metastasis suppressors in the kidney, the loss of which leads to greater tumor cell motility and consequent metastasis. Moreover, tumorigenesis in the human kidney may be facilitated by a general downregulation of Tensins. Therefore, anti-metastatic therapies may benefit from restoring or preserving Tensin expression in primary

Metastatic renal cell carcinoma management

Directory of Open Access Journals (Sweden)

Flavio L. Heldwein

2009-06-01

Full Text Available PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy

DEFF Research Database (Denmark)

Andersen, Rikke; Westergaard, Marie Christine Wulff; Kjeldsen, Julie Westerlin

2018-01-01

In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC...

Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

Directory of Open Access Journals (Sweden)

Kiersten Marie Miles

Full Text Available The Notch ligand Delta-like 4 (Dll4 is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC.Severe combined immunodeficiency (SCID mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62% that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54% and ziv-aflibercept (46%. Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition, including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.

Science.gov (United States)

Gu, Yi-Feng; Cohn, Shannon; Christie, Alana; McKenzie, Tiffani; Wolff, Nicholas; Do, Quyen N; Madhuranthakam, Ananth J; Pedrosa, Ivan; Wang, Tao; Dey, Anwesha; Busslinger, Meinrad; Xie, Xian-Jin; Hammer, Robert E; McKay, Renée M; Kapur, Payal; Brugarolas, James

2017-08-01

Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl ) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1 -deficient tumors were of high grade and showed greater mTORC1 activation than Pbrm1 -deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1 , in Pbrm1 -deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells. Significance: Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that Bap1 and Pbrm1 loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. Cancer Discov; 7(8); 900-17. ©2017 AACR. See related commentary by Leung and Kim, p. 802 This article is highlighted in the In This Issue feature, p. 783 . ©2017 American Association for Cancer Research.

Rhein inhibits malignant phenotypes of human renal cell carcinoma by impacting on MAPK/NF-κB signaling pathways

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Ma YL

2018-03-01

Full Text Available Ya-Li Ma,* Fang Chen,* Jun ShiDepartment of Nephrology, Huaihe Hospital Henan University, Kaifeng, People’s Republic of China*These authors contributed equally to this workBackground: Rhein, an anthraquinone derivative of rhubarb, is traditionally used in Chinese herbal medicine. Now emerging studies suggest its antitumor properties in many human cancers. The present study aims to investigate the antitumor role of Rhein and its possible mechanism in human renal cell carcinoma (RCC.Materials and methods: Three RCC cell lines (A489, 786-O and ACHN were used as the cell models. We applied CCK-8, cell counting, colony formation, wound healing and Transwell assays to assess the antitumor roles of Rhein in RCC cells in vitro. The therapeutic efficacy of Rhein was further evaluated by intraperitoneal administrations in tumor formation of mice. Western blot was used to investigate the underlying mechanisms of action of Rhein.Results: Rhein inhibited RCC cell proliferation in a dose- and time-dependent manner. It also suppressed RCC cell migration and invasion in vitro. Moreover, Rhein was able to inhibit tumor growth in nude mice by intraperitoneal administration in vivo. Mechanistically, the protein levels of phosphorylated MAPK (mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase, phosphorylated Akt and two targets of NF-κB (nuclear factor kappa-light-chain enhancer of activated B cells pathway, matrix metalloproteinase 9 and CCND1 were all markedly reduced by Rhein treatment.Conclusion: Rhein processed the antitumor effects in RCC cells by inhibiting cell proliferation, migration and invasion, and these tumor-suppressing functions might be mediated by MAPK/NF-κB signaling pathways.Keywords: Rhein, renal cell carcinoma, antitumor effects, MAPK, NF-κB

Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

International Nuclear Information System (INIS)

Costa, Vera L; Henrique, Rui; Ribeiro, Franclim R; Pinto, Mafalda; Oliveira, Jorge; Lobo, Francisco; Teixeira, Manuel R; Jerónimo, Carmen

2007-01-01

Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors. A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP) in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC), 13 papillary (pRCC), 10 chromophobe (chRCC), and 10 oncocytomas) and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters. Significant differences in methylation levels among the four subtypes of renal tumors were found for CDH1 (p = 0.0007), PTGS2 (p = 0.002), and RASSF1A (p = 0.0001). CDH1 hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (p = 0.00016 and p = 0.0034, respectively), whereas PTGS2 methylation levels were significantly higher in ccRCC compared to pRCC (p = 0.004). RASSF1A methylation levels were significantly higher in pRCC than in normal tissue (p = 0.035). In pRCC, CDH1 and RASSF1A methylation levels were inversely correlated with tumor stage (p = 0.031) and nuclear grade (p = 0.022), respectively. The major subtypes of renal epithelial neoplasms display differential aberrant CDH1, PTGS2, and RASSF1A promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses

Unusual Spread of Renal Cell Carcinoma to the Clivus with Cranial Nerve Deficit.

Science.gov (United States)

Okudo, Jerome; Anusim, Nwabundo

2016-01-01

Renal cell carcinoma (RCC) has unusual presentation affecting elderly males with a smoking history. The incidence of RCC varies while the incidence of spread of RCC to the clivus is rare. The typicality of RCC presentation includes hematuria, flank pain, and a palpable flank mass; however, RCC can also present with clival metastasis. The unique path of the abducens nerve in the clivus makes it susceptible to damage in metastasis. We report a case of a 54-year-old African American female that was evaluated for back pain, weakness, numbness, and tingling of bilateral lower extremities and subsequently disconjugate gaze and diplopia. Brain MRI confirmed metastasis to the clivus. She was started on radiotherapy and was planned for chemotherapy and transfer to a nursing home. When a patient presents with sudden unusual cranial nerve pathology, the possibility of metastatic RCC should be sought.

Review of the Interaction Between Body Composition and Clinical Outcomes in Metastatic Renal Cell Cancer Treated With Targeted Therapies

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Steven M Yip

2016-03-01

Full Text Available Treatment of metastatic renal cell cancer (mRCC currently focuses on inhibition of the vascular endothelial growth factor pathway and the mammalian target of rapamycin (mTOR pathway. Obesity confers a higher risk of RCC. However, the influence of obesity on clinical outcomes in mRCC in the era of targeted therapy is less clear. This review focuses on the impact of body composition on targeted therapy outcomes in mRCC. The International Metastatic Renal Cell Carcinoma Database Consortium database has the largest series of patients evaluating the impact of body mass index (BMI on outcomes in mRCC patients treated with targeted therapy. Overall survival was significantly improved in overweight patients (BMI ≥ 25 kg/m2, and this observation was externally validated in patients who participated in Pfizer trials. In contrast, sarcopenia is consistently associated with increased toxicity to inhibitors of angiogenesis and mTOR. Strengthening patients with mRCC and sarcopenia, through a structured exercise program and dietary intervention, may improve outcomes in mRCC treated with targeted therapies. At the same time, the paradox of obesity being a risk factor for RCC while offering a better overall survival in response to targeted therapy needs to be further evaluated.

Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

International Nuclear Information System (INIS)

Hillman, Gilda G; Wang, Yu; Che, Mingxin; Raffoul, Julian J; Yudelev, Mark; Kucuk, Omer; Sarkar, Fazlul H

2007-01-01

We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more

Renal cell carcinoma in children and adolescence: Our experience ...

African Journals Online (AJOL)

Background: Literature on renal cell carcinoma (RCC) in children is lacking. Occasional case report has been mentioned. Aims and objective of our study are to evaluate the clinical presentation and outcome in children with RCC. Patients and Methods: Records of 11 children and adolescence, from January 2007 to June ...

Combination of mTOR and MAPK Inhibitors—A Potential Way to Treat Renal Cell Carcinoma

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Ashutosh Chauhan

2016-10-01

Full Text Available Renal cell carcinoma (RCC is the most common neoplasm that occurs in the kidney and is marked by a unique biology, with a long history of poor response to conventional cancer treatments. In the past few years, there have been significant advancements to understand the biology of RCC. This has led to the introduction of novel targeted therapies in the management of patients with metastatic disease. Patients treated with targeted therapies for RCC had shown positive impact on overall survival, however, no cure is possible and patients need to undergo treatment for long periods of time, which raises challenges to manage the associated adverse events. Moreover, many patients may not respond to it and even response may not last long enough in the responders. Many inhibitors of the Mammalian target of Rapamycin (mTOR signaling pathway are currently being used in treatment of advanced RCC. Studies showed that inhibitions of mTOR pathways induce Mitogen-Activated Protein Kinase (MAPK escape cell death and cells become resistant to mTOR inhibitors. Because of this, there is a need to inhibit both pathways with their inhibitors comparatively for a better outcome and treatment of patients with RCC.

The von Hippel-Lindau tumor suppressor regulates programmed cell death 5-mediated degradation of Mdm2

NARCIS (Netherlands)

Essers, P B; Klasson, T D; Pereboom, T C; Mans, D A; Nicastro, M; Boldt, K; Giles, R H; MacInnes, A W

2015-01-01

Functional loss of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex, initiates most inherited and sporadic clear-cell renal cell carcinomas (ccRCC). Genetic inactivation of the TP53 gene in ccRCC is rare, suggesting that an alternate

Proper understanding of relevant articles in RCC-M and PANE G-7-002

International Nuclear Information System (INIS)

Sun Zaozhan

2005-01-01

The French code, 'Design and construction rules for mechanical components of PWR nuclear island' RCC-M and the Russian code 'Regulations for strength analysis of equipment and pipelines of atomic power plants' PANE G-7-002, both for nuke plant design, are sometimes used in China, and discrepancies in understanding some articles of such foreign design codes will some times give different conclusions as 'acceptable' or 'unacceptable' the concerned material or product. Section IV of RCC-M concerns with qualification and performance of welding operations. Article S 3150 in this section covers the retesting procedures and article S 3152 in it relates to destructive tests. One sentence in Article S 3152 reads like this, 'Where an unsatisfactory result is due to the poor execution of the test or the presence of a defect in the specimen, the relevant result must be discarded and the test shall be repeated.' The 'presence of a defect' arose discrepancies in understanding the sentence because there is no definition in RCC-M to clarify their scopes such as how big a defect should be considered as a 'defect' that can invalidate the test results. Section 5.5 of PANE G-7-002 concerns the determination of critical brittle temperature. It stipulates that critical brittle temperature T k is a temperature at which the impact strength values must be higher than the specified ones. The specified criterion values of impact strength are related to the yield strength but it is not quite definite that the yield strength values in the table should be the documented minimum values for different materials or that they should be the tested results of the concerned lots of materials the specimen represents. The two different understandings of the yield strength values will sometimes give contrary conclusions. This paper introduces the different opinions in understanding the code texts, makes clear what it supports, and states in detail the reasons it so believes. (authors)

A Rare Case of a Renal Cell Carcinoma Confined to the Isthmus of a Horseshoe Kidney

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Michael Kongnyuy

2015-01-01

Full Text Available Horseshoe kidney (HSK is the most common renal anomaly. Reports of the incidence of renal cell carcinoma (RCC in HSK are conflicting. Very few cases of isthmus-located RCC have been reported in the literature. We report a unique case of an isthmus-located RCC. Proper vascular and tumor imaging prior to surgery is key to successful tumor removal.

Chronic lymphocytic lymphoma and concomitant renal cell carcinoma (Clear Cell Type: Review of the literature

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Burak Uz

2016-01-01

Full Text Available In the present report, a 73 years-old male patient who developed clear cell type renal cell carcinoma (RCC 5 years after the diagnosis of chronic lymphocytic lymphoma (CLL and plausible explanations for this association were discussed by the authors. The incidence of CLL and RCC occurring in the same patient is higher than that expected in the general population. Various explicative hypotheses of this concurrence include treatment-related development of a second malignancy, immunomodulatory mechanisms, viral aetiology, cytokine (interleukin 6 release from a tumor, and common genetic mutations. Further investigations are warranted.

Telemetry Standards, RCC Standard 106-17, Chapter 27, RF Network Access Layer

Science.gov (United States)

2017-07-01

to the physical media (i.e., the wireless RF network). On the transmission side, it is responsible for framing IP packets for physical transmission ...resolution bandwidth of 30 kHz. It was measured during the steady power condition during a burst transmission . Telemetry Standards, RCC Standard... power levels available for modulated burst transmission . Table 27-1. Transceiver Phase Noise Mask dBc/Hz Frequency Offset −30 dBc/Hz 10 Hz −60 dBc

Cytotoxic chemotherapy in the treatment of advanced renal cell carcinoma in the era of targeted therapy.

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Diamond, E; Molina, A M; Carbonaro, M; Akhtar, N H; Giannakakou, P; Tagawa, S T; Nanus, D M

2015-12-01

Renal cell carcinoma (RCC) is a heterogeneous disease with regards to histology, progression, and response to treatment. Cytotoxic chemotherapy has been extensively studied in metastatic RCC (mRCC). Responses in most studies are modest and the mechanisms of resistance remain poorly understood. Targeted therapies have significantly improved outcomes in mRCC; however, most patients eventually relapse and die of their disease. Early clinical data suggest that combinations of chemotherapy and targeted agents are clinically active and are well tolerated. We reviewed the available literature for published clinical trials incorporating traditional chemotherapeutic agents in the treatment of mRCC. These papers were identified through a Medline search and were included if they employed at least one chemotherapeutic agent in the treatment of mRCC. The literature was also reviewed for information regarding mechanisms of chemotherapy resistance. The data regarding the use of cytotoxic chemotherapy in mRCC consist of small, non-randomized phase I and II studies. The major response proportions with single agent chemotherapies are low but combination regimens either with other cytotoxic agents, cytokines, or targeted agents have demonstrated moderate activity. Disparate trial designs and lack of head to head clinical trials make it difficult to compare the efficacy of chemotherapy with that of immunotherapy or targeted agents. Chemotherapy is particularly useful in patients with collecting duct histology and predominantly sarcomatoid differentiation. Chemotherapy resistance may be mediated by overexpression of p-glycoprotein efflux pumps and the dysregulation of the microtubule-hypoxia inducible factor signaling axis. The role of cytotoxic chemotherapy in the treatment for clear cell RCC remains poorly defined. Cytotoxic chemotherapy is considered a standard of care in patients with mRCC with predominantly sarcomatoid differentiation and collecting duct RCC variants (Motzer et al

Quantitative promoter methylation analysis of multiple cancer-related genes in renal cell tumors

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Oliveira Jorge

2007-07-01

Full Text Available Abstract Background Aberrant promoter hypermethylation of cancer-associated genes occurs frequently during carcinogenesis and may serve as a cancer biomarker. In this study we aimed at defining a quantitative gene promoter methylation panel that might identify the most prevalent types of renal cell tumors. Methods A panel of 18 gene promoters was assessed by quantitative methylation-specific PCR (QMSP in 85 primarily resected renal tumors representing the four major histologic subtypes (52 clear cell (ccRCC, 13 papillary (pRCC, 10 chromophobe (chRCC, and 10 oncocytomas and 62 paired normal tissue samples. After genomic DNA isolation and sodium bisulfite modification, methylation levels were determined and correlated with standard clinicopathological parameters. Results Significant differences in methylation levels among the four subtypes of renal tumors were found for CDH1 (p = 0.0007, PTGS2 (p = 0.002, and RASSF1A (p = 0.0001. CDH1 hypermethylation levels were significantly higher in ccRCC compared to chRCC and oncocytoma (p = 0.00016 and p = 0.0034, respectively, whereas PTGS2 methylation levels were significantly higher in ccRCC compared to pRCC (p = 0.004. RASSF1A methylation levels were significantly higher in pRCC than in normal tissue (p = 0.035. In pRCC, CDH1 and RASSF1A methylation levels were inversely correlated with tumor stage (p = 0.031 and nuclear grade (p = 0.022, respectively. Conclusion The major subtypes of renal epithelial neoplasms display differential aberrant CDH1, PTGS2, and RASSF1A promoter methylation levels. This gene panel might contribute to a more accurate discrimination among common renal tumors, improving preoperative assessment and therapeutic decision-making in patients harboring suspicious renal masses.

Unusual Spread of Renal Cell Carcinoma to the Clivus with Cranial Nerve Deficit

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Jerome Okudo

2016-01-01

Full Text Available Renal cell carcinoma (RCC has unusual presentation affecting elderly males with a smoking history. The incidence of RCC varies while the incidence of spread of RCC to the clivus is rare. The typicality of RCC presentation includes hematuria, flank pain, and a palpable flank mass; however, RCC can also present with clival metastasis. The unique path of the abducens nerve in the clivus makes it susceptible to damage in metastasis. We report a case of a 54-year-old African American female that was evaluated for back pain, weakness, numbness, and tingling of bilateral lower extremities and subsequently disconjugate gaze and diplopia. Brain MRI confirmed metastasis to the clivus. She was started on radiotherapy and was planned for chemotherapy and transfer to a nursing home. When a patient presents with sudden unusual cranial nerve pathology, the possibility of metastatic RCC should be sought.

