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Abstract Background Recently, we introduced Stroma-AReactive-Invasion-Front-Areas (SARIFA) as a novel hematoxylin–eosin (H&E)-based histopathologic prognostic biomarker for various gastrointestinal cancers, closely related to lipid metabolism. To date, no studies on SARIFA, which is defined as direct tumor-adipocyte-interaction, beyond the alimentary tract exist. Hence, the objective of our current investigation was to study the significance of SARIFA in pT3a prostate cancer (PCa) and explore its association with lipid metabolism in PCa as lipid metabolism plays a key role in PCa development and progression. Methods To this end, we evaluated SARIFA-status in 301 radical prostatectomy specimens and examined the relationship between SARIFA-status, clinicopathological characteristics, overall survival, and immunohistochemical expression of FABP4 and CD36 (proteins closely involved in fatty-acid metabolism). Additionally, we investigated the correlation between SARIFA and biochemical recurrence-free survival (BRFS) and PSMA-positive recurrences in PET/CT imaging in a patient subgroup. Moreover, a quantitative SARIFA cut-off was established to further understand the underlying tumor biology. Results SARIFA positivity occurred in 59.1% (n = 178) of pT3a PCas. Our analysis demonstrated that SARIFA positivity is strongly associated with established high-risk features, such as R1 status, extraprostatic extension, and higher initial PSA values. Additionally, we observed an upregulation of immunohistochemical CD36 expression specifically at SARIFAs (p = 0.00014). Kaplan–Meier analyses revealed a trend toward poorer outcomes, particularly in terms of BRFS (p = 0.1). More extensive tumor-adipocyte interaction, assessed as quantity-dependent SARIFA-status on H&E slides, is also significantly associated with high-risk features, such as lymph node metastasis, and seems to be associated with worse survival outcomes (p = 0.16). Moreover, SARIFA positivity appeared to be linked to more distant lymph node and bone metastasis, although statistical significance was slightly not achieved (both p > 0.05). Conclusions This is the first study to introduce SARIFA as easy-and-fast-to-assess H&E-based biomarker in locally advanced PCa. SARIFA as the histopathologic correlate of a distinct tumor biology, closely related to lipid metabolism, could pave the way to a more detailed patient stratification and to the development of novel drugs targeting lipid metabolism in pT3a PCa. On the basis of this biomarker discovery study, further research efforts on the prognostic and predictive role of SARIFA in PCa can be designed.

Photocathode laser pulse shaping is a crucial technology for enhancing the performance of X-ray free-electron lasers by optimizing the quality of electron beams generated from photocathodes within high-gradient radio frequency guns. By precisely shaping these laser pulses, it is possible to significantly reduce the transverse emittance of produced electron bunches. The optimal pulse shape is an ellipsoidal distribution, commonly referred to as the Kapchinskij–Vladimirskij profile. A pulse-shaping scheme utilizing a commercial Yb:KGW laser operating at 514 nm with a repetition rate of 1 MHz and duration of 260 fs has been developed for generating electron bunches with high peak and average power. This study presents the experimental realization of ellipsoidal pulses via three-dimensional amplitude shaping using spatial light modulators at 514 nm, followed by conversion to UV (257 nm) suitable for Cs 2Te photocathodes. The preservation of pulse shape and a high conversion efficiency during this process are investigated and our experiments pave the way for future emittance minimization for X-ray free-electron lasers.

The high peak current of the electron beam was found to be the key parameter for the THz SASE FEL at the Photo Injector Test facility at DESY in Zeuthen (PITZ). A multipurpose bunch compressor was implemented at PITZ to expand the parameter space of proof-of-principle studies on the tunable high-power accelerator-based THz source for pump-probe experiments at the European XFEL. The magnetic chicane, consisting of four rectangular dipole magnets, is designed with a bending angle of 19 degrees, due to limited space in the PITZ original beamline, to compress electron bunches with a beam momentum of 15–20 MeV/c and a charge up to 2 nC. The space charge effect and coherent synchrotron radiation are expected to drastically affect the bunch compressor performance for these parameters, thereby challenging the beam transport throughout the bunch compressor. A staged commissioning strategy was developed in order to achieve optimum bunch compressor operation. The first commissioning procedure establishes electron beam transport throughout the reference path and provides minimum beam momentum dispersion after the bunch compressor. This procedure yielded correlations between dipole magnet currents. As a result, the first bunch compression experiments were performed.

