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mhn: A Python Package for Analyzing Cancer Progression with Mutual Hazard Networks
No full textBackground
Mutual Hazard Networks (MHNs) are statistical models for analyzing (genetic) cancer progression. Many cancers develop silently and are only noticeable when they have significantly progressed, creating an observational gap until diagnosis. MHNs bridge this gap by reconstructing the underlying dynamics of disease progression.
Summary
We present mhn, a Python package for dynamic cancer progression analysis using MHNs. It trains an MHN model from tumor genotypes. mhn overcomes challenges of numerical efficiency in model training by making use of state space restriction, allowing training MHNs with more than 100 mutational events, 5 times more than was possible before. The package offers (a) reconstruction of the most likely evolutionary history of tumors, (b) sampling of artificial tumor histories, and (c) visualization of genomic interactions and likely progression trajectories. These features substantially extend earlier implementations, providing a fast and user-friendly framework for researchers and clinicians to study cancer dynamics.
Availability and Documentation
mhn can be installed from PyPI using pip and is available under the MIT License on GitHub (https://github.com/spang-lab/LearnMHN). Installation instructions and package functionalities are detailed on GitHub and PyPI, with a comprehensive guide on Read the Docs (https://learnmhn.readthedocs.io/en/latest/index.html) and a Jupyter notebook on GitHub to help users explore the package
Ein quantitativer empirischer Vergleich 14 verschiedener Visualisierungsformate zu Bayesianischen Aufgaben
No full textBayesianische Aufgaben, in denen bedingte Wahrscheinlichkeiten eine zentrale Rolle einnehmen, werden häufig falsch gelöscht. Es ist bekannt, dass 1) natürliche Häufigkeiten (z.B. „80 von 100 Erkrankten erhalten ein positives Testergebnis“) statt Wahrscheinlichkeiten und 2) manche Visualisierungen die Lösungsfindung unterstützen. Jedoch gibt es uneinheitliche Befunde bezüglich des Vergleichs von Visualisierungen und es steht die Frage im Raum, ob Anteile besser verstanden werden als Wahrscheinlichkeiten. Diese Fragen werden im Rahmen des DFG-Projekts FehlBa in einer Studie mit 2400 beantwortet
Inflammatory Cytokines as Early Predictors of Weaning Failure From Extracorporeal Life Support
No full textBackground
Weaning from extracorporeal life support (ECLS) in patients with refractory shock still remains a complex decision. Despite considerable advances in ECLS management, reliable biomarkers to predict weaning success are still not available. Inflammatory cytokines including interleukin-6 (IL6), interleukin-8 (IL8), and tumor necrosis factor-alpha (TNF-α) may reflect systemic immune response and have been proposed as potential predictors of deterioration or recovery.
Methods
A retrospective, single-center study analyzed 809 patients with ECLS between 2012 and 2024. Serum levels of IL6, IL8, and TNF-α were measured before ECLS and 24 h after initiation. Receiver operating characteristic (ROC) analysis and subgroup comparisons between clinical phenotypes were used to assess the cytokine predictive value.
Results
Weaning was achieved in 66.9% of patients. IL8 levels after 24 h demonstrated the highest predictive accuracy for weaning failure (area under the curve AUC = 0.73), outperforming IL6 and TNF-α. The decline of IL8 levels during the first 24 h was associated (p = 0.008) with successful weaning. Subgroup analysis revealed that the predictive values of IL6 and IL8 were pronounced in patients with pulmonary embolism (AUC = 0.72, IL6) and septic shock (AUC = 0.77, IL8), with significantly elevated cytokine levels. Patients with structural heart disease (AUC = 0.85, IL6) and ventricular arrhythmias (AUC = 0.82, IL6) showed cytokine levels comparable to the whole cohort and a better prediction.
