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Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.

Mit dem Gesetz zum Neustart der Digitalisierung der Energiewende hat die Bundesregierung ein klares Signal zum forcierten Umbau der Energieversorgung gesendet. Der Rollout intelligenter Messsysteme als Kerntechnologie der Digitalisierung soll deutlich beschleunigt werden. Bringt das Gesetz alles mit, was dazu nötig ist? Wo gibt es noch Hemmnisse? Welche Chancen eröffnen sich? Der Beitrag analysiert die aktuelle Situation. 1)

Supplementary Figure from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas.Significance:Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.See related commentary by Beytagh and Weiss, p. 2730.See related article by Mo et al., p. 2906.This article is highlighted in the In This Issue feature, p. 2711

Background Spinal tuberculosis is a manifestation of extrapulmonary tuberculosis. The incidence of tuberculosis is low in high-income countries; however, globally, it still remains one of the most frequent fatal infectious diseases. Because of its rarity in developed countries, spinal tuberculosis can be mistaken for malignant tumors of the spine, especially in case of an atypical radiologic manifestation and without pulmonary affection. Methods We present the case of a 39-year-old man from South India with quickly progressing gait disturbance and hypesthesia below the Th10 level. Magnetic resonance imaging revealed an osteolytic lesion of the vertebral arch Th2 with central necrosis and compression of the spinal cord altogether highly suspicious for spinal metastasis. Results After surgical removal of the mass by laminectomy, the patient regained normal neurologic function. Histology revealed a severe granulomatous inflammation and DNAhybridization of polymerase chain reaction (PCR) products detected Mycobacterium tuberculosis-specific DNA in the sample. Biopsy of an enlarged hilar lymphnode allowed us to obtain material to successfully perform a drug resistance test to start specific antimicrobial therapy. Conclusion Spinal tuberculosis, even with atypical radiologic appearance, has to be considered a differential diagnosis in patients with provenance from endemic countries. A multidisciplinary diagnostic approach helps perform antimicrobial susceptibility testing to avoid delaying the start of antibiotic therapy.

In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial.Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (/≥) served as threshold.Out of 248 patients receiving maintenance therapy, 211 were evaluable for DpR analyses (FU/FA + Pmab, n = 106; FU/FA alone, n = 105). The overall DpR in all patients was 56.5%. DpR of induction therapy (42.5%) accounted for the largest proportion (75.2%) of the overall DpR. While greater DpR to induction therapy was significantly associated with prolonged PFS (HR 0.70, 95% CI 0.52-0.93, p = 0.013) and OS (HR 0.38, 95% CI 0.28-0.51, p 0.001), there was no significant correlation of DpR and maintenance treatment arm.In the PanaMa trial, the overall DpR was similar to DpR achieved by other epidermal growth factor receptor-based regimens. DpR to induction therapy accounted for three quarters of the total tumour shrinkage potentially suggesting that FOLFOX plus Pmab can be de-escalated following induction without substantially compromising efficacy. DpR to induction therapy was prognostic but not predictive for efficacy of consecutive maintenance therapy.NCT01991873.

A partir de la identificación de ciertos recursos metafóricos implícitos en los versos del libro La Eneida del poeta Virgilio, la propuesta de este artículo es develar el contenido sacro-político implícito en la la operación escritural del mantuano, más su adscripción a la política restauradora y fundacional del emperador César Augusto en la Roma del siglo I a.C. En lo medular, se observa el modo en que Virgilio, al recuperar elementos y figuras propias de la tradición y de la configuración de la familia romana antigua, signa a su texto de una potencia alegórica que dota de sacralidad y trascendencia la épica del César.