Abstract The current handling of data in earth observation, modelling and prediction measures gives cause for critical consideration, since we all too often carelessly ignore data uncertainty. We think that Earth scientists are generally aware of the importance of linking data to quantitative uncertainty measures. But we also think that uncertainty quantification of Earth observation data too often fails at very early stages. We claim that data acquisition without uncertainty quantification is not sustainable and machine learning and computational modelling cannot unfold their potential when analysing complex natural systems like the Earth. Current approaches such as stochastic perturbation of parameters or initial conditions cannot quantify uncertainty or bias arising from the choice of model, limiting scientific progress. We need incentives stimulating the honest treatment of uncertainty starting during data acquisition, continuing through analysis methodology and prediction results. Computational modellers and machine learning experts have a critical role, since they enjoy high esteem from stakeholders and their methodologies and their results critically depend on data uncertainty. If both want to advance their uncertainty assessment of models and predictions of complex systems like the Earth, they have a common problem to solve. Together, computational modellers and machine learners could develop new strategies for bias identification and uncertainty quantification offering a more all‐embracing uncertainty quantification than any known methodology. But since it starts for computational modellers and machine learners with data and their uncertainty, the fundamental first step in such a development would be leveraging shareholder esteem to insistently advocate for reduction of ignorance when it comes to uncertainty quantification of data.

The DigiMon project aims to develop and demonstrate an affordable, flexible, societally embedded, and smart digital monitoring early warning system for any subsurface CO2 storage field. The societal embeddedness level (SEL) assessment is a novel methodology which provides insight into the societal requirements for technological innovation to be deployed. The SEL assessment framework was applied in four case studies, concerning CCS development in Norway, the Netherlands, Greece, and Germany. The resulting societal embeddedness levels of CCS, on a scale of 1–4, were SEL 3 in Norway with considerable progress towards level 4, followed by the Netherlands with SEL 2 with several initiatives towards offshore demonstration projects, and then by Greece and Germany with SEL 1. The outcomes of the SEL assessments show which societal requirements have been met in current CCS developments and which ones should be improved for CCS deployment. They also show that monitoring currently is a regulatory requirement as part of permitting procedures, while it may alleviate community concerns on safety, provided that it has certain attributes. The insights from the four national case studies are further used in the DigiMon project to develop the innovative societal embedded DigiMon monitoring system.

A key issue of X-ray free-electron lasers is the quality of the photoelectron beams generated from a photocathode by laser pulses in the high-gradient RF gun. Controlling the shape of these laser pulses can strongly reduce the transverse emittance of the generated electron bunch. For this purpose, a laser pulseshaper at 515 nm is presented that can be used directly with alkali antimonide photocathodes for photoemission. The first results regarding generation and measurement of flattop and parabolic pulses as well as introduction of modulations for THz generation are presented and show the potential for emittance optimization with 3D ellipsoidal pulses with the proposed pulseshaper. The experiments are carried out for Cs2Te photocathodes, which require second harmonic generation of the shaped pulses and thus allow investigation of pulseshape preservation in nonlinear frequency conversion processes.

Despite some well-characterized functions in cancer, the impact of most long non-coding RNAs remains unknown. Here, the authors discover the lncRNA lincNMR which is upregulated in cancer and drives cell proliferation by interacting with YBX1 and controlling nucleotide metabolism.

Photoinjectors are the main high brightness electron sources for x-ray free electron lasers (XFELs). Photoinjector emittance reduction is one of the key knobs for improving XFEL lasing, so precise emittance measurement is critical. It is well known that rms emittance is very sensitive to low intensity tails of particle distributions in the phase space, whose measurement depends on the signal to noise ratio and image processing procedures. Such sensitivities make the interpretations of beam transverse brightness challenging, leading to different emittance definitions to reduce the impact of tail particles. In this paper, transverse phase space is analyzed in action and phase coordinates for both analytical models and experiments, which gives a more intuitive way to calculate the beam core brightness.

Energy transitions inherit complex processes full of surprises, unintended consequences, erroneous decisions, uncertainties, paradoxical situations, and sometimes sheer failures [...]

Slice energy spread is one of the key parameters in free electron laser optimizations, but its accurate measurement is not straightforward. Two recent studies from high energy (≥100 MeV) photoinjectors at SwissFEL and European x-ray free electron laser (XFEL) have reported much higher slice energy spread than expected at their XFEL working points (200–250 pC). In this paper, a new method for measuring slice energy spread at lower beam energy (∼20 MeV) is proposed and demonstrated at the PhotoInjector Test facility at DESY Zeuthen, and the results for 250 pC are much lower than those measured at high energy injectors.

