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Artificial intelligence (AI) promises to be the next revolutionary step in modern society. Yet, its role in all fields of industry and science need to be determined. One very promising field is represented by AI‐based decision‐making tools in clinical oncology leading to more comprehensive, personalized therapy approaches. In this review, the authors provide an overview on all relevant technical applications of AI in oncology, which are required to understand the future challenges and realistic perspectives for decision‐making tools. In recent years, various applications of AI in medicine have been developed focusing on the analysis of radiological and pathological images. AI applications encompass large amounts of complex data supporting clinical decision‐making and reducing errors by objectively quantifying all aspects of the data collected. In clinical oncology, almost all patients receive a treatment recommendation in a multidisciplinary cancer conference at the beginning and during their treatment periods. These highly complex decisions are based on a large amount of information (of the patients and of the various treatment options), which need to be analyzed and correctly classified in a short time. In this review, the authors describe the technical and medical requirements of AI to address these scientific challenges in a multidisciplinary manner. Major challenges in the use of AI in oncology and decision‐making tools are data security, data representation, and explainability of AI‐based outcome predictions, in particular for decision‐making processes in multidisciplinary cancer conferences. Finally, limitations and potential solutions are described and compared for current and future research attempts. [ABSTRACT FROM AUTHOR]

Model‐based development and implementation of the digital building file – BIM from construction to operation The use of BIM in bridge construction is currently limited to the design and construction phases, but BIM can be particularly useful for the operation of structures. The basis for the use of BIM in the operation life cycle phase is the transfer of relevant information from the planning and construction life cycle phases to operation. The creation of a model‐based digital building file enables the transfer of relevant information for operation. The article classifies the creation and use of model‐based digital construction files both in the scientific context and in the current working methodology with analog construction files and construction files. It also includes the practical implementation of a specific project. Furthermore, the reference to the standardized use cases 190 "Project and building documentation" and 200 "Use for operation and maintenance" is presented. The implementation of the model‐based digital construction file is demonstrated using the example of the Cologne Heumar highway interchange. The objectives and principles associated with the use of BIM, the project development and the background are discussed. The implementation and handover of the model‐based digital construction file is described in detail for the practical example. [ABSTRACT FROM AUTHOR]

Background: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences. Objective: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma. Methods: A German‐wide, cross‐sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient‐reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list. Results: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients. Conclusions: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient‐reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment. [ABSTRACT FROM AUTHOR]

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In recent years, innovative ride‐sharing systems have gained significant attention. In such systems, dynamic fleet management covers demand and fulfillment control to determine which stochastically incoming requests are to be satisfied and how vehicle resources are utilized for their fulfillment, respectively. Demand and fulfillment control can be implemented ranging from straightforward myopic to more sophisticated anticipatory. In this paper, our aim is twofold: (1) we want to classify how policies implement demand and fulfillment control in the related literature on dynamic fleet management; (2) we want to explore the effectiveness of demand and fulfillment control under varying conditions in order to identify benefits and risks for ride‐sharing systems. To this end, we define policies that differ in the optimization of demand and/or fulfillment control through the exploitation of either confirmed or complete information. Our experimental results demonstrate that demand and fulfillment control affect the performance and service quality of ride‐sharing systems quite differently. [ABSTRACT FROM AUTHOR]

Overexpression of the vacuolar sugar transporter TST1 in Arabidopsis leads to higher seed lipid levels and higher total seed yield per plant. However, effects on fruit biomass have not been observed in crop plants like melon, strawberry, cotton, apple, or tomato with increased tonoplast sugar transporter (TST) activity. Thus, it was unclear whether overexpression of TST in selected crops might lead to increased fruit yield, as observed in Arabidopsis. Here, we report that constitutive overexpression of TST1 from sugar beet in the important crop species Camelina sativa (false flax) resembles the seed characteristics observed for Arabidopsis upon increased TST activity. These effects go along with a stimulation of sugar export from source leaves and not only provoke optimised seed properties like higher lipid levels and increased overall seed yield per plant, but also modify the root architecture of BvTST1 overexpressing Camelina lines. Such mutants grew longer primary roots and showed an increased number of lateral roots, especially when developed under conditions of limited water supply. These changes in root properties result in a stabilisation of total seed yield under drought conditions. In summary, we demonstrate that increased vacuolar TST activity may lead to optimised yield of an oil‐seed crop species with high levels of healthy ω3 fatty acids in storage lipids. Moreover, since BvTST1 overexpressing Camelina mutants, in addition, exhibit optimised yield under limited water availability, we might devise a strategy to create crops with improved tolerance against drought, representing one of the most challenging environmental cues today and in future. [ABSTRACT FROM AUTHOR]