With new open data policies in place, the European Commission aims to speed up the development of innovative services and products, thereby playing a significant role in economic growth. In particular, the reuse of so-called high value data sets is expected to bring remarkable benefits to society and economics. By being defined as high value information, meteorological data sets need to be made available by public sector bodies free of charge and with minimal legal restrictions, published via APIs and in machine readable formats. Austria's national weather service Zentralanstalt für Meteorologie und Geodynamik (ZAMG) is aiming to realize those directives by publishing public sector data on the ZAMG Data Hub. Data sets are made available for the public in a step wise approach, which has started in 2021 with providing station measurement data and raster data sets and continues with the preparation of forecasts. Besides the open data sector, the ZAMG Data Hub provides commercial data for registered users and serves as a data platform for universities and ZAMG internal users. The main services and interfaces for the end user are a CKAN based web portal, a REST API, and an associated Metadata Hub, which are connected to the underlying Zarr and S3 file storage infrastructure by state-of-the-art technologies and components. The numerous use cases and actors, the large amount of data to be stored and processed together with the demand of offering a highly available and reliable infrastructure brings challenging questions regarding the architecture of the system and its components. Key aspects are the need for a powerful access control system, scalable and performant data access and easy-to-use metadata information. Besides continuous improvements, ZAMG wants to provide further data sets and implement additional data services to fulfill open data directives and maximize customer satisfaction.

127 Background: Despite molecular selection, patients with RAS wildtype mCRC represent a heterogeneous population, including different metastatic patterns and number of organs involved. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. Methods: The study population was stratified according to number of organs involved and also to different patterns including liver metastases alone or in combination with additional organs. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints (i.e. progression-free survival (PFS) and overall survival (OS) of maintenance therapy) in the aforementioned populations. Results: Of 248 patients (pts) receiving maintenance therapy, 133 pts had a one-metastatic site disease (53.6%). Of those, 102 pts had liver-only metastases. Furthermore, liver metastases plus one additional involved organ was observed in 61/248 patients (24.6%), and liver metastases plus two or more organs in 40/248 patients (16.1%). In general, one organ disease was associated with favourable PFS of maintenance therapy compared to patients with ≥2 organs involved (HR 0.68, 95% CI 0.52–0.88; P = 0.004). A predictive impact of disease spread in terms of pmab-containing maintenance therapy was present for the PFS of maintenance therapy in patients with ≥ 2 organ disease (HR 0.58, 95% CI 0.39–0.86; P = 0.006) unlike in patients with only one-organ disease (HR 0.83, 95% CI, 0.57-1.21; P = 0.332) and also specifically in patients with a 2-organ disease including the liver (HR 0.57, 95% CI 0.33–0.99; P = 0.046). Conclusions: Consistent with previous reports, organ spread has prognostic impact in mCRC. The efficacy of more intensive maintenance therapy (including pmab and 5-FU/FA) is predominantly seen in patients with more than one organ involved in the metastatic spread, while less striking effects were seen in patients with only one organ disease. These data may support clinical decisions when EGFR-based maintenance therapy is considered. Clinical trial information: NCT01991873 .

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.

Histone 3 lysine27-to-methionine mutant diffuse midline gliomas (H3-K27M DMGs) are among the most lethal brain tumors. Their putative cellular hierarchy has been shown to be driven by self-renewing stem-like cells arrested in an oligodendrocyte precursor-like (OPC-like) state, of which few cells are able to differentiate towards more mature astrocyte (AC)-like and oligodendrocyte (OC)-like cells. However, the spatial organization underlying this tumor cell architecture and its microenvironmental interactions in intact H3-K27M DMG tissues remain unknown. Here, we profiled the single cell transcriptomes of 45 patient H3-K27M DMGs and derived cell population-specific marker gene combinations to characterize the single cell spatial organization of 16 tumors using targeted in situ sequencing. We thereby resolved different malignant and non-malignant cell populations including cycling, OPC-like, AC-like, OC-like, mesenchymal tumor cells, and non-malignant oligodendrocytes, astrocytes, neurons, myeloid cells, T cells, and vascular cells directly in situ. Global neighborhood analyses indicate a higher tendency of cycling OPC-like cells, vascular cells, and neurons to localize within a more restricted homogeneous compartment, whereas AC-like cells, non-malignant astrocytes and myeloid cells tend to intermingle with different cell populations in a more diffuse manner. Among malignant cells, we observed cycling OPC-like and OC-like cells to co-localize within a niche-like structure that is surrounded by more differentiated AC-like cells. We further validated this stem-like niche at the protein level using multiplexed immunofluorescence via the CODEX system. Finally, we characterized relationships between malignant and non-malignant cells, consistently identifying preferred neighborhoods of mesenchymal tumor cells with vascular and myeloid cells. Together, this study resolves the spatial architecture of H3-K27M DMG malignant and non-malignant cells at single cell resolution and identifies a local niche of the oligodendroglial lineage containing the OPC-like cancer stem-like cells, thus providing novel insights into the cancer stem-like compartment in H3-K27M DMGs and suggesting potential avenues for its perturbation.

