Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.

Nano-Confined Effect and Heterojunction Promoted Exciton Separation for Light-Boosted Osmotic Energy Conversion.

The osmotic energy conversion properties of biomimetic light-stimulated nanochannels have aroused great interest. However, the power output performance is limited by the low light-induced current and energy conversion efficiency. Here, nanochannel arrays with simultaneous modification of ZnO and di-tetrabutylammonium cis-bis(isothiocyanato)bis(2,20-bipyridyl-4,40-dicarboxylato) ruthenium (II) (N719) onto anodic aluminum oxide (AAO) to combine the nano-confined effect and heterojunction is designed, which demonstrate rectified ion transport behavior due to the asymmetric composition, structure and charge. High cation selectivity and ion flux contribute to the high power density of ≈7.33 W m-2 by mixing artificial seawater and river water. Under light irradiation, heterojunction promoted the production and separation of exciton, enhanced cation selectivity, and improved the utilization efficiency of osmotic energy, providing a remarkable power density of ≈18.49 W m-2 with an increase of 252% and total energy conversion efficiency of 30.43%. The work opens new insights into the biomimetic nanochannels for high-performance energy conversion.

Defect characterization in optical coatings using scattered light.

Optical coatings play a vital role in sensing technologies. The development of new coatings that exhibit minimal optical losses requires a detailed understanding of the development of defects within them. Current methods of defect characterization involve direct microscope imaging or x-ray diffraction studies in the case of crystallites. In this paper, we demonstrate the characterization of coating defects using light scattering, which can yield information about their size, location, and index of refraction. The method requires measuring the scattered power of each individual defect as a function of angle and comparing the data with theoretical models. Finally, we argue that this method can be used for the determination of the defect location within a multi-layer stack.