Background: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small‐molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC. Objectives: The aim of this non‐interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany. Methods: This non‐interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive. Results: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression‐free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified. Conclusions: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice. [ABSTRACT FROM AUTHOR]

Summary: The introduction of clinical antibodies against programmed death‐1 (PD‐1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) has revolutionized cancer treatment. Immune checkpoint blockade has enormous therapeutic potential and is widely prescribed for treating various cancers. However, immune‐related adverse events in checkpoint blockade‐treated patients are common and limit its clinical application. Despite efforts to understand the etiology of immune‐related adverse events, the underlying cellular reactions remain elusive. Recently, our group identified a subset of patients with metastatic melanoma that are predisposed to hepatitis after combined PD‐1 and CTLA‐4 blockade. These patients are characterized by pre‐treatment expansion of effector memory CD4+ T cells (TEM cells) in blood. We attributed this expansion to chronic or recurrent subclinical immune responses against cytomegalovirus (CMV) infection. Accordingly, baseline expansion of TEM cells is a reliable biomarker of hepatitis risk that identifies a subgroup of patients who might benefit from prophylactic CMV treatment with valganciclovir. [ABSTRACT FROM AUTHOR]

Aim: To analyze the influence of implantation volume of artificial sphincters (AMS 800) on outcome in a large central European multicenter cohort study. Methods: As part of the DOMINO (Debates on Male Incontinence) project, the surgical procedures and outcomes were retrospectively analyzed in a total of 473 patients who received an artificial sphincter (AMS 800) between 2010 and 2012. Clinics that implanted at least 10 AMS 800 per year were defined as high‐volume centers. Results: Sixteen centers had a mean rate of 9.54 AMS 800/y of which five clinics were identified as high‐volume centers. They implanted significantly more double cuffs (55% vs 12.1%; P <.001), used the perineal approach significantly more often (78% vs 67.7%; P =.003) and chose larger mean cuff sizes (4.63 cm vs 4.42 cm; P =.002). With a mean follow‐up of 18 months, the revision rate was significantly higher at low‐volume centers (38.5% vs 26.7%; P =.037), urethral erosion being the main reason for revision. Social continence (0‐1 pads/24 h) was achieved significantly more often in high‐volume centers (45.5% vs 24.2%; P =.002). Conclusions: Our study showed significantly better continence results and lower revision rates at high‐volume centers, confirming earlier results that are still true in this decade. We, therefore, recommend surgery for male incontinence at qualified centers. [ABSTRACT FROM AUTHOR]

Aims: To comparatively analyse outcomes after ARGUS classic and ArgusT adjustable male sling implantation in a real‐world setting. Methods: Inclusion criteria encompassed: non‐neurogenic, moderate‐to‐severe stress urinary incontinence (≥2 pads), implantation of an ARGUS classic or ArgusT male sling between 2010 and 2012 in a high‐volume center (>150 previous implantations). Functional outcomes were assessed using daily pad usage, 24‐hour pad testing, and International Consultation on Incontinence (ICIQ‐SF) questionnaires. Continence was defined as zero pads per 24 hours. Complications were graded using Clavien‐Dindo scale. For multivariate analysis, binary logistic regression models were used (P <.05). Results: A total of 106 patients (n = 74 [ARGUS classic], n = 32 [ArgusT]) from four centers were eligible. Median follow‐up was 44.0 months (24‐64). Patient cohorts were well‐balanced. We observed a statistical trend in favor of ARGUS classic regarding postoperative urine loss based on standardized 24‐hour pad test (71 ± 162 g [ARGUS classic] vs 160 ± 180 g [ArgusT]); P =.066]. Dry rates were 33.3% (ARGUS classic) and 11.8% (ArgusT, P =.114). In multivariable analysis, ArgusT male sling could not be confirmed as an independent predictor of decreased success (OR, 0.587; 95% CI; 0.166‐2.076, P =.408). There were no Clavien IV and V complications. Inguinal pain was significantly higher after ArgusT implantation (P =.033). Explantation rates were higher for ArgusT compared to ARGUS classic (14.0 vs 23.3%; P =.371). Longer device survival for the ARGUS classic male sling was observed in Kaplan‐Meier analysis (P =.198). Conclusions: In the largest comparative analysis of ARGUS classic and ArgusT male sling with the longest follow‐up to date, we observed low continence rates with superior functional outcomes and decreased explantation rates after ARGUS classic implantation. [ABSTRACT FROM AUTHOR]

