Background-Left ventricular (LV) remodeling after acute myocardial infarction is associated with adverse prognosis.MicroRNAs (miRNAs) regulate the expression of several genes involved in LV remodeling. Our aim was to identify miRNAs associated with LV remodeling after acute myocardial infarction. Methods and Results-We studied 90 patients after first ST-segment-elevation acute myocardial infarction. A derivation cohort consisted of 60 patients characterized by echocardiography predischarge and at 6-month follow-up. Thirty patients characterized by magnetic resonance imaging predischarge and at 4-month follow-up were the validation cohort. Remodeling was defined as an increase in LV end-diastolic volume (ΔEDV>0) between discharge and follow-up. Circulating miRNAs were measured by microarrays and polymerase chain reaction. Using a systems-based approach, we identified several miRNAs potentially involved in LV remodeling. In the derivation cohort, one of these miRNAs, miR-150, was downregulated in patients with remodeling (ΔEDV>0) compared with patients without remodeling (ΔEDV≤0). In the validation cohort, patients with remodeling had 2-fold lower levels of miR-150 than those without (P=0.03). miR-150 outperformed N-terminal pro-brain natriuretic peptide to predict remodeling (area under the receiver-operating characteristic curve of 0.74 and 0.60, respectively). miR-150 reclassified 54% (95% confidence interval, 5-102; P=0.03) of patients misclassified by N-terminal pro-brain natriuretic peptide and 59% (95% confidence interval, 9-108; P=0.02) of patients misclassified by a multiparameter clinical model, including age, sex, and admission levels of troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide. hypertrophic heart 10-13 and in the circulation of patients with heart failure. Conclusions-Low14 Because miRNAs play functional roles in the development of heart failure, 15 modulation of their expression and activity has emerged as an attractive potential tool to limit the development of this condition. However, the prognostic value of miRNAs after AMI has received less attention.In a study by Widera et al, 16 circulating levels of 6 cardiacenriched miRNAs were measured in patients with acute coronary syndrome. Levels of miR-133a and miR-208b were upregulated in patients with AMI (compared with patients with unstable angina) and were associated with the risk of death. However, this association was lost after adjustment for high-sensitivity cardiac troponin T. Interestingly, circulating miRNAs follow a typical expression profile post-AMI that may be used for prognostic purposes.17 For instance, miR-208a increased 5 days post-AMI and remained elevated up to 90 days later. In a recent study evaluating the diagnostic value of circulating miRNAs in patients with AMI, we observed a weak association between cardiac-enriched miR-208b and miR-499 and LV dysfunction. 18Using a systems-based approach, combining analyses of miRNA profiles, obtained by microarrays, with networks of miRNA gene interactions, ...
Background T cell Ig and ITIM domain (TIGIT)/CD226 pathway has a critical role in regulating T cell responses and has come to the forefront in cancer as a promising immunotherapeutic target. However, its role in autoimmune diseases is just beginning to be elucidated. Dermatomyositis (DM) is an autoimmune disease, in which T cell dysregulation plays a pivotal role, and importantly, it is a common immune-related adverse event in response to treatment of cancers with immune checkpoint inhibitors, but no studies have implicated the TIGIT/CD226 axis in DM. Methods We recruited 30 treatment-naïve DM patients and 26 healthy controls. Flow cytometry analysis was used to investigate the co-expression of TIGIT and CD226 on T cells in blood samples. Magnetic bead or FACS-based cell isolation, T cell proliferation assay, and intracellular cytokine staining were performed to analyze the functions of different TIGIT/CD226 phenotypes. Recombinant proteins CD155, CD112, and anti-CD226 antibodies were used to suppress the function of TIGIT/CD226-expressing CD4 T cells. Results Four distinct subsets of T cells based on TIGIT/CD226 co-expression, TIGIT+CD226−, TIGIT+CD226+, TIGIT−CD226+, and TIGIT−CD226−, were identified and characterized in DM patients. Our data showed that the function of CD4 T cell subset varied by the TIGIT/CD226 phenotype. An elevated TIGIT+CD226+ CD4 subset with enhanced effector function was observed in patients with DM, especially the patients complicated with interstitial lung disease. This subpopulation was closely related to DM activity and decreased significantly in DM remission after treatment. Furthermore, the effector function of TIGIT+CD226+ CD4 subset could be suppressed by blocking CD226. Conclusion Our data revealed that the TIGIT and CD226 expression profiles could be used to identify functionally distinct subsets of CD4 T cells and TIGIT+CD226+ CD4 T cells is a significant subset in DM with enhanced frequency and effector function. This abnormal subset could be suppressed by blocking CD226, providing insight into the therapeutic target of the TIGIT/CD226 axis.
