Humoral and cellular immune responses in fully vaccinated individuals with or without SARS-CoV-2 breakthrough infection: Results from the CoV-ADAPT cohort.

Despite recent advances in prophylactic vaccination, SARS-CoV-2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS-CoV-2 breakthrough infection is urgently needed. CoV-ADAPT is a prospective long-term study comparing humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon-γ [IFN-γ] release) immune responses in individuals vaccinated against SARS-CoV-2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS-CoV-2 breakthrough infections vs 151 without infection 3-7 months following third vaccination. Breakthrough infections significantly increased anti-spike-RBD-IgG (p < 0.01), but not spike-directed T-cell IFN-γ release (TC) or antibody avidity. Despite comparable surrogate neutralization indices, the functional neutralization capacity against SARS-CoV-2-assessed via a tissue culture-based assay-was significantly higher following breakthrough vs no breakthrough infection. Anti-spike-RBD-IgG and antibody avidity decreased with age (p < 0.01) and females showed higher anti-spike-RBD-IgG (p < 0.01), and a tendency towards higher antibody avidity (p = 0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p = 0.807). Finally, a machine-learning approach based on our large immunological dataset (a total of 49 variables) from different time points was unable to predict breakthrough infections (area under the curve: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g., virus exposure) in individualized risk assessment.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

Predicting 1-, 3- and 5-year outcomes in patients with coronary artery disease: A comparison of available risk assessment scores.

BACKGROUND AND AIMS: Thromboischemic and bleeding events are rare but life-threatening complications after percutaneous coronary intervention (PCI). Various risk assessment models have been established to predict short- and long-term adverse events in patients with chronic and acute coronary syndromes (CCS, ACS). The aim of the present study was to compare available risk assessment systems based on their performance in identifying high-risk patients with symptomatic coronary artery disease (CAD). METHODS: We enrolled 1565 consecutive patients with symptomatic CAD (n = 821 CCS, n = 744 ACS). CALIBER, DAPT, GRACE 2.0, PARIS-CTE, PARIS-MB, PRECISE-DAPT and PREDICT-STABLE scores were calculated in appropriate patient subgroups. All patients were followed-up for 1, 3 and 5 years for all-cause death (ACD), myocardial infarction (MI), ischemic stroke (IS) and bleeding. The primary combined ischemic endpoint (CE) consisted of ACD, MI and/or IS. Secondary endpoints were defined as single occurrence of either ACD, MI, IS, or bleeding. RESULTS: GRACE 2.0 score showed good discrimination performance (AUC>0.7) for CE in a 3- and 5-year follow-up. CALIBER, GRACE 2.0 and PARIS-CTE showed best performance (AUC>0.7) in predicting ACD throughout the follow-up, whereas IS was best predicted by PARIS-CTE and CALIBER scores. None of the scores performed well (AUC>0.7) in predicting MI or bleeding. CONCLUSIONS: In a consecutive German CAD cohort, CALIBER, GRACE 2.0 and PARIS-CTE scores performed best in predicting CE, ACD and/or IS whereas none of the selected scores could predict MI and bleeding efficiently.