The Expression of a Subset of Aging and Antiaging Markers Following the Chondrogenic and Osteogenic Differentiation of Mesenchymal Stem Cells of Placental Origin.

Mesenchymal stem cells (MSCs) of placental origin hold great promise in tissue engineering and regenerative medicine for diseases affecting cartilage and bone. However, their utility has been limited by their tendency to undergo premature senescence and phenotypic drift into adipocytes. This study aimed to explore the potential involvement of a specific subset of aging and antiaging genes by measuring their expression prior to and following in vitro-induced differentiation of placental MSCs into chondrocytes and osteoblasts as opposed to adipocytes. The targeted genes of interest included the various LMNA/C transcript variants (lamin A, lamin C, and lamin A∆10), sirtuin 7 (SIRT7), and SM22α, along with the classic aging markers plasminogen activator inhibitor 1 (PAI-1), p53, and p16INK4a. MSCs were isolated from the decidua basalis of human term placentas, expanded, and then analyzed for phenotypic properties by flow cytometry and evaluated for colony-forming efficiency. The cells were then induced to differentiate in vitro into chondrocytes, osteocytes, and adipocytes following established protocols. The mRNA expression of the targeted genes was measured by RT-qPCR in the undifferentiated cells and those fully differentiated into the three cellular lineages. Compared to undifferentiated cells, the differentiated chondrocytes demonstrated decreased expression of SIRT7, along with decreased PAI-1, lamin A, and SM22α expression, but the expression of p16INK4a and p53 increased, suggesting their tendency to undergo premature senescence. Interestingly, the cells maintained the expression of lamin C, which indicates that it is the primary lamin variant influencing the mechanoelastic properties of the differentiated cells. Notably, the expression of all targeted genes did not differ from the undifferentiated cells following osteogenic differentiation. On the other hand, the differentiation of the cells into adipocytes was associated with decreased expression of lamin A and PAI-1. The distinct patterns of expression of aging and antiaging genes following in vitro-induced differentiation of MSCs into chondrocytes, osteocytes, and adipocytes potentially reflect specific roles for these genes during and following differentiation in the fully functional cells. Understanding these roles and the network of signaling molecules involved can open opportunities to improve the handling and utility of MSCs as cellular precursors for the treatment of cartilage and bone diseases.

Carbodiimides as catalysts for the reduction of a cadmium hydride complex.

A rare terminal cadmium hydride complex [(BDI)CdH] (BDI = [{N(2,6-iPr2C6H3)C(Me)}2CH]) has been synthesised from [(BDI)CdCl] and LiEt3BH. The hydride can be reduced to the cadmium(i) dimer, [(BDI)CdCd(BDI)] upon treatment with a catalytic amount of diisopropyl- or dicyclohexylcarbodiimide.

Novel compounds with antiangiogenic and antiproliferative potency for growth control of testicular germ cell tumours.

BACKGROUND: Testicular germ cell tumour (TGCT) is the most common cause of death from solid tumours in young men and especially for platinum-refractory patients novel treatment approaches are urgently needed. Using an in silico screening approach for the detection of novel cancer drugs with inhibitory effects on the tyrosine kinase activity of growth factors (e.g., VEGFR, PDGFR), we identified two compounds (HP-2 and HP-14) with antiangiogenic and antiproliferative potency, which were evaluated in endothelial cell models and TGCT cells. RESULTS: HP-2 and HP-14 effectively inhibited the growth of VEGFR-2-expressing TGCT cell lines (Tera-1, Tera-2 and 2102EP) and endothelial cell models, while they failed to supress the growth of VEGFR-2-lacking tumour cells. cDNA-microarrays revealed an inhibition of the expression of several growth factor receptors and related signal transduction molecules. Vascular endothelial growth factor (VEGF)-induced cell migration was also potently inhibited. Cell cycle-regulating proteins such as p21 and p27 were upregulated, leading to an S-phase arrest. Additional in vivo evaluations confirmed the antiangiogenic potency and good tolerability of the novel substances. CONCLUSION: Our data show that the identified novel compounds inhibit the growth of TGCT cells and decrease angiogenic microvessel formation. The mode of action involves cell cycle arresting effects and changes in the expression pattern of several angiogenic genes. The novel compounds may qualify as new candidates for targeted treatment of TGCT and merit further evaluation.

[What is most important is what comes across : Urological guidelines from the target group's point of view]. / Entscheidend ist, was ankommt : Urologische Leitlinien aus Sicht der Zielgruppe.

