Gutenberg Open Science (Univ. Mainz)
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Immunologische Wirkungen von BRAF- und MEK-Inhibitoren und deren Kombination auf humane PMBC, Dendritische Zellen und Melanomzellen
Get PDFDas maligne Melanom ist eine aggressive Hautkrebserkrankung mit bis vor Kurzem begrenzten Behandlungsoptionen. Etwa 40–50 % der kutanen Melanome weisen eine v-raf murine sarcoma viral oncogene homolog B (BRAF)-V600E-Mutation auf, die zu einer konstitutiven Aktivierung des extrazellulär signalregulierten Kinasewegs (ERK) führt und die Regulation des Zellwachstums und der Zellteilung entscheidend beeinflusst Fortschritte in der molekularen Onkologie führten zur Entwicklung von BRAF-Inhibitoren (BRAFi), die sich gezielt gegen diese Mutation richten. Die BRAFi-Therapie weist jedoch diverse Nebenwirkungen auf und führt in vielen Fällen zur Resistenzbildung. Kombinationen mit Mitogen-aktivierten Proteinkinase-Kinase-(MEK)-Inhibitoren (MEKi) tragen zur Überwindung dieser Resistenzen bei und verbessern das Überleben der Betroffenen. Neben einer antitumoralen Wirkung zeigen BRAFi/MEKi auch immunmodulatorische Effekte wie die Modulation des Tumormikromilieus, die Veränderung des Immunphänotyps, die Modifikation der T-Zell-Aktivierung und der Antigenpräsentation sowie unerwünschte Nebenwirkungen wie Phototoxizität oder Pyrexie.
Die vorliegende Arbeit analysiert diese immunologischen Effekte in vitro an humanen Immunzellen (periphere mononukleäre Blutzellen, PBMC; monocyte-derived dendritic cells, MO-DC) und Melanomzellen anhand der Produktion proinflammatorischer Zytokine (Interleukin-(IL)1β, IL-6 und IL-8). BRAFi (insbesondere Dabrafenib (DAB)) induzierten bei den PBMC einiger Spender eine erhöhte IL-1β- und IL-6-Produktion, die durch eine gleichzeitige MEKi-Behandlung möglicherweise aufgrund der paradoxen ERK-Aktivierung aufgehoben wurde. Eine erhöhte IL-1β-Produktion unter Basalbedingungen prädisponierte in einigen Fällen für die BRAFi-induzierte Expressionssteigerung. Dieser Befund lässt darauf schließen, dass BRAFi allein IL-1β nicht induzieren, sondern als Koaktivatoren wirken. BRAFi (DAB > Encorafenib (ENC)) induzierten IL-8 vorwiegend bei IL-1β-respondierenden Spendern.
Es konnte keine Verbindung zwischen dem Alter, dem Geschlecht oder der Blutgruppe der PBMC-Spender und der Reaktion der PBMCs auf BRAFi und MEKi nachgewiesen werden. Zudem fehlte eine Korrelation zwischen dem Verhalten der PBMC und MO-DC desselben Spenders hinsichtlich der Zytokinproduktion unter BRAFi/MEKi-Inkubation. In MO-DC war keine spezifische Expressionssteigerung der drei Zytokine unter BRAFi/MEKi nachweisbar. Kokulturen aus PBMC und Melanom-Zellen (BRAF-WT/BRAF-V600E) zeigten veränderte Zytokin-Muster als Reaktion auf BRAFi/MEKi-Behandlung, die sich jedoch von denen der Monokulturen unterschieden.
