The effect of pelvic floor muscle training in men with benign prostatic hyperplasia and overactive bladder.

BACKGROUND: Men with overactive bladder (OAB) and benign prostatic hyperplasia (BPH), will have deterioration in the quality of life. OBJECTIVE: The aim of this study was to evaluate the effect of combining pelvic floor muscle training with the urgency suppression technique (PFMT-st) and silodosin in comparison with silodosin in men with benign prostatic hyperplasia (BPH) and overactive bladder (OAB) after 12 weeks of treatment. PATIENTS AND METHODS: A total of 158 patients were randomized into two groups. The control group received oral silodosin at a daily dose of 8 mg. The experimental group was administered PFMT-st and silodosin. The evaluation methods included the number of voids and intensity of urgencies over 24 h using a micturition diary, the International Prostate Symptom Score (IPSS), the Overactive Bladder Questionnaire (OAB-q), and the patient global impression of improvement (PGI-I). RESULTS: 142 of 172 (86.6%) men were assessed (70 in the control group, 72 in the experimental group). The significant changes were in favor of the experimental group (p < 0.001) in the number of voids per 24 h (- 1.95 ± 1.94 vs. - 0.90 ± 1.44), the OAB-q symptom score (- 14.25 ± 10.05 vs. - 9.28 ± 10.60), the intensity of urgencies (- 0.97 ± 0.53 vs. 0.24 ± 0.57), the IPSS (- 4.59 ± 3.00 vs. - 2.30 ± 3.63), and in the PGI-I (2.24 ± 0.79 vs. 3.60 ± 0.92). CONCLUSIONS: The addition of PFMT-st to silodosin treatment significantly improved OAB in men with BPH. This is the first study to confirm that PFMT-st should be the first-choice treatment for OAB in BPH.

Innervation density and types of nerves in prostate cancer.

Innervation of cancerous tissue represents an important pathway enabling the nervous system to influence the processes associated with the initiation, progression, and metastasis of a neoplastic process. In the context of prostate cancer, several papers report the presence of innervation and its modulating effect on the cancer prognosis. However, most of the data are experimental, with limited information on human prostate cancer innervation. Morphometric analysis of archival prostate specimen immunohistochemistry with neural markers PGP9.5 and S100 showed a significant decrease of nerve density in the prostate cancer (n=44) compared to the normal prostate tissue (n=18) and benign prostatic hyperplasia (n=28). Sympathetic nerves were detected with TH, parasympathetic with VAChT, and sensory nerves with SP and CGRP protein detection. Dual immunofluorescence revealed numerous sympathetic nerves in normal prostate and benign prostatic hyperplasia, especially in the peripheral parts. Only a few parasympathetic nerves were found between the glands and in the peripheral parts of the prostate and benign hyperplasia. Sporadic positivity for sensory innervation was present only in approximately 1/10 of nerve fibers, especially in the larger nerves. The pattern of innervation in prostate cancer was analogous to that in normal prostate gland and benign prostatic hyperplasia but there was a significantly lower amount of all nerve types, especially in high-grade carcinoma cases. Although not significant, there was a tendency of decreasing innervation density with increasing Gleason score. Regarding the low density of nerves in prostate carcinoma, the significantly lower PCNA counts in nerves of the cancer specimens cannot be ascribed to lower proliferation activity. Our data confirmed the lower nerve density in the prostate cancer compared to the benign prostate tissue. We could not approve an increased nerve proliferation activity in prostate cancer. All nerve types, most the sympathetic, less the parasympathetic, and the sensory nerves, are present in prostate cancer. The highest nerve density at the periphery of the cancer tissue implies this to be the result of an expansive tumor growth. It is evident that the results of experimental prostate cancer models can be applied to human pathology only to a certain extent. The relation between the range of innervation and the biology of prostate cancer is very complex and will require more detailed information to be applied in therapeutic solutions.

Early recurrence of focal segmental glomerulosclerosis as an unusual cause of primary kidney transplant malfunction.

