Current Opinion in Hematology最新文献

Purpose of review: The incidence of mental health conditions within hematopoietic stem cell transplant (HSCT) patients is high and has profound impacts on quality of life after transplant. Mental health is an underexplored and underutilized outcome in this patient population.

Recent findings: Standard mental health interventions in this patient population have shown limited results. Multiple factors including acuity of systemic illness, proinflammatory states, heterogeneous patient populations, and use of specific therapeutics could impact results. This presents the opportunity to identify new areas of improvement, such as focusing on leukocyte recovery, exogenous steroid use, and cytokine response to inform new bedside interventions.

Summary: Overall, interventions incorporating the biological mechanisms of mental health are underutilized in the HSCT patient population and offer a novel approach to improving morbidity, mortality and quality of life.

Purpose of review: This review encompasses the recently published information on clonal hematopoiesis of indeterminate potential (CHIP) and discusses its future prospects. By announcing advances in the research of CHIP risk factors and related diseases, with the purpose of offering new insights to treat both hematologic and nonhematologic disorders.

Recent findings: The majority of studies have shown that CHIP is a common biological condition associated with aging and the incidence of clonal hematopoiesis increases with age. The pathophysiology of blood diseases is projected to be significantly influenced by CHIP. Nevertheless, increasing studies have expanded the application of CHIP to cover nonhematologic diseases such as cardiovascular, renal, liver, and pulmonary diseases. Furthermore, with the fast advancement of genetic testing technology and preventive medicine, the involvement of CHIP in a variety of disorders shows promise as an essential target for preventing disease onset and progression.

Summary: CHIP is linked to a variety of illnesses and has a significant influence on an individual's health outlook. Thus, identifying and managing CHIP is critical for improving the clinical results of the individuals concerned.

Purpose of review: This review evaluates the known mechanisms of regulating erythroid regeneration via the sterile alpha motif protein-14 ( Samd14 ) enhancer, Samd14's role in stem cell factor/Kit and erythropoietin (Epo) signaling, possible SAMD14 functions beyond erythropoiesis, and extrapolation to other anemia-response pathways.

Recent findings: Samd14 expression is controlled by an anemia-activated E-box-GATA transcriptional enhancer required for erythroid regeneration, and the Samd14 protein is needed for acute anemia recovery. Samd14 interacts with actin capping proteins to elevate Kit signaling via MAPK and PI3K/Akt pathways in stress erythroid precursors and promotes Epo signaling at later stages. Whereas canonical cellular stress transcriptional mechanisms are involved in anemia (e.g. hypoxia-inducible HSF1, Nrf2, ATF4, and others), enhancers with sequence and molecular features resembling the Samd14 S14E cis -element - occupied by GATA1 and TAL1 - regulate anemia-activated proteins. Relative to physiological replacement of red blood cells, unique signaling cues are involved in erythroid regeneration at multiple stages.

Summary: Anemia-activated proteins coordinate an acute increase in red blood cell production from erythroid progenitors to regenerate lost cells and restore homeostasis. The Samd14 locus provides an exemplary examination of cell signaling - through both stem cell factor/Kit and Epo as well as transcriptional mechanisms involved in erythroid regeneration.

Purpose of review: Adenosine signaling is emerging as a key regulator of hematopoietic lineage commitment, influencing both erythropoiesis and myelopoiesis. This review explores the distinct roles of adenosine receptors in balancing these processes, particularly under stress conditions. Since adenosine extracellular levels are increased in multiple hematological disorders, including sickle cell disease, deciphering the mechanisms downstream of adenosine receptor activation is crucial to understand the pathophysiology of these conditions.

Recent findings: Extracellular adenosine levels in the bone marrow microenvironment are tightly regulated by CD39/CD73 activity and ENT1 uptake. Recent studies have shown that ENT1-mediated adenosine transport is crucial for adenosine intracellular metabolism and normal erythropoiesis, while increased extracellular adenosine levels impact hematopoietic differentiation through adenosine receptor activation. . High dose of exogenous adenosine inhibits erythroid proliferation by inducing G1 arrest and p53-mediated apoptosis. Furthermore, A 2B and A 3 receptor signaling inhibits erythroid differentiation, while adenosine signaling through A 3 also favors granulopoiesis.

Summary: Collectively, these findings highlight adenosine signaling as a critical and multifaceted regulator of hematopoietic balance, offering novel insights into its therapeutic potential for managing disorders characterized by ineffective erythropoiesis and aberrant myelopoiesis.

Purpose of review: Megakaryocytes are large, polyploid cells that produce platelets and originate from hematopoietic stem cells (HSCs) in the bone marrow. While in the classical paradigm, megakaryocytes are generated in a stepwise fashion through increasingly committed progenitor stages, studies using in-vivo barcoding, transplantation, and in-vitro culture have suggested that, in addition, a more direct pathway existed. The relevance of this direct pathway and its functional and phenotypic characteristics were unclear, however.

