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Osteoarthritis and Cartilage Jun 2024To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with...
OBJECTIVE
To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function.
DESIGN
ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by magnetic resonance imaging, function and pain by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression.
RESULTS
S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post-treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope -0.8×10 [-2.9×10, 1.3×10]) or change in WOMAC pain and function (slopes -30×10 [-64×10, 5.2×10] and -97×10 [-214×10, 20×10], respectively) at week 52.
CONCLUSION
Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function.
PubMed: 38862084
DOI: 10.1016/j.joca.2024.06.003 -
JCI Insight Jun 2024
Topics: Diet, High-Fat; Animals; Bile Acids and Salts; Intestinal Mucosa; Mice; Cell Proliferation; Up-Regulation; Humans; Thrombospondins; Male
PubMed: 38855870
DOI: 10.1172/jci.insight.181492 -
Circulation. Genomic and Precision... Jun 2024Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM.
METHODS
Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels.
RESULTS
Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; =0.044).
CONCLUSIONS
In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.
Topics: Humans; Cardiomyopathy, Hypertrophic; Biomarkers; Child; Female; Male; Child, Preschool; Adolescent; Prognosis; Proteomics; Infant; Adult
PubMed: 38847081
DOI: 10.1161/CIRCGEN.123.004448 -
Clinical Epigenetics Jun 2024Stroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Stroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis.
METHODS AND RESULTS
To that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N = 316] and St. Pau [replication, N = 92]). Functional outcome was assessed using the modified Rankin Scale (mRS) at three months after stroke, being poor outcome defined as mRS > 2. DNAm was determined using the 450K and EPIC BeadChips in whole-blood samples collected within the first 24 h. We searched for differentially methylated positions (DMPs) in 370,344 CpGs, and candidates below p-value < 10 were subsequently tested in the replication cohort. We then meta-analyzed DMP results from both cohorts and used them to identify differentially methylated regions (DMRs). After doing the epigenome-wide association study, we found 29 DMPs at p-value < 10 and one of them was replicated: cg24391982, annotated to thrombospondin-2 (THBS2) gene (p-value = 1.54·10; p-value = 9.17·10; p-value = 6.39·10). Besides, four DMRs were identified in patients with poor outcome annotated to zinc finger protein 57 homolog (ZFP57), Arachidonate 12-Lipoxygenase 12S Type (ALOX12), ABI Family Member 3 (ABI3) and Allantoicase (ALLC) genes (p-value < 1·10 in all cases).
DISCUSSION
Patients with poor outcome showed a DMP at THBS2 and four DMRs annotated to ZFP57, ALOX12, ABI3 and ALLC genes. This suggests an association between stroke outcome and DNAm, which may help identify new stroke recovery mechanisms.
Topics: Humans; DNA Methylation; Female; Prognosis; Male; Genome-Wide Association Study; Aged; Middle Aged; Epigenesis, Genetic; Epigenome; Stroke; CpG Islands; Ischemic Stroke; Thrombospondins
PubMed: 38845005
DOI: 10.1186/s13148-024-01690-2 -
Cureus May 2024Introduction This study aims to evaluate the histology of the ligamentum teres and its relationship with matrix metalloproteinases (MMPs) and a disintegrin and...
Introduction This study aims to evaluate the histology of the ligamentum teres and its relationship with matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which are involved in the destruction of extracellular matrix proteins in patients with developmental dysplasia of the hip (DDH). Methodology The patients who underwent open reduction and pelvic osteotomy due to DDH were included in the study. Patient groups were formed according to Tönnis stages, positive family history, consanguineous marriage, age, and bilateral involvement. The histology and immunohistochemical properties (MMP-2, MMP-9, and ADAMTS-7) of ligamentum teres tissue obtained from the patients were evaluated according to these groups. Results Thirty-five patients (female 30, 85.7%; male 5, 14.3%) with DDH between the ages of 14 and 99 months were included in the study. Preoperative and postoperative Tönnis stages, positive family history, consanguineous marriage, age, and bilaterality did not cause a significant difference between histological parameters. A significant correlation was found between MMP-2, MMP-9, and ADAMTS-7 and all histological parameters. Conclusions The histological structure of ligamentum teres in patients with DDH shows moderate inflammation, fibrosis, neovascularization, hyalinization, and fatty infiltration regardless of age and radiological stage. ADAMTS-7, MMP-2, and MMP-9 correlate positively with the histological parameters of the ligamentum teres in patients with DDH.
PubMed: 38841047
DOI: 10.7759/cureus.59748 -
Biology Direct Jun 2024Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. The intercellular communication in post-infarction angiogenesis remains unclear.
