Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair.

Molecular profiling of human biopsies and surgical specimens is frequently complicated by their inherent biological heterogeneity and by the need to conserve tissue for clinical diagnosis. We have developed a set of novel 'tissue print' and 'print-phoresis' technologies to facilitate tissue and tumor-marker profiling under these circumstances. Tissue printing transfers cells and extracellular matrix components from a tissue surface onto nitrocellulose membranes, generating a two-dimensional anatomical image on which molecular markers can be visualized by specific protein and RNA- and DNA-detection techniques. Print-phoresis is a complementary new electrophoresis method in which thin strips from the print are subjected to polyacrylamide gel electrophoresis, providing a straightforward interface between the tissue-print image and gel-based proteomic techniques. Here we have utilized these technologies to identify and characterize markers of tumor invasion of the prostate capsule, an event generally not apparent to the naked eye that may result in tumor at the surgical margins ('positive margins'). We have also shown that tissue-print technologies can provide a general platform for the generation of marker maps that can be superimposed directly onto histopathological and radiological images, permitting molecular identification and classification of individual malignant lesions.

To describe and compare patient and event characteristics and outcomes in pediatric massive pulmonary embolism (MPE) and submassive pulmonary embolism (SMPE). METHODS: A retrospective cohort study at a quaternary-care pediatric hospital was conducted. Patients age ,19 years with MPE (acute pulmonary embolism [PE] with cardiac arrest, hypotension, or compensated shock due to PE) or SMPE (right ventricular strain due to acute PE) between January 1997 and June 2019 were included. RESULTS: Thirty-three patients were identified, including 9 (27%) patients with MPE and 24 (73%) patients with SMPE. The most commonly identified risk factor was use of oral contraceptive pills in 16 (49%) patients. Six (18%) patients died, 3 (9%) of which were PE-related deaths. Before PE, patients with MPE were more likely to be hospitalized (89% vs 13%, P , .001), have major comorbidities (89% vs 25%, P 5 .002), central venous catheters (67% vs 17%, P 5 .01), critical illness (56% vs 8%, P 5 .009), immobility (67% vs 13%, P 5 .005), and be postoperative (44% vs 4%, P 5 .01). MPE patients were also more likely to die before discharge (56% vs 4%, P 5 .003). Both groups were equally likely to have primary reperfusion attempts (78% of MPE versus 67% of SMPE, P 5 .69). CONCLUSIONS: Pediatric MPE and SMPE differed in presentation, comorbidities, and risk factors, many of which were associated with hospitalization status. Pediatric-specific studies are warranted to determine risk assessment and management strategies, which may differ from adult guidelines.

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