Refine
Year of publication
Document Type
- Article (5087)
- Doctoral Thesis (1462)
- Part of Periodical (210)
- Conference Proceeding (164)
- Preprint (158)
- Book (85)
- Contribution to a Periodical (60)
- Review (38)
- Working Paper (22)
- Part of a Book (16)
Language
Is part of the Bibliography
- no (7322) (remove)
Keywords
- inflammation (79)
- COVID-19 (57)
- SARS-CoV-2 (48)
- apoptosis (38)
- glioblastoma (38)
- Inflammation (37)
- cancer (36)
- breast cancer (34)
- autophagy (28)
- Cancer (25)
Institute
- Medizin (7322) (remove)
Untersuchung der Expression von Wachstumsfaktoren in reseziertem Hirngewebe von Epilepsiepatienten
(2023)
Hintergrund: Die Epilepsie gehört zu den häufigsten chronischen neurologischen Erkrankungen beim Menschen. Bei Patienten mit mesialer TLE und Hippocampussklerose besteht die höchste Wahrscheinlichkeit, eine medikamentöse Therapierefraktärität zu entwickeln. Die Ursache der Hippocampussklerose sowie die ursächlichen Mechanismen sind nicht bekannt. Allerdings kann eine initiale Schädigung, wie etwa komplizierte Fieberkrämpfe im Kindesalter, Schädel-Hirn-Traumata, Schlaganfälle, entzündliche Prozesse oder Ähnliches, für die Entwicklung einer Hippocampussklerose prädisponieren. Diese kann anschließend nach einer klinisch stummen Latenzperiode zur Entwicklung spontaner epileptischer Anfälle und der Diagnose einer Epilepsie führen. Im Rahmen der Epileptogenese, also der Entstehung und Progression der Epilepsie kommt es zu Wachstumsprozessen, weshalb eine Beteiligung von neurotrophen Wachstumsfaktoren naheliegend war. Das Ziel dieser Arbeit war die vergleichende Untersuchung resezierter Hippocampi auf Wachstumsfaktoren, um semiquantitative Daten zu deren Verteilung bei Epilepsiepatienten zu erhalten. Des Weiteren war die Korrelation mit den klinischen Daten der Patienten von besonderem Interesse, da so Hinweise auf mögliche Zusammenhänge zwischen dem klinischen Erscheinungsbild und der Expression der Wachstumsfaktoren gewonnen werden konnten.
Methoden: Bei dem in der vorliegenden Arbeit untersuchten Gewebe handelt es sich um Hippocampi von 21 Patienten mit TLE, die epilepsiechirurgisch therapiert wurden. Die Schnitte der paraffinierten Hippocampi wurden mittels Immunhistochemie auf die Wachstumsfaktoren BDNF, FGF2, GDNF, GMFB und PDGF-B untersucht. Im Anschluss wurden die Schnitte gescannt und die Zellen mittels eines Algorithmus identifiziert und ausgewertet. Diese experimentellen Daten wurden anschließend mit den klinischen Daten der Patienten korreliert.
Ergebnisse: Es fand sich eine signifikante Korrelation zwischen der Expression von GMFB und dem postoperativen Outcome der Patienten. Des Weiteren fanden sich auch Korrelationen zwischen der präoperativen Anfallsfrequenz und der Expression von BDNF sowie GDNF. Auch die Epilepsiedauer korrelierte mit der Expression von BDNF. Zudem fanden sich Korrelationen zwischen den Ergebnissen der neuropsychologischen Testungen und der Expression von BDNF, sowie PDGF-B.
Diskussion: Die vorliegende Arbeit liefert einige Daten, die Hinweise für nachfolgende Untersuchungen geben können. Sowohl für die Anfallsfrequenz, als auch für die Epilepsiedauer fanden sich signifikante Korrelationen mit BDNF. Beides ist passend zu den vermuteten und zum Teil in der Literatur beschriebenen Mechanismen im Rahmen der Epilepsie, also einer postiktalen Hochregulation von Wachstumsfaktoren beziehungswiese des Zugrundegehens von Zellen im Verlauf der Erkrankung und damit zu einer reduzierten Expression von Wachstumsfaktoren. Geschlechterabhängige Unterschiede in der Expression der Wachstumsfaktoren fanden sich, passend zu der vorhandenen Literatur, nicht. Interessant ist, dass sowohl Geschlechtshormone als auch anfallssuppressive Medikamente einen Einfluss auf die Expression der Wachstumsfaktoren haben können.