Abschließend lässt sich schlussfolgern, dass humane Immunzellen bezüglich der Zytokin-Expression eine große Heterogenität aufweisen, was die Interpretation der Befunde erschwert. Zur Validierung der nachgewiesenen Tendenzen sollten daher Studien mit Tumormausmodellen und größeren Spenderkollektiven durchgeführt werden.VII, 136 Seiten ; Illustrationen, Diagramm
Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance
Get PDFIκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ’s function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppresses Cxcl9, Cxcl10, and Ccl5 expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8+ T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses
1,4-Oxazepan-7-one trifluoroacetate: a modular monomer precursor for the synthesis of functional and biodegradable poly(amino esters)
Get PDFN-Acylated poly(amino esters) (PAEs) synthesized via organocatalytic ring-opening polymerization (ROP) offer potential for tailored, functional and degradable polymers. In this study, a universal monomer precursor toward N-acylated-1,4-oxazepan-7-ones (OxP)s was synthesized using a three-step approach, allowing for the introduction of various functional groups. Two novel oxidation sensitive OxP monomers bearing a double bond and a sulfide group were designed, as well as two monomers with alkyl moieties. The organocatalytic ROP of the OxP monomers using 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) and 1-(3,5-bis(trifluoromethyl)phenyl)-3-cyclohexyl thiourea (TU) as catalysts was investigated. Polymerizations were performed under ambient temperature, affording homopolymers with narrow dispersities (Ð = 1.09–1.13). As a proof of concept, a post-polymerization thiol–ene functionalization of the allyl functional PAE was performed via photo-rheology experiments. Finally, the (bio)degradability of the N-acylated poly(amino esters) was evaluated through a series of degradation studies under mild enzymatic catalysis, in neutral phosphate-buffered saline solution and under accelerated conditions
RMapAlign3N : fast mapping of 3N-Reads
Get PDFNucleotide conversion sequencing techniques are frequently used for the detection of various types of chemical modifications at nucleotide level. However, mapping of chemically treated reads to large reference sequences that contain only three nucleotides can be highly compute-intensive. We present RMapAlign3N—an efficient yet accurate tool for mapping of 3 N-reads to reference genomes or transcriptomes that leverages the power of modern multi-core CPUs. Our performance evaluation using real and simulated data shows that RMapAlign3N is faster and more scalable than prior CPU-based approaches including HISAT-3N, BSMAP, Bismark, and SLAM-DUNK for BS-seq and SLAM-seq data at competitive accuracy
Morphometrische Untersuchung der Fibrae circumolivares des Menschen
Get PDFIV, 54 Seiten ; Illustrationen, Diagramm
Burden of atherosclerosis and outcomes of acute pulmonary embolism : a post hoc analysis of the Hokusai‐VTE trial
No full textBackground:
The burden of atherosclerosis may have prognostic implications for patients affected by venous thromboembolism (VTE). We aimed to assess the association of the presence and extent of atherosclerotic disease with long‐term clinical outcomes in patients with acute pulmonary embolism (PE).
Methods:
In patients with PE from the Hokusai‐VTE trial, we assessed the association between the presence of atherosclerotic disease in multiple (polyvascular disease), one, or no vascular territories (coronary, cerebral, and/or peripheral arteries) and 1‐year risk of VTE or PE recurrence, major bleeding, and all‐cause death. We used univariable and multivariable Cox regression analysis, with adjustment for relevant comorbidities and anticoagulation modeled as a time‐varying covariate.
Results:
Of 2800 patients, 67 (2.4%) had polyvascular and 357 (12.7%) had single vascular atherosclerotic disease. During 12‐month follow‐up, recurrent VTE was reported for a total of 356 patients, including 208 PE events. A total of 52 patients had a major bleeding event and 91 deaths were recorded. Polyvascular atherosclerotic disease was strongly associated with VTE (adjusted hazard ratio,1.91 [95% CI, 1.05–3.49]) and PE recurrence (adjusted hazard ratio, 2.06 [95% CI, 1.03–4.16]). Polyvascular and single vascular disease were associated with major bleeding and all‐cause death in univariable analysis; however, these associations attenuated after adjustment.
Conclusions:
The pre‐existing burden of atherosclerosis may have prognostic value with respect to secondary prevention in patients who experienced an acute PE. Optimization of overall cardiovascular risk may be considered by management studies in the follow‐up of this patient population.