The protein melanoma inhibitory activity (MIA) is known to be expressed in melanoma and to support melanoma progression. Interestingly, previous studies also observed the expression of MIA in nevi. Concentrating on these findings, we revealed that MIA expression is correlated with a senescent state in melanocytes. Induction of replicative or oncogene‐induced senescence resulted in increased MIA expression in vitro. Notably, MIA knockdown in senescent melanocytes reduced the percentage of senescence‐associated beta‐Gal‐positive cells and enhanced proliferation. Using the melanoma mouse model Tg(Grm1), MIA‐deficient mice supported the impact of MIA on senescence by showing a significantly earlier tumor onset compared to controls. In melanocytes, MIA knockdown led to a downregulation of the cell cycle inhibitor p21 in vitro and in vivo. In contrast, after induction of hTERT in human melanoma cells, p21 regulation by MIA was lost. In summary, our data show for the first time that MIA is a regulator of cellular senescence in human and murine melanocytes. [ABSTRACT FROM AUTHOR]

Purpose: To predict the persistence of storage symptoms after transurethral resection of the prostate (TURP) using a nomogram derived from the ice water test (IWT). Methods: The IWTs of 73 men with lower urinary tract symptoms and prostatic bladder outlet obstruction were retrospectively analyzed. The strength of the detrusor contraction was approximated by using the detrusor gradient of Δpdet/Δt at maximum detrusor pressure and the area under the curve. The parameters were utilized in a nomogram, which facilitated a severity categorization from 1 to 10. Patients with a positive IWT in the categories 1 to 2 were assigned to group A, categories 3 to 4 to group B and categories 5 and higher to group C. After TURP, patients with persisting storage symptoms were offered a botulinum toxin injection. Results: There were 32 patients (44%) with negative and 41 patients (56%) with positive IWTs. Patients with negative IWTs were classified in category 1. Regarding patients with positive IWTs, 14 (34%) were correlated to group A, 14 (34%) to group B, and 13 (32%) to group C. The necessity of a subsequent botulinum toxin injection correlated significantly with a higher nomogram category (P < .001) as well as higher severity categorization (P < .001). In multivariate analysis, the nomogram category was an independent predictor for botulinum toxin injection (P = .002, OR, 6.9, CI, 2.0‐23.9). Conclusion: The quantification of the detrusor contraction during the IWT allowed stratification of patients in risk categories for persistent storage symptoms after TURP and the potential need for later botulinum toxin injections. [ABSTRACT FROM AUTHOR]

For the first time in melanoma, novel therapies have recently shown efficacy in the adjuvant therapy setting, which makes companion diagnostics to guide treatment decisions a desideratum. Early spread of disseminated cancer cells (DCC) to sentinel lymph nodes (SLN) is indicative of poor prognosis in melanoma and early DCCs could therefore provide important information about the malignant seed. Here, we present a strategy for enrichment of DCCs from SLN suspensions using a microfluidic device (Parsortix™, Angle plc). This approach enables the detection and isolation of viable DCCs, followed by molecular analysis and identification of genetic changes. By optimizing the workflow, the established protocol allows a high recovery of DCC from melanoma patient‐derived lymph node (LN) suspensions with harvest rates above 60%. We then assessed the integrity of the transcriptome and genome of individual, isolated DCCs. In LNs of melanoma patients, we detected the expression of melanoma‐associated transcripts including MLANA (encoding for MelanA protein), analyzed the BRAF and NRAS mutational status and confirmed the malignant origin of isolated melanoma DCCs by comparative genomic hybridization. We demonstrate the feasibility of epitope‐independent isolation of LN DCCs using Parsortix™ for subsequent molecular characterization of isolated single DCCs with ample application fields including the use for companion diagnostics or subsequent cellular studies in personalized medicine. What's new? Early metastatic spread to sentinel lymph nodes provides important staging information for melanoma patients. In addition, adjuvant therapies are increasingly explored in node‐positive patients, making the availability of companion diagnostics necessary. Thus, here the authors established a protocol for the analysis of single disseminated cancer cells (DCCs) from lymph nodes applying a commercially available epitope‐independent microfluidic enrichment method. They show that cell suspension from lymph nodes can be processed and that microfluidics‐enriched cells are viable and amenable for subsequent molecular analysis. The presented workflow represents a novel tool for in‐depth characterization of lymph node‐derived cancer cells, including early metastasis precursors. [ABSTRACT FROM AUTHOR]

