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Journal of Neuroinflammation Nov 2023Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the...
BACKGROUND
Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury.
METHODS
A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test.
RESULTS
The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH.
CONCLUSIONS
Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.
Topics: Humans; Mice; Male; Animals; Monocytes; Subarachnoid Hemorrhage; Brain Injuries; Macrophages; Stroke; Mice, Inbred C57BL
PubMed: 37978532
DOI: 10.1186/s12974-023-02939-y -
JACC. Cardiovascular Interventions Oct 2023Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases.
OBJECTIVES
The authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI).
METHODS
In the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables.
RESULTS
The incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566).
CONCLUSIONS
In the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.
Topics: Humans; Ticagrelor; Platelet Aggregation Inhibitors; Percutaneous Coronary Intervention; Hemorrhage; Treatment Outcome; Drug Therapy, Combination; Aspirin; Dyspnea
PubMed: 37879803
DOI: 10.1016/j.jcin.2023.08.019 -
The Journal of Experimental Medicine Dec 2023T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as...
T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to proapoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM derepression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
Topics: Transcription Factor AP-1; Bcl-2-Like Protein 11; Clonal Anergy; T-Lymphocytes, Regulatory; Autoantigens
PubMed: 37862030
DOI: 10.1084/jem.20230183 -
Clinical Journal of Sport Medicine :... Sep 2023Recombinant human erythropoietin (rHuEpo) abuse by athletes threatens the integrity of sport. Due to the overlap in physiological response to rHuEpo and altitude...
BACKGROUND
Recombinant human erythropoietin (rHuEpo) abuse by athletes threatens the integrity of sport. Due to the overlap in physiological response to rHuEpo and altitude exposure, it remains difficult to differentiate changes in hematological variables caused by rHuEpo or altitude, and therefore, other molecular methods to enhance anti-doping should be explored.
OBJECTIVE
To identify the hematological and transcriptomic response to prolonged altitude exposure typical of practices used by elite athletes.
DESIGN
Longitudinal study.
SETTING
University of Cape Town and Altitude Training Centre in Ethiopia.
PARTICIPANTS AND INTERVENTION
Fourteen well-trained athletes sojourned to an altitude training camp in Sululta, Ethiopia (∼2400-2500 m above sea level) for 27 days. Blood samples were taken before arrival, 24 hours, and 9, 16, and 24 days after arrival at altitude in addition to 24 hours and 6, 13, and 27 days upon return to sea level.
MAIN OUTCOME MEASURES
Blood samples were analyzed for hemoglobin concentration, hematocrit, and reticulocyte percentage. The transcriptomic response in whole blood and peripheral blood mononuclear cells (PBMC) were analyzed using gene expression microarrays.
RESULTS
A unique set of 29 and 10 genes were identified to be commonly expressed at every altitude time point in whole blood and PBMC, respectively. There were no genes identified upon return to sea level in whole blood, and only one gene within PBMC.
CONCLUSIONS
The current study has identified a series of unique genes that can now be integrated with genes previously validated for rHuEpo abuse, thereby enabling the differentiation of rHuEpo from altitude exposure.
Topics: Humans; Leukocytes, Mononuclear; Altitude; Longitudinal Studies; Leukocytes; Athletes
PubMed: 37656978
DOI: 10.1097/JSM.0000000000001046 -
Biochemical and Biophysical Research... Nov 2023Acute cholangitis (AC) is a key pathogeny of septic shock, which has a high mortality rate. AC has significant clinical heterogeneity, but no study has analyzed the...
BACKGROUND
Acute cholangitis (AC) is a key pathogeny of septic shock, which has a high mortality rate. AC has significant clinical heterogeneity, but no study has analyzed the discrepancies in immunoresponsiveness between AC and its secondary septic shock. The immune inflammatory responses play a critical role in the development of septic shock.
METHODS
We performed single-cell RNA sequencing (scRNA-seq) to analyze the differences of immunocytes in immunoresponse and inflammation between the early stages of AC (A1, A2, and A3) and its secondary septic shock (B1, B2, and B3).
RESULTS
This study has identified seven cell types, including T cells, B cells, plasma cells, neutrophils, monocytes, platelets and erythrocytes. We mainly focused on neutrophils, monocytes, and T cells. Neutrophil subpopulation analysis indicated that neutrophil progenitors (proNeus) were identified in neutrophil subsets. Compared with patients suffering from AC, the gene phenotypes of proNeus (ELANE, AZU1, MPO, and PRTN3) were significantly upregulated in septic shock. The differentiation direction of neutrophil subsets in peripheral blood mononuclear cells (PBMCs) was determined; Moreover, the proNeus in septic shock presented a state of "expansion", with upregulation of neutrophil degranulation and downregulation of monocyte and T cell proliferation. Neutrophils-7 (CCL5, RPL23A, RPL13, RPS19 and RPS18) were mainly involved in the regulation of cellular functions. The neutrophils-7 subpopulation in septic shock were in a state of "exhaustion", and its biological functions showed the characteristics of weakening neutrophil migration and phagocytosis, etc., which maked infection difficult to control and aggravated the development of septic shock. Analysis of monocyte and T cell subpopulations showed that the expression genes and biological functions of subpopulations were closely related to immunoinflammatory regulation. In addition, CCL3 - CCR1, CXCL1 - CXCR2 and other ligand-receptors were highly expressed in neutrophils and monocytes, enhancing interactions between immune cells.
