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Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression.

The growth inhibitory efficacy of methylseleninic acid (MSA) in prostate cancer cells has been documented extensively. However, our understanding of the immediate targets that are key to the growth inhibitory effects of MSA remains limited. Here, using multiple preclinical prostate cancer models, we demonstrated in vitro and in vivo that GDF15 is a most highly induced, immediate target of MSA. We further showed that knockdown of GDF15 mitigates MSA inhibition of cell proliferation and induction of apoptosis. Analysis of gene expression data from over 1000 primary and 200 metastatic prostate cancer samples revealed that GDF15 expression is decreased in metastatic prostate cancers compared to primary tumors and that lower GDF15 levels in primary tumors are associated with higher Gleason scores and shorter survival of the patients. Additionally, pathways that are negatively correlated with GDF15 levels in clinical samples are also negatively correlated with MSA treatment in cultured cells. Since most, if not all, of these pathways have been implicated in prostate cancer progression, suppressing their activities by inducing GDF15 is consistent with the anticancer effects of MSA in prostate cancer. Overall, this study provides support for GDF15 as an immediate target of MSA in prostate cancer cells., Competing Interests: The authors have declared that no competing interests exist.

Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene-expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequently occurring autosomal diseases inherited in the dominant manner. Due to this, lesions in the cardiovascular system of ADPKD patients have caught the attention of clinical investigators worldwide. The aim of the study was to analyse cardiovascular complications in ADPKD patients with a focus on left ventricular hypertrophy (LVH) and selected components of its systolic/diastolic function based on echocardiography. The study was conducted on 55 patients with ADPKD (24 males, 31 females), subdivided into three groups according to the stage of chronic kidney disease (CKD). The patient group with ADPKD and ESRD (group C) manifested an increased incidence of the D allele as compared to group A and group B (χ(2) = 4.217, P = 0.04). In all ADPKD patients with the DD genotype, left ventricular mass (LVM), posterior wall thickness (PWT), and interventricular septal thickness (IVS) were significantly higher compared to patients possessing the II and ID genotypes (P < 0.02, P < 0.003, and P < 0.009, resp.). The DD genotype exists more frequently in ADPKD patients with ESRD and is associated with a higher occurrence of LVH and disturbances in systolic-diastolic function when compared to ADPKD ESRD patients with the II and ID genotypes.

Introduction: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor treatment., Objectives: The aim of the study was to evaluate the frequency of BCR-ABL gene mutations in patients with CML (the MAPTEST study) treated with imatinib (IM)., Patients and Methods: Direct sequencing analysis of BCR-ABL gene was performed in 92 patients treated with IM for more than 3 months. The mean time of IM treatment was 18 months. At the time of the analysis, 75 patients were in the first chronic phase (CP), 4 in the second CP, 5 in the acceleration and 8 in the blastic phase. Fifty-seven patients (62%) were treated with IM at a daily dose of 400 mg and 35 patients with higher doses (600 or 800 mg daily). Inclusion criteria were based on the European Leukemia Net definitions for failure and suboptimal response to IM., Results: Twelve mutations were detected in 11 of 92 patients, including 4 mutations (36.7%) diagnosed during CP, 3 (27.3%) in acceleration, and 4 (36.7%) in blast crisis. In 1 patient with lymphoid blast crisis of CML coexisting F359V and Y253F mutations were detected. In the whole group mutations were detected in 2 of 5 patients (40%) with primary resistance (M351T, F359V + Y253F) and in 9 of 87 patients (10.3%) (E255K, T315I-3x, M351T, E355G, F359V-2x) with acquired resistance to IM., Conclusions: The study confirmed the usefulness of BCR-ABL gene mutation screening in patients with CML resistant to IM therapy.

