Cilostazol plus Aspirin vs. Clopidogrel plus Aspirin in Acute Minor Stroke or Transient Ischemic Attack.

AIM: This study compared the effectiveness, safety, and mortality risks between cilostazol plus aspirin and clopidogrel plus aspirin treatment for patients with acute minor ischemic stroke or transient ischemic attack (TIA). METHODS: This retrospective cohort study employed a new-user design and utilized data from the nationwide Health and Welfare Database in Taiwan. Patients were included if they were discharged with newly initiated cilostazol plus aspirin or clopidogrel plus aspirin after primary acute minor ischemic stroke or TIA hospitalization between 2009 and 2018. Inverse probability of treatment weighting was applied to balance covariates between study groups. Effectiveness outcomes were the risks of acute ischemic stroke, acute myocardial infarction (AMI), TIA, and composite cardiovascular events; Safety outcomes were the risks of intracranial hemorrhage (ICH), gastrointestinal bleeding, and composite bleeding events; Mortality outcomes were the risks of fatal stroke, cardiovascular mortality, and all-cause mortality. RESULTS: A total of 3,403 patients were included, of which 578 were treated with cilostazol plus aspirin and 2,825 were treated with clopidogrel plus aspirin. Cilostazol plus aspirin was associated with a higher risk of ICH (HR: 1.82; 95% CI: 1.16-2.84) compared to clopidogrel plus aspirin. No significant differences in the risks of effectiveness or mortality outcomes between the two groups were found. CONCLUSIONS: The effectiveness and mortality of the two groups were similar for patients with acute minor ischemic stroke or TIA. However, cilostazol plus aspirin was associated with a higher risk of ICH compared to clopidogrel plus aspirin. Patients treated with cilostazol plus aspirin among this population should be monitored carefully to ensure their safety.

Correction: Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0221750.].

Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.

BACKGROUND: Several clinical trials reported that clopidogrel was superior to aspirin in secondary stroke prevention by reducing the risk of major adverse cardiovascular events (MACE). We aimed to compare the efficacy of clopidogrel with aspirin in reducing one-year risk of MACE based on real-world evidence from Taiwan Health Insurance Database. METHODS: We identified ischemic stroke patients between 2000 and 2012 who took aspirin or clopidogrel within 7 days of stroke onset for 1-year follow-up. The primary outcome was one-year MACE including recurrent stroke, acute myocardial infarction, and death. Propensity score matching and conditional Cox proportional hazards regression were conducted to control the confounding factors. RESULTS: From 9,089 ischemic stroke patients, we found 654 patients on aspirin and 465 patients on clopidogrel who met the selective inclusion criteria. After propensity score matching, 379 patients were selected from each group. The clopidogrel group had a 1.78-fold MACE risk compared with the aspirin group at one-year follow-up (95% CI = 1.41-2.26, p<0.01). The MACE-free rate in the aspirin group was 15.74% higher than in the clopidogrel group at one-year follow-up. Sub-analysis of the three components of MACE showed that clopidogrel conferred higher risk of recurrent stroke (OR 1.43, 95% CI = 1.06-1.92, p 0.02) and acute myocardial infarction (OR 3.72, 95% CI = 1.04-13.3, p 0.04), but no different risk of death than that of aspirin. CONCLUSIONS: Among first-ever ischemic stroke patients, secondary stroke prevention using clopidogrel was associated with higher rates of MACE than aspirin. Aspirin might have better efficacy in secondary stroke prevention and was associated with lower risk of MACE. The real-world evidence raises the need to re-assess the current therapeutic options in secondary stroke prevention applying aspirin vs. clopidogrel.

Comparative analysis of novel autoantibody isotypes against citrullinated-inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3)(542-556) peptide in serum from Taiwanese females with rheumatoid arthritis, primary Sjögren's syndrome and secondary Sjögren's syndrome in rheumatoid arthritis.

