Biology subjects

Lorenz, K.

Publications and source records attributed to Lorenz, K..

11 recordsLinked to original sources

bioRxiv2026

Targeting poorly differentiated thyroid cancer with bispecific antibodies and CAR T cells from the human anti-TSHR autoantibody repertoire

Background: Poorly differentiated thyroid carcinoma (PDTC) has no effective systemic treatment option once radioactive iodine and tyrosine kinase inhibitors fail. The thyroid-stimulating hormone receptor (TSHR) is highly tissue-restricted and the anti-TSHR autoantibody repertoire of thyroid autoimmunity offers sequence-defined, fully human binders. We asked whether this repertoire can be converted into an off-the-shelf T cell-redirecting therapy for PDTC. Methods: TSHR expression was profiled on a 151-case thyroid cancer tissue microarray (TMA), 50 healthy controls and on fresh tumor material. Eight anti-TSHR clones, four of human autoimmune origin (M22, K1-18, K1-70, 5C9) and four murine (IRI-SAb2, IRI-SAb3, 9D33, 1H7), were reformatted as CD3-engaging bispecific antibodies (bsAbs; anti-TSHR Fab x anti-CD3 scFv) and, for leading clones, as chimeric antigen receptor (CAR) T cells. Activity was compared in vitro, across graded and mixed antigen densities and in a CAL-62-Luc-TSHR xenograft model, using healthy-donor (HD) or thyroid cancer-patient T cells. Results: TSHR was retained on a substantial fraction of PDTC, including metastatic lesions. Both formats mediated potent, antigen-selective killing and the leading bsAbs suppressed xenograft growth in vivo. For CAR T cells, scFv heavy/light-chain orientation was decisive. Anti-TSHR bsAbs cleared mixed cultures far beyond the antigen-positive fraction matching mosunetuzumab and indicating a modality-intrinsic bystander effect. Patient-derived T cells obtained on or after oncological treatment retained full effector function. Conclusions: The anti-TSHR autoantibody repertoire provides a promising source of binders for off-the-shelf bispecific antibodies targeting TSHR-positive thyroid cancer, while CAR T cells offer an autologous alternative.

cancer biology↗

bioRxiv2026

Utilizing single-cell data for per-cell type eQTL mapping in the human pancreas

Aims/hypothesis The human pancreas is a central organ for metabolic regulation that is comprised of diverse cell types that uniquely contribute to its function. Previous studies have performed expression quantitative trail loci (eQTL) discovery in either whole pancreas or in pancreatic islets, but due to differences between pancreatic cell types, this approach does not reveal cell type-specific effects. In this study, we sought to either implicate the cell type of action for known eQTLs or identify new eQTLs that may have been masked in bulk studies by performing eQTL discovery in individual pancreatic cell types. Methods We clustered 153,018 single-cell RNA sequencing (scRNA-seq) data from 71 pancreatic islet donors from the Human Pancreas Analysis Program (HPAP). We performed eQTL discovery in six pancreatic cell types using this resource directly. We further utilized this single cell resource as a reference to deconvolute bulk pancreatic RNA sequencing data from 305 Genotype Tissue Expression (GTEx) project donors and performed eQTL discovery in four pancreatic cell types. Finally, we performed fine-mapping and co-localization of pancreatic cell type eQTLs with metabolic GWAS to connect our findings to metabolic disease risk. Results From analyzing 71 individuals with single cell profiles, we identified 112 unique eGenes across six pancreatic cell types, 99 of which had been identified previously and 13 unique to this study. From the deconvoluted eQTLs, we identified 3,134 unique eGenes across four pancreatic cell types, 116 of which were unique to our study. Fine-mapping and co-localization of eQTLs with metabolic GWAS yielded key leads that warrant further investigation, such as the association of rs2168101 with LMO1 expression in alpha cells. Conclusions/interpretation We identified new signals that were previously not found in bulk pancreatic eQTL studies and potential cell type of action for several signals that were identified previously. Although there are limitations to the power, and therefore, discoverability of this study, it provides insights into how individual pancreatic cells differently contribute to metabolic disease.

