Current Opinion in Hematology最新文献

Purpose of review: Sepsis-induced inflammatory lung injury includes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There are currently no effective treatments for ALI/ARDS, but clinical outcomes could be improved by inhibiting lung injury and/or promoting post-sepsis vascular repair. In this review, we describe studies of endothelial cell metabolic pathways in sepsis-induced ALI/ARDS and vascular repair and identify areas of research that deserve attention in future studies. We also describe studies of metabolic interventions that aim to inhibit ALI/ARDS and/or promote post-sepsis vascular repair, including those that target endothelial cell metabolites, endothelial cell metabolic signaling pathways, and endothelial cell metabolism.

Recent findings: Endothelial cells are integral to both the injury and repair phases of ALI/ARDS. During the injury phase of ALI/ARDS, lung endothelial cell survival decreases, and lung endothelial cell-to-endothelial cell (EC-EC) junctions are weakened. During the repair phase after sepsis-induced lung injury, lung endothelial cell proliferation and lung EC-EC junction reannealing occur. These crucial aspects of ALI/ARDS and post-sepsis vascular repair, that is, endothelial cell viability, growth, and junction integrity, are controlled by a myriad of metabolites and metabolic signaling pathways in endothelial cells.

Summary: Metabolic signaling pathways in endothelial cells represent a novel class of putative targets for the prevention and treatment of sepsis-induced inflammatory lung injury. Therapies that target metabolic signaling in endothelial cells are currently being explored as potential treatments for sepsis-induced inflammatory lung injury.

Purpose of review: To explore the use of large datasets in predicting and managing cancer-associated venous thromboembolism (CAT) by stratifying patients into risk groups. This includes evaluating current predictive models and identifying potential improvements to enhance clinical decision-making.

Recent findings: Cancer patients are at an elevated risk of developing venous thromboembolism (VTE), which significantly impacts mortality and quality of life. Traditional approaches to risk assessment fail to account for the procoagulant changes associated with cancer, making individualized risk prediction a challenge. Current clinical guidelines as per ASCO recommend risk assessment before chemotherapy and endorse thromboprophylaxis as a standard preventive measure. Since any cancer population is highly heterogeneous in terms of VTE risk, predicting the risk of CAT is an oncological challenge. To address this, different predictive models have been developed to stratify patients by risk, enabling targeted thromboprophylaxis. However, these models vary in accuracy and utility. The present review discusses the pros and cons of these different models.

Summary: The review examines existing CAT risk prediction models, highlighting their strengths, limitations, and diagnostic performance. It also identifies additional variables that could enhance these models to improve their effectiveness in guiding clinicians toward better risk stratification and treatment decisions for cancer patients.

Purpose of review: Patients with cancer have an increased risk of venous thromboembolism (VTE). Guidelines suggest to use risk assessment tools to guide decisions about thromboprophylaxis, but current tools have modest discriminatory ability. Genetic information from the germline or tumor has the potential to improve VTE prediction. Here, we provide a clinical overview of the current role of genetics in cancer-associated VTE.

Recent findings: Germline mutations, such as factor V Leiden and prothrombin G20210A, are associated with a 2- to 2.5-fold increased VTE risk in patients with cancer. Tumor-specific somatic mutations also contribute to VTE risk, such as ALK rearrangements increasing the risk in nonsmall cell lung cancer and IDH1 mutations decreasing the risk in gliomas. Other somatic mutations associated with VTE independent of tumor type include KRAS , STK11 , MET , KEAP1 , CTNNB1 , and CDKN2B . Incorporating data on germline or somatic mutations in risk scores improves discriminatory ability compared with the Khorana score.

Summary: Specific germline and somatic mutations are associated with an increased VTE risk in patients with cancer and potentially improve performance of clinical risk scores. The increasing and widespread use of genetic testing in cancer care provides an opportunity for further development of prediction models incorporating genetic predictors.

Purpose of review: This review focuses on recent advances in the understanding of red blood cell (RBC) metabolism as a function of hypoxia and oxidant stress. In particular, we will focus on RBC metabolic alterations during storage in the blood bank, a medically relevant model of erythrocyte responses to energy and redox stress.

Recent findings: Recent studies on over 13 000 healthy blood donors, as part of the Recipient Epidemiology and Donor Evaluation Study (REDS) III and IV-P RBC omics, and 525 diversity outbred mice have highlighted the impact on RBC metabolism of biological factors (age, BMI), genetics (sex, polymorphisms) and exposure (dietary, professional or recreational habits, drugs that are not grounds for blood donor deferral).

Summary: We review RBC metabolism from basic biochemistry to storage biology, briefly discussing the impact of inborn errors of metabolism and genetic factors on RBC metabolism, as a window on systems metabolic health. Expanding on the concept of clinical chemistry towards clinical metabolomics, monitoring metabolism at scale in large populations (e.g., millions of blood donors) may thus provide insights into population health as a complementary tool to genetic screening and standard clinical measurements.

Purpose of review: This review aims to summarize the histological differences among thrombi in acute myocardial infarction, ischemic stroke, venous thromboembolism, and amniotic fluid embolism, a newly identified thrombosis.

Recent findings: Acute coronary thrombi have a small size, are enriched in platelets and fibrin, and show the presence of fibrin and von Willebrand factor, but not collagen, at plaque rupture sites. Symptomatic deep vein thrombi are large and exhibit various phases of time-dependent histological changes. Cancer-associated venous thromboemboli contain invasive cancer cells that penetrate the vascular walls, and small cancer cell aggregates are observed within the thrombi. The thrombus composition in atherosclerotic and cardioembolic ischemic strokes varies from case to case, while the thrombi in cancer-associated ischemic stroke are rich in platelets and fibrin. A pathological study on amniotic fluid embolism identified uterine vein thrombi and massive platelet-rich microthrombi in the lungs.

Summary: Atherothrombus formation is induced by plaque disruption and may occlude a narrow lumen within a short time. Venous thrombi may grow to a large size in a multistage or chronic manner. Cancer cells can directly contribute to venous thrombus formation. The thrombus formation in amniotic fluid embolism may explain the occurrence of consumptive coagulopathy and cardiopulmonary collapse.

Purpose of review: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematological malignancies characterized by complex genetic alterations, leading to poor clinical outcomes. Despite advances in treatment, there is an urgent need for novel therapeutic approaches. This review outlines recent progress in humanized models of MDS and AML and highlight their role in advancing our understanding of these diseases.

Recent findings: Patient derived xenografts (PDXs) were among the first humanized models for studying MDS and AML, allowing researchers to analyze patient-specific cancer properties in vivo . However, they face challenges related to sample availability and consistent engraftment in mice. New methods, including specialized mouse strains and human tissue scaffolds, have been developed to address these issues. Induced pluripotent stem cells (iPSCs) offer the advantage of indefinite expansion and genetic modification, making them valuable for in vitro research, though protocols to enhance their engraftment in vivo are still being refined. Genetically engineered human primary hematopoietic stem and progenitor cells (HSPCs) provide reliable in vivo models with good engraftment in mice, and recent advancements in culture systems and gene-editing techniques are helping to overcome challenges related to ex vivo expansion and genetic modification.

Summary: PDXs, iPSCs, and genetically engineered HSPCs are crucial models for the study of MDS and AML. This review discusses strengths, limitations, and recent advancements of these humanized models, which provide insights into human-specific disease biology and therapeutic development.

Purpose of review: To date, there is relatively limited research investigating changes in red blood cells (RBCs), particularly qualitative changes, in cancer patients and cancer patients receiving treatment. These changes may be important in better understanding cancer-associated anemia, which is the most prevalent hematological disorder in cancer patients with wide-ranging implications on patient care and quality of life. This review aims to summarize available evidence regarding qualitative and quantitative changes in RBCs in individuals with cancer prior to treatment and in patients undergoing treatment.

Recent findings: The most commonly reported changes in RBCs in cancer patients were increased mean corpuscular volume (MCV) and decreased hemoglobin, RBC count, and hematocrit. There were increased lipid peroxidation products and decreased antioxidants. There were increased polyunsaturated fatty acids (PUFAs) and decreased monounsaturated fatty acids (MUFAs) and saturated fatty acids (FAs). Additionally, RBC shape alterations with various atypical morphologies, membrane structure abnormalities, and impaired fluidity were also reported. These and various other reported findings are discussed in depth.

Summary: There are several reported quantitative and qualitative RBC changes in individuals with cancer, with some studies exhibiting conflicting results. Further research is needed to solidify the data and to better understand hematological-associated comorbidities in those patients.

Purpose of review: The aim of this review is to highlight the importance of lipids' intricate and interwoven role in mediating diverse acute myeloid leukemia (AML) processes, as well as potentially novel lipid targeting strategies. This review will focus on new studies of lipid metabolism in human leukemia, particularly highlighting work in leukemic stem cells (LSCs), where lipids were assessed directly as a metabolite.

Recent findings: Lipid metabolism is essential to support LSC function and AML survival through diverse mechanisms including supporting energy production, membrane composition, signaling pathways, and ferroptosis. Recent work has highlighted the role of lipid rewiring in metabolic plasticity which can underlie therapy response, the impact of cellular and genetic heterogeneity in AML on lipid metabolism, and the discovery of noncanonical roles of lipid related proteins in AML.

Summary: Recent findings around lipid metabolism clearly demonstrates their importance to our understanding and therapeutic targeting of AML. We have only begun to unravel the regulation and utilization of lipids in this disease. Further, understanding the layered dynamics of lipid homeostasis could provide novel opportunities to target lipid metabolism in AML and LSCs with the potential of improving outcomes for patients with AML.