Objectives: The aim of this study was to analyze the influence of combined therapy with L-carnitine and erythropoietin on selected blood morphology parameters in patients treated with hemodialysis and to assess whether combined therapy could decrease the requirement for exogenous erythropoietin., Patients and Methods: The results of anemia treatment were compared in three groups of patients: 27 patients treated with L-carnitine and erythropoietin, 15 patients treated with erythropoietin and 9 patients treated only with L-carnitine. The patients were treated for 6 months. L-carnitine was given orally at a dose of 4 x 250 mg daily. Erythropoietin was administered intravenously after each hemodialysis session and the mean dose of erythropoietin at the beginning of observation was 5642 +/- 2134 units/week. Before treatment serum concentrations of free and total carnitine, parathormone (PTH), aluminium, lead were determined and basic laboratory examinations were performed. The blood morphology was evaluated once a month., Results: Combined therapy resulted in the improvement of blood morphology parameters (hemoglobin [Hb] before treatment 9.9 +/-1.4 g/dl, during treatment 10.7 +/- 1.6 g/dl), compared to treatment with erythropoietin (Hb before treatment 9.5 +/- 1.2 g/dl, during treatment 9.9 +/- 1.4 g/dl) or L-carnitine alone (Hb before treatment 11.3 +/- 1.0 g/dl, during treatment 12.0 +/- 1.1 g/dl). Combined therapy was associated with the reduction of erythropoietin dosage during treatment from 6287 +/- 1987 units/week to 2286 +/- 1684 units/week. The correlation between serum carnitine concentration and erythrocyte osmotic resistance indicates indirectly the beneficial effect of L-carnitine administration on erythrocyte cell membrane stabilization.

Patients with chronic kidney disease (CKD) often suffer from anemia due to erythropoietin deficiency. Anemia treatment with erythropoietin in patients with chronic kidney disease can effectively maintain hemoglobin target level > 11g/dl. In this study we presented the results of anemia treatment with darbepoietin alfa in 18 patients with chronic kidney disease (3-5 stage of CKD) in predialysis period. After 10 weeks of darbepoietin alfa administration at the dose 10 microg/week, hemoglobin serum level had increased over 11 g/dl in 15 patients. In the 3 patients serum hemoglobin level during the darbepoietin alfa treatment did not increased. Between 15 patients, in 4 after 10 weeks of darbepoietin alfa treatment at the dose 10 microg/week and in 7 after 15 weeks of the treatment at the dose 15 microg/2 weeks hemoglobin serum level had increased over 13 g/dl. After 2 months with out darbepoietin alfa treatment hemoglobin serum level had decreased but still maintain the target level 11 g/dl. darbepoietin alfa was well tolerated. The results of this study demonstrate that darbepoietin alfa administered s.c. once weekly or once other week at a small doses is effective in renal anemia treatment and comfortable for a patients.

Pregnancy is a rare finding in females with CRF. It is well known that in these cases pregnancy worsens the renal function and accelerates the beginning of dialysis therapy. Pregnancies in uremic females are complicated by a worsening of anemia as well as hypertension, fluid imbalance, electrolyte difficulties, malnutrition, polyhydramnios and preterm labor or sudden intrauterine death. The use of erythropoiesis stimulating agents (ESA) allows a better hematocrit control. Data concerning anemia treatment in pregnants with CRF and data regarding the use of ESA in these patients is scarce. We report two cases of anemia treatment with darbepoetin alpha in pregnant women with CRF in predialysis period and during the hemodialysis therapy. Both patients during the darbepoetin treatment did not require any blood transfusions and at 32nd and 37th weeks of pregnancy delivered healthy infants. The high darbepoetin doses did not cause any side effects, were well tolerated and safe for both gravida and fetus. The effective anemia treatment in pregnants with CRF improves the prognosis for a successful pregnancy.

In this study we report three patients, in whom arterial hypertension was induced by compression of the kidney parenchyma due to perirenal or subcapsular hematoma following percutaneous blind renal biopsy with use of Vim-Silverman type needle.