genetics↗

bioRxiv2026

Tonsillar expression quantitative trait loci verify and expand genetic contributors to childhood atopic diseases

The spectrum of causal variants, mechanisms, and immunologic gene networks that influence pediatric atopic traits are not completely understood. Human genetic variation associated with transcript abundance (eQTLs) can help to advance our understanding, yet prior work has focused on profiling immune cell populations collected from peripheral blood primarily in adult populations, leaving uncharacterized tissue-resident lymphocytes collected from children. Here, we paired genotyping with gene expression profiling across four populations of tonsil-derived immune cell types - including previously uncharacterized germinal center B cells - collected from 103 children across development (ages 1-18). Using these data, we report cell-type specific gene networks and identify 13,393 eGenes (1,793 eGenes not previously reported in similar datasets) influenced by 27,603 eQTLs (5,199 not previously reported). We link discovered eQTLs to associations identified in pediatric and adult asthma and atopy traits, nominating 78 eGenes like TRAF3, ZBTB10 and JAZF1 in disease relevant cell types. Our resource is freely available and exemplifies the importance of discovery in native tissues and across human development.

immunology↗

bioRxiv2025

Short-term but not long-term triiodothyronine treatment improved cardiac function after myocardial infarction in male wild-type mice

ObjectivesThyroid hormone (TH), especially triiodothyronine (T3), plays an important role in cardiac physiology and in the remodeling process following myocardial infarction (MI). We investigated the effects of short-term (until day 5) and long-term (until day 56) post-MI T3 treatment on cardiac function, infarct size, hypertrophy, and gene expression in mice without and with deletion of TR, the main cardiac thyroid hormone receptor (wild-type (WT) and TRKO, respectively) MethodsWT and TRKO mice underwent permanent left anterior descending coronary artery (LAD) ligation or sham surgery followed by either short-term T3 for 5 days post-MI or long-term T3 until day 56, including a subgroup in which T3 treatment commenced 14 days post-MI; all groups were followed up for 4 weeks. T3 was delivered via drinking water at 500 ng/ml. Cardiac function was studied with echocardiography (ejection fraction, EF), infarct size by histology (Sirius red), heart weight normalized to tibia length, and transcriptomic profiling (RNA-seq) in WT hearts. ResultsShort-term T3 improved EF in WT but not in TRKO mice without induction of hypertrophy or changes in infarct size in either genotype. Long-term T3 induced cardiac hypertrophy in both WT and TRKO mice. However, long-term T3 did not improve EF or reduce infarct size. In TRKO mice, baseline EF post-MI was preserved without T3, but T3 treatment decreased EF. RNA-seq in long-term treated WT mice suggested modulation of Rho-GTPase signaling, mitochondrial biogenesis, and immune activation by T3. ConclusionsT3 therapy post-MI improved cardiac function only when applied acutely and for a short term. Long-term exposure led to cardiac hypertrophy without functional improvement and may even worsen cardiac function in TR-deficient settings. Timing, duration, and receptor status are highly relevant for TH-based interventions in MI.

physiology↗

bioRxiv2025

Automatic colocalization of high resolution MALDI MSI and Raman imaging applied to cardiac tissue of Fabry disease mouse models