Recurrence of the primary disease is one of the most common causes of graft failure in the first decade after kidney transplantation. We present a case of a patient with an unusually rapid recurrence of focal segmental glomerulonephritis in the graft, the recognition of its occurrence was hampered by the primary graft affection and oligoanuria and by insignificant histological changes in the first two biopsy samples in the early post-transplant period, as well as by unawareness of the disease leading to terminal renal failure, as no renal biopsy was performed due to grade 3 obesity. Only worsening of hypoalbuminemia and finding of massive proteinuria despite oligoanuria were crucial for further management. Disease recurrence in the graft was confirmed by electron microscopy. However, complex targeted therapy did not result in restoration of graft function and decrease in proteinuria. This case history was aimed to draw attention to the knowledge of the importance of the primary disease confirmed by renal biopsy and early (so called pre-emptive) treatment in case of diseases with a high potential of recurrence (Fig. 7, Ref. 10). Text in PDF www.elis.sk Keywords: kidney transplantation, recurrence, minimal changes in glomeruli, focal segmental glomerulosclerosis.

Overview of urological complications before, during and after kidney transplantation.

The result of a kidney transplantation may be affected by certain congenital or acquired urological diseases that need to be addressed before, during or after the kidney transplant. Complications accompanying kidney transplantation are not fundamentally different from the events that accompany other difficult surgical procedures. However, their course is usually modified by adverse circumstances in the recipient - uremia, dialysis treatment, immunosuppression. The incidence of urological complications is reported in the range of 1 to 30 % of the transplants, and they represent up to one half of all surgical complications. They can cause a significant morbidity and mortality and can lead to a delayed onset of the function and even to a loss of the transplanted kidney.Urological complications that need to be addressed before kidney transplantation include anomalies or pathological changes in the lower urinary tract, pelvic involvement in atherosclerosis or previous kidney transplants, infectious foci in lithiasis or pyonephrosis, large polycystic kidneys and malignancies. During the kidney transplantation itself, vascular complications, and complications connected with the reconstruction of the lower urinary tract can occur. Other complications are bacterial and viral infections and malignancies. All these complications require a rapid and accurate diagnosis and subsequent targeted treatment with intention to maintain a functional kidney transplant (Fig. 11, Ref. 36). Text in PDF www.elis.sk Keywords: kidney transplantation, urological, vascular, infectious, bleeding, complications.

Improvement in cardiovascular risk markers by the combined effect of natural polyphenols and vitamins in patients after kidney transplantation.

OBJECTIVES: The aim of this study was to evaluate the potential of supportive therapy by natural polyphenols combined with vitamins C and E on kidney function and risk factors of cardiovascular diseases in renal transplant recipients (RTR). BACKGROUND: Transplant patients have an altered lipid profile associated with the development of cardiovascular disease, which is a major cause of graft loss and mortality in patients. METHODS: The study included 29 renal transplant recipients with mean graft function levels. The lipoprotein (atherogenic and non-atherogenic) subfractions were identified and quantified in plasma by polyacrylamide gel electrophoresis. RESULTS: After supplementation, glomerular filtration rate (GFR) was increased by 8 %, serum creatinine was decreased by 6.7 % and significant changes were found in atherogenic LDL subfractions. The effect of supplementation was observed in arylesterase and lactonase activities of paraoxonase 1 which increased by 9.3 % and 8.1 %, respectively. In addition, significantly decreased levels of neopterin (by 16 %) and asymmetric dimethylarginine (ADMA) (by 7.9 %) were found. CONCLUSION: We could summarize that supportive therapy improves the renal function (GFR, serum creatinine), and reduces the risk of cardiovascular disease by affecting important risk markers of atherosclerosis (lipid profile, paraoxonase 1 activity, neopterin and ADMA) in RTR (Tab. 4, Fig. 1, Ref. 53).

Arterial Hypertension and Plasma Glucose Modulate the Vasoactive Effects of Nitroso-Sulfide Coupled Signaling in Human Intrarenal Arteries.

