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Nature Communications Jun 2024Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic...
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Topics: Animals; Humans; Dendritic Cells; Mice; Phosphatidylinositol 3-Kinases; CD11c Antigen; Morpholines; Cell Line, Tumor; Immunotherapy; Neoplasms; Mice, Inbred C57BL; Female; Immune Checkpoint Inhibitors; NF-kappa B; T-Lymphocytes; Protein Kinase Inhibitors; Hydrazones; Pyrimidines
PubMed: 38942798
DOI: 10.1038/s41467-024-48931-9 -
Medicine Jun 2024Neutrophil to lymphocyte ratio (NLR) has been considered a prognostic biomarker of mortality and other major cardiac events. This study investigates NLR's efficacy in... (Meta-Analysis)
Meta-Analysis
Neutrophil to lymphocyte ratio as a prognostic marker for cardiovascular outcomes in patients with ST-segment elevation myocardial infarction after percutaneous coronary intervention: A systematic review and meta-analysis.
BACKGROUND
Neutrophil to lymphocyte ratio (NLR) has been considered a prognostic biomarker of mortality and other major cardiac events. This study investigates NLR's efficacy in predicting in-hospital and long-term outcomes in patients with ST-segment elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).
METHODS
Electronic databases (PUBMED, Cochrane CENTRAL, ERIC, Embase, Ovid, and Google Scholar) were searched till June 2022 to identify studies having STEMI patients who underwent PCI. Risk ratios and mean differences (MDs), along with their corresponding 95% confidence intervals (Cis) and standard deviations (SDs), were pooled using a random-effect model. This meta-analysis has been registered on Prospero (ID: CRD42022344072).
RESULTS
A total of 35 studies with 28,756 patients were included. Pooled estimates revealed an increased incidence of primary outcomes; in-hospital all-cause mortality (RR = 3.52; 95% CI = 2.93-4.24), long-term all-cause mortality (HR = 1.07; 95% CI = 1.00-1.14), (RR = 3.32; 95% CI = 2.57-4.30); in-hospital cardiovascular mortality (RR = 2.66; 95% CI = 2.04-3.48), long-term cardiovascular mortality (RR = 6.67; 95% CI = 4.06-10.95); in-hospital major adverse cardiovascular events (MACE) (RR = 1.31; 95% CI = 1.17-1.46), long-term MACE (RR = 2.92; 95% CI = 2.16-3.94); length of hospital stay (WMD = 0.60 days; 95% CI = 0.40-0.79) in patients with high NLR compared to those with a low NLR.
CONCLUSION
NLR might be a valuable tool for prognostication (in-hospital) and stratification of patients with STEMI who underwent PCI.
Topics: Humans; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Neutrophils; Prognosis; Lymphocytes; Biomarkers; Lymphocyte Count; Hospital Mortality
PubMed: 38941418
DOI: 10.1097/MD.0000000000038692 -
Medicine Jun 2024Although the link between hepatic steatosis and lung function has been confirmed, the focus has largely been on central airways. The association between hepatic... (Observational Study)
Observational Study
Elevated neutrophil-to-lymphocyte ratio combined with decreased lymphocyte-to-monocyte ratio is associated with increased peripheral airway resistance in patients with hepatic steatosis.
Although the link between hepatic steatosis and lung function has been confirmed, the focus has largely been on central airways. The association between hepatic steatosis and increased peripheral airway resistance has not yet been explored. Hepatic steatosis and increased peripheral resistance are connected with immunity dysregulation. High neutrophil-to-lymphocyte ratio (NLR) and low lymphocyte-to-monocyte ratio (LMR) have been recognized as indicators of immunity dysregulation. In this study, the association between hepatic steatosis and increased peripheral airway resistance was evaluated, and the effect of immunity dysregulation (high NLR/low LMR) on the increased peripheral airway resistance among patients with hepatic steatosis was explored. In this retrospective study, chest or abdomen CT scans and spirometry/impulse oscillometry (IOS) from 2018 to 2019 were used to identify hepatic steatosis and increased central/peripheral airway resistance in patients. Among 1391 enrolled patients, 169 (12.1%) had hepatic steatosis. After 1:1 age and abnormal ALT matching was conducted, clinical data were compared between patients with and without hepatic steatosis. A higher proportion of patients with hepatic steatosis had increased peripheral airway resistance than those without hepatic steatosis (52.7% vs 40.2%, P = .025). Old age, high body mass index, history of diabetes, and high NLR/low LMR were significantly correlated with increased peripheral airway resistance. The presence of hepatic steatosis is associated with increased peripheral airway. High NLR/low LMR is an independent associated factor of increased peripheral airway resistance in patients with hepatic steatosis. It is advisable for patients with hepatic steatosis to regularly monitor their complete blood count/differential count and undergo pulmonary function tests including IOS.
