Mechanical softening of CuX alloys at elevated temperatures studied via high temperature scanning indentation

The thermal stability and temperature dependent hardness of ultrafine-grained Cu-alloys CuSn5 and CuZn5 after high pressure torsion are investigated using the high temperature scanning indentation (HTSI) method. Fast indentations are carried out during thermal cycling of the samples (heating-holding-cooling) to measure hardness and strain rate sensitivity as a function of temperature and time. The microstructures after each thermal cycle are investigated to characterize the coarsening behaviour of both alloys. Results show that the thermal stability of the tested alloys can be expressed in terms of several temperature regimes: A fully stable regime, a transient regime in which growth of individual grains occurs, and finally a regime in which the microstructure is fully coarsened. The onset of grain growth is accompanied by high strain rate sensitivity on the order of 0.2–0.3. Furthermore, the obtained hardness and strain rate sensitivity values are in good agreement with continuous stiffness measurement (CSM) and strain rate jump (SRJ) experiments. This highlights the applicability of the HTSI method to the characterization of the thermomechanical properties of ultrafine-grained alloys

Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients

Nanoindentation creep testing using the constant contact pressure method

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Microstructure and mechanical properties of additively manufactured AlSi10Mg lattice structures from single contour exposure

Metal-based additive manufacturing techniques offer the ability to produce complex, near net shape parts that would be impossible or prohibitively expensive to manufacture via traditional casting and machining methods. Low density lattice structures for lightweight construction are one such example. However, there currently are no well-developed guidelines for designing and reliably manufacturing these structures. Literature on the topic is fragmented and usually only covers a limited aspect of the complex relations between process parameters, microstructure, lattice geometry and mechanical properties. This work covers the edge case of small diameter struts manufactured from AlSi10Mg via Laser Powder Bed Fusion (L-PBF) using the single contour exposure strategy, which is necessary to ensure sufficient geometric accuracy. Various cubic strut-based lattice geometries are manufactured using four laser parameter combinations corresponding to different area energy densities and beam offsets. The influence of process parameters and heat treatment on the microstructure and mechanical properties is investigated. Results show that the microstructure of filigree lattice struts can be tailored by the selection of process parameters, resulting in either uniform or core–shell structures depending on the laser power, while the macroscopic mechanical properties are mainly determined by the lattice geometry and relative density

Data_2023_Sos-Bruder_MaterDes_AlSi10Mg-lattices

Research and raw data to publication: Sos M, Meyer G, Durst K, Mittelstedt C, Bruder E. Microstructure and mechanical properties of additively manufactured AlSi10Mg lattice structures from single contour exposure. Materials & Design. 2023;227:111796. https://doi.org/10.1016/j.matdes.2023.11179

Mechanical softening of CuX alloys at elevated temperatures studied via high temperature scanning indentation

The thermal stability and temperature dependent hardness of ultrafine-grained Cu-alloys CuSn5 and CuZn5 after high pressure torsion are investigated using the high temperature scanning indentation (HTSI) method. Fast indentations are carried out during thermal cycling of the samples (heating-holding-cooling) to measure hardness and strain rate sensitivity as a function of temperature and time. The microstructures after each thermal cycle are investigated to characterize the coarsening behaviour of both alloys.Results show that the thermal stability of the tested alloys can be expressed in terms of several temperature regimes: A fully stable regime, a transient regime in which growth of individual grains occurs, and finally a regime in which the microstructure is fully coarsened. The onset of grain growth is accompanied by high strain rate sensitivity on the order of 0.2–0.3. Furthermore, the obtained hardness and strain rate sensitivity values are in good agreement with continuous stiffness measurement (CSM) and strain rate jump (SRJ) experiments. This highlights the applicability of the HTSI method to the characterization of the thermomechanical properties of ultrafine-grained alloys

CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 HeterodimerizationCD74-NRG1 Gene Fusion as a Bona Fide Oncogene

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1-expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors