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1.  Identification of novel long non-coding RNAs in clear cell renal cell carcinoma 
Clinical Epigenetics  2015;7(1):10.
Background
Long non-coding RNAs (lncRNA) play an important role in carcinogenesis; knowledge on lncRNA expression in renal cell carcinoma is rudimental. As a basis for biomarker development, we aimed to explore the lncRNA expression profile in clear cell renal cell carcinoma (ccRCC) tissue.
Results
Microarray experiments were performed to determine the expression of 32,183 lncRNA transcripts belonging to 17,512 lncRNAs in 15 corresponding normal and malignant renal tissues. Validation was performed using quantitative real-time PCR in 55 ccRCC and 52 normal renal specimens. Computational analysis was performed to determine lncRNA-microRNA (MiRTarget2) and lncRNA-protein (catRAPID omics) interactions. We identified 1,308 dysregulated transcripts (expression change >2-fold; upregulated: 568, downregulated: 740) in ccRCC tissue. Among these, aberrant expression was validated using PCR: lnc-BMP2-2 (mean expression change: 37-fold), lnc-CPN2-1 (13-fold), lnc-FZD1-2 (9-fold), lnc-ITPR2-3 (15-fold), lnc-SLC30A4-1 (15-fold), and lnc-SPAM1-6 (10-fold) were highly overexpressed in ccRCC, whereas lnc-ACACA-1 (135-fold), lnc-FOXG1-2 (19-fold), lnc-LCP2-2 (2-fold), lnc-RP3-368B9 (19-fold), and lnc-TTC34-3 (314-fold) were downregulated. There was no correlation between lncRNA expression with clinical-pathological parameters. Computational analyses revealed that these lncRNAs are involved in RNA-protein networks related to splicing, binding, transport, localization, and processing of RNA. Small interfering RNA (siRNA)-mediated knockdown of lnc-BMP2-2 and lnc-CPN2-1 did not influence cell proliferation.
Conclusions
We identified many novel lncRNA transcripts dysregulated in ccRCC which may be useful for novel diagnostic biomarkers.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0047-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-015-0047-7
PMCID: PMC4326488
2.  Analysis of Tissue and Serum MicroRNA Expression in Patients with Upper Urinary Tract Urothelial Cancer 
PLoS ONE  2015;10(1):e0117284.
Introduction
MicroRNAs play an important role in many human malignancies; so far, their expression remains to be studied in upper urinary tract urothelial cancer (UUTUC).
Materials and Methods
The expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) formerly shown to be upregulated in urothelial bladder cancer were studied in corresponding normal and cancerous tissue samples of patients undergoing nephroureterectomy for UUTUC. Upregulated microRNAs were then measured in serum samples of patients with UUTUC and patients with non-malignant urological diseases to evaluate their potential as non-invasive biomarkers for UUTUC.
Results
MicroRNA expression allowed differentiation of normal and cancerous tissue: miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were significantly overexpressed. Furthermore, miR-205 was upregulated in poorly differentiated UUTUC. The analysis of circulating RNA in serum demonstrated an increase of miR-141 in patients with UUTUC; receiver operator characteristic analysis demonstrated an area under the curve of 0.726 for miR-141 as a diagnostic biomarker. Furthermore, we observed lower levels of miR-10a and miR-135 in UUTUC patients.
Conclusions
MicroRNA expression is altered in UUTUC. The analysis of circulating miR-141 may be useful to identify patients with UUTUC.
doi:10.1371/journal.pone.0117284
PMCID: PMC4309610  PMID: 25629698
3.  Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer 
Prostaglandins, especially prostaglandin E2 (PGE2), and COX-2 play an important role in carcinogenesis of many tumors including bladder cancer (BCA). The PGE2 receptors EP1-4 regulate tumor cell growth, invasion and migration in different tumor entities but EP expression in BCA remains to be determined. In the present study we examined the expression of EP1-4 in non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and normal urothelial tissue (NU) using immunohistochemistry. Nuclear and cytoplasmic EP1-4 expression was correlated with clinicopathological parameters and survival of BCA patients. EP1, EP2 and EP3 were significantly less expressed in the cytoplasm und nucleus of NMIBC and MIBC than in NU; EP4 cytoplasmic staining in MIBC was significantly higher compared to NU. The cytoplasmic staining was significantly more abundant in MIBC than in NMIBC in all investigated receptors except EP2. The level of EP staining in NMIBC was correlated with staging and grading, especially cytoplasmic EP1. Nuclear staining of EP1 was an independent predictor of BCA recurrence-free survival in NMIBC patients. EP receptors are dysregulated in BCA. The increase of EP1 may be used as prognostic parameter in NMIBC patients and its dysregulation could be targeted by specific EP1 inhibitors.