INTRODUCTION: DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) will implement an innovative clinical trial design of combinatorial arms for patients with DMG at all disease stages, that is adaptive to pre-clinical and correlate data generated in eight collaborating institutions. The goal of the team is to rapidly identify and validate i) promising drugs and drug combinations for clinical use, and ii) predictive biomarkers of promising drugs. METHODS: In vitro (n=30) and in vivo (n=8) models of DMG across fourteen institutions were used to assess single and combination treatment of over 80 drugs and drug combinations. Predictive biomarkers of response for top candidate drugs were identified using extensive molecular assays including proteomics, CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS: Inhibitory concentration (IC50) of all drugs were established and validated across all participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), ONC201+panobinostat (p=0.01). Marizomib was highly toxic in murine PDX and zebrafish larvae assays. Murine pharmacokinetic analysis showed peak brain levels of ONC201, and ONC206 above pre-clinical IC50 concentrations. Molecular testing and analyses of existing drug screen across 578 cancer cells validated mitochondrial stress and additional proteins, as the main targets induces by ONC201/6. CONCLUSION: Thorough preclinical testing in a multi-site laboratory setting identified promising therapeutics for DMGs, resulting in launch of two clinical trials (PNOC022, ONOC023). Validation of identified biomarkers are ongoing using clinical specimen as well as in vivo PDX models.

Mannosylerythritol lipids (MELs) are glycolipid biosurfactants produced by fungi of the Ustilaginaceae family in the presence of hydrophobic carbon sources like plant oils. In the present study, we investigated the structural composition of MELs produced from castor oil using seven different microorganisms and compared them to MEL structures resulting from other plant oils. Castor oil is an industrially relevant plant oil that presents as an alternative to currently employed edible plant oils like rapeseed or soybean oil. The main fatty acid in castor oil is the mono-hydroxylated ricinoleic acid, providing the possibility to produce novel MEL structures with interesting features. Analysis of the produced MELs from castor oil by different chromatographic and mass spectrometry techniques revealed that all seven microorganisms were generally able to integrate hydroxylated fatty acids into the MEL molecule, although at varying degrees. These novel MELs containing a hydroxy fatty acid (4-O-[2′-O-alka(e)noyl-3′-O-hydroxyalka(e)noyl-4′/6′-O-acetyl-β-D-mannopyranosyl]-erythritol) were more hydrophilic than conventional MEL and therefore showed a different elution behavior in chromatography. Large shares of novel hydroxy MELs (around 50% of total MELs) were found for the two MEL-B/C producing species Ustilago siamensis and Ustilago shanxiensis, but also for the MEL-A/B/C producer Moesziomyces aphidis (around 25%). In addition, tri-acylated hydroxylated MELs with a third long-chain fatty acid esterified to the free hydroxyl group of the hydroxy fatty acid were identified for some species. Overall, production of MEL from castor oil with the investigated organisms provided a complex mixture of various novel MEL structures that can be exploited for further research.

