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Journal of Extracellular Biology Mar 2024Extracellular vesicles (EVs) frequently express human leukocyte antigen class I (HLA-I) molecules. The immunopeptidomes presented on EV HLA-I are being mapped to provide...
Extracellular vesicles (EVs) frequently express human leukocyte antigen class I (HLA-I) molecules. The immunopeptidomes presented on EV HLA-I are being mapped to provide key information on both specific cancer-related peptides, and for larger immunopeptidomic signatures associated with disease. Utilizing HLA-I immunoisolation and mass spectrometry, we characterised the HLA-I immunopeptidome of EVs derived from the melanoma cancer cell line, ESTDAB-026, and the plasma of 12 patients diagnosed with advanced stage melanoma, alongside 11 healthy controls. The EV HLA-I immunopeptidome derived from melanoma cells features T cell epitopes with known immunogenicity and peptides derived from known tumour associated antigens (TAAs). Both T cell epitopes with known immunogenicity and peptides derived from known TAAs were also identifiable in the melanoma patient samples. Patient stratification into two distinct groups with varying immunological profiles was also observed. The data obtained in this study suggests for the first time that the HLA-I immunopeptidome of EVs derived from blood may aid in the detection of important diagnostic or prognostic biomarkers and also provide new immunotherapy targets.
PubMed: 38939414
DOI: 10.1002/jex2.146 -
JACC. Advances Feb 2024Cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (KIM)-1 are renal biomarkers increasingly appreciated for their role in the...
BACKGROUND
Cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (KIM)-1 are renal biomarkers increasingly appreciated for their role in the risk stratification and prognostication of heart failure (HF) patients. However, very few have been adopted clinically, owing to the lack of consistency.
OBJECTIVES
The authors aimed to study the association between cystatin C, NGAL, and KIM-1 and outcomes, mortality, hospitalizations, and worsening renal function (WRF) in patients with acute and chronic HF.
METHODS
We included peer-reviewed English-language articles from PubMed and EMBASE published up to December 2021. We analyzed the above associations using random-effects meta-analysis. Publication bias was assessed using funnel plots.
RESULTS
Among 2,631 articles, 100 articles, including 45,428 patients, met the inclusion criteria. Top-tertile of serum cystatin C, when compared to the bottom-tertile, carried a higher pooled hazard ratio (pHR) for mortality (pHR: 1.59, 95% CI: 1.42-1.77) and for the composite outcome of mortality and HF hospitalizations (pHR: 1.49, 95% CI: 1.23-1.75). Top-tertile of serum NGAL had a higher hazard for mortality (pHR: 2.91, 95% CI: 1.49-5.67) and composite outcome (HR: 4.11, 95% CI: 2.69-6.30). Serum and urine NGAL were significantly associated with WRF, with pHRs of 2.40 (95% CI: 1.48-3.90) and 2.01 (95% CI: 1.21-3.35). Urine KIM-1 was significantly associated with WRF (pHR: 1.60, 95% CI: 1.24-2.07) but not with other outcomes. High heterogeneity was noted between studies without an obvious explanation based on meta-regression.
CONCLUSIONS
Serum cystatin C and serum NGAL are independent predictors of adverse outcomes in HF. Serum and urine NGAL are important predictors of WRF in HF.
PubMed: 38939376
DOI: 10.1016/j.jacadv.2023.100765 -
Frontiers in Oncology 2024Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is a severe medical emergency associated with high mortality rates and poor prognosis. Prompt and urgent...
BACKGROUND
Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is a severe medical emergency associated with high mortality rates and poor prognosis. Prompt and urgent treatment is crucial to address this medical emergency. This study aims to elucidate appropriate diagnostic thresholds for HL and investigate underlying mechanisms and potential targeted therapies.
METHODS
X-tile software was employed to analyze white blood cell (WBC) count thresholds in AML patients using data from TCGA and TARGET AML databases. METASCAPE and Gene Set Enrichment Analysis (GSEA) were conducted to explore the molecular mechanisms underlying HL in AML. Potential molecular targeted drugs were identified using the CELLMINER platform.
