ID1 and ID3 functions in the modulation of the tumour immune microenvironment in adult patients with B-cell acute lymphoblastic leukaemia.

Introduction: B-cell acute lymphoblastic leukemia (B-ALL) in adults often presents a poor prognosis. ID1 and ID3 genes have been identified as predictors of poor response in Colombian adult B-ALL patients, contributing to cancer development. In various cancer models, these genes have been associated with immune regulatory populations within the tumor immune microenvironment (TIME).

Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity.

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy.

The Roadmap to Integrate Diversity, Equity, and Inclusion in Hematology Clinical Trials: An American Society of Hematology Initiative.

Clinical trial design for classical hematologic diseases is difficult because samples sizes are often small and not representative of the disease population. ASH initiated a Roadmap project to identify barriers and make progress to integrate diversity, equity, and inclusion into trial design and conduct. Focus groups of international experts from across the clinical trial ecosystem were conducted.

Elevated frequencies of activated memory B cells in multiple sclerosis are reset to healthy control levels after B cell depletion with Ocrelizumab.

In multiple sclerosis (MS) the B cell depleting drug ocrelizumab has shown high efficacy in reducing inflammatory activity. Its mechanism of action is unclear due to B cell subset complexity and unknown roles in pathogenesis. Here, we comprehensively phenotyped and quantitated peripheral blood B cell subsets before and after ocrelizumab infusion to gain insight into the fate of B cell subsets with pathogenic potential.

High rates of MHC mismatches in HLA matched unrelated donor/recipient pairs and potential impact on hematopoietic cell transplant outcome.

Introduction: Donors for patients requiring hematopoietic cell transplant (HCT) are selected based on matching genetic sequences encoding the antigen recognition domain of specific HLA loci. However, differences in transplant outcomes in fully matched unrelated HCT compared with sibling HCT suggest that other genetic regions within the major histocompatibility complex (MHC) may contribute to HCT outcomes.

Methods: We sequenced the non-classical MHC loci (NCML) HLA-E, -F, -G, -H, MICA and MICB on a well-characterized retrospective cohort of 157 unrelated donor/recipient HCT pairs to determine the extent of MHC mismatching in matched pairs.

IQGAP1 promotes early B cell development, is essential for the development of marginal zone (MZ) B cells, and is critical for both T-dependent and T-independent antibody responses.

IQGAP1 is a multi-functional scaffold protein. However, its role in B cell development and function is unknown. Here, we show IQGAP1 as an essential scaffold that regulates early B cell development and function.

Prothrombotic Antibodies Targeting the Spike Protein's Receptor-Binding Domain in Severe COVID-19.

Thromboembolic complication is common in severe coronavirus disease (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients collected 3.6 days after COVID-19 diagnosis, 80% had IgG antibodies recognizing complexes of heparin and platelet factor 4 (PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG-treated normal platelets.

Alternative splicing modulates chromatin interactome and phase separation of the RIF1 C-terminal domain.

RIF1 (RAP1 interacting factor) fulfills diverse roles in DNA double-strand break repair, DNA replication, and nuclear organization. RIF1 is expressed as two splice variants, RIF1-Long (RIF1-L) and RIF1-Short (RIF1-S), from the alternative splicing (AS) of Exon 32 (Ex32) which encodes a 26 aa Ser/Lys-rich cassette peptide in the RIF1 C-terminal domain (CTD). Here we demonstrate that Ex32 inclusion was repressed by DNA damage and oncogenesis but peaked at G/M phase of the cell cycle.

Examining downstream effects of concizumab in hemophilia A with a mathematical modeling approach.

Background: Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits factor (F)Xa, the TF-FVIIa-FXa complex, and early forms of the prothrombinase complex. Concizumab is a monoclonal antibody that blocks FXa inhibition by TFPI and reduces bleeding in hemophilia.

Objectives: To examine how concizumab impacts various reactions of TFPI to restore thrombin generation in hemophilia A using mathematical models.

Antigen-specific immunotherapy for platelet alloimmune disorders.

Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT) is a significant hematologic disorder arising from maternal immune responses to fetal platelet alloantigens, predominantly Human Platelet Antigen (HPA)-1a. This review first describes the pathogenesis of FNAIT, highlighting the roles of HPA-specific antibodies, particularly HPA-1a, in causing severe thrombocytopenia and intracranial hemorrhage in affected neonates. Current management strategies, including intravenous immunoglobulin and investigational therapies like Nipocalimab, are evaluated for their efficacy and limitations.