CONCLUSION
ScRNA-seq revealed significant differences in immune cells between AC and its secondary septic shock, which were primarily manifested in the cellular numbers, differentially expressed genes, functions of cellular subsets, differentiation trajectories, cell-cell interactions and so on. We identified many subsets of neutrophil, T cell and monocyte were associated with inflammation and immunosuppression induced by septic shock. These provided a reference for accurately evaluating the pathological severity of patients with AC and discovering the targets for therapy.
Topics: Humans; Shock, Septic; Leukocytes, Mononuclear; Neutrophils; Cholangitis; Sequence Analysis, RNA; Neoplasm Proteins; Ribosomal Proteins
PubMed: 37864923
DOI: 10.1016/j.bbrc.2023.149121 -
Biomedicine & Pharmacotherapy =... Dec 2023Acute myeloid leukemia (AML) is a heterogeneous disease developed from the malignant expansion of myeloid precursor cells in the bone marrow and peripheral blood. The... (Review)
Review
Acute myeloid leukemia (AML) is a heterogeneous disease developed from the malignant expansion of myeloid precursor cells in the bone marrow and peripheral blood. The implementation of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) has improved outcomes associated with AML, but relapse, along with suboptimal outcomes, is still a common scenario. In the past few years, exploring new therapeutic strategies to optimize treatment outcomes has occurred rapidly. In this regard, natural killer (NK) cell-based immunotherapy has attracted clinical interest due to its critical role in immunosurveillance and their capabilities to target AML blasts. NK cells are cytotoxic innate lymphoid cells that mediate anti-viral and anti-tumor responses by producing pro-inflammatory cytokines and directly inducing cytotoxicity. Although NK cells are well known as short-lived innate immune cells with non-specific responses that have limited their clinical applications, the discovery of cytokine-induced memory-like (CIML) NK cells could overcome these challenges. NK cells pre-activated with the cytokine combination IL-12/15/18 achieved a long-term life span with adaptive immunity characteristics, termed CIML-NK cells. Previous studies documented that using CIML-NK cells in cancer treatment is safe and results in promising outcomes. This review highlights the current application, challenges, and opportunities of CIML-NK cell-based therapy in AML.
Topics: Humans; Cytokines; Immunity, Innate; Killer Cells, Natural; Leukemia, Myeloid, Acute; Immunotherapy
PubMed: 37857247
DOI: 10.1016/j.biopha.2023.115718 -
Redox Report : Communications in Free... Dec 2023Acquired aplastic anemia (AA) is a life-threatening disease associated with an imbalance in Th17/Treg cells. Regulating this balance may be an effective treatment...
BACKGROUND
Acquired aplastic anemia (AA) is a life-threatening disease associated with an imbalance in Th17/Treg cells. Regulating this balance may be an effective treatment approach for AA. Rhodiola rosea has shown efficacy in AA treatment, but its mechanisms remain unclear.
PURPOSE
We investigated salidroside's effect (a component of ) on Th17/Treg balance in adult AA patients and a mouse model.
METHODS
HIF-1α mRNA and protein levels were measured in AA patients' peripheral blood. Flow cytometry, qRT-PCR, and WB analyzed salidroside's impact on T cell differentiation, Th17 cells, Treg cells, STAT3, HIF-1α, and RORγt expression. ELISA measured hematopoietic growth factors in mouse serum.
RESULTS
AA patients exhibited elevated HIF-1α levels. Salidroside improved hematopoietic function, increasing blood cell count and enhancing bone marrow. Salidroside induced SCF, TPO, and IL-3 expression while inhibiting IL-2 in mice. Salidroside reduced STAT3, HIF-1α, RORγt, and IL-17a, while increasing FoxP3 expression, correcting the Th17/Treg imbalance and .
CONCLUSION
Salidroside has potential as a novel AA treatment by correcting the Th17/Treg imbalance through the STAT3/HIF-1α/RORγt pathway.
