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Circulation Research Sep 2017
Topics: Adipose Tissue, Brown; Atherosclerosis; Humans; Monocytes; Uncoupling Protein 1
PubMed: 28860315
DOI: 10.1161/CIRCRESAHA.117.311721 -
Arteriosclerosis, Thrombosis, and... May 2015Myocardial infarction (MI) is the leading cause of death in developed countries. Though timely revascularization of the ischemic myocardium and current standard therapy... (Review)
Review
Myocardial infarction (MI) is the leading cause of death in developed countries. Though timely revascularization of the ischemic myocardium and current standard therapy reduce acute mortality after MI, long-term morbidity and mortality remain high. During the first 1 to 2 weeks after MI, tissues in the infarcted myocardium undergo rapid turnover, including digestion of extracellular matrix and fibrosis. Post-MI repair is crucial to survival. Monocytes recruited to the infarcted myocardium remove debris and facilitate the repair process. However, exaggerated inflammation may also impede healing, as demonstrated by the association between elevated white blood cell count and in-hospital mortality after MI. Monocytes produced in the bone marrow and spleen enter the blood after MI and are recruited to the injured myocardium in 2 phases. The first phase is dominated by Ly-6c(high) monocytes and the second phase by Ly-6c(low) monocytes. Yet the number of Ly6C(low) monocytes recruited to the infarct is much lower, and Ly6C(high) monocytes can differentiate to Ly6C(low) macrophages in later healing stages. Understanding the signals regulating monocytosis after MI will help design new therapies to facilitate cardiac healing and limit heart failure.
Topics: Cell Movement; Extracellular Matrix; Female; Hematopoiesis; Humans; Macrophages; Male; Monocytes; Myocardial Infarction; Wound Healing
PubMed: 25792449
DOI: 10.1161/ATVBAHA.114.304652 -
Frontiers in Pediatrics 2022Acute monoblastic/monocytic leukemia (AMoL), previously defined as M5 according to FAB classification, is one of the most common subtypes of Acute Myeloid Leukemia (AML)... (Review)
Review
Acute monoblastic/monocytic leukemia (AMoL), previously defined as M5 according to FAB classification, is one of the most common subtypes of Acute Myeloid Leukemia (AML) in children, representing ~15-24% of all pediatric AMLs. Currently, the characterization of monocytic-lineage neoplasia at diagnosis includes cytomorphology, cytochemistry, immunophenotyping by multiparametric flow cytometry, cytogenetics, and molecular biology. Moreover, measurable residual disease (MRD) detection is critical in recognizing residual blasts refractory to chemotherapy. Nonetheless, diagnosis and MRD detection may still be challenging in pediatric AMoL since the morphological and immunophenotypic features of leukemic cells potentially overlap with those of normal mature monocytic compartment, as well as differential diagnosis can be troublesome, particularly with Juvenile Myelomonocytic Leukemia and reactive monocytosis in infants and young children. A failure or delay in diagnosis and inaccuracy in MRD assessment may worsen the AMoL prognosis. Therefore, improving diagnosis and monitoring techniques is mandatory to stratify and tailor therapies to the risk profile. This Mini Review aims to provide an updated revision of the scientific evidence on pediatric AMoL diagnostic tools.
PubMed: 36245718
DOI: 10.3389/fped.2022.911093 -
Scandinavian Journal of Immunology Nov 2021During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such... (Review)
Review
During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL-6 expression, which promotes scar and thrombus formation. Excess IL-6 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto-inflammatory feedback loop. The perforin/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID-19. In addition, we outline the manner in which a pathogenic auto-inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID-19. Such an auto-inflammatory loop may be amenable to synergistic multimodal therapy.
