open_UMR

Aaron Beller

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Welcome to open_UMR!

Open_UMR is a cross faculty publication hub. We collect scientific publications, resources, research data and software from members of Philipps-University Marburg and make it openly accessible. To ensure high standards of quality and re-usability, submissions to open_UMR are subject to curation.

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Recent Submissions

Open Access
Funktionelle Analyse der B-Plexine in intestinalen Tumorstammzellen
(2026-09-01)
Hillert, Nele
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Worzfeld, Thomas
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Worzfeld, Thomas
;
Hollenbach, Marcus
Colorectal carcinoma is one of the most frequently diagnosed cancers and has a high mortality rate. The majority of cases, around 85%, are caused by the gradual accumulation of somatic mutations that lead to the development of benign adenomas and invasive carcinomas. Cancer stem cells play an important role in the development and therapy resistance of carcinomas. Semaphorin-plexin signaling was originally identified as an axon-regulating system in the central nervous system. In the meantime, the involvement of signaling in a variety of physiological and pathophysiological processes has been described. The intestines contain mainly B-plexins, mostly plexin-B1 and plexin-B2. A plexin B1/plexin-B2 doubleknockout was previously characterised by an impaired function of intestinal stem cells due to a reduced ability to form organoids, and a lower incidence of adenomas. To further characterize the influence of plexin-B1 and plexin-B2 on intestinal stem cells in colorectal carcinoma, a plexin-B1/plexin-B2 double knockdown was performed by lentiviral transduction of shRNAs into a murine tumor organoid culture. The knockdown did not reach statistical significance, meaning that no associated change in the expression of the stem cell markers Lgr5, CD44 or EphB2 could be observed. Moreover, no change in proliferative activity, visualized by BrdU, could be shown. However, the cell culture, displayed an altered cell architecture of the tumor organoids compared to murine physiological intestinal organoids. Ultimately, a statement regarding the influence of semaphorin plexin-signaling on colorectal carcinoma cannot be made, but it should be held under consideration while thinking of new treatment methods for colorectal carcinoma
Open Access
Entwicklung und Implementierung regionaler, intersektoraler Behandlungspfade zur Diagnostik bei Patienten mit Brustschmerzen und äquivalenten Symptomen: Eine Analyse
(0026-07-08)
Jung-Henrich, Jutta
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Donner-Banzhoff, Norbert
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Sitter, Helmut
This dissertation investigates the persistently high rate of diagnostic invasive coronary angiography in patients with suspected stable coronary artery disease (CAD) in Germany. Despite national and European guidelines recommending the preferential use of non-invasive diagnostic strategies in appropriate patients, their implementation in routine clinical practice remains insufficient. The study therefore aimed to characterize current diagnostic care pathways and to evaluate whether regionally developed clinical pathways could facilitate evidence-based and guideline-concordant diagnostic decision-making. A mixed-methods design was applied across four German regions characterized by high rates of invasive coronary angiography. Quantitative data were collected on diagnostic procedures, diagnoses, patient counseling, and quality of life at baseline and at three-month follow-up. In parallel, physicians involved in the care of patients with suspected CAD participated in moderated workshops to develop regional clinical pathways for the diagnostic evaluation of chest pain and equivalent symptoms. Following the implementation phase, physicians’ experiences with pathway development and utilization were evaluated through semi-structured interviews and qualitative content analysis. The findings demonstrate a substantial discrepancy between evidence-based guideline recommendations and routine clinical practice. Invasive coronary angiography remained a preferred diagnostic strategy among many physicians and was frequently performed without prior non-invasive evidence of myocardial ischemia. The regional care pathways developed within the study did not result in meaningful changes in clinical practice or measurable improvements in quality of care. Major barriers included reservations regarding recommended non-invasive diagnostic procedures, limited regional availability, and a perceived lack of need to modify established diagnostic practices. Overall, the findings indicate that regional clinical pathways alone are insufficient to achieve sustainable implementation of guideline-concordant diagnostic strategies. Effective implementation requires broader structural and health-policy interventions, including improved professional education and training, greater availability and appropriate reimbursement of non-invasive diagnostic modalities, and enhanced patient information and risk communication. In this context, the inclusion of coronary computed tomography angiography in the German statutory health insurance benefits catalogue in 2024 represents an important structural development. Improved access to and reimbursement of non-invasive coronary imaging may contribute to more appropriate indications for invasive coronary angiography and reduce the number of procedures performed primarily for diagnostic purposes.
Open Access
Targeting der Radioresistenz von HNSCC-Tumorzellen: Molekulare Mechanismen der strahleninduzierten Seneszenz und des Seneszenz-assoziierten sekretorischen Phänotyps