We have investigated the vasoactive effects of the coupled nitro-sulfide signaling pathway in lobar arteries (LAs) isolated from the nephrectomized kidneys of cancer patients: normotensive patients (NT) and patients with arterial hypertension (AH). LAs of patients with AH revealed endothelial dysfunction, which was associated with an increased response to the exogenous NO donor, nitrosoglutathione (GSNO). The interaction of GSNO with the H2S donor triggered a specific vasoactive response. Unlike in normotensive patients, in patients with AH, the starting and returning of the vasorelaxation induced by the end-products of the H2S-GSNO interaction (S/GSNO) was significantly faster, however, without the potentiation of the maximum. Moreover, increasing glycemia shortened the time required to reach 50% of the maximum vasorelaxant response induced by S/GSNO products so modulating their final effect. Moreover, we found out that, unlike K+ channel activation, cGMP pathway and HNO as probable mediator could be involved in mechanisms of S/GSNO action. For the first time, we demonstrated the expression of genes coding H2S-producing enzymes in perivascular adipose tissue and we showed the localization of these enzymes in LAs of normotensive patients and in patients with AH. Our study confirmed that the heterogeneity of specific nitroso-sulfide vasoactive signaling exists depending on the occurrence of hypertension associated with increased plasma glucose level. Endogenous H2S and the end-products of the H2S-GSNO interaction could represent prospective pharmacological targets to modulate the vasoactive properties of human intrarenal arteries.

Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells.

Although the involvement of type 1 (IP3R1) and type 2 (IP3R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP3R (IP3R3) is still elusive. Therefore, in this work we focused on the role of IP3R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP3R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP3R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells. These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.

Endogenous H2S producing enzymes are involved in apoptosis induction in clear cell renal cell carcinoma.

BACKGROUND: Knowledge about the expression and thus a role of enzymes that produce endogenous H2S - cystathionine-ß-synthase, cystathionine γ-lyase and mercaptopyruvate sulfurtransferase - in renal tumors is still controversial. In this study we aimed to determine the expression of these enzymes relatively to the expression in unaffected part of kidney from the same patient and to found relation of these changes to apoptosis. To evaluate patient's samples, microarray and immunohistochemistry was used. METHODS: To determine the physiological importance, we used RCC4 stable cell line derived from clear cell renal cell carcinoma, where apoptosis induction by a mixture of five chemotherapeutics with/without silencing of H2S-producing enzymes was detected. Immunofluorescence was used to determine each enzyme in the cells. RESULTS: In clear cell renal cell carcinomas, expression of H2S-producing enzymes was mostly decreased compared to a part of kidney that was distal from the tumor. To evaluate a potential role of H2S-producing enzymes in the apoptosis induction, we used RCC4 stable cell line. We have found that silencing of cystathionine-ß-synthase and cystathionine γ-lyase prevented induction of apoptosis. Immunofluorescence staining clearly showed that these enzymes were upregulated during apoptosis in RCC4 cells. CONCLUSION: Based on these results we concluded that in clear cell renal cell carcinoma, reduced expression of the H2S-producing enzymes, mainly cystathionine γ-lyase, might contribute to a resistance to the induction of apoptosis. Increased production of the endogenous H2S, or donation from the external sources might be of a therapeutic importance in these tumors.

Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results.

BACKGROUND: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03). OBJECTIVE: To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS). DESIGN, SETTING, AND PARTICIPANTS: Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade. RESULTS AND LIMITATIONS: Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively. CONCLUSIONS: A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy. PATIENT SUMMARY: Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib. TRIAL REGISTRATION: ClinicalTrials.gov NCT00375674.

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster.

Recently, activating mutations of the hypoxia-inducible factor 2α gene (HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas (PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic (cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors or abnormalities. In the present study, we aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudohypoxic PGLs. RNA expression patterns of HIF2A PGLs (n=6) from 2 patients were compared with normal adrenal medullas (n=8) and other hereditary pseudohypoxic PGLs (VHL: n=13, SDHB: n=15, and SDHD: n=14). Unsupervised hierarchical clustering showed that HIF2A PGLs made up a separate cluster from other pseudohypoxic PGLs. Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudohypoxic PGLs after normalization to adrenal medulla (false discovery rate 0.01). Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes (TRHDE, LRRC63, IGSF10; error rate: 0.02). Genes with the highest expression difference between normal medulla and HIF2A PGLs were selected for confirmatory quantitative reverse transcriptase polymerase chain reaction. In conclusion, HIF2A PGLs show a characteristic expression signature that separates them from non-HIF2A pseudohypoxic PGLs. Unexpectedly, the most significantly differentially expressed genes have not been previously described as HIF target genes.

