Exosome-mediated delivery of super-repressor IκBα alleviates inflammation and joint damages in rheumatoid arthritis.

BACKGROUND: This study aims to investigate the potential anti-inflammatory effects of exosomes engineered to carry super-repressor IκB (Exo-srIκB), an exosome-based NF-κB inhibitor, in the context of RA. METHODS: Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from patients diagnosed with RA and treated with Exo-srIκB to test the therapeutic potential. Flow cytometry analysis was performed to assess the production of inflammatory cytokines (IL-17A and GM-CSF) by the cells. ELISA was utilized to measure the levels of TNF-α, IL-17A, IL-6, and GM-CSF. Arthritis was induced in SKG mice by intraperitoneal injection of curdlan. DBA/1 J mice were used in collagen-induced arthritis (CIA) experiments. After the development of arthritis, mice were injected with either Exo-Naïve (control exosome) or Exo-srIκB. Arthritis scores were recorded biweekly, and histological observations of the ankle joint were conducted using H&E and safranin-O staining. Additionally, bone erosion was evaluated using micro-CT imaging. RESULTS: In the ex vivo study involving human PBMCs and SFMCs, treatment with Exo-srIκB demonstrated a notable reduction in inflammatory cytokines. Furthermore, in both the SKG and CIA models, Exo-srIκB treatment exhibited significant reductions in inflammation, cartilage destruction, and bone erosion within the joint tissues when compared to the Exo-Naive control group. Additionally, the radiographic score assessed through microCT showed a significant decrease compared to the Exo-Naive control group. CONCLUSION: Overall, these findings suggest that Exo-srIκB possesses anti-inflammatory properties in human RA cells and animal models, making it a promising therapeutic candidate for the treatment of RA.

Angiotensin receptor blockers, but not angiotensin-converting enzyme inhibitors, inhibit abnormal bone changes in spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disease that results in bone ankylosis. The tissue renin-angiotensin system (RAS) is an emerging pathway potentially implicated in SpA-associated bone changes. The aim of the present study was to determine the mechanisms underlying this relationship. Sakaguchi (SKG) mice injected with curdlan (SKGc), animal models for SpA, were treated with RAS modulators, angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis). Disease activity was assessed using clinical scores and computed tomography scans. Mouse primary bone marrow monocytes (BMMs), osteoblast (OB) progenitor cells, peripheral blood monocytes (PBMCs), and bone-derived cells (BdCs) from patients with radiographic axial SpA (r-axSpA) were used to investigate the role of RAS in SpA pathogenesis. The expression of RAS components was significantly increased in SKGc mouse joints, and ARBs significantly reduced erosion and systemic bone loss, whereas ACEis did not. Osteoclast (OC) differentiation from primary BMMs, mediated by TRAF6, was inhibited by ARBs but promoted by ACEis; the modulators also exerted opposite effects on OB differentiation. Expression of RAS molecules was higher in PBMCs and BdCs of patients with r-axSpA than in control participants. ARBs inhibited OB differentiation in the BdCs of patients with r-axSpA, whereas ACEis did not. Neither ARBs nor ACEis affected OB differentiation in the control participants. In SpA, a condition characterized by RAS overexpression, ARBs, but not ACEis, inhibited OC and OB differentiation and bone progression. The findings should be taken into account when treating patients with SpA using RAS modulators.

Effective Chemical Lift-Off for Air-Tunnel GaN on a Trapezoid-Patterned Sapphire Substrate.

We fabricated an air-tunnel structure between a gallium nitride (GaN) layer and trapezoid-patterned sapphire substrate (TPSS) through the in situ carbonization of a photoresist layer to enable rapid chemical lift-off (CLO). A trapezoid-shaped PSS was used, which is advantageous for epitaxial growth on the upper c-plane when forming an air tunnel between the substrate and GaN layer. The upper c-plane of the TPSS was exposed during carbonization. This was followed by selective GaN epitaxial lateral overgrowth using a homemade metal organic chemical vapor deposition system. The air tunnel maintained its structure under the GaN layer, whereas the photoresist layer between the GaN layer and TPSS disappeared. The crystalline structures of GaN (0002) and (0004) were investigated using X-ray diffraction. The photoluminescence spectra of the GaN templates with and without the air tunnel showed an intense peak at 364 nm. The Raman spectroscopy results for the GaN templates with and without the air tunnel were redshifted relative to the results for free-standing GaN. The CLO process using potassium hydroxide solution neatly separated the GaN template with the air tunnel from the TPSS.