Bis heute ist kein Biomarker bekannt, der eine Vorhersage über den Erfolg einer operativen Therapie bei therapierefraktären TLE treffen kann. Da meine Daten eine Korrelation von GMFB und dem postoperativen Outcome zeigen, bietet es sich für weitere Untersuchungen an, GMFB als präoperativen Biomarker zu nutzen. zu können, wäre eine einfachere Probengewinnung beispielsweise aus Blut, Liquor, Urin oder Speichel notwendig. Im Sinne einer „Liquid Biopsy“ könnte so der Erfolg einer chirurgischen Therapie weiter objektiviert werden, was die Entscheidungsfindung einfacher und risikoärmer gestalten würde.
Background: Trauma-related guilt and shame are crucial for the development and maintenance of PTSD (posttraumatic stress disorder). We developed an intervention combining cognitive techniques with loving-kindness meditations (C-METTA) that specifically target these emotions. C-METTA is an intervention of six weekly individual treatment sessions followed by a four-week practice phase.
Objective: This study examined C-METTA in a proof-of-concept study within a randomized wait-list controlled trial.
Method: We randomly assigned 32 trauma-exposed patients with a DSM-5 diagnosis to C-METTA or a wait-list condition (WL). Primary outcomes were clinician-rated PTSD symptoms (CAPS-5) and trauma-related guilt and shame. Secondary outcomes included psychopathology, self-criticism, well-being, and self-compassion. Outcomes were assessed before the intervention phase and after the practice phase.
Results: Mixed-design analyses showed greater reductions in C-METTA versus WL in clinician-rated PTSD symptoms (d = −1.09), guilt (d = −2.85), shame (d = −2.14), psychopathology and self-criticism.
Conclusion: Our findings support positive outcomes of C-METTA and might contribute to improved care for patients with stress-related disorders. The study was registered in the German Clinical Trials Register (DRKS00023470).
HIGHLIGHTS
C-METTA is an intervention that addresses trauma-related guilt and shame and combines cognitive interventions with loving-kindness meditations.
A proof-of-concept study was conducted examining C-METTA in a wait-list randomized controlled trial
C-METTA led to reductions in trauma-related guilt and shame and PTSD symptoms.
Inhibition of the soluble epoxide hydrolase (sEH) has beneficial effects on vascular inflammation and hypertension indicating that the enzyme may be a promising target for drug development. As the enzymatic core of the hydrolase domain of the human sEH contains two tyrosine residues (Tyr383 and Tyr466) that are theoretically crucial for enzymatic activity, we addressed the hypothesis that the activity of the sEH may be affected by nitrosative stress. Epoxide hydrolase activity was detected in human and murine endothelial cells as well in HEK293 cells and could be inhibited by either authentic peroxynitrite (ONOO−) or the ONOO− generator 3-morpholino-sydnonimine (SIN-1). Protection of the enzymatic core with 1-adamantyl-3-cyclohexylurea in vitro decreased sensitivity to SIN-1. Both ONOO− and SIN-1 elicited the tyrosine nitration of the sEH protein and mass spectrometry analysis of tryptic fragments revealed nitration on several tyrosine residues including Tyr383 and Tyr466. Mutation of the latter residues to phenylalanine was sufficient to abrogate epoxide hydrolase activity. In vivo, streptozotocin-induced diabetes resulted in the tyrosine nitration of the sEH in murine lungs and a significant decrease in its activity. Taken together, these data indicate that the activity of the sEH can be regulated by the tyrosine nitration of the protein. Moreover, nitrosative stress would be expected to potentiate the physiological actions of arachidonic acid epoxides by preventing their metabolism to the corresponding diols.
Highlights
• TAM polarization induces CP RNA.
• CP RNA expression is regulated by HIF-2 and STAT1.
• CP RNA is transferred from TAMs to HT1080 cells.
• CP RNA is translated by HT1080 cells and protects from ferroptosis.
• Co-cultured HT1080 cells decrease iron and lipid peroxidation.
Abstract
Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.
