Scientific publications of the Saarland University
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Delivery of siRNA and Chloroquine Through an Aspherical, Nanostructured Microparticle for Passive Targeting of Alveolar Macrophages and Inhibition of Local TNF-α Secretion
No full textBackground/Objectives: Alveolar macrophages represent the main path of defense in the
peripheral pulmonary tissue, though their role in chronic inflammatory lung diseases shows
that their protective function can turn pathological. This study focused on developing a
system to passively target the release of the pro-inflammatory cytokine TNF-α through
the local delivery of siRNA. Methods: An inhalable aspherical microparticle made up of
mesoporous silica nanoparticles, crosslinked by an electrostatic LbL-system embedding the
siRNA, was developed. Results: Through testing with the NGI, adequate aerodynamic
properties with an MMAD as low as 3.37 µm could be determined, with a GSD as low
as 1.46, suggesting a relatively small size distribution even during inhalation. To further
understand the interaction of the microrods with the lung parenchyma and the resident
cells, the disintegration of the rods in different simulant body fluids, their toxicity, and the
cell uptake through dTHP-1 and A549 were observed. This showed slow but continuous
disintegration, no toxicity in A549 cells, and high microrod uptake by dTHP-1 cells. To
demonstrate the effect of the delivered siRNA on the release of TNF-α, ELISAs were carried
out, establishing an inhibitory effect of the siRNA-carrying microcarrier system compared
to those without siRNA or loaded with scrambled siRNA. To increase the efficacy of the
siRNA, chloroquine as an endosomal escape-enhancing compound was loaded onto the
mesoporous silica nanoparticles. This resulted in a significant improvement in siRNA
inhibition. Conclusions: The developed formulation is able to reach the targeted structure
and inhibit the secretion of TNF-α, with CQ increasing the inhibitory effect of the siRNA
Microsatellite Instability Status and Mismatch Repair Defects Testing in Endometrial Cancer—Insights from the Multicenter E-PEC Trial
No full textBackground: Mismatch repair (MMR) and microsatellite instability (MSI) testing have
become essential biomarkers in the molecular classification of endometrial cancer (EC),
guiding adjuvant treatment decisions and eligibility for immune checkpoint inhibition.
Although international guidelines recommend universal testing, real-world implemen tation remains heterogeneous. This study aimed to evaluate trends in MMR and MSI
testing and associated molecular diagnostics in Germany between 2018 and 2022. Methods:
A retrospective multicenter analysis was conducted across German tertiary care centers.
Data from patients with histologically confirmed EC between 2018 and 2022 were extracted
from standardized electronic pathology records. Annual testing rates for MSI, MMR, POLE,
TP53, and L1CAM were analyzed using descriptive statistics and trend analysis (Chi square test for trend, p < 0.05). Therapeutic data were collected to assess the use of immune
checkpoint inhibitors. Results: There was a significant increase in the annual rates of
molecular testing for MSI, POLE, TP53, and L1CAM over the five-year observation period
(all p < 0.05). TP53 testing showed the highest increase (13.1% → 78.6%), while MSI testing
rose from 82.9% to 97.4%. Both POLE and L1CAM testing were virtually absent in 2018 (0%
and 1.6%) but reached 15.7% by 2022. Conclusions: This study demonstrates a rapid and
substantial implementation of MMR and MSI testing in German clinical practice, reflecting
successful translation of trial results into routine care. However, implementation of testing
in guidelines appeared time-shifted. For bridging this gap, annual guideline updates seem
to be necessary
Toxicometabolomics Characterization of Two N1-Sulfonated Dimethyltryptamine Derivatives in Zebrafish Larvae and Human Liver S9 Fractions Using Liquid Chromatography–High-Resolution Mass Spectrometry
No full textIntroduction: The availability of toxicokinetic data is critical for detecting and monitoring
the intake of psychoactive substances. Timely characterization of novel psychoactive sub stances (NPS) is particularly important to assess their abuse potential and inform public
health responses. Methods: Toxicometabolomics offers a powerful approach to characterize
xenobiotic metabolism through high-resolution profiling of biochemical transformations.
