Liver fibrosis, a common outcome of chronic liver disease characterized by excessive accumulation of extracellular matrix (ECM), is a leading cause of mortality worldwide. The tyrosine kinase inhibitor neratinib is a human epidermal growth factor receptor 2 (HER2) inhibitor approved by the FDA for HER2-positive breast cancer treatment; however, it has not yet been evaluated for liver fibrosis treatment. We elucidated the anti-fibrotic effects of neratinib in hepatic stellate cells (HSCs) and in vivo models of CCl4-induced liver fibrosis. HSC activation is a key step in liver fibrogenesis and has a crucial role in collagen deposition, as it is primarily responsible for excessive ECM production. The effect of neratinib on HSC was evaluated in transforming growth factor (TGF-β)-incubated LX-2 cells and culture-activated primary human HSCs. In vivo study results indicated that neratinib inhibited the inflammatory response, HSC differentiation, and collagen accumulation induced by CCl4. Moreover, the anti-fibrotic effects of neratinib were not associated with the HER2 signaling pathways. Neratinib inhibited FGF2 expression in activated HSCs and serum FGF2 level in the model, suggesting that neratinib possessed therapeutic potency against liver fibrosis and the potential for application against other fibrotic diseases.
When groundwater drought occurs, baseflow discharges to surface-water bodies will be reduced and then domestic and agricultural water usage becomes at risk of insufficient supply. Thus, in this study, several methods for groundwater drought assessment were tested with long-term monitoring water-level data in the study area to preserve groundwater sustainability from drought, principally caused by reduced precipitation and propagated through agricultural drought and groundwater drought. Because of the Monsoon climate on the Korean Peninsula, the groundwater storage (or water-level) is secured until the end of summer, then falls by natural discharge during the dry seasons of autumn, winter and the following spring. Thus, the rainfall in the wet season seems to mainly influence groundwater storage until the spring of the following year. As the groundwater level (GWL) declines due to natural drainage and the use of agricultural water increases by the end of the dry season (October–May), the GWL will become lowered below the critical level. Below this level, sufficient water supply is not secured. Using the Standardized Precipitation Index (SPI), threshold method and 95% probability occurrence method, drought detection and the frequency of drought are compared. Groundwater drought using the threshold method results in more frequent occurrence than using the SPI method. The 95% occurrence method responds to severe drought but it also has weakness in missing the man-induced GWL decline in every spring season. For groundwater drought assessment, an appropriate drought index should be utilized according to climatic conditions and catchment characteristics. In the study area, variations of the both natural and anthropogenic effects are mixed and the threshold method is more suitable as a measure for preventing water resources shortage.
Background: Acute pulmonary thromboembolism (APTE) is often confused with myocardial infarction. Previous studies have shown that patients with APTE exhibit lower initial and peak cardiac troponin I (CTI) levels, but higher D-dimer (DD) levels, than patients with myocardial infarction. The present study aimed to reaffirm the tree model algorithm using an entirely new set of data.Methods: We reviewed retrospective clinical and laboratory data from patients who were diagnosed with APTE or non-ST-elevation myocardial infarction (NSTEMI) between 2015 and 2016. Subjects who were not classified with a diagnosis or did not have their CTI or DD levels assessed were excluded. We categorized patients according to the previous algorithm and compared the outcomes with the previous test dataset.Results: The analysis involved data from 156 patients with APTE and 363 patients with NSTEMI. In the validation data set, the APTE group showed higher initial DD levels (9.80±10.84 μg/mL) and lower initial CTI levels (0.17±0.54 μg/mL) than the NSTEMI group. The accuracy rate for the test dataset and the validation set were similar. The test set accuracy rate was 91.0%, while the accuracy rate in the validation set improved to 88.6%.Conclusions: Patients with APTE exhibited lower initial and peak CTI levels, but higher DD levels than NSTEMI patients. The accuracy rate estimates were similar between the test set obtained from the tree model algorithm and the validation set. The study findings demonstrate that the assessment of cardiac biomarkers can be useful for differentiating between APTE and NSTEMI.