PMCID: PMC4266727  PMID: 25520883
Bladder cancer; EP1; EP2; EP3; EP4; prostaglandin receptors; immunohistochemistry
4.  Continent ileovesicostomy after bladder neck closure as salvage procedure for intractable incontinence 
Introduction
We evaluated the success rate of continent vesicostomy using an ileal segment with seroserosally embedded, tapered ileum for bladder augmentation with continent stoma following bladder neck closure (BNC) for severely damaged bladders or persistent urinary incontinence.
Material and methods
A total of 15 patients were treated for persistent urinary incontinence or non–reconstructible bladder outlet between 2003 and 2012. Underlying diagnosis included post–prostatectomy incontinence (n = 5), recurrent bladder neck stenosis (n = 5), neurogenic bladder (n = 3), urethral tumor recurrence following orthotopic neobladder (n = 1) and post–TVT and colposuspension incontinence (n = 1). All patients underwent open BNC, omental interposition and continent vesicoileostomy. The continent outlet was placed in the lower abdomen using a circumferential subcutaneous and skin plasty to avoid retraction. Data collected included age, underlying diagnosis, stoma site, time to complications and need for subsequent surgical revisions. All patients received a standardized questionnaire at the time of data acquisition and were personally interviewed.
Results
Median follow–up was 24 months (range: 2–111). Primary BNC was successful in all patients and primary continence rate was 86.7%. Two patients (13.3%) suffered from failure of the continence mechanism, caused by stoma stenosis at skin level and insufficiency of the bladder augmentation and stoma due to local infection. One additional patient developed a mild stomal incontinence without need for further reconstruction. Regardless of the number of revisions, at the last follow–up 93.3% of patients had a functional channel. All complications occurred within the first postoperative year.
Conclusions
This technique is an effective last resort treatment for patients with non–reconstructible bladder outlet.
doi:10.5173/ceju.2013.04.art25
PMCID: PMC3992445  PMID: 24757550
continent vesicostomy; tapered ileum; urinary diversion; catheterization; incontinence
5.  Identification of prostaglandin receptors in human ureters 
BMC Urology  2012;12:35.
Background
Prostaglandins play an important role in ureteral obstruction, but the detailed expression profiles of the prostaglandin receptors (PTGER1, PTGER2, PTGER3, PTGER4, PTGFR) remain unknown in the different parts of the human ureter.
Methods
The expression pattern of PTGER1, PTGER2, PTGER3, PTGER4 and PTGFR was determined in human distal, mid and proximal ureter and renal pelvis samples using immunohistochemistry (protein levels) and quantitative real-time PCR (mRNA).
Results
PTGER1 was highly expressed in most samples irrespective of the ureteral localization; however, urothelial cells had higher levels of PTGER1 than smooth muscle cells. PTGFR was also moderately to strongly expressed in urothelial and smooth muscle cells. In comparison, PTGER2-4 expression was mostly unexpressed or weakly expressed in urothelial and smooth cells in all regions.
Conclusions
Our data indicate high levels of PTGER1 in ureters.
doi:10.1186/1471-2490-12-35
PMCID: PMC3576244  PMID: 23227994
Prostaglandin receptor; PTGER1; EP1; Ureter; Cyclooxygenase
6.  Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma 
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.
doi:10.1155/2012/473245
PMCID: PMC3501961  PMID: 23193418
7.  Alterations of global histone H4K20 methylation during prostate carcinogenesis 
BMC Urology  2012;12:5.
Background
Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis.
Methods
Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels.
Results
Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy.
Conclusions
H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.
doi:10.1186/1471-2490-12-5
PMCID: PMC3323457  PMID: 22413846
Histone; Methylation; H4K20; Prostate cancer; Epigenetics
8.  MicroRNAs in Renal Cell Carcinoma: Diagnostic Implications of Serum miR-1233 Levels 
PLoS ONE  2011;6(9):e25787.
Background
MicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC).
Methodology/Principal Findings
We first explored microRNA expression profiles in tissue and serum using TaqMan Low Density Arrays in each six malignant and benign samples: Although 109 microRNAs were circulating at higher levels in cancer patients' serum, we identified only 36 microRNAs with up-regulation in RCC tissue and serum of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients: miR-7-1*, miR-93, miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum of healthy controls (n = 30) and RCC (n = 33) patients were determined using quantitative real-time PCR (TaqMan MicroRNA Assays). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of 84 RCC patients and 93 healthy controls using quantitative real-time PCR (sensitivity 77.4%, specificity 37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters.
Conclusions/Significance
MicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a tumor-specific origin. We identify circulating miR-1233 as a potential biomarker for RCC patients. Larger-scaled studies are warranted to fully explore the role of circulating microRNAs in RCC.
doi:10.1371/journal.pone.0025787
PMCID: PMC3184173  PMID: 21984948
9.  Phase I trial of metastatic renal cell carcinoma with oral capecitabine and thalidomide 
Background: The highly vascular nature of renal carcinoma cells suggests that inhibition of angiogenesis may be beneficial in this disease. Thalidomide has been described as inhibitor of the fibroblast growth factor (FGF) and the vascular endothelial growth factor (VEGF). Therefore and in consideration of the promising response rates of the combination of IL-2, IFN-alpha and 5-FU [1] in metastatic renal cancer, we found it reasonable to test the combination of 5-FU and thalidomide. Thus, we conducted a phase I trial to determine safety, side effects and responses to such a treatment.
Methods: Patients with metastasized renal cell cancer after nephrectomy and progress after IL-2 and interferon treatment, received oral 5-FU at a dose of 1250 mg/qm2 twice a day for two weeks, then after pausing a week, the oral application was restarted. In addition, oral thalidomide was applied constantly at a maximum dose of 400 mg/d. The combined therapy was given for three months. The primary endpoint was duration until disease progression, the secondary endpoint the response to treatment. Response was determined by CT scans three months after the end of treatment.
Results: In total, 12 male patients participated in the trial and received the combined oral therapy. Concerning clinical response, one mixed response (8%), a stable disease in 4/12 patients (33%) and progression was seen in 7 patients (58%). The survival from the start of the therapy showed a median of 21 months with three patients being alive. At present, the longest survival after the therapy is 51 months.
Conclusions: The combination of oral 5-FU and thalidomide showed clinical response with tolerable side effects. Further studies will be required to assess the outcome of this treatment regimen.
doi:10.3205/000063
PMCID: PMC2716555  PMID: 19675744
metastasized renal cell carcinoma; 5-FU; thalidomide; phase I trial
10.  Reconstruction of cellular variability from spatiotemporal patterns of Dictyostelium discoideum 
Variability in cell properties can be an important driving mechanism behind spatiotemporal patterns in biological systems, as the degree of cell-to-cell differences determines the capacity of cells to locally synchronize and, consequently, form patterns on a larger spatial scale. In principle, certain features of spatial patterns emerging with time may be regulated by variability or, more specifically, by certain constellations of cell-to-cell differences. Similarly, measuring variability in a system (i.e. the spatial distribution of cell-cell differences) may help predict properties of later-stage patterns.
Here we apply and compare different statistical methods of extracting such systematic cell-to-cell differences in the case of patterns generated with a simple model system of an excitable medium and of experimental data by the slime mold Dictyostelium discoideum. We demonstrate with the help of a correlation analysis that these methods produce systematic (i.e. stationary) results for cell properties. Furthermore, we discuss possible applications of our method, in particular how these cell properties may serve as predictors of certain later-stage patterns.
doi:10.1186/1753-4631-1-10
PMCID: PMC2034575  PMID: 17908287

Results 1-10 (10)