Understanding early molecular changes in biological tissues is crucial for diagnosing pathological and genetic diseases and for elucidating their underlying mechanisms. However, localized molecular alterations of low molecular-weight compounds are not inferred from conventional staining or genetic methods. Here, we established a multimodal imaging approach that integrates Raman spectroscopy and atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-MALDI MSI): two complementary, label-free techniques enabling molecular profiling of a broad spectrum of biomolecules from one single tissue section. This method was applied to detect Gb3 accumulation in heart tissue of murine models of Fabry disease, including mice deficient in -galactosidase A (GLA) activity (GLA knock-out) and transgenic mice with a GLA knock-out and an upregulation of globotriaosylceramides (Gb3) synthase. With AP-MALDI MSI we were able to discern the heterogenous expression of Gb3 lipoforms with down to 5 {micro}m pixel size and reveal the significantly increased Gb3 content in mice containing a GLA knock-out combined with human Gb3 synthase overexpression compared to GLA knock-out and wild type samples. By employing Raman microscopy with a pixel size of 2 {micro}m, we were able to contextualize the physiological alterations in cardiac tissue by identifying components associated with nuclei, tissue, collagen, and lipids for the same three genotypes. An automated co-localization algorithm aligned Raman and AP-MALDI-MSI data from the same tissue section with (5.1 {+/-} 1.6) {micro}m precision, enabling overlay at 5 {micro}m and 2 {micro}m resolution. The method resolved heterogeneous Gb3 distributions and distinct lipid species in cardiac mouse tissue.

molecular biology↗

bioRxiv2024

Redirecting full-length FLT1 expression towards its soluble isoform promotes postischemic angiogenesis

Vascular endothelial growth factors and their tyrosine kinase receptors are key mediators of vasculogenesis and angiogenesis with FLT1 (VEGFR1) serving as a decoy receptor. A truncated mRNA transcript encoding soluble (s) FLT1 can be generated by premature cleavage and polyadenylation (APA). Although a shortening of transcripts is described in pathological settings, including heart diseases, the functional in vivo impact of FLT1 gene isoform generation and relevance for angiogenesis remain unknown. Here, we show that specific splice site mutations within Flt1 inhibit telescripting and activate APA in vivo to efficiently modulate gene isoform expression, inducing a complete loss of full-length (fl) Flt1 and a switch towards sFlt1 in mice. FLT1 is a high-affinity decoy receptor of VEGF limiting vessel overgrowth. We show that sFLT1 was sufficient for developmental vasculogenesis, whereas flFLT1 controlled ischemia-driven angiogenesis. Our results demonstrate that telescripting is essential in vivo for controlling Flt1 isoform expression and angiogenesis and can be harnessed to improve reparative revascularization. Furthermore, given the widespread abundance of APA signals, our approach may serve as a blueprint for studying telescripting and generating other truncated gene isoforms in vivo.

cell biology↗

bioRxiv2024

Enhanced cardiac mitochondrial biogenesis by nitro-oleic acid remedies diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

Prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunctions contribute to HFpEF progression. Nitro-oleic acid (NO2-OA) impacts metabolic processes by improving glucose tolerance and adipocyte function. In this study, 4 week treatment with NO2-OA ameliorated diastolic dysfunction in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. A proteomic analysis of left ventricular tissue revealed, that one third of the identified proteins, mostly mitochondrial proteins, were upregulated in hearts of NO2-OA-treated HFpEF mice compared to controls and vehicle-treated HFpEF mice, which was confirmed by immunoblot. Activation of the 5-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediated an enhancement of mitochondrial biogenesis in hearts of NO2-OA-treated HFpEF mice. In cardiomyocytes under metabolic stress, NO2-OA increased mitochondrial protein level accompanied by enhanced oxidative phosphorylation. In conclusion, targeting mitochondrial integrity in HFpEF leads to improved diastolic function.

pathology↗

bioRxiv2023

Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice

BackgroundStimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), or {beta}, and which mode of TR action, canonical gene expression or DNA-binding independent noncanonical action, mediate these effects. Material and methodsWe compared global TR and TR{beta} knockout mice (TRKO; TR{beta}KO) with WT mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA- binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRGS; TR{beta}GS). Hearts were studied with echocardiography at baseline and after seven weeks T3-treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. ResultsT3 induced ventricular hypertrophy in WT and TR{beta}KO mice, but not in TRKO mice. Hypertrophy was also induced in TRGS mice. Thus, hypertrophy is mostly mediated by noncanonical TR action. Similarly, repression of Mhy7 occurred in WT and TRGS mice. Basal heart rate was largely dependent on canonical TR action. But responsiveness to hypothyroidism and T3-treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRKO mice, demonstrating that TR{beta} could compensate for absence of TR. ConclusionT3-induced cardiac hypertrophy could be attributed to noncanonical TR action, whereas heart rate regulation was mediated by canonical TR action. TR{beta} could substitute for canonical, but not noncanonical TR action.