Unlabelled: Elevated serum concentration of cardiac troponin I (cTnl) is a highly sensitive and specific marker of myocardial damage. Patients with chronic renal failure (crf) treated by hemodialysis often have increased serum cTnl level without evidence of acute myocardial ischemia. In chronic HD patients, elevated serum concentration of endothelin-1 (ET-1) and angiotensin II have been reported which may be associated with ischemic heart disease. The aim of the present study was to investigate possible association between cTnl serum level, ET-I, angiotensin II, other cardiac markers and the structural changes of myocardium assessed by echocardiographic (ECHO) method. Fifty nine patients with crf treated by HD were studied. ECHO and ECG examinations were performed in all patients and serum levels of cTnl, endothelin-1 (ET-1), angiotensin II were evaluated. In all patients left ventricular mass (LVM) was increased, and in 78% of patients was found concentric hypertrophy of the heart while in 22% excentric hypertrophy was found. In 54 patients there was no ECG changes and ST segment depression in V4-V6 leads, less than 1 mm was found in 5 patients. Arterial hypertension was found in 44 patients (75%), systolic and diastolic pressure was significantly higher (p<0.05) than in a control group. Increased serum level of cTnl was found in 12.0% of HD patients, increased serum level of endothelin-1 and angiotensin II were found in all patients. LVM in HD patients with elevated cTnl levels was significantly higher than in patients with normal cTnl concentration. There was a positive correlation between LVM and cTnl levels, and between angiotensin II serum concentration and cTnl levels and between ET-1 serum level and RWT., In Conclusion: our findings suggest that elevated cTnl serum level reflect left ventricular hypertrophy and/or myocardial ischemia in HD patients, and indicate that ET-1 and angiotensin II might be associated with these conditions.

A case of 45-year-old patient with chronic renal failure treated by hemodialysis associated with skin changes typical for porphyria cutanea tarda is reported. The diagnosis was based on clinical manifestations and on histopathologic examination of the skin segment. The skin was low sensitive for UVA rays, serum levels of aluminium and lead were significantly elevated. We did not find porphyrins in the urine (24-hour collection 100 ml) as well as in the dialysis fluid.

Left ventricular hypertrophy (LVH) is common and important predictor of risk of death in end-stage renal failure. In the present study we have analysed the relationship between 24-h ambulatory blood pressure (BP) profile and LVH. The effect of parathyroid hormone (PTH) on was also assessed. From a cohort of 85 patients with crf we selected for analysis 59 stable patients. Ambulatory BP 24-h monitoring, echocardiography (ECHO), body mass index (BMI), serum creatinine, hemoglobin, total protein, albumin, electrolytes and PTH concentrations were assessed in all patients. Concentric LVH was detected by ECHO in 46 patients, in 13 patients excentric LVH was observed. Mean 24-h ambulatory sBP, dBP, mean 24-h ambulatory day sBP, dBP as well as night sBP and dBP were significantly higher than in a control group 60 healthy subjects. It was a correlation between mean 24-h ambulatory sBP and left ventricular mas (LVM) r = 0.606 (p < 0.0001), between mean dBP and (LVM) r = 0.498 (p < 0.001), between mean day sBP and (LVM) r = 0.591 (p < 0.0001), between mean day dBP and (LVM) r = 0.479 (p < 0.001), between mean night dBP and (LVM) r = 0.548 (p < 0.0001), between left ventricular mass index (LVMI) and mean sBP r = 0.428 (p < 0.05), between LVMI and mean day sBP r = 0.442 (p < 0.05). The loss in physiological night-time BP was observed in all patients. It was also correlations between PTH and (LVM) r = 0.704 (p < 0.001), and between BMI and LVMI r = -0.451 (p < 0.05). LVH is common in crf patients. These results confirmed that strong correlations between BP values and LVH and between serum PTH concentrations and LVH indicate that both hypertension and hyperparathyroidism play an important role in the LVH development.