https://opendata.uni-halle.de//handle/1981185920/35794 2026-06-07T23:33:17Z https://opendata.uni-halle.de//handle/1981185920/125545 Title: Contemporary adjuvant chemotherapy for intraductal papillary mucinous neoplasms Author(s): Lucocq, James; Haugk, Beate; White, Steven; Marchegiani, Giovanni; Holmberg, Marcus; Kleeff, Jörg H. Abstract: Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated. 2026-01-01T00:00:00Z https://opendata.uni-halle.de//handle/1981185920/125544 Title: Sex-dependent effects of Angiotensin II and calcineurin in the vasculature of mice Author(s): Nolze, Alex; Rabe, Sindy; Ruhs, Stefanie; Strätz, Nicole; Quarch, Katja; Köhler, Conny; Großmann, Claudia Abstract: Aim Cardiovascular diseases display strong sex differences. Angiotensin II (AngII) is implicated in this process. The ubiquitously expressed enzymatic beta subunit of calcineurin (PPP3CB), a serine/threonine phosphatase, can mediate pathological effects of AngII in the heart. Our aim was to explore the role of calcineurin in sex-dependent AngII-mediated vascular changes. Methods We used female and male mice with a global PPP3CB knockout that were treated with AngII for 4 weeks as an in vivo model. For validation experiments and investigation of signaling pathways, primary aortic vascular smooth muscle cells (aVSMCs) isolated from respective female and male WT mice were utilized. Results AngII-induced increase in blood pressure was less pronounced and not calcineurin-dependent in female compared to male mice with no changes in media thickness or lumen area. Wire and pressure myography showed an AngII-induced calcineurin-dependent endothelial dysfunction in males but not in females. In aVSMCs from female mice, AngII did not influence wound closure or cell proliferation as was detectable in aVSMCs of male mice. As an underlying mechanism for these sex differences in long-term AngII effects, RNA-seq data and IPA revealed differentially regulated genes and pathways, involving extracellular matrix components, calcineurin, Ctgf, Egfr, and Tgfb1. Downstream of Egfr, we identified sex-dependent activation of PKC signaling in male and ERK/MAPK signaling in female as mediators of Ctgf expression. Conclusion Overall, the relevance of AngII-calcineurin signaling for pathophysiological effects in the vasculature differs between female and male mice, suggesting both sexes require customized prevention and treatment strategies for cardiovascular disorders. 2026-01-01T00:00:00Z https://opendata.uni-halle.de//handle/1981185920/125543 Title: Bisamidine derivatives as candidates for tegumentary leishmaniasis therapy : phenotypic screening in infection of macrophages and mechanistic insights with dual RNA-seq Author(s): Agripino, Joice; Tahira, Ana C.; de Souza, Luciana Ângelo; e Bastos, Matheus Silva; Sauer, Benjamin; Schmidt, Matthias; Bressan, Gustavo Costa; de Souza Vasconcellos, Raphael; Sippl, Wolfgang Abstract: Leishmania braziliensis is the primary causative agent of American tegumentary leishmaniasis (ATL), a critical parasitic tropical neglected disease. The chemotherapeutic arsenal has limited efficacy and significant toxic effects that lead to an urgent need to develop new medicines. Using the “drug repurposing” approach, histone-modifying enzyme inhibitors have been the subject of developing new drugs against neglected parasitic diseases. In this work, furamidine, a known diphenyl furan inhibitor of human Protein Arginine Methyltransferase (PRMT), along with a library of 31 developed analogues, was tested for leishmanicidal activity against L. braziliensis in the in vitro infection of macrophage assay. The most active and selective leishmanicidal analogue, BSF2 (EC50 of 0.64 μM (95% CI: 0.56–0.72), SI of 17.36), was further investigated by dual RNA-seq at 0.16 μM BSF2. The dual-transcriptome detected only 10 genes with significant differential expression (FDR ≤10%) in L. braziliensis related to ubiquitination, chromatin remodeling, and peroxisomal membrane transport pathways, following BSF2 treatment of infected macrophages. In addition, BSF2 had a significant effect (FDR ≤5%) on the expression of 577 genes in the infected macrophages, including the downregulation of TNF, IL-17, NF-κB, and Toll-like receptor pathways. This work opens new venues for developing new chemotherapy for leishmaniasis based on BSF2 or derivatives and highlights the dual transcriptome as a valuable phenotypic assay tool to investigate host–parasite interactions for antileishmanial drug discovery. 2026-01-01T00:00:00Z https://opendata.uni-halle.de//handle/1981185920/125542 Title: A native nepenthesin reactor for improved proteolytic digestion of intrinsically disordered proteins in proteomics workflows Author(s): Wall, Christian; Hause, Frank; Grimm, Wiebke; Otto, Florian W.; Siefke, Erik; Kipping, Marc; Sinz, Andrea Abstract: Intrinsically disordered proteins and proteins containing intrinsically disordered regions often harbor sequences that are difficult to digest with conventional proteases, such as trypsin, Asp-N, or pepsin. In particular, proline-rich regions (PRRs) resist efficient proteolysis and limit sequence coverage in proteomic workflows. Nepenthesins originate from pitcher plants, combining high catalytic activity and stability under acidic conditions with a broad substrate specificity. We describe a workflow for the extraction and purification of native nepenthesin (NEP-NAT) from greenhouse-cultivated Nepenthes species, followed by the enzyme's covalent immobilization on POROS-AL chromatographic material. The performance of the NEP-NAT reactor was evaluated in an online digestion liquid chromatography/tandem mass spectrometry setup for accelerated proteolysis, showing a high proteolytic activity for myoglobin, α-synuclein, and insulin-like growth factor 2 mRNA-binding protein 1. While commercial nepenthesin columns yielded broad coverage for structured proteins, the NEP-NAT reactor generated the largest number of peptides for the intrinsically disordered protein α-synuclein. Cleavages at Pro residues showed enhanced digestion in the PRR of the tumor suppressor protein p53, where conventional proteases show limited activity. These results confirm NEP-NAT as a potent protease in proteomics workflows, offering enhanced access to Pro-rich and disordered domains that are largely inaccessible to common proteases. 2026-01-01T00:00:00Z