A5062790616- Neuroblastoma Research and Treatments
- CRISPR and Genetic Engineering
- Advanced Breast Cancer Therapies
- Cancer therapeutics and mechanisms
- Genetics, Bioinformatics, and Biomedical Research
- Epigenetics and DNA Methylation
- Science, Research, and Medicine
- DNA Repair Mechanisms
- PARP inhibition in cancer therapy
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Sarcoma Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- Eicosanoids and Hypertension Pharmacology
- PI3K/AKT/mTOR signaling in cancer
- Computational Drug Discovery Methods
- Nitric Oxide and Endothelin Effects
- Hormonal Regulation and Hypertension
- Single-cell and spatial transcriptomics
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Liver Disease and Transplantation
Charité - Universitätsmedizin Berlin
2008-2025
Helios Hospital Berlin-Buch
2022-2024
Humboldt-Universität zu Berlin
2019-2020
Freie Universität Berlin
2019-2020
Max Delbrück Center
2008-2013
Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, high-content imaging resolve intratumoral heterogeneity patient-derived primary RMS cultures. We show that the aggressive alveolar (aRMS) subtype contains plastic muscle stem-like cells cycling progenitors drive tumor growth, subpopulation...
DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 genomes followed by the interrogation CRISPR-Cas9 loss-of-function screens across >700 cell lines, we determined that are accompanied distinct dependency profiles. In a proof-of-principle study, demonstrate coamplification bona fide gene DEAD-Box Helicase 1 (DDX1) creates increased on mTOR...
Exercise-induced cardiac hypertrophy has been recently identified to be regulated in a sex-specific manner. In parallel, women exhibit enhanced exercise-mediated lipolysis compared with men, which might linked responses. The aim of the present study was assess if previously reported sex-dependent differences hypertrophic response during exercise are associated energy substrate availability/utilization. Female and male C57BL/6J mice were challenged active treadmill running for 1.5 h/day (0.25...
Abstract Background Histone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated. Methods Their role was determined using different inhibitors including TSA, Romidepsin, Entinostat PCI-34051 as well CRISPR/Cas9 HDAC knockouts RNAi. To analyze resulting changes microarray analysis, qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays xenograft-mouse...
Telomerase is reactivated by genomic TERT rearrangements in ~30% of diagnosed high-risk neuroblastomas. Dismal patient prognosis results if the RAS/MAPK/ALK signaling transduction network also harbors mutations. We present a liquid biopsy-based monitoring strategy for this particularly vulnerable pediatric subgroup, whom real-time molecular diagnostic tools are limited to date. Droplet digital PCR assays quantifying patient-individualized rearrangement breakpoint copies, ALK copy numbers and...
<div>Abstract<p>Telomerase is reactivated by genomic <i>TERT</i> rearrangements in ∼30% of diagnosed high-risk neuroblastomas. Dismal patient prognosis results if the RAS/MAPK/ALK signaling transduction network also harbors mutations. We present a liquid biopsy–based monitoring strategy for this particularly vulnerable pediatric subgroup which real-time molecular diagnostic tools are limited to date. Droplet digital PCR assays quantifying patient-individualized...
<p>A ddPCR assay detecting unique <i>TERT</i> rearrangement breakpoints for improved in-time molecular disease monitoring. <b>A,</b> Representative original data output from the uniplex designed to quantify copies of breakpoint GI-ME-N cell line (left). The 1D amplitude plot depicts event number (droplets) versus fluorescence with positive (blue) and negative (gray) droplets separated by threshold (pink). Quantification detected in cells grown <i>in...
<p>Longitudinal <i>TERT</i> breakpoint monitoring in ctDNA detects molecular relapse of high-risk neuroblastoma patient P4. copies (top) and <i>ALK</i> copy numbers (bottom; both detected by ddPCR purified genomic DNA) as well selected clinical case information (below<i> time line</i>) are shown for longitudinally collected samples (type indicated the graphical display) from Light yellow white backgrounds represent different treatment modules. BM,...
<p>Targeted ctDNA-based <i>TERT</i> breakpoint and <i>ALK</i> p.R1275Q markers persist in patient P3. <b>A,</b> The graphical display integrates biosample analysis type along the P3 course timeline for rearrangement (violet) copies (green, top time line) selected clinical case information (bottom line). Light yellow white backgrounds represent different treatment modules. <b>B, </b><i>TERT</i> quantification tumor...