BACKGROUND: Guidelines are developed to improve the quality of patient care. The effect of German urologic guidelines has not been evaluated so far. Therefore, we aimed to systematically investigate the acceptance, use, and quality of the published guidelines from a user's perspective. METHODS: A link to an online questionnaire concerning use and barriers to the application of guidelines was distributed via e-mail by the German Society of Urology (DGU). German urologists' opinions on differences in national guideline quality were evaluated regarding prostate cancer (PCA), bladder cancer, germ cell tumors (GCT), renal cell carcinomas, and erectile dysfunction. RESULTS: Four hundred sixty-seven German urologists participated. More than 90% of the participants considered guidelines to be helpful. The Internet as the main tool for guideline distribution was favored by 28.4%, followed by publication in Urologe A. The main barrier to guideline usage was attributed to the lack of up-to date clinical data. Guidelines for GCT scored best in all quality categories and reached the highest level of use (65.8%), and 40.5% of participating urologists considered the additional establishment of comprehensive care centers for GCT as more effective for quality improvement than guideline development alone. For the other urologic tumors, especially PCA, guideline development was favored as a tool for quality improvement. CONCLUSION: More than 90% of participating urologists accept clinical guidelines as useful instruments in clinical practice and for therapeutic decisions. Our results should be integrated into guideline dissemination and implementation strategies in order to achieve a higher degree of treatment conformation to guidelines.

[New biomarkers and application of multivariate models for detection of prostate cancer]. / Neue Biomarker und Anwendung multivariater Modelle zur Detektion des Prostatakarzinoms.

The specificity of PSA has been enhanced by using molecular forms of PSA and free PSA (fPSA) such as percent free PSA (%fPSA), proPSA, intact PSA or BPHA and / or new serum markers. Most of these promising new serum markers like EPCA2 or ANXA3 still lack confirmation of the outstanding initial results or show only marginally enhanced specificity at high sensitivity levels. PCA3, TMPRSS2-ERG, and other analytes in urine collected after digital rectal examination with application of mild digital pressure have the potential to preferentially detect aggressive PCa and to decrease the number of unnecessary repeat biopsies. The combination of these new urinary markers with new and established serum markers seems to be most promising to further increase specificity of tPSA. Multivariate models, e. g., artificial neural networks (ANN) or logistic regression (LR) based nomograms have recently been performed by incorporating these new markers in several studies. There is generally an advantage to include the new markers and clinical data as additional parameters to PSA and %fPSA within ANN and LR models. Results of these studies and also unexpected pitfalls are discussed in this review.

[MicroRNA in uro-oncology : New hope for the diagnosis and treatment of tumors?]. / Mikro-RNA in der Uroonkologie : Neue Hoffnungen für die Diagnostik und Therapie von Tumoren?

MicroRNAs (miRNAs) are non-coding RNAs that regulate basic cellular processes and are associated with cancer characteristics. The aim of this review is to summarize the principles of miRNA biogenesis and function and to describe their contribution to tumor development, especially in uro-oncology. Therefore a PubMed search was conducted. Up to March 2009 approximately 4,500 miRNA-related articles were cited in this database. Studies of miRNA expression and functional analyses prove their impact in carcinogenesis and their potential as diagnostic or prognostic markers or as novel therapeutic targets. Only a few miRNA-related studies have been published in uro-oncology so far. Although tumor-specific miRNA expression has been shown for urological neoplasms, the contradicting data show that miRNA research is still in its infancy in this field. A systematic elucidation of characteristic miRNA abnormalities could decisively improve diagnostics as well as therapy of urological tumors.

[New developments in minimally invasive urology: NOTES (Natural Orifice Transluminal Endoscopic Surgery) and LESS (Laparo-Endoscopic Single-Site Surgery) in urology]. / Neue Entwicklungen in der minimalinvasiven Urologie: NOTES (Natural Orifice Transluminal Endoscopic Surgery) und LESS (Laparoendoscopic Single-Site Surgery) in der Urologie.