It thus allows the finding of exogenous biomarkers, such as new drug metabolites, and
endogenous biomarkers, which could be indications of acute drug ingestions or sample
manipulation, as well as offering information on the mode of action of drugs. In this study,
we applied a liquid chromatography–high-resolution mass spectrometry workflow to
investigate the toxicometabolomics of two N1-sulfonated N,N-dimethyltryptamine deriva tives with potential for both therapeutic use and recreational abuse. Results: Zebrafish
(Danio rerio), an increasingly valuable model for preclinical pharmacology and toxicology
studies, along with pooled human liver S9 fractions were used to elucidate metabolic
pathways and identify key phase I and phase II biotransformations. Furthermore, untar geted metabolomics revealed significant downregulation of L-threonine associated with
compound exposure. Conclusions: These findings advance the current understanding of
tryptamine metabolism and underscore the utility of toxicometabolomics in the analytical
evaluation of NPS
FAK modulates immune response and fibroblast activation in biomaterial-induced fibrosis
No full textFibrotic capsule formation remains a major barrier in the clinical performance of biomedical implants. Here, we
demonstrate that synthetic hydrogels mimicking the mechanical properties of fibrotic tissue trigger stromal cell
activation and immune remodeling via focal adhesion kinase (FAK)-mediated mechanotransduction. Using a
mechanically tunable poly(ethylene glycol) hydrogel platform and subcutaneous implantation in mice, we show
that pharmacological inhibition of FAK activity significantly reduces α-smooth muscle actin (α-SMA)-positive
myofibroblast activation, collagen I deposition, and fibrotic capsule thickness in a hydrogel stiffness-dependent
manner. Flow cytometry and cytokine profiling revealed that FAK inhibition alters the fibrotic niche by reducing
CD163-positive M2c macrophages and significantly downregulating pro-fibrotic cytokines including IL-6, and
VEGF, while transiently increasing regulatory T cells and elevating IL-10 levels. Importantly, these changes
occurred without parallel increases in canonical pro-inflammatory cytokines, indicating selective modulation
rather than global immune suppression or activation. These findings position FAK as a central hub translating
mechanical cues into coordinated stromal and immune responses. Targeting FAK mechanotransduction may
provide a therapeutic strategy to mitigate foreign body responses and improve implant integration across
regenerative applications
A Maturation-Aware Machine Learning Framework for Screening the Nutritional Status of Adolescents
No full textBackground: Malnutrition in adolescents remains a significant public health issue world wide, with undernutrition and overweight often coexisting. Accurate nutritional screening
during adolescence is complicated by variability in biological maturation and class imbal ance, particularly among underweight adolescents. Objective: This study aims to develop
and validate machine learning models for classifying the nutritional status of adolescents,
accounting for class imbalance and biological maturation, and to evaluate model stability
and variable importance at different stages of peak height velocity (PHV). Methods: In
this cross-sectional study, 4232 adolescents aged 11 to 18 years were recruited from nine
educational institutions in Tunisia. Their nutritional status was classified according to the
International Obesity Task Force (IOTF) BMI thresholds into three categories: underweight
(14.4%), normal weight (68.3%), and overweight (17.2%). Ten anthropometric, behav ioral, and maturation-related predictors were analyzed. Six supervised machine learning
algorithms were evaluated using a 70/30 stratified split between training and test sets,
with five-fold cross-validation. Class imbalance was addressed by ROSE combined with
cost-sensitive learning. Model performance was assessed using accuracy, Cohen’s kappa
coefficient, macro F1 score, sensitivity, specificity, and AUC. Results: The cost-sensitive
Random Forest (RF) model achieved the best overall performance, with an accuracy of
0.830, a macro F1 score of 0.767, a macro-AUC of 0.921, and a macro- sensitivity of 0.743.
The class-specific sensitivities were 0.70 (underweight), 0.91 (normal weight), and 0.62
(overweight), with no major misclassification between the extreme categories. Perfor mance remained stable across the different maturation phases (accuracy from 0.823 to
0.839), with optimal discrimination in the pre-PHV (macro-AUC = 0.936; sensitivity for
underweight = 0.82) and post-PHV (macro-AUC = 0.931) periods. Body mass was the main predictor (importance = 1.00), followed by waist circumference (0.34–0.53). The importance
of age for classifying underweight increased significantly from the pre-PHV (0.10) to the
post-PHV (0.75) period. A two-stage hierarchical model further improved underweight
detection (stage 1 AUC = 0.911; sensitivity = 0.732). Conclusions: A cost-sensitive RF
model, combined with ROSE, provides robust classification of adolescents’ nutritional
status maturation, significantly improving underweight detection while preserving overall
accuracy. This approach is particularly well-suited to public health screening in schools as a
first-stage assessment that requires clinical confirmation and promotes a maturation-aware
interpretation of nutritional risk among adolescents
The Human Right to Democracy in Multilevel Systems at a Time of Democratic Backsliding: Global, Regional and European Union Perspectives
No full textMicrobiome as a Tool to Monitor Aquarium Systems
No full textThe bacterial microbiome in aquaria plays an essential role in system stability by metaboliz ing toxic compounds like ammonia. This study monitored microbiome changes in seven