RESULTS
Analysis revealed that a WBC count threshold of 75×10/L, rather than the conventional 100×10/L, is more appropriate for diagnosing HL in adult AML patients. This revised threshold could aid clinicians in identifying a greater number of patients requiring immediate intervention. Significant correlations were observed between HL and specific mutations, including NPM1, FLT3, and DNMT3A. For pediatric AML patients, the HL threshold was determined to be 165×10/L. Achieving complete remission (CR) or deeper levels of remission significantly reduces the risks associated with HL. The reduction in risk can lead to survival outcomes for HL patients that are comparable to those of non-hyperleukocytosis patients. Differential gene expression analysis indicated that downregulation of cell adhesion molecules is implicated in HL pathogenesis. Potential targeted therapies for AML with HL include Bcl2 inhibitors and histone deacetylase inhibitors. Clinical observations demonstrated that the addition of Bcl2 inhibitors, such as Venetoclax, to standard therapy results in a rapid reduction in WBC counts, thereby reducing tumor burden and providing prompt symptom relief. Combining these targeted drugs with conventional therapies appears promising in mitigating risks associated with HL.
CONCLUSIONS
Lower diagnostic thresholds for HL in AML, identifies critical genetic correlations, and highlights effective molecular targeted therapies. Proactive early treatment is crucial for achieving deep remission and reducing HL risk. Future therapeutic strategies should consider integrating molecular targeted drugs with conventional therapies to improve outcomes for patients facing this high-risk hematological emergency.
PubMed: 38939329
DOI: 10.3389/fonc.2024.1412583 -
Frontiers in Microbiology 2024While significant progress has been made in understanding and applying gene silencing mechanisms and the treatment of human diseases, there have been still several... (Review)
Review
While significant progress has been made in understanding and applying gene silencing mechanisms and the treatment of human diseases, there have been still several obstacles in therapeutic use. For the first time, ONPATTRO, as the first small interfering RNA (siRNA) based drug was invented in 2018 for treatment of hTTR with polyneuropathy. Additionally, four other siRNA based drugs naming Givosiran, Inclisiran, Lumasiran, and Vutrisiran have been approved by the US Food and Drug Administration and the European Medicines Agency for clinical use by hitherto. In this review, we have discussed the key and promising advances in the development of siRNA-based drugs in preclinical and clinical stages, the impact of these molecules in bacterial and viral infection diseases, delivery system issues, the impact of administration methods, limitations of siRNA application and how to overcome them and a glimpse into future developments.
PubMed: 38939184
DOI: 10.3389/fmicb.2024.1393646 -
Experimental and Therapeutic Medicine Aug 2024Aberrant expression of long non-coding RNAs (lncRNAs) serves a crucial role in the biological function of trophoblasts and contributes to preeclampsia (PE). lncRNA...
Aberrant expression of long non-coding RNAs (lncRNAs) serves a crucial role in the biological function of trophoblasts and contributes to preeclampsia (PE). lncRNA MIR193BHG expression is increased in PE placental tissues. In the present study, the effects of MIR193BHG on the function of trophoblasts were assessed to elucidate its underlying molecular mechanisms. The subcellular localization of MIR193BHG in HTR-8/SVneo human first-trimester extravillous trophoblast cells was determined using a fluorescent hybridization assay and by conducting nucleocytoplasmic separation. The effect of MIR193BHG knockdown or overexpression on proliferation, migration, invasion and apoptosis was evaluated using Cell Counting Kit-8, wound healing, Transwell and flow cytometry assays. RNA-sequencing, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and protein-protein interaction network construction were subsequently performed to screen the downstream molecules regulated by MIR193BHG. Finally, rescue experiments were conducted to ascertain whether MIR193BHG influenced the biological function of trophoblasts via p53. MIR193BHG was predominantly localized in the nucleus of HTR-8/SVneo cells and overexpression of MIR193BHG significantly inhibited proliferation, migration and invasion, while increasing the rate of apoptosis of HTR-8/SVneo cells. Knockdown of MIR193BHG had the opposite effect. Furthermore, overexpression of MIR193BHG led to increases in both mRNA and protein levels of p53 compared with the control group, and knockdown of p53 rescued the effects induced by overexpression of MIR193BHG on cell proliferation, migration and invasion, while partially counteracting its effects on apoptosis of HTR-8/SVneo cells. In conclusion, the findings of the present study suggested that MIR193BHG served a critical role in progression of PE by regulating the expression of p53, and may be a novel therapeutic target for PE.
PubMed: 38939173
DOI: 10.3892/etm.2024.12609 -
Chemical Science Jun 2024Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There...
Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant ; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in . This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.
PubMed: 38939155
DOI: 10.1039/d4sc00995a -
Chemical Science Jun 2024Alkali metal alkoxides play a pivotal role in nucleophilic alkoxylation reactions, offering pathways for the synthesis of ethers, including the increasingly sought-after...
