Ludwig-Maximilians-Universität München
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Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates
No full textRefractory disease and relapse are major challenges in acute myeloid leukemia (AML) therapy attributed to survival of leukemic stem cells (LSC). To target LSCs, antibody-drug conjugates (ADCs) provide an elegant solution, combining the specificity of antibodies with highly potent payloads. We aimed to investigate if FLT3-20D9h3-ADCs delivering either the DNA-alkylator duocarmycin (DUBA) or the microtubule-toxin monomethyl auristatin F (MMAF) can eradicate quiescent LSCs. We show here that DUBA more potently kills cell-cycle arrested AML cells compared to microtubule-targeting auristatins. Due to limited stability of 20D9h3-DUBA ADC in vivo, we analyzed both ADCs in advanced in vitro stem cell assays. 20D9h3-DUBA successfully eliminated leukemic progenitors in vitro in colony-forming unit and long-term culture initiating cell assays, both in patient cells and in patient-derived xenograft (PDX) cells. Further, it completely prevented engraftment of AML PDX leukemia-initiating cells in NSG mice. 20D9h3-MMAF had a similar effect in engraftment assays, but a less prominent effect in colony assays. Both ADCs did not affect healthy stem and progenitor cells at comparable doses providing the rationale for FLT3 as therapeutic LSC target. Collectively, we show that FLT3-directed ADCs with DUBA or MMAF have potent activity against AML LSCs and represent promising candidates for further clinical development
Fairness in Algorithmic Profiling: The AMAS Case
No full textWe study a controversial application of algorithmic profiling in the public sector, the Austrian AMAS system. AMAS was supposed to help caseworkers at the Public Employment Service (PES) Austria to allocate support measures to job seekers based on their predicted chance of (re-)integration into the labor market. Shortly after its release, AMAS was criticized for its apparent unequal treatment of job seekers based on gender and citizenship. We systematically investigate the AMAS model using a novel real-world dataset of young job seekers from Vienna, which allows us to provide the first empirical evaluation of the AMAS model with a focus on fairness measures. We further apply bias mitigation strategies to study their effectiveness in our real-world setting. Our findings indicate that the prediction performance of the AMAS model is insufficient for use in practice, as more than 30% of job seekers would be misclassified in our use case. Further, our results confirm that the original model is biased with respect to gender as it tends to (incorrectly) assign women to the group with high chances of re-employment, which is not prioritized in the PES’ allocation of support measures. However, most bias mitigation strategies were able to improve fairness without compromising performance and thus may form an important building block in revising profiling schemes in the present context
Multi‐Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self‐ and Cross‐Seeded Amyloid Self‐Assembly of α‐Synuclein
Full text linkAmyloid self-assembly of α-synuclein (αSyn) is linked to the pathogenesis of Parkinson's disease (PD). Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross-interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross-seed αSyn amyloidogenesis and αSyn and IAPP colocalize in PD brains. Inhibition of both self- and IAPP-cross-seeded αSyn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or Alzheimer's disease (AD) amyloid-β peptide Aβ40(42), are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn. Anti-amyloid function is mediated by nanomolar affinity interactions with αSyn via three αSyn regions which are identified as key sites of both αSyn self-assembly and its cross-interactions with IAPP. We also show that the peptides block Aβ42-mediated cross-seeding of αSyn as well. Based on their broad spectrum anti-amyloid function and additional drug-like features, these peptides are leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified αSyn key segments are valuable targets for novel, multi-site targeting amyloid inhibitors in PD and related synucleinopathies
Repetitive concussions promote microglia-mediated engulfment of presynaptic excitatory input associated with cognitive dysfunction
Full text linkConcussions are a current health concern and account for the vast majority of head trauma. While symptoms after a single impact are usually transient, repetitive concussions, as often occur in sports, are responsible for persistent acute and chronic deficits. Here, we used a model of bilateral midline-centered concussions in mice to show that repetitive concussions selectively induce impairments in learning ability compared to single-impact injuries. Since microglial cells and their activation are considered key factors in degenerative pathology after brain trauma, we examined their structure and function after single and repetitive concussions in the cortex underlying the concussions and in the hippocampus. We found that only repetitive concussions led to a significant long-lasting structural activation of microglia and an increase in microglia-mediated engulfment of presynaptic excitatory synapses, while the elimination of inhibitory synapses was not altered. Since the density of excitatory input did not change during the 6-week study period, we hypothesize that there is a turnover of excitatory synapses following repetitive concussion that can be compensated for, anatomically but not behaviorally