Background: Testicular germ cell tumor (TGCT) is one the most common solid tumors in men between the age of 15 and 35 with an overall incidence rate of 1–1.5 %. Epidemiologic studies have demonstrated different incidence patterns in western civilized countries with overall rising incidence trends. Objective: To analyze differences in regional tumor incidence rates for TGCT and perform a trend analysis for TGCT between 2003 and 2014 in Germany. Material and methods: TGCT cases in Germany which were diagnosed between 2003 and 2014 were provided by the Robert‐Koch‐Institute, Berlin. For statistical analysis, cluster and spatial scan tests according to Kulldorff were used for cases with seminoma and non‐seminoma. Results are presented in administrative districts and graphically illustrated. We performed a trend‐analysis in order to evaluate age‐adjusted incidence trends in Germany. Tests were two‐sided with a level of significance of α=0.05. Results: In total we included 35,066 patients. Overall, 22,634 cases had newly diagnosed seminoma and 12,432 were diagnosed as non‐seminoma. Maximum incidence of seminoma and non‐seminoma was observed for age‐group 38–40 years and 26–28 years, respectively. No second peak for the incidences of seminoma and non‐seminoma with respect to age were observed. Cluster analysis revealed areas with high and low incidence rates as well as slightly different spatial distribution in Germany between seminoma and nonseminoma. Furthermore, there was no significant increase in age‐adjusted incidence rates over the reviewed time period in both cohorts. Discussion: In this study differences in reginal tumor incidence rates for seminoma and non‐seminoma are reported with both tumor entities revealing distinct clusters. Furthermore, tumor incidence trends for seminoma and nonseminoma between 2003 and 2014 were stable which might indicate the beginning of a plateau phase for TGCT incidence rates in Germany. Conclusion: In this analysis we were able to identify regions with significantly higher tumor incidence rates for both seminoma and non‐seminoma which were specific for these two subtypes. Furthermore, trend analysis revealed a steady incidence rate for testicular cancer in Germany. [ABSTRACT FROM AUTHOR]

