Biology subjects

Braun, V.

Publications and source records attributed to Braun, V..

4 recordsLinked to original sources

bioRxiv2024

Personalized Medicine for Meningiomas: Drug Screening on Tumor Organoids Exposes Therapeutic Vulnerabilities to HDAC1/2i Panobinostat

Managing aggressive meningiomas remains challenging due to limited treatment options besides surgical tumor removal and radiotherapy. To identify novel therapies for aggressive meningiomas, we established a multi-step drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissues genotype and phenotype. Individual drug responses were assessed in TOs from 60 molecularly characterized meningioma cases. Especially the FDA-approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through HDAC1/2 inhibition. In addition, treatment in an orthotopic in vivo model revealed a significantly improved survival. In a heavily pretreated patient suffering from an anaplastic meningioma, oral panobinostat treatment could delay the tumor growth rate. In search of the molecular mechanism underlying a potential intrinsic panobinostat resistance, we identified upregulation of the HDAC8-TGF{beta}-EMT axis in the TO model and subsequent HDAC8 depletion substantially increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for a more effective treatment of clinically aggressive meningiomas and help to advance our understanding of counteracting resistance mechanisms. One Sentence SummaryThis study provides strong in vitro, in vivo, ex vivo, and patient evidence for the efficacy of the HDACi panobinostat to treat clinically aggressive meningiomas and uncovered a potential intrinsic resistance mechanism by activation of the HDAC8-TGF{beta}-EMT axis.

cancer biology↗

bioRxiv2023

Virus-encoded Shemin pathway highlights the importance of tetrapyrrole metabolism during host infection

Tetrapyrroles such as heme, chlorophyll, or vitamin B12 are among the most complex molecules synthesised by nature and play a crucial role in many vital processes such as respiration, photosynthesis, methanogenesis, and catalysis. All modified tetrapyrroles are derived from the common precursor molecule 5-aminolevulinic acid (5-ALA). However, 5-ALA can be synthesised in two different ways. While alphaproteobacteria, mammals, and birds use the so-called Shemin pathway, all other bacteria, archaea, and plants use the C5 pathway. Here, we present evidence for the presence of 5-ALA synthase genes of the Shemin pathway in the genomes of viruses (valaS) that infect bacteria (bacteriophages) in marine and freshwater environments. These genes either occur in a three-gene cassette with two heme catabolising enzymes involved in linear tetrapyrrole biosynthesis, as broken cassettes or as individual genes. valaS encodes a functional enzyme, as shown by the enzymatic turnover of the co-substrates succinyl-Coenzyme A and glycine in an Escherichia coli strain overexpressing valaS. Phylogenetic analysis in combination with three-dimensional structure prediction supported our data that the viral sequences encode active enzymes. Interestingly, the viral valaS sequence is capable of functionally complementing a 5-ALA-auxotrophic Escherichia coli strain, which lacks one of the two enzymes of the C5 pathway. Host prediction suggests that different valaS carrying phages might infect bacteria that either utilise the Shemin or the C5 pathway for 5-ALA biosynthesis. Our results thus support the hypothesis that metabolic reprogramming and maintenance of the host bacteriums energy metabolism are crucial during bacteriophage infection and that tetrapyrroles play a key role in this process.

microbiology↗

bioRxiv2021

Slow rTMS to the left DLPFC enhances verbal memory formation

Encoding of episodic memories relies on stimulus-specific information processing and involves the left prefrontal cortex. We here present an incidental finding from a simultaneous EEG-TMS experiment as well as a replication of this unexpected effect. Our results reveal that stimulating the left dorsolateral prefrontal cortex (DLPFC) with slow repetitive transcranial magnetic stimulation (rTMS) leads to enhanced word memory performance. 40 healthy human participants engaged in a list learning paradigm. Half of the subjects (N=20) received 1 Hz rTMS to the left DLPFC while the other half (N=20) received 1 Hz rTMS to the vertex and served as a control group. Subjects receiving left DLPFC stimulation demonstrated enhanced memory performance compared to the control group. This effect was replicated in a double-blind within-subjects experiment where 24 participants received 1 Hz rTMS to the left DLPFC and vertex. In this second experiment, DLPFC stimulation also induced better memory performance compared to vertex stimulation. In addition to these behavioural effects, we found that 1 Hz rTMS to DLPFC induced stronger beta power modulation in posterior areas, a state which is known to be beneficial for memory encoding. Further analysis indicated, that beta modulations did not have an oscillatory origin. Instead, the observed beta modulations were a result of a spectral tilt, suggesting inhibition of these parietal regions. These results show that applying 1 Hz rTMS to DLPFC, an area involved in episodic memory formation, improves memory performance via modulating neural activity in parietal regions.

neuroscience↗

bioRxiv2020

Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked

BackgroundTranscranial ultrasound stimulation (TUS) is emerging as a potentially powerful, non-invasive technique for focal brain stimulation. Recent animal work suggests, however, that TUS effects may be confounded by indirect stimulation of early auditory pathways. ObjectiveWe aimed to investigate in human participants whether TUS elicits audible sounds and if these can be masked by an audio signal. MethodsIn 18 healthy participants, T1-weighted magnetic resonance brain imaging was acquired for 3D ultrasound simulations to determine optimal transducer placements and source amplitudes. Thermal simulations ensured that temperature rises were <0.5 {degrees}C at the target and <3 {degrees}C in the skull. To test for non-specific auditory activation, TUS (500 kHz, 300 ms burst, modulated at 1 kHz with 50% duty cycle) was applied to primary visual cortex and participants were asked to distinguish stimulation from non-stimulation trials. EEG was recorded throughout the task. Furthermore, ex-vivo skull experiments tested for the presence of skull vibrations during TUS. ResultsWe found that participants can hear sound during TUS and can distinguish between stimulation and non-stimulation trials. This was corroborated by EEG recordings indicating auditory activation associated with TUS. Delivering an audio waveform to participants through earphones while TUS was applied reduced detection rates to chance level and abolished the TUS-induced auditory EEG signal. Ex vivo skull experiments demonstrated that sound is conducted through the skull at the pulse repetition frequency of the ultrasound. ConclusionFuture studies using TUS in humans need to take this auditory confound into account and mask stimulation appropriately.

neuroscience↗