Harnessing cold adaptation for postglacial colonisation: Galactinol synthase expression and raffinose accumulation in a polyploid and its progenitors.

Allotetraploid white clover (Trifolium repens) formed during the last glaciation through hybridisation of two European diploid progenitors from restricted niches: one coastal, the other alpine. Here, we examine which hybridisation-derived molecular events may have underpinned white clover's postglacial niche expansion. We compared the transcriptomic frost responses of white clovers (an inbred line and an alpine-adapted ecotype), extant descendants of its progenitor species and a resynthesised white clover neopolyploid to identify genes that were exclusively frost-induced in the alpine progenitor and its derived subgenomes. From these analyses we identified galactinol synthase, the rate-limiting enzyme in biosynthesis of the cryoprotectant raffinose, and found that the extant descendants of the alpine progenitor as well as the neopolyploid white clover rapidly accumulated significantly more galactinol and raffinose than the coastal progenitor under cold stress. The frost-induced galactinol synthase expression and rapid raffinose accumulation derived from the alpine progenitor likely provided an advantage during early postglacial colonisation for white clover compared to its coastal progenitor.

Pilot study for bladder cancer detection with volatile organic compounds using ion mobility spectrometry: a novel urine-based approach.

PURPOSE: Despite many efforts, no reliable urinary marker system has so far shown the potential to substitute cystoscopy. Measuring volatile organic compounds (VOCs) from urine is a promising alternative. VOCs are metabolic products which can be measured from the headspace of urine samples. Previous studies confirmed that the urine of bladder tumor patients has a different VOC profile than healthy controls. In this pilot study, the feasibility of discriminating VOCs from urine of bladder cancer patients from that of healthy control subjects was investigated. Aim of this study was to investigate whether VOC-based diagnosis of bladder cancer from urine samples is feasible using multicapillary column ion mobility spectrometry (MCC/IMS) and to identify potential molecular correlates to the relevant analytes. METHODS: Headspace measurements of urine samples of 30 patients with confirmed transitional cell carcinoma (TCC) and 30 healthy controls were performed using MCC/IMS. In the results of the measurements, peaks showing significant differences between both groups were identified and implemented into a decision tree with respect to achieve group separation. Molecular correlates were predicted using a pre-defined dataset. RESULTS: Eight peaks with significantly differing intensity were identified, 5 of which were highly significant. Using a six-step decision tree, MCC/IMS showed a sensitivity of 90% and specificity of 100% in group separation. CONCLUSION: VOC-based detection of bladder cancer is feasible. MCC/IMS is a suitable method for urine-based diagnosis and should be further validated. The molecular characteristics and metabolic background of the analytes require further workup.

Responses to water stress extremes in diverse red clover germplasm accessions.

Red clover (Trifolium pratense L.), a key perennial pastoral species used globally, can strengthen pastural mixes to withstand increasingly disruptive weather patterns from climate change. Breeding selections can be refined for this purpose by obtaining an in-depth understanding of key functional traits. A replicated randomized complete block glasshouse pot trial was used to observe trait responses critical to plant performance under control (15% VMC), water deficit (5% VMC) and waterlogged conditions (50% VMC) in seven red clover populations and compared against white clover. Twelve morphological and physiological traits were identified as key contributors to the different plant coping mechanisms displayed. Under water deficit, the levels of all aboveground morphological traits decreased, highlighted by a 41% decrease in total dry matter and 50% decreases in both leaf number and leaf thickness compared to the control treatment. An increase in root to shoot ratio indicated a shift to prioritizing root maintenance by sacrificing shoot growth, a trait attributed to plant water deficit tolerance. Under waterlogging, a reduction in photosynthetic activity among red clover populations reduced several morphological traits including a 30% decrease in root dry mass and total dry matter, and a 34% decrease in leaf number. The importance of root morphology for waterlogging was highlighted with low performance of red clover: there was an 83% decrease in root dry mass compared to white clover which was able to maintain root dry mass and therefore plant performance. This study highlights the importance of germplasm evaluation across water stress extremes to identify traits for future breeding programs.