Mannosylerythritol lipids (MEL) are microbial glycolipid biosurfactants with great potential for application in cosmetics and household detergents. In current biotechnological processes, they are produced by basidiomycetous fungi, the Ustilaginaceae, as a complex mixture of different chemical structures. It was the aim of this paper to study the influence of producer organisms and substrates on the resulting MEL structures with a novel high-resolution HPTLC–MALDI-TOF method. Given the seven different microbes and four plant oils, our analysis revealed that the product concentrations varied strongly between organisms, while they were similar for the different substrates. Coconut oil presented an exception, since only one organism was able to synthesize MEL from this substrate in considerable yields. Analysis by GC-FID further showed that the chain length pattern of hydrophobic fatty acid side-chains was very specific for individual organisms, while substrates had only a minor influence on the chain length. Our novel HPTLC–MALDI-TOF combination method finally demonstrated the presence of multiple MEL sub-variants with differing acetylation and fatty acid chain lengths. It also revealed the production of a more hydrophilic biosurfactant mannosylmannitol lipid (MML) as a side-product in certain fungi. Overall, it was concluded that the pattern of produced biosurfactant structures are mainly governed by producer organisms rather than substrates.

Existing models for the shear strength of steel fibre reinforced concrete (SFRC) in general, and for the transfer of shear stresses across cracks, typically assume that the shear strength of plain concrete is increased by a so-called “fibre contribution”. This is usually assumed to be independent of the roughness of the cracks. While being relatively simple to implement in practice, such approaches fail to capture the physical-mechanical behaviour of the transfer of shear stresses across cracks. Hence, in order to exploit the full potential of SFRC in shear, rational and mechanically consistent models capable of describing this behaviour are essential. This paper presents such a model, which relates the shear and normal stresses transferred across cracks in SFRC to the crack opening and slip displacements. The novelty of the proposed model consists in the fact that it not only accounts for fibre stresses bridging the crack, as done in many previous models, but also for the aggregate interlocking behaviour along the faces of the crack, and the interaction of these effects. Regardless of the aggregate interlock relationship used, the proposed model predicts that except at large crack openings (in the order of half the size of the maximum aggregate particle), only a minor portion of the applied shear stresses are resisted directly by inclined fibres crossing the crack, even for high fibre contents. Rather, it is shown herein that shear stresses are primarily transmitted via the interlocking of aggregates along the crack faces. Nonetheless, the addition of fibres to concrete is highly beneficial to the transfer of shear across cracks since fibre stresses normal to the crack plane are equilibrated by compressive stresses on the crack faces. These compressive stresses greatly enhance aggregate interlock. A comparison of predictions by the proposed model with a wide range of reported experimental data shows a good correlation. However, the results also indicate that existing relationships for aggregate interlock in plain concrete are highly variable, and their applicability to SFRC needs to be carefully examined.

Induced seismicity in mining is possibly the least managed risk in current rock mechanics practice. In some Australian mines, an increase in the occurrence of damage and injury related to seismicity has resulted in severe restrictions on previous operating practices. In some cases, the viability of mines has been challenged.A method is proposed in this work for managing seismic hazard in mines by comparing proposed excavation options in terms of a quantitative assessment of seismic hazard. This quantitative assessment is produced from three-dimensional, elastic, boundary element modelling of a continuum. Parameters from the modelling can be compared to historical observations of seismicity to generate probabilistic relations between seismic event occurrence and event strength.The parameters used in the event spatial occurrence relations and event strength estimates are the Factor of Safety against seismic failure for seismic types inferred from back analysis and the Modeled Ground Work (MGW). The MGW is a new concept in the field of seismicity.The modeled estimates of these parameters, are analagous to the controlling quantities for a seismic event. Namely, an unstable accumulation of energy - energy in excess of that which can be released non-violently - and a sufficient stress condition to allow failure of rock.At Brunswick Mining and Smelting, Number 12 Mine and at Kalgoorlie Consolidated Gold Mines, Mount Charlotte Mine, the method produced useable relations in case studies. In both mines, a prediction of seismicity for selected mining steps was demonstrated that would have allowed adaptation of the mining plan to achieve a better seismic outcome.The method requires considerable analytical effort, comprising detailed analysis of mining steps with well measured seismic histories, before it can be applied in a predictive manner. The steps that must be achieved to develop and apply the method in a mine are:i. identification of the mechanics of seismic source types from numerical back analysis of historic seismicity. The types can usually be defined in terms of analytical measures of rock strength - typically an oriented Coulomb slip criterion for deviatoric behaviour or a simple relation between major and minor principal stresses for other events;ii. generation of volumetric grids or test blocks around a volume exceeding that of the seismic influence of existing excavations, related to induction of events in the seismic history;iii. modelling of the Factor of Safety for different seismic source types and the MGW, associated with generation of the possible seismic source types in each test block, by substitution of alternative materials or introduction of an appropriately oriented displacement discontinuity;iv. comparison of the relative proportions of test blocks at given paired values of MGW and Factor of Safety, containing and not containing inferred events (the event/non-event ratio);v. Generation of an event spatial occurrence relation, on the basis of the event/non-event ratio, at given paired values of FOS and MGW;vi. Generation of event strength relation to MGW, from historical data and back analysis;vii. Generation of proposed mining geometries and test blocks in the likely volume of seismic influence;viii. Modelling of the FOS and MGW of all test blocks, subject to all possible seismic source types, to generate event probabilities and most likely event strength estimates. This uses the observed event spatial occurrence relation and the observed MGW/event strength relations as predictors;ix. Generation of predicted seismic populations from the predicted event probability and the strength relations.