Metastatic Renal Cell Carcinoma Presenting as Gastric Ulcer: Case Report and Literature Review

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Alhareth Al Juboori

2017-01-01

Full Text Available Renal cell carcinoma (RCC accounts for approximately 3% of all adult malignancies. True gastrointestinal metastases, specifically to gastric wall, have been rarely observed. Herein we describe a case of delayed metastasis to gastric wall occurring more than a decade after previously curative nephrectomy for RCC. A 67-year-old male with history of right radical nephrectomy in 2001 for RCC was found to have an asymptomatic right lower lobe solitary lung mass upon routine follow-up in 2011, with final biopsy results showing metastatic RCC for which he was treated accordingly. In 2014, patient was evaluated for dyspepsia with microcytic anemia and underwent an esophagogastroduodenoscopy and colonoscopy. EGD revealed a solitary one-centimeter atypical ulcer in the posterior mid gastric body with biopsy results being consistent with metastatic RCC. Our literature review has yielded thirty-six reported cases of RCC in association with gastric wall metastases.

A case–control study of occupation/industry and renal cell carcinoma risk

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Karami Sara

2012-08-01

Full Text Available Abstract Background The role of occupation in the etiology of renal cell carcinoma (RCC is unclear. Here, we investigated associations between employment in specific occupations and industries and RCC, and its most common histologic subtype, clear cell RCC (ccRCC. Methods Between 2002 and 2007, a population-based case–control study of Caucasians and African Americans (1,217 cases; 1,235 controls was conducted within the Detroit and Chicago metropolitan areas to investigate risk factors for RCC. As part of this study, occupational histories were ascertained through in-person interviews. We computed odds ratios (ORs and 95% confidence intervals (CIs relating occupation and industry to RCC risk using adjusted unconditional logistic regression models. Results Employment in the agricultural crop production industry for five years or more was associated with RCC (OR = 3.3 [95% CI = 1.0-11.5] and ccRCC in particular (OR = 6.3 [95% CI = 1.7-23.3], P for trend with duration of employment = 0.0050. Similarly, RCC risk was elevated for employment of five years or longer in non-managerial agricultural and related occupations (ORRCC = 2.1 [95% CI = 1.0-4.5]; ORccRCC = 3.1 [95% CI = 1.4-6.8]. Employment in the dry-cleaning industry was also associated with elevated risk (ORRCC = 2.0 [95% CI = 0.9-4.4], P for trend = 0.093; ORccRCC = 3.0 [95% CI = 1.2-7.4], P for trend = 0.031. Suggestive elevated associations were observed for police/public safety workers, health care workers and technicians, and employment in the electronics, auto repair, and cleaning/janitorial services industries; protective associations were suggested for many white-collar jobs including computer science and administrative occupations as well employment in the business, legislative, and education industries. Conclusions Our findings provide support for an elevated risk of RCC in the agricultural and dry-cleaning industries and

Testicular Metastasis from Renal Cell Carcinoma: A Case Report and Review of the Literature

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Keren Rouvinov

2017-04-01

Full Text Available Testicular metastases from renal cell carcinoma (RCC are extremely rare. To the best of our knowledge, only 33 cases have been described in the literature. Most of the reported cases are of unilateral testicular metastasis from RCC. We report a case of metachronous ipsilateral testicular metastasis from RCC in a 78-year-old man 6 years after nephrectomy. Scrotal ultrasonography showed a 4 × 5 cm mass in the right testis. Right inguinal orchiectomy was performed for diagnosis. Computed tomography revealed liver and lung metastases. First-line therapy with sunitinib was started in November 2016 for metastatic RCC.

Current Trends in the Molecular Classification of Renal Neoplasms

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Andrew N. Young

2006-01-01

Full Text Available Renal cell carcinoma (RCC is the most common form of kidney cancer in adults. RCC is a significant challenge for pathologic diagnosis and clinical management. The primary approach to diagnosis is by light microscopy, using the World Health Organization (WHO classification system, which defines histopathologic tumor subtypes with distinct clinical behavior and underlying genetic mutations. However, light microscopic diagnosis of RCC subtypes is often difficult due to variable histology. In addition, the clinical behavior of RCC is highly variable and therapeutic response rates are poor. Few clinical assays are available to predict outcome in RCC or correlate behavior with histology. Therefore, novel RCC classification systems based on gene expression should be useful for diagnosis, prognosis, and treatment. Recent microarray studies have shown that renal tumors are characterized by distinct gene expression profiles, which can be used to discover novel diagnostic and prognostic biomarkers. Here, we review clinical features of kidney cancer, the WHO classification system, and the growing role of molecular classification for diagnosis, prognosis, and therapy of this disease.

Outcome of Patients With Metastatic Sarcomatoid Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium

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Kyriakopoulos, Christos E; Chittoria, Namita; Choueiri, Toni K

2015-01-01

BACKGROUND: Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking. PATIENTS AND METHODS: Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology......% intermediate risk, and 40% vs. 24% poor risk; P system metastases (6...... of second- (P = .018) and third-line (P systemic therapy. The median progression-free survival (PFS)/overall survival (OS) was 4.5/10.4 months in sRCC patients and 7.8/22.5 months in non-sRCC patients (P

Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

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Penttilä, P; Donskov, F; Rautiola, J

2017-01-01

BACKGROUND: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: Eighty-five mRCC patients received everolimus at Helsinki University...

Metabonomic profiling of renal cell carcinoma: High-resolution proton nuclear magnetic resonance spectroscopy of human serum with multivariate data analysis

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Gao Hongchang; Dong Baijun; Liu Xia; Xuan Hanqing; Huang Yiran; Lin Donghai

2008-01-01

Metabonomic profiling using proton nuclear magnetic resonance ( 1 H NMR) spectroscopy and multivariate data analysis of human serum samples was used to characterize metabolic profiles in renal cell carcinoma (RCC). We found distinct, easily detectable differences between (a) RCC patients and healthy humans, (b) RCC patients with metastases and without metastases, and (c) RCC patients before and after nephrectomy. Compared to healthy human serum, RCC serum had higher levels of lipid (mainly very low-density lipoproteins), isoleucine, leucine, lactate, alanine, N-acetylglycoproteins, pyruvate, glycerol, and unsaturated lipid, together with lower levels of acetoacetate, glutamine, phosphatidylcholine/choline, trimethylamine-N-oxide, and glucose. This pattern was somewhat reversed after nephrectomy. Altered metabolite concentrations are most likely the result of the cells switching to glycolysis to maintain energy homeostasis following the loss of ATP caused by impaired TCA cycle in RCC. Serum NMR spectra combined with principal component analysis techniques offer an efficient, convenient way of depicting tumour biochemistry and stratifying tumours under different pathophysiological conditions. It may be able to assist early diagnosis and postoperative surveillance of human malignant diseases using single blood samples

Sunitinib-induced hypertension, neutropenia and thrombocytopenia as predictors of good prognosis in metastatic renal cell carcinoma patients

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Rautiola, Juhana; Donskov, Frede; Peltola, Katriina

2016-01-01

OBJECTIVES: To evaluate the clinical significance of hypertension, neutropenia and thrombocytopenia as possible new biomarkers of sunitinib efficacy in non-trial metastatic renal cell carcinoma (mRCC) patients. MATERIALS AND METHODS: 181 consecutive mRCC patients were treated with sunitinib. Thir...... of sunitinib efficacy patients with mRCC. Our results may help to individualize sunitinib dosing during therapy based on these common sunitinib-related AEs....

Store-Operated Ca2+ Entry Does Not Control Proliferation in Primary Cultures of Human Metastatic Renal Cellular Carcinoma

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Turin, Ilaria; Potenza, Duilio Michele; Bottino, Cinzia; Glasnov, Toma N.; Ferulli, Federica; Mosca, Alessandra; Guerra, Germano; Rosti, Vittorio; Luinetti, Ombretta; Porta, Camillo; Pedrazzoli, Paolo

2014-01-01

Store-operated Ca2+ entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+ levels within the endoplasmic reticulum (ER) Ca2+ reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients. SOCE was induced following pharmacological depletion of the ER Ca2+ store, but not by InsP3-dependent Ca2+ release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+ and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI). Neither Gd3+ nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+ signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors. PMID:25126575

Store-Operated Ca2+ Entry Does Not Control Proliferation in Primary Cultures of Human Metastatic Renal Cellular Carcinoma

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Silvia Dragoni

2014-01-01

Full Text Available Store-operated Ca2+ entry (SOCE is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3-sensitive Ca2+ pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+ levels within the endoplasmic reticulum (ER Ca2+ reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7 family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC patients. SOCE was induced following pharmacological depletion of the ER Ca2+ store, but not by InsP3-dependent Ca2+ release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+ and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI. Neither Gd3+ nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+ signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors.