Adjuvant vs. progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial.

BACKGROUND: Cisplatin-based chemotherapy (ChT) is the preferred perioperative treatment in muscle-invasive urothelial carcinoma of the urinary bladder (UCUB). Nevertheless, a certain number of patients are ineligible for platinum-based ChT. This trial compared immediate adjuvant vs. delayed gemcitabine ChT at progression in platinum-ineligible patients with high-risk UCUB. METHODS: High-risk platinum-ineligible UCUB patients (n = 115) were randomized 1:1 to adjuvant gemcitabine (n = 59) or gemcitabine at progression (n = 56). Overall survival was analyzed. Additionally, we analyzed progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: After a median follow-up of 3.0 years (inter quartile range [IQR]: 1.3-11.6), adjuvant ChT did not significantly prolong overall survival (OS) (HR: 0.84; 95% CI: 0.57-1.24; P = 0.375), with 5-year OS of 44.1% (95% CI: 31.2-56.2) and 30.4% (95% CI: 19.0-42.5), respectively. We noted no significant difference in PFS (HR: 0.76; 95% CI: 0.49-1.18; P = 0.218), with 5-year PFS of 36.2% (95% CI: 22.8-49.7) in the adjuvant group and 22.2% (95% CI: 11.5%-35.1%) when treated at progression. Patients with adjuvant treatment showed a significantly worse QoL. The trial was prematurely closed after recruitment of 115 of the planned 178 patients. CONCLUSIONS: There was no statistically significant difference in terms of OS and PFS for patients with platinum-ineligible high-risk UCUB receiving adjuvant gemcitabine compared to patients treated at progression. These findings underline the importance of implementing and developing new perioperative treatments for platinum-ineligible UCUB patients.

Modulation of immune checkpoint regulators in interferon γ induced urothelial carcinoma and activated T-lymphocyte cells by cytostatics.

Exploring the regulation of co-inhibitory (PD-1, PD-L1, CTLA-4) and co-stimulatory (CD28) genes by chemotherapeutic drugs is important for combined immune checkpoint blockade (ICB) therapy. ICB interferes with T-cell receptor and major histocompatibility complex (MHC) signaling by antibody drugs directed against the co-inhibitors. Here, we analyzed urothelial (T24) cell line with respect to cytokine signaling by interferon γ (IFNG) and the leukemia lymphocyte (Jurkat) cell line with respect to T-cell activation as mimicked by phorbolester and calcium ionophore (pma/iono). Alongside, we considered possible intervention with the chemotherapeutics gemcitabine, cisplatin and vinflunine. Noteworthy, cisplatin significantly induced PD-L1-mRNA in naïve and IFNG treated cells whereas gemcitabine and vinflunine had no effect on PD-L1-mRNA. At the protein level, PD-L1 showed typical induction in IFNG treated cells. In Jurkat cells, cisplatin significantly induced PD-1-mRNA and PD-L1-mRNA. Pma/iono administration did not alter PD-1-mRNA and PD-L1-mRNA but significantly increased CTLA-4-mRNA and CD28-mRNA levels where vinflunine suppressed the CD28-mRNA induction. In sum, we demonstrated that certain cytostatic drugs being relevant for the therapy of urothelial cancer, affect co-inhibitory and co-stimulatory modulators of immune signaling with potential impact for perspective combined ICB therapy of patients. MHC-TCR signaling between antigen presenting cells and T-lymphocytes with co-stimulator (blue) and co-inhibitors (red) and interacting proteins (blank). Co-inhibitory connections are shown by lines and co-stimulatory connections by dotted lines. The inducible or suppressive actions of the drugs (underlined) on the respective targets are indicated.

Increased Density of Growth Differentiation Factor-15+ Immunoreactive M1/M2 Macrophages in Prostate Cancer of Different Gleason Scores Compared with Benign Prostate Hyperplasia.

Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy.

Quantitative genetic analysis reveals potential to breed for improved white clover growth in symbiosis with nitrogen-fixing Rhizobium bacteria.