We provide in this paper a comprehensive comparison of various transfer learning strategies and deep learning architectures for computer-aided classification of adult-type diffuse gliomas. We evaluate the generalizability of out-of-domain ImageNet representations for a target domain of histopathological images, and study the impact of in-domain adaptation using self-supervised and multi-task learning approaches for pretraining the models using the medium-to-large scale datasets of histopathological images. A semi-supervised learning approach is furthermore proposed, where the fine-tuned models are utilized to predict the labels of unannotated regions of the whole slide images (WSI). The models are subsequently retrained using the ground-truth labels and weak labels determined in the previous step, providing superior performance in comparison to standard in-domain transfer learning with balanced accuracy of 96.91% and F1-score 97.07%, and minimizing the pathologist's efforts for annotation. Finally, we provide a visualization tool working at WSI level which generates heatmaps that highlight tumor areas; thus, providing insights to pathologists concerning the most informative parts of the WSI.
Attention-Deficit/Hyperactivity Disorder (ADHD) is frequently comorbid with other psychiatric disorders and also with somatic conditions, such as obesity. In addition to the clinical overlap, significant genetic correlations have been found between ADHD and obesity as well as body mass index (BMI). The biological mechanisms driving this association are largely unknown, but some candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the link between ADHD and obesity measures. Using the largest GWAS summary statistics currently available for ADHD (N=53,293), BMI (N=681,275), and obesity (N=98,697), we first tested the association of dopaminergic and circadian rhythm gene sets with each phenotype. This hypothesis-driven approach showed that the dopaminergic gene set was associated with both ADHD (P=5.81×10−3) and BMI (P=1.63×10−5), while the circadian rhythm gene set was associated with BMI only (P=1.28×10−3). We then took a data-driven approach by conducting genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. This approach further supported the implication of dopaminergic signaling in the link between ADHD and obesity measures, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was significantly enriched in both the ADHD-BMI and ADHD-obesity gene-based meta-analysis results. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering the shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of preventive interventions and/or efficient treatment of these conditions.
Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N=53,293, N=681,275, and N=98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N=10,720–10,928; replication data N=9,428). The dopaminergic gene set was associated with both ADHD (P=5.81×10−3) and BMI (P=1.63×10−5), the circadian rhythm was associated with BMI (P=1.28×10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P=7.7×10−3; replication data P=3.9×10−2) – a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.
Evaluation of 2‑methoxyestradiol serum levels as a potential prognostic marker in malignant melanoma
(2021)
Experimental findings indicated that 2‑methoxyestradiol (2‑ME), an endogenous metabolite of 17β‑estradiol, may exhibit anti‑tumorigenic properties in various types of tumour, such as melanoma and endometrial carcinoma. In patients with endometrial cancer, the serum levels of 2‑ME are decreased compared with those in healthy controls, and this finding has been associated with a poor outcome. The aim of the present study was to examine whether the serum levels of 2‑ME are decreased in patients with melanoma, and whether this decrease may be correlated with disease stage and, therefore, serve as a prognostic indicator. ELISA was used to detect serum levels of 2‑ME in patients with stage I‑IV malignant melanoma (MM). A cohort of 78 patients with MM was analysed, along with 25 healthy controls, among whom 15 were women in the second trimester of pregnancy (positive control). As expected, significantly elevated levels of serum 2‑ME were observed in pregnant control patients compared with those in patients with MM and healthy controls. There was no observed correlation between 2‑ME serum levels in patients with MM and disease stage, tumour thickness, lactate dehydrogenase or S100 calcium‑binding protein B levels. In addition, the 2‑ME levels of patients with MM did not differ significantly from those of normal healthy controls. Overall, the findings of the present study indicated that the 2‑ME serum levels in patients with MM were not decreased, and there was no correlation with early‑ or advanced‑stage disease. Therefore, in contrast to published results on endometrial cancer, endogenous serum 2‑ME levels in MM were not found to be correlated with tumour stage and did not appear to be a suitable prognostic factor in MM.
Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based protein degraders has evolved over the past two decades and has now established molecular tags that are already in clinical use, as well as chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for the two E3 ligases CRBN and VHL. The large size of the human E3 ligase family suggests that PROTACs can be developed by targeting a large diversity of E3 ligases, some of which have restricted expression patterns with the potential to design disease- or tissue-specific degraders. Indeed, many new E3 ligands have been published recently, confirming the druggability of E3 ligases. This review summarises recent data on E3 ligases and highlights the challenges in developing these molecules into efficient PROTACs rivalling the established degrader systems.