Objective Myofiber necrosis is a significant pathologic characteristic of idiopathic inflammatory myopathies (IIMs), and its molecular mechanism is largely unknown. Necroptosis is a recently identified form of regulated necrotic cell death, and its activation might have crucial biologic consequences. The aim of the present study was to investigate the role of necroptosis in IIM muscle damage. Methods Western blot and immunohistochemistry analyses were performed to examine the expression of receptor‐interacting protein 3 (RIP‐3) and mixed‐lineage kinase domain–like (MLKL) proteins in 26 IIM patients and 4 healthy controls, as well as necroptosis‐related damage–associated molecular pattern molecules. Tumor necrosis factor (TNF) was used to stimulate cultured C2C12 myoblasts, and the involvement of necroptosis in cell death of C2C12 cells was studied in vitro. Results The expression of RIP‐3 and MLKL proteins and their phosphorylated forms was significantly increased in the muscle tissue of IIM patients compared to that of healthy controls. The expression levels of RIP‐3 and MLKL proteins were associated with the severity of muscle damage in patients with IIM. Significant colocalization of MLKL with high mobility group box chromosomal protein 1 in necrotizing myofibers was observed in muscle biopsy tissue from patients with IIM. Stimulation of C2C12 myoblasts with TNF and a pan‐caspase inhibitor, Z‐VAD, resulted in the overactivation of necroptosis and significantly increased necrotic cell death. Strategies involving either inhibition of necroptosis with necrostatin‐1 or knockdown of MLKL expression successfully prevented necroptosis‐induced cell death of C2C12 cells. Conclusion These findings demonstrate that overactivated necroptosis contributes to muscle damage in IIMs and suggest that necroptosis inhibitors could represent a new therapeutic target in the treatment of IIMs.
BackgroudAnti-mitochondrial antibodies (AMAs) can be detected in some idiopathic inflammatory myopathy (IIM) patients. We aimed to investigate the clinical features of IIM patients with AMAs.Methods We retrospectively analysed consecutive 1,167 patients with IIM for AMAs-associated myositis and compared them to age- and sex-matched AMA-negative patients. ResultsTwenty-nine patients (2.5%) were identified with AMAs-positive myositis; eight of them had primary biliary cholangitis (PBC). There were no significant differences in skin rash, dysphagia, interstitial lung disease, and muscle strength between AMAs-positive patients and disease controls. 12/23(52.2%) cases showed immune-mediated necrotizing myopathy (IMNM)-like pathological features. Among AMAs-positive patients, 11 of 16 patients with isolated anti-AMA were classified as IMNM which was significantly higher than that of patients with coexistent anti-AMAs and myositis-specific antibodies (p=0.026). Moreover, AMAs-positive patients had a significantly higher cardiac involvement ratio (P<0.001) compared to controls. Comparsion in AMAs-positive IIM patients show the incidence of abnormal echocardiography findings was significantly higher in patients without primary biliary cholangitis (PBC) than in patients with PBC(P=0.009). Patients without heart abnormalities took significantly less time to achieve disease remission and prednisone tapering to <10 mg than patients with heart abnormalities (P<0.001 and P=0.001, respectively).ConclusionsIMNM was a major histopathological finding in IIM patients with isolated anti-AMAs antibody. AMAs was significantly associated with cardiac involvement in IIM. PBC seemed to be a protective factor for abnormal echocardiography findings in AMAs-positive patients. Patients without heart involvement took less time to achieve disease remission and prednisone tapering off.