Objectives: Radiography remains the mainstay of diagnostic and follow-up imaging. In view of the risks and the increasing use of ionizing radiation, dose reduction is a key issue for research and development. The introduction of digital radiography and the associated access to image postprocessing have opened up new opportunities to minimize the radiation dosage. These advances are contingent upon quality controls to ensure adequate image detail and maintenance of diagnostic confidence. The purpose of this study was to investigate the clinical applicability of postprocessed low-dose images in skeletal radiography. Methods: In our study setting, the median radiation dose for full dose X-rays was 9.61 dGy*cm2 for pelvis, 1.20 dGy*cm2 for shoulder and 18.64 dGy*cm2 for lumbar spine exams. Based on these values, we obtained 200 radiographs for each anatomic region in four consecutive steps, gradually reducing the dose to 84%, 71%, 60% and 50% of the baseline using an automatic exposure control (AEC). 549 patients were enrolled for a total of 600 images. All X-rays were postprocessed with a spatial noise reduction algorithm. Two radiologists assessed the diagnostic value of the radiographs by rating the visualization of anatomical landmarks and image elements on a five-point Likert scale. A mean-sum score was calculated by averaging the two reader’s total scores. Given the non-parametric distribution, we used the Mann-Whitney U test to evaluate the scores. Results: Median dosage at full dose accounted for 38.4%, 48 and 53.2% of the German reference dose area product for shoulder, pelvis and lumbar spine, respectively. The applied radiation was incrementally reduced to 21.5%, 18.4% and 18.7% of the respective reference value for shoulder, pelvis and lumbar spine. Throughout the study, we observed an estimable tendency of superior quality at higher dosage in overall image quality. Statistically significant differences in image quality were restricted to the 50% dose groups in shoulder and lumbar spine images. Regardless of the applied dosage, 598 out of 600 images were of sufficient diagnostic value. Conclusion: In digital radiography image postprocessing allows for extensive reduction of radiation dosage. Despite a trend of superior image detail at higher dose levels, overall quality and, more importantly, diagnostic utility of low-dose images was not significantly affected. Therefore, our results not only confirm the clinical utility of postprocessed low-dose radiographs, but also suggest a widespread deployment of this advanced technology to ensure further dose limitations in clinical practice. Advances in knowledge: The diagnostic image quality of postprocessed skeletal radiographs is not significantly impaired even after extensive dose reduction by up to 20% of the reference value.

Background Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound—ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. Methods Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017–2020) was analyzed. Results GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012). Conclusions This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy.