Expression of HLA-G transcripts in graft biopsy samples of renal transplant recipients.

BACKGROUND: The HLA-G molecule has a high potential to modulate immune response towards the improvement of graft survival after transplantation. In this work, we have analyzed the total HLA-G mRNA expression in graft tissues of dysfunctional transplanted kidneys. MATERIAL AND METHODS: We examined 84 kidney biopsy samples obtained from 65 renal transplant recipients with dysfunctional graft (50 males, 15 females; average age 46.8 ± 11.9 years). 52 specimens were with signs of acute rejection and 32 without any rejection characteristics (diagnosed as glomerulonephritis, ATN and IFTA). Patients with acute rejection were divided into three groups: antibody-mediated rejection (AMR; n = 23), T cell mediated rejection (TCMR; n = 16) and combined antibody and T cell-mediated rejection (AMR + TCMR; n=13). The biopsy samples were taken from a dysfunctional graft at different time periods after kidney transplantation. The relative expression of total HLA-G mRNA in biopsy specimens was determined by real time RT-PCR. The correlation between HLA-G mRNA expression and dysfunctional graft state was investigated. The impact of different factors (post-transplantation interval, gender,mismatch, induction therapy and cold ischemia time) on relative expression of total HLA-G mRNA was also studied. RESULTS: We have found that the levels of HLA-G transcripts in kidneys with rejection were higher than those in non-rejected but dysfunctional grafts (P = 0.0003). The highest levels of HLA-G mRNA were detected at combined AMR + TCMR rejection (P= 0.005). The time-course analysis of total HLA-G mRNA expression was also studied. In both dysfunctional graft groups (rejected and non-rejected) the lower levels of HLA-G transcripts were detected during early post-transplant period (1­3 months), however a substantial increase of HLA-G mRNA expression was observed after an extended period of time(N3 months). It was also revealed that antibody induction therapy may reduce HLA-G expression (P=0.0004) and in female samples were higher levels of HLAG transcripts than those in male recipients (P=0.003). It was found no significant impact of age, cold ischemic time, PRA (Panel Reactive Antibody) score, and a number of HLA-mismatches on HLA-G mRNA expression. CONCLUSIONS: We have demonstrated that the expression of total HLA-GmRNA in renal grafts can be influenced by different factors such as clinical state of transplanted kidney, elapsed time after transplantation, gender and antibody induction therapy. We have proved that HLA-G mRNA expression was significantly higher in recipients with acute rejection in comparison to patients with dysfunctional but non-rejected grafts.

Deregulation of energetic metabolism in the clear cell renal cell carcinoma: A multiple pathway analysis based on microarray profiling.

Clear cell renal cell carcinoma (ccRCC) is the most frequent type of kidney cancer. In order to better understand the biology of ccRCC, we accomplished the gene profiling of fresh tissue specimens from 11 patients with the renal tumors (9 ccRCCs, 1 oncocytoma and 1 renal B-lymphoma), in which the tumor-related data were compared to the paired healthy kidney tissues from the same patients. All ccRCCs exhibited a considerably elevated transcription of the gene coding for carbonic anhydrase IX (CAIX). Moreover, the ccRCC tumors consistently displayed increased expression of genes encoding the glycolytic pathway enzymes, e.g. hexokinase II (HK2) and lactate dehydrogenase A (LDHA) and a decreased expression of genes for the mitochondrial electron transport chain components, indicating an overall reprogramming of the energetic metabolism in this tumor type. This appears to be accompanied by altered expression of the genes of the pH regulating machinery, including ion and lactate transporters. Immunohistochemical staining of tumor tissue sections confirmed the increased expression of CAIX, HK2 and LDHA in ccRCC, validating the microarray data and supporting their potential as the energetic metabolism-related biomarkers of the ccRCC.

