Optimized monitoring for immune checkpoint inhibitor induced myocarditis using high-sensitivity troponin-T.

Background: Immune checkpoint inhibitor (ICI)-induced Myocarditis (irMyocarditis) is a rare adverse event with a high mortality rate of 40-50 % and which is mostly not diagnosed until clinical symptoms emerge.

Objectives: This study aims to screen patients for irMyocarditis using high-sensitivity cardiac troponin-T (hs-TnT) before and regularly during therapy with ICI.

Methods: A cohort of 280 cancer patients were prospectively screened for levels of hs-TnT at baseline and prior to every ICI infusion.

Procoagulant platelet activation promotes venous thrombosis.

Platelets are key players in cardiovascular disease, and platelet aggregation represents a central pharmacologic target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating the inhibition of the plasmatic coagulation cascade in this disease entity. Anticoagulation carries a significantly higher risk of bleeding complications, highlighting the need of alternative therapeutic approaches.

Application of Unsupervised Multi-Omic Factor Analysis to Uncover Patterns of Variation and Molecular Processes Linked to Cardiovascular Disease.

Disease mechanisms are usually complex and governed by the interaction of several distinct molecular processes. Complex, multidimensional datasets are a valuable resource to generate more insights into those processes, but the analysis of such datasets can be challenging due to the high dimensionality resulting, for example, from different disease conditions, timepoints, and omics capturing the process at different resolutions. Here, we showcase an approach to analyze and explore such a complex multiomics dataset in an unsupervised way by applying multi-omics factor analysis (MOFA) to a dataset generated from blood samples that capture the immune response in acute and chronic coronary syndromes.

Myeloid cells take ischemic insult to heart.

Morbidity and mortality associated with stroke cannot be attributed solely to the acute ischemic event, but are also rooted in long-term complications, including heart disease. Simats, Zhang, and colleagues now demonstrate that interleukin (IL)-1ß-mediated innate immune memory after brain ischemic stroke leads to proinflammatory changes in the heart causing myocardial fibrosis.

Antibodies and complement are key drivers of thrombosis.

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown.

Multiomic analyses uncover immunological signatures in acute and chronic coronary syndromes.

Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered a key pathogenic driver of these diseases, but the underlying immune states and their clinical implications remain poorly understood. Multiomic factor analysis (MOFA) allows unsupervised data exploration across multiple data types, identifying major axes of variation and associating these with underlying molecular processes.

Procoagulant platelets promote immune evasion in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive tumor entity in which immune checkpoint (IC) molecules are primarily synthesized in the tumor environment. Here, we report that procoagulant platelets bear large amounts of such immunomodulatory factors and that the presence of these cellular blood components in TNBC relates to protumorigenic immune-cell activity and impaired survival. Mechanistically, tumor-released nucleic acids attract platelets to the aberrant tumor microvasculature, where they undergo procoagulant activation, thus delivering specific stimulatory and inhibitory IC molecules.

Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment.

Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile human and murine neutrophil transcriptomes and proteomes during steady state and bacterial infection.

Hemostasis without clot formation: how platelets guard the vasculature in inflammation, infection, and malignancy.

Platelets are key vascular effectors in hemostasis, with activation signals leading to fast recruitment, aggregation, and clot formation. The canonical process of hemostasis is well-characterized and shares many similarities with pathological thrombus formation. However, platelets are also crucially involved in the maintenance of vascular integrity under both steady-state and inflammatory conditions by ensuring blood vessel homeostasis and preventing microbleeds.

Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation.

Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages.

Nucleocapsid-specific T cell responses associate with control of SARS-CoV-2 in the upper airways before seroconversion.

Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. Here, we perform a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We find that soluble and transcriptional markers of systemic inflammation peak during the first week after symptom onset and correlate directly with upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4 and CD8 T cells correlate inversely with various inflammatory markers and UA-VLs.

Thromboinflammation in long COVID-the elusive key to postinfection sequelae?

Long COVID is a public health emergency affecting millions of people worldwide, characterized by heterogeneous symptoms across multiple organ systems. Here, we discuss the current evidence linking thromboinflammation to postacute sequelae of COVID-19. Studies have found persistence of vascular damage with increased circulating markers of endothelial dysfunction, coagulation abnormalities with heightened thrombin generation capacity, and abnormalities in platelet counts in postacute sequelae of COVID-19.

Immobility-associated thromboprotection is conserved across mammalian species from bear to human.

Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE.

Mechanosensing via a GpIIb/Src/14-3-3ζ axis critically regulates platelet migration in vascular inflammation.

Platelets are not only the first responders in thrombosis and hemostasis but also central players in inflammation. Compared with platelets recruited to thrombi, immune-responsive platelets use distinct effector functions including actin-related protein complex 2/3-dependent migration along adhesive substrate gradients (haptotaxis), which prevents inflammatory bleeding and contributes to host defense. How platelet migration in this context is regulated on a cellular level is incompletely understood.

Novel insights into mouse models of ectopic proplatelet release.

Mature bone marrow (BM) megakaryocytes (MKs) produce platelets by extending proplatelets into sinusoidal blood vessels. Defects in this process can lead to thrombocytopenia and increased risk of bleeding. Mice lacking the actin-regulatory proteins Profilin 1 (PFN1), Wiskott-Aldrich Syndrome protein (WASp), Actin Related Protein 2/3 complex (Arp2/3), or adhesion and degranulation-promoting adapter protein (ADAP) display thrombocytopenia and ectopic release of (pro)platelet-like particles into the BM compartment, pointing to an important axis of actin-mediated directional proplatelet formation.

Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently, a novel complication of SARS-CoV-2-targeted adenovirus vaccines has emerged: immune thrombocytopenia, either isolated, or accompanied by thrombosis (then termed VITT). This complication is characterized by low platelet counts, and in the case of VITT, also by platelet-activating platelet factor 4 antibodies reminiscent of heparin-induced thrombocytopenia, leading to a prothrombotic state with clot formation at unusual anatomic sites.

Procoagulant platelet sentinels prevent inflammatory bleeding through GPIIBIIIA and GPVI.

Impairment of vascular integrity is a hallmark of inflammatory diseases. We recently reported that single immune-responsive platelets migrate and reposition themselves to sites of vascular injury to prevent bleeding. However, it remains unclear how single platelets preserve vascular integrity once encountering endothelial breaches.

Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection.

The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment.

Neutrophil-Platelet Interactions as Novel Treatment Targets in Cardiovascular Disease.

Neutrophils and platelets are among the most abundant cell types in peripheral blood and characterized by high plasticity and a readily available reservoir of surface proteins and secretable granule contents. Receptor-mediated activation and granule release predispose both cell types for rapid responses to various stimuli. While neutrophils provide the first line of defense to microbial infections and platelets are known for their aggregatory functions in hemostasis and thrombosis, research of the past decade has highlighted that both cell types jointly shape local and systemic immune responses and clot formation alike.

Single platelet and megakaryocyte morpho-dynamics uncovered by multicolor reporter mouse strains and .

Visualizing cell behavior and effector function on a single cell level has been crucial for understanding key aspects of mammalian biology. Due to their small size, large number and rapid recruitment into thrombi, there is a lack of data on fate and behavior of individual platelets in thrombosis and hemostasis. Here we report the use of platelet lineage restricted multi-color reporter mouse strains to delineate platelet function on a single cell level.