Laparoscopic surgery in urology has undergone a rapid development in the last decade. In general, many studies have underlined the benefits of laparoscopy in urology. The latest innovations in the field of minimally invasive urology are aimed at a further reduction of the morbidity associated with minimally invasive surgery. Two novel innovations are currently being developed, natural orifice transluminal endoscopic surgery (NOTES), whereby intraperitoneal access is gained through natural orifices and laparo-endoscopic single-site surgery (LESS), wherein one surgical access is used both for introducing instruments and for retrieving the specimen. Many case reports and small patient series have been published rapidly in the past two years. However, comparative randomised studies to conventional laparoscopy or open surgery do not yet exist. LESS and NOTES are two new innovative approaches, whereby feasibility studies not only for simple nephrectomy but also for complex procedures like partial nephrectomy, radical prostatectomy, ureterocystoneostomy have been published. In the next few years, comparative studies between these techniques and conventional laparoscopy can be expected.

[Testicular cancer - explanatory models for high cisplatin chemosensibility and new therapeutic options]. / Testikuläre Keimzelltumoren - Erklärungsmodelle für die hohe Ansprechrate auf Cisplatin-basierte Chemotherapien und neue Therapieoptionen.

This article offers a review about the current facts of chemotherapy in testicular cancer. Besides a short presentation of the guideline-standard therapy the authors deal with the question as to why testicular cancer shows an extraordinarily high chemosensibility compared to other tumours. Furthermore, the current data on alternative chemotherapies as well as of molecular, molecular-genetic and pharmacogenetic therapeutic concepts are explored. Data were obtained from researches in Medline of the Pubmed database.

GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue-based diagnostics.

GOLPH2 is coding the 73-kDa type II Golgi membrane antigen GOLPH2/GP73. Upregulation of GOLPH2 mRNA has been recently reported in expression array analyses of prostate cancer. As GOLPH2 protein expression in prostate tissues is currently unknown, this study aimed at a comprehensive analysis of GOLPH2 protein in benign and malignant prostate lesions. Immunohistochemically detected GOLPH2 protein expression was compared with the basal cell marker p63 and the prostate cancer marker alpha-methylacyl-CoA racemase (AMACR) in 614 radical prostatectomy specimens. GOLPH2 exhibited a perinuclear Golgi-type staining pattern and was preferentially seen in prostatic gland epithelia. Using a semiquantitative staining intensity score, GOLPH2 expression was significantly higher in prostate cancer glands compared with normal glands (P<0.001). GOLPH2 protein was upregulated in 567 of 614 tumours (92.3%) and AMACR in 583 of 614 tumours (95%) (correlation coefficient 0.113, P = 0.005). Importantly, GOLPH2 immunohistochemistry exhibited a lower level of intratumoral heterogeneity (25 vs 45%). Further, GOLPH2 upregulation was detected in 26 of 31 (84%) AMACR-negative prostate cancer cases. These data clearly suggest GOLPH2 as an additional ancillary positive marker for tissue-based diagnosis of prostate cancer.

[Adjuvant and neoadjuvant drug therapy for prostate cancer]. / Adjuvante und neoadjuvante medikamentöse Therapie beim Prostatakarzinom.

Neoadjuvant and adjuvant therapeutic strategies are widely employed for a variety of cancer entities. The basic aim and the potential benefit for the patient are to eradicate micrometastases, with the downside being side effects and overtreatment. Neoadjuvant and adjuvant hormone therapy for prostate cancer have been investigated in a number of clinical studies. Based on these studies, the following recommendations can be given: there is currently no indication for neoadjuvant therapy prior to radical prostatectomy. Adjuvant therapy using LHRH analogs for patients with lymph node-positive tumors following radical prostatectomy can be considered but should be weighed against early"biochemical progression triggered" treatment. For locally advanced tumors the same is true (bicalutamide): adjuvant treatment has shown an advantage in clinically progression-free survival; however, no systematic comparison is available with early"biochemical progression triggered" treatment. Before radiotherapy 2 months of neoadjuvant LHRH analog treatment has shown a survival advantage in patients with locally advanced tumors and a low risk of systemic spread (Gleason <7). For high-risk patients, long-term (2-3 years) adjuvant LHRH analog treatment is indicated.

[Fast-track laparoscopic radical prostatectomy]. / "Fast-track" bei laparoskopisch radikaler Prostatektomie.