Selective-Area Growth Mechanism of GaN Microrods on a Plateau Patterned Substrate.

This study provides experimental evidence regarding the mechanism of gallium nitride (GaN) selective-area growth (SAG) on a polished plateau-patterned sapphire substrate (PP-PSS), on which aluminum nitride (AlN) buffer layers are deposited under the same deposition conditions. The SAG of GaN was only observed on the plateau region of the PP-PSS, irrespective of the number of growth cycles. Indirect samples deposited on the bare c-plane substrate were prepared to determine the difference between the AlN buffer layers in the plateau region and silicon oxide (SiO2). The AlN buffer layer in the plateau region exhibited a higher surface energy, and its crystal orientation is indicated by AlN [001]. In contrast, regions other than the plateau region did not exhibit crystallinity and presented lower surface energies. The direct analysis results of PP-PSS using transmission electron microscopy (TEM) and electron backscattered diffraction (EBSD) are similar to the results of the indirect samples. Therefore, under the same conditions, the GaN SAG of the deposited layer is related to crystallinity, crystal orientation, and surface energy.

ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation.

Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe-/- mice and analyzed the atherosclerotic lesion size, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the control group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFα-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in the attenuation of KLF4-mediated SMC phenotypic changes. We showed that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than AMI patients with lower levels of ANGPTL4 (p < 0.05). Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques.

Predictors of In-Hospital Mortality in Korean Patients with Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a fatal cardiovascular disease, and mortality is relatively high; therefore, integrated assessment is necessary for its management. There are several risk predictive models, but treatment trends have changed due to newly introduced medications and the universal use of percutaneous coronary intervention (PCI). The author aimed to find out predictive factors of in-hospital mortality in Korean patients with AMI. A group of 13,104 patients with AMI enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) registry were divided into two groups. One was a derivation group for evaluating mortality prediction; the other was a validation group for the application of risk prediction. In-hospital mortality was 4.2% (n=552). With hierarchical and stepwise multivariate analyses, nine factors were shown to predict in-hospital mortality for Korean patients with AMI. These were 1) being over 65 years of age, 2) high Killip class over II, 3) hyperglycemia over 180 mg/dl, 4) tachycardia over 100/min, 5) serum creatinine over 1.5 mg/dl, 6) atypical chest pain, 7) low systolic blood pressure under 90 mmHg, 8) low Thrombolysis In Myocardial Infarction (TIMI) flow (TIMI 0-II) before PCI and 9) low TIMI flow (TIMI 0-II) after PCI. The validation group showed a predictive power of 88.3%. Old age, high Killip class, hyperglycemia, tachycardia, renal dysfunction, atypical chest pain, low systolic blood pressure, and low TIMI flow are important risk factors of in-hospital mortality in Korean patients with AMI.

Combination of anti-PD-1 therapy and stereotactic radiosurgery for a gastric cancer patient with brain metastasis: a case report.

BACKGROUND: Brain metastases from gastric cancer are difficult to treat and their prognosis is poor. Despite various possible treatments, the survival rate of such patients is still unsatisfactory; therefore, new treatment modalities or combinations of therapies need to be explored. CASE PRESENTATION: We herein discuss a case of a 38-year-old man initially diagnosed with a gastric cancer brain metastasis. At first, only stereotactic radiosurgery (SRS) was performed, but it was not effective. After the brain and systemic metastases progressed, SRS and anti-PD-1 therapy were administered in combination, and the brain and intra-abdominal metastatic lesions responded satisfactorily. CONCLUSION: The combination of anti-PD-1 therapy and SRS could be effective against gastric cancer with brain metastases.

Impact of Complete Revascularization on Six-Year Clinical Outcomes and Incidence of Acute Decompensated Heart Failure in Patients With ST-Segment Elevation Myocardial Infarction and Multivessel Coronary Artery Disease.

