Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.
Ribosome production is an essential, but highly energy-demanding and complex cellular process. High-fidelity ribosome assembly is critical to ensure integrity of the proteome, and during their biogenesis, the pre-ribosomal subunits undergo surveillance so that defective complexes are removed. Currently, knowledge on the mechanisms of pre-ribosome quality control lag behind understanding of other RNA surveillance pathways. Interestingly, a family of “guard proteins” has been shown to monitor mRNA maturation in S. cerevisiae and act as maturation switches by either licensing ongoing biogenesis or, in case assembly defects are detected, recruiting components of the RNA degradation machinery. Here, we reveal association of the mRNA guard protein Npl3 with RNA polymerase I, the ribosomal DNA (rDNA) locus and early pre-ribosomal particles. Consistent with this, our data show that Npl3 is required for recruitment of a subset of ribosome assembly factors to the nascent pre-rRNA transcript, and we demonstrate a role for Npl3 in the turn-over of aberrant precursor ribosomal RNA (pre-rRNA). Aberrant pre-rRNAs polyadenylated by Trf5 are bound by Npl3, which in turn interacts with Air1 to recruit the RNA exosome for degradation. Thus, Npl3 is a multifunctional RNA surveillance factor, recognizing different types of aberrant pre-RNAs and promoting recruitment of the RNA degradation machinery to clear these transcripts.
Abstract Background Neuromyelitis optica spectrum disorders (NMOSD) are associated with a high burden of depression, pain, and physical disability, all of which significantly impair quality of life. At the same time, discussions on the cost-effectiveness of treatment strategies are gaining importance. However, it is not yet known whether specific symptom burdens are particularly cost-driving. This study aims to provide a comprehensive cost analysis considering depression and pain to optimise future healthcare strategies. Methods This prospective cross-sectional multicentre study was conducted at twelve centres of the Neuromyelitis Optica Study Group (NEMOS). Over a three-year period, 115 NMOSD patients were recruited. Disease-related costs, pain, and depression were assessed using standardised questionnaires. A generalised linear model analysis and graphical sub-cost analysis were performed to identify key cost drivers. The robustness of our findings was confirmed using two independent depression rating scales. Results In our sample of 115 patients, 77% suffered from chronic pain with a median pain intensity of 4.0 on the numeric rating scale (NRS). Moreover, 56% of patients reported depressive symptoms. In multivariate regression analysis, depression emerged as a significant predictor of total costs (p < 0.001) alongside the EDSS score (p < 0.001) and age (p = 0.004). In contrast, pain was not significantly influencing total costs (p = 0.057), despite being reported by the majority of patients. Graphical analyses highlighted informal costs as the main cost driver in patients with increasing depressive symptoms. Conclusions Depressive symptoms are not only common in NMOSD patients but also represent a major cost driver alongside neurological disability. Addressing these symptoms is essential for optimal patient care and may help reduce the socioeconomic burden.
Vascular allografts represent a potential alternative to autologous grafts when suitable vessels are unavailable. However, current preservation methods, particularly cryopreservation, lead to substantial endothelial damage and poor clinical outcomes. This study evaluated the long-term efficacy of an N-acetylhistidine-buffered, potassium-chloride-enriched and amino-acid-fortified solution augmented with iron chelators, as an advanced preservation solution (NTK-Chel), compared to histidine-tryptophan-ketoglutarate (HTK) and normal saline for vascular graft storage. Abdominal aortae from male Wistar rats (n = 75) were stored for 2 weeks at 4 °C in NTK-Chel (n = 24), HTK (n = 26), or normal saline (n = 25), then transplanted orthotopically. Grafts were harvested at 8, 16, and 26 weeks post-transplantation for vascular function testing and histological analysis. Upon explantation, smooth muscle contractility was severely impaired in all preservation solutions at 8, 16, and 26 weeks post-transplantation. At 8 weeks, only NTK-Chel-preserved grafts demonstrated detectable contractile responses to KCl, though these did not meet criteria for comprehensive vasomotor testing. By 16 and 26 weeks, all grafts had lost measurable contractility. The NTK-Chel group was associated with significantly reduced intimal hyperplasia compared to HTK and normal saline, particularly at 8 and 26 weeks. However, progressive smooth muscle cell loss occurred in all groups, with NTK-Chel showing only delayed rather than prevented degeneration. While NTK-Chel resulted in significantly less intimal hyperplasia compared to conventional solutions, prolonged cold storage combined with transplantation-associated remodeling ultimately compromises long-term vasomotor function regardless of preservation strategy.
Persistierende Infektionen mit Hochrisiko-HPV (humane Papillomviren) stellen die zentrale Ursache der Entstehung des Zervixkarzinoms dar und bilden die Grundlage moderner Screeningstrategien. Der molekularbiologische Nachweis von HPV ermöglicht eine deutlich höhere Sensitivität für die Detektion hochgradiger zervikaler intraepithelialer Neoplasien als die alleinige Zytologie und erlaubt aufgrund der hohen negativen Vorhersagewahrscheinlichkeit verlängerte Screeningintervalle. Randomisierte Studien und populationsbasierte Programme zeigen, dass HPV-basierte Screeningstrategien die Prävention invasiver Zervixkarzinome verbessern können. International kommen unterschiedliche Strategien zum Einsatz, darunter zytologiebasiertes Screening, Ko-Testung sowie primäres HPV-Screening mit zytologischer Triage. In Deutschland wurde 2020 ein organisiertes Screeningprogramm mit altersabhängigen Untersuchungsstrategien eingeführt. Zukünftige Entwicklungen, wie HPV-Self-Sampling, risikoadaptierte Screeningmodelle und KI(Künstliche Intelligenz)-gestützte Diagnostik, könnten die HPV-basierte Früherkennung weiter optimieren.