BACKGROUND: Fast-track surgery describes perioperative treatment concepts ensuring a faster postoperative convalescence phase. By using a multimodal fast-track concept in patients undergoing laparoscopic radical prostatectomy, we aimed to investigate the feasibility of this procedure after elective surgery and a possible discharge 3 days postoperatively. PATIENTS AND METHODS: Twenty-five patients per group were randomized for conventional or fast-track treatment, respectively. Perioperative data, early complications, possible hospital discharge, and readmission rate were analyzed. Before hospital discharge, all patients were interviewed about their evaluation of the received regimen and their overall satisfaction perioperatively. RESULTS: The mean postoperative hospital stay was 3.6 days in the fast-track group vs. 6.7 days in the conventional group (p<0.01). Overall complications were low but were significant between the two groups, with the fast-track procedure being more favorable. Readmission rate was also low but was not significant. Overall satisfaction was significantly higher in the fast-track group, whereas the subjective evaluation did not differ between the two regimens. CONCLUSIONS: Fast-track concepts are well transferable in laparoscopic radical prostatectomy settings. Patients receiving this procedure, as well as clinics offering it, may benefit from a suitable fast-track concept.

[Results of German "Men's Health Awareness Days" in 2006]. / Ergebnisse der Männergesundheitstage 2006.

Of visitors to the Men's Health Awareness Days (Männergesundheitstage) in different German cities, 2,200 were asked to answer a standardised questionnaire about the quality of the information presented. Fifty-one per cent of the visitors answered; of those 80% gave mainly positive feedback, especially for a walk-through prostate model and for the presentations and discussions. Visitors represented only partial groups concerning age (64 years on average), existing prostate disease (51%), and participation in examinations for early detection (cancer screening). Therefore, many of the visitors did not represent the target group (healthy and under 60 years old). Qualified urologists could make better use of consultations by informing patients about local or general information events such as these. As men are burdened with multiple health risks, future Health Days should make use of interdisciplinary schemes.

Treatment of varicocele with reference to age: a retrospective comparison of three minimally invasive procedures.

BACKGROUND: This study investigated whether the therapeutic efficacy and morbidity of three minimally invasive techniques for varicocele correction--laparoscopic varicocelectomy (LV), antegrade sclerotherapy (AS), and retrograde embolization (RE)--differed between children and adults. METHODS: During a 10-year period, 356 procedures for varicocele correction, including 122 cases of LV, 108 cases of AS, and 126 cases of RE, were performed for 314 patients at our institution. Of these patients, 223 were 19 years of age or younger (group 1), and 133 were older than 19 years (group 2). Diagnosis and postoperative results were established clinically and with the use of Doppler ultrasonography. The failure rates and complications for each procedure were retrospectively evaluated and compared between the two age groups. RESULTS: The median follow-up period was 69 months (range, 6-122 months). For 25 patients (19.8%), RE was not feasible for technical reasons. In both groups, LV had a lower failure rate than AS or RE, but the difference between LV and AS was not significant in group 1 (7.7(% vs 11.9%; p > 0.5). Also in group 1, AS was associated with fewer complications than LV 1 (4.5% vs 15.4%; p < 0.05). In group 2, LV was significantly more effective in correcting varicoceles than the other two techniques (p < 0.01). In this group, the complication rates for all three procedures did not differ significantly (p > 0.05). CONCLUSIONS: In our experience, LV was more effective than AS or RE in correcting varicoceles. For children and adolescents, AS may be more indicated because of the slightly lower complication rate and similar recurrence rates, as compared with LV, for this age group. The higher incidence of postoperative hydrocele formation after LV warrants more refined techniques such as the lymphatic-sparing approach.

Fast-track surgery in laparoscopic radical prostatectomy: basic principles.

Fast-track surgery describes innovative treatment concepts ensuring a faster convalescence phase. The aim of this study was to allow hospital discharge 3 days after surgery without additional complications in patients receiving LRPE for localized prostate cancer. Twenty-five patients each were randomized in the study groups to verify if a fast-track regimen could be transferred into clinical routine. The perioperative data, early complications, hospital stay as well as readmission rate were analyzed. The mean postoperative stay was 3.6 days in the fast-track group versus 6.7 days in the conventional group. The overall complications were significantly less in the fast-track procedure. The readmission rate was low and not significant. Patients receiving an LRPE benefit from a suitable fast-track concept. The postoperative hospital stay could be shortened nearly by half with a significantly decreased overall complication rate. Thus, fast-track concepts might contribute to saving resources in the long term. However, more evidence based on larger prospective trials is needed to achieve optimal quality of life for patients perioperatively.

[Clinical pathway "laparoscopic prostatectomy". Analysis of anesthesiological procedures in a randomized study]. / Klinischer Behandlungspfad "laparoskopische Prostatektomie". Anästhesiologische Prozessanalyse in einer randomisierten Studie.