White clover (Trifolium repens) is integral to mixed pastures in New Zealand and temperate agriculture globally. It provides quality feed and a sustainable source of plant-available nitrogen (N) via N-fixation through symbiosis with soil-dwelling Rhizobium bacteria. Improvement of N-fixation in white clover is a route to enhancing sustainability of temperate pasture production. Focussing on seedling growth critical for crop establishment and performance, a population of 120 half-sibling white clover families was assessed with either N-supplementation or N-fixation via inoculation with a commercial Rhizobium strain (TA1). Quantitative genetic analysis identified significant (p < 0.05) family additive genetic variance for Shoot and Root Dry Matter (DM) and Symbiotic Potential (SP), and Root to Shoot ratio. Estimated narrow-sense heritabilities for above-ground symbiotic traits were moderate (0.24-0.33), and the strong (r ≥ 0.97) genetic correlation between Shoot and Root DM indicated strong pleiotropy or close linkage. The moderate (r = 0.47) phenotypic correlation between Shoot DM under symbiosis vs. under N-supplementation suggested plant growth with mineral-N was not a strong predictor of symbiotic performance. At 5% among-family selection pressure, predicted genetic gains per selection cycle of 19 and 17% for symbiotic traits Shoot DM and Shoot SP, respectively, highlighted opportunities for improved early seedling establishment and growth under symbiosis. Single and multi-trait selection methods, including a Smith-Hazel index focussing on an ideotype of high Shoot DM and Shoot SP, showed commonality of top-ranked families among traits. This study provides a platform for proof-of-concept crosses to breed for enhanced seedling growth under Rhizobium symbiosis and is informative for other legume crops.

Soluble PD-L1 in blood correlates positively with neutrophil and negatively with lymphocyte mRNA markers and implies adverse sepsis outcome.

Sepsis causes a myriad of immunological reactions that result in life-threatening alterations in the human body. Immunosuppression in sepsis is partly attributed to the programmed death receptor (PD-1) and its associated ligand (PD-L1) via the regulation of lymphocytes and neutrophils. Although the soluble forms of these proteins (i.e., sPD-1 and sPD-L1, respectively) are recognized as possible sepsis biomarkers, their functional implications are yet to be elucidated. Our research assessed the correlation between sPD-1 and sPD-L1 and blood mRNA markers and sepsis outcome. Blood samples of septic patients of urogenital origin versus control patients (both groups: n = 18) were analyzed. Blood serum sPD-1 and sPD-L1 levels were determined using the enzyme-linked immunosorbent assay (ELISA). The whole blood mRNA concentrations of PD-1, PD-L1, neutrophil markers (CEACAM8 and MPO), and T-lymphocyte markers (TCRß, CD4 and CD8) were determined via reverse transcriptase quantitative PCR (RT-qPCR). sPD-L1 levels were significantly increased in septic patients when compared to the controls, whereas sPD-1 levels were unaltered. Patients with high sPD-L1 levels, as dichotomized to the median, had a significantly shorter survival rate than those with low sPD-L1 levels. The sensitivity/specificity characteristics of sPD-L1 proved significant for sepsis detection. Furthermore, sPD-L1 correlated with the mRNA concentrations of PD-L1, CEACAM, and MPO, as well as major inflammatory markers (C-reactive protein and procalcitonin). However, sPD-L1 negatively correlated with TCRß, CD4, and CD8 mRNAs. sPD-L1 was found to be significantly increased in septic patients. Notably, sPD-L1 correlated with PD-L1 mRNA and neutrophil markers and was indicative of adverse outcomes.

Effects of UV-B and Water Deficit on Aroma Precursors in Grapes and Flavor Release during Wine Micro-Vinification and Consumption.

UV-B radiation and water availability can affect amino acids(AAs) concentration in berries, resulting in the evolution of aroma compounds during alcoholic fermentation. This study investigated the effects of UV-B exposure and water availability onwine aroma compounds in Pinot noir, focusing on the role of AAs in the process.Enhanced UV-B radiation significantly decreased total AA concentrations and most individual AAs inberries and wines, while water deficitincreased some individual AAsin wines. Higher alcohols, fatty acids, esters, monoterpenes, and C13-norisoprenoids were affected by UV-B interaction with water deficit in wines. These results suggested individual or combined UV-B exposure and water deficit had direct effects on fruit AAs, leading to significant differences in some wine aroma compounds.