Recent findings: Recent publications using fate-mapping and single-cell transplantation now unequivocally demonstrate the existence of a direct megakaryocyte differentiation pathway, provide molecular characterization, and indicate distinct roles and regulation of both pathways. The direct pathway originates from a separate subset of 'top' HSCs, is enhanced by hematopoietic stress, inflammation and aging, bypasses multipotential progenitors, may be more active in myeloproliferative neoplasms, and generates phenotypically distinct megakaryocyte progenitors and more reactive platelets.

Summary: Novel insights into the direct megakaryocyte differentiation pathway provide a deeper understanding of HSC biology, hematological recovery after myeloablation, and aging of the hematopoietic system, and suggest that this pathway may contribute to the increase in thrombotic incidents with age and in myeloproliferative neoplasms.

Purpose of review: In this review, we aim to highlight recent insights into the mechanisms through which platelets contribute to vascular inflammation. We will discuss how platelets interact with other cellular players in the vascular milieu, their role in shaping inflammatory responses, and the potential therapeutic implications of targeting platelet function in inflammatory vascular diseases.

Recent findings: Platelets are essential components in the processes of hemostasis and thrombosis. Their role is now widely acknowledged as far more complex than merely acting as "band-aids" or helping to "clog a pipe". Platelets are now recognized as crucial mediators in inflammatory reactions, particularly in various diseases of the vasculature, where they contribute to the onset and progression of injury. Through their interactions with leukocytes, vascular cells, and by supporting the coagulation cascade, platelets are able to finely regulate the extent and intensity of vascular damage.

Summary: Recent findings underscore the remarkable diversity and functionality of platelets in vascular diseases. Mechanistic studies in preclinical models reveal promising therapeutic opportunities, which require further validation before being translated into clinical practice.

Purpose of review: Thalassemia and sickle cell disease are among the most frequent monogenic hereditary diseases. Access to transfusions, iron chelation therapies and drugs such as hydroxyurea have improved life expectancy and quality of life. However, these diseases still cause significant disability. The first available curative therapy, bone marrow transplantation, is unfortunately not feasible for all patients. Over the past decade, numerous studies have focused on finding new curative therapies, and many clinical trials have evaluated different gene therapy approaches.

Recent findings: The therapeutic targets focus on adding functional copies of the gene encoding β-globin in defective CD34 + cells, mainly using lentiviral vectors directed towards HSCs. More recently, the focus has shifted to inducing fetal hemoglobin production at therapeutic levels or repairing the underlying molecular defect, using novel gene editing techniques involving CRISPR-Cas9, transcription activation-like effector protein nucleases, zinc finger nucleases and base editing. Preclinical and clinical studies now focus on optimizing how gene therapy is performed and delivered to reduce or eliminate myeloablative treatment and its potential adverse events.

Summary: In this review, we explore the potential to induce fetal hemoglobin production at therapeutic levels or to repair the underlying molecular defect that causes the disease genetically. Here, we review recent gene editing studies that are opening a new era in curative treatment for hemoglobinopathies.

Purpose of review: This review summarizes mechanisms that regulate endothelial vascular permeability in health and disease. In systemic inflammation, the endothelial barrier integrity is disrupted, which exacerbates vascular permeability, leading to organ failure and death. Herein we provide an overview of emerging therapeutic targets to reverse barrier dysfunction and preserve vascular permeability in inflammatory diseases like sepsis.

Recent findings: Endothelial barrier function is regulated in part by the endothelial cell-specific protein, Roundabout 4 (ROBO4), and vascular endothelial (VE)-cadherin, a critical adherens junction protein, which act in concert to suppresses vascular permeability by stabilizing endothelial cell-cell interactions. We recently discovered a pathway by which activation of coagulation factor XI (FXI) enhances the cleavage of VE-cadherin by the metalloproteinase ADAM10, contributing to sepsis-related endothelial damage and loss of barrier function. Targeting FXI improved survival and reduced sVE-cadherin levels in a baboon model of sepsis while enhancing Robo4 expression decreased mortality in LPS-treated mice.

Summary: Endothelial cell barrier dysfunction is a hallmark of excessive immune responses characteristic of systemic inflammatory diseases such as sepsis. Advances in understanding the molecular mechanisms regulating vascular permeability, for instance the newly discovered roles of FXI or ROBO4, may help identify novel therapeutic targets for mitigating vascular hyperpermeability in septic patients.

Purpose of review: The lack of optimal treatments for haematological disorders has led to the need for prediction models for diagnosis, therapeutic decision-making and life planning. In this review, the worrying current state of predictive models in the field is discussed.

Recent findings: Here, we reviewed 100 studies on prediction models in this field. Our analysis revealed a concerning state of affairs, with a prevalence of suboptimal research methodologies and questionable statistical practices. This includes insufficient sample sizes, inadequate model evaluations, lack of necessary reports of model results, etc. In this regard, we present statistical considerations in the development and validation process of numerous models. This will provide the reader with the statistical knowledge related to prediction model necessary to assess bias in studies, compare other published models and determine the clinical utility of models.

Summary: Awareness among authors, reviewers and editors of the required statistical considerations is crucial. Reinforcing these in all studies involving prediction models is needed. We all should encourage their use in evaluating existing studies and taking them fully into account in future studies.