Anti tumor vaccination with hybrid dendritic-tumour cells

International Nuclear Information System (INIS)

Barbuto, Jose Alexandre M.; Neves, Andreia R.; Ensina, Luis Felipe C.; Anselmo, Luciene B.

2005-01-01

Dendritic cells are the most potent antigen-presenting cells, and the possibility of their use for cancer vaccination has renewed the interest in this therapeutic modality. Nevertheless, the ideal immunization protocol with these cells has not been described yet. In this paper we describe the preliminary results of a protocol using autologous tumor and allogeneic dendritic hybrid cell vaccination every 6 weeks, for metastatic melanoma and renal cell carcinoma (RCC) patients. Thirty-five patients were enrolled between March 2001 and March 2003. Though all patients included presented with large tumor burdens and progressive diseases, 71% of them experienced stability after vaccination, with durations up to 19 months. Among RCC patients 3/22 (14%) presented objective responses. The median time to progression was 4 months for melanoma and 5.7 months for RCC patients; no significant untoward effects were noted. Furthermore, immune function, as evaluated by cutaneous delayed-type hypersensitivity reactions to recall antigens and by peripheral blood proliferative responses to tumor-specific and nonspecific stimuli, presented a clear tendency to recover in vaccinated patients. These data indicate that dendritic cell-tumor cell hybrid vaccination affects the natural history of advanced cancer and provide support for its study in less advanced patients, who should, more likely, benefit even more from this approach. (author)

Renal cell carcinoma: histological classification and correlation with imaging findings

Energy Technology Data Exchange (ETDEWEB)

Muglia, Valdair F., E-mail: fmuglia@fmrp.usp.br [Universidade de Sao Paulo (CCIFM/FMRP/USP), Ribeirao Preto, SP (Brazil). Centro de Ciencias das Imagens e Fisica Medica. Faculdade de Medicina; Prando, Adilson [Universidade Estadual de Campinas (UNICAMP), SP (Brazil); Hospital Vera Cruz, Campinas, SP (Brazil). Dept. de Imaginologia

2015-05-15

Renal cell carcinoma (RCC) is the seventh most common histological type of cancer in the Western world and has shown a sustained increase in its prevalence. The histological classification of RCCs is of utmost importance, considering the significant prognostic and therapeutic implications of its histological subtypes. Imaging methods play an outstanding role in the diagnosis, staging and follow-up of RCC. Clear cell, papillary and chromophobe are the most common histological subtypes of RCC, and their preoperative radiological characterization, either followed or not by confirmatory percutaneous biopsy, may be particularly useful in cases of poor surgical condition, metastatic disease, central mass in a solitary kidney, and in patients eligible for molecular targeted therapy. New strategies recently developed for treating renal cancer, such as cryo and radiofrequency ablation, molecularly targeted therapy and active surveillance also require appropriate preoperative characterization of renal masses. Less common histological types, although sharing nonspecific imaging features, may be suspected on the basis of clinical and epidemiological data. The present study is aimed at reviewing the main clinical and imaging findings of histological RCC subtypes. (author)

Role of RPLND and Metastasectomy in the Management of Oligometastatic Renal Cell Carcinoma.

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Nagaraja, H; Srivatsa, N; Hemalatha, S; Shweta, S; Raghunath, S K

2018-03-01

Although lymphadenectomy is currently accepted as most accurate and reliable staging procedure for lymph node metastases, its therapeutic benefit in renal cell carcinoma (RCC) still remains controversial. Although the new, targeted therapy paradigms have changed the treatment of patients with advanced RCC and offer prolonged survival, cure is extremely uncommon in the absence of surgical resections. In this paper, the current role of metastasectomy is reviewed. Review the available literature concerning the role of retroperitoneal lymph node dissection and metastasectomy in outcome of oligometastatic RCC. A PubMed search was conducted to identify original articles, review articles, and editorials addressing the role of retroperitoneal lymph node dissection and metastasectomy in outcome of oligometastatic RCC. Keywords included renal tumors, renal cell cancer, kidney cancer, lymphadenectomy, metastasectomy, and oligometastases. While there is no randomized study available, recent large observational studies have better defined the prognosis of patients with metastatic RCC with or without metastasectomy and RPLND. To date, the available evidence suggests that RPLND and metastasectomy may be beneficial when technically feasible in patients with locally advanced (unfavorable clinical and pathologic characteristics) and oligometastatic disease. A proportion of patients will achieve long-term survival with aggressive surgical resection.

Pattern of Care Study in Metastatic Renal-Cell Carcinoma in the Preimmunotherapy Era in Switzerland.

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Sandmeier, Nadja; Rothschild, Sacha I; Rothermundt, Christian; Cathomas, Richard; Schardt, Julian; Berthold, Dominik; von Burg, Philippe; Müller, Beat; Beyer, Jörg; Vogt, Deborah R; Stenner, Frank

2018-02-02

In metastatic renal-cell carcinoma (mRCC), physicians have a plethora of therapeutic choices, with the latest addition of checkpoint inhibitors. However, many questions regarding the best use of the respective drugs remain unanswered. Therefore, it is important to examine and summarize the outcome of real-world experiences to understand the practical value of the various drugs in daily use and foster optimal treatment algorithms for patients with renal-cell carcinoma. We sought to describe the pattern of care in mRCC under circumstances with access to all therapeutic options for patients. We examined the outcome of patients with mRCC who were treated at 8 major centers in Switzerland, mainly with vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibitors. Data from 110 patients with mRCC who had undergone more than one systemic therapy were collected and analyzed. We assessed the pattern of care for patients with mRCC in an unrestricted health care system and outcomes with regard to the respective treatment sequences. We also studied the compliance of individual therapies with published guidelines and correlated the adherence to outcome. Finally, immediate versus deferred treatment and the number of received therapeutic drug lines were analyzed. Median survival of patients treated with targeted agents for mRCC was 2.0 years. Exposure to more than 2 lines of systemic drugs did not improve outcome of patients with mRCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Rhabdoid and Undifferentiated Phenotype in Renal Cell Carcinoma: Analysis of 32 Cases Indicating a Distinctive Common Pathway of Dedifferentiation Frequently Associated With SWI/SNF Complex Deficiency.

Science.gov (United States)

Agaimy, Abbas; Cheng, Liang; Egevad, Lars; Feyerabend, Bernd; Hes, Ondřej; Keck, Bastian; Pizzolitto, Stefano; Sioletic, Stefano; Wullich, Bernd; Hartmann, Arndt

2017-02-01

Undifferentiated (anaplastic) and rhabdoid cell features are increasingly recognized as adverse prognostic findings in renal cell carcinoma (RCC), but their molecular pathogenesis has not been studied sufficiently. Recent studies identified alterations in the Switch Sucrose nonfermentable (SWI/SNF) chromatin remodeling complex as molecular mechanisms underlying dedifferentiation and rhabdoid features in carcinomas of different organs. We herein have analyzed 32 undifferentiated RCCs having in common an undifferentiated (anaplastic) phenotype, prominent rhabdoid features, or both, irrespective of the presence or absence of conventional RCC component. Cases were stained with 6 SWI/SNF pathway members (SMARCB1, SMARCA2, SMARCA4, ARID1A, SMARCC1, and SMARCC2) in addition to conventional RCC markers. Patients were 20 males and 12 females aged 32 to 85 years (mean, 59). A total of 22/27 patients with known stage presented with ≥pT3. A differentiated component varying from microscopic to major component was detected in 20/32 cases (16 clear cell and 2 cases each chromophobe and papillary RCC). The undifferentiated component varied from rhabdoid dyscohesive cells to large epithelioid to small monotonous anaplastic cells. Variable loss of at least 1 SWI/SNF complex subunit was noted in the undifferentiated/rhabdoid component of 21/32 cases (65%) compared with intact or reduced expression in the differentiated component. A total of 15/17 patients (88%) with follow-up died of metastatic disease (mostly within 1 y). Only 2 patients were disease free at last follow-up (1 and 6 y). No difference in survival, age distribution, or sex was observed between the SWI/SNF-deficient and the SWI/SNF-intact group. This is the first study exploring the role of SWI/SNF deficiency as a potential mechanism underlying undifferentiated and rhabdoid phenotype in RCC. Our results highlight the association between the aggressive rhabdoid phenotype and the SWI/SNF complex deficiency, consistent

Renal cell carcinoma primary cultures maintain genomic and phenotypic profile of parental tumor tissues

International Nuclear Information System (INIS)

Cifola, Ingrid; Magni, Fulvio; Signorini, Stefano; Battaglia, Cristina; Perego, Roberto A; Bianchi, Cristina; Mangano, Eleonora; Bombelli, Silvia; Frascati, Fabio; Fasoli, Ester; Ferrero, Stefano; Di Stefano, Vitalba; Zipeto, Maria A

2011-01-01

Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches

Beta-2-glycoprotein-1 and alpha-1-antitrypsin as urinary markers of renal cancer in von Hippel-Lindau patients.