Topics: Humans; Male; Female; Middle Aged; Retrospective Studies; Neutrophils; Lymphocytes; Monocytes; Airway Resistance; Fatty Liver; Adult; Aged; Leukocyte Count; Lymphocyte Count
PubMed: 38941417
DOI: 10.1097/MD.0000000000038530 -
Cancer Medicine Jul 2024Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and...
INTRODUCTION
Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98-BPTF (NB) fusion in patients with T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing. The FG-repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown.
MATERIALS AND METHODS
To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline-inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T-ALL cells.
RESULTS
NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto-oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB-induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T-ALL cells by inactivating the pro-apoptotic protein BCL2-associated agonist of cell death (BAD).
CONCLUSION
We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.
Topics: Humans; Proto-Oncogene Proteins c-pim-1; Animals; Mice; Cell Transformation, Neoplastic; Nuclear Pore Complex Proteins; Oncogene Proteins, Fusion; Jurkat Cells; Up-Regulation; NIH 3T3 Cells; Proto-Oncogene Mas; Transcription Factors; Apoptosis; Cell Proliferation
PubMed: 38940430
DOI: 10.1002/cam4.7445 -
Bioinformatics (Oxford, England) Jun 2024Profiling of gene expression and chromatin accessibility by single-cell multi-omics approaches can help to systematically decipher how transcription factors (TFs)...
MOTIVATION
Profiling of gene expression and chromatin accessibility by single-cell multi-omics approaches can help to systematically decipher how transcription factors (TFs) regulate target gene expression via cis-region interactions. However, integrating information from different modalities to discover regulatory associations is challenging, in part because motif scanning approaches miss many likely TF binding sites.
RESULTS
We develop REUNION, a framework for predicting genome-wide TF binding and cis-region-TF-gene "triplet" regulatory associations using single-cell multi-omics data. The first component of REUNION, Unify, utilizes information theory-inspired complementary score functions that incorporate TF expression, chromatin accessibility, and target gene expression to identify regulatory associations. The second component, Rediscover, takes Unify estimates as input for pseudo semi-supervised learning to predict TF binding in accessible genomic regions that may or may not include detected TF motifs. Rediscover leverages latent chromatin accessibility and sequence feature spaces of the genomic regions, without requiring chromatin immunoprecipitation data for model training. Applied to peripheral blood mononuclear cell data, REUNION outperforms alternative methods in TF binding prediction on average performance. In particular, it recovers missing region-TF associations from regions lacking detected motifs, which circumvents the reliance on motif scanning and facilitates discovery of novel associations involving potential co-binding transcriptional regulators. Newly identified region-TF associations, even in regions lacking a detected motif, improve the prediction of target gene expression in regulatory triplets, and are thus likely to genuinely participate in the regulation.
AVAILABILITY AND IMPLEMENTATION
All source code is available at https://github.com/yangymargaret/REUNION.
Topics: Transcription Factors; Humans; Single-Cell Analysis; Binding Sites; Chromatin; Genomics; Software; Computational Biology; Protein Binding; Algorithms; Leukocytes, Mononuclear; Multiomics
PubMed: 38940155
DOI: 10.1093/bioinformatics/btae234 -
Frontiers in Bioscience (Landmark... Jun 2024Persistent hyperuricemia can lead to the generation and deposition of monosodium urate (MSU) crystals. This can trigger gouty arthritis (GA), which in turn induces...
BACKGROUND
Persistent hyperuricemia can lead to the generation and deposition of monosodium urate (MSU) crystals. This can trigger gouty arthritis (GA), which in turn induces inflammation. Activation of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the onset and progression of GA. Autophagy may have a dual effect on GA with regard to the NLRP3 inflammasome. Therefore, the present study aimed to gain a deeper comprehension of the interaction between autophagy and NLRP3 inflammasome activation is imperative for developing more efficacious treatments for GA.
METHODS
Peripheral blood monocytes (PBMCs) were first isolated from GA patients and healthy controls and underwent bulk RNA sequencing analysis. Overexpression and knockdown of dual specificity phosphatase 1 (DUSP1) was performed in THP-1 monocytes to investigate its role in the immune response and mitochondrial damage. The luciferase assay and Western blot analysis were used to study the interaction between autophagy and NLRP3 inflammasome activation.