zoo aquatic systems during their first year to assess responses to external influences. Over
one year (October 2021–October 2022), water and swab samples were collected from one
seawater tank and six filtration systems at regular intervals. Bacterial cultivation included
total bacterial counts. Metagenomic analysis was performed on samples corresponding
to environmental events using Oxford Nanopore sequencing. Taxonomical analysis at
the phylum and genus levels used EPI2ME software. Diversity analyses and statistical
tests were performed using R. Total bacterial counts increased steadily after inoculation
and stabilized by the end of the collection period. Diversity analysis revealed significant
differences within and between freshwater and saltwater tanks. Each aquarium exhibited a
distinct bacterial community with frequent compositional changes. Despite environmental
conditions and maintenance interventions and resulting disturbances that affected the
microbiome, the overall nitrifying capacity remained unaffected. Nitrifying taxa emerged as potential indicators for environmental effects. Combined with investigations of ecolog ical function, next-generation sequencing could facilitate the development of aquarium
management protocols, ultimately improving fish welfare
Fasting and Nutrition as Promising Treatment Strategies for Women with Rheumatoid Arthritis in Transitional Hormonal Stages
No full textRheumatoid arthritis (RA) is a systemic and chronic autoimmune disease affecting about
1% of the global population, with a higher prevalence in women. Its treatment has been
improved greatly over the past 30 years but there is no definitive cure available, and another
unmet need exists for transitional hormonal stages such as pregnancy or menopause, which
spurs the need to research new therapy options. In recent years, dietary interventions,
particularly fasting and plant-based nutrition, have gained attention for their potential to
alleviate RA symptoms. Fasting has been shown to reduce systemic inflammation, promote
autophagy, and modulate immune cell activity, possibly leading to decreased joint pain
and swelling. Nutritional strategies, such as anti-inflammatory and plant-based diets, have
been shown to impact the gut microbiome and potentially support weight management,
improve metabolic health, and reduce oxidative stress, all of which might contribute to
better RA disease outcomes. Although the precise mechanisms remain under investigation,
these approaches offer promising complementary strategies for enhancing RA management
and improving patients’ quality of life. This review explores the preventive and therapeutic
potential of fasting and nutrition in RA, and their possible application in the context of
hormonal fluctuations and transitional stages during a women’s life
mRNA Sequencing of Limbal Epithelial Cells and mRNA/miRNA Profiling of Limbal Stromal Cells in PAX6-Related Congenital Aniridia
No full textThe dysfunction of limbal epithelial cells (LECs) and limbal stromal cells (LSCs) in congen ital aniridia remains incompletely understood. We aimed to analyze mRNA expression
profiles of primary human LECs and LSCs, as well as microRNA (miRNA) expression in
LSCs, from patients with congenital aniridia (AN-LECs and AN-LSCs). mRNA sequencing
of primary human LECs and mRNA and miRNA sequencing of LSCs were performed
from patients with aniridia and healthy controls. Gene ontology and pathway analyses
were used to evaluate biological processes, cellular components, and molecular functions.
Selected deregulated mRNAs and miRNAs were validated by quantitative real-time PCR
(RT-qPCR). A total of 188 differentially expressed genes (DEGs) were identified in AN LECs, and 3001 DEGs in AN-LSCs. In AN-LECs, the top hub genes were associated with
inflammatory and interferon-related responses. In contrast, AN-LSCs showed predominant
deregulation of mitochondrial and metabolic genes. Pathway analysis revealed involve ment of inflammation-related pathways in AN-LECs and metabolic pathways in AN-LSCs.
Additionally, 48 deregulated miRNAs were identified in AN-LSCs. This study provides
comprehensive mRNA profiles of LECs and LSCs and miRNA profiles of LSCs in congeni tal aniridia. The findings emphasize the importance of LSC influence and offer insights
into molecular mechanisms underlying aniridia-associated keratopathy (AAK), supporting
future research and potential therapeutic target identification
Sarcopenia in Older Adults with Hematologic Malignancies: A Comprehensive Review of Epidemiology, Prognosis, and Interventions
No full textHematologic malignancies, including leukemias, lymphomas, and multiple myeloma,
are diseases of older adults (age ≥ 60 years). Treatment decisions in older adults with
cancer are heavily influenced by patient fitness: the ability of an individual patient to
tolerate the off-target effects of anti-cancer therapy. Sarcopenia, defined as low muscle mass
and strength, is increasingly recognized as an important marker of fitness. Furthermore,
sarcopenia is known to be modifiable with nutrition and exercise interventions in older
adults without cancer, but such evidence is limited for patients with cancer. Much of the
literature on sarcopenia in older adults with cancer has focused on patients with solid
tumors. However, there is an increasing body of literature on the impact of sarcopenia in
older adults with hematologic malignancies. In this comprehensive review, we attempt to
(i) describe the most up-to-date diagnostic criteria and diagnostic approach to sarcopenia, (ii) summarize the prognostic impact of sarcopenia among older adults with hematologic
malignancies, (iii) discuss the proposed mechanisms of sarcopenia and its pathogenesis,
(iv) review the evidence for interventions targeting sarcopenia, and (v) provide future
directions for the advancement of sarcopenia management among older adults with
hematologic malignancies