<p>Figure S4</p>
<p>Figure S3</p>
<p>Figure S2</p>
<p>Bone marrow (BM) plasma is sufficient to detect <i>TERT</i> breakpoint, <i>ALK</i> p.R1275Q mutation, and copy numbers in the novel ddPCR assay. Comparative analysis of breakpoints, cell free DNA separated liquid component (BM plasma) cellular fraction samples from BM aspirates patients P2 (days 0, 148, 310 after diagnosis), P3 423 482 P4 (day 134 hospital). Pairs same patient sample are connected by lines.</p>
<p>Clearance of <i>TERT</i> breakpoint sequence from ctDNA during induction therapy in patient P2. rearrangement copies (detected by ddPCR purified and genomic DNA) selected clinical case information (below time line) are shown for longitudinally collected samples (type indicated the graphical display) Light yellow white backgrounds represent different treatment modules. BM, bone marrow; CR, complete remission; DD, detectable disease; HVA, homovanillic acid urine/g...
<p>Figure S1</p>
<p>supplementals pdf file</p>
We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure–independent left ventricular hypertrophy, but only in male mice. To test the hypothesis estrogen receptor-β (ERβ) protects females from we treated and female ERβ-deficient (ERβ −/− ) mice their littermates (wild-type [WT]) with made them telemetrically normotensive hydralazine. WT males had increased (+16%) heart weight/tibia length ratios compared (+7%) at 6 weeks. In ERβ mice, this situation was...
Vascular regeneration depends on intact function of progenitors vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal (MSC). Deregulated MSC differentiation maladaptive cell fate programs associated with age metabolic diseases may exacerbate arteriosclerosis due to excessive transformation osteoblast-like calcifying cells. Targeting mTOR, a central controller fates, could offer novel therapeutic perspectives. In culture model for osteoblastic...
Imbalances in cytochrome P450 (CYP)-dependent eicosanoid formation may play a central role ischemic acute kidney injury (AKI). We reported previously that inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) action ameliorated ischemia/reperfusion (I/R)-induced AKI rats. Now we tested the hypothesis enhancement epoxyeicosatrienoic (EET) actions counteract detrimental effects 20-HETE and prevent initiation AKI.Male Lewis rats underwent right nephrectomy ischemia was induced by 45 min...
Abstract Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression muscle progenitor is not only sufficient increase sensitivity ATR inhibition, but also exhibit increased structurally diverse inhibitors ATR....
The deoxycorticosterone acetate (DOCA)-salt mouse model exhibits adverse cardiac remodeling in male mice and protection female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling necessary for females. first tested sex differences intracellular after mTOR targeting with wild-type mice. Radio-telemetric was maintained at normal 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection...
We tested the hypothesis that female and male mice differ in terms of cardiac hypertrophy after deoxycorticosterone acetate (DOCA)+salt hypertension (uninephrectomy 1% saline drinking water) focused on calcineurin signaling. excluded confounding effects blood pressure elevation or sex-related differences by treating DOCA-salt with hydralazine (250 mg/L water). found directly measured mean arterial was lowered to control values corroborated this finding separate mouse groups radiotelemetry....
Aim 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-dependent eicosanoids that play opposite roles in the regulation of vascular tone, inflammation, apoptosis. 20-HETE aggravates, whereas EETs ameliorate ischemia/reperfusion (I/R)-induced organ damage. rapidly metabolized to dihydroxyeicosatrienoic (DHETs) by soluble epoxide hydrolase (sEH). We hypothesized sEH gene (EPHX2) deletion would increase endogenous EET levels thereby protect...
Adaptive cardiac remodeling is characterized by enhanced signaling of mTORC2 downstream kinase Akt. In females, 17ß-estradiol (E2), as well Akt contribute essentially to sex-related premenopausal cardioprotection. Pharmacologic mTOR targeting with rapamycin increasingly used for various clinical indications, yet burdened heterogeneity in therapy responses. The drug inhibits mTORC1 and less-so mTORC2. male rodents, decreases maladaptive hypertrophy whereas it leads detrimental dilative...