RESULTS
Bulk RNA sequencing analysis showed significant upregulation of DUSP1 expression in PBMCs from GA patients compared to healthy controls. This result was subsequently verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). DUSP1 expression in human THP-1 monocytes was also shown to increase after MSU treatment. Downregulation of DUSP1 expression increased the secretion of inflammatory cytokines after MSU treatment, whereas the overexpression of DUSP1 decreased the secretion levels. Lipopolysaccharides (LPS) combined with adenosine-triphosphate (ATP) led to mitochondrial damage, which was rescued by overexpressing DUSP1. DUSP1 overexpression further increased the level of autophagy following MSU treatment, whereas downregulation of DUSP1 decreased autophagy. Treatment with the autophagy inhibitor 3-Methyladenine (3-MA) restored inflammatory cytokine secretion levels in the DUSP1 overexpression group. MSU caused pronounced pathological ankle swelling . However, DUSP1 overexpression significantly mitigated this phenotype, accompanied by significant downregulation of inflammatory cytokine secretion levels in the joint tissues.
CONCLUSIONS
This study revealed a novel function and mechanism for DUSP1 in promoting autophagy to mitigate the MSU-induced immune response in GA. This finding suggests potential diagnostic biomarkers and anti-inflammatory targets for more effective GA therapy.
Topics: Humans; Autophagy; Dual Specificity Phosphatase 1; Arthritis, Gouty; Uric Acid; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; THP-1 Cells; Male; Monocytes; Case-Control Studies; Female; Leukocytes, Mononuclear; Middle Aged
PubMed: 38940057
DOI: 10.31083/j.fbl2906222 -
Frontiers in Immunology 2023Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus...
Inhibition of miRNA associated with a disease-specific signature and secreted via extracellular vesicles of systemic lupus erythematosus patients suppresses target organ inflammation in a humanized mouse model.
INTRODUCTION
Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice.
METHODS
Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination.
RESULTS
EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3.
DISCUSSION
These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE.
Topics: Lupus Erythematosus, Systemic; Humans; Animals; MicroRNAs; Extracellular Vesicles; Mice; Disease Models, Animal; Female; Leukocytes, Mononuclear; Toll-Like Receptor 7; Inflammation; Toll-Like Receptor 8; Adult; Male; Middle Aged; Mice, SCID
PubMed: 38939646
DOI: 10.3389/fimmu.2023.1090177 -
Oncoimmunology 2024The need for reliable biomarkers to predict clinical benefit from anti-PD1 treatment in metastatic melanoma (MM) patients remains unmet. Several parameters have been...
The need for reliable biomarkers to predict clinical benefit from anti-PD1 treatment in metastatic melanoma (MM) patients remains unmet. Several parameters have been considered in the tumor environment or the blood, but none has yet achieved sufficient accuracy for routine clinical practice. Whole blood samples from MM patients receiving second-line anti-PD1 treatment (NCT02626065), collected longitudinally, were analyzed by flow cytometry to assess the immune cell subsets absolute numbers, the expression of immune checkpoints or ligands on T cells and the functionality of innate immune cells and T cells. Clinical response was assessed according to Progression-Free Survival (PFS) status at one-year following initiation of anti-PD1 (responders: PFS > 1 year; non-responders: PFS ≤ 1 year). At baseline, several phenotypic and functional alterations in blood immune cells were observed in MM patients compared to healthy donors, but only the proportion of polyfunctional memory CD4+ T cells was associated with response to anti-PD1. Under treatment, a decreased frequency of HVEM on CD4+ and CD8+ T cells after 3 months of treatment identified responding patients, whereas its receptor BTLA was not modulated. Both reduced proportion of CD69-expressing CD4+ and CD8+ T cells and increased number of polyfunctional blood memory T cells after 3 months of treatment were associated with response to anti-PD1. Of upmost importance, the combination of changes of all these markers accurately discriminated between responding and non-responding patients. These results suggest that drugs targeting HVEM/BTLA pathway may be of interest to improve anti-PD1 efficacy.
Topics: Humans; Melanoma; Male; Receptors, Immunologic; Female; Middle Aged; Aged; Programmed Cell Death 1 Receptor; Receptors, Tumor Necrosis Factor, Member 14; Immune Checkpoint Inhibitors; Adult; Treatment Outcome; CD8-Positive T-Lymphocytes
PubMed: 38939518
DOI: 10.1080/2162402X.2024.2372118 -
Frontiers in Cellular and Infection... 2024Recent studies have demonstrated a positive role of hyaluronic acid (HA) on periodontal clinical outcomes. This study aimed to investigate the impact of four different...
