Refine
Year of publication
Document Type
- Article (120)
- Part of a Book (3)
- Preprint (3)
- Conference Proceeding (2)
- Working Paper (1)
Keywords
Institute
- Mathematisch-Naturwissenschaftlich-Technische Fakultät (70)
- Institut für Physik (69)
- Lehrstuhl für Experimentalphysik I (44)
- Medizinische Fakultät (41)
- Fakultät für Angewandte Informatik (22)
- Universitätsklinikum (21)
- Institut für Geographie (17)
- Lehrstuhl für Physische Geographie mit Schwerpunkt Klimaforschung (17)
- Lehrstuhl für Psychiatrie und Psychotherapie (10)
- Nachhaltigkeitsziele (9)
Background
Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PSPGSs) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder.
Methods
Using sets of genes involved in pathways affected by lithium, we developed 9 PSPGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) (N = 105) and BipoLife (N = 102) cohorts. The association between each PSPGS and lithium response—defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)—was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was p < .05 after multiple testing correction.
Results
The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PSPGSs that showed significant associations in the univariate analysis (combined PSPGS) increased the percentage of variance explained (R2) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile).
Conclusions
PSPGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.
Background and aims
Nuclear protein of the testis (NUT) carcinoma (NC) is a rare and highly aggressive tumor defined by the presence of a somatic NUTM1 rearrangement, occurring mainly in adolescents and young adults. We analyzed the clinical and biological features of German pediatric patients (≤18 years) with NC.
Methods
This study describes the characteristics and outcome of 11 children with NC registered in the German Registry for Rare Pediatric Tumors (STEP).
Results
Eleven patients with a median age of 13.2 years (range 6.6–17.8) were analyzed. Malignant misdiagnoses were made in three patients. Thoracic/mediastinal tumors were found to be the primary in six patients, head/neck in four cases; one patient had multifocal tumor with an unknown primary. All patients presented with regional lymph node involvement, eight patients (72.7%) with distant metastases. Seven patients underwent surgery, eight radiotherapy with curative intent; polychemotherapy was administered in all patients. Novel treatment strategies including immunotherapy, targeted therapies, and virotherapy were applied in three patients. Median event-free survival and overall survival were 1.5 and 6.5 months, respectively.
Conclusions
Every undifferentiated or poorly differentiated carcinoma should undergo testing for the specific rearrangement of NUTM1, in order to initiate an intense therapeutic regimen as early as possible. As in adults, only few pediatric patients with NC achieve prolonged survival. Thus, novel therapeutic strategies should be included and tested in clinical trials.
Background
Community-acquired pneumonia (CAP) is a major global cause of death and hospitalization. Bacteria or community-acquired viruses (CARVs) cause CAP. COVID-19 associated restrictions effectively reduced the circulation of CARVs.
Objectives
The aim of this study was to analyze the proportion of CARVs in adult patients with CAP from mid-2020 to mid-2023. Specifically, we aimed to compare the rate of influenza virus, SARS-CoV-2, and RSV detections in patients aged 18–59 years and ≥60 years.
Study design
We analyze the proportion of 21 community-acquired respiratory viruses (CARVs) and three atypical bacteria (Bordetella pertussis, Legionella pneumophila, and Mycoplasma pneumoniae) in nasopharyngeal swab samples using molecular multiplex methods within the prospective, multicentre, multinational study of the German study Group CAPNETZ. We used stringent inclusion criteria throughout the study.
Results
We identified CARVs in 364/1,388 (26.2 %) patients. In detail, we detected SARS-CoV-2 in 210/1,388 (15.1 %), rhino-/enterovirus in 64/1,388 (4.6 %), influenza virus in 23/1,388 (1.6 %) and RSV in 17/1,388 (1.2 %) of all patients. We detected RSV and influenza more frequently in patients ≥60 years, especially in 22/23 compared to the previous season. None of the atypical bacteria were detected.
Conclusions
Beginning in 2023, we demonstrate a re-emergence of CARVs in CAP patients. Effective vaccines or specific antiviral therapies for more than two thirds of the detected viral infections are currently available. High detection rates of vaccine-preventable viruses in older age groups support targeted vaccination campaigns.
Semaphorin 7A is protective during inflammatory peritonitis through integrin receptor signaling
(2023)
Background
Desmoplastic small round cell tumor (DSRCT) is an ultra-rare soft-tissue sarcoma characterized by an EWSR1::WT1 gene fusion that affects predominantly male adolescents and young adults. Despite intensive multi-modality treatment outcomes remain dismal, with only 25% of patients being alive after five years. Beyond conventional therapies, novel, molecular mechanism-aware therapies are urgently needed.
Methods
Patients with advanced DSRCT underwent multilayered molecular profiling as part of NCT/DKFZ/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a prospective, multicenter observational study that applies whole-genome/exome, transcriptome, methylome, and – more recently – mass spectrometry-based (phospho-)proteome analysis in young adults with advanced malignancies and patients with rare cancers to inform clinical decision-making and the design of molecularly stratified clinical trials.
Results
Between 2013 and 2022, 29 patients with DSRCT were analyzed with a median follow-up of 17 months (range, 0–48). The median age at the time of molecular analysis was 30 years (range, 18–56). The median time between diagnosis and molecular analysis was 12 months (range, 1–216). The median survival and the 4-year survival rate from registration were 2.4 years (95% confidence interval [CI], 1.4–3 years) and 7.4% (95% CI, 1.2–45.2%), respectively. In 8 of 9 samples with available proteomics data, we observed pronounced activation of ERBB (also called HER) signaling and high ERBB2 mRNA expression levels, providing a rationale for personalized therapy with ERBB2-specific antibody-drug conjugates. In addition, selected somatostatin receptor family members, i.e., SSTR3 and 5, were highly expressed in all patients with available transcriptome data, providing the basis for treatment with pasireotide, a novel multireceptor-targeted somatostatin receptor ligand, within an academic clinical trial, which is currently being prepared.
Conclusions
We describe the molecular profiles of patients with DSRCT enrolled in MASTER and demonstrate the utility of broad molecular profiling for the clinical management of this disease, including the application of targeted treatment strategies.
The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