Background: In humans, there are four known proton‐sensing G‐Protein‐coupled receptors (pH‐GPCRs): GPR4 (GPR19), TDAG8 (GPR65, T‐cell death‐associated gene 8), OGR1 (GPR68, ovarian cancer GPCR1) and G2A (GPR132, G2 accumulation protein). They are known to be involved in sensing changes of extracellular proton concentrations in the acidic microenvironment of tumors, which leads to altered cell proliferation, migration, metastasis, immune cell function and inflammation. However, little is known about the expression of pH‐GPCRs in the skin and especially skin cancers. Aim: We studied the expression of pH‐GPCRs in selected skin cancers, that is Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Methods: We did immunohistochemistry and immunofluorescence to analyse the expression of GPR4, TDAG8, OGR1 and G2A using paraffin‐embedded tissue samples (n = 4, exceptions: PDS GPR4/GPR65 n = 5, AFX GPR132 n = 3) from patients suffering from MCC, DFSP, AFX and PDS. Results: (a) GPR4 was expressed on all AFX and PDS specimens. All AFX and MCC showed a positive expression of G2A. All PDS exhibited a strong positive expression of G2A. (b) MCCs neither expressed GPR4 nor TDAG8. All DFSP showed no expression of TDAG8. (c) For any other combination of GPCR and skin disease, we found positive/negative mixed results. Conclusions: These are the first results on pH‐GPCRs in selected skin cancers. We provide evidence that these GPCRs are differentially expressed on the various types of skin cancers and that they can potentially be addressed as a therapeutic target in extensive disease. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the significance of the ice water test in patients with multiple sclerosis and to evaluate a novel ice water test nomogram in a large patient cohort. Methods: A total of 201 ice water tests of patients with multiple sclerosis were retrospectively evaluated. Incontinence episodes in 24 h and sex were correlated with the ice water test. Furthermore, an ice water test nomogram was developed in order to categorize the detrusor overactivity in severity degrees. Descriptive statistics were carried out for population characteristics. Correlations of categorical variables were calculated by the χ2‐test. The independent t‐test was carried out for correlations of continuous variables. Furthermore, the data were evaluated in the novel ice water test nomogram. Results: The patient population consisted of 141 (70.1%) women and 60 (39.9%) men. A clinically positive ice water test (maximum detrusor pressure >15 cmH2O) was identified in 75 patients (37.3%). Significantly more men presented a clinically positive ice water test (P = 0.006). In 16.5%, the ice water test unmasked an involuntary detrusor contraction, although routine cystometry did not show any detrusor overactivity. The ice water test nomogram could be successfully applied. The incontinence episodes and maximum detrusor pressure correlated positively with a higher categorization in the nomogram. Therapeutic interventions and follow‐up controls could be successfully illustrated by the nomogram. Conclusions: The ice water test is a simple tool for unmasking non‐identified detrusor overactivity in neurogenic bladder dysfunction. A severity categorization of the detrusor overactivity can be facilitated by the use of the ice water test nomogram. After further validation, the ice water test could be ultimately used in future as objective assessment for bladder dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: Zur Untersuchung von Mahlreaktionen in Echtzeit wurden drei analytische Methoden gekoppelt: Synchrotron‐Röntgenbeugung mit Raman‐Spektroskopie und Thermographie. Diese Methodenkombination ermöglicht es, die strukturelle Entwicklung mit Temperaturinformationen zu korrelieren. Die Temperaturinformation ist entscheidend für das Verständnis von Thermodynamik und Reaktionskinetik. Exemplarisch wurde der Reaktionsmechanismus von drei mechanochemischen Modell‐Synthesen, einer Cokristallbildung, einer C‐C‐Bindungsknüpfung (Knoevenagel‐Kondensation) und der Bildung einer metallorganischen Verbindung, eines Mangan‐Phosphonats, aufgeklärt. Allgemeine Trends bezüglich der Temperaturentwicklung beim Mahlen konnten identifiziert werden. Die Reaktions‐ und Kristallisationswärme tragen zur gesamten Temperaturerhöhung bei. Eine Erniedrigung der Temperatur tritt bei Freisetzung von z. B. Wasser als Nebenprodukt auf. Die drei unabhängigen Methoden ergänzen sich gegenseitig, wodurch der Informationsgewinn maximiert und der Nachweis fester sowie flüssiger Intermediate ermöglicht wird. Schließlich konnte der Einfluss der mechanischen Einwirkung von den durch die Reaktion hervorgerufenen Temperatureinflüssen unterschieden werden. [ABSTRACT FROM AUTHOR]

Abstract: We present an in situ triple coupling of synchrotron X‐ray diffraction with Raman spectroscopy, and thermography to study milling reactions in real time. This combination of methods allows a correlation of the structural evolution with temperature information. The temperature information is crucial for understanding both the thermodynamics and reaction kinetics. The reaction mechanisms of three prototypical mechanochemical syntheses, a cocrystal formation, a C−C bond formation (Knoevenagel condensation), and the formation of a manganese‐phosphonate, were elucidated. Trends in the temperature development during milling are identified. The heat of reaction and latent heat of crystallization of the product contribute to the overall temperature increase. A decrease in temperature occurs via release of, for example, water as a by‐product. Solid and liquid intermediates are detected. The influence of the mechanical impact could be separated from temperature effects caused by the reaction. [ABSTRACT FROM AUTHOR]