INTRODUCTION
Recent studies have demonstrated a positive role of hyaluronic acid (HA) on periodontal clinical outcomes. This study aimed to investigate the impact of four different HAs on interactions between periodontal biofilm and immune cells.
METHODS
The four HAs included: high-molecular-weight HA (HHA, non-cross-linked), low-molecular-weight HA (LHA), oligomers HA (OHA), and cross-linked high-molecular-weight HA (CHA). Serial experiments were conducted to verify the influence of HAs on: (i) 12-species periodontal biofilm (formation and pre-existing); (ii) expression of inflammatory cytokines and HA receptors in monocytic (MONO-MAC-6) cells and periodontal ligament fibroblasts (PDLF) with or without exposure to periodontal biofilms; (iii) generation of reactive oxygen species (ROS) in MONO-MAC-6 cells and PDLF with presence of biofilm and HA.
RESULTS
The results indicated that HHA and CHA reduced the bacterial counts in a newly formed (4-h) biofilm and in a pre-existing five-day-old biofilm. Without biofilm challenge, OHA triggered inflammatory reaction by increasing IL-1β and IL-10 levels in MONO-MAC cells and IL-8 in PDLF in a time-dependent manner, whereas CHA suppressed this response by inhibiting the expression of IL-10 in MONO-MAC cells and IL-8 in PDLF. Under biofilm challenge, HA decreased the expression of IL-1β (most decreasing HHA) and increased IL-10 levels in MONO-MAC-6 cells in a molecular weight dependent manner (most increasing CHA). The interaction between HA and both cells may occur via ICAM-1 receptor. Biofilm stimulus increased ROS levels in MONO-MAC-6 cells and PDLF, but only HHA slightly suppressed the high generation of ROS induced by biofilm stimulation in both cells.
CONCLUSION
Overall, these results indicate that OHA induces inflammation, while HHA and CHA exhibit anti-biofilm, primarily anti-inflammatory, and antioxidant properties in the periodontal environment.
Topics: Biofilms; Hyaluronic Acid; Humans; Reactive Oxygen Species; Fibroblasts; Cytokines; Monocytes; Periodontal Ligament; Cell Line; Interleukin-1beta; Interleukin-10
PubMed: 38938883
DOI: 10.3389/fcimb.2024.1414861 -
Frontiers in Immunology 2024Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer...
Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer development. Conventional therapies achieve only limited efficiency, especially in recurrent or metastatic HNSCC. As the immune landscape decisively impacts the survival of patients and treatment efficacy, this study comprehensively investigated the immunological tumor microenvironment (TME) and its association with patient outcome, with special focus on several dendritic cell (DC) and T lymphocyte subpopulations. Therefore, formalin-fixed paraffin-embedded tumor samples of 56 HNSCC patients, who have undergone resection and adjuvant radiotherapy, were analyzed by multiplex immunohistochemistry focusing on the detailed phenotypic characterization and spatial distribution of DCs, CD8 T cells, and T-helper cell subsets in different tumor compartments. Immune cell densities and proportions were correlated with clinical characteristics of the whole HNSCC cohort and different HPV- or hypoxia-associated subcohorts. Tumor stroma was highly infiltrated by plasmacytoid DCs and T lymphocytes. Among the T-helper cells and CD8 T cells, stromal regulatory T cells and intraepithelial exhausted CD8 T cells expressing programmed cell death protein-1 (PD-1) and/or lymphocyte-activation gene-3 (LAG-3) were the predominant phenotypes, indicating an immunosuppressive TME. HPV-associated tumors showed significantly higher infiltration of type I and type II conventional DCs (cDC1, cDC2) as well as several CD8 T cell phenotypes including exhausted, activated, and proliferating T cells. On the contrary, tumors with hypoxia-associated gene signatures exhibited reduced infiltration for these immune cells. By multivariate Cox regression, immune-related prognostic factors were identified. Patient clusters defined by high infiltration of DCs and T lymphocytes combined with HPV positivity or low hypoxia showed significantly prolonged survival. Thereby, cDC1 and CD8 T cells emerged as independent prognostic factors for local and distant recurrence. These results might contribute to the implementation of an immune cell infiltration score predicting HNSCC patients' survival and such patient stratification might improve the design of future individualized radiochemo-(immuno)therapies.
Topics: Humans; Dendritic Cells; Squamous Cell Carcinoma of Head and Neck; Male; Female; CD8-Positive T-Lymphocytes; Middle Aged; Tumor Microenvironment; Head and Neck Neoplasms; Aged; Lymphocytes, Tumor-Infiltrating; Prognosis; Adult; Papillomavirus Infections
PubMed: 38938577
DOI: 10.3389/fimmu.2024.1414298