Malignant brain tumors are the leading cause of childhood death in Germany, with Diffuse Midline Glioma (DMG) being the most lethal of all paediatric brain tumors. Current treatment strategies are limited to irradiation which prolongs survival only by a few months. Preclinical studies have identified effective drug candidates, but translation into the clinic remains a major obstacle. It is known that interactions between tumor cells and components of the TME (tumor microenvironment), such as cell to cell contacts between malignant and non-malignant cells or secreted factors, can increase therapy resistance and progression of brain tumors. However, these important factors are not present in most conventional cell culture models for drug testing. Consequently, there is a need for more realistic DMG models to improve the relevance and translational potential of current drug screening. Therefore, the goal of this study was to develop a new DMG model for drug testing, consisting of induced pluripotent stem cell (iPSC) derived human brain cells and patient derived DMG cells to better mimic the complex tumor microenvironment. We co-cultured three-dimensional cerebral organoids with DMG tumor spheres resulting in the formation of DMG-Brain-Organoids (DBO). Preliminary results show that co-culture induces distinct tumor cell subpopulations corresponding to those detected in DMG tumors by single cell RNA sequencing (Filbin et al., 2018). These subpopulations mainly differ in their proliferative capacity and their differential response to clinical interventions may be critical for therapeutic success. DBOs subjected to drug treatments (single or combination) were sectioned and individual therapy effects on tumor cell subpopulations and proliferative capacity were monitored using multiplexed immunofluorescence imaging. By observing drug effects in a realistic setup, we hope to improve the predictive power of our preclinical drug screens and to find new combination therapies for DMG.

The cracked membrane model with fixed, interlocked cracks (CMM-F), whose basic concepts were already outlined in this journal more than 20 years ago, is the most general approach for cracked reinforced concrete members subjected to in-plane stresses as long as one set of uniformly spaced cracks is considered and steel and bond stresses are modeled by equivalent, uniformly distributed stresses. However, the CMM-F was not implemented so far, due to the numerical intricacy of the general solution procedure. In this paper, these issues are overcome by determining the variation of steel and concrete stresses and strains between cracks using the tension chord model (TCM), rather than by iteratively integrating over a crack element. After a discussion of the compression field approaches, the TCM and the CMM-F, including the constitutive relationships of concrete and reinforcement and aggregate-interlock models, response predictions obtained from the CMM-F are validated against experimental data. While the agreement is generally good, the predicted stresses at the cracks and the crack kinematics differ significantly between the different aggregate-interlock relationships. These values should be measured in future experiments, using appropriate instrumentation, to validate the aggregate-interlock models., Journal of Structural Engineering, 146 (2), ISSN:0733-9445, ISSN:1943-541X

Mannosylerythritol lipids (MEL) are microbial biosurfactants belonging to the class of glycolipids. They can be produced biotechnologically by smut fungi and have the potential to replace current chemical surfactant products, for example in household detergents or cosmetics. In this article, we highlight our latest research on the various producer organisms as well as the genetics and regulation of MEL biosynthesis, aiming for the development of an industrial production process in the future., Ministerium für Wissenschaft, Forschung und Kunst des Landes Baden-Württemberg, Projekt DEAL

Conventional techniques to measure boundary layer clouds such as research aircraft are unable to sample in orographically diverse or densely populated areas. In this paper, we present a newly developed measurement platform on a tethered balloon system (HoloBalloon) to measure in situ vertical profiles of microphysical and meteorological cloud properties up to 1 km above ground. The main component of the HoloBalloon platform is a holographic imager, which uses digital in-line holography to image an ensemble of cloud particles in the size range from small cloud droplets to precipitation-sized particles in a three-dimensional volume. Based on a set of two-dimensional images, information about the phase-resolved particle size distribution, shape and spatial distribution can be obtained. The velocity-independent sample volume makes holographic imagers particularly well suited for measurements on a balloon. The unique combination of holography and balloon-borne measurements allows for observations with high spatial resolution, covering cloud structures from the kilometer down to the millimeter scale. The potential of the measurement technique in studying boundary layer clouds is demonstrated on the basis of a case study. We present observations of a supercooled low stratus cloud during a Bise situation over the Swiss Plateau in February 2018. In situ microphysical profiles up to 700 m altitude above the ground were performed at temperatures down to −8 ∘C and wind speeds up to 15 m s−1. We were able to capture unique microphysical signatures in stratus clouds, in the form of inhomogeneities in the cloud droplet number concentration and in cloud droplet size, from the kilometer down to the meter scale., Atmospheric Measurement Techniques, 13 (2), ISSN:1867-1381, ISSN:1867-8548