(2026-09-04)
Kohl, Sibylla
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Theiß, Ulrike
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Mandic, Robert
Head and neck squamous cell carcinomas (HNSCC) are among the most common malignant tumours worldwide causing poor therapeutical outcomes, especially for patients with the HPV negative subtype. Despite multimodal therapy concepts including radiotherapy, local control rates often remain inadequate. A key reason for this is the development of radiation resistance, which is associated with ionising radiation-induced senescence and the senescence-associated secretory phenotype (SASP). The work of Tiwari et al. (2022) and Kohl et al. (2026) collectively serves to elucidate the molecular mechanisms of radiation-induced senescence and its therapeutic influence. In Tiwari et al. (2022), for the first time the influence of different radiation qualities (photons vs. carbon ions) on the relationships between radiation response, senescence and SASP induction in five HPV-negative HNSCC cell lines was systematically investigated. In addition to determining clonogenic survival and DNA damage repair, the expression of key SASP components was analysed. Carbon ions with up to three times higher relative biological effectiveness (RBW10 = 2.22 – 3.16) cause more effective tumour cell killing. Correlation of functional and mechanistic data identified the NFκB-dependent IL1 signalling pathway with the upstream ligands IL1A and IL1B as predictive markers for radiation resistance – but without direct functional involvement in cell survival after irradiation. The data suggested that compensatory autocrine signalling axes can offset this effect. The CXCR2 signalling pathway in particular proved to be a potential amplifier of SASP, as the binding of its ligands CXCL1/2 and IL-8 triggers PI3K/IKK-dependent NFκB activation. This feedback loop can stabilise the senescent phenotype autocrinally. Therefore, the hypothesis was formulated that the inflammatory CXCR2-mediated SASP arm plays a central role in maintaining radiation-induced resistance. These findings formed the basis for the subsequent work by Kohl et al. (2026), the therapeutic influence of the senolytic agent ABT-263 (Navitoclax) on radiation-induced senescence was investigated. The aim was to achieve radiosensitisation of HPV-negative HNSCC cells by eliminating senescent cells. Building on the results from Tiwari et al., the most radioresistant cell lines Cal33 and UPCI:SCC040 were selected for the investigation. After photon irradiation, both cell lines showed a significant induction of senescence, accompanied by upregulation of the anti-apoptotic Bcl-2 family protein Bcl-xL. Treatment with ABT-263 led to significant radiosensitisation in Cal33 cells, while UPCI:SCC040 remained largely resistant. To explain these differences mechanistically, the expression of NFκB-dependent SASP factors and their receptors was investigated. In particular, a contrasting regulation of the CXCR2 receptor was noticed: after combined irradiation and ABT-263 treatment, CXCR2 was reduced in Cal33, but increased in UPCI:SCC040. A transient siRNA-mediated knockdown of CXCR2 confirmed its functional significance and resulted in a restitution of radiosensitisation. DNA damage response and repair remained unaffected, indicating that the effect is independent of classical DDR mechanisms. This allowed to show that the CXCR2 signalling pathway acts as a functional mediator of resistance to radiation and senolytic treatment. Expression was decisive in determining whether senescent cells were eliminated by ABT-263 or survived and thus contributed to radioresistance. In conjunction with the results from Tiwari et al., this led to a model of SASP-mediated feedback, in which persistent DDR signals via NFκB and p38-MAPK lead to SASP induction. Its components – including IL-1, IL-6, IL-8 and CXCL1/2 – activate autocrine CXCR2 and stabilise the senescent phenotype via PI3K/AKT-dependent signalling pathways. Pharmacological blockade of CXCR2 could therefore attenuate senescence-associated resistance and, in combination with ABT-263 or optimised Bcl-2 inhibitors, enable effective elimination of radiation-induced senescent cells and represent a concept for improving radiotherapy in HPV-negative HNSCC. While it was possible to identify the IL1 signalling pathway as a marker in Tiwari et al., but without functional involvement in radioresistance, Kohl et al. showed that the CXCR2 signalling pathway is a critical amplifier of this resistance and a determinant of the senolytic efficacy of ABT-263. The results demonstrate that the targeted modulation of senescent signalling pathways, in particular via CXCR2 and anti-apoptotic Bcl-2 proteins, represents a promising strategy for reducing therapy-mediated radioresistance in HPV-negative HNSCC. This preclinical work provides initial indications for future combination therapies based on the selective elimination of radiation-induced senescent cells, which could contribute to improved tumour control and a reduction in therapy-related side effects in the long term.
Open Access
Biophysical analysis of unconventional voltage-sensitive proteins in sensory cells
(2026-07-02)
Kuwabara Yamaguchi, Makoto
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Oliver, Dominik
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Schütz, Burkhard