UNLABELLED: The purpose of this study was to discover and validate inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) as novel biomarkers, and evaluate autoantibody isotypes against an unmodified and citrullinated ITIH3(542-556) peptide among Taiwanese female patients with rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), secondary Sjögren's syndrome in rheumatoid arthritis (RA-sSS), and healthy controls (HCs). We used concanavalin A (Con A) affinity chromatography, 1-D SDS-PAGE, and label-free nano-LC-MS/MS to screen biomarker candidates (serum-derived Con A-captured proteins) and then identify PTMs of validated biomarkers (serum proteins) using pooled serum from 7 RA-sSS female patients and 7 age-matched HCs (the discovery set). Furthermore, the protein level and autoantibody isotype analyses were further validated against individual serum from 18 HCs, 18 RA, 18 pSS, and 18 RA-sSS patients (the validation set). Con A-bound ITIH3 was identified and validated as the only differentially expressed protein, which was elevated. Additionally, 2 novel PTMs in ITIH3 were identified and included citrullination at arginine-(546) and arginine-(556), and hexosamine at tryptophan-(558). Further, concentrations of anti-citrullinatd-ITIH3(542-556) peptide autoantibodies significantly increased in patients with RA, pSS, and RA-sSS compared to HCs. Especially, autoantibody IgM against the citrullinated-ITIH3(542-556) peptide showed better diagnostic performance in discriminating both RA versus pSS and pSS versus RA-sSS. SIGNIFICANCE: By using comparative proteomic analysis of serum samples, the current study discovered and validates differentially expressed Con A-bound ITIH3 as a potential biomarker for secondary Sjögren's syndrome (SS) in rheumatoid arthritis (RA) patients and healthy controls (HCs). Besides, hexosamine and citrullination on ITIH3 were further identified. Through analyzing autoantibody isotypes against the citrullinated ITIH3 peptide, patients with RA, primary SS, and RA-secondary SS, and HCs can be further discriminated. The current strategy can be applied for identifying potential diagnostic and pathologic markers for autoimmune diseases.

Analysis of differentially expressed novel post-translational modifications of plasma apolipoprotein E in Taiwanese females with breast cancer.

APOE ε2 or ε4 alleles being used as indicators of breast cancer risk are controversial in Taiwanese females. We provide a concept for relative comparisons of post-translational modifications (PTMs) of plasma apolipoprotein E (ApoE) between normal controls and breast cancer patients to investigate the association of ApoE with breast cancer risk. APOE polymorphisms (ApoE isoforms) were not assessed in this study. The relative modification ratio (%) of 15 targeted and 21 modified peptides were evaluated by 1D SDS-PAGE, in-gel digestion, and label-free nano-LC/MS to compare normal controls with breast cancer patients. Plasma levels of the ApoE protein did not significantly differ between normal controls and breast cancer patients. Eleven sites with novel PTMs were identified from 7 pairs of differentially expressed targeted and modified peptides according to the relative modification ratio including methylation at the E3 (↑1.45-fold), E7 (↑1.45-fold), E11 (↑1.19-fold), E77 (↑2.02-fold), E87 (↑2.02-fold), and Q98 (↑1.62-fold) residues; dimethylation at the Q187 (↑1.44-fold) residue; dihydroxylation at the R92 (↑1.25-fold), K95 (↑1.25-fold), and R103 (↑1.25-fold) residues; and glycosylation at the S129 (↑1.14-fold) residue. The clustered methylation and dihydroxylation of plasma ApoE proteins may play a role in breast cancer.

Comparative proteomics, network analysis and post-translational modification identification reveal differential profiles of plasma Con A-bound glycoprotein biomarkers in gastric cancer.

In the study, we used Con A affinity chromatography, 1-D gel electrophoresis, and nano-LC-MS/MS to screen biomarker candidates in plasma samples obtained from 30 patients with gastric cancer and 30 healthy volunteers. First, we pooled plasma samples matched by age and sex. We identified 17 differentially expressed Con A-bound glycoproteins, including 10 upregulated proteins and 7 downregulated proteins; these differences were significant (Student's t-test, p-value<0.05). Furthermore, 2 of the upregulated proteins displayed expression levels that were increased by 2-fold or more in gastric cancer samples when compared with normal control samples. These proteins included leucine-rich alpha-2-glycoprotein (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), and the expression levels were validated by Western blot analysis. Pathway and network analysis of the differentially expressed proteins by Ingenuity Pathway Analysis revealed vital canonical pathways involving acute phase response signaling, the complement system, LXR/RXR activation, hematopoiesis from pluripotent stem cells, and primary immunodeficiency signaling. Our results suggest that Con A-bound LRG1 and ITIH3 may not be practically applicable as a robust biomarker for the early detection of gastric cancer. Additionally, three novel PTMs in ITIH3 were identified and include hexose-N-acetyl-hexosamine at asparagine-(41), trimethylation at aspartic acid-(290), and flavin adenine dinucleotide at histidine-(335). BIOLOGICAL SIGNIFICANCE: Our study was to describe a combinatorial approach of Con A affinity chromatography, 1-D SDS-PAGE, and nano-LC/MS/MS that provides a label-free, comparative glycoproteomic quantification strategy for the investigation of glycoprotein profiles in plasma from gastric cancer patients versus healthy volunteers and to identify glycoprotein biomarkers for the early clinical detection of gastric cancer. Three novel PTMs, HexHexNAc, trimethylation and FAD, in Con A-bound ITIH3 were identified and built in molecular modeling. The aspartic acid-(290) trimethylation site was located in a metal ion-dependent adhesion site (MIDAS motif; (290)-DXSXS…T…D-(313)) that may influence important function for binding protein ligands.