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Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRAS G12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRAS G12C -inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRAS G12C -mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRAS G12C -inhibitor efficacy, guiding clinical trial design and molecular tumor boards., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Pancreatic cancer, renowned for its aggressive nature and poor prognosis, necessitates the optimization of treatment strategies. The sequence of procedures in clinical trials is critical, such as evaluating the potential benefits of preoperative chemo-radio-therapy for pancreatic cancer. Nevertheless, we might not be aware of other temporal sequences which have an effect on therapy response or the general outcome. Extracting transitive sequential patterns from patients' medical trajectories allows researchers to identify temporal characteristics for complex diseases. We illustrate how such sequential patterns can be discovered and might be utilized in pancreatic cancer research as well as patient care.

The interaction of the human user with equipment and software is a central aspect of the work in the life science laboratory. The enhancement of the usability and intuition of software and hardware products, as well as holistic interaction solutions are a demand from all stakeholders in the scientific laboratory who desire more efficient workflows. Shorter training periods, parallelization of workflows, improved data integrity, and enhanced safety are only a few advantages innovative intuitive human-device-interfaces can bring. With recent advances in artificial intelligence (AI), the availability of smart devices, as well as unified communication protocols, holistic interaction solutions are on the rise. Future interaction in the laboratory will not be limited to pushing mechanical buttons on equipment. Instead, the interplay between voice, gestures, and innovative hard- and software components will drive interactions in the laboratory into a more streamlined future., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Introduction: Ensuring scientific reproducibility and compliance with documentation guidelines of funding bodies and journals is a topic of greatly increasing importance in biomedical research. Failure to comply, or unawareness of documentation standards can have adverse effects on the translation of research into patient treatments, as well as economic implications. In the context of the German Research Foundation-funded collaborative research center (CRC) 1002, an IT-infrastructure sub-project was designed. Its goal has been to establish standardized metadata documentation and information exchange benefitting the participating research groups with minimal additional documentation efforts., Methods: Implementation of the self-developed menoci-based research data platform (RDP) was driven by close communication and collaboration with researchers as early adopters and experts. Requirements analysis and concept development involved in person observation of experimental procedures, interviews and collaboration with researchers and experts, as well as the investigation of available and applicable metadata standards and tools. The Drupal-based RDP features distinct modules for the different documented data and workflow types, and both the development and the types of collected metadata were continuously reviewed and evaluated with the early adopters., Results: The menoci-based RDP allows for standardized documentation, sharing and cross-referencing of different data types, workflows, and scientific publications. Different modules have been implemented for specific data types and workflows, allowing for the enrichment of entries with specific metadata and linking to further relevant entries in different modules., Discussion: Taking the workflows and datasets of the frequently involved experimental service projects as a starting point for (meta-)data types to overcome irreproducibility of research data, results in increased benefits for researchers with minimized efforts. While the menoci-based RDP with its data models and metadata schema was originally developed in a cardiological context, it has been implemented and extended to other consortia at GÃűttingen Campus and beyond in different life science research areas.

Smoking-induced COPD is characterized by chronic airway inflammation, which becomes enhanced by bacterial infections resulting in accelerated disease progression called exacerbation. Alveolar macrophages (AM) release endothelin-1 (ET-1), IL-6, CCL-2 and MMP-9, all of which are linked to COPD pathogenesis and exacerbation. ET-1 signals via ETA- and ETB-receptors (ETAR, ETBR). This is blocked by endothelin receptor antagonists (ERAs), like bosentan, which targets both receptors, ETAR-selective ambrisentan and ETBR-specific BQ788. Therefore, ERAs could have anti-inflammatory potential, which might be useful in COPD and other inflammatory lung diseases. We hypothesized that ERAs suppress cytokine release from AM of smokers and COPD subjects induced by lipopolysaccharide (LPS), the most important immunogen of gram-negative bacteria. AM were isolated from the broncho-alveolar lavage (BAL) of n=29 subjects (11 non-smokers, 10 current smokers without COPD, 8 smokers with COPD), cultivated and stimulated with LPS in the presence or absence of ERAs. Cytokines were measured by ELISA. Endothelin receptor expression was investigated by RT-PCR and western blot. AM expressed ETAR and ETBR mRNA, but only ETBR protein was detected. LPS and ET-1 both induced IL-6, CCL-2 and MMP-9. LPS-induced IL-6 release was increased in COPD versus non-smokers and smokers. Bosentan, ambrisentan and BQ788 all partially reduced all cytokines without differences between cohorts. Specific ETBR inhibition was most effective. LPS induced ET-1, which was exclusively blocked by BQ788. In conclusion, LPS induces ET-1 release in AM, which in turn leads to CCL-2, IL-6 and MMP-9 expression rendering AM sensitive for ERAs. ERAs could have anti-inflammatory potential in smoking-induced COPD., (Copyright © 2015. Published by Elsevier B.V.)