Search

Background: The major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI., Methods: Serum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45)., Results: In the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: p PFS  = 0.012, p OS  = 0.001; Hamburg ICI: p PFS  = 0.040, p OS  = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules ("multi-CD27" score) enhanced the predictive ability (HR PFS : 17.21 with p < 0.001, HR OS : 6.47 with p = 0.011)., Conclusion: Soluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy., (© 2024. The Author(s).)

Patients with cancer are at increased risk of venous thromboembolism (VTE). Treatment of VTE remains challenging due to a significant risk of both VTE recurrence and bleeding compared with patients without underlying malignancy. Moreover, patients with cancer often present with several comorbidities such as tumor- or treatment-induced bone marrow failure, renal impairment, and extensive concomitant anticancer or supportive medication, resulting in potential drug-drug interactions. Further challenging circumstances include gastrointestinal (GI) disorders, in the context of a GI intraluminal tumor itself, GI surgery, or systemic therapy-induced GI toxicity. However, treatment options and study data in the management of cancer-associated thrombosis (CAT) have expanded over the last few years. As a result, it is becoming increasingly important to assess the patient's individual risk of bleeding and its comorbidities, and the patient's personal preferences. Prospectively, further therapeutic strategies such as factor XIa inhibitors are under clinical investigation. The aim of our narrative review is to summarize the current literature on therapy options for CAT, including common treatment situations encountered in the management of patients with cancer., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

During metastasis, cancer cells traverse the vasculature by squeezing through very small gaps in the endothelium. Thus, nuclei in metastatic cancer cells must become more malleable to move through these gaps. Our lab showed invasive breast cancer cells have 50% less emerin protein resulting in smaller, misshapen nuclei, and higher metastasis rates than non-cancerous controls. Thus, emerin deficiency was predicted to cause increased nuclear compliance, cell migration, and metastasis. We tested this hypothesis by downregulating emerin in noninvasive MCF7 cells and found emerin knockdown causes smaller, dysmorphic nuclei, resulting in increased impeded cell migration. Emerin reduction in invasive breast cancer cells showed similar results. Supporting the clinical relevance of emerin reduction in cancer progression, our analysis of 192 breast cancer patient samples showed emerin expression inversely correlates with cancer invasiveness. We conclude emerin loss is an important driver of invasive transformation and has utility as a biomarker for tumor progression., (© 2024. The Author(s).)

This article explores the multifaceted approach of food allergy (FA) advocacy, research, and education to address the diverse challenges associated with FA, such as disparities in socioeconomic status, food security, quality of life, and the overall burden of the disease. Advocacy initiatives are instrumental in driving policy changes, raising public awareness, and directing substantial research funding, with a focus on reducing disparities. They have influenced allergen labeling regulations and improved access to epinephrine, emphasizing the importance of school-based management plans, especially in underserved communities. Research in FA informs medical practices and offers them hope for improved treatments. Recent breakthroughs in peanut allergy prevention and oral immunotherapy trials exemplify the potential for advancements while highlighting the need to address disparities in health care access. Education is a critical tool for prevention, raising awareness, and reducing the risk of allergic reactions. Efforts should be tailored to reach marginalized communities, particularly in schools where education on FA management is essential. Collaborating directly with communities is imperative to ensure inclusivity and address disparities. Barriers such as mistrust, language and cultural differences, and lack of diversity among researchers must be overcome to encourage diverse participation in research studies. This article concludes by emphasizing the significance of a comprehensive approach to FA research that prioritizes equity and inclusivity. The call to action highlights the need for global initiatives to reshape the landscape of FA care and address disparities in health care access and outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Platelets are mediators of inflammation with immune effector cell properties and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet-associated lectin, galactoside-binding, soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE and as a potential biomarker associated with clinical phenotypes., Methods: We performed RNA sequencing on platelets from patients with SLE (n = 54) and on platelets from age-, sex-, and race/ethnicity-matched healthy controls (n = 18) and measured LGALS3BP levels in platelet releasate and in circulating serum. We investigated the association between LGALS3BP levels and the prevalence, disease severity, and clinical phenotypes of SLE and studied platelet-mediated effects on myeloid inflammation., Results: Platelets from patients with SLE exhibited increased expression of LGALS3BP (fold change 4.0, adjusted P = 6.02 × 10 -11 ). Platelet-released LGALS3BP levels were highly correlated with circulating LGALS3BP (R = 0.69, P < 0.0001), and circulating LGALS3BP levels were correlated with the severity of disease according to the SLE Disease Activity Index (r = 0.32, P = 0.0006). Specifically, circulating LGALS3BP levels were higher in SLE patients with lupus nephritis than in patients with inactive disease (4.0 μg/ml versus 2.3 μg/ml; P < 0.001). Interferon-α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG-01) in a dose-dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced proinflammatory cytokine production by macrophages., Conclusions: Our results support that platelets act as potent effector cells that contribute to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity., (© 2022 American College of Rheumatology.)

