Predicting Static Stability with Data-Driven Physics in Air Cargo Palletizing

Proposing air cargo palletizing solutions requires an assessment by a physics engine of whether a solution is physically stable, which can take up a disproportionate amount of computation and, thus, produce a bottleneck in the optimization pipeline. This problem can be tackled by replacing the physics engine with a data-driven model that learns to map proposed packing pattern solutions directly to its stability value. We develop a prototype of such a datadriven model and find that this approach yields practicable results and does so multiple orders of magnitudes faster than a commonly used physics engine

Remission of Invasive, Cancer Stem-Like Glioblastoma Xenografts Using Lentiviral Vector-Mediated Suicide Gene Therapy

Background: Glioblastoma is the most frequent and most malignant primary brain tumor with a poor prognosis. The translation of therapeutic strategies for glioblastoma from the experimental phase into the clinic has been limited by insufficient animal models, which lack important features of human tumors. Lentiviral gene therapy is an attractive therapeutic option for human glioblastoma, which we validated in a clinically relevant animal model. Methodology/Principal Findings: We used a rodent xenograft model that recapitulates the invasive and angiogenic features of human glioblastoma to analyze the transduction pattern and therapeutic efficacy of lentiviral pseudotyped vectors. Both, lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) and vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral vectors very efficiently transduced human glioblastoma cells in vitro and in vivo. In contrast, pseudotyped gammaretroviral vectors, similar to those evaluated for clinical therapy of glioblastoma, showed inefficient gene transfer in vitro and in vivo. Both pseudotyped lentiviral vectors transduced cancer stem-like cells characterized by their CD133-, nestin- and SOX2-expression, the ability to form spheroids in neural stem cell medium and to express astrocytic and neuronal differentiation markers under serum conditions. In a therapeutic approach using the suicide gene herpes simplex virus thymidine kinase (HSV-1-tk) fused to eGFP, both lentiviral vectors mediated a complete remission of solid tumors as seen on MRI resulting in a highly significant survival benefit (p<0.001) compared to control groups. In all recurrent tumors, surviving eGFP-positive tumor cells were found, advocating prodrug application for several cycles to even enhance and prolong the therapeutic effect. Conclusions/Significance: In conclusion, lentiviral pseudotyped vectors are promising candidates for gene therapy of glioma in patients. The inefficient gene delivery by gammaretroviral vectors is in line with the results obtained in clinical therapy for GBM and thus confirms the high reproducibility of the invasive glioma animal model for translational research

High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

Purpose: High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods: During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results: Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions: Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy

EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials

Long-Term Drainage Reduces CO2 Uptake and CH4 Emissions in a Siberian Permafrost Ecosystem

Permafrost landscapes in northern high latitudes with their massive organic carbon stocks are an important, poorly known, component of the global carbon cycle. However, in light of future Arctic warming, the sustainability of these carbon pools is uncertain. To a large part, this is due to a limited understanding of the carbon cycle processes because of sparse observations in Arctic permafrost ecosystems. Here we present an eddy covariance data set covering more than 3 years of continuous CO2 and CH4 flux observations within a moist tussock tundra ecosystem near Chersky in north-eastern Siberia. Through parallel observations of a disturbed (drained) area and a control area nearby, we aim to evaluate the long-term effects of a persistently lowered water table on the net vertical carbon exchange budgets and the dominating biogeochemical mechanisms. Persistently drier soils trigger systematic shifts in the tundra ecosystem carbon cycle patterns. Both, uptake rates of CO2 and emissions of CH4 decreased. Year-round measurements emphasize the importance of the non-growing seasonin particular the zero-curtain period in the fallto the annual budget. Approximately 60% of the CO2 uptake in the growing season is lost during the cold seasons, while CH4 emissions during the non-growing season account for 30% of the annual budget. Year-to-year variability in temperature conditions during the late growing season was identified as the primary control of the interannual variability observed in the CO2 and CH4 fluxes.Peer reviewe

Identification of CIITA Regulated Genetic Module Dedicated for Antigen Presentation

The class II trans-activator CIITA is a transcriptional co-activator required for the expression of Major Histocompatibility Complex (MHC) genes. Although the latter function is well established, the global target-gene specificity of CIITA had not been defined. We therefore generated a comprehensive list of its target genes by performing genome-wide scans employing four different approaches designed to identify promoters that are occupied by CIITA in two key antigen presenting cells, B cells and dendritic cells. Surprisingly, in addition to MHC genes, only nine new targets were identified and validated by extensive functional and expression analysis. Seven of these genes are known or likely to function in processes contributing to MHC-mediated antigen presentation. The remaining two are of unknown function. CIITA is thus uniquely dedicated for genes implicated in antigen presentation. The finding that CIITA regulates such a highly focused gene expression module sets it apart from all other transcription factors, for which large-scale binding-site mapping has indicated that they exert pleiotropic functions and regulate large numbers of genes

Molecular heterogeneity of brain tumors

In der vorliegenden Arbeit wurden verschiedene Determinanten molekulärer und zellulärer Heterogenität hinsichtlich ihrer Bedeutung für die klinische Neuroonkologie untersucht. Tumorzellgehalt wurde als prognostischer Marker in Glioblastomen identifiziert und deutet auf eine klinisch bedeutsame Rolle der Immuninfiltration hin. Gleichzeitig konnte gezeigt werden, dass die Untersuchung der Methylierung des MGMT-Promoters ausreichend robust gegenüber Schwankungen des Tumorzellgehalts ist. Die Charakterisierung des Transkriptionsfaktors ZEB1 hingegen stellte sich nach Berücksichtigung der zellulären Komposition nicht weiter als prognostisch relevant heraus. Umfassende molekulare Charakterisierung seltener Astroblastome erlaubte eine Reklassifikation in bekannte, molekular gut definierte Entitäten und zeigt die Schwächen einer rein histologischen Diagnose auf. Ein Zusammenhang zwischen EGFR-Amplifikationen, Invasion und Angiogenese in Glioblastomen konnte experimentell in vitro und in vivo gezeigt werden. Die methylierungsbasierte Klassifikation mittels Nanopore-Sequenzierung erlaubt eine zeitnahe und hypothesenfreie Identifikation von Tumoridentitäten aus nativen DNA-Proben durch Vergleich eines genomweiten Methylierungsprofil mit Referenzprofilen nahezu aller bekannter Hirntumoren unter Anwendung Methoden maschinellen Lernens. Darüber hinaus erlaubt die Methode die Bestimmung von Kopienzahlveränderungen und strukturelle Charakterisierung extrachromosomaler DNA-Amplifikationen.In the present work, molecular and cellular determinants of tumor heterogeneity were studied with respect to their role in clinical neuro-oncology. Tumor cell content was identified as a prognostic biomarker in glioblastoma, which indicates a clinically relevant role of immune cell infiltration in this tumor type. Importantly, current methods to determine MGMT promoter methylation status were shown not to be affected by variation of tumor cell content. In contrast, the transcription factor ZEB1 was shown not to be of prognostic value after correction for cellular composition. Comprehensive molecular characterization of astroblastomas resulted in their reclassification into known, molecularly well-characterized tumor entities and illustrates limitations of histomorphology. Correlations between EGFR amplifications, invasion and angiogenesis in glioblastoma were established experimentally in vitro and in vivo. DNA methylation-based classification using nanopore sequencing enables rapid and unbiased identification of brain tumors from native DNA samples by comparison of genome-wide methylation profiles with reference data from most known brain tumors using supervised machine learning. In addition, the method allows detection of copy number alterations and resolving the structure of extrachromosomal DNA amplifications