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Finding gut microbiome signature in clinical intervention trials
No full textThe gut microbiome plays a crucial role in the gut brain axis, especially by modulating the immune system, influencing metabolism, protecting against pathogens, and impacting mental well-being. Therefore, it can be modulated through various lifestyle changes, medications, and clinical interventions for specific metabolic goals. The aim of this thesis is to identify gut microbiome signatures in different clinical interventions and explore their potential to enhance overall health outcomes.
In our first clinical intervention, we use synbiotics to modulate specific microbiome signatures that could potentially delay the progression of Metabolic-Dysfunction-Associated Fatty Liver Disease. Regression analysis revealed how baseline microbiome composition can influence social decision-making through the dopamine precursor tyrosine. Additionally, partial least squares analysis demonstrated that a personalized synbiotic approach can improve gut health by targeting participants with insufficient dietary fiber intake.
In this thesis, we also explored the impact of dietary interventions, such as oats, in participants with metabolic syndrome. Using partial least squares model analysis, we identified gut microbiome and multi-omics signatures that explain the physiological mechanisms behind the cholesterol-lowering effects of these interventions. In particular, the bacterium Ruminococcus torques was associated with HDL-cholesterol. We also demonstrated that oats could improve gut barrier integrity in participants with metabolic syndrome traits by altering microbiome signatures, enhancing zonulin and short-chain fatty acid levels.
In conclusion, our findings indicate that the gut microbiome plays an essential role in enhancing our metabolism through various interventions and can be analyzed to discover new bacterial biomarkers. We also conclude that there is a need for a personalized machine learning model utilizing microbiome or multi-omics datasets to predict dietary responses accurately
Chemical fingerprints of stellar evolution in Galactic massive stars
No full text(noch nicht zugänglich / not yet accessible
The role of primary cilia in controlling metaflammation
No full textThe primary cilium is a cellular antenna that senses and integrates external stimuli. Its composition is regulated by specialized proteins, such as BBS proteins, and mutations in any of the genes that encode BBS proteins cause a rare disease called the Bardet-Biedl syndrome (BBS). Although most patients with BBS develop a severe form of central obesity, their metabolic outcomes per se seems to be better than in patients with non- syndromic obesity. Obesity-triggered inflammation, known as metaflammation, is a key player in cardiometabolic diseases; however, the regulatory mechanisms remain ill- defined. I hypothesized that BBS patients are protected from developing metaflammation and, thereby, obesity-related metabolic disorders. To address that, I performed deep immunophenotyping of BBS patients using high-dimensional flow cytometry and multi- omics analyses in a nationwide cohort of patients and compared the results to non- syndromic obese patients as well as matching healthy controls. To gain mechanistic insight, I analyzed different global and cell-specific BBS mouse models and performed in vitro assays. I identified genotype-dependent differences in the metabolomic and lipidomic profile as well as in circulating concentrations of metaflammation-related cytokines among BBS patients, indicating a healthy obesity phenotype in BBS1 patients, but not in others. The differences were mirrored by changes in the circulating Treg cells, pointing towards an “anti-inflammatory” phenotype in BBS1 patients, exerted by an expanded Treg cell pool. By examining the underlying molecular mechanisms in an obese BBS mouse model (Bbs8KO) that resembles the phenotype of BBS1 patients, I demonstrated that these mice showed an expansion of Treg cells in the visceral adipose tissue, which is linked with an enhanced metabolic function. These differences occurred already at an early age in the thymus during Treg development, driven by thymic epithelial cells (TECs), which regulate Treg cell development. Taken together, I demonstrated that BBSome-dependent signaling in TEC cells controls Treg development. Loss BBSome function promotes Treg expansion, which exerts an immunomodulatory effect during obesity, ameliorating metaflammation
Ärztliches Verordnungsverhalten von Laboranalysen am Beispiel des Serummagnesiums : Eine Vorher-/Nachher-Studie mit unterbrochenen Zeitreihen
No full textDie strukturellen Einflüsse auf die Entscheidungsfindung in der medizinischen Versorgung wurden bislang nur unzureichend untersucht.