Cellular and soluble immune checkpoint signaling forms PD-L1 and PD-1 in renal tumor tissue and in blood.

Immune checkpoint blockade therapy is a treatment option of various metastatic cancer diseases including renal cell carcinoma (RCC). Approved antibody drugs target the co-inhibitory signaling of Programmed Cell Death Ligand-1 (PD-L1) and its receptor Programmed Cell Death-1 (PD-1). The combined evaluation of PD-L1 and PD-1 at the mRNA and protein levels in tumor tissue with differentiation of tumor and immune cells as well as of soluble forms (sPD-L1) and (sPD-1) in blood is of basic interest in assessing biomarker surrogates. Here, we demonstrate that PD-L1 determined as fraction of stained tumor cells (TPS-score) correlates with PD-L1-mRNA in tumor tissue, reflecting the predominant expression of PD-L1 in tumor cells. Conversely, PD-1 in immune cells of tumor tissue (IC-score) correlated with PD-1-mRNA tissue levels reflecting the typical PD-1 expression in immune cells. Of note, sPD-L1 in blood did not correlate with either the TPS-score of PD-L1 or with PD-L1-mRNA in tumor tissue. sPD-L1 released into the supernatant of cultured RCC cells closely followed the cellular PD-L1 expression as tested by interferon γ (IFNG) induction and siRNA knockdown of PD-L1. Further analysis in patients revealed that sPD-L1 significantly increased in blood following renal tumor resection. In addition, sPD-L1 correlated significantly with inflammation marker C-reactive protein (CRP) and with PD-L1 mRNA level in whole blood. These results indicate that the major source of sPD-L1 in blood may be peripheral blood cells and not primarily tumor tissue PD-L1.

Urolithiasis in Germany: Trends from the National DRG Database.

INTRODUCTION: Urolithiasis is a common disease leading to a high socioeconomic burden due to treatment costs and sickness leave. The aim of this study was to evaluate recent trends in the incidence of urolithiasis in Germany and in the use of therapeutic interventions. METHODS: Treatment data for all in-patient hospital episodes for urolithiasis between 2005 and 2016 were extracted from the national DRG statistics at DESTATIS and analysed with regard to the corresponding procedures according to the OPS code. RESULTS: Incidence for urolithiasis was stable at around 120,000 cases per year during the observation period with a male:female ratio of 2:1. Rising numbers were noted for patients >80 years. Nevertheless, the number of coded procedures rose significantly with a marked disproportionate transition from extracorporeal shock wave lithotripsy towards ureterorenoscopy. Percutaneous nephrolithotomy was performed more frequently on a smaller scale. DISCUSSION/CONCLUSION: While the global incidence of urolithiasis is still rising, Germany, as other Western countries, has reached a plateau. There is a remarkable trend towards invasive treatment of even asymptomatic kidney stones. Besides the effects on individual patients with increased risk for complications, this results in a higher monetary burden to the health care system and society.

Prospects for Trifolium Improvement Through Germplasm Characterisation and Pre-breeding in New Zealand and Beyond.

Trifolium is the most used pastoral legume genus in temperate grassland systems, and a common feature in meadows and open space areas in cities and parks. Breeding of Trifolium spp. for pastoral production has been going on for over a century. However, the breeding targets have changed over the decades in response to different environmental and production pressures. Relatively small gains have been made in Trifolium breeding progress. Trifolium breeding programmes aim to maintain a broad genetic base to maximise variation. New Zealand is a global hub in Trifolium breeding, utilising exotic germplasm imported by the Margot Forde Germplasm Centre. This article describes the history of Trifolium breeding in New Zealand as well as the role and past successes of utilising genebanks in forage breeding. The impact of germplasm characterisation and evaluation in breeding programmes is also discussed. The history and challenges of Trifolium breeding and its effect on genetic gain can be used to inform future pre-breeding decisions in this genus, as well as being a model for other forage legumes.

