The unfolded protein response affects readthrough of premature termination codons

One-third of monogenic inherited diseases result from premature termination codons (PTCs). Readthrough of in-frame PTCs enables synthesis of full-length functional proteins. However, extended variability in the response to readthrough treatment is found among patients, which correlates with the level of nonsense transcripts. Here, we aimed to reveal cellular pathways affecting this inter-patient variability. We show that activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts carrying PTCs. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTCs, correlating with their response. We further found a significant inverse correlation between the UPR and nonsense-mediated mRNA decay (NMD), suggesting a feedback loop between these homeostatic pathways. We uncovered and characterized the mechanism underlying this NMD-UPR feedback loop, which augments both UPR activation and NMD attenuation. Importantly, this feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Altogether, our study demonstrates the importance of the UPR and its regulatory network for genetic diseases caused by PTCs and for cell homeostasis under normal conditions

Finite Element Simulation für HIP-Bauteile

Endkonturnahe Bauteile werden hauptsächlich durch spanende Bearbeitung, Schmieden, Gießen und pulvermetallurgische Verfahren hergestellt. Das heißisostatische Pressen (HIP) ist eines der pulvermetallurgischen Verfahren zur Herstellung von Hochleistungswerkstoffen, Verbundwerkstoffen und Werkstoff- verbunden. HIP wird üblicherweise bei der Herstellung einfacher Geometrien benutzt, aber auch für die Fertigung von großvolumigen, schwer zu bearbeitenden, geometrisch kom plexen Bauteilen eingesetzt. Ein Problem beim HIPpen ist die anisotrope Verformung der Bauteilgeometrie. Mit Hilfe der Prozeßsimulation kann die auftretende Verformung des Bauteils berechnet werden. Ziel ist es, die HIP-Kapsel so zu bauen, daß ein Bauteil in der geforderten Geometrie mittels HIP hergestellt werden kann, ohne mechanisch nacharbeiten zu müsse

A remarkable response to palliative treatment in metastatic breast cancer: A case report and comprehensive literature review

The case report describes a patient with stage IV breast cancer which metastasized to the lungs. The patient's initial computed tomography (CT) scan revealed a malignant lesion in the upper outer quadrant of the left breast and multiple pulmonary nodules, suggesting pulmonary metastasis. After starting palliative chemotherapy with intravenous paclitaxel and subcutaneous injections of Herceptin, a follow-up CT scan 3 months after the initiation of treatment showed the disappearance of metastasis, and her cancer regressed to stage II breast cancer that could be surgically resected. This case report highlights the importance of timely and appropriate palliative treatment measures, which can lead to unexpected outcomes, such as the regression of metastatic lesions and the possibility of curative treatment in such advanced cancer. © 202