Die durchgeführte Studie widmet sich einem Teilaspekt dieser Problemstellung, indem untersucht wurde, inwieweit sich das ärztliche Verordnungsverhalten verändert, wenn zum Routine-Aufnahmelabor die Magnesiumbestimmung hinzugefügt wird.
Dabei ging es vor allem um die Fragen, ob die Verfügbarkeit einer Magnesiumbestimmung im Routine-Aufnahmelabor die Anordnung weiterer Magnesiumbestimmungen beeinflusst, ob Prädiktorvariablen für eine gezielte Magnesiumbestimmung identifiziert werden können und ob sich aus den Magnesiumbestimmungen Verordnungen von Magnesiumpräparaten ergeben.
Die Auswertung erfolgte mittels unterbrochener Zeitreihenanalyse, bei der wöchentliche Raten an Magnesiumbestimmungen bezogen auf die in dieser Woche aufgenommene Patientenanzahl gebildet wurden. Der ausgewertete Zeitraum umfasste insgesamt 52 Wochen, wovon jeweils 26 Wochen vor und nach der Hinzunahme des Magnesiums in das Aufnahmelabor untersucht wurden. Der Zeitpunkt der Hinzunahme des Magnesiums zum Aufnahmelabor wurde als Intervention definiert. Die erhobenen Kovariablen wurden ausgewertet, um mögliche Trigger für eine Magnesiumbestimmung zu identifizieren.
Die durchgeführte Studie konnte nachweisen, dass die Hinzunahme der Magnesiumbestimmung in das Aufnahmelabor zu einem sprunghaften Anstieg der gezielten Magnesiumanordnungen und zu häufigeren Wiederholungsbestimmungen führte. Abgesehen von der Interventionsphase konnten keine überzeugenden Prädiktoren für eine gezielte Magnesiumbestimmung gefunden werden. Insbesondere war die Höhe des Magnesiumspiegels kein signifikanter Prädiktor.
Die Ergebnisse der Studie haben gezeigt, dass eine gezielte Magnesiumbestimmung die Wahrscheinlichkeit sowohl für eine Magnesiumneuverordnung als auch für eine Entlassung aus der Klinik mit einer Magnesiumsubstitution signifikant erhöht.
Die komplexen Entscheidungsprozesse bei der Anordnung von Laborparametern und potenzielle Einflussfaktoren und Störgrößen sind noch nicht hinreichend wissenschaftlich untersucht. Folglich bedarf es weiterer Studien, die sich mit den Einflussfaktoren auf die ärztliche Entscheidungsfindung bezogen auf die Anordnung klinisch-chemischer Analytik befassen, um nachfolgend Störfaktoren auszuschalten und die Patientenversorgung zu verbessern
Retrospektive Erfassung der Lebensqualität und des Langzeitüberlebens nach Behandlung mit extrakorporaler Membranoxygenierung
No full textBei schwerwiegenden Erkrankungen, die den Gausautausch in der Lunge oder die Pumpfunktion des Herzens betreffen, kann im Rahmen des Intensivaufenthaltes eine Therapie mittels extrakorporaler Membranoxygenierung (ECMO) notwendig sein. Die ECMO ist ein Organunterstützungsverfahren, bei dem für eine begrenzte Zeit Herz- und/oder Lungenfunktion des Körpers übernommen werden.
Trotz weltweit zunehmender Durchführungshäufigkeit der ECMO in den letzten Jahren und der stetigen Weiterentwicklung berichten Patienten nach überlebter ECMO-Therapie häufig über Einschränkungen und Folgeerkrankungen, die direkte Auswirkungen auf die gesundheitsbezogene Lebensqualität haben. In der aktuellen Literatur gibt es nur wenige Studien, die sich auf die Lebensqualität konzentrieren und kaum Kohorten mit einer aussagekräftigen Größe.