Science.gov (United States)

Mandili, Giorgia; Notarpietro, Agata; Khadjavi, Amina; Allasia, Marco; Battaglia, Antonino; Lucatello, Barbara; Frea, Bruno; Turrini, Francesco; Novelli, Francesco; Giribaldi, Giuliana; Destefanis, Paolo

2018-03-01

Von Hippel-Lindau disease (VHLD) is a rare inherited neoplastic syndrome. Among all the VHLD-associated tumors, clear cell renal cell carcinoma (ccRCC) is the major cause of death. The aim of this paper is the discovery of new non-invasive biomarker for the monitoring of VHLD patients. We compared the urinary proteome of VHLD patients, ccRCC patients and healthy volunteers. Among all differentially expressed proteins, alpha-1-antitrypsin (A1AT) and APOH (beta-2-glycoprotein-1) are strongly over-abundant only in the urine of VHLD patients with a history of ccRCC. A1AT and APOH could be promising non-invasive biomarkers.

Clear cell renal cell carcinoma: validation of World Health Organization/International Society of Urological Pathology grading.

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Dagher, Julien; Delahunt, Brett; Rioux-Leclercq, Nathalie; Egevad, Lars; Srigley, John R; Coughlin, Geoffrey; Dunglinson, Nigel; Gianduzzo, Troy; Kua, Boon; Malone, Greg; Martin, Ben; Preston, John; Pokorny, Morgan; Wood, Simon; Yaxley, John; Samaratunga, Hemamali

2017-12-01

In 2012, the International Society of Urological Pathology (ISUP) introduced a novel grading system for clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma. This system is incorporated into the latest World Health Organization renal tumour classification, being designated WHO/ISUP grading. This study was undertaken to compare WHO/ISUP and Fuhrman grading and to validate WHO/ISUP grading as a prognostic parameter in a series of clear cell RCC. Analysis of 681 cases of ccRCC showed that 144 tumours could not be assigned a Fuhrman grade on the basis of ambiguous grading features. The application of WHO/ISUP grading resulted in a general down-grading of cases when compared with Fuhrman grading. In a sub-group of 374 cases, for which outcome data were available, 9.3% were WHO/ISUP grade 1, 50.3% were grade 2, 24.1% grade 3 and 16.3% grade 4, while the distribution of Fuhrman grades was 0.4% grade 1, 48.7% grade 2, 29.4% grade 3 and 21.5% grade 4. There were no recurrence/metastases amongst patients with WHO/ISUP grade 1 tumours and there was a significant difference in outcome for WHO/ISUP grades 2, 3 and 4. For Fuhrman grading the cancer-free survival was not significantly different for grade 2 and grade 3 tumours. On multivariate analysis WHO/ISUP grade and pT staging category were found to retain prognostic significance. The study demonstrates that FG cannot be applied in >20% of cases of ccRCC and the WHO/ISUP provides superior prognostic information. © 2017 John Wiley & Sons Ltd.

Ethnic variation of the histological subtypes of renal cell carcinoma in Singapore

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E.V. Ezenwa

2014-12-01

Conclusion: The commonest histological subtype of RCC in each of the studied ethnic groups in Singapore is clear cell carcinoma. However, most of the cancer deaths in Chinese (16.9% and Malays (66.7% were associated with the papillary cell type, while in Indians the sarcomatoid component prevailed (9.7%. Thus, the usual prognostic trend for RCC subtypes cannot be applied to all Singaporean ethnicities, necessitating individualization of prognosis for each group.

SEISMIC B E H AV I OUR OF R.C.C BUILDING WITH AND WITHOUT FLOATING COLUMNS

OpenAIRE

E. ANUSHA; E. V. RAGHVA RAO; N. CHENNA KESAVA

2018-01-01

The main purpose of the project is to study the seismic behaviour of R.C.C building with and without floating column,G+5 structures has been selected for carrying out the project work. The building models are generated using software STAAD.

Hepatitis C infection and renal cell carcinoma: A systematic review and meta-analysis

Institute of Scientific and Technical Information of China (English)

Karn; Wijarnpreecha[1; Pitchaphon; Nissaisorakarn[2; Suthanya; Sornprom[1; Charat; Thongprayoon[1; Natanong; Thamcharoen[1; Kunlatida; Maneenil[3; Alexander; J; Podboy[4; Wisit; Cheungpasitporn[5

2016-01-01

AIM To investigate the association between hepatitis C virus (HCV) infection and risk of renal cell carcinoma (RCC). METHODS A literature search was performed from inception until February 2016. Studies that reported relative risks,odd ratios, hazard ratios or standardized incidence ratio comparing the risk of RCC among HCV-infected participants vs those without HCV infection were included. Participants without HCV infection were used as comparators. Pooled odds ratios and 95%CI were calculated using a random-effect, generic inverse variance method.RESULTS Seven observational studies were with 196826 patients were included in the analysis to assess the risk of RCC in patients with HCV. A significantly increased risk of RCC among participants with HCV infection was found with a pooled RR of 1.86 (95%CI: 1.11-3.11). The association between RCC and HCV was marginally insignificant after a sensitivity analysis limited only to studies with adjusted analysis, with a pooled RR of 1.50 (95%CI:0.93-2.42).CONCLUSION Our study demonstrated a potential association between HCV infection and RCC. Further studies of RCC surveillance in patients with HCV are required.

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

DEFF Research Database (Denmark)

Mitchell, Thomas J.; Turajlic, Samra; Rowan, Andrew

2018-01-01

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the...

Non-invasive spectroscopy of transfusable red blood cells stored inside sealed plastic blood-bags.

Science.gov (United States)

Buckley, K; Atkins, C G; Chen, D; Schulze, H G; Devine, D V; Blades, M W; Turner, R F B

2016-03-07

After being separated from (donated) whole blood, red blood cells are suspended in specially formulated additive solutions and stored (at 4 °C) in polyvinyl chloride (PVC) blood-bags until they are needed for transfusion. With time, the prepared red cell concentrate (RCC) is known to undergo biochemical changes that lower effectiveness of the transfusion, and thus regulations are in place that limit the storage period to 42 days. At present, RCC is not subjected to analytical testing prior to transfusion. In this study, we use Spatially Offset Raman Spectroscopy (SORS) to probe, non-invasively, the biochemistry of RCC inside sealed blood-bags. The retrieved spectra compare well with conventional Raman spectra (of sampled aliquots) and are dominated by features associated with hemoglobin. In addition to the analytical demonstration that SORS can be used to retrieve RCC spectra from standard clinical blood-bags without breaking the sterility of the system, the data reveal interesting detail about the oxygenation-state of the stored cells themselves, namely that some blood-bags unexpectedly contain measurable amounts of deoxygenated hemoglobin after weeks of storage. The demonstration that chemical information can be obtained non-invasively using spectroscopy will enable new studies of RCC degeneration, and points the way to a Raman-based instrument for quality-control in a blood-bank or hospital setting.

French RSE-M and RCC-MR code appendices for flaw analysis: Presentation of the fracture parameters calculation-Part I: General overview

International Nuclear Information System (INIS)

Marie, S.; Chapuliot, S.; Kayser, Y.; Lacire, M.H.; Drubay, B.; Barthelet, B.; Le Delliou, P.; Rougier, V.; Naudin, C.; Gilles, P.; Triay, M.