physiology↗

bioRxiv2023

Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice

1Thyroid hormones (TH) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases are still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Mice at the age of 12 months underwent TAC and after induction of left ventricular pressure overload, received T4 or anti-thyroid medication in the drinking water over the course of 4 weeks. T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis and interstitial fibrosis) and mortality. This is surprising, because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure induced cardiac damage. This suggests that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.

physiology↗

bioRxiv2022

Multi-Echo Investigations of Positive and Negative CBF and Concomitant BOLD Changes

Unlike the positive blood oxygenation level-dependent (BOLD) response (PBR), commonly taken as an indication of an activated brain region, the physiological origin of negative BOLD signal changes (i.e. a negative BOLD response, NBR), also referred to as deactivation is still being debated. In this work, an attempt was made to gain a better understanding of the underlying mechanism by obtaining a comprehensive measure of the contributing cerebral blood flow (CBF) and its relationship to the NBR in the human visual cortex, in comparison to a simultaneously induced PBR in surrounding visual regions. To overcome the low signal-to-noise ratio (SNR) of CBF measurements, a newly developed multi-echo version of a center-out echo planar-imaging (EPI) readout was employed with pseudo-continuous arterial spin labeling (pCASL). It achieved very short echo and inter-echo times and facilitated a simultaneous detection of functional CBF and BOLD changes at 3 T with improved sensitivity. Evaluations of the absolute and relative changes of CBF and the effective transverse relaxation rate, [Formula], the coupling ratios, and their dependence on CBF at rest, CBFrest, indicated differences between activated and deactivated regions. Analysis of the shape of the respective functional responses also revealed faster negative responses with more pronounced post-stimulus transients. Resulting differences in the flow-metabolism coupling ratios were further examined for potential distinctions in the underlying neuronal contributions. HighlightsO_LIIntroduction of multi-echo center-out EPI for investigating concomitant CBF and BOLD changes in regions of positive (PBR) and negative BOLD response (NBR). C_LIO_LI{Delta}CBF timecourses closely follow those of [Formula] with negative signals exhibiting faster responses and more pronounced post-stimulus transients. C_LIO_LIDecreases in CBF appear to warrant a larger change in NBR than CBF increases in PBR regions. C_LIO_LIConsideration of baseline CBF values is important in comparisons of relative coupling ratios ({delta}sBOLD/{delta}cbf) between brain regions. C_LIO_LIDiscussion of potential excitatory and inhibitory neuronal feed forward control of CBF and CMRO2 in PBR and NBR. C_LI

neuroscience↗

bioRxiv2019

Machine learning-based identification and cellular validation of Tropomyosin 1 as a genetic inhibitor of hematopoiesis.

Identifying causal variants and genes from human genetics studies of hematopoietic traits are important to enumerate basic regulatory mechanisms underlying these traits, and could ultimately augment translational efforts to generate platelets and/or red blood cells in vitro. To identify putative causal genes from these data, we performed computational modelling using available genome-wide association data sets for platelet traits. Our model identified a joint collection of genomic features enriched at established platelet trait associations and plausible candidate variants. Additional studies associating variation at these loci with change in gene expression highlighted the Tropomyosin 1 (TPM1) among our top-ranked candidate genes. CRISPR/Cas9-mediated TPM1 knockout in human induced pluripotent stem cells (iPSCs) enhanced hematopoietic progenitor development, increasing total megakaryocyte as well as erythroid cell yields. Our findings may help explain human genetics associations and identify a novel genetic strategy to enhance in vitro hematopoiesis.

genomics↗