In der vorliegenden Arbeit wurde, neben dem Langzeitüberleben, die gesundheitsbezogene Lebensqualität von Patienten nach einer ECMO-Therapie untersucht.
Dazu wurden retrospektiv 72 Patienten befragt, die im Studienzeitraum zwischen dem 1. Juni 2013 und dem 31. Dezember 2019 eine ECMO-Behandlung auf den Intensivstationen der Klinik für Anästhesie und operativen Intensivmedizin des Universitätsklinikums Bonn erhalten haben. Die Untersuchung erfolgte mittels des standardisierten World Health Organization Disability Assessment Schedule 2.0 und einigen ergänzenden Fragen.
Die Antworten aus den Fragebögen, verschiedene demographischen Daten, medizinische Parameter und Untersuchungsvariablen der Patienten, sowie die berechneten Scores wurden erhoben und mit aktuellen Literaturergebnissen verglichen. Zusätzliche wurde mittels linearer Regressionsanalyse nach Parametern gesucht, die möglicherweise Einfluss auf die mittelfristige gesundheitsbezogene Lebensqualität haben.
In der vorliegenden Untersuchung konnte, verglichen mit der aktuellen Literatur, eine große ECMO-Kohorte mit langer Überlebensdauer untersucht werden. Hierbei zeigt sich eine verminderte Lebensqualität gegenüber dem Ausgangszustand der Studienteilnehmer, sowie gegenüber der Normalbevölkerung, jedoch ein ähnliches Maß an Problemen und Einschränkungen im Vergleich mit anderen ECMO-Kohorten. Gegenüber anderen schwerwiegenden Erkrankungen zeigt sich in der vorliegenden Untersuchung eine ähnliche oder sogar teils bessere Lebensqualität.
Zwischen wichtigen Parametern des klinischen Verlaufs, wie beispielsweise der Dauer der ECMO-Therapie oder des Intensivaufenthaltes und der späteren Lebensqualität konnte keine Korrelation aufgezeigt werden. Jedoch konnten andere Faktoren identifiziert werden, die möglicherweise Einfluss auf die spätere Lebensqualität haben.
Limitierend hierbei ist die Heterogenität der ECMO-Kohorte, sowie die retrospektive Erfassung des Ausgangszustandes der Studienteilenehmer. Für weitere Forschung und eine bedarfsgerechte Koordination von Unterstützungsangeboten und Therapie könnte zukünftig eine eigene Anlaufstelle für Patienten nach überlebter ECMO-Therapie hilfreich sein
Investigation and discovery of targetable markers in urological tumors
Full text linkUrological cancers are among the cancers with the highest incidence. In recent years, several therapeutic solutions have been suggested and accepted in the clinic for treatment, but tumors, especially the most aggressive forms, frequently develop resistance to the available therapies. Thus, we focused on investigating novel solutions for treating the most aggressive forms of urological cancers. Specifically, we aimed to:
1) Investigate the application of nanobodies (Nbs) as targeting agents for CUB domain-containing protein 1 (CDCP1) in prostate cancer (PCa) and epithelial growth factor receptor (EGFR) in the basal/squamous (Ba/Sq) subtype of bladder cancer (BCa).
2) Study the correlation of CDCP1 with tumor-associated macrophage (TAM) infiltration in PCa and BCa.
3) Characterize senescence for the discovery of new senescence markers in advanced PCa.
CDCP1 is a transmembrane protein that correlates with tumor stage in several cancers. In our experience, CDCP1 is a promising target for treating advanced PCa. Thus, we tested Nbs as an innovative strategy for its targeting. Nbs are the smallest existing region of an antibody (Ab) that maintains the binding to their target and have several advantages compared to Abs. They are 10 times smaller, making them ideal for treating solid tumors since they can diffuse better in the tumor mass. Moreover, they are characterized by cheaper and easier production and higher stability. We also considered the application of Nbs for targeting EGFR, a transmembrane receptor known for sustaining tumor growth. Drugs targeting EGFR are already used in lung and head and neck cancers. In this work, we investigated EGFR targeting in the Ba/Sq subtype of BCa. This subtype is characterized by high levels of EGFR and greater aggressiveness. Both targeting CDCP1 and EGFR with Nbs in these cancers revealed promising results. Indeed, Nb dimers targeting CDCP1 reduced tumor growth in a PCa cell model, and Nbs targeting EGFR reduced cell growth in a Ba/Sq BCa cell model.