2007-01-01

Two French nuclear codes include flaw assessment procedures: the RSE-M code 'Rules for In-service Inspection of Nuclear Power Plant Components' and the RCC-MR code 'Design and Construction rules for mechanical components of FBR nuclear islands and high temperature applications'. An important effort of development of these analytical methods has been made for the last 10 years in the frame of a collaboration between CEA, EDF and AREVA-NP, and in the frame of R and D actions involving CEA and IRSN. These activities have led to a unification of the common methods of the two codes. The calculation of fracture mechanics parameters, and in particular the stress intensity factor K I and the J integral, has been widely developed for industrial configurations. All developments have been integrated in the 2005 edition of RSE-M and in the 2007 edition of RCC-MR. This series of articles is composed of five parts: this first one presents an overview of the methods proposed in the RCC-MR and RSE-M codes. Parts II-IV provide compendia for specific components: plates (part II), pipes (part III) and elbows (part IV). Finally, part V presents the validation elements of the methods, with details on the process followed for their development and on evaluation of the accuracy of the proposed analytical methods. This first article of the series presents an overview of the calculation of K I and J in these two codes and describes briefly the defect assessment analyses. Specific details in the Appendix A16 of RCC-MR (LBB procedure and creep analyses) are also introduced in this article

Interventional Management of a Renal Cell Carcinoma by Radiofrequency Ablation with Tagging and Cooling

International Nuclear Information System (INIS)

Mahnken, Andreas H.; Penzkofer, Tobias; Bruners, Philipp; Gunther, Rolf W.; Brehmer, Bernhard

2009-01-01

Over the last few years, percutaneous radiofrequency (RF) ablation has been successfully established as a viable treatment modality for small peripheral renal cell carcinoma (RCC). This technique is limited by central tumor location and tumor size. We report the interventional management of a 5.3 cm mixed RCC with central and exophytic parts by combining the RF ablation with embolization, tagging, and retrograde, as well as anterograde cooling. The potential pitfalls of complex hybrid interventions for treating RCC are discussed

Telemetry Standards, RCC Standard 106-17. Chapter 8. Digital Data Bus Acquisition Formatting Standard

Science.gov (United States)

2017-07-01

incorrect word count/message and illegal mode codes are not considered bus errors. 8.6.2 Source Signal The source of data is a signal conforming to...Telemetry Standards, RCC Standard 106-17 Chapter 8, July 2017 CHAPTER 8 Digital Data Bus Acquisition Formatting Standard Acronyms...check FCS frame check sequence HDDR high-density digital recording MIL-STD Military Standard msb most significant bit PCM pulse code modulation

ROLE OF THE MORPHOMETRIC PARAMETERS OF INTRATUMORAL MICROVESSELS AND THE PROLIFERATIVE ACTIVITY OF TUMOR CELLS IN RENAL CELL CARCINOMA

Directory of Open Access Journals (Sweden)

N. A. Gorban

2014-08-01

Full Text Available Tumor cell proliferation and angiogenesis are essential factors for tumor growth, progression, and metastasis.Objective: to assess the relationship between the values of proliferative activity and the morphometric parameters of intratumoral microvessels in metastatic and localized carcinomas of the kidney.Materials and methods. Surgical specimens taken from 54 patients (32 men and 22 women aged 26 to 69 years (mean age 55 ± 1.5 years with the verified diagnosis of clear-cell renal cell carcinoma (RCC were studied.Conclusion. Proliferative activity and angioarchitectonics are an important biological characteristic of a tumor of unequal clinical value in RCC. Metastatic carcinoma has a higher proliferative activity and a low tumor vascularization than those of localized carcinoma.

Present and future perspectives on immunotherapy for advanced renal cell carcinoma: Going to the core or beating around the bush?

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Hidenori Kawashima

2015-03-01

Full Text Available Metastatic lesions of renal cell carcinoma (RCC occasionally regress spontaneously after surgical removal of the primary tumor. Although this is an exceptionally rare occurrence, RCC has thus been postulated to be immunogenic. Immunotherapies, including cytokine therapy, peptide-based vaccines, and immune checkpoint inhibitors have therefore been used to treat patients with advanced, metastatic RCC. We review the history, trends, and recent progress in immunotherapy for advanced RCC and discuss future perspectives, with consideration of our experimental work on galectin 9 and PINCH as promising specific immunotherapy targets. 

Clinical presentation of renal cell carcinoma

International Nuclear Information System (INIS)

Rehman, R.A.; Ashraf, S.; Jamil, N.

2015-01-01

Most common malignant tumour of the kidney is Renal Cell Carcinoma (RCC) and is known for its unpredictable clinical behaviour. Aetiology and risk factors are not completely understood. Extensive workup is being done in the understanding of the disease, especially to diagnose early and to treat promptly. The objective of this study was to determine the clinical presentation and pathological pattern of RCC. Methods: After approval from ethical committee a retrospective review of records was conducted extending from January 2012 to January 2014 to identify clinical characteristics of renal cell carcinomas. The study included all renal cancer patients presented to Sheikh Zayed Hospital Lahore with in this specified period. The data was retrieved regarding, history, physical examination and necessary investigations such as ultrasonography of abdomen and pelvis and CT scan of abdomen and pelvis. Results: There were total of 50 cases. The male to female ratio was 3:2. Mean age of patients were 52.38 (18-93) years old. Most common clinical presentation was gross haematuria(66%).The mean tumour size was 8.34 (3-24) cm. Tumour histology were clear cell (84%), papillary transitional cell carcinoma (12%) and oncosytoma contributed 4%. Conclusion: We observed that large number of the patients with RCC presented with haematuria and most of them were male. Common pathological type was clear cell carcinoma. (author)

Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

Science.gov (United States)

Zeng, Yizhou; Tian, Xiaofang; Wang, Quan; He, Weiyang; Fan, Jing; Gou, Xin

2018-01-01

Aim The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway. Methods and results: RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis. Conclusion These results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001. PMID:29719377

Urinary volatile organic compounds as potential biomarkers for renal cell carcinoma

Science.gov (United States)

WANG, DONGCHUN; WANG, CHANGSONG; PI, XIN; GUO, LEI; WANG, YUE; LI, MINGJUAN; FENG, YUE; LIN, ZIWEI; HOU, WEI; LI, ENYOU

2016-01-01

Currently, there is no adequate, sensitive, reproducible, specific and noninvasive biomarker that can reliably be used to detect renal cell carcinoma (RCC). Previous studies have elucidated the urinary non-volatile metabolic profile of RCC. However, whether urinary volatile organic compound (VOC) profiles are able to identify RCC remains to be elucidated. In the present study, urine was collected from 22 patients with RCC and 25 healthy subjects. Principal component analysis and orthogonal partial least square discriminant analysis were used to compare the data of patients and healthy subjects, and preoperative and postoperative patients undergoing radical nephrectomy. In total, 11 VOC biomarkers were elevated in the RCC patients compared to the healthy subjects, which were phenol; decanal; 1,6-dioxacyclododecane-7,12-dione; 1-bromo-1-(3-methyl-1-pentenylidene)-2,2,3,3-tetramethyl-cyclopropane; nonanal; 3-ethyl-3-methylheptane; isolongifolene-5-ol; 2,5-cyclohexadiene-1,4-dione, 2,6-bis(1,1-dimethylethyl); tetradecane; aniline; and 2,6,10,14-tetramethyl-pentadecane. Three biomarkers were decreased in RCC patients: styrene, 4-heptanone and dimethylsilanediol. In preoperative patients, 2-ethyl-1-hexanol and cyclohexanone were elevated, while 6-t-butyl-2,2,9,9-tetramethyl-3,5-decadien-7-yne were decreased when compared to postoperative patients. Compared with the healthy subjects, RCC has a unique VOC profile, suggesting that VOC profiles may be a useful diagnostic assay for RCC. PMID:27347408

Expression of heparanase in basal cell carcinoma and squamous cell carcinoma.

Science.gov (United States)

Pinhal, Maria Aparecida Silva; Almeida, Maria Carolina Leal; Costa, Alessandra Scorse; Theodoro, Thérèse Rachell; Serrano, Rodrigo Lorenzetti; Machado, Carlos D'Apparecida Santos

2016-01-01

Heparanase is an enzyme that cleaves heparan sulfate chains. Oligosaccharides generated by heparanase induce tumor progression. Basal cell carcinoma and squamous cell carcinoma comprise types of nonmelanoma skin cancer. Evaluate the glycosaminoglycans profile and expression of heparanase in two human cell lines established in culture, immortalized skin keratinocyte (HaCaT) and squamous cell carcinoma (A431) and also investigate the expression of heparanase in basal cell carcinoma, squamous cell carcinoma and eyelid skin of individuals not affected by the disease (control). Glycosaminoglycans were quantified by electrophoresis and indirect ELISA method. The heparanase expression was analyzed by quantitative RT-PCR (qRTPCR). The A431 strain showed significant increase in the sulfated glycosaminoglycans, increased heparanase expression and decreased hyaluronic acid, comparing to the HaCaT lineage. The mRNA expression of heparanase was significantly higher in Basal cell carcinoma and squamous cell carcinoma compared with control skin samples. It was also observed increased heparanase expression in squamous cell carcinoma compared to the Basal cell carcinoma. The glycosaminoglycans profile, as well as heparanase expression are different between HaCaT and A431 cell lines. The increased expression of heparanase in Basal cell carcinoma and squamous cell carcinoma suggests that this enzyme could be a marker for the diagnosis of such types of non-melanoma cancers, and may be useful as a target molecule for future alternative treatment.

Cost-Effectiveness of Everolimus for Second-Line Treatment of Metastatic Renal Cell Carcinoma in Serbia

NARCIS (Netherlands)

Mihajlovic, Jovan; Pechlivanoglou, Petros; Sabo, Ana; Tomic, Zdenko; Postma, Maarten J.