It remains unclear whether complete revascularization (CR) reduces the incidences of acute decompensated heart failure (ADHF) and adverse cardiac outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). A total of 453 hemodynamically stable patients with STEMI and MVD were retrospectively evaluated; the patients were divided into 2 groups according to interventional strategy: CR (n = 240) and incomplete revascularization (IR) (n = 213). We analyzed the incidences of ADHF and major adverse cardiac events (MACE; a composite of all-cause mortality, myocardial infarction, and any revascularization) over a long follow-up period (median 6.3 years). MACE developed in 158 patients (34.9%), and 40 patients (8.8%) were re-admitted because of ADHF developing during follow-up. Results after propensity matching showed that CR did not reduce the incidence of ADHF (hazard ratio [HR] for IR 1.63, 95% confidence interval [CI] 0.63 to 4.22, p = 0.311). However, IR increased the risk of MACE (HR 1.73, 95% CI 1.09 to 2.74, p = 0.021), attributable principally to an increased risk of nontarget vessel revascularization (HR 3.12, 95% CI 1.23 to 7.92, p = 0.039). Although CR did not reduce the incidence of ADHF, CR might reduce repeat revascularization to treat non-infarct-related arteries in hemodynamically stable patients with STEMI and MVD.

A Case of Schnitzler's Syndrome without Monoclonal Gammopathy-Associated Chronic Urticaria Treated with Anakinra.

Chronic urticaria may often be associated with interleukin (IL)-1-mediated autoinflammatory disease, which should be suspected if systemic inflammation signs are present. Here, we report a case of Schnitzler's syndrome without monoclonal gammopathy treated successfully with the IL-1 receptor antagonist anakinra. A 69-year-old man suffered from a pruritic urticarial rash for 12 years. It became aggravated episodically and was accompanied by high fever, arthralgia, leukocytosis, and an elevated C-reactive protein and erythrocyte sedimentation rate. The episodes each lasted for over one week. Neutrophilic and eosinophilic inflammation was found on skin biopsy. However, serum and urine electrophoresis showed no evidence of monoclonal gammopathy. The cutaneous lesions were unresponsive to various kinds of anti-histamines, systemic glucocorticoids, colchicine, cyclosporine, dapsone, and methotrexate, which were administered over a span of 3 years immediately preceding successful treatment. A dramatic response, however, was observed after a daily administration of anakinra. This observation suggests that the correct diagnosis of this case is Schnitzler's syndrome without monoclonal gammopathy. For an adult patient with refractory chronic urticaria and systemic inflammation, Schnitzler's syndrome could be considered as a possible differential diagnosis. Although the typical form of Schnitzler's syndrome exhibits the presence of monoclonal gammopathy as a diagnostic criterion, monoclonal gammopathy may be absent in an atypical form. In such a situation, an IL-1 antagonist should be effective for the management of chronic urticaria.

The reliability and validity of a Korean translation of the ASAS Health Index and Environmental Factors in Korean patients with axial spondyloarthritis.

The objective of this study was to develop a Korean version of the Assessment of Spondyloarthritis International Society-Health Index/Environmental Factor (ASAS HI/EF) and to evaluate its reliability and validity in Korean patients with axial spondyloarthritis (SpA). A total of 43 patients participated. Translation and cross-cultural adaptation of the ASAS HI/EF was performed according to international standardized guidelines. We also evaluated validity by calculating correlation coefficients between the ASAS-HI/EF score and the clinical parameters. Test-retest reliability was excellent. The correlations among the mean ASAS-HI score and all tools of assessment for SpA were significant. When it came to construct validity, the ASAS HI score was correlated with nocturnal back pain, spinal pain, patients's global assessment score, the Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), Bath ankylosing spondylitis metrology index (BASMI) and EuroQoL visual analogue scale (EQ VAS) (r = 0.353, 0.585, 0.598, 0.637, 0.690, 0.430, and -0.534). The ASAS EF score was also correlated with the patient's global assessment's score, BASDAI, BASFI, BASMI, and EQ VAS score (r = 0.375, 0.490, 0.684, 0.485, and -0.554). The Korean version of the ASAS HI/EF can be used in the clinical field to assess and evaluate the state of health of Korean axial SpA patients.