In the second part of this work, we studied the correlation of CDCP1 with TAM infiltration. CDCP1 correlates with the Ba/Sq subtype of BCa which is typically infiltrated by immune cells. Our results showed that CDCP1-expressing tumor cells produce high levels of CCL2 and IL6, contributing to macrophage recruitment. Macrophages infiltrating CDCP1 tumors in our PCa mouse model overexpressing CDCP1 have the typical characteristics of tumor-associated macrophages (TAMs), which are reported to create an environment that promotes tumor growth and reduces immune responses. Thus, their elimination from the tumor microenvironment (TME) proves essential to dampen tumor aggressiveness and improve tumor responsiveness to immune therapy. Treatment with mAbs targeting CDCP1 efficiently reduced CCL2 and IL6 production and the migration potential of macrophages.
In the final part of this work, we aimed to discover new senescence markers to combine chemotherapy, such as docetaxel, with more efficient senolytic drugs. This proves fundamental since senescent cells could cause tumor relapse or aggravate tumor growth due to the production of growth factors and cytokines. However, targeting senescent cells is challenging due to their similarities with normal cells. To find a suitable marker for senescent cell elimination, we first developed a new model for senescence individuation using the CRISPaint technology. This technology allowed for the visualization of senescent cells in real-time and suggested that the situation after treatment with docetaxel in PCa is more complicated than expected. Indeed, we did not observe the formation of a senescent population but the presence of 3 different populations. We separated these populations and performed mRNA sequencing to identify specific population markers. We obtained a set of 8 genes that are progressively up- or down-regulated along the 3 populations, suggesting that different levels of senescence characterize these populations. To investigate this further, we plan to perform single-cell sequencing.
Altogether, the results presented in this thesis suggest some solutions for treating aggressive BCa or PCa. In particular, using Nbs to target CDCP1 or EGFR and targeting CDCP1 to reduce TAM infiltration. Finally, this thesis reveals the complexity of the senescent phenotype that requires a deeper investigation and an improved definition before being targeted efficiently
Genetic basis of biomarkers of aging
No full textAging is a gradual and irreversible process that substantially increases the risk of numerous diseases. Elucidating the genetic basis of biomarkers of age-related traits and diseases could facilitate the understanding of their underlying biological pathways, which is crucial for their prevention, early diagnosis and/or treatment. Therefore, in my dissertation research, I aimed to (1) identify the genetic basis of different well-established biomarkers of age-related diseases, including blood-based, sensory and lipid biomarkers, through genome-wide association studies (GWASs), (2) assess the association of polygenic risk scores (PRS) of Alzheimer’s disease (AD) with cognitive performance, and (3) examine the potentially causal association of microRNAs and cognition using the Mendelian randomization framework. Using aggregated data from different population-based studies, I conducted a GWAS meta-analysis of plasma levels of neurofilament light chain (NfL), an ultrasensitive biomarker of neurodegeneration, in individuals from European and African-American ancestry. This analysis identified several novel genetic loci associated with an increased risk of neurodegeneration. I also conducted a GWAS on olfactory dysfunction and identified a genetic locus enriched for olfactory receptor genes to be associated with performance on a smell discrimination task. Through a two-sample Mendelian randomization approach, I found evidence for a potentially causal detrimental effect of olfactory dysfunction on various health outcomes. Furthermore, I conducted GWASs on both the levels and composition of ~1000 complex lipid species, which revealed numerous novel genetic determinants of circulating lipid species, some of which were also related to cardiometabolic traits and diseases. Moreover, I generated PRS scores for AD and identified significant associations of these PRS scores with specific measures of cognitive performance, including working memory and measures derived from detailed eye movement assessments (e.g., anti-saccade error rate). Finally, I conducted a two-sample Mendelian randomization study to examine the causal association of circulating microRNA levels with cognition, which did not yield evidence for a causal association. This could be either