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The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations., Competing Interests: Disclosure and competing interests statement. BK is co-founder and shareholder of OmicScouts and MSAID. He has no operational role in either company. JTS receives honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech, and Servier. His institution receives research funding from Abalos Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio, and Roche/Genentech; he holds ownership in FAPI Holding (< 3%); all outside the submitted work. HS received travel support from Servier, with no financial benefit and outside the submitted work. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Human chorionic gonadotropin (hCG) has structural similarities with thyroid-stimulating hormone (TSH) and may stimulate TSH receptors at higher concentrations. During pregnancy, placental hCG causes TSH suppression, contributing to hyperemesis. However, in males, clinical manifestations caused by excess hCG are rare. Herein, we describe complications of life-threatening thyroid storm caused by paraneoplastic hCG secretion from testicular germ cell tumours (GCTs) and aim to identify high-risk groups through retrospective analysis in n = 20 males (aged 17-55 years) with testicular hCG-positive GCTs. Seven hCG-positive testicular GCTs were classified as seminoma, and 13 were classified as non-seminomatous GCTs (NSGCTs). In 3/7 males with seminomas (43%), serum β-hCG concentrations were mildly elevated (median: 0.3 U/L; range: 0.3-82.1 U/L). In contrast, β-hCG was increased in 12/13 (92%) males with a NSGCT (median: 71.1 U/L; range: 0.3-1,600,000 U/L). In 10/13 males with NSGCT (77%), we detected components of embryonal cell carcinoma (EC), and in 7/13 (54%), we detected components of a choriocarcinoma (ChC). TSH was suppressed with high free thyroxine levels in two cases with NSGCT and excessively elevated β-hCG concentrations, but there was no TSH suppression in a further case with high β-hCG. One patient with NSGCT and high β-hCG levels presented with thyroid storm and imminent decompensation refractory to anti-thyroid treatment, requiring a total thyroidectomy. In the second patient, anti-thyroid treatment was initiated shortly after the diagnosis, successfully normalizing hyperthyroxinaemia. In conclusion, paraneoplastic β-hCG production, occurring in NSGCTs with components of ECs or ChCs, is a rare cause of thyrotoxicosis. Early recognition and treatment are critical to prevent a life-threatening thyroid storm.

Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant molecular subtypes that are currently determined using tissue biopsies, which are spatially biased and highly invasive. We used whole transcriptome sequencing of 10 plasma samples with tumor-informed subtypes, complemented by proteomic analysis for minimally invasive identification of PDAC subtype markers. Data were validated in independent large cohorts and correlated with treatment response and patient outcome. Differential transcript abundance analyses revealed 32 subtype-specific, protein-coding cell-free RNA (cfRNA) transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease-relevant cfRNA-defined subtype markers (DEGS1, KDELC1, and RPL23AP7) that consistently associated with basal-like tumors across all cohorts were identified. In both tumor and liquid biopsies, the overexpression of these markers correlated with poor survival. Moreover, elevated levels of the identified markers were linked to a poor response to systemic therapy and early relapse in resected patients. Our data indicate clinical applicability of cfRNA markers in determining tumor subtypes and monitoring disease recurrence., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Mechanisms keeping leukocytes distant of local inflammatory processes in a resting state despite systemic release of inflammatory triggers are a pivotal requirement for avoidance of overwhelming inflammation but are ill defined. Dimers of the alarmin S100A8/S100A9 activate Toll-like receptor-4 (TLR4) but extracellular calcium concentrations induce S100A8/S100A9-tetramers preventing TLR4-binding and limiting their inflammatory activity. So far, only antimicrobial functions of released S100A8/S100A9-tetramers (calprotectin) are described. It is demonstrated that extracellular S100A8/S100A9 tetramers significantly dampen monocyte dynamics as adhesion, migration, and traction force generation in vitro and immigration of monocytes in a cutaneous granuloma model and inflammatory activity in a model of irritant contact dermatitis in vivo. Interestingly, these effects are not mediated by the well-known binding of S100A8/S100A9-dimers to TLR-4 but specifically mediated by S100A8/S100A9-tetramer interaction with CD69. Thus, the quaternary structure of these S100-proteins determines distinct and even antagonistic effects mediated by different receptors. As S100A8/S100A9 are released primarily as dimers and subsequently associate to tetramers in the high extracellular calcium milieu, the same molecules promote inflammation locally (S100-dimer/TLR4) but simultaneously protect the wider environment from overwhelming inflammation (S100-tetramer/CD69)., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Podosomes are mechanosensitive protrusive actin structures that are prominent in myeloid cells, and they have been linked to vascular extravasation. Recent studies have suggested that podosomes are hierarchically organized and have coordinated dynamics on the cell scale, which implies that the local force generation by single podosomes can be different from their global combined action. Complementary to previous studies focusing on individual podosomes, here we investigated the cell-wide force generation of podosome-bearing ER-Hoxb8 monocytes. We found that the occurrence of focal tractions accompanied by a cell-wide substrate indentation cannot be explained by summing the forces of single podosomes. Instead, our findings suggest that superimposed contraction on the cell scale gives rise to a buckling mechanism that can explain the measured cell-scale indentation. Specifically, the actomyosin network contraction causes peripheral in-plane substrate tractions, while the accumulated internal stress results in out-of-plane deformation in the central cell region via a buckling instability, producing the cell-scale indentation. Hence, we propose that contraction of the actomyosin network, which connects the podosomes, leads to a substrate indentation that acts in addition to the protrusion forces of individual podosomes. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)