Introduction: Protein disulfide isomerase (PDI) contributes to tissue factor (TF) regulation in monocytes. While bacitracin and quercetin-3-rutinoside mitigate myeloid TF production, the effect of PACMA-31, a more specific PDI inhibitor with distinct pharmacologic properties, remains unclear., Materials and Methods: Lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells (PBMCs) or citrate-anticoagulated whole blood was carried out in the presence of PACMA-31 or DMSO vehicle before monocytes were analyzed for TF expression, including antigen, procoagulant activity (PCA) and mRNA, release of IL-6 and TNFα, and LPS-induced signaling pathways., Results: While PACMA-31 alone had no effect, coincubation with LPS and PACMA-31 (25 μM) enhanced LPS-induced monocyte TF production in whole blood. The effect was at least partially regulated on the transcriptional level and could not be explained by increased phosphatidylserine membrane exposure. In contrast, the same PACMA-31 concentrations were cytotoxic in isolated PBMCs. A lower dose of PACMA-31, however, restored the stimulating effect by enhancing IκB-NFκB signaling that also increased the release of IL-6 and TNFα. The protease-activated receptor 2 (PAR2) inhibitor ENMD 547 but not TF antibody 10H10 or factor Xa inhibitor rivaroxaban prevented the stimulatory effect of PACMA-31 on inflammatory monocytes. In sharp contrast, short time incubation of LPS-stimulated PBMCs with 25 μM PACMA-31 was non-cytotoxic and significantly inhibited cellular TF PCA but not surface antigen expression., Conclusions: PACMA-31 regulates monocyte TF in a concentration-dependent manner by opposing transcriptional and posttranscriptional mechanisms. While low concentrations of PACMA-31 augment monocyte TF production by amplifying LPS-dependent PAR2 signaling, high concentrations convert monocyte TF into its non-coagulant state., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), particularly those carrying the JAK2 V617F mutation, are at increased risk of thrombosis. While an association of MPNs with autoimmune disorders has been established, the prevalence of inherited or acquired thrombophilias in JAK2 V617F -positive patients remains obscure. We therefore investigated the coincidence of the JAK2 V617F mutation with additional thrombogenic risk factors., Methods: In a retrospective study, we analyzed all patients referred for thrombophilia work-up between 01/2011 and 08/2019, in whom additional JAK2 V617F mutation analysis was performed because of thromboembolic events that were recurrent, atypically located and/or associated with abnormal blood counts., Results: Of 472 tested patients, 49 (10.4%) were JAK2 V617F -positive. While the frequency of inherited thrombophilias (factor V Leiden and prothrombin G20210A mutation, deficiency of antithrombin, protein C, protein S) was not different between the two groups, the prevalence of definite antiphospholipid syndrome (APS), mostly associated with a moderate- or high-risk antibody profile, was significantly higher in patients with (22.4%) than in those without (8.4%) JAK2 V617F mutation (p < 0.01). All evaluable JAK2 V617F -positive patients with APS were subsequently diagnosed with MPN. In patients with JAK2 V617F mutation, presence of concomitant APS was associated with a significantly younger age (49 ± 14 vs. 60 ± 15 years) at the time of thrombophilia work-up (p < 0.05)., Conclusion: We found a significant association between JAK2 V617F -positive MPN and definite APS. The presence of concomitant APS in patients carrying the JAK2 V617F mutation may lead to earlier manifestation of thromboembolic events and may warrant more aggressive antithrombotic treatment strategies to prevent recurrence., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Inflammation with leukocyte activation is a hallmark of cancer-associated thrombosis (CAT), and elevated leukocytes predict venous thromboembolism in cancer outpatients. In a recent trial, rivaroxaban was more efficacious than dalteparin in preventing CAT recurrence., Objectives: In a proof-of-concept study, we aimed to provide a mechanistic basis for improved efficacy of rivaroxaban compared to low molecular weight heparin in CAT treatment., Methods: We studied the effects of rivaroxaban, dalteparin, and tinzaparin at peak and trough levels on tumor cell-induced procoagulant activity and platelet aggregation in the presence or absence of the cationic leukocyte-derived enzyme, myeloperoxidase (MPO). Furthermore, pro-inflammatory conditions were generated by stimulating whole blood with lipopolysaccharide (LPS) or phorbol-myristate-acetate (PMA), before measuring thrombin generation in plasma supernatants., Results: All three anticoagulants inhibited thrombin generation, fibrin clot formation, and platelet aggregation induced by the tissue factor-expressing prostate carcinoma cell line, 22Rv1. Pre-incubation with MPO partially attenuated the anticoagulant activity of dalteparin and tinzaparin, but not rivaroxaban, at trough levels. The effect of MPO did not involve the enzyme's catalytic properties, but required its structural integrity, as indicated by heat denaturation. In plasma obtained from LPS- or PMA-stimulated whole blood, elevated MPO antigen levels inversely correlated with the ability of tinzaparin to inhibit 22Rv1-induced thrombin generation., Conclusions: Myeloperoxidase release may partially attenuate the anticoagulant activity of trough levels of dalteparin and tinzaparin in the context of paraneoplastic leukocyte activation. However, this effect is likely not sufficient to explain the improved efficacy of rivaroxaban, and possibly other oral factor Xa inhibitors, in CAT treatment., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

IL13 induces the same biological effects as IL4 in normal human B cells. We show that as in the IL4R complex, both IL4R alpha and IL2R gamma c are components of the IL13R and that both cytokines induced STAT6, STAT3 and STAT5 activation in B cells. In spite of this similar downstream signalling, IL4 and IL13 used a different set of Janus kinases: IL13 is unable to activate JAK1 and JAK3.

In human B cells, interleukin 4 (IL4) acts in regulating proliferation, antigen expression, isotype switching and differentiation. These different effects are mediated through the IL4R complex including the IL2R gamma chain (gamma c) and a specific p130/140 binding unit referred below as human Interleukin 4 Receptor (IL4-R). Here, we studied the signal transduction events following IL4R activation and leading to CD23 expression on resting B cells. We demonstrate that IL4R triggering induced the tyrosine phosphorylation of JAK3 and of a p170 protein. Coimmunoprecipitation of JAK3 with the IL4R suggests a physical association which exists prior to IL4R complex stimulation. Orthovanadate treatment, while having no effect on IL4-induced p130 phosphorylation, leads to the hyperphosphorylation of the p170 and inhibits IL4-induced CD23 expression. These suggest that two mandatory steps exist in early IL4 signaling: one controlled by JAK3 activation and the other by the p170 phosphoprotein.