due to the relatively small sample size available for the Mendelian randomization analysis, or indicate that although circulating microRNAs could be useful as markers of cognition, they may not be caudally involved in the pathogenesis of cognitive impairment. In conclusion, I systematically explored the genetic basis of several important age-related biomarkers and traits by leveraging a combination of GWAS, in silico functional analysis, PRS and Mendelian randomization approaches. These analyses not only revealed numerous novel genetic determinants of age-related traits and diseases, but also yielded crucial biological insights into the mechanisms underlying aging and age-related diseases that warrant further investigation in future studies
G-quadruplex stabilization potentiates anti-tumor immune responses and sensitizes cold tumors for checkpoint therapy
No full textCheckpoint inhibitors have revolutionized cancer therapy and improved patient survival in many cancers. However, even in well-responding entities such as melanoma, about 50% of patients are primarily resistant or develop resistance throughout the therapy. Among non-responding tumors, so-called "cold" tumors are found particularly often. These are tumors that contain only low amounts of tumor-infiltrating lymphocytes, especially T cells. Therefore, enhancing T cell infiltration into the tumor microenvironment is a promising approach to increase response rates to checkpoint therapy.
G-quadruplexes, DNA secondary structures that can form in guanine-rich sequences, are important for genome stability, telomere stability, and oncogene expression. Small molecules binding these structures (G4 ligands) were shown to inhibit cancer cell growth by causing apoptosis through DNA damage induction, reducing telomerase activity, and down-regulation of critical oncogenes like KRAS. Recent data further showed that G4 ligands can cause the activation of STING in cancer cells, followed by the induction of a type 1 interferon response in vitro. Additionally, it was shown that G4 ligands can induce markers of immunogenic cell death in vitro. Together these observations led to the hypothesis that G4 ligands, besides their direct apoptotic and anti-proliferative effects, could also harbor the potential to increase the immunogenicity of tumors and thereby sensibilize tumors for checkpoint therapy.
To test this hypothesis the checkpoint therapy-resistant B16OVA melanoma mouse model was used to investigate the effect of intratumoral PDS application on checkpoint therapy.
PDS treatment alone led to a significant reduction in tumor growth and prolonged survival of B16OVA-bearing mice. Additionally, mice receiving PDS responded to checkpoint therapy, leading to further increased survival and a complete response in 20% of double-treated animals. Using single-cell sequencing this study could show that PDS directly and PDS-induced DAMP release activate intratumoral myeloid cells, leading to increased production of pro-inflammatory cytokines and chemokines. In turn, on day nine post-treatment tumor immune cell infiltration is two-fold increased, and especially T cells and NK cells are three-fold enriched compared to vehicle-treated tumors. In addition, cytotoxic T cells and NK cells both produce increased levels of effector molecules, especially granzymes.
Besides the effects on immune cells, this study could also show that PDS increases the immunogenicity of B16OVA cells in vivo. PDS treatment induces the expression of CCL5 and CXCL10, increases the expression of antigen processing and presentation on both MHC I and MHC II, and induces non-silent mutations in actively expressed genes, potentially leading to the formation of neo-antigens.
In sum, PDS has pro-inflammatory effects on both tumor cells as well as different immune cell subsets, transforms the TME towards an immunological hot state, and thereby induces a response to checkpoint blockade in originally resistant B16OVA tumors
Strategies to recover liver regeneration after partial hepatectomy in obese mice
No full textLiver regeneration is vital for recovering liver function after surgical resection or transplantation. Using a mouse model for HpX, we were capable of identifying the role of different subsets of hepatic macrophages during liver regeneration. Specifically, we identified that KC, and not moM, are the key necessary cell type in the production of cytokines and growth factors to promote liver regeneration. KC depletion with clodronate liposomes led to decreased liver regeneration and increased mortality in mice after operation. CCR2-/- mice, where monocytes are not capable of migrating into tissue, and have no moM, showed minimal impairment in liver regeneration, compared to WT.