BACKGROUND
Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. The intercellular communication in post-infarction angiogenesis remains unclear.
METHODS
In this study, we explored the role and mechanism of action of M2 macrophage-derived exosomes (M2-exos) in angiogenesis after MI. M2-exos were harvested and injected intramyocardially at the onset of MI. Two distinct endothelial cells (ECs) were cultured with M2-exos to explore the direct effects on angiogenesis.
RESULTS
We showed that M2-exos improved cardiac function, reduced infarct size, and enhanced angiogenesis after MI. Moreover, M2-exos promoted angiogenesis in vitro; the molecules loaded in the vesicles were responsible for its proangiogenic effects. We further validated that higher abundance of miR-132-3p in M2-exos, which recapitulate their functions, was required for the cardioprotective effects exerted by M2-exos. Mechanistically, miR-132-3p carried by M2-exos down-regulate the expression of THBS1 through direct binding to its 3´UTR and the proangiogenic effects of miR-132-3p were largely reversed by THBS1 overexpression.
CONCLUSION
Our findings demonstrate that M2-exos promote angiogenesis after MI by transporting miR-132-3p to ECs, and by binding to THBS1 mRNA directly and negatively regulating its expression. These findings highlight the role of M2-exos in cardiac repair and provide novel mechanistic understanding of intercellular communication in post-infarction angiogenesis.
Topics: Myocardial Infarction; Exosomes; Animals; MicroRNAs; Macrophages; Neovascularization, Physiologic; Mice; Male; Humans; Endothelial Cells; Thrombospondin 1; Mice, Inbred C57BL; Angiogenesis
PubMed: 38840223
DOI: 10.1186/s13062-024-00485-y -
Hepatology Research : the Official... Jun 2024Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after a...
Ratio of von Willebrand factor to ADAMTS13 is a useful predictor of esophagogastric varices progression after sustained virologic response in patients with hepatitis C virus-related liver cirrhosis.
AIM
Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after a sustained virologic response (SVR) is achieved with direct-acting antiviral (DAA) treatment; however, in some cases, EGV exacerbation occurs after HCV elimination. We investigated whether von Willebrand factor (VWF) and a disintegrin-like metalloproteinase with thrombospondin type-1 motif 13 (ADAMTS13) can predict EGV progression with HCV-LC after SVR achievement.
METHODS
This retrospective study enrolled 47 patients with HCV-LC who achieved an SVR after DAA treatment. Eighteen patients experienced EGV progression after the SVR was achieved (EGV progression group). Twenty-nine patients did not experience EGV progression after the SVR was achieved (non-EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment.
RESULTS
The EGV progression group had significantly higher plasma VWF antigen levels (p = 0.00331) and VWF-to-ADAMTS13 ratios (p = 0.000249) than the non-EGV progression group. Multivariate logistic regression models found that a VWF-to-ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after the SVR was achieved (hazard ratio [HR], 18.4; 95% confidence interval [CI], 3.08-109; p = 0.00138). During the observation period, patients with a VWF-to-ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after SVR achievement than patients with a VWF-to-ADAMTS13 ratio ≤2.3 (HR, 6.4; 95% CI, 1.78-22.96; p = 0.0044).
CONCLUSIONS
The VWF-to-ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR achievement.
PubMed: 38838066
DOI: 10.1111/hepr.14077 -
Single-Cell Spatial Transcriptomics Unveils Platelet-Fueled Cycling Macrophages for Kidney Fibrosis.Advanced Science (Weinheim,... Jun 2024With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including...
With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, the detrimental role of platelets in renal recovery following ischemia/reperfusion injury and its contribution to acute kidney injury to chronic kidney disease transition is aimed to investigated. In this study, it is shown that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single-cell and spatial transcriptomic techniques, macrophages as the primary mediators modulated by platelet signals is identified. A novel subset of macrophages, termed "cycling M2", which exhibit an M2 phenotype combined with enhanced proliferative activity is uncovered. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet-derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, targeted inhibition of THBS1 markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, this findings highlight the adverse role of platelet THBS1-boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating inflammation and kidney fibrosis.
PubMed: 38838052
DOI: 10.1002/advs.202308505 -
Computational and Structural... Dec 2024Acting as mediators in cell-matrix and cell-cell communication, matricellular proteins play a crucial role in cancer progression. Thrombospondins (TSPs), a type of...
BACKGROUND
Acting as mediators in cell-matrix and cell-cell communication, matricellular proteins play a crucial role in cancer progression. Thrombospondins (TSPs), a type of matricellular glycoproteins, are key regulators in cancer biology with multifaceted roles. Although TSPs have been implicated in anti-tumor immunity and epithelial-mesenchymal transition (EMT) in several malignancies, their specific roles to colon cancer remain elusive. Addressing this knowledge gap is essential, as understanding the function of TSPs in colon cancer could identify new therapeutic targets and prognostic markers.
