Multiomics Analysis Reveals the Prognostic Non-tumor Cell Landscape in Glioblastoma Niches

A comprehensive characterization of non-tumor cells in the niches of primary glioblastoma is not fully established yet. This study aims to present an overview of non-malignant cells in the complex microenvironment of glioblastoma with detailed characterizations of their prognostic effects. We curate 540 gene signatures covering a total of 64 non-tumor cell types. Cell type-specific expression patterns are interrogated by normalized enrichment score across four large gene expression profiling cohorts of glioblastoma with a total number of 967 cases. The glioblastoma multiforms (GBMs) in each cohort are hierarchically clustered into negative or positive immune response classes with significantly different overall survival. Our results show that astrocytes, macrophages, monocytes, NKTs, and MSC are risk factors, while CD8 T cells, CD8 naive T cells, and plasma cells are protective factors. Moreover, we find that the immune system and organogenesis are uniformly enriched in negative immune response clusters, in contrast to the enrichment of nervous system in positive immune response clusters. Mesenchymal differentiation is also observed in the negative immune response clusters. High enrichment status of macrophages in negative immune response clusters is independently validated by analyzing scRNA-seq data from eight high-grade gliomas, revealing that negative immune response samples comprised 46.63 to 55.12% of macrophages, whereas positive immune response samples comprised only 1.70 to 8.12%, with IHC staining of samples from six short-term and six long-term survivors of GBMs confirming the results.

Longitudinal changes in IgG levels among COVID-19 recovered patients: A prospective cohort study

Objectives To quantify SARS-CoV2 IgG antibody titers over time and assess the longevity of the immune response in a multi-ethnic population setting. Setting This prospective study was conducted in a tertiary hospital in Abu Dhabi city, UAE, among COVID-19 confirmed patients. The virus-specific IgG were measured quantitatively in serum samples from the patients during three visits over a period of 6 months. Serum IgG levels ≥15 AU/ml was used to define a positive response. Participants 113 patients were analyzed at first visit, with a mean (SD) age of participants of 45.9 (11.8) years 87.5% of the patients were men. 63 and 27 participants had data available for visits 2 and 3, respectively. Primary outcome Change in SARS-CoV2 IgG antibody titers over the visits. Results No mortality or re-infection were reported. 69% of the patients developed positive IgG response within the first month after the onset of symptoms. The levels of IgG showed a consistent increase during the first three months with a peak level during the third month. Increasing trend in the levels of IgG were observed in 82.5%, 55.6% and 70.4% of patients between visit 1 to visit 2, visit 2 to visit 3, and from visit 1 to visit 3, respectively. Furthermore, about 64.3% of the patients showed sustained increase in IgG response for more than 120 days. Conclusions Our study indicates a sustained and prolonged positive immune response in COVID-19 recovered patients. The consistent rise in antibody and positive levels of IgG titers within the first 5 months suggest that immunization is possible, and the chances of reinfection minimal.

Landscape of glioblastoma niches reveals the prognostic effects of tumor-infiltrating cells

A comprehensive characterization of non-tumor cells in the niches of primary glioblastoma is not fully established yet. This study aims to present an overview of tumor-infiltrating non-malignant cells in the complex microenvironment of glioblastoma with detailed characterizations of their prognostic effects. We curate 540 gene signatures covering a total of 64 non-tumor cell types. Cell type-specific expression patterns are interrogated by normalized enrichment score (NES) across four large gene expression profiling cohorts of glioblastoma with a total number of 967 cases. The GBMs in each cohort are hierarchically clustered into negative or positive immune response classes with significantly different overall survival. Our results show that astrocytes, macrophages, monocytes, NKTs, preadipocytes, smooth muscle cells, and MSC are risk factors, while CD8 T cells, CD8+ T cells, and plasma cells are protective factors. Moreover, we find that the immune system and organogenesis are uniformly enriched in negative immune response clusters, in contrast to the enrichment of nervous system in positive immune response clusters. Mesenchymal differentiation is also observed in the negative immune response clusters. High enrichment status of macrophages in negative immune response clusters are independently validated by analyzing scRNA-seq data from eight high-grade gliomas, revealing that negative immune response samples comprised 46.63% to 55.12% of macrophages, whereas positive immune response samples comprised only 1.70% to 8.12%, with IHC staining of samples from six short-term and six long-term survivors of GBMs confirming the results.Simple SummaryThe landscape of infiltrating non-tumor cells in glioblastoma niches remains unclear. In this study, we explore the enrichment status of a total of 64 non-tumor cell types predicted by applying 540 gene signatures curated from literature and normalized enrichment score (NES) across four large gene expression profiling cohorts of glioblastoma with 967 cases. Based on non-tumor cell type-based enrichment status, GBMs in each cohort are classified into positive or negative immune response clusters, showing a statistically significant different overall survival. Astrocytes, macrophages, monocytes, NKTs, preadipocytes, smooth muscle cells, and MSC are identified as risk factors, as well as protector factors of CD8 T cells, CD8+ T cells, and plasma cells. Our results also find that immune system- and organogenesis-related GO terms are uniformly enriched in negative immune response clusters, whereas positive immune response clusters are enriched with GO terms concerning the nervous system. The mesenchymal differentiation is observed in the negative immune response clusters. Particularly, the high presence of macrophages in the negative immune response clusters is further validated using scRNA-seq analysis and IHC staining of GBMs from independent cohorts.

Safety and Immunogenicity of a Novel Staphylococcus aureus Vaccine: Results from the First Study of the Vaccine Dose Range in Humans

ABSTRACT Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 μg, 30 μg, or 90 μg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB-specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 μg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-μg (86%; geometric mean concentration of 116 μg/ml) and 90-μg (87%; geometric mean concentration of 131 μg/ml) dose groups than in the V710 5-μg (29%; geometric mean concentration of 51 μg/ml) or placebo (4%; geometric mean concentration of 23 μg/ml) groups. Immune responses were durable through day 84. Subjects <40 and ≥40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-μg or 90-μg dose was more immunogenic than the 5-μg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders.

Immune Response to Verotoxin 1 and 2 in Children withEscherichia ColiO157:H7 Hemorrhagic Colitis and Classic Hemolytic Uremic Syndrome

Objectives: To compare neutralizing antibody titres against verotoxin (vt)-1andvt-2between children with uncomplicated hemorrhagic colitis (hc) and those with classic hemolytic uremic syndrome (hus).vtantibody titres were also compared in children withhcwho received trimethoprim-sulfamethoxazole with those who did not.Design: Prospective study.Setting: Tertiary pediatric hospital.Population Studied: Children withhc(n=41) or classichus(n=12).Interventions: Serum antibodies againstvt-1andvt-2were determined by quantitative neutralization.Main Results: Antibodies were detected in 40% (21 of 53) of serum samples forvt-1and in 100% (53 of 53) of samples forvt-2. A positive immune response, defined as a fourfold increase invtantibody titres or as a single titre of 1/64 or greater, was found in 0% (0 of 12) of patients withhuscompared with 7% (three of 41) of those withhcforvt-1(P=0.4); and in 17% (two of 12) of patients withhuscompared with 22% (nine of 41) of those withhcforvt-2(P=0.3). The rate of seroconversion against eithervt-1orvt-2was comparable in treated and untreated patients with uncomplicatedhc.Conclusions: There was no evidence that neutralizing antibody levels againstvt-1orvt-2in classichusor after antibiotic therapy are substantially different from those in patients with uncomplicatedhc.