Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identifi ed, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specifi c candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplifi cation (identifi ed by whole-genome sequencing) and changes in gene expression as identifi ed by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specifi c SCNAs leads to signifi cant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. SIGNIFICANCE: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specifi c dependencies could be identifi ed within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for "genome-matched" therapies, demonstrating the utility of a targeted genome-informed approach.

We aimed to assess the crystallography, microstructure and flexural strength of zirconia-based ceramics made by stereolithography (SLA). Two additively manufactured 3 mol% yttria-stabilized tetragonal zirconia polycrystals (3Y-TZP: LithaCon 3Y 230, Lithoz; 3D Mix zirconia, 3DCeram Sinto) and one alumina-toughened zirconia (ATZ: 3D Mix ATZ, 3DCeram Sinto) were compared to subtractively manufactured 3Y-TZP (control: LAVA Plus, 3M Oral Care). Crystallographic analysis was conducted by X-ray diffraction. Top surfaces and cross-sections of the subsurface microstructure were characterized using scanning electron microscopy (SEM). Biaxial flexural strength was statistically compared using Weibull analysis. The additively and subtractively manufactured zirconia grades revealed a similar phase composition. The residual porosity of the SLA 3Y-TZPs and ATZ was comparable to that of subtractively manufactured 3Y-TZP. Weibull analysis revealed that the additively manufactured LithaCon 3Y 230 (Lithoz) had a significantly lower biaxial flexural strength than 3D Mix ATZ (3D Ceram Sinto). The biaxial flexural strength of the subtractively manufactured LAVA Plus (3M Oral Care) was in between those of the additively manufactured 3Y-TZPs, with the additively manufactured ATZ significantly outperforming the subtractively manufactured 3Y-TZP. Additively manufactured 3Y-TZP showed comparable crystallography, microstructure and flexural strength as the subtractively manufactured zirconia, thus potentially being a good option for dental implants.

Data from an S‐band Doppler radar system and a three‐dimensional very high frequency (VHF) radiation source location system in Chongqing, China, were combined to analyze the characteristics of stratiform lightning flashes associated with the charge layer near the 0 °C isotherm (SL0s) in 10 mesoscale convective systems during the summers of 2014–2015. Most of the SL0 events occurred during the dissipating stage of two thunderstorms. The bright band was found to have a very close relationship with the initiation of the SL0 events. The noninductive and inductive charging mechanisms associated with the process of melting ice particles were inferred to contribute to the charge of the bright band area. The reflectivity at the first located VHF radiation source (FirstS) of the SL0s was always weaker than that in the reflectivity core within the lightning area. The stronger the reflectivity core, the greater the difference between the reflectivity and the reflectivity core. The SL0s generated by the thunderstorms with low SL0 frequency tended to have weaker reflectivity at the FirstS but a stronger reflectivity core in the lightning area than that of the thunderstorms with high SL0 frequency. In the storms with low SL0 frequency, SL0s occurred only when the initiation height of the stratiform lightning flashes decreased gradually toward the height range of the SL0s; but in one storm with high SL0 frequency, the SL0s were generated simultaneously with the stratiform lightning flashes initiated at a high level. It gives a clue that the melting charging mechanisms may enhance the charge density of the bright band area.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations.Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients.Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.