High-grade glioma with pleomorphic and pseudopapillary features (HPAP): a proposed type of circumscribed glioma in adults harboring frequent TP53 mutations and recurrent monosomy 13.

Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.

Vaccination against the M protein of Streptococcus pyogenes prevents death after influenza virus: S. pyogenes super-infection.

Influenza virus infections are associated with a significant number of illnesses and deaths on an annual basis. Many of the deaths are due to complications from secondary bacterial invaders, including Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The ß-hemolytic bacteria S. pyogenes colonizes both skin and respiratory surfaces, and frequently presents clinically as strep throat or impetigo. However, when these bacteria gain access to normally sterile sites, they can cause deadly diseases including sepsis, necrotizing fasciitis, and pneumonia. We previously developed a model of influenza virus:S. pyogenes super-infection, which we used to demonstrate that vaccination against influenza virus can limit deaths associated with a secondary bacterial infection, but this protection was not complete. In the current study, we evaluated the efficacy of a vaccine that targets the M protein of S. pyogenes to determine whether immunity toward the bacteria alone would allow the host to survive an influenza virus:S. pyogenes super-infection. Our data demonstrate that vaccination against the M protein induces IgG antibodies, in particular those of the IgG1 and IgG2a isotypes, and that these antibodies can interact with macrophages. Ultimately, this vaccine-induced immunity eliminated death within our influenza virus:S. pyogenes super-infection model, despite the fact that all M protein-vaccinated mice showed signs of illness following influenza virus inoculation. These findings identify immunity against bacteria as an important component of protection against influenza virus:bacteria super-infection.

Contribution of murine innate serum inhibitors toward interference within influenza virus immune assays.

BACKGROUND: Prior to detection of an antibody response toward influenza viruses using the hemagglutination inhibition assay (HAI), sera are routinely treated to inactivate innate inhibitors using both heat inactivation (56°C) and recombinant neuraminidase [receptor-destroying enzyme (RDE)]. OBJECTIVES: We revisited the contributions of innate serum inhibitors toward interference with influenza viruses in immune assays, using murine sera, with emphasis on the interactions with influenza A viruses of the H3N2 subtype. METHODS: We used individual serum treatments: 56°C alone, RDE alone, or RDE + 56°C, to treat sera prior to evaluation within HAI, microneutralization, and macrophage uptake assays. RESULTS: Our data demonstrate that inhibitors present within untreated murine sera interfere with the HAI assay in a manner that is different from that seen for the microneutralization assay. Specifically, the γ class inhibitor α(2) -Macroglobulin (A2-M) can inhibit H3N2 viruses within the HAI assay, but not in the microneutralization assay. Based on these findings, we used a macrophage uptake assay to demonstrate that these inhibitors can increase uptake by macrophages when the influenza viruses express an HA from a 1968 H3N2 virus isolate, but not a 1997 H3N2 isolate. CONCLUSIONS: The practice of treating sera to inactivate innate inhibitors of influenza viruses prior to evaluation within immune assays has allowed us to effectively detect influenza virus-specific antibodies for decades. However, this practice has yielded an under-appreciation for the contribution of innate serum inhibitors toward host immune responses against these viruses, including contributions toward neutralization and macrophage uptake.