Chromatin interaction maps of human arterioles reveal new mechanisms for the genetic regulation of blood pressure.

Arterioles are small blood vessels located just upstream of capillaries in nearly all tissues. The constriction and dilation of arterioles regulate tissue perfusion and are primary determinants of systemic blood pressure (BP). Abnormalities in arterioles are central to the development of major diseases such as hypertension, stroke, and microvascular complications of diabetes.

Duration of anticoagulation for venous thromboembolism in pediatric patients: Evaluation of the Duration of Therapy for Thrombosis in Children (Kids-DOTT) trial outcomes at 2 years.

Background: The Multicenter Evaluation of the Duration of Therapy for Thrombosis in Children multinational, randomized clinical trial revealed noninferiority of a 6-week vs 3-month duration of anticoagulation for the treatment of provoked venous thromboembolism (VTE) in patients <21 years old in regard to net clinical benefit at 1 year.

Objectives: To evaluate noninferiority at 2 years.

Methods: Patients whose repeat imaging 6 weeks after VTE diagnosis did not show complete veno-occlusion were randomized to discontinue anticoagulation vs receive a total 3-month course and followed for 2 years for the occurrence of symptomatic recurrent VTE (efficacy outcome) and clinically relevant bleeding (safety outcome).

A Pilot Study of the Role of Semaphorin 4A (sema4A) and 3C (sema3C) in Non-Muscle-Invasive Bladder Cancer (NMIBC).

Bladder cancer is a very important issue in contemporary urology. The aim of this pilot study was to assess for the first time the clinical utility of semaphorin 3C (sema3C) and 4A (sema4A) in patients with non-muscle-invasive bladder cancer (NMIBC). The experiment involved 15 patients with NMIBC and 5 patients without malignancies as the control group.

Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD.

Impaired secretion of an essential blood coagulation factor fibrinogen leads to hepatic fibrinogen storage disease (HFSD), characterized by the presence of fibrinogen-positive inclusion bodies and hypofibrinogenemia. However, the molecular mechanisms underlying the biogenesis of fibrinogen in the endoplasmic reticulum (ER) remain unexplored. Here we uncover a key role of SEL1L-HRD1 complex of ER-associated degradation (ERAD) in the formation of aberrant inclusion bodies, and the biogenesis of nascent fibrinogen protein complex in hepatocytes.

CXCL13/CXCR5 axis facilitates TFH expansion and correlates with disease severity in adults with immune thrombocytopenia.

Background: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder defined by a diminished platelet count. ITP pathogenesis involves intricate changes to both cellular and humoral immunity. The pivotal roles of follicular helper T (TFH) cells in the maturations of B cells and the production of antibodies are well-established.

The SWI/SNF subunit ARID1B is important for regenerative ability of hematopoietic stem cells in normal hematopoiesis.

The Switch/Sugar non-fermenting (SWI/SNF) nucleosome remodeling complexes are essential for normal hematopoiesis. The Brg1/Brm associated factor (BAF) is a form of mammalian SWI/SNF that is distinguished by the presence of either ARID1A or ARID1B protein. In this study, we used hematopoietic specific Cre mouse models to assess the function of Arid1b in blood development.

Combination of proviral and antiviral roles of B cell-intrinsic STAT1 expression defines parameters of chronic gammaherpesvirus infection.

Gammaherpesviruses are species-specific, ubiquitous pathogens that establish lifelong infection in their hosts and are associated with cancers, including B cell lymphomas. Type I and II interferons (IFNs) are critical for the control of acute and chronic gammaherpesvirus infection. However, the cell type-specific role of IFN signaling during natural infection is poorly defined and is masked by the altered viral pathogenesis observed in hosts with global IFN deficiencies.

Genetic engineering of megakaryocytes from blood progenitor cells using messenger RNA lipid nanoparticles.

Background: Platelets are an essential component of hemorrhage control and management, and engineering platelets to express therapeutic proteins could expand their use as a cell therapy. Genetically engineered platelets can be achieved by modifying the platelet precursor cells, megakaryocytes (MKs). Current strategies include transfecting MK progenitors ex vivo with viral vectors harboring lineage-driven transgenes and inducing the production of in vitro modified platelets.

Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer.

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression-a state where ECs resist cytotoxic CD8 T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise.