• Soluble GPVI is elevated in patients with thermal injury with sepsis, and sGPVI levels augment severity score prediction of mortality.• The GPVI ligand, fibrin, induces GPVI shedding without requirement for platelet activation or signaling Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU)for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28-and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 59-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

BackgroundAPOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system.MethodsIn this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT.ResultsThe minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values < 0.05). Analysis of breast cancers from METABRIC revealed breast cancers from APOBEC3B deletion carriers to have significantly higher abundance of tumour-infiltrating immune cells (P < 0.001).ConclusionsTaken together, our data suggests that tumour-infiltrating immune cells may be an important feature of breast cancers arising in women with APOBEC3B germline deletion, and that this may be of particular interest in Asian women where the germline deletion is more common.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0717-1) contains supplementary material, which is available to authorized users.

Vaccine-induced (immune) thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which are aimed to prevent and minimize coronavirus disease 2019 and related pathophysiology. 1,2 Alternatively called thrombocytopenia with thrombosis syndrome (TTS) by government reporting agencies, such as the Therapeutic Goods Administration (TGA) in Australia, VITT affects 1 in 50 000 to 100 000 individuals vaccinated with adenovirus-based vaccines. 1 VITT mimics heparin-induced thrombocytopenia with thrombosis (HIT or HITT), and reflects generation of platelet activating antibodies directed to complexed platelet factor 4 (PF4). [1][2][3][4] In HIT, the antibodies are directed against PF4 complexed to heparin, whereas different PF4 complexes form in VITT. [1][2][3][4][5] Early case series of VITT formed the basis upon which other laboratories began to investigate this immune-mediated disorder. [6][7][8] Although many diagnostic guidelines have been published, 9,10 VITT is clinically suspected when a patient develops thrombosis with associated suggestive laboratory findings, following recent exposure to an adenovirus vaccine. Two of the well-established early laboratory signs of potential VITT are thrombocytopenia (or a sharp drop in platelet count; similar to HIT), and highly elevated D-dimer. 3,[9][10][11] However, as VITT is mostly identified in the community (versus HIT being identified in the hospital setting), a sharp