2013-01-01

Background: New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had

Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine.

Science.gov (United States)

Shinagare, Atul B; Krajewski, Katherine M; Braschi-Amirfarzan, Marta; Ramaiya, Nikhil H

2017-08-01

For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. © RSNA, 2017.

Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma

Directory of Open Access Journals (Sweden)

Yan Song

2015-01-01

Full Text Available Background: Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC, but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL gene status, vascular endothelial growth factor receptor (VEGFR or stem cell factor receptor (KIT expression, and their relationships with characteristics and clinical outcome of advanced ccRCC. Methods: A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS and overall survival (OS were calculated and then compared based on expression status. The Chi-square test, the Kaplan-Meier method, and the Lon-rank test were used for statistical analyses. Results: Of 59 patients, objective responses were observed in 28 patients (47.5%. The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6% had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%. VHL mutation status did not correlate with either overall response rate (P = 0.938 or PFS (P = 0.277. The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043. Conclusion

Papillary type 2 versus clear cell renal cell carcinoma: Survival outcomes.

Science.gov (United States)

Simone, G; Tuderti, G; Ferriero, M; Papalia, R; Misuraca, L; Minisola, F; Costantini, M; Mastroianni, R; Sentinelli, S; Guaglianone, S; Gallucci, M

2016-11-01

To compare the cancer specific survival (CSS) between p2-RCC and a Propensity Score Matched (PSM) cohort of cc-RCC patients. Fifty-five (4.6%) patients with p2-RCC and 920 cc-RCC patients were identified within a prospectively maintained institutional dataset of 1205 histologically proved RCC patients treated with either RN or PN. Univariable and multivariable Cox regression analyses were used to identify predictors of CSS after surgical treatment. A 1:2 PSM analysis based on independent predictors of oncologic outcomes was employed and CSS was compared between PSM selected cc-RCC patients using Kaplan-Meier and Cox regression analysis. Overall, 55 (4.6%) p2-RCC and 920 (76.3%) cc-RCC patients were selected from the database; p2-RCC were significantly larger (p = 0.001), more frequently locally advanced (p p2-RCC for age (p = 0.81), tumor size (p = 0.39), pT (p = 1.00) and pN (p = 0.62) stages, cM stage (p = 0.71) and Fuhrman grade (p = 1). In this PSM cohort, 5 yr CSS was significantly lower in the p2-RCC (63% vs 72.4%; p = 0.047). At multivariable Cox analysis p2 histology was an independent predictor of CSM (HR 2.46, 95% CI 1.04-5.83; p = 0.041). We confirmed the tendency of p2-RCC to present as locally advanced and metastatic disease more frequently than cc-RCC and demonstrated p2-RCC histology as an independent predictor of worse oncologic outcomes. Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Renal Cell Carcinoma Metastasis to Ipsilateral Parotid and Submandibular Glands: Report of a Case with Sonoelastographic Findings

International Nuclear Information System (INIS)

Balaban, Mehtap; Dogruyol, Sureyya Vudali; Idilman, Ilkay S.; Unal, Ozlem; Ipek, Ali

2016-01-01

Renal cell carcinoma (RCC) – also known as hypernephroma or grawitz tumor – accounts for 3% of the adulthood malignancies. Approximately 30–40% of the patients have metastasis at the time of the diagnosis and most common sites for metastasis are lung, regional lymph nodes, bone and liver. A total of 8–14% of the patients with RCC has head and neck metastasis. However, metastasis to major salivary glands is rarely seen. In this paper, we aimed to report a RCC case with metastasis to parotid and submandibular glands that has the same sonographic and sonoelastographic findings with the primary tumor. 66-year old woman with RCC history was referred to our radiology department for neck ultrasound (US) with painful swelling in the right parotid gland region. A well-defined, 37×21 mm sized hypoechoic heterogeneous solid mass was detected in the superficial-deep lobe of the right parotid gland. The mass was prominently hypervascular in color Doppler ultrasonography scan. Coincidentally, a 13×13 mm hypoechoic lobulated solid mass was detected in the right submandibular gland with similar sonographic findings. Real-time sonoelastography (SEL) was performed to the masses and both of them were blue-green colored that indicates hard tissue. An US and SEL evaluation was also performed to the renal mass (RCC) of the patient. The primary mass was also similar in sonographic and SEL appearance as salivary gland masses. In the patient history, she revealed chemotherapy-radiotherapy treatment 1.5 years ago due to inoperable mass in the mid-lower pole of the left kidney diagnosed as clear cell RCC with vascular invasion, liver, lung and brain metastasis. Because of known primary tumor, the masses in the salivary glands were suspected to be metastatic and a tru-cut biopsy was performed. Pathological result was reported as clear cell RCC metastasis. The etiology of RCC is still unknown and metastatic involvement can be seen at unexpected tissue and organs. Metastatic disease

Quantitative computer-aided diagnostic algorithm for automated detection of peak lesion attenuation in differentiating clear cell from papillary and chromophobe renal cell carcinoma, oncocytoma, and fat-poor angiomyolipoma on multiphasic multidetector computed tomography.

Science.gov (United States)

Coy, Heidi; Young, Jonathan R; Douek, Michael L; Brown, Matthew S; Sayre, James; Raman, Steven S

2017-07-01

To evaluate the performance of a novel, quantitative computer-aided diagnostic (CAD) algorithm on four-phase multidetector computed tomography (MDCT) to detect peak lesion attenuation to enable differentiation of clear cell renal cell carcinoma (ccRCC) from chromophobe RCC (chRCC), papillary RCC (pRCC), oncocytoma, and fat-poor angiomyolipoma (fp-AML). We queried our clinical databases to obtain a cohort of histologically proven renal masses with preoperative MDCT with four phases [unenhanced (U), corticomedullary (CM), nephrographic (NP), and excretory (E)]. A whole lesion 3D contour was obtained in all four phases. The CAD algorithm determined a region of interest (ROI) of peak lesion attenuation within the 3D lesion contour. For comparison, a manual ROI was separately placed in the most enhancing portion of the lesion by visual inspection for a reference standard, and in uninvolved renal cortex. Relative lesion attenuation for both CAD and manual methods was obtained by normalizing the CAD peak lesion attenuation ROI (and the reference standard manually placed ROI) to uninvolved renal cortex with the formula [(peak lesion attenuation ROI - cortex ROI)/cortex ROI] × 100%. ROC analysis and area under the curve (AUC) were used to assess diagnostic performance. Bland-Altman analysis was used to compare peak ROI between CAD and manual method. The study cohort comprised 200 patients with 200 unique renal masses: 106 (53%) ccRCC, 32 (16%) oncocytomas, 18 (9%) chRCCs, 34 (17%) pRCCs, and 10 (5%) fp-AMLs. In the CM phase, CAD-derived ROI enabled characterization of ccRCC from chRCC, pRCC, oncocytoma, and fp-AML with AUCs of 0.850 (95% CI 0.732-0.968), 0.959 (95% CI 0.930-0.989), 0.792 (95% CI 0.716-0.869), and 0.825 (95% CI 0.703-0.948), respectively. On Bland-Altman analysis, there was excellent agreement of CAD and manual methods with mean differences between 14 and 26 HU in each phase. A novel, quantitative CAD algorithm enabled robust peak HU lesion detection

Evaluation of EGFR, KRAS and BRAF gene mutations in renal cell carcinoma

Directory of Open Access Journals (Sweden)

Omer Bayrak

2014-08-01

Full Text Available A subset of renal cell carcinoma (RCC patients has been shown to respond to anti-EGFR therapy. As KRAS and BRAF mutations are associated with poor response to anti-EGFR therapy in some cancers, it has been suggested that screening for KRAS and BRAF mutations in RCC may be a promising strategy to identify patients who might respond to EGFR-targeted therapy. The aim of this study was to investigate the mutation status of EGFR, KRAS and BRAF in RCC patients. Renal tumors and normal renal samples from forty-eight patients who underwent radical or partial nephrectomy for kidney cancer were used in this study. Histological classification of the tumors was performed according to International Union against Cancer (UICC / American Joint Committee on Cancer (AJCC classification. Seventeen patients (48% had clear-cell RCC, 7 (20% had chromophobe RCC, and 11 patients (32% had papillary RCC. DNA isolated from the samples was subjected to melting curve mutation analysis for EGFR, BRAF and KRAS using ABI-3130 DNA sequencer. DNA sequencing analysis of RCC samples, when compared with morphologically normal matched regions, did not show any exon mutations. Our results do not support the notion that EGFR, KRAS and BRAF might be mutated in RCC. Normal 0 false false false TR X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0cm; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-ansi-language:TR; mso-fareast-language:EN-US;}

Next-Generation Sequencing to Detect Deletion of RB1 and ERBB4 Genes in Chromophobe Renal Cell Carcinoma: A Potential Role in Distinguishing Chromophobe Renal Cell Carcinoma from Renal Oncocytoma.

