T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of ...action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract Background Transient receptor potential vanilloid type 1 (TRPV1) is a cation channel activated by diverse obnoxious stimuli like capsaicin, low pH or heat. Recently, it was revealed that ...TRPV1 might be deeply associated with skin permeability barrier function, suggesting that modulation of TRPV1 might be beneficial for the skin disorders with barrier damages. Objective We aimed to investigate whether the blockade of TRPV1 activation might accelerate skin barrier recovery and alleviate atopic dermatitis (AD)-like symptoms, employing a novel TRPV1 antagonist, PAC-14028. Methods TRPV1 antagonistic effects of PAC-14028 in human keratinocytes and skin were confirmed through capsaicin-evoked calcium influx assay and capsaicin-induced blood perfusion increase. Effects of PAC-14028 on skin barrier recovery were examined in vivo tape-stripping-induced barrier disruption in hairless mice. To determine the effects of PAC-14028 on AD, Dermatophagoides farina (Df)- and oxazolone (OXZ)-induced AD models were employed. Results PAC-14028 could inhibit capsaicin-evoked calcium influx in keratinocytes at sub-micromolar concentrations. This potent TRPV1 antagonistic activity in keratinocytes was manifested in vivo as the blockade of capsaicin-induced blood perfusion increase, and the accelerated barrier recovery from tape-stripping-induced barrier damages in hairless mice. PAC-14028 could also attenuate dermatitis-associated barrier damages in Df and OXZ models as determined by lower TEWL (trans-epidermal water loss), reformation of neutral lipid layer and reversion of changes in loricrin and filaggrin expression. Importantly, along with accelerated recovery of skin barrier function, PAC-14028 alleviated the general AD-like symptoms, including serum IgE increase, mast cell degranulation, scratching behavior and clinical severity of dermatitis. Conclusions These results reflect that the blockade of TRPV1 activation can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery.
Background:
Optimal antithrombotic regimens to prevent recurrent stroke in patients with ischemic stroke due to atrial fibrillation (AF) and atherosclerotic large-vessel stenosis remain unknown.
...Aims:
This study aimed to evaluate the effect of multiple antithrombotic therapies on outcomes at 1 year after ischemic stroke due to two or more causes.
Methods:
We identified 862 patients with ischemic stroke due to AF and large artery atherosclerosis from the linked data. These patients were categorized into three groups according to antithrombotic therapies at discharge: (1) antiplatelets, (2) oral anticoagulants (OAC), and (3) antiplatelets plus OAC. The study outcomes were recurrent ischemic stroke, composite outcomes for cardiovascular events, and major bleeding after 1 year. Inverse probability of treatment weighting (IPTW) was used to balance the three groups using propensity scores.
Results:
Among 862 patients, 169 (19.6%) were treated with antiplatelets, 405 (47.0%) were treated with OAC, and 288 (33.4%) were treated with antiplatelets and OAC. After applying IPTW, only OAC had a significant beneficial effect on the 1-year composite outcome (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.23–0.60, p < 0.001) and death (HR: 0.35, 95% CI: (0.19–0.63), p < 0.001). The combination of antiplatelet agents and OAC group had an increased risk of major bleeding complications (HR: 5.27, 95% CI: (1.31–21.16), p = 0.019). However, there was no significant difference in 1-year recurrent stroke events among the three groups.
Conclusion:
This study demonstrated that OAC monotherapy was associated with lower risks of composite outcome and death in patients at 1 year after ischemic stroke due to AF and atherosclerotic stenosis. In addition, the combination of an antiplatelet and OAC had a high risk of major bleeding.
In order to examine the species specific accumulation of heavy metals in medicinal crops, seven different common medicinal plants were cultivated on a Cd (55mgkg−1) and Pb (1283mgkg−1) contaminated ...soil. Subsequently, the effect of