Transpiration Rate of White Clover (Trifolium repens L.) Cultivars in Drying Soil.

Determining the performance of white clover cultivars under drought conditions is critical in dry climates. However, comparing the differences in cultivar performance requires equivalent soil water content for all plants, to reduce the water deficit threshold eliciting stomatal closure. In this study, the objective was to compare the rate of stomatal closure in eighty white clover cultivars in response to soil drying. Two glasshouse experiments were conducted, and the daily transpiration rate was measured by weighing each pot. The transpiration rate of the drought-stressed plants were normalized against the control plants to minimize effects from transpiration fluctuations and was recorded as the normalized transpiration rate (NTR). The daily soil water content was expressed as the fraction of transpirable soil water (FTSW). The FTSW threshold (FTSWc) was estimated after which the NTR decreases linearly. The FTSWc marks the critical point where the stomata start to close, and transpiration decreases linearly. The significant difference (p < 0.05) between the 10 cultivars with the highest and lowest FTSWc demonstrates the cultivars would perform better in short- or long-term droughts.

[CpG-ODN instillation boosts ICAM-1 expression in an orthotopic murine UCC model: immunohistochemical evaluation of the local response to immunostimulatory DNA]. / ICAM-1-Induktion durch CpG-ODN im murinen, orthotopen UCC-Modell ­ Immunhistochemische Analyse der lokalen Immunantwort auf immunstimulatorische DNA-Sequenzen.

BACKGROUND: Immunostimulatory CpG oligodeoxynucleotides (CpG-ODN) have been verified as an effective antineoplastic agent for intravesical application in a murine orthotopic C57-BL6 /MB-49 urothelial cell carcinoma (UCC). To date, many details in the mode of action have remained unclear. Preceding studies pointed towards a Th1-weighted response. The aim of this work was to identify the local lymphocyte subsets in murine tumour-bearing bladders and to examine effects on the expression of Intercellular Adhesion Molecule 1 (ICAM-1) after treatment with CpG-ODN. MATERIAL AND METHODS: Different instillation schedules were applied in an established orthotopic C57-BL6 /MB49 UCC model. After 13 days, fresh frozen sections of the harvested bladders were immunohistochemically examined for the infiltration density of lymphocytes expressing CD 3, CD4, CD8 and CD19. In a second series of the same animal model, healthy and tumour-bearing bladders were exposed to CpG-ODN or PBS and later stained for the expression of ICAM-1. RESULTS: CpG-ODN instillation led to augmented T-cell infiltration (represented by CD3). Further T-cell subdifferentiation between T-helper cells (CD4) and cytotoxic T cells (CD 8a) did not show a perceptible variety between groups. The B-cell population (CD19) was found to decrease over the course of treatment. In the second series, treatment provoked a strong expression of ICAM-1 by infiltrating leukocytes, endothelial cells and particularly by the cancer cells themselves. DISCUSSION: The previously observed augmented lymphocyte density was classified as T-cell infiltration. The decline of the B-cell concentration over the course of treatment suggests a Th2 suppression in favour of a Th-1 polarisation. These findings support the assumption that a cell-mediated immune response is the mode of action underlying the antineoplastic CpG-ODN capacities. The marked upregulation of ICAM-1 expression, especially on tumour cells, suggests a crucial role of this membrane protein for the initiation and maintenance of anticancer immune response. CONCLUSION: CpG-ODN might be a prospective alternative to established instillation therapies. With a view to the current BCG shortage and the well-known toxicities, an amplification of the topic therapy armamentarium could be achievable. The now described capability of ICAM-1 induction on carcinoma cells and, by association, the reversal of escape strategies to cancer immunity may also make the agent interesting as an adjuvant for modern checkpoint inhibition.

Chemotherapy of Locally Advanced or Metastatic Urothelial Cell Carcinoma: Monocentric Real-Life Data.