Conclusion
Among the evaluated cytokines, IL8 exhibited the strongest predictive benefit for weaning failure, especially on Day 1. Due to its early clearance dynamics, it may be a useful parameter in the appropriate clinical situation to achieve a better outcome
Generalized many-body exciton g factors: Magnetic hybridization and nonmonotonic Rydberg series in monolayer WSe₂
No full textThe magneto-optical response of excitons in monolayer transition metal dichalcogenides is governed by a complex interplay of Bloch-state quantum geometry—reflected in the electronic magnetic moment—coupled with interband mixing and many-body interactions. Here, we develop a robust and general first-principles framework for many-body exciton g factors (magnetic moments) by incorporating off-diagonal terms for the spin and orbital angular momenta of single-particle bands and many-body states for magnetic fields pointing in arbitrary spatial directions. We implement our framework using many-body perturbation theory via the GW-Bethe-Salpeter equation and supplement our analysis with robust symmetry-based models. Focusing on the archetypal monolayer WSe₂, we accurately reproduce the known results of the low-energy excitons including the Zeeman splitting and the dark/gray exciton brightening. Furthermore, our theory naturally reveals the magnetic-field hybridization of higher-energy excitons (s, p, and d like) and shows that the magnetic moments of nodal excitons (p and d like) do not acquire additional contributions of ±mⱼµB (mⱼ=1,2), characteristic of the hydrogenic picture. Our general approach also allows us to resolve the long-standing puzzle of the experimentally measured nonmonotonic Rydberg series (1s−4s) of exciton g factors. Our framework offers a comprehensive approach to investigate, rationalize, and predict the nontrivial interplay between magnetic fields, angular momenta, and many-body exciton physics in van der Waals systems, offering different opportunities to probe signatures of quantum geometry within many-body states
ECP-induced Apoptosis: How Noninflammatory Cell Death Counterbalances Ischemia/Reperfusion Injury
No full textExtracorporeal photopheresis (ECP) is a therapeutic procedure that is increasingly recognized for its efficacy in treating immune-mediated diseases, including transplant rejection. Its main mechanism is ex vivo apoptosis induction in leukocytes from patients by incubation with 8-methoxypsoralen and irradiation with ultraviolet A light. The process involves DNA cross-linking, which leads to a cascade of events within the cell and ultimately to apoptosis induction. Although ECP has been used for almost 40 y, there remain many questions about its immunological mechanisms and therapeutic potential. Here, we review current knowledge about mechanisms of apoptosis induction in subsets of peripheral blood mononuclear cells and interactions of apoptotic leukocytes with immune cells. We also highlight the challenges of reproducibly inducing cell death in a clinical manufacturing procedure and propose innovative ways to improve and quality-control ECP photopheresates
Exercise-Dependent effects of substance P deficiency on joint degeneration and inflammation in a surgical mouse model of osteoarthritis
No full textBackground
Osteoarthritis (OA) is a chronic degenerative joint disease driven by multifactorial causes, including aging, mechanical stress, and inflammation. Mechanical loading through exercise can either exacerbate or alleviate OA symptoms depending on intensity. Substance P (SP), a neuropeptide involved in inflammation and mechanotransduction, has been implicated in cartilage and bone remodeling. This study aimed to investigate how SP deficiency plus exercise intensity interact to influence disease progression in a surgical murine OA model.
Methods
OA was induced in male wild-type (WT) and SP knockout (Tac1-/-) mice via destabilization of the medial meniscus (DMM). Mice were then exposed to moderate or intense treadmill exercise for up to eight weeks. Cartilage degeneration was assessed histologically using OARSI scoring. Cartilage stiffness was evaluated via atomic force microscopy (AFM), and subchondral and metaphyseal bone morphology was analyzed by high-resolution nanoCT. Serum cytokine levels were measured with multiplex ELISA.
Results
DMM surgery induced OA-like cartilage damage in most groups, and moderate exercise failed to prevent degeneration. However, SP-deficient mice subjected to intense exercise showed preserved cartilage matrix stiffness and morphology comparable to Sham controls. In contrast, SP deficiency as well as intense exercise promoted meniscal ossification and subchondral bone sclerosis, with increased bone volume fraction and trabecular thickness. These changes were consistent with prior findings in SP-deficient mice without exercise. Serum analysis revealed elevated levels of proinflammatory cytokines (e.g., CXCL10, VEGF-A, CCL2, CCL4) in SP-deficient mice after Sham surgery, although these did not correspond to the cartilage degradation timeline.
