The cyclooxygenase (COX) signaling pathway is frequently dysregulated in cancer, resulting in the aberrant production of prostaglandins, a distinct class of bioactive lipids with immunoregulatory functions. One of these factors, prostaglandin E2 (PGE2), has over the years emerged as a predominant COX-derived factor in tumors, with numerous studies exploring its downstream signaling and functional impact across diverse cell types. Recent studies have substantially advanced our understanding of how PGE2 promotes cancer immune evasion through its deleterious effects on tumor-infiltrating immune cells. Here, we summarize some key principles of PGE2-mediated immune regulation in tumors, focusing on the current knowledge of PGE2 production mechanisms and recent advances in our understanding of molecular features and functional consequences of PGE2 signaling in innate and adaptive immune cells. We further discuss how strategies aimed at disrupting the local activity of prostaglandins in tumors, or interfering with the distinct molecular features characteristic of PGE2 signaling in immune cells, may provide attractive new avenues for cancer therapy.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative treatment for hematological malignancies, yet its potential to drive lymphomagenesis poses significant clinical concerns. In this study, we investigated the mechanisms underlying CAR T-cell-associated lymphomagenesis in the gastrointestinal (GI) tract on a single case, focusing specifically on the role of integrin α4β7 expression and a predisposing somatic SH2B3 mutation. We observed oligoclonal CAR T cells homing to, and clonally expanding in, the GI tract, with the dominant expanded clone harboring both a pathogenic SH2B3 mutation and a CAR transgene integration within a TFCP2 locus. The clonal CAR T cells subsequently transitioned beyond the GI tract into the peripheral blood, suggesting a potential pathway for systemic dissemination. We found clinical, histological, and molecular evidence demonstrating the efficacy of cyclosporine in reducing the expanded malignant clone and achieving durable clinical remission for more than a year. Our findings highlight the complex interplay between CAR T-cell therapy, preexisting genetic vulnerabilities, and the GI microenvironment, emphasizing the need for vigilant monitoring and tailored therapeutic strategies to address the risks associated with CAR T-cell lymphomagenesis.

We show that somatic genetic rescue is frequent in telomere biology disorders (TBDs) caused by germ line ZCCHC8 variants. Our results highlight the critical intrinsic role of ZCCHC8 in human hematopoiesis and a potential mechanism for disease modification in TBDs.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. Primary HLH typically presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, whereas secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. However, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult-onset secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis, and management of this life-threatening condition. Primary HLH is reviewed separately as a companion article in this review series.

Critically ill children have a high risk of hospital associated venous thromboembolism (HA-VTE). Developing a validated risk assessment model (RAM) to identify children who may benefit from thromboprophylaxis is essential. We aimed to prospectively validate the Children's Healthcare Advancements in Thrombosis (CHAT) intensive care unit (ICU) VTE RAM containing five clinically significant variables: CVC, immobility, congenital heart disease, autoimmune or inflammatory conditions and hospital stay of ≥3 days in a multicenter cohort study. Randomly selected patients aged 0-21 years admitted to a pediatric ICU (PICU) at 32 institutions were monitored via medical record review for HA-VTE. Discrimination was assessed using the area under the receiver operating characteristic (AUROC) curve. Calibration was assessed using calibration plots. Complete case and imputed analyses were performed and model risk scores were generated along with post-test probability. The RAM was validated in 4,674 patients with an AUROC of 0.71 [95% CI:0.64-0.78], calibration slope of 1.0 (95% CI:0.87-1.14) and intercept of 1.81x10-5 (95% CI: -5.40x10-3-5.44x10- 3). The AUROC for the imputed model was 0.69 (95% CI:0.68-0.70) with the calibration slope of 1.03 (95% CI: 0.85-1.21) and intercept of 1.22x10-3 (95% CI: -7.80x10-3-5.36x10-3). Calculated risk scores were 1 or 2 for each variable in the RAM with a total risk score ranging from 0 to 6. The estimated probability for developing HA-VTE ranged from 1% to 17.4% depending on the total score. In conclusion, the CHAT-ICU RAM has good discriminatory validity, is well-calibrated and reliably identifies children in the PICU at high and low risk of HA-VTE.

Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders characterized by joint hypermobility, skin hyperelasticity, perivascular tissue fragility, easy bruising, and increased bleeding risk. Abnormal bleeding in EDS ranges from mild ecchymoses to life-threatening hemorrhage. Platelet function abnormalities have been reported in people with EDS, but the broad nature and extent of these defects remain poorly defined. Herein, we evaluated blood samples from people with the hypermobile, classical, classical-like, and vascular types of EDS, and used a Col5a1+/- mouse model of classical EDS to characterize the extent of platelet dysfunction. Our findings suggest that platelet dysfunction in EDS is an outcome of reduced integrin αIIbβ3 activation resulting from decreased phosphorylation of talin-1, leading to defects in aggregation and spreading. The observed platelet dysfunction was associated with reduced expression of the platelet surface receptors glycoprotein VI (GPVI) and proteinase-activated receptor 1 (PAR1) and impaired downstream signaling. Col5a1+/- mice demonstrated increased tail bleeding time, reproduced the signaling defects observed in platelets from people with EDS, and exhibited decreased susceptibility to FeCl3-induced carotid artery thrombosis. Collectively, our data indicate that platelet dysfunction in EDS is likely contributing to hemorrhagic complications.

Recent analyses have suggested a possible negative impact of prior autologous stem cell transplantation on outcomes with idecabtagene vicleucel (ide-cel) chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma. Our registry-based analysis of >800 ide-cel recipients did not identify any such association.

Sickle cell disease (SCD) and β-thalassemia, caused by mutations or deletions in the β-globin gene, are among the most prevalent genetic disorders worldwide, significantly affecting global health and mortality. Recently, reactivation of δ-globin gene expression has been proposed as a potential therapeutic strategy for these conditions. In this study, we found that interferon gamma (IFN-γ) and IFN-β significantly enhance δ-globin expression and activate the JAK/STAT signaling pathway in erythroid cells, with IFN-γ exerting a stronger effect than IFN-β. In erythroid cells derived from CD34+ progenitors, IFN-γ not only increased δ-globin expression but also promoted differentiation, as confirmed by quantitative polymerase chain reaction, western blotting, high-performance liquid chromatography, and flow cytometry. Inhibition of the JAK/STAT pathway, either through a JAK1/2 inhibitor (AZD1840 or ruxolitinib) or via small interfering RNAs targeting JAK1, JAK2, STAT1, or STAT3, significantly decreased both basal and IFN-γ-induced δ-globin expression in HBD-HiBiT knockin HUDEP2 cells. Mutation or removal of the putative IRF-1/STAT2 binding site (-265 to -242) and the adjacent STAT binding site (-243 to -231) in the δ-globin promoter impaired IFN-γ-induced δ-promoter activity. Chromatin immunoprecipitation assays confirmed enhanced binding of interferon regulatory factor 1 (IRF-1) and STAT1 upon IFN-γ treatment. Our elucidation of the mechanism by which a specific molecule induces δ-globin expression suggests that IFN-γ may hold therapeutic potential for patients with SCD, and that screening for compounds that can induce δ-globin could offer a novel pharmaceutical strategy for treating β-hemoglobinopathies.