BACKGROUND/AIM: Up to 30% of all patients will present with an advanced or a metastatic stage (mUCC) at the moment of the initial diagnosis of urothelial cell carcinoma of the bladder (UCC). We investigated the numbers, the efficacy and toxicity of different chemotherapies for mUCC in daily practice and "real-life" conditions and evaluated them substance-specifically. PATIENTS AND METHODS: All patients with a mUCC, who were treated between January 1, 2006 and October 31, 2016 at the Department of Urology and Pediatric Urology at University Hospital Marburg (Germany), were retrospectively analyzed. We set the focus on demographic and tumor-specific data as well as on effectiveness, therapy sequences, and drug tolerance. RESULTS: Forty-one patients were identified. Of the 41 patients, 85.4% of the patients in first-line therapy received gemcitabine/cisplatin. A large proportion of 85.4% received a second-line therapy and 40% a third-line therapy due to progress or relapse. Median overall survival (mOS) was 18 months including all patients and increased up to 29.5 months in the cases of three therapy lines. CONCLUSION: Our data reveal that chemotherapy of mUCC is effective and side effects are manageable in daily clinical practice.

Co-Regulation of Immune Checkpoint PD-L1 with Interferon-Gamma Signaling is Associated with a Survival Benefit in Renal Cell Cancer.

BACKGROUND: Programmed death ligand (PD-L1)-based immune checkpoint blockade therapy for metastatic renal cell carcinoma (RCC) achieves significant response rates in a subgroup of patients. The relevance of PD-L1 gene regulation for disease outcome is not clear. OBJECTIVE: To evaluate PD-L1 expression and its dependence on interferon-γ (IFN-γ) in RCC cell lines and tissues in relation to disease outcome. METHODS AND PATIENTS: Regulation of PD-L1-mRNA and PD-L1 protein was studied in cell lines from clear cell RCC (ccRCC) and papillary RCC (pRCC) by quantitative RT-PCR and Western-blot analysis. PD-L1-mRNA correlation and gene-set enrichment analysis (GSEA) of the IFN-γ pathway were conducted with RNA-Seq from ccRCC, pRCC, and skin cutaneous melanoma (SKCM) tissue. In addition, patient overall survival (OS) and disease-free survival (DFS) (cBioPortal for Cancer Genomics) were considered. RESULTS: In ccRCC-like cell lines, PD-L1 was induced by canonical IFN-γ signaling, whereas in a pRCC-like cell line, PD-L1 was refractory towards IFN-γ signaling. In ccRCC and SKCM tissues, GSEA revealed significant IFN-γ pathway activation in tissue samples with high PD-L1-mRNA levels. This was not observed in pRCC tissue. ccRCC and SKMC patients with low PD-L1-mRNA levels had significantly shorter OS and DFS than those with high PD-L1-mRNA levels. In pRCC patients, no significant difference in OS and DFS with regard to PD-L1-mRNA tissue levels was obvious. CONCLUSIONS: The findings suggest that ccRCC and pRCC differ with respect to PD-L1 regulation by IFN-γ-signaling. High PD-L1-mRNA levels in tumor tissues with a positive IFN-γ signature favorably affect OS and DFS.

Burkitt's lymphoma of the prostate presenting as acute urinary retention: a case report.

BACKGROUND: Non-Hodgkin lymphomas, which include Burkitt's lymphoma, affect the prostate in only 0.1% of cases. They most commonly present as painless lymphadenopathy elsewhere in the body and can cause abdominal or thoracic pain and systemic symptoms such as fever, weight loss and night sweats. Here we report a rare case of sporadic Burkitt's lymphoma of the prostate whose initial clinical presentation was acute urinary retention. CASE PRESENTATION: A 28-year-old Caucasian male presented repeatedly with urinary retention. First, he was misdiagnosed with alcohol-induced urinary retention and later with benign prostatic hyperplasia. After the appearance of new symptoms, including hematuria and hydronephrosis, endoscopic and radiographic evaluation was performed. Transurethral biopsy of the prostate secured the diagnosis of Burkitt's lymphoma. The symptoms receded under chemotherapy and complete remission of the disease was established. CONCLUSION: This case report brings lymphomas into focus as a differential diagnosis for urinary retention in young males. Early use of extensive diagnostic measures is advised in patients with urinary retention for uncertain reasons to make prompt diagnosis and start appropriate treatment early.