Science.gov (United States)

Liu, Qingqing; Cornejo, Kristine M; Cheng, Liang; Hutchinson, Lloyd; Wang, Mingsheng; Zhang, Shaobo; Tomaszewicz, Keith; Cosar, Ediz F; Woda, Bruce A; Jiang, Zhong

2018-04-01

Overlapping morphologic, immunohistochemical, and ultrastructural features make it difficult to diagnose chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO). Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to identify genetic markers that distinguish ChRCC from RO by using next-generation sequencing (NGS). NGS for hotspot mutations or gene copy number changes was performed on 12 renal neoplasms, including seven ChRCC and five RO cases. Matched normal tissues from the same patients were used to exclude germline variants. Rare hotspot mutations were found in cancer-critical genes (TP53 and PIK3CA) in ChRCC but not RO. The NGS gene copy number analysis revealed multiple abnormalities. The two most common deletions were tumor-suppressor genes RB1 and ERBB4 in ChRCC but not RO. Fluorescence in situ hybridization was performed on 65 cases (ChRCC, n = 33; RO, n = 32) to verify hemizygous deletion of RB1 (17/33, 52%) or ERBB4 (11/33, 33%) in ChRCC, but not in RO (0/32, 0%). In total, ChRCCs (23/33, 70%) carry either a hemizygous deletion of RB1 or ERBB4. The combined use of RB1 and ERBB4 fluorescence in situ hybridization to detect deletion of these genes may offer a highly sensitive and specific assay to distinguish ChRCC from RO. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Review of succinate dehydrogenase-deficient renal cell carcinoma with focus on clinical and pathobiological aspects

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Naoto Kuroda

2016-05-01

Full Text Available Succinate dehydrogenase (SDH-deficient renal cell carcinoma (RCC was first identified in 2004 and has been integrated into the 2016 WHO classification of RCC. Succinate dehydrogenase (SDH is an enzyme complex composed of four protein subunits (SDHA, SDHB, SDHC and SDHD. The tumor which presents this enzyme mutation accounts for 0.05 to 0.2% of all renal carcinomas. Multiple tumors may occur in approximately 30% of affected patients. SDHB-deficient RCC is the most frequent, and the tumor histologically consists of cuboidal cells with eosinophilic cytoplasm, vacuolization, flocculent intracytoplasmic inclusion and indistinct cell borders. Ultrastructurally, the tumor contains abundant mitochondria. Immunohistochemically, tumor cells are positive for SDHA, but negative for SDHB in SDHB-, SDHC- and SDHD-deficient RCCs. However, SDHA-deficient RCC shows negativity for both SDHA and SDHB. In molecular genetic analyses, a germline mutation in the SDHB , SDHC or SDHD gene (in keeping with most patients having germline mutations in an SDH gene has been identified in patients with or without a family history of renal tumors, paraganglioma/pheochromocytoma or gastrointestinal stromal tumor. While most tumors are low grade, some tumors may behave in an aggressive fashion, particularly if they are high nuclear grade, and have coagulative necrosis or sarcomatoid differentiation.

Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.

Directory of Open Access Journals (Sweden)

Bray Denard

Full Text Available Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1, a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin.Mice transplanted with 6 lines of renal cell carcinoma (RCC were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin.Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis. From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC.Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.

Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.

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Song, Yimeng; Zhong, Lijun; Zhou, Juntuo; Lu, Min; Xing, Tianying; Ma, Lulin; Shen, Jing

2017-12-01

Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Renal Cell Carcinoma Metastatic to Thyroid Gland, Presenting Like Anaplastic Carcinoma of Thyroid

Directory of Open Access Journals (Sweden)

Khalid Riaz

2013-01-01

Full Text Available Background. Renal cell carcinoma (RCC has unpredictable and diverse behavior. The classic triad of hematuria, loin pain, and abdominal mass is uncommon. At time of diagnosis, 25%–30% of patients are found to have metastases. Bones, lungs, liver, and brain are the frequent sites of metastases. RCC with metastasis to the head and neck region and thyroid gland is the rarest manifestation and anaplastic carcinoma behaving metastatic thyroid mass is an extremely rare presentation of RCC. Case Presentation. A 56-year-old Saudi man with past history of right radical nephrectomy 5 years back presented with 3 months history of rapid increasing neck mass with dysphagia, presenting like anaplastic thyroid carcinoma. Tru-cut biopsy turned out to be metastatic renal cell carcinoma. Patient was treated with radiation therapy 30 Gy in 10 fractions to mass. Patient died 4 months after the discovery of anaplastic thyroid looking metastasis. Conclusion. Rapidly progressing thyroid metastases secondary to RCC are rare and found often unresectable which are not amenable to surgery. Palliative radiotherapy can be considered for such patients.

Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor.

LENUS (Irish Health Repository)

Ambrose, Monica

2012-02-03

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1\\/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH(2)-terminal kinase or p38alpha and -beta mitogen-activated protein kinase activation. In contradiction, reintroduction of p38delta by stable transfection or overexpression of p38gamma dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x(L) and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl l-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1\\/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.

Late simultaneous metastasis of renal cell carcinoma to the submandibular and thyroid glands seven years after radical nephrectomy.

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Miah, Mohammed S; White, Sharon J; Oommen, George; Birney, Esther; Majumdar, Samit

2010-01-01

Background. Renal cell carcinoma (RCC) metastasis to the salivary glands is extremely rare. Most cases reported previously have involved the parotid gland and only six cases involving the submandibular gland exist in the current literature. Metastasis of RCC to thyroid gland is also rare but appears to be more common than to salivary glands. Methods and Results. We present the first case of simultaneous metastasis to the submandibular and thyroid glands from clear cell RCC in a 61-year-old woman who presented seven years after the primary treatment. The submandibular and thyroid glands were excised completely with preservation of the marginal mandibular and recurrent laryngeal nerves, respectively. Conclusion. Metastatic disease should always be considered in the differential diagnosis for patients who present with painless salivary or thyroid gland swelling with a previous history of RCC. If metastatic disease is confined only to these glands, prompt surgical excision can be curative.

Renal cell carcinoma primary cultures maintain genomic and phenotypic profile of parental tumor tissues.

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Cifola, Ingrid; Bianchi, Cristina; Mangano, Eleonora; Bombelli, Silvia; Frascati, Fabio; Fasoli, Ester; Ferrero, Stefano; Di Stefano, Vitalba; Zipeto, Maria A; Magni, Fulvio; Signorini, Stefano; Battaglia, Cristina; Perego, Roberto A

2011-06-13

Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.

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Zhang, Liang; Wang, Xiaoen; Bullock, Andrea J; Callea, Marcella; Shah, Harleen; Song, Jiaxi; Moreno, Kelli; Visentin, Barbara; Deutschman, Douglas; Alsop, David C; Atkins, Michael B; Mier, James W; Signoretti, Sabina; Bhasin, Manoj; Sabbadini, Roger A; Bhatt, Rupal S

2015-04-15

VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC. In this study, we performed transcriptome analysis of VEGFR TKI-resistant tumors in a murine model and discovered that the SPHK-S1P pathway is upregulated at the time of resistance. We tested sphingosine-1-phosphate (S1P) pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Resistant tumors expressed several hypoxia-regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC, suggesting that human RCC behavior could, in part, be due to overproduction of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy. ©2015 American Association for Cancer Research.

Management of metastatic renal cell carcinoma in patients with poor prognosis

International Nuclear Information System (INIS)

Bullock, Andrea; McDermott, David F; Atkins, Michael B

2010-01-01

An improved understanding of renal cell carcinoma (RCC) biology has translated into major advances in the treatment of patients with metastatic RCC in recent years. Clinical and pathologic criteria can be used to identify RCC patients with poor prognoses. Such patients, however, are often excluded from the cancer clinical trials that guide treatment recommendations. This article reviews available information on the management of patients with metastatic RCC and poor risk features, focusing on the role of vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR) inhibitors. While patients with poor risk features have a more guarded outcome, treatment with temsirolimus has produced meaningful improvements in overall survival for this population. Definitive phase III trial data are lacking for the VEGF pathway inhibitors in patients with poor prognostic features. However, available data suggest that such patients tolerate VEGF pathway blockade reasonably well and are likely to achieve some benefit relative to treatment with interferon. Ongoing translational research efforts may help to define novel treatment approaches specific for patients with metastatic RCC and poor prognostic features