Mild TBI Changes Brain and Plasma Neurosteroid Levels in Mice
Full text linkMild traumatic brain injury (mTBI) accounts for 80% of all TBI, may be associated with chronic impairments, and is difficult to diagnose due to a lack of objective markers. In this study, we investigated whether neurosteroids can serve as blood biomarkers for mTBI. Two cohorts of C57BL/6 mice were subjected to a model of mTBI combining impact with rotational acceleration or sham surgery. The first cohort underwent neurological testing for anxiety, balance, and locomotion before and after mTBI. For the second cohort, brains and plasma were collected 6 or 24 h after mTBI to measure steroid and neurosteroid levels by gas chromatography-tandem mass spectrometry. Traumatized mice exhibited significantly prolonged wake-up time from anesthesia, transiently increased beam-walk time, and mild astrogliosis compared with their control counterparts, but did not suffer from skull fractures, intracranial hemorrhage, or mortality. Isopregnanolone and 3β,5α-tetrahydrodeoxycorticosterone (ISODOC) were significantly decreased by more than 50% in brain parenchyma at 6 and 24 h after mTBI, while ISODOC was also significantly decreased in plasma (−75%). Therefore, ISODOC may be a candidate diagnostic biomarker for mTBI
A quantitative Lewy-fold-specific alpha-synuclein seed amplification assay as a progression marker for Parkinson’s disease
Full text linkMisfolded α-synuclein (αSyn) is the hallmark of α-synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While seed amplification assays (SAA) have demonstrated ultrasensitive detection of misfolded αSyn, they have been primarily used reliably to provide binary (positive/negative) results for diagnostic purposes. We developed an SAA with enhanced specificity for Lewy-fold α-synucleinopathies and introduced a quantifiable measure correlating with clinical severity. Cerebrospinal fluid (CSF) of 170 patients with neurodegenerative diseases and controls was analyzed. Blinded measurements demonstrated 97.8% sensitivity and 100% specificity for Lewy-fold α-synucleinopathies, correctly identifying PD and DLB while excluding MSA. In addition, we validated the strain specificity of the assay by testing brain homogenates from 30 neuropathologically confirmed cases. A novel Lewy-fold pathology (LFP) score based on positive signals in a dilution series provided a quantitative measure of αSyn seeds. The LFP score significantly correlated with motor and cognitive impairment presented by Hoehn and Yahr stage, MDS-UPDRS III, and MoCA. Longitudinal tracking in seven PD cases showed progressive LFP score increases corresponding with clinical deterioration, highlighting the assay’s potential for monitoring disease progression at an individual level. Our Lewy-fold-specific SAA enhances ante-mortem diagnosis and differentiates Lewy-fold α-synucleinopathies from MSA. Unlike previous assays, the LFP score offers a quantitative assessment, showing promise as a progression marker and pharmacodynamic biomarker for αSyn-targeting therapies. This represents an important step toward developing an αSyn SAA that could help to track disease progression quantitatively, with potential applications in both clinical diagnostics and therapeutic trials
Evaluation of a transdiagnostic mental health intervention in German primary care: study protocol for a parallel-group, two-arm, cluster randomised controlled pilot study
Full text linkBackground: General practitioners play an important role in the first-line care of individuals with mental health conditions. However, factors such as time constraints, limited experience in managing mental health conditions and high rates of comorbidity may hinder adequate treatment. To improve psychological care, adopting a transdiagnostic approach shows potential. Research on transdiagnostic interventions delivered by general practitioners is scarce. Thus, a transdiagnostic intervention adapted from the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders was developed specifically for primary care. In a parallel-group, two-arm, cluster randomised controlled pilot study, the transdiagnostic intervention will be evaluated for feasibility, acceptability and potential effectiveness in German primary care.
Methods: A total of 100 adult patients with a mental health condition will be recruited by general practitioners. In the intervention group, general practitioners will administer the transdiagnostic intervention, introducing patients to psychological concepts based on transdiagnostic factors (i.e., understanding emotions, cognitive flexibility, countering emotion-based avoidance). In the control group, general practitioners will provide improved treatment as usual oriented on official German treatment guidelines for depression, anxiety and somatoform disorders. In both study groups, treatment will be carried out in four 20-min sessions over 12-weeks. Self-report questionnaires will be completed before treatment initiation (only patients) and after treatment completion (patients and general practitioners) to assess feasibility and acceptability (i.e., treatment recruitment, delivery, response, effectiveness, unintended consequences and maintenance) as well as potential effectiveness (i.e., change in transdiagnostic factors).