Conclusions
SP plays a dual role in OA pathogenesis: its absence may protect cartilage from mechanical stress–induced stiffening but also promotes ectopic meniscal ossification and subchondral bone alterations. Additionally, SP appears to modulate systemic inflammatory responses independently of joint degeneration. These findings position SP as a key regulator of neuroimmune and mechanobiological processes in OA and highlight its potential as a therapeutic target for load-induced joint pathology
Eine reduzierte Expression von IRF4 erhöht die Antigenempfindlichkeit und funktionelle Persistenz von CAR-T-Zellen
No full textDie Zelltherapie mit synthetischen Chimären-Antigenrezeptor-T-Zellen (CAR-T-Zellen) konnte bei Patienten mit fortgeschrittenen chemorefraktären hämatologischen Neoplasien langanhaltende Komplettremissionen induzieren. Leider erleiden jedoch mehr als die Hälfte aller behandelten Patienten einen Krankheitsrückfall. Ferner ist bei Patienten mit soliden Tumoren die Wirksamkeit der CAR-T-Zellen bisher begrenzt. Zu den größten Hindernissen für den langfristigen Erfolg der Therapie mit CAR-T-Zellen gehören die funktionelle Erschöpfung der CAR-T-Zellen und die Herunterregulierung von CAR-Zielantigenen auf Tumorzellen. In diesem Zusammenhang wurde der Transkriptionsfaktor Interferon Regulatory Factor 4 (IRF4) zuvor als wichtiger Faktor bei der funktionellen Erschöpfung von T-Zellen identifiziert. Um die Funktionalität von CAR-T-Zellen zu verbessern, haben wir die IRF4-Expression in CEAspezifischen CAR-T-Zellen mithilfe von Short-Hairpin (sh)-RNA-vermittelter Gen-Interferenz herunterreguliert. Dennoch zeigen die CAR-T-Zellen mit IRF4-Herunterregulierung im Vergleich zu herkömmlichen CAR-T-Zellen die gleiche Zytotoxizität, IFNγ-Sekretion und IL-2- Sekretion. Allerdings offenbarten CAR-T-Zellen mit IRF4-Herunterregulierung in einem repetitiven in-vitro-Antigenstimulationsmodell, das auf BxPC-3-Pankreaskarzinomzellen als Zielzellen basiert, eine verbesserte Tumorzellkontrolle. Mechanistisch gesehen zeigten CART- Zellen mit IRF4-Herunterregulierung eine Hochregulierung von CD27, dessen Expression auf CAR-T-Zellen mit einer verbesserten Funktionalität und gedächtnisähnlichen Eigenschaften in Verbindung gebracht wurde. Schließlich offenbarten CAR-T-Zellen mit IRF4- Herunterregulierung eine verstärkte Zytotoxizität gegenüber Tumorzellen mit geringer CEAExpression, was eine Erhöhung der Antigenempfindlichkeit zeigt. Basierend auf unseren Daten nehmen wir an, dass die CAR T-zellen mit Herunterregulierung von IRF4 eine therapeutische Bedeutung erlangen könnten, wenn die Sensitivität gegenüber Tumorzellen mit geringer Antigenlast erhöht und eine hinreichende anti-Tumor Aktivität erzielt warden soll
Influence of digital crown design software on morphology, occlusal characteristics, fracture force and marginal fit
No full textObjectives:
The study evaluated the influence of digital design software on crown morphology, occlusal characteristics, fracture force, and marginal fit across varying preparation designs for an identical target tooth.
Methods:
A resin-based tooth (tooth 36) was digitized, manufactured (
), individually prepared and re-digitized. Five design groups were established using conventional software proposals, technician designs, two AI-based software solutions, and natural tooth-based reference designs. All systems employed consistent parameters. Crown designs were digitally assessed using quantitative morphological and occlusal metrics in reference to the original tooth. Crowns were milled, marginal fit was measured via digital microscopy, and fracture resistance was determined after thermal cycling and mechanical loading.
Results:
Morphological metrics revealed statistically significant deviations across groups, with the technician design achieving the best performance. Occlusal metrics showed high deviations in the positional accuracy of the contact points across all groups. Technician and AI-based designs exhibited comparable functional results. None of the design groups were able to achieve contact with all relevant antagonist teeth, due to high deviations in the mesiolingual cusp. Conventional software designs exhibited the lowest fracture forces. Significant improvements were achieved through technician intervention. Vertical marginal discrepancies remained comparable across groups.
Significance:
Improved functional and morphological design combined with high fracture resistance can reduce the need for clinical adjustments, minimize wear, and enhance crown longevity. Digital design software significantly influences crown morphology, occlusal characteristics and fracture forces. Vertical marginal discrepancies remain similar. AI-driven approaches demonstrate comparability with technician designs in terms of fracture forces, functional performance, and marginal fit