Objective To evaluate the impact of preoperative risk category on metastatic disease and prostate cancer-specific mortality ( CSM) in patients with prostate cancer ( PCa) with adverse pathology at radical prostatectomy ( RP). Patients and Methods The records of 6 943 patients who underwent RP at a European tertiary centre were analysed. Biochemical recurrence ( BCR), metastatic disease and CSM were assessed for patients with adverse pathology at RP, and stratified according to preoperative low- vs intermediate-/high-risk PCa groups. Kaplan-Meier, cumulative incidence, Cox regression and competing risk regression analyses were performed. Results In patients with extracapsular extension, the metastatic disease rate was 1.6% vs 8% ( P < 0.001) and the CSM rate was 2% vs 5% ( P = 0.041) for low vs intermediate-/high-risk patients, respectively, at 10 years. In patients with pathological Gleason score ≥3+4, the metastatic disease rate was 3.0% vs 12% ( P < 0.001) and the CSM rate was 3% vs 8%, respectively ( P < 0.001). In patients with positive surgical margins ( PSMs), the metastatic disease rate was 2.9% vs 15% ( P < 0.001) and the CSM rate was 4% vs 10%, respectively ( P = 0.0001). Low-risk status was a predictive factor for metastatic disease in patients with pathological Gleason score ≥3+4 (hazard ratio [ HR] 0.51), pathological Gleason score ≥4+3 ( HR 0.41) and PSMs ( HR 0.46) and was a predictive factor for CSM risk in patients with pathological Gleason score ≥3+4 ( HR 0.62). Conclusions Patients with low-risk PCa were at significantly lower risk of metastatic disease and CSM than their intermediate-/high-risk counterparts, when adverse pathological features were identified at RP. This should be emphasized in the decision-making process after RP. [ABSTRACT FROM AUTHOR]

Background Gathering health information from Internet websites is increasingly utilized by patients. No data exist about hidradenitis suppurativa ( HS)-related online health information. Thus, we aimed to study the quality, popularity, readability, and timeliness of the most frequented websites on HS. Methods Google Trends was used to evaluate the public interest in HS. An Internet search on Google was performed for the terms 'hidradenitis suppurativa,' 'acne inversa,' and 'Verneuil's disease.' Readability scores, HONcode quality certification, Alexa popularity rank, and content were assessed. Results Google search queries on HS have steadily risen in the last 10 years. The website analysis revealed 39 unique websites, which were difficult to read. Ten websites (26%) had HONcode quality certification, and the median ( IQR) Alexa popularity rank was 48871 (2333-361275). Thirteen websites (33%) yielded disease-specific photos with a median rating between 'quite useful' and 'uncertain.' A therapy option with adalimumab was mentioned on 11 websites (28%). Conclusions In addition to an increasing interest, we found a broad variation in the quality, readability, popularity, and timeliness of content on HS-related websites. Improvement of the quality and readability of HS-related websites is desirable to potentially raise disease awareness and contribute to an earlier presentation of patients suffering with undiagnosed HS. [ABSTRACT FROM AUTHOR]

Diatom plastids show several peculiarities when compared with primary plastids of higher plants or algae. They are surrounded by four membranes and depend on nucleotide uptake because, unlike in plants, nucleotide de novo synthesis exclusively occurs in the cytosol. Previous analyses suggest that two specifically adapted nucleotide transporters ( NTTs) facilitate the required passage of nucleotides across the innermost plastid membrane. However, nucleotide transport across the additional plastid membranes remains to be clarified., Phylogenetic studies, transport assays with the recombinant protein as well as GFP-based targeting analyses allowed detailed characterization of a novel isoform ( Pt NTT5) of the six NTTs of Phaeodactylum tricornutum., Pt NTT5 exhibits low amino acid similarities and is only distantly related to all previously characterized NTTs. However, in a heterologous expression system, it acts as a nucleotide antiporter and prefers various (deoxy-) purine nucleotides as substrates. Interestingly, Pt NTT5 is probably located in the endoplasmic reticulum, which in diatoms also represents the outermost plastid membrane., Pt NTT5, with its unusual transport properties, phylogeny and localization, can be taken as further evidence for the establishment of a sophisticated and specifically adapted nucleotide transport system in diatom plastids. [ABSTRACT FROM AUTHOR]

