SUMMARY Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells.

Reconstruction of segmental bone defects by autologous bone grafting is still the standard of care but presents challenges including anatomical availability and potential donor site morbidity. The process of 3D bioprinting, the application of 3D printing for direct fabrication of living tissue, opens new possibilities for highly personalized tissue implants, making it an appealing alternative to autologous bone grafts. One of the most crucial hurdles for the clinical application of 3D bioprinting is the choice of a suitable cell source, which should be minimally invasive, with high osteogenic potential, with fast, easy expansion. In this study, mesenchymal progenitor cells were isolated from clinically relevant human bone biopsy sites (explant cultures from alveolar bone, iliac crest and fibula; bone marrow aspirates; and periosteal bone shaving from the mastoid) and 3D bioprinted using projection-based stereolithography. Printed constructs were cultivated for 28 days and analyzed regarding their osteogenic potential by assessing viability, mineralization, and gene expression. While viability levels of all cell sources were comparable over the course of the cultivation, cells obtained by periosteal bone shaving showed higher mineralization of the print matrix, with gene expression data suggesting advanced osteogenic differentiation. These results indicate that periosteum-derived cells represent a highly promising cell source for translational bioprinting of bone tissue given their superior osteogenic potential as well as their minimally invasive obtainability.

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Purpose: Triple-negative breast cancers (TNBC) are often resistant to treatment with ionizing radiation (IR). We sought to investigate whether pharmacologic inhibition of Chk1 kinase, which is commonly overexpressed in TNBC, preferentially sensitizes TNBC cells to IR. Methods:Ten breast cancer cell lines were screened with small molecule inhibitors against Chk1 and other kinases. Chk1 inhibition was also tested in isogenic KRAS mutant or wild-type cancer cells. Cellular radiosensitization was measured by short-term and clonogenic survival assays and by staining for the DNA double-strand break (DSB) marker γ-H2AX. Radiosensitization was also assessed in breast cancer biopsies using an ex vivo assay. Aurora B kinase-dependent mitosis-like chromatin condensation, a marker of radioresistance, was detected using a specific antibody against co-localized phosphorylation of serine 10 and trimethylation of lysine 9 on histone 3 (H3K9me3/S10p). Expression of CHEK1 and associated genes was evaluated in TNBC and lung adenocarcinoma.Results: Inhibition of Chk1 kinase preferentially radiosensitized TNBC cells in vitro and in patient biopsies. Interestingly, TNBC cells displayed lower numbers of IR-induced DSBs than non-TNBC cells, correlating with their observed radioresistance. We found that Chk1 suppressed

Objectives To assess inter- and intrareader agreement of the Neck Imaging Reporting and Data System (NI-RADS) used in contrast-enhanced magnetic resonance imaging (MRI) including analysis of diffusion-weighted imaging (DWI), which is currently not part of the NI-RADS criteria. Methods This retrospective study included anonymized surveillance contrast-enhanced MRI datasets of 104 patients treated for different head and neck cancers. Three radiologists experienced in head and neck imaging reported findings for the primary site and the neck using NI-RADS criteria in a first step and evaluated DWI sequences for the primary site in a second step. Thirty randomly selected imaging datasets were again presented to the readers. Kappa statistics and observed agreement (Ao) were calculated. Results Interreader agreement across all MRI datasets was moderate (κFleiss = 0.53) for NI-RADS categories assigned to the primary site, substantial for NI-RADS categories of the neck (κFleiss = 0.67), and almost perfect for DWI of the primary site (κFleiss = 0.83). Interreader agreement for the primary site was particularly low in cases of cancer recurrence (κFleiss = 0.35) and when categories 2a, 2b, and 3 were combined (κFleiss = 0.30). Intrareader agreement was considerably lower for NI-RADS categories of the primary site (range Ao = 53.3–70.0%) than for NI-RADS categories of the neck (range Ao = 83.3–90.0%) and DWI of the primary site (range Ao = 93.3–100.0%). Conclusion Interreader agreement of NI-RADS for reporting contrast-enhanced MRI findings is acceptable for the neck but limited for the primary site. Here, DWI has the potential to serve as a reliable additional criterion. Key Points • NI-RADS was originally designed for contrast-enhanced computed tomography with or without positron emission tomography but can also be used for contrast-enhanced magnetic resonance imaging alone. • Overall interreader agreement was acceptable for NI-RADS categories assigned to the neck but should be improved for the primary site, where it was inferior to DWI; similar tendencies were found for intrareader agreement. • DWI is currently no criterion of NI-RADS, but has shown potential to improve its reliability, especially for categories 2a, 2b, and 3 of the primary site.

Objectives: The Neck Imaging Reporting and Data System (NI-RADS) is an increasingly utilized risk stratification tool for imaging surveillance after treatment for head and neck cancer. This study aims to measure the impact of supervision by subspecialized radiologists on diagnostic accuracy of NI-RADS when initial reading is performed by residents. Methods: 150 CT and MRI datasets were initially read by two trained residents, and then supervised by two subspecialized radiologists. Recurrence rates by NI-RADS category were calculated, and receiver operating characteristic (ROC) curves were plotted. After dichotomization of the NI-RADS system (category 1 vs categories 2 + 3+4 and categories 1 + 2 vs 3 + 4), sensitivity, specificity, positive and negative predictive value were calculated. Results: 26% of the reports were modified by the supervising radiologists. Area under the curve of ROC plots values of the supervision session were higher than those of the initial reading session for both the primary site (0.89 vs 0.86) and the neck (0.94 vs 0.91), but the difference was not statistically significant. For dichotomized NI-RADS category assignments, differences between the initial reading and the supervision session were statistically significant regarding specificity and PPV for the primary site (1 + 2 vs 3 + 4 and 1 vs 2 + 3+4) or even for both sites combined (1 vs 2 + 3+4). Conclusion: NI-RADS enables trained resident radiologists to report surveillance imaging in patients with treated oral squamous cell carcinoma with high discriminatory power. Additional supervision by a subspecialized head and neck radiologist particularly improves specificity of radiological reports.

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