Topics: Animals; Autoimmunity; COVID-19; Cytokine Release Syndrome; Disease Resistance; Humans; Interleukin-6; Killer Cells, Natural; Lymphohistiocytosis, Hemophagocytic; Neutrophils; Perforin; SARS-CoV-2
PubMed: 34755902
DOI: 10.1111/sji.13102 -
Blood Cancer Journal Feb 2016Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform to acute myeloid... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform to acute myeloid leukemia. CMML has overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Clonal cytogenetic changes are seen in ~30%, whereas gene mutations are seen in >90% of patients. Common cytogenetic abnormalities include; trisomy 8, -Y, -7/del(7q), trisomy 21 and del(20q), with the Mayo-French risk stratification effectively risk stratifying patients based on cytogenetic abnormalities. Gene mutations frequently involve epigenetic regulators (TET2 ~60%), modulators of chromatin (ASXL1 ~40%), spliceosome components (SRSF2 ~50%), transcription factors (RUNX1 ~15%) and signal pathways (RAS ~30%, CBL ~15%). Of these, thus far, only nonsense and frameshift ASXL1 mutations have been shown to negatively impact overall survival. This has resulted in the development of contemporary, molecularly integrated (inclusive of ASXL1 mutations) CMML prognostic models, including Molecular Mayo Model and the Groupe Français des Myélodysplasies model. Better understanding of the prevalent genetic and epigenetic dysregulation has resulted in emerging targeted treatment options for some patients. The development of an integrated (cytogenetic and molecular) prognostic model along with CMML-specific response assessment criteria are much needed future goals.
Topics: Animals; Cell Cycle Proteins; Chromatin; Chromosomal Proteins, Non-Histone; Chromosome Aberrations; DNA Damage; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Histones; Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Prognosis; Protein Multimerization; Signal Transduction; Spliceosomes; Transcription Factors; Cohesins
PubMed: 26849014
DOI: 10.1038/bcj.2016.5 -
European Journal of Haematology Apr 2023Monocytosis (≥0.5 × 10 /L in peripheral blood) is the hallmark of chronic myelomonocytic leukaemia (CMML) but may be present in a spectrum of diseases including...
Monocytosis (≥0.5 × 10 /L in peripheral blood) is the hallmark of chronic myelomonocytic leukaemia (CMML) but may be present in a spectrum of diseases including other haematological malignancies. In the primary care sector, monocytosis is a relatively common finding, but its predictive value for haematological malignancy is unknown. We included 663 184 adult primary care patients from the greater Copenhagen area with one or more differential cell counts registered between 2000 and 2016 and followed them in the extensive nationwide Danish health data registers for 3 years after blood sampling. We used logistic regression to model the risk of haematological malignancy and death following monocytosis. Monocytosis was associated with an increased risk of all types of haematological malignancy with the greatest relative risk increase observed in CMML with an OR of 105.22 (95% confidence interval: 38.27-289.30). Sustained monocytosis (at least two requisitions in 3 months) further increased CMML risk, although the diagnosis was still very rare, that is, observed in only 0.1% of these individuals. Outside the haematological setting, the absolute risk of haematological malignancy associated with monocytosis is low and haematological malignancy should mainly be suspected when monocytosis is sustained or the clinical presentation raises suspicion of malignancy.
Topics: Adult; Humans; Monocytes; Leukocytosis; Leukemia, Myelomonocytic, Chronic; Hematologic Neoplasms; Primary Health Care
PubMed: 36479724
DOI: 10.1111/ejh.13911 -
European Journal of Case Reports in... 2021Chronic neutrophilic leukaemia is a very rare disease with diagnosis based on persistent leucocytosis >25×10/μl and monocytes <1×10/μl. The revised WHO criteria 2016...
UNLABELLED
Chronic neutrophilic leukaemia is a very rare disease with diagnosis based on persistent leucocytosis >25×10/μl and monocytes <1×10/μl. The revised WHO criteria 2016 included CSF3R gene mutations as a diagnostic finding. We report the case of a 77-year-old man who was found to have asymptomatic persistent mature neutrophilic leucocytosis with monocytosis. Molecular study confirmed the presence of a CSF3R gene mutation in the absence of morphological or genetic features of myelodysplasia or other forms of myelodysplastic syndrome. The patient's medical history was significant for coronary artery disease, hypertension, chronic obstructive pulmonary disease, bilateral cystic bronchiectasis, moderate pulmonary hypertension, tuberculosis treated 27 years previously, hypothyroidism, and a thyroid nodule. He had hepatosplenomegaly but no lymphadenopathy, and no other malignancy was seen on computed tomography (CT) scanning. At the time of evaluation, he was free of symptoms and had no evidence of infection or drug-induced leucocytosis. The patient was referred to an oncology centre and treated with hydroxyurea and subsequently azacitidine. However, he developed pancytopenia with bone marrow aplasia. He died with neutropenia sepsis. The presence of persistent monocytosis in this case created a diagnostic dilemma as to whether the disease was a variant of chronic neutrophilic leukaemia or was reactive monocytosis.