The long-term propagation of basal prostate progenitor cells ex vivo has been very difficult in the past. The development of novel methods to expand prostate progenitor cells in vitro allows determining their cell surface phenotype in greater detail. Mouse (Lin−Sca-1+ CD49f+ Trop2high-phenotype) and human (Lin− CD49f+ TROP2high) basal prostate progenitor cells were expanded in vitro. Human and mouse cells were screened using 242 anti-human or 176 antimouse monoclonal antibodies recognizing the cell surface protein profile. Quantitative expression was evaluated at the single-cell level using flow cytometry. Differentially expressed cell surface proteins were evaluated in conjunction with the known CD49f+/ TROP2high phenotype of basal prostate progenitor cells and characterized by in vivo sandwich-transplantation experiments using nude mice. The phenotype of basal prostate progenitor cells was determined as CD9+/ CD24+/ CD29+/ CD44+/ CD47+/ CD49f+/ CD104+/ CD147+/ CD326+/Trop2high of mouse as well as human origin. Our analysis revealed several proteins, such as CD13, Syndecan-1 and stage-specific embryonal antigens ( SSEAs), as being differentially expressed on murine and human CD49f+ TROP2+ basal prostate progenitor cells. Transplantation experiments suggest that CD49f+ TROP2high SSEA-4high human prostate basal progenitor cells to be more potent to regenerate prostate tubules in vivo as compared with CD49f+ TROP2high or CD49f+ TROP2high SSEA-4low cells. Determination of the cell surface protein profile of functionally defined murine and human basal prostate progenitor cells reveals differentially expressed proteins that may change the potency and regenerative function of epithelial progenitor cells within the prostate. SSEA-4 is a candidate cell surface marker that putatively enables a more accurate identification of the basal PESC lineage. [ABSTRACT FROM AUTHOR]

Merkel cell polyomavirus (MCPyV) is regarded as a major causal factor for Merkel cell carcinoma (MCC). Indeed, tumor cell growth of MCPyV-positive MCC cells is dependent on the expression of a truncated viral Large T antigen (LT) with an intact retinoblastoma protein (RB)-binding site. Here we determined the phosphorylation pattern of a truncated MCPyV-LT characteristically for MCC by mass spectrometry revealing MCPyV-LT as multi-phospho-protein phosphorylated at several serine and threonine residues. Remarkably, disruption of most of these phosphorylation sites did not affect its ability to rescue knockdown of endogenous T antigens in MCC cells indicating that phosphorylation of the respective amino acids is not essential for the growth promoting function of MCPyV-LT. However, alteration of serine 220 to alanine completely abolished the ability of MCPyV-LT to support proliferation of MCC cells. Conversely, mimicking the phosphorylated state by mutation of serine 220 to glutamic acid resulted in a fully functional LT. Moreover, MCPyV-LTS220A demonstrated reduced binding to RB in co-immunoprecipitation experiments as well as weaker induction of RB target genes in MCC cells. In conclusion, we provide evidence that phosphorylation of serine 220 is required for efficient RB inactivation in MCC and may therefore be a potential target for future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective To externally validate the pT4a-specific risk model for cancer-specific survival ( CSS) proposed by May et al. ( Urol Oncol 2013; 31: 1141-1147) and to develop a new pT4a-specific nomogram predicting CSS in an international multicentre cohort of patients undergoing radical cystectomy ( RC) for urothelial carcinoma of the bladder ( UCB), Patients and Methods Data from 856 patients with pT4a UCB treated with RC at 21 centres in Europe and North- America were assessed., The risk model proposed by May et al., which includes female gender, presence of positive lymphovascular invasion ( LVI) and lack of adjuvant chemotherapy administration as adverse predictors for CSS, was applied to our cohort., For the purpose of external validation, model discrimination was measured using the receiver-operating characteristic-derived area under the curve., A nomogram for predicting CSS in pT4a UCB after RC was developed after internal validation based on multivariable Cox proportional hazards regression analysis evaluating the impact of clinicopathological variables on CSS., Decision-curve analyses were applied to determine the net benefit derived from the two models., Results The estimated 5-year- CSS after RC was 34% in our cohort., The risk model devised by May et al. predicted individual 5-year- CSS with an accuracy of 60.1%., In multivariable Cox proportional hazards regression analysis, female gender (hazard ratio [ HR] 1.45), LVI ( HR 1.37), lymph node metastases ( HR 2.54), positive soft tissue surgical margins ( HR 1.39), neoadjuvant ( HR 2.24) and lack of adjuvant chemotherapy ( HR 1.67, all P < 0.05) were independent predictors of an adverse CSS rate and formed the features of our nomogram with a predictive accuracy of 67.1%., Decision-curve analyses showed higher net benefits for the use of the newly developed nomogram in our cohort over all thresholds., Conclusions The risk model devised by May et al. was validated with moderate discrimination and was outperformed by our newly developed pT4a-specific nomogram in the present study population., Our nomogram might be particularly suitable for postoperative patient counselling in the heterogeneous cohort of patients with pT4a UCB. [ABSTRACT FROM AUTHOR]