Registration:
URL: www.clinicaltrials.gov; Unique identifier: identifier: NCT0098615
Understanding production, interconversion and effects of reactive oxygen species in atmospheric aerosols and the epithelial lining fluid using numerical modelling techniques
No full textxix, 242 Seiten : Illustrationen, Diagramm
Psychische Belastung, Lebensqualität und Resilienz von Wirbelsäulenchirurgen
No full text66 Seiten ; Illustrationen ; Diagramm
Mortality within three months after nonfatal ischemic stroke treated by mechanical thrombectomy in routine care : data from the German Stroke Registry
No full textBackground
Mechanical thrombectomy (MT) is a highly effective treatment for large vessel occlusion (LVO) ischemic stroke. However, a substantial share of patients have lethal outcome within 3 months. Individualization of outcome prognostication is needed to support clinical decision-making throughout the care pathway after MT. We investigate predictors of lethal outcome in patients with nonfatal LVO, defined by discharge alive from primary treating hospital, in a large prospective registry study of MT under routine care conditions.
Methods
6,518 patients with nonfatal LVO treated by MT enrolled in the German Stroke Registry-Endovascular Treatment from May 2015-December 2021 were analysed with regard to lethal outcome by 3 month follow-up. Univariate group comparisons and multiple logistic regression analysis were performed to identify patients with high odds for survival or lethal outcome.
Results
We report 11.6% (757/6,518) 3 month mortality following hospital discharge after LVO treated by MT. Besides better functional outcome at discharge (modified Rankin scale < 4, odds ratio, OR [95% confidence interval, CI]: 2.38 [1.71–3.32], p < 0.001; National Institute of Health Stroke scale < 8, OR [95%CI]: 3.45 [2.55–4.66], p < 0.001), intravenous thrombolysis (OR [95%CI]: 1.48 [1.17–1.88], p = 0.001), successful recanalization (OR [95%CI]: 1.43 [1.08–1.90], p = 0.014) and discharge to a neurorehabilitative facility (versus nursing home: OR [95%CI]: 0.39 [0.26–0.58], p < 0.001; versus home: OR [95%CI]: 0.69 [0.49–0.97], p = 0.032) were independent predictors of survival. Predictors of lethal outcome were older age (OR [95%CI]: 1.09 [1.07–1.10], p < 0.001), male sex (OR [95%CI]: 1.24 [1.00–1.55], p = 0.049), premorbid disability (OR [95%CI]: 1.47 [1.08–2.02], p = 0.016), active smoking (OR [95%CI]: 1.51 [1.06–2.14], p = 0.023), anticoagulation therapy prior to LVO (OR [95%CI]: 1.45 [1.09–1.92], p = 0.010), stroke etiology, general anaesthesia during MT (OR [95%CI]: 1.31 [1.02–1.69], p = 0.035) and intracerebral haemorrhage (OR [95%CI]: 1.50 [1.13–1.99], p = 0.005).
Conclusions
Lethal outcome after hospital discharge within 3 months after MT is frequent, accounting for more than one quarter of overall 3-month mortality after MT of LVO. Predictors of survival enable individual outcome prognostication, which assists clinical decision-making with regard to surveillance concerning complications, rehabilitative resource allocation and counselling about goals of care
Literaturrecherche in PubMed
Get PDFDieses Kursskript vermittelt grundlegende Fähigkeiten zur effektiven und zielgerichteten Literaturrecherche für den medizinischen Bereich. Lernziele sind, eine wissenschaftliche Fragestellung mit dem PICO-Schema klar zu formulieren, und passende Suchbegriffe (Schlagworte und Stichworte) zu finden und die Suche in der Datenbank umzusetzen. Der Schwerpunkt liegt auf der Nutzung von PubMed, einschließlich der MeSH-Datenbank und erweiterten Suchoptionen, um relevante Studien und Artikel zu identifizieren. Es werden die wesentlichen Recherchewerkzeuge in PubMed vorgestellt. Dazu gehören Filtermöglichkeiten, das MyNCBI-Konto sowie Techniken zur schnellen und präzisen Suche.
Darüber hinaus werden Methoden vorgestellt, um schnell auf Volltexte zuzugreifen und weitere wichtige medizinische Datenbanken zu nutzen.39 Seite