Prostate specific membrane antigen (PSMA) in urothelial cell carcinoma (UCC) is associated with tumor grading and staging.

INTRODUCTION: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC). METHODS: Immunhistochemical PSMA-staining was performed in 89 UCC samples. PSMA expression in tumor tissue, adjacent healthy tissue and blood vessels was examined. We furthermore analyzed PSMA-mRNA expression in nine human UCC cell lines. We correlated our findings with clinical data regarding recurrence and progression of UCC. RESULTS: UCC tissue showed a significantly higher PSMA expression compared to healthy urothelial tissue (p < 0.001). Non muscle invasive bladder cancer revealed significantly higher PSMA expression compared to muscle invasive bladder cancer (p < 0.05). PSMA expression significantly differed between various T-stages (p < 0.05) and tumor differentiation (p < 0.001). In four human UCC cell lines PSMA-mRNA was detectable. Those patients who suffered recurrence showed a higher rate of PSMA expression but no correlation to recurrence-free survival was evident. Progression of disease correlated significantly with a higher PSMA expression (p = 0.036). CONCLUSIONS: Both UCC tissue and healthy urothelial tissue express PSMA, with significantly higher levels in UCC. We confirmed these findings in human UCC cell lines. In this small first cohort expression of PSMA correlates significant with progression of disease but not with recurrence and recurrence-free survival. These first results make PSMA a promising target for future diagnosis and therapy of UCC.

Prostate cancer tissues with positive TMPRSS2-ERG-gene-fusion status may display enhanced nerve density.

Innervation of prostate cancer (CaP) tissue favors tumor progression and metastasis but the regulation of innervation in CaP is unclear. The oncogenic transcription factor ERG is commonly induced by a typical TMPRSS2-ERG (TE) gene fusion in CaP and may affect innervation. Here, we analyzed whether nerve density of CaP tissue is related to TE status or perineural infiltration status of CaP tissue. In parallel, we measured several members of the neuropilin/plexin/semaphorin family (NRP, PLXN, and SEMA) as possible targets mediating innervation. The TE-gene-fusion status was determined at the mRNA level in CaP tissues by nested RT-PCR. Transcript levels were analyzed by quantitative RT-PCR in CaP tissue or cell line homogenate. ERG was analyzed by immunostaining, and the nerve density was evaluated by immunostaining for PGP9.5 and axonal neurofilament. Data were analyzed by correlation (Spearman), linear regression, Mann-Whitney U test, and contingency table analyses. TE-positive (TE-1) vs. TE-negative (TE-0) CaP tissues displayed significantly enhanced ERG-mRNA levels (TE-0: -4.183; TE-1: -2.994, P < 0.001) and ERG immunostaining (Erg-IH score; TE-0: 0.4211; TE-1: 1.391; P < 0.0001). Notably, the nerve density was significantly increased in CaP tissue samples with positive TE status compared to negative TE status (TE-0, ND score = 1.5; TE-1, ND score = 2.0; P <0.01). NRP1, NRP2, PLXNA2, PLXNB1, SEMA3A, and SEMA4B mRNAs were detectable in CaP tissues and CaP cell lines at quite heterogeneous levels. In CaP tissues, we observed significant positive correlations of ERG with NRP2, PLXNA2, PLXNB1, and SEMA4B. TE-positive CaP tissues displayed enhanced nerve density. ERG correlated with some NRP/PLXN/SEMA components suggesting possible regulatory relevance of ERG for CaP innervation.

Management of an Extremely Low Birth Weight Infant with Bilateral Renal Obstruction Caused by Candida albicans Fungus Balls.

We report an extremely low birth weight infant with anuria caused by bilateral Candida albicans fungus balls it was treated with a combination of antifungal therapy, irrigation and pyelotomy. This lead to a recovery of renal function, after a follow-up of 77 month no more Candida was cultured from urine.