Alkali metal alkoxides play a pivotal role in nucleophilic alkoxylation reactions, offering pathways for the synthesis of ethers, including the increasingly sought-after trifluoromethyl ethers. However, the synthesis of long-chain perfluoroalkyl ethers remains a substantial challenge in this field. Through the innovative use of triglyme to encapsulate potassium ions, we enhanced the stability of short-lived, longer-chain perfluoroalkoxy anions, thereby facilitating efficient nucleophilic perfluoroalkoxylation reactions. This method provides a new precedent for the halo-perfluoroalkoxylation of -difluoroalkenes and offers a versatile tool for the design of perfluoroalkyl ethers, including those containing complex moieties of heterocycles and drug molecules. We also demonstrated the utility of the resulting halo-perfluoroalkoxyl adducts through various chemical transformations to valuable diverse perfluoroalkyl ethers.
PubMed: 38939153
DOI: 10.1039/d4sc02084g -
Chemical Science Jun 2024Secreted phospholipase A2 (sPLA2) is a Ca-dependent, widely distributed enzyme superfamily in almost all mammalian tissues and bacteria. It is also a critical component...
Secreted phospholipase A2 (sPLA2) is a Ca-dependent, widely distributed enzyme superfamily in almost all mammalian tissues and bacteria. It is also a critical component of the venom of nearly all snakes, as well as many invertebrate species. In non-venomous contexts, sPLA2 assumes significance in cellular signaling pathways by binding cell membranes and catalyzing ester bond hydrolysis at the sn-2 position of phospholipids. Elevated levels of GIIA sPLA2 have been detected in the synovial fluid of arthritis patients, where it exhibits a pro-inflammatory function. Consequently, identifying sPLA2 inhibitors holds promise for creating highly effective pharmaceutical treatments. Beyond arthritis, the similarities among GIIA sPLA2s offer an opportunity for developing treatments against snakebite envenoming, the deadliest neglected tropical disease. Despite decades of study, the details of PLA2 membrane-binding, substrate-binding, and reaction mechanism remain elusive, demanding a comprehensive understanding of the sPLA2 catalytic mechanism. This study explores two reaction mechanism hypotheses, involving one or two water molecules, and distinct roles for the Ca cofactor. Our research focuses on the human synovial sPLA2 enzyme bound to lipid bilayers of varying phospholipid compositions, and employing adiabatic QM/MM and QM/MM MD umbrella sampling methods to energetically and geometrically characterize the structures found along both reaction pathways. Our studies demonstrate the higher frequency of productive conformations within the single-water pathway, also revealing a lower free energy barrier for hydrolyzing POPC. Furthermore, we observe that the TS of this concerted one-step reaction closely resembles transition state geometries observed in X-ray crystallography complexes featuring high-affinity transition state analogue inhibitors.
PubMed: 38939148
DOI: 10.1039/d4sc02315c -
Chemical Science Jun 2024Cells are covered with a thick layer of sugar molecules known as glycans. Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis...
Cells are covered with a thick layer of sugar molecules known as glycans. Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis by promoting immune evasion and inducing tumor cell invasion and migration. Inhibiting sialylation is thus a potential anticancer treatment strategy. However, targeting sialic acids is difficult because of the lack of selective delivery tools. Here, we present a prodrug strategy for selectively releasing the global inhibitor of sialylation peracetylated 3F-Neu5Ac (PFN) in cancer cells using the reaction between phenyl azide and endogenous acrolein, which is overproduced in most cancer cells. The prodrug significantly suppressed tumor growth in mice as effectively as PFN without causing kidney dysfunction, which is associated with PFN. The use of sialylated glycans as immune checkpoints is gaining increasing attention, and the proposed method for precisely targeting aberrant sialylation provides a novel avenue for expanding current cancer treatments.
PubMed: 38939146
DOI: 10.1039/d4sc00969j -
Chemical Science Jun 2024Highly efficient degradation of antibiotics is a huge challenge due to the extremely stable molecules and the potential for biological resistance. However, conventional...
Highly efficient degradation of antibiotics is a huge challenge due to the extremely stable molecules and the potential for biological resistance. However, conventional degradation methods are limited to lower degradation rate, higher energy consumption and secondary pollution. Herein, we report a new Cu-based metal-organic framework (MOF), featuring classical planar trinuclear [Cu(µ-O)] clusters within the pores. The presence of the rich open metal sites and the large pore ratio, as well as the high catalytic activity of Cu ions, are conducive to boosting the degradation of various antibiotics (>95%) under the activation of peroxymonosulfate. Remarkably, this is the first MOF to achieve such exceptional catalytic performance under neutral and even alkaline conditions, which exceeds those of most reported materials. Mechanism investigation demonstrates that multiple active species were produced and promoted the degradation synergistically during the advanced oxidation processes.
PubMed: 38939145
DOI: 10.1039/d4sc02850c