Among various proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), tumor necrosis factor (TNF)-α plays a pivotal role in the release of other cytokines and induction of chronic inflammation. Even though siRNA has the therapeutic potential, they have a challenge to be delivered into the target cells because of their poor stability in physiological fluids. Herein, we design a nanocomplex of polymerized siRNA (poly-siRNA) targeting TNF-α with thiolated glycol chitosan (tGC) polymers for the treatment of RA. Poly-siRNA is prepared through self-polymerization of thiol groups at the 5' end of sense and antisense strand of siRNA and encapsulated into tGC polymers, resulting in poly-siRNA-tGC nanoparticles (psi-tGC-NPs) with an average diameter of 370 nm. In the macrophage culture system, psi-tGC-NPs exhibit rapid cellular uptake and excellent in vitro TNF-α gene silencing efficacy. Importantly, psi-tGC-NPs show the high accumulation at the arthritic joint sites in collagen-induced arthritis (CIA) mice. Treatment monitoring data obtained by the matrix metalloproteinase 3-specific nanoprobe and microcomputed tomography show that intravenous injection of psi-tGC-NPs significantly inhibits inflammation and bone erosion in CIA mice, comparable to methotrexate (5 mg/kg). Therefore, the availability of psi-tGC-NP therapy that target specific cytokines may herald new era in the treatment of RA.
Purpose To determine the activity and toxicities of low dose leucovorin (LV) plus fluorouracil (5-FU) regimen, combined with oxaliplatin every two weeks (modified FOLFOX 4), as a first-line therapy for patients with metastatic colorectal cancer. Materials and Methods Between March 2001 and August 2003, fifty-five patients were enrolled in this study. Patients were treated with oxaliplatin 85 mg/m2 as a 2-hour infusion at days 1 plus LV 20 mg/m2 over 10 minutes, followed by 5-FU bolusa 400 mg/m2 bolus and 22 hour continuous infusion of 600 mg/m2 5-FU at day 1~2. This treatment was repeated in 2 week intervals. Results The objective response rate was 40% on an intent-to-treatment analysis. Three patients (6%) demonstrated a complete response and nineteen patients (38%) showeda partial response. Sixteen patients (32%) showed a stable disease and eleven patients (22%) progressed during the course of the treatment. The median time to progression and overall survival time wereas 6.6 months (95% CI: 4.98~8.02 months) and the median overall survival time was 17.0 months (95% CI: 9.15~24.85 months) from the start of the chemotherapy, respectively. A total of 275 cycles were analyzed for toxicity. Major hematologic toxicities included grade 1~2 anemia (23.5%), neutropenia (25.3%) and thrombocytopenia (10.6%). There were only 2 cycles of neutropenic fever. The most common non-hematologic toxicities were grade 1~2 nausea/vomiting (10.9%), diarrhea (9.1%) and grade 1 neuropathy (18.0%). There was no treatment related death. Conclusion The modified folfox 4 regimen is safe and effective regimen as a first-line therapy in advanced colorectal cancer patients. Key words: Colorectal neoplasm, Chemotherapy, Oxaliplatin, 5-FU, Leucovorin
Introduction: Heart failure with preserved ejection fraction (HFpEF) is a common comorbidity in atrial fibrillation (AF) patients and contributes to AF progression and stroke risk. Hypothesis: We explore the hemodynamic effects of left atrial pressure (LAP), which was directly measured during AF catheter ablation (AFCA), on HFpEF based on the H 2 FPEF score. Methods: We included 1,426 patients (73.3% male, median age, 61.0 [54.0-68.0] years; 45.7% persistent AF) who underwent AFCA, LAP measurements at both AF and sinus rhythm (SR), echocardiogram, and H 2 FPEF score, and excluded the patients with EF <50%. We divided patients into low-risk (< 6 points) and high-risk ( ≥ 6 points) HFpEF groups and measured LAP-mean depending on heart rates 90, 100, 110, and 120 bpm during right atrial pacing (Pace-HR) and isoproterenol (ISO-HR) infusion in all patients. Results: The LAP-mean was sequentially and significantly higher according to the H 2 FPEF score (p<0.001) and had an independent association with the high-risk HFpEF group (OR 1.37 per 10mmHg increase [1.13-1.67], p=0.001). LAP-mean increased significantly with increasing Pace-HR (90-120 bpm, 10.4 to 11.6 mmHg, p<0.001) but decreased with ISO-HR (90-120 bpm, 10.2 to 8.1 mmHg, p<0.001). In patients with paroxysmal AF, LAP-mean[AF] was significantly higher than LAP-mean[SR] (p<0.001), but not in those with non-paroxysmal AF (p=0.557). In patients with paroxysmal AF, ΔLAP-mean[Pace-HR, 120-90bpm] was significantly higher than that of non-paroxysmal AF (p<0.001). Conclusions: LAP is independently associated with H 2 FPEF score and has inverse rate-dependent response depending on pacing or ISO infusion. Higher increase of LAP during AF or higher Pace-HR contributes to more severe symptoms in patients with paroxysmal AF than in non-paroxysmal AF.