METHODS
Analyzing 1981 samples from 10 high-throughput datasets, including six bulk RNA-seq, three scRNA-seq, and one spatial transcriptome dataset, our study investigated the prognostic relevance, risk stratification value, immune heterogeneity, and cellular origin of TSPs, as well as their influence on cancer-associated fibroblasts (CAFs). Utilizing survival analysis, unsupervised clustering, and functional enrichment, along with multiple correlation analyses of the tumor-microenvironment (TME) via Gene Set Variation Analysis (GSVA), spatial localization, Monocle2, and CellPhoneDB, we provided insights into the clinical and cellular implications of TSPs.
RESULTS
First, we observed significant upregulation of and in colon cancer, both of which displayed significant prognostic value. Additionally, we detected a significant positive correlation between TSPs and immune cells, as well as marker genes of EMT. Second, based on TSPs expression, patients were divided into two clusters with distinct prognoses: the high TSPs expression group (TSPs-H) was characterized by pronounced immune and stromal cell infiltration, and notably elevated T-cell exhaustion scores. Subsequently, we found that and may be associated with the differentiation of CAFs into pan-iCAFs and pan-dCAFs, which are known for their heightened matrix remodeling activities. Moreover, enhanced CAFs communication with vascular endothelial cells and monocyte-macrophages. CAFs expressing ( CAFs) demonstrated higher scores across multiple signaling pathways, including angiogenic, EMT, Hedgehog, Notch, Wnt, and TGF-β, when compared to CAFs. These observations suggest that may be associated with stronger pro-carcinogenic activity in CAFs.
CONCLUSIONS
This study revealed the crucial role of TSPs and the significant correlation between THBS2 and CAFs interactions in colon cancer progression, providing valuable insights for targeting TSPs to mitigate cancer progression.
PubMed: 38827236
DOI: 10.1016/j.csbj.2024.05.021 -
BioFactors (Oxford, England) May 2024Despite advancements in cancer research, the prognostic implications of competing endogenous RNA (ceRNA) networks in prostate cancer (PCa) remain incompletely...
Despite advancements in cancer research, the prognostic implications of competing endogenous RNA (ceRNA) networks in prostate cancer (PCa) remain incompletely understood. This study aimed to elucidate the prognostic relevance of ceRNA networks in PCa, utilizing a comprehensive bioinformatics approach alongside experimental validation. After searching The Cancer Genome Atlas (TCGA) database, RNA sequencing (RNA-Seq) data were extracted to identify differentially expressed RNAs (DERs) between 491 PCa samples and 51 normal prostate tissues, following which a comprehensive bioinformatics strategy was implemented to construct a ceRNA network. An optimal prognostic signature comprising these DERs was then established and validated using TCGA data. In addition, functional validation was performed through RNA pull-down, dual-luciferase reporter assays, quantitative real-time PCR, and western blot analysis conducted in PC-3 and DU145 cell lines, thereby complementing the bioinformatics analysis. A total of 613 DERs, comprising 103 long noncoding RNAs (lncRNAs), 60 microRNAs (miRNAs), and 450 messenger RNAs (mRNAs), were identified and utilized in constructing a ceRNA network, which encompassed 23 lncRNAs, 9 miRNAs, and 52 mRNAs. An optimal prognostic signature was established, including VPS9D1 antisense RNA 1 (VPS9D1-AS1), miR-449a, cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1), targeting protein for Xklp2 (TPX2), solute carrier family 7 member 11 (SLC7A11), copine7 (CPNE7), and maternal embryonic leucine zipper kinase (MELK), yielding area under the curve (AUC) values exceeding 0.8 across training, validation, and entire datasets. Our experiments results revealed an interaction between lncRNA TRHDE antisense RNA 1 (TRHDE-AS1) and miR-449a and that miR-449a could target the ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) mRNA. Knockdown of miR-449a significantly impeded cell proliferation, G1/S transition, migration and invasion, and promoted apoptosis in PC-3 and DU145 cells. Furthermore, knockdown of miR-449a notably downregulated protein expression of CDK4, cyclin D1, N-cadherin and vimentin, while upregulating protein expression of cleaved caspase-3 and E-cadherin. This study contributes to a deeper understanding of the prognostic-linked ceRNA network in PCa, providing fundamental insights that could improve diagnostic and therapeutic approaches for PCa management.
PubMed: 38818922
DOI: 10.1002/biof.2083