METHODS: In this study we investigated the anesthesiological module of a clinical pathway. We chose the pathway of "laparoscopic prostatectomy" as an example for time-consuming minimally invasive surgery and 40 patients were randomly assigned to 2 groups receiving either total intravenous anesthesia (TIVA) using propofol/ remifentanil or balanced minimal flow anesthesia using desflurane/ remifentanil. During this module the indicators of quality such as vigilance, pain, postoperative nausea and vomiting (PONV) and mobilization were measured. Costs were evaluated and analyzed by a bottom-up procedure. RESULTS: There were no anesthesia-related deviations from clinical pathways and both forms of anesthesia management were equally well tolerated by the patients. No significant difference was observed regarding hemodynamic measurements or PONV. The patients in the desflurane/ remifentanil group recovered more rapidly (p=0.037) and had more pain. The amount of analgesic agents given immediately following anesthesia was significantly higher than in the TIVA group (p=0.017). The median anesthesia costs per minute for laparoscopic prostatectomy in the propofol group were 2.79 EUR (minimum cost 2.41 EUR, maximum cost 3.21 EUR) and in the desflurane group 2.68 EUR (minimum cost 2.45 EUR, maximum cost 3.39 EUR). The total anesthesia costs for both groups were within the proceeds matrix range for diagnosis-related groups (DRG). However, the cost analysis for medication was slightly higher than the proceeds matrix range for DRGs. CONCLUSION: Both forms of anesthesia can be implemented for time-consuming surgical procedures and allow a cost-effective anesthesia management. Anesthesiological procedures must go hand-in-hand with the type of anesthesia selected. The prophylactic use of analgetics for desflurane/ remifentanil anesthesia should be given earlier and in higher doses than in propofol/ remifentanil anesthesia. The prophylactic use of antiemetics following laparoscopic procedures of long duration is indicated. Optimizing anesthesiological procedures could lead to a continuous improvement in the quality of therapeutic pathways.

[An artificial neural network as a tool in risk evaluation of prostate cancer. Indication for biopsy with the PSA range of 2-20 microg/l]. / Nutzung von artifiziellen neuronalen Netzwerken zur Risikoabschätzung eines Prostatakarzinoms. Biopsieindikationen im PSA-Bereich von 2-20 microg/l.

In this prospective study covering 5.5 years we evaluated the diagnostic power of an artificial neural network (ANN) based on PSA, %fPSA, and clinical data in the PSA range 2-20 microg/l as prostate biopsy indicator. A total of 944 patients with prostate cancer or benign hyperplasia (BPH) were analyzed. The calculation of the individual patient's risk before prostate biopsy was performed at the 90% and 95% specificity and sensitivity levels within the PSA ranges 2-4, 4.1-10, and 10.1-20 microg/l. For the low PSA range 2-4 microg/l, we recommend a first time biopsy at an ANN specificity level of 95%. For PSA range 4.1-10 microg/l, we recommend a first time biopsy at an ANN sensitivity level of 95%. A rebiopsy at the PSA range 10.1-20 micro g/l should be performed based on a 95% sensitivity level. The use of an ANN at PSA 2-20 microg/l enhances the specificity and sensitivity of %fPSA by 9-39%. The application of an ANN based on %fPSA and clinical data improves the diagnostic performance compared to %fPSA only.

Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in the serum of healthy adults.

AIMS: Osteoprotegerin and the receptor activator of the nuclear factor-kappaB ligand (RANKL) are decisive factors for maintaining the balance between bone formation and bone resorption. As new, sensitive ELISAs have been developed recently, reference serum ranges should be established to use these analytes for possible diagnostic purposes. METHODS: Measurements were performed in serum samples of 142 healthy adults (82 women, 60 men) between 20 and 70 years of age (mean age: 46 years) using ELISA kits from Immundiagnostik, Bensheim, Germany. RESULTS: Serum concentrations of osteoprotegerin were age and gender independent and showed a Gaussian distribution, while RANKL concentrations were also age independent but differed between males and females, with a non-Gaussian distribution. For osteoprotegerin a gender-independent upper 97.5 percentile limit of 3.6 pmol/L was calculated while the corresponding limits for RANKL and the ratio of RANKL to osteoprotegerin amounted to 3.29 pmol/L and 2.78 in women and 1.66 pmol/L and 2.18 in men, respectively. CONCLUSIONS: Both osteoprotegerin and RANKL were quantifiable in serum of healthy adults, which means that these compounds can be used as potential diagnostic tools.