Electrostatic Complementarities of Glioblastoma-Resident T-Cell Receptors and Cancer Testis Antigens Linked to Poor Outcomes and High Levels of Sphingosine Kinase-2 Expression.

INTRODUCTION: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Despite a growing understanding of glioblastoma pathology, the prognosis remains poor. METHODS: In this study, we used a previously extensively benchmarked algorithm to retrieve immune receptor (IR) recombination reads from GBM exome files available from the cancer genome atlas. The T-cell receptor complementarity determining region-3 (CDR3) amino acid sequences that represent the IR recombination reads were assessed and used for the generation of chemical complementarity scores (CSs) that represent potential binding interactions with cancer testis antigens (CTAs), which is an approach particularly suited to a big data setting. RESULTS: The electrostatic CSs representing the TRA and TRB CDR3s and the CTAs, SPAG9, GAGE12E, and GAGE12F, indicated that an increased electrostatic CS was associated with worse disease-free survival (DFS). We also assessed the RNA expression of immune marker genes, which indicated that a high-level expression of SPHK2 and CIITA genes also correlated with high CSs and worse DFS. Furthermore, apoptosis-related gene expression was revealed to be lower when the TCR CDR3-CTA electrostatic CSs were high. CONCLUSION: Adaptive IR recombination reads from exome files have the potential to aid in GBM prognoses and may provide opportunities to detect unproductive immune responses.

Lobar intracerebral hemorrhage and risk of subsequent uncontrolled blood pressure.

Background: Uncontrolled blood pressure (BP) in intracerebral hemorrhage (ICH) survivors is common and associated with adverse clinical outcomes. We investigated whether characteristics of the ICH itself were associated with uncontrolled BP at follow-up. Methods: Subjects were consecutive patients aged ⩾18 years with primary ICH enrolled in the prospective longitudinal ICH study at Massachusetts General Hospital between 1994 and 2015. We assessed the prevalence of uncontrolled BP (mean BP ⩾140/90 mmHg) 6 months after index event. We used multivariable logistic regression models to assess the effect of hematoma location, volume, and event year on uncontrolled BP. Results: Among 1492 survivors, ICH was lobar in 624 (42%), deep in 749 (50%), cerebellar in 119 (8%). Lobar ICH location was associated with increased risk for uncontrolled BP after 6 months (OR 1.35; 95% CI [1.08-1.69]). On average, lobar ICH survivors were treated with fewer antihypertensive drugs compared to the rest of the cohort: 2.1 ± 1.1 vs 2.5 ± 1.2 (p < 0.001) at baseline and 1.8 ± 1.2 vs. 2.4 ± 1.2 (p < 0.001) after 6 months follow-up. After adjustment for the number of antihypertensive drugs prescribed, the association of lobar ICH location with risk of uncontrolled BP was eliminated. Conclusions: ICH survivors with lobar hemorrhage were more likely to have uncontrolled BP after 6 months follow-up. This appears to be a result of being prescribed fewer antihypertensive medications. Future treatment strategies should focus on aggressive BP control after ICH independent of hemorrhage location.

Shared genetic background between SARS-CoV-2 infection and large artery stroke.

BACKGROUND AND AIMS: Increased risk of stroke, particularly large artery stroke (LAS), has been observed in patients with COVID-19. The biological processes underlying the observed higher risk are still unknown. We explored the association between stroke subtypes and COVID-19 susceptibility to understand whether biological mechanisms specific to SARS-CoV-2 uptake/infection could be leading to excess stroke risk in this population. PATIENTS AND METHODS: We constructed a polygenic risk score (PRS) of COVID-19 susceptibility and tested its association with stroke subtypes using individual- and summary-level genetic data (SiGN, MEGASTROKE). We generated co-expression networks of genes involved in SARS-CoV-2 uptake/infection (ACE2, TMPRSS2, BEST3, ISLR2 and ADAM17) based on existing tissue expression libraries. Gene-based association testing was performed using S-PrediXcan and VEGAS2. Permutation independence tests were performed to assess SARS-CoV-2-related gene enrichment in stroke and its subtypes. RESULTS: Our PRS demonstrated an association between COVID-19 susceptibility and LAS in SiGN (OR = 1.05 per SD increase, 95% CI: (1.00, 1.10), p = 0.04) and MEGASTROKE (ß = 0.510, 95% CI: (0.242, 0.779), FDR-p = 0.0019). The SARS-CoV-2 risk-related ISLR2 co-expression gene network was significantly associated with genetic risk of LAS in aorta, tibial arteries, and multiple brain regions (P < 0.05). CONCLUSION: Presence of genetic correlation and significant pathway enrichment suggest that increases in LAS risk reported in COVID-19 patients may be intrinsic to the viral infection, rather than a more generalized response to severe illness.

Mendelian Randomization Study of Obesity and Cerebrovascular Disease.

OBJECTIVE: To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. METHODS: We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. RESULTS: Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (ß = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose. INTERPRETATION: Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524.