Background: The high accuracy of feature-tracking cardiac magnetic resonance (CMR) imaging qualifies this novel modality as potential gold standard for myocardial strain analyses in ST-elevation myocardial infarction patients; however, the incremental prognostic validity of feature-tracking-CMR over left ventricular ejection fraction (LVEF) and myocardial damage remains unclear. This study therefore aimed to determine the value of myocardial strain measured by feature-tracking-CMR for the prediction of clinical outcome following ST-elevation myocardial infarction. Methods: This prospective observational study enrolled 451 revascularized ST-elevation myocardial infarction patients. Comprehensive CMR investigations were performed 3 (interquartile range, 2–4) days after infarction to determine LVEF, global longitudinal strain (GLS), global radial strain, and global circumferential strain as well as myocardial damage. Primary end point was a composite of death, re-infarction, and congestive heart failure (major adverse cardiac events [MACE]). Results: During a follow-up of 24 (interquartile range, 11–48) months, 46 patients (10%) experienced a MACE event. All 3 strain indices were impaired in patients with MACE (all P P =0.005) than LVEF (area under the curve, 0.64 [95% CI, 0.59–0.68]). The association between GLS and MACE remained significant ( P P Conclusions: GLS by feature-tracking-CMR strongly and independently predicted the occurrence of medium-term MACE in contemporary revascularized ST-elevation myocardial infarction patients. Importantly, the prognostic value of GLS was superior and incremental to LVEF and CMR markers of infarct severity.

During typical field campaigns, millions of cloud particle images are captured with imaging probes. Our interest lies in classifying these particles in order to compute the statistics needed for understanding clouds. Given the large volume of collected data, this raises the need for an automated classification approach. Traditional classification methods that require extracting features manually (e.g. decision trees and support vector machines) show reasonable performance when trained and tested on data coming from a unique dataset. However, they often have difficulties to generalize to test sets coming from other datasets where the distribution of the features might be significantly different. In practice, we found that each new dataset requires labeling a huge amount of data by hand using those methods. Convolutional neural networks have the potential to overcome this problem due to their ability to learn complex non-linear models directly from the images instead of pre-engineered features, as well as by relying on powerful regularization techniques. We show empirically that a convolutional neural network trained on cloud particles from holographic imagers generalizes well to unseen datasets. Moreover, fine-tuning the same network with a small number (256) of training images improves the classification accuracy. Thus, the automated classification with a convolutional neural network not only reduces the hand-labeling effort for new datasets but is also no longer the main error source for the classification of small particles., Atmospheric Measurement Techniques Discussions, ISSN:1867-8610

The paper proposes a method based on different security-related factors to dynamically calculate the validity period of digital certificates. Currently validity periods are most often defined statically without scientific justification. This approach is not sufficient to objectively consider the actual need for security. Therefore the approach proposed in this paper considers relevant security criteria in order to calculate a meaningful validity period for digital certificates. This kind of security assessment can be executed periodically in order to dynamically respond to changing conditions. Especially in the context of complex systems and infrastructures that have an increased need for security, privacy and availability this issue is highly relevant.

Microbial biosurfactants represent a promising alternative for current petrochemical or oleochemical surfactants. Mannosylerythritol lipids (MEL) are highly promising glycolipids produced mainly by basidiomycetous fungi of the Ustilaginomycetes class. A large variety of structures has already been found in wild-type strains. Moreover, novel structures can be designed by combining different strains and substrates, by genetic engineering or by enzymatic modification. Nevertheless, large-scale production of the different structures in bioreactors leading to higher yields and thus a more economic process still needs to be addressed in more detail. So far, it has only been investigated for two different strains, leaving space for further process optimization. This chapter is intended to give an overview of state of the art from a scientific perspective on mannosylerythritol lipids, focusing on its structural variety and how this can be tailored by employing different microorganisms and cultivation strategies to fit the various fields of application.