In sensory transduction, sensory cells convert an external stimulus into a change in the membrane potential, i.e. an electrical signal. This electrical signal can trigger action potentials and/or other downstream signaling pathways. At center stage of sensory transduction are classical and well-studied voltage-gated ion channels. By contrast, much less is known about unconventional voltage-sensitive membrane proteins that use unusual voltage-sensing mechanisms. In my cumulative dissertation I investigated how unconventional voltage-sensitive membrane proteins in sensory cells convert voltage into downstream signals. First, I investigated how voltage-driven conformational changes of prestin generate outer hair cell electromotility, rapid somatic length changes that underlie cochlear amplification. By combining my voltage-clamp fluorometry experiments with molecular dynamics simulations performed by my collaborators, I found that prestin undergoes elevator-like reorientation of its transport domain relative to the scaffold domain, which changes the membrane cross-sectional area of the protein. I showed that these voltage-dependent conformational changes have the same voltage dependence as the non-linear capacitance, an electrophysiological readout of electromotility. This data link transport-domain reorientation directly to prestin-driven outer hair cell electromotility and support the idea that an elevator transport mechanism conserved among SLC26 anion transporters has been adapted to drive cochlear amplification in the mammalian inner ear. Second, I examined how the membrane scaffolding protein Paralemmin-3 influences prestin-dependent function in the specialized lateral wall of outer hair cells. Motivated by collaborative work that identified Paralemmin-3 as a key lateral-wall scaffolding protein, I focused on prestin-dependent function by measuring voltage-dependent membrane capacitance in outer hair cells from Palm3-deficient and wild-type cochleae. I found that Palm3 loss reduces linear membrane capacitance, consistent with a reduction in lateral membrane area, whereas the voltage dependence of prestin-associated non-linear capacitance remains largely unchanged in young pre-hearing animals and declines only at later stages. These results indicate that Paralemmin-3 is important for maintaining the lateral wall of outer hair cells and a stable membrane distribution of prestin, while the basic voltage-driven conformational changes of prestin that generate electromotility are initially preserved. Third, I studied an unusual voltage-gated ion channel in the exotic “sensory” sperm cell: the HCNL1 proton channel. HCNL1 is activated by hyperpolarization and might control the intracellular pH in zebrafish sperm. I identified zinc ion as an inhibitor of HCNL1. Using two-electrode voltage clamp, voltage-clamp fluorometry, macropatch recordings, and histidine-to-alanine mutagenesis, I showed that zinc inhibits HCNL1 from both the extracellular and intracellular sides of the plasma membrane at submillimolar concentrations. Zinc slows channel kinetics, shifts the voltage dependence of activation, and alters hyperpolarization-evoked conformational changes of the voltage-sensing domain. My study also identifies distinct histidine residues that contribute to zinc coordination and suggests a role for zinc as a physiological modulator of intracellular pH in zebrafish sperm.
Open Access
Die diagnostische Bedeutung der Körperposition bei der Untersuchung des arteriellen Thoracic-Outlet-Syndrom mittels farbkodierter Duplexsonografie
(2026-08-14)
Rössel, Henrik Bertrand Ulrich
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Stegemann, Emilia
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Görg, Christian
Abstract The diagnostic role of body position in arterial thoracic Outlet Syndrome using colour-coded duplex sonography Background Thoracic outlet syndrome (TOS) encompasses a range of compression syndromes affecting the upper thoracic aperture, leading to vascular and neurological symptoms. Accurate diagnosis, particularly of arterial TOS (aTOS), is essential to prevent severe complications. While colour-coded duplex sonography (CCDS) is increasingly recognised as a diagnostic tool for TOS, the influence of patient positioning during the examination remains unclear. This study investigates whether performing CCDS in a seated position improves diagnostic accuracy compared with the supine position. Patients and Methods This prospective, blinded diagnostic study included 53 consecutive patients with clinical suspicion of TOS recruited from a specialised vascular medicine centre. Each patient underwent CCDS examination in both seated and supine positions. Arterial compression was dynamically assessed using pulsed-wave Doppler frequency profiles of the subclavian artery in the neutral position, abduction-elevation-rotation (AER), and hyperabduction. Examinations were performed by an experienced examiner and a novice examiner; in the latter, an additional post hoc assessment of the stored images was performed by the experienced examiner. The primary endpoint was the effect of body position on diagnostic outcome. Inter-rater agreement was evaluated using Cohen’s kappa (κ). Results Seated examinations detected significantly more cases of arterial compression than supine examinations (78,3% vs. 28,3%, p < 0,05). The seated position demonstrated higher sensitivity in identifying aTOS-associated flow abnormalities. Inter-rater agreement between the experienced examiner and the novice examiner was excellent (κ = 0,85). Dynamic testing in the seated position proved particularly useful for identifying borderline findings and anatomical variants. Conclusions Patient positioning significantly affects the diagnostic performance of CCDS in aTOS. The seated position improves sensitivity for detecting compression of the subclavian artery and should therefore be routinely applied in clinical practice. Structured training enables less experienced examiners to achieve reliable results. These findings highlight the importance of standardised patient positioning and examination protocols in CCDS to improve diagnostic accuracy in aTOS.