Discussion: The pilot study will address the research gap concerning general practitioner-led psychological interventions in primary care and will give insights into whether the adoption of a transdiagnostic approach is of benefit to general practitioners and patients. Findings may inform the design of a main trial by identifying barriers to the transdiagnostic intervention’s feasibility and acceptability, whilst advancing treatment delivery protocols to support effectiveness
Distal Endovascular Extension After FET: Short and Mid-Term Outcome in a High-Volume Single-Center Experience
Full text linkBackground
This study aims to investigate results and outcomes of distal endovascular extensions after frozen elephant trunk (FET) procedure.
Methods
Between September 2018 and December 2022, all consecutive patients who underwent thoracic endovascular aortic repair (TEVAR) or complex thoraco-abdominal repair (TAA-EVAR) after FET were included in the study. Patients were assigned to “Aneurysm” group or to “Dissection” group according to underlying patology before FET repair. The primary end points were overall technical success and early reintervention rate. Secondary end points included 30-day and mid-term overall survival.
Results
A total of 29 patients were included in the study and divided as follows: n = 12 in the aneurysm group and n = 17 in the dissection group. The mean age of the population was 64.6 ± 10.2 years, and 69% were male. All patients received TEVAR as primary extension while 9 of them underwent further extension to a subsequent TAA-EVAR in a second stage. Among the dissection group, 7 patients experienced a distal stent-graft-induced new entries caused by the stent-graft portion of the FET. Technical success of the first stage (TEVAR) was fully achieved as well as for the second stage (TAA-EVAR). Within the first 30 days, no patient expired or required early reinterventions. Freedom-from-reintervention at 36 months was 72% and 64% in the aneurysm and dissection group, respectively. Overall, 1 major adverse event (3.4%) and 3 access-related complication (10.3%) occurred among the entire cohort. The Kaplan–Meier survival estimation showed a nonsignificant log-rank value (P = 0.248) with a survival rate of 91.7% and 100% at 12, 24, and 36 months each for aneurysm and dissection group, respectively.
Conclusions
Distal endovascular extensions after FET repair are feasible with low perioperative morbidity and mortality regardless of the underlying pathology. Technical success rate of endovascular extension is high, but aortic-related reintervention rate remains quite consistent over time. Thus, a close surveillance is advocated for such patients.
Introductio
Characterization of Post Coronary Artery Bypass Grafting Atrial Fibrillation Patterns: Rationale and Design of an Investigator-Initiated Observational Study
Full text linkNew-onset postoperative atrial fibrillation (POAF) after cardiac surgery is associated with increased rates of adverse events (including mortality and stroke). Its incidence after coronary artery bypass grafting (CABG) is considered to be approximately 30%, and it is believed to be a transient condition. However, studies investigating POAF after CABG fail to provide appropriate data on incidence and arrhythmia patterns due to the use of intermittent rhythm detection strategies. These methods have a low sensitivity as compared with continuous monitoring. Subsequently, studies using these techniques most likely do not identify all patients with arrhythmia and do not adequately demonstrate the long-term incidence of arrhythmia, which in turn may affect its association with adverse events. The Characterization of Post Coronary Artery Bypass Grafting Atrial Fibrillation Patterns (CABG-AF) study (German Clinical Trials Register Number: DRKS00018887) tests the hypothesis that the incidence of AF in the first 12 months after CABG is significantly underestimated. CABG-AF is an investigator-initiated multicenter, prospective, observational study in which 196 patients with no history of arrhythmia who underwent first-time CABG receive an insertable cardiac monitor for continuous postoperative rhythm monitoring. The primary end point of the study is any episode of AF within the first 12 months after surgery. Secondary end points include AF burden, AF density, and the ratio of silent to symptomatic AF episodes. End points will be investigated by automatic and patient-initiated data transfers from the implanted device, by telephone interview of patients, and by follow-up forms sent to patients by mail. The patients will be followed for a planned follow-up of 3 years. In conclusion, the CABG-AF study will provide information on the true incidence of AF after CABG and on the temporal patterns of the arrhythmia