Methotrexate (MTX) is a first‐line disease‐modifying antirheumatic drug for rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. The differences in drug efficacy and adverse drug reactions may be caused by genetic variations. We investigated the effects of single‐nucleotide polymorphisms (SNPs) in 2 genes encoding membrane‐spanning proteins, namely, reduced folate carrier‐1 RFC‐1/SLC19A1 (G>A [rs7499], A>G [rs2838956] and 180G>A [rs1051266]) and adenosine triphosphate–binding cassette B1 (rs1045642). Tagged SNPs were genotyped in 162 patients with RA in China. Then, we analyzed the relationships between these SNPs and therapeutic outcomes related to MTX in Chinese RA patients. No significant associations were found between the RFC‐1/SLC19A1 (G>A [rs7499] and A>G [rs2838956]) and adenosine triphosphate–binding cassette B1 (rs1045642) gene polymorphisms and the response to MTX in RA patients. However, MTX‐related toxicity was associated with one SNP, RFC‐1 rs1051266 AA vs GG (odds ratio, 6.523; 95% confidence interval, 1.596–26.565; P = .009). SLC19A1 A>G rs2838956 showed a trend toward a significant association (odds ratio, 0.377; 95% confidence interval, 0.124–1.143; P = .085) with toxicity. Our results suggest that the RFC‐1 80G>A (rs1051266) SNP exerts a potentially protective effect against the risk of adverse drug reactions in Chinese RA patients treated with MTX. Further studies are required to validate these findings.
IntroductionTo investigate the clinical, radiographic and pathological features of interstitial lung disease (ILD) in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (anti-MDA5+DM).MethodsWe retrospectively analysed the medical records of patients with anti-MDA5+DM who had undergone radiological examination, and lung histopathology was performed on 17 of them.ResultsThis study examined 329 patients with anti-MDA5+DM, of whom 308 (93.6%) were diagnosed with ILD and 177 (53.8%) exhibited rapidly progressive ILD (RPILD). The most common radiographic patterns were organising pneumonia (OP) (43.2%), non-specific interstitial pneumonia (NSIP) (26.4%) and NSIP+OP (18.5%). Histological analysis showed NSIP (41.2%) and NSIP+OP (47.1%) to be the predominant patterns. However, in the 17 patients who underwent lung histopathology, the coincidence rate between radiological and histopathological diagnoses was only 11.8%. Compared with patients without RPILD, those with RPILD showed a higher prevalence of NSIP+OP (26.6% vs 10.7%, p=0.001) and a lower prevalence of NSIP pattern (21.5% vs 37.4%, p=0.002) on high-resolution CT. Furthermore, patients with radiographic patterns of NSIP+OP or diffuse alveolar damage (DAD) had more risk factors for poor prognosis, with 12-month mortality rates of 45.9% and 100%, respectively.ConclusionsRPILD was commonly observed in patients with anti-MDA5+DM. OP was identified as the predominant radiographic pattern, which corresponded to a histopathological pattern of NSIP or NSIP+OP. Notably, patients exhibiting radiographic patterns of NSIP+OP or DAD were shown to have a poor prognosis.
Systemic lupus erythematosus predominantly affects young women during childbearing age. It is rare after the age of 90, and there is no report of very late onset in persons over 90 in China. Here, we reported a case of a female patient, the onset age of whom was 90, analyzing her clinical features and treatments. And when conducting a pooled analysis of late-onset cases in the literature, we found that the organ damages and severity of lupus disease of old-onset SLE were not benign, and considering their ages, comorbidities and high rate of mortalities, appropriate interventions and close follow-up for this age group are needed.
Behçet's disease (BD) with chylothorax and/or chylopericardium is uncommon. Here, we report a case of a 32-year-old man suffering BD with chylothorax and chylopericardium complications. We also review the literature and discuss clinical characteristics, possible pathogenesis, and treatment strategy of patients suffering BD with chylothorax and/or chylopericardium complications.
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