Interdisciplinary and transdisciplinary collaboration has become a common practice in technology development projects. Rarely, however, the integration (and translation) of knowledge from different disciplines and different societal contexts is reported in detail. In this article, we address this gap and present the inter- and transdisciplinary technology development in the international research project “DigiMon—Digital Monitoring of CO2 Storage Projects” that aims to develop a human-centered monitoring system. Based on interviews, surveys and stakeholder workshops in Norway, Greece, Germany and The Netherlands, we identify characteristics of CO2 storage monitoring systems that reflect the concerns and expectations of publics and stakeholders. We document the translation of social scientific findings into technical expertise for the design of a monitoring system. We discuss how the interdisciplinary and transdisciplinary process has affected the technology development. In outlining how this process was set up, carried out and validated, we are able to show a viable route for the meaningful incorporation of heterogeneous knowledge in complex energy infrastructures. Furthermore, we discuss the features of the project organization that made this comprehensive process possible. Thus, our results contribute to inter- and transdisciplinary research organization in general and to the development of methods for monitoring CO2 storage in particular.

Synonymous mutations do not alter amino acid sequence but may exert oncogenic effects in other ways. Here, the authors present a catalogue of synonymous mutations in cancer and characterise their properties.

The next generation of accelerator based scientific facilities, such as the megahertz repetition rate free electron laser and electron-ion collider, relies on photoelectron sources of high peak and high average brightness. Therefore, photocathodes with both low transverse momentum spread (TMS) and high quantum efficiency (QE) are required. The conventional positive correlation between QE and TMS leads to a tradeoff between peak and average brightness. In this study, a negative correlation between QE and TMS is experimentally observed for the first time on a semiconductor photocathode (Cs_{2}Te). Two models are proposed to explain such an anomalous correlation. One model considers the junction between the semiconductor cathode and the metal substrate in the case of slightly excessive cesium deposition, and the other model considers different Cs-Te composites. Our studies inspire a new way to break the conventional correlation between QE and TMS, and open a new perspective to advance the beam brightness frontiers.

Anti-NMDA receptor encephalitis is the most common type of antibody mediated autoimmune encephalitis (AIE). Patients often develop neuropsychiatric symptoms and seizures, women are affected about four times more than men, and in about 50% the disease is associated with a neoplasia, especially teratomas of the ovary. We describe the case of a 20-year-old woman suffering from a severe therapy refractory course of anti-NMDA receptor encephalitis. Treatment included glucocorticoids, plasma exchange, intravenous immunoglobulins, rituximab, and bortezomib without clinical improvement. Due to a therapy refractive course 28 weeks after disease onset, the patient received 10 cycles of daratumumab. Therapy escalation was performed with the anti-CD38 monoclonal antibody daratumumab as off label treatment, based on the therapy of refractory myeloma and led to an improvement of her clinical status. She spent about 200 days on the intensive care unit, followed by several weeks on the intermediate care unit with close follow ups every 4–6 weeks afterward. During follow-up, the patient was able to resume everyday and self-care activities, reflected by the modified Rankin scale (mRS) and Barthel index. Because this disease is potentially life threatening and can lead to irreversible brain atrophy, development of further therapy strategies are of great importance. Our case describes a successful treatment for therapy refractory anti-NMDA receptor encephalitis using the anti-CD38 antibody daratumumab.

Abstract In recent years, long non-coding RNA (lncRNA) research has identified essential roles of these transcripts in virtually all physiological cellular processes including tumorigenesis, but their functions and molecular mechanisms are poorly understood. In this study, we performed a high-throughput siRNA screen targeting 638 lncRNAs deregulated in cancer entities to analyse their impact on cell division by using time-lapse microscopy. We identified 26 lncRNAs affecting cell morphology and cell cycle including LINC00152. This transcript was ubiquitously expressed in many human cell lines and its RNA levels were significantly upregulated in lung, liver and breast cancer tissues. A comprehensive sequence analysis of LINC00152 revealed a highly similar paralog annotated as MIR4435-2HG and several splice variants of both transcripts. The shortest and most abundant isoform preferentially localized to the cytoplasm. Cells depleted of LINC00152 arrested in prometaphase of mitosis and showed reduced cell viability. In RNA affinity purification (RAP) studies, LINC00152 interacted with a network of proteins that were associated with M phase of the cell cycle. In summary, we provide new insights into the properties and biological function of LINC00152 suggesting that this transcript is crucial for cell cycle progression through mitosis and thus, could act as a non-coding oncogene.

In state of the art photoinjector electron sources, thermal emittance from photoemission dominates the final injector emittance. Therefore, low thermal emittance cathode developments and diagnostics are very important. Conventional thermal emittance measurements for the high gradient gun are time-consuming and thus thermal emittance is not measured as frequently as quantum efficiency during the lifetime of photocathodes, although both are important properties for the photoinjector optimizations. In this paper, a single shot measurement of photoemission transverse momentum, i.e., thermal emittance per rms laser spot size, is proposed for photocathode rf guns. By tuning the gun solenoid focusing, the electrons’ transverse momenta at the cathode are imaged to a downstream screen, which enables a single shot measurement of both the rms value and the detailed spectra of the photoelectrons’ transverse momenta. Both simulations and proof of principle experiments are reported.

