Haematologica最新文献

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Patients with chronic lymphocytic leukemia (CLL) have impaired response to vaccination, which calls for improved vaccination strategies. This study aimed to evaluate antibody persistence five years after pneumococcal vaccination and response to revaccination. Seventyfour CLL patients and 31 controls, all primary immunized with 13-valent conjugated pneumococcal vaccine (PCV13) or 23-valent polysaccharide vaccine (PPSV23), were included. Antibody persistence was assessed, followed by revaccination with PCV13 and a second revaccination with PCV13 or PPSV23. Serological protection (SP), defined as serum serotype specific IgG concentration ≥0.35 μg/mL for ≥70% of shared serotypes, did not differ significantly in CLL patients primary immunized with PCV13 or PPSV23 (RR 2.7 (95% CI 0.5-13.1)), but was lower in patients compared to controls (10% vs 32%; RR 0.3 (0.1-0.7)). Following revaccination with PCV13, serological response (SR), defined as ≥2-fold increase for ≥70% of shared serotypes, was 24% in patients primary immunized with PCV13 vs 12% with PPSV23 (RR 2.0 (0.6-6.9)). A second revaccination with PCV13 significantly improved SR while PPSV23 did not further improve immunity. Our findings suggest that repeated doses of a T-cell dependent pneumococcal vaccine improve protection in CLL patients. The study is registered at www.clinicaltrials.gov (NCT05316831).

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Connexin (Cx) gap junction proteins are expressed by a multitude of cells and function as plasma membrane hemichannels or dock to form intercellular communication tunnels. Whilst Cx43 has garnered considerable attention, less is known about the structure and function of Cx62 channels. Platelets and megakaryocytes express Cx37, Cx40 and Cx62, which contribute to hemostatic and thrombotic responses. Our study explores an unexpected finding that following platelet activation, an extracellular region of Cx62 undergoes proteolytic cleavage by calpain-1. We adopted an interdisciplinary approach to evaluate structural and functional consequences of calpain-mediated cleavage of Cx62. Cellular signaling was assayed by immunoblotting, aggregation and calcium flux assays. Gap junction function and thrombus formation were assessed under arteriolar flow. In silico modelling was used to predict calpain-mediated changes to the pore diameter and design a decoy peptide (62Pept-NT). Mechanistically, Cx62 cleavage is Ca2+-dependent and requires calpain-1 externalization. Modelling a predicted calpain-1 cleavage site on the first extracellular loop, shows that calpain can dock to Cx62 monomers, promoting stepwise channel cleavage. Consequently, we predict a significant pore dilation enhancing diffusion of signaling molecules between cells and into the extracellular milieu. We designed a decoy peptide that abrogated calpain-1-mediated cleavage, reduced intercellular communication and restricted thrombus growth. Cx62 cleavage was dependent upon sequential action of protein kinase A, protein phosphatase 2A and Ca2+ release from intracellular stores. Extracellular calpain cleavage represents a fundamentally new regulatory mechanism for connexin 62, culminating in an irreversible open state.

Bernard Soulier Syndrome (BSS) is a severe bleeding disorder with moderate to severe thrombocytopenia, giant platelets, and platelet dysfunction, caused by biallelic mutations in GP1BA, GP1BB, or GP9 genes. We generated induced pluripotent stem cells (iPSC) from a BSS patient with a novel heterozygous GP1BA p.N103D mutation, resulting in moderate macrothrombocytopenia. The mutation does not affect megakaryocyte (MK) differentiation or GPIb-GPIX complex expression but reduces affinity to von Willebrand factor (VWF). It induces increased signaling independent of VWF and αIIbβ3-mediated outside-in signaling, causing a profound defect in proplatelet formation after adhesion on fibrinogen. Pre-activation of αIIbβ3 integrin and heightened stress fiber formation linked to RhoA pathway overactivation were observed, likely due to increased phosphorylation of SRC at Y419 downstream of GPIbα. Dasatinib, a SRC inhibitor, restored stress fiber formation. Using a 3D bone marrow model to mimic platelet release under flow, we demonstrated that the ROCK1/2 inhibitor Y27632 increased platelet number and restored platelet size in GPIbα N103D MKs, as well as in MKs from two other patients with heterozygous GP1BA mutations (p.L160P and p.N150S). However, Y27632 had no additional effect on platelet generation from MKs of two patients with biallelic BSS, suggesting a distinct molecular mechanism in biallelic cases.

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Most children diagnosed with acute lymphoblastic leukemia (ALL) will achieve remission and be cured of their disease. However, this high cure rate comes at the cost of acute and chronic treatment-related toxicities. In fact, a similar number of children die from either ALL itself or the toxicities associated with its treatment. Therapy-related toxicities, whether acute or chronic, can impact treatment efficacy, overall survival (OS), and the patient's quality of life. This review focused on six major acute toxicities of ALL therapy, venous thromboembolism, osteonecrosis, neurological sequels, delayed MTX elimination, asparaginase-associated pancreatitis, and toxicities of the new biological therapies. Most of these severe acute toxicities of ALL treatment can be mitigated through tailored therapy adaptations for individual patients and careful incorporation of immunotherapy. These adaptations will soon become a central component of contemporary pediatric ALL protocols and ultimately improve patients' OS and Wellness.