Topics: Animals; Mice; Anemia, Aplastic; Glucosides; Nuclear Receptor Subfamily 1, Group F, Member 3; T-Lymphocytes, Regulatory; Humans; STAT3 Transcription Factor; Hypoxia-Inducible Factor 1, alpha Subunit; Th17 Cells
PubMed: 37439434
DOI: 10.1080/13510002.2023.2225868 -
Leukemia Feb 2024T follicular helper (T) cell lymphomas (TFHLs) are characterized by T-like properties and accompanied by substantial immune-cell infiltration into tumor tissues....
T follicular helper (T) cell lymphomas (TFHLs) are characterized by T-like properties and accompanied by substantial immune-cell infiltration into tumor tissues. Nevertheless, the comprehensive understanding of tumor-cell heterogeneity and immune profiles of TFHL remains elusive. To address this, we conducted single-cell transcriptomic analysis on 9 lymph node (LN) and 16 peripheral blood (PB) samples from TFHL patients. Tumor cells were divided into 5 distinct subclusters, with significant heterogeneity observed in the expression levels of T markers. Copy number variation (CNV) and trajectory analyses indicated that the accumulation of CNVs, together with gene mutations, may drive the clonal evolution of tumor cells towards T-like and cell proliferation phenotypes. Additionally, we identified a novel tumor-cell-specific marker, PLS3. Notably, we found a significant increase in exhausted CD8 T cells with oligoclonal expansion in TFHL LNs and PB, along with distinctive immune evasion characteristics exhibited by infiltrating regulatory T, myeloid, B, and natural killer cells. Finally, in-silico and spatial cell-cell interaction analyses revealed complex networking between tumor and immune cells, driving the formation of an immunosuppressive microenvironment. These findings highlight the remarkable tumor-cell heterogeneity and immunoevasion in TFHL beyond previous expectations, suggesting potential roles in treatment resistance.
Topics: Humans; T-Lymphocytes, Helper-Inducer; CD8-Positive T-Lymphocytes; DNA Copy Number Variations; Lymphoma, Follicular; Biomarkers, Tumor; Phenotype; Killer Cells, Natural; Tumor Microenvironment
PubMed: 38012392
DOI: 10.1038/s41375-023-02093-7 -
Laboratory Investigation; a Journal of... Aug 2023We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after...
We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after cocultures with cancer cells using mass cytometry. In this study, a 43-marker mass cytometry panel was applied to a coculture of immune cells from healthy donors' peripheral blood mononuclear cells with diverse cancer cell lines. DNA content combined with classical CD45 surface staining was used as gating parameters for cocultures of immune cells (CD45/DNA) with hematological (CD45/DNA) and solid cancer cell lines (CD45/DNA). This strategy allows for universal discrimination of cancer cells from immune populations without the need for a specific cancer cell marker and simultaneous assessment of phenotypical changes in both populations. The use of mass cytometry allows for simultaneous detection of changes in natural killer, natural killer T cell, and T cell phenotypes and degranulation of immune populations upon target recognition, analysis of target cells for cytotoxic protein granzyme B content, and cancer cell death. These findings have broad applicability in research and clinical settings with the aim to phenotype and assess functional changes following not only NK-cancer cell interactions but also the effect of those interactions on other immune populations.
Topics: Cytotoxicity, Immunologic; Leukocytes, Mononuclear; Killer Cells, Natural; T-Lymphocytes; Coculture Techniques; Flow Cytometry; Neoplasms
PubMed: 37169083
DOI: 10.1016/j.labinv.2023.100174 -
International Journal of Laboratory... Jun 2024Schistocytes are fragmented red blood cells produced as a result of mechanical damage to erythrocytes, usually due to microangiopathic thrombotic diseases or mechanical... (Review)
Review
Schistocytes are fragmented red blood cells produced as a result of mechanical damage to erythrocytes, usually due to microangiopathic thrombotic diseases or mechanical factors. The early laboratory detection of schistocytes has a critical impact on the timely diagnosis, effective treatment, and positive prognosis of diseases such as thrombocytopenic purpura and hemolytic uremic syndrome. Due to the rapid development of science and technology, laboratory hematology has also advanced. The accuracy and efficiency of tests performed by fully automated hematology analyzers and fully automated morphology analyzers have been considerably improved. In recent years, substantial improvements in computing power and machine learning (ML) algorithm development have dramatically extended the limits of the potential of autonomous machines. The rapid development of machine learning and artificial intelligence (AI) has led to the iteration and upgrade of automated detection of schistocytes. However, along with significantly facilitated operation processes, AI has brought challenges. This review summarizes the progress in laboratory schistocyte detection, the relationship between schistocytes and clinical diseases, and the progress of AI in the detection of schistocytes. In addition, current challenges and possible solutions are discussed, as well as the great potential of AI techniques for schistocyte testing in peripheral blood.
Topics: Humans; Artificial Intelligence; Erythrocytes, Abnormal; Machine Learning
PubMed: 38472155
DOI: 10.1111/ijlh.14260