Giant seborrheic keratoses on penis.

INTRODUCTION: Seborrheic keratoses are very common benign epidermal tumors. Despite the high frequency, the pathogenesis is still unknown. They are extremely rare in the genital area. The participation of human papilloma viruses (HPVs) in pathogenesis of seborrheic keratoses is being discussed. AIMS: The aims of this case report are to inform about extremely rare lesion in genital area in a young man and evaluate the association of HPVs in the development of seborrheic keratoses. METHODS: We used histopathological examination to establish the correct diagnosis, which revealed signs of seborrheic keratosis. The real-time polymerase chain reaction method confirmed low-risk HPV 6 from the lesions. MAIN OUTCOME MEASURES: HPVs may play a role in pathogenesis of seborrheic keratoses. RESULTS: The patient was successfully treated with shave excision under spinal anesthesia. Six-month follow-up was without any recurrence. We suggest that HPVs can be considered as etiologic factor in creation of seborrheic keratosis. CONCLUSIONS: Seborrheic keratoses are very common on sun-exposed skin, but they are rare in the genital area, such as on the shaft of penis. This localization may lead to misdiagnosis. Seborrheic keratoses in genital area might negatively influence the sexual life of the patient. Containing HPV 6 low-risk virus, they never lead to malignant transformation.

[Extraadrenal paraganglioma]. / Extraadrenálny paraganglióm.

Various symptoms may be present in pheochromocytoma and paraganglioma. The tumor can imitate numbers of diseases and often leads to misdiagnosis. Current advances in laboratory techniques (determination of free plasma metanephrines), tumor localization (using positron emission tomography) and surgery techniques together with better understanding of pathophysiology and genetics (role of subunit B of succinate dehydrogenase) lead to earlier diagnosis, changes in strategy and treatment options. Authors introduce case report of retroperitoneal paraganglioma in 59 years old patient. In conclusion, interdisciplinary cooperation in diagnosis and treatment was successful.

The effect of natural polyphenols on the oxidative stress markers in patients with diabetic nephropathy.

BACKGROUND: Nephropathy remains a significant cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure, hence kidney transplantations. As a result of the diabetic milieu, increased generation of reactive oxygen species is thought to play a key role in the progression of diabetic nephropathy. Aim of this study was to evaluate the effect of Pycnogenol (Pyc), the extract from Pinus pinaster, on the level of glucose, advanced glycation end products (AGE) and oxidative stress markers in patients with Diabetic nephropathy (DN). SUBJECT AND METHODS: To double blind randomised placebo controlled exploratory study were enrolled 20 men with DN received daily Pyc (120mg) or a placebo. Patients were investigated before, one and three months after Pyc administration and after termination of drugs supplementation. RESULTS: The level of glucose, AGEs, malondialdehyde (MDA), 8-isoprostanes (8-Iso), as well as protein carbonyls (PC) were increased in comparison to control group. We have found lower level of glucose, AGEs, MDA and 8-Iso after 3 months of Pyc administration in comparison to the beginning state and to placebo group, but these results did not reach significance. CP and TAS were not affected. CONCLUSION: Our data allow us to conclude that Pycnogenoladministration reduces oxidative damage to lipids rather through the decreased glucose level than through the influence of antioxidant capacity of plasma. This study was supported by grant Ministry of Health 2012/8-ukba-8.

The relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors.

BACKGROUND: Renal cell carcinoma (RCC) is a urologic malignancy with a steady rise in incidence and high mortality rate. Between 60 to 70% of patients with renal cell carcinoma can only be cured with surgery but despite advances in early diagnostis, in around 20-30% of cases there is metastasis. For these patients, chemotherapy and radiotherapy are ineffective and hence the prognosis is poor. Retinoids are biologically active compounds of either natural or synthetic origin that are involved in complex physiological and developmental processes in many tissues including cell proliferation and activation of tumour suppression genes. This article reviews the role of retinoids and their cognate nuclear retinoid/rexinoid receptors in relation to renal cell carcinoma. METHODS: A literature search using ScienceDirect and Medline with a focus on the relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors. RESULTS: Use of retinoids/rexinoids in the treatment of locally advanced and metastatic RCC significantly prolongs median time of tumour progression and overall survival of patients. Combination therapy with other preparations has greater efficacy than treatment with retinoids alone. Patient survival can be predicted on the basis of the expression of different all-trans retinoic acid receptor (RAR) and 9-cis retinoic acid receptor (RXR) subtypes. CONCLUSIONS: Since nuclear retinoid receptors play a crucial role as ligand-activated, DNA binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes, retinoids might be an alternative approach for the treatment of renal cell carcinoma.

