Biology subjects

Muth, A.

Publications and source records attributed to Muth, A..

4 recordsLinked to original sources

bioRxiv2025

A platform of robust patient-derived leukemia models covering subgroups for which no cell lines exist

Preclinical cancer research requires robust model systems, especially for poor prognosis entities like acute myeloid leukemia (AML), a highly aggressive blood cancer. Here, primary tumor cells from 137 AML patients of all age groups were transplanted into immune compromised mice to generate patient-derived xenografts (PDX). From these, 23 models enable robust, virtually endless serial re-transplantation and are amenable to lentiviral genetic engineering (*PDX AML models). These models primarily originate from patients with highly aggressive, relapsed disease. Comprehensive genomic, transcriptomic, and epigenomic analyses confirmed that they replicate primary AML biology more faithfully than conventional cell lines. Notably, *PDX AML models include AML subgroups that are underrepresented or absent in existing model systems, such as cytogenetically normal or IDH1/2-mutant AML. They withstand freeze-thaw cycles, making them suitable for broad distribution and reproducibility across research institutions. Luciferase-based in vivo imaging enables real-time monitoring of tumor progression and treatment responses in preclinical trials. Surprisingly, long-term treatment, including repeated cytarabine therapy over a period of one year, showed a gradual reduction in leukemia cell proliferation, which decreased continuously after each treatment block. Collectively, our *PDX models represent a robust, versatile, and relevant platform that holds great promise to accelerate translational research for the benefit of cancer patients. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/677299v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1ead31eorg.highwire.dtl.DTLVardef@1ca702corg.highwire.dtl.DTLVardef@18a7137org.highwire.dtl.DTLVardef@edbe6_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIWe present new robust AML PDX models covering subgroups for which no cell lines exist for use in various ex vivo and in vivo applications. C_LIO_LI*PDX models enable serial transplantation, genetic engineering and better representation of primary AML biology than cell lines. C_LIO_LIOne-year in vivo trials mimicking clinical chemotherapy showed surprising gradual decline in leukemia growth after each treatment block. C_LI

cancer biology↗

bioRxiv2022

Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features and presenting as a useful resource. Mutations in the pseudohypoxic marker EPAS1/HIF-2 correlates to an aggressive tumor phenotype. We show that HIF-2 unexpectedly localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2 was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that cytoplasmic HIF-2 expression serves as a useful clinical marker to differentiate subtypes and predicting outcome, and hence can be used for improved targeted treatment in PPGLs.

cancer biology↗

bioRxiv2021

Spatial neglect in the digital age - Influence of presentation format on patients' test behavior

Computerization of diagnostic neglect tests can deepen our knowledge of neglect specific abnormalities, by effortlessly providing additional behavioral markers that are hardly extractable from existing paper-and-pencil versions. However, so far it is not known whether the digitization and/or a change in size format impact neglect patients search behavior and test scores and thus require adjustments of cut-off criteria. We compared the Center of cancellation (CoC) measure of right hemisphere stroke patients with spatial neglect in two cancellation tasks across different modalities (paper-and-pencil vs. digital) and display sizes (small, medium, large). We found that the CoC measure did neither vary considerably between paper-and-pencil versus digital versions, nor between different digital size formats. The CoC derived from cancellation tasks thus seems robust to test digitization. A further aim of the present study was to evaluate three additional parameters of search behavior which became available through digitization. We observed slower search behavior, increased distance between two consecutively identified items, and signs of a more strategic search for neglect patients than control patients without neglect. Machine learning classifications indicated that - beyond the CoC measure - the latter three variables can help to differentiate stroke patients with spatial neglect from thosewithout.

neuroscience↗

bioRxiv2020

Multifocal small intestine neuroendocrine tumors form by independent somatic evolution

BackgroundSmall intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several intestinal tumors centered around a regional lymph node metastasis. Although SI-NET patients often present with metastatic disease at the time of diagnosis, there is an unusual absence of somatic driver mutations explaining tumor initiation and metastatic spread. The evolutionary trajectories that underlie multifocal SI-NET lesions could provide insight into the underlying tumor biology, but this question remains unresolved. Here, we determined the complete genome sequences of 65 tumor and tissue samples from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within individual patients. Intra-individual comparisons of whole genome sequences revealed a lack of shared somatic single-nucleotide variants and copy number alterations among the sampled intestinal lesions, supporting that they were of independent clonal origin. Furthermore, each metastasis originated from a single intestinal tumor, and in three of the patients, two independent tumors had metastasized. We conclude that primary multifocal SI-NETs generally arise from clonally independent cells, suggesting a contribution from of a cancer-priming local factor.

genomics↗