Obesity causes severe difficulties to liver regeneration after HpX in patients and animals. HFD-induced obesity led to a disruption in KC function and numbers, replacing them with pro-inflammatory moM. Using the Microfetti mouse model we found that KC from obese mice have impaired clonal expansion after HpX. Transcriptomic and metabolic analyses revealed that KC from obese mice exhibit diminished cytokine and growth factor production as well as impaired reactive oxygen species generation.
Obesity leads to gut dysbiosis and microbial translocation. These led to increased levels of pathogenic bacteria in the liver, as identified by 16S rRNA sequencing. Type I interferons emerged as a key negative regulator of liver regeneration in our transcriptomic data set. IFNAR1 mediated sensing of IFN I caused an impaired proliferation capacity in KC and led to increased recruitment of moM. Targeting IFNAR1 with a blocking antibody was sufficient to rescue liver regeneration in obese mice after HpX. IFNAR blockade did not fully restore KC numbers. Bulk RNA sequencing of KC after IFNAR blockade showed an increase in production of the growth factor HB-EGF as well as increasing OXPHOS. IFNAR blockade also contributed to reduce amounts of IL-6 production by KC and its concentration in the plasma of mice.
In conclusion, this study highlights the crucial role of KC in liver regeneration, the detrimental effects of obesity on KC function, and the potential of the IFNAR signaling pathway as a therapeutic target to improve liver regeneration in obese patients
RIG-I-like receptors in aortic inflammation and calcification
No full textIt has been already well established that erroneous detection of endogenous nucleic acids by the innate immune system drives pathogenic processes of autoimmunity. Along with that, gain-of function mutations in the RIG-I-like receptors, RIG-I and MDA5, are associated with Singleton-Merten Syndrome. This rare interferonopathy is characterized by dental and skeletal abnormalities, as well as early and severe aortic calcification. This leads to the hypothesis that an increased availability of endogenous RNA ligands could also activate RLR without SMS mutation, resulting in a constitutive receptor activity and the development of aortic inflammation and calcification.
This thesis investigated the effect of RIG-I and MDA5 in pathogenic processes of aortic cells. For human aortic smooth muscle cells, it was determined that RLR activation did not only induce a type I IFN response, but also osteogenic differentiation was triggered. When cells were additionally cultivated in a pro-calcifying medium, the production of calcium deposits was induced. Lack of RLR or their downstream signaling molecule MAVS decreased the expression of ISGs and osteogenic factors. Additionally, calcification was reduced. Furthermore, it was revealed that the Wnt signaling molecules G3BP1 and FZD5 are both involved in osteogenic differentiation and calcification. For G3BP1, this process was clearly connected to RIG-I and MAVS, but not to MDA5, while for FZD5 no connection was revealed. Furthermore, the ISG response was reduced in G3BP1-deficient cells, suggesting a feedback loop between RIG-I/ MAVS signaling and G3BP1. The JAK-STAT pathway was shown to play a role in these processes, as its inhibition led to a reduced ISG response, decreased expression of BMP-2 and Wnt molecules, and fewer calcium particles. Even though self-RNA ligands have not been identified so far, it could be revealed that cyclic stretch on HAoSMCs induces an ISG response, even without additional RLR activation. Activation of the cGAS-STING pathway also induced an ISG response, osteogenic differentiation and calcification, but to a lower extent than RLR activation.
In human aortic endothelial cells, RLR activation also induced an ISG response. While RIG-I activation did not lead to endothelial activation, MDA5 and TLR3 stimulation with poly(I:C), induced the upregulation of proinflammatory and adhesion molecules.
In summary, this work reveals new insights into the role of RLR in aortic pathogenesis, especially in the context of osteogenic differentiation and calcification. A better understanding of the exact pathways might contribute to the development of new therapies for the treatment of calcification processes resulting from erroneous nucleic acid detection