Carbonic anhydrase IX is a clinically significant tissue and serum biomarker associated with renal cell carcinoma.

Carbonic anhydrase IX (CA IX) is regarded as one of the most prominent markers of tumor hypoxia with potential to serve as a diagnostic biomarker, prognostic indicator as well as tumor therapeutic target. The aim of the present study was to perform an in-depth analysis of CA IX expression in blood and tissue samples and to evaluate the significance of CA IX status for different renal cell carcinomas (RCCs). The expression of CA IX was determined in blood and tissue samples from 74 kidney cancer patients using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), Western blotting (WB) and immunohistochemistry (IHC). The CA IX status was correlated with RCC type and tumor stage. IHC and WB provided evidence for a significantly higher expression of CA IX in clear cell RCC (CCRCC) specimens compared to other RCCs. RT-PCR assay revealed that 32.42% of all RCC patients possess CA9-positive cells in peripheral blood and three-quarters of CA9-positive patients were diagnosed with CCRCC. When the patients were subdivided according to tumor stage, decreased positivity was observed with higher tumor stage (50% in T1 vs. 17% in T3). Serum CA IX levels determined by ELISA were significantly higher in CCRCC patients than in non-CCRCC. A significant association between s-CA IX and CCRCC tumor stage was also determined (T1-87.51 vs. T3-341.98 pg/ml, p=0.046). We demonstrated that the CA IX expression profiles in blood and tissue samples from 74 kidney cancer patients are closely correlated with their histological subtypes. This is the first study reporting CA IX expression in blood and tissue samples from kidney cancer patients determined by four different methods.

Patients with prostate cancer treated by ADT have significantly higher fibrinogenemia than healthy control.

PURPOSE: Androgen deprivation therapy (ADT) for prostate cancer (PCa) may increase peripheral insulin resistance, induce type 2 diabetes, change body composition, and alter lipoprotein profile. Some studies have reported an association between ADT and increased risk of cardiovascular events. It is known that serum level of fibrinogen (SF) is associated with coronary artery disease and increased cardiovascular risk (CVR). The aim of this study is to determine the increase in SF and C-reactive protein (CRP) of PCa patients on ADT. METHODS: Ninety-seven patients with locally advanced PCa (study group) were analyzed [mean age 73.4 years ± 6.3 SD, mean prostate specific antigen (PSA) 15.4 ng/ml ± 7.5 SD]. They were examined with blood chemistry including serum cholesterol (CHL), high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins, triacylglycerol (TAG), serum fibrinogen (FB), CRP and serum fasting glucose (SFG), serum testosterone, free testosterone at baseline, and after 12 months of ADT. RESULTS: Patients after 12 months of ADT (study group) had significantly higher overall serum CHL (p < 0.001), higher LDL (p = 0.01), higher FB (p < 0.001), higher serum SFG (p = 0.03) in comparison with the control group. Increase in HDL (p = 0.245) and CRP (p = 0.1) was not significant. Two patients from the study group were diagnosed with new-onset diabetes. CONCLUSIONS: This is the first study that demonstrates the significant increase in FB in PCa patients on ADT, while CRP as inflammatory marker did not increase. Elevation of SF may contribute to increased CVR in PCa patients. Further prospective studies are warranted to confirm this association.

Warburg effect's manifestation in aggressive pheochromocytomas and paragangliomas: insights from a mouse cell model applied to human tumor tissue.

A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human PHEOs/PGLs, which may lead to identifying new diagnostic and prognostic markers in the near future.