Inhibition of Notch signalling has shown anti-inflammatory properties in vivo and in vitro models of rheumatoid arthritis (RA). The objective of this study was to determine whether Notch1 might play a role in regulating T-regulatory cells (Tregs) in animal models of RA. Methods: Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) were induced in C57BL/6, Notch1 antisense transgenic (NAS) or DBA1/J mice. We examined whether pharmacological inhibitors of γ-secretase (an enzyme required for Notch1 activation) and antisense-mediated knockdown of Notch1 could attenuate the severity of inflammatory arthritis in CIA and CAIA mice. Proportions of CD4+CD25+Foxp3+ Treg cells were measured by flow cytometry. To assess the suppressive capacity of Treg toward responder cells, CFSE-based suppression assay of Treg was performed. Results: γ-secretase inhibitors and antisense-mediated knockdown of Notch1 reduced the severity of inflammatory arthritis in both CIA and CAIA mice. Pharmacological and genetic inhibition of Notch1 signalling induced significant elevation of Treg cell population in CIA and CAIA mice. We also demonstrated that inhibition of Notch signalling suppressed the progression of inflammatory arthritis through modulating the expansion and suppressive function of regulatory T (Treg) cells. Conclusion: Pharmacological and genetic inhibition of Notch1 signalling suppresses the progression of inflammatory arthritis through modulating the population and suppressive function of Treg cells in animal models of RA.
Atrial tachycardias (ATs) from noncoronary aortic cusp (NCC) uncovered after radiofrequency ablation for atrial fibrillation (AF) are rarely reported. This study was conducted to investigate the prevalence and clinical characteristics of NCC ATs detected during AF ablation and compare their characteristics with de novo NCC ATs without AF.Consecutive patients who underwent radiofrequency catheter ablation for AF were reviewed from the multicenter AF ablation registry of 11 tertiary hospitals. The clinical and electrophysiological characteristics of NCC AT newly detected during AF ablation were compared with its comparators (de novo NCC AT ablation cases without AF).Among 10,178 AF cases, including 1,301 redo ablation cases, 8 (0.08%) NCC AT cases were discovered after pulmonary vein isolation (PVI; 0.07% in first ablation and 0.15% in redo ablation cases). All ATs were reproducibly inducible spontaneously or with programmed atrial stimulation without isoproterenol infusion. The P-wave morphological features of tachycardia were variable depending on the case, and most cases exhibited 1:1 atrioventricular conduction. AF recurrence rate after PVI and NCC AT successful ablation was 12.5% (1 of 8). Tachycardia cycle length was shorter than that of 17 de novo ATs from NCC (303 versus 378, p=0.012). No AV block occurred during and after successful AT ablation.Uncommon NCC ATs (0.08% in AF ablation cases) uncovered after PVI, showing different characteristics compared to de-novo NCC ATs, should be suspected irrespective of P-wave morphologies when AT shows broad propagation from the anterior interatrial septum.
Abstract Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-κB, and expression of proinflammatory cytokines, including IL-1β, macrophage-inflammatory protein-2, and TNF-α. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA−/−) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1β, macrophage-inflammatory protein-2, and TNF-α cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.
Left transradial coronary angiography may result in damage of both radial arteries in patients who experienced right radial access. In some patients, the left radial artery has been used as a graft. We investigated whether graft angiography using right radial access is feasible in patients with bypass surgery to preserve the left radial artery as a future graft.A total of 109 consecutive patients with bypass surgery who had undergone right radial access underwent graft angiography via the same access.Sixteen (15%) patients were excluded because of the presence of a severely tortuous right subclavian artery. Bypass graft angiography via right radial or brachial access was completed successfully in 90 (97%) out of 93 patients. In 3 (3%) of patients, femoral access was needed to complete the angiography. Saphenous vein grafts were cannulated selectively in 150 (90%) of 167 grafts with satisfactory image quality and not found even on the aortogram in the other 17 (10%) grafts. Ninety-two (89%) out of 103 left mammary grafts were cannulated selectively or semi-selectively using a modified Simmons catheter, resulting in satisfactory image quality. The other 11 (11%) grafts were visualized non-selectively using a Judkins Left catheter, and resulting in acceptable image quality in 10 (91%) grafts. There were no procedure-related complications.Graft angiography via right radial access can be performed reliably in most patients that lack severe subclavian tortuosity.
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