LEARNING POINTS
The presence of a CSF3R gene mutation is diagnostic for chronic neutrophilic leukaemia (CNL).The monocytosis in this patient might have been a new variant of CNL.
PubMed: 34123950
DOI: 10.12890/2021_002595 -
Circulation Research Sep 2020Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation....
RATIONALE
Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear.
OBJECTIVE
To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis.
METHODS AND RESULTS
To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C subset, and neutrophils. Hematopoietic-restricted deletion of , , or its cognate receptor prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis.
CONCLUSIONS
Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.
Topics: Animals; Atherosclerosis; Biomarkers; Blood Glucose; Calgranulin A; Calgranulin B; Diet, High-Fat; Disease Models, Animal; Glucose Transporter Type 1; Glycolysis; Hyperglycemia; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Monocytes; Myelopoiesis; Neutrophils; Plaque, Atherosclerotic; Receptor for Advanced Glycation End Products; Signal Transduction
PubMed: 32564710
DOI: 10.1161/CIRCRESAHA.120.316653 -
American Journal of Hematology Jul 2017Monocytosis (absolute monocyte count, AMC ≥ 1 × 10 /L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the...
Monocytosis (absolute monocyte count, AMC ≥ 1 × 10 /L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)-defined PV, 55 (21%) patients displayed an AMC of ≥1 × 10 /L and 18 (7%) an AMC of ≥1.5 × 10 /L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC ≥1 × 10 /L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC ≥ 1.5 × 10 /L). In univariate analysis, AMC ≥1.5 × 10 /L adversely affected overall (OS; P = .004; HR 2.6, 95% CI 1.4-4.8) and myelofibrosis-free (MFFS; P = .02; HR 4.4, 95% CI 1.3-15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P = .05) and MFFS (P = .06). Other independent risk factors for OS included unfavorable karyotype (P = .02, HR 3.39, 95% CI 1.17-9.79), older age (P < .0001, HR 3.34 95% CI 1.97-5.65), and leukocytosis ≥15 × 10 /L (P = .004, HR 2.04, 95% CI 1.26-3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; DNA Mutational Analysis; Female; Humans; Kaplan-Meier Estimate; Karyotyping; Leukocyte Count; Leukocytosis; Male; Middle Aged; Monocytes; Mutation; Phenotype; Polycythemia Vera; Prognosis; Young Adult
PubMed: 28370365
DOI: 10.1002/ajh.24740 -
Frontiers in Cardiovascular Medicine 2020With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular... (Review)
Review
With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular complications, with atherosclerotic cardiovascular disease (CVD) being the leading cause of death in adults with diabetes. The exact mechanisms for how diabetes promotes CVD risk are still unclear, although it is evident that monocytes and macrophages are key players in all stages of atherosclerosis both in the absence and presence of diabetes, and that phenotypes of these cells are altered by the diabetic environment. Evidence suggests that at least five pro-atherogenic mechanisms involving monocytes and macrophages contribute to the accelerated atherosclerotic lesion progression and hampered lesion regression associated with diabetes. These changes include (1) increased monocyte recruitment to lesions; (2) increased inflammatory activation; (3) altered macrophage lipid accumulation and metabolism; (4) increased macrophage cell death; and (5) reduced efferocytosis. Monocyte and macrophage phenotypes and mechanisms have been revealed mostly by different animal models of diabetes. The roles of specific changes in monocytes and macrophages in humans with diabetes remain largely unknown. There is an ongoing debate on whether the changes in monocytes and macrophages are caused by altered glucose levels, insulin deficiency or insulin resistance, lipid abnormalities, or combinations of these factors. Current research in humans and mouse models suggests that reduced clearance of triglyceride-rich lipoproteins and their remnants is one important mechanism whereby diabetes adversely affects macrophages and promotes atherosclerosis and CVD risk. Although monocytes and macrophages readily respond to the diabetic environment and can be seen as protagonists in diabetes-accelerated atherosclerosis, they are likely not instigators of the increased CVD risk.
PubMed: 32118048
DOI: 10.3389/fcvm.2020.00010