A significant proportion of men diagnosed with prostate cancer ( PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase ( HDAC) inhibitor valproic acid ( VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha ( IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and β subtypes were investigated by flow cytometry, western blotting and RT- PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients. [ABSTRACT FROM AUTHOR]

Merkel cell polyomavirus (MCPyV)-positive Merkel cell carcinoma (MCC) tumor cell growth is dependent on the expression of a viral Large T antigen (LT) with an intact retinoblastoma protein (RB)-binding site. This RB-binding domain in MCPyV-LT is-in contrast to other polyomavirus LTs ( e.g., SV40)-embedded between two large MCPyV unique regions (MUR1 and MUR2). To identify elements of the MCPyV-LT necessary for tumor cell growth, we analyzed the rescue activity of LT variants following knockdown of the endogenous LT in MCC cells. These experiments demonstrate that nuclear localization is essential for LT function, but that a motif previously described to be a nuclear localization sequence is neither required for nuclear accumulation of truncated MCPyV-LT nor for promotion of MCC cell proliferation. Furthermore, large parts of the MURs distal to the RB binding domain as well as ALTO-a second protein encoded by an alternative reading frame in the MCPyV-LT mRNA-are completely dispensable for MCPyV-driven tumor cell proliferation. Notably, even MCPyV-LTs in which the entire MURs have been removed are still able to promote MCC cellular growth although rescue activity is reduced which may be due to MUR1 being required for stable LT expression in MCC cells. Finally, we provide evidence implying that-while binding to Vam6p is not essential-HSC-70 interaction is significantly involved in mediating MCPyV-LT function in MCC cells including growth promotion and induction of E2F target genes. [ABSTRACT FROM AUTHOR]

In the first part of this article, the deductive hazard analysis and its extension by a semi-quantitative risk assessment of sources of hazards were presented. This was done by using a calibrated risk graph. In this second part now, the semi-quantitative assessment of the dependability of safety measures is pointed out. The safety check is carried out by comparing the risk classes with dependability classes which are applied to both operational and technical measures. Now this paper describes the requirements for ROGA arising from the stipulations of the international standards like IEC 61508/11. [ABSTRACT FROM AUTHOR]

This paper proposes a new method, risk-oriented hazard analysis (ROGA), for carrying out the risk-based hazard analysis of chemical plants. The aim of ROGA method is to determine the status of a plant's safety technology by determining the risk that arises as a result of a source of hazard taking effect and by evaluating all measures taken to control this risk. The contribution consists of two parts. In this first part, the deductive hazard analysis and its extension by a semi-quantitative risk assessment associated with sources of hazards is explained with the help of a risk graph. [ABSTRACT FROM AUTHOR]

Sequential application of target drugs is standard procedure after renal cell carcinoma ( RCC) patients develop resistance. To optimize the sequence, antitumour effects of the mTOR inhibitor RAD001 or the tyrosine kinase inhibitor ( TKI) sorafenib on RCC cells with acquired resistance to the TKI sunitinib was evaluated. RCC cells were exposed to 1 μM sunitinib for 24 hrs (as control) and for 8 weeks (to induce resistance) and then switched to RAD001 (5 nM) or sorafenib (5 μM) for a further 8 weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short-term application of sunitinib (24 hrs) induced cell growth blockade with accumulation in the G2/M phase. RCC cells became resistant to sunitinib after 8 weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant RCC cells and molecular analysis indicated distinct cross-resistance. In contrast, full response was achieved when the cancer cells were treated with RAD001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0/G1. It is concluded that an mTOR-inhibitor for second-line therapy could be the strategy of choice after first-line sunitinib failure. [ABSTRACT FROM AUTHOR]