Los combustibles fósiles no-renovables hicieron posible lo que se ha llamado el mundo moderno. Dado que los recursos no renovables son cada vez más difíciles y costosos de extraer, la transición a fuentes de energías renovables es una tarea crucial. En orden a enmarcar posibles caminos hacia la innovación responsable y transición dentro de las sociedades democráticas, este artículo se construye en torno al concepto de experimentos “terrenales” o fuera-del-laboratorio para destacar algunas de las condiciones y procesos que pueden promover procesos colectivos de aprendizaje. Esto es hecho por medio de ejemplos empíricos con respecto al establecimiento de sistemas de energía geotérmicas. El artículo trabajará sobre la noción sociológica de experimentos terrenales, entendiéndolos como parte sustantiva de la sociedad, con el fin de destacar críticamente qué podría significar una “ciencia” así concebida para una ciudadanía democráticamente constituida. El artículo mostrará cómo estos procesos experimentales lidian con cuestiones referentes a la aceptabilidad y la gobernanza democrática, y de qué manera aparecen y se gestionan los límites de la experimentalidad de cara a sus desafíos políticos. Mostramos que los “experimentos a la intemperie” tendrán que enfrentarse con incertidumbres crecientes y la inevitable ignorancia que complica las condiciones para la transición hacia energías renovables, pero que también pueden abrir nuevos caminos para involucrar a la ciudadanía en procesos de exploración tecnocientífica.

Recently, muscle-invasive bladder cancer (MIBC) has been subclassified by gene expression profiling, with a substantial impact on therapy response and patient outcome. We tested whether these complex molecular subtypes of MIBC can be determined by mRNA detection of keratin 5 (KRT5) and keratin 20 (KRT20). Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was applied to quantify gene expression of KRT5 and KRT20 using TaqMan®-based assays in 122 curatively treated MIBC patients (median age 68.0 years). Furthermore, in silico analysis of the MD Anderson Cancer Center (MDACC) cohort (GSE48277 + GSE47993) was performed. High expression of KRT5 and low expression of KRT20 were associated with significantly improved recurrence-free survival (RFS) and disease-specific survival disease specific survival (DSS: 5-year DSS for KRT5 high: 58%; 5-year DSS for KRT20 high: 29%). KRT5 and KRT20 were associated with rates of lymphovascular invasion and lymphonodal metastasis. The combination of KRT5 and KRT20 allowed identification of patients with a very poor prognosis (KRT20+/KRT5−, 5-year DSS 0%, p < 0.0001). In silico analysis of the independent MDACC cohorts revealed congruent results (5-year DSS for KRT20 low vs. high: 84% vs. 40%, p = 0.042). High KRT20-expressing tumors as well as KRT20+/KRT− tumors were significantly enriched with aggressive urothelial carcinoma variants (micropapillary, plasmacytoid, nested).

Whereas different types of risk assessments are important, real world decision making in processes of restoring contaminated land often necessitates an open acknowledgement that ignorance cannot be avoided. In this presentation a sociological reconstruction of different examples of real world decision making is offered to discuss some of the strategies used to cope with ongoing situations involving ignorance in the remediation of areas containing multiple contaminant sources. Analysis of these processes of dealing with the unknown indicates that planning and policy making benefit when limits to knowledge are openly acknowledged and communicated and when scientific‐technical risk assessments are calibrated with these limits in mind. If ignorance is taken as unavoidable, the allocation of blame radically changes its meaning. Such processes can be seen as a lynchpin of successful planning and acting in face of unknowns during remediation processes on contaminated land.

Open source software is software designed to allow anyone to use and make changes in the software. This practice often renders the product superior to more centralized models such as those used in commercial software companies. How is such a phenomenon possible in a time where nothing seems to be acquirable save by purchase? Niels C. TAUBERT's book Productive Anarchy? Networks of Open Source Software Development aims at a sociological understanding of the prerequisites and conditions for the success of open source software. One of the conclusions of TAUBERT's book is that the process of open software development needs to be understood as adaptive and experimental. A continuous feedback between the context of production and the context of application is the basis for robust and successful software production. One of the surprising results of the book is that the most important requirement for this feedback process is a set of norms—neutrality, communism, disinterestedness, and universalism—norms that Robert MERTON associated with academic science in the 1940s. If TAUBERT is right that these norms are to be found outside the world of institutional science in open source software development projects today, then his case study can be seen as an indicator for a new form of knowledge production in the 21st century, where the social relevance and responsibility of a research process are keys to successful innovation. With this book, which deserves a wide readership, TAUBERT makes an important contribution to our understanding of the successful organization of technology development. URN: urn:nbn:de:0114-fqs0701109