Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The ...factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population
and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity
, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10
). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.
We aimed to determine whether presence of AD neuropathology predicted cognitive, gait and balance measures in patients with idiopathic normal pressure hydrocephalus (iNPH) after shunt surgery. This ...is a prospective study of gait and balance measured by Timed Up and Go (TUG) and Tinetti tests, and cognitive function measured by Mini Mental Status Exam (MMSE), before and after shunt surgery in participants 65 years and older with iNPH at the Johns Hopkins University. Random effects models were used and adjusted for confounders. 88 participants were included in the analysis with a median (IQR) time of 104 (57-213) days between surgery and follow-up. 23 (25%) participants had neuritic plaques present (NP+) and were significantly older 76.4 (6.0) years, but were otherwise similar in all demographics and outcome measures, when compared to the group without neuritic plaques (NP-). NP- and NP+ participants equally improved on measures of TUG (β = -3.27, 95% CI -6.24, -0.30, p = 0.03; β = -2.37, 95% CI -3.90, -0.86, p = 0.02, respectively), Tinetti-total (β = 1.95, 95% CI 1.11, 2.78, p<0.001; β = 1.72, 95% CI 0.90, 2.53, p<0.001, respectively), -balance (β = 0.81, 95% CI 0.23, 1.38, p = 0.006; β = 0.87, 95% CI 0.40, 1.34, p<0.001, respectively) and -gait (β = 1.03, 95% CI 0.61, 1.45, p<0.001; β = 0.84, 95% CI 0.16, 1.53, p = 0.02, respectively), while neither NP- nor NP+ showed significant improvement on MMSE (β = 0.10, 95% CI -0.27, 0.46, p = 0.61, β = 0.41, 95% CI -0.27, 1.09, p = 0.24, respectively). In summary, 26% of participants with iNPH had coexisting AD pathology, which does not significantly influence the clinical response to shunt surgery.
Interferon signaling mediates resistance to immune checkpoint blockade therapy, but the underlying mechanisms are poorly understood. In this issue of Immunity, Cucolo et al. identify RIPK1 as an ...interferon-stimulated gene with potent effects on cell extrinsic and intrinsic immunotherapy resistance.
To describe the association between active, environmental tobacco smoke (ETS) exposure and the prevalence of eustachian tube dysfunction (ETD) in the U.S. pediatric population.
Cross-sectional.
U.S. ...representative demographic and audiometric data from the National Health and Nutrition Examination Survey (NHANES);2005-2010.
The study consisted of 2,977 children aged 12-19 years. ETD was defined as middle ear pressure <100mm H20. ETS was defined as non-active smoking in individuals with serum cotinine over the limit of detection (≥0.015 ng/mL) and <10 ng/mL(N = 1559).
The prevalence of ETD was 6.1%. After multivariate adjustment for age, sex, body mass index, education level, ethnicity, or having a cold, sinus problem or earache during the last 24 hours, compared to unexposed children, the odds ratios (95% confidence interval) of ETD for those exposed to ETS ages 12-15 in the first, second and third tertile of cotinine concentrations were, respectively, 1.38 (0.53-3.60), 0.99 (0.53-3.60) and 2.67 (1.12-6.34). Similarly, the odds ratios (95% confidence interval) of ETD for those exposed to ETS ages 16-19 in the first, second and third tertile of cotinine concentrations were, respectively, 1.28 (0.48-3.41), 0.99 (0.40-2.48) and 2.86 (1.19-6.88).
These data suggest that children and adolescents exposed to high concentrations of ETS may have an increased prevalence of ETD.
The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel ...therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.
Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies ...demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation.
Substrate-mediated fusion of small polymersomes, derived from mixtures of lipids and amphiphilic block copolymers, produces hybrid, supported planar bilayers at hydrophilic surfaces, monolayers at ...hydrophobic surfaces, and binary monolayer/bilayer patterns at amphiphilic surfaces, directly responding to local measures of (and variations in) surface free energy. Despite the large thickness mismatch in their hydrophobic cores, the hybrid membranes do not exhibit microscopic phase separation, reflecting irreversible adsorption and limited lateral reorganization of the polymer component. With increasing fluid-phase lipid fraction, these hybrid, supported membranes undergo a fluidity transition, producing a fully percolating fluid lipid phase beyond a critical area fraction, which matches the percolation threshold for the immobile point obstacles. This then suggests that polymer-lipid hybrid membranes might be useful models for studying obstructed diffusion, such as occurs in lipid membranes containing proteins.
•Post-RT PSA ≥0.09 ng/mL after prostate radiotherapy and ADT correlated with worse prognosis.•Post- RT PSA reduction of >95% correlated with reduced biochemical recurrence and distant failure.•These ...findings may identify patients who require early aggressive systemic therapy.
To identify early biochemical predictors of survival in intermediate- and high-risk prostate cancer patients with a pre-treatment PSA <20 ng/mL following definitive radiation therapy (RT) and androgen deprivation therapy (ADT).
A single-institution review of 2566 intermediate and high-risk prostate cancer patients treated with definitive RT and neoadjuvant and concurrent ADT from 1990 to 2012 was performed. The first prostate-specific antigen (PSA) value within three months of ADT initiation (post-ADT PSA) and the first PSA within three months after RT completion (post-RT PSA) were recorded. 1275 had baseline PSA <20 ng/mL and either post-ADT or post-RT PSA available. Median follow-up was 7.6 years. The relationship between post-treatment PSA kinetics and biochemical relapse (BR), distant metastasis (DM), prostate cancer specific death (PCSD) and overall survival (OS) was modeled using Cox regression univariate and multivariate analysis (MVA).
MVA demonstrated a strong association between a post-RT PSA ≥0.09 ng/mL and a significantly higher risk of BR (HR: 1.93; 95% CI: 1.45–2.57; p < 0.001), DM (HR: 2.97; 95% CI: 2.01–4.39; p < 0.001), PCSD (HR: 2.99; 95% CI: 1.73–5.15; p < 0.001) and OS (HR: 1.49; 95% CI: 1.18–1.86; p < 0.001). Post-RT PSA reduction of ≥95% relative to the baseline PSA was associated with a significantly lower risk of BR (MVA HR: 0.58; 95% CI: 0.41–0.83; p = 0.003) and DM (MVA HR: 0.47; 95% CI: 0.30–0.76; p = 0.002).
A PSA value ≥0.09 ng/mL early after RT completion is associated with significantly worse prognosis across all clinical outcomes, and an early PSA reduction of ≥95% is associated with reduced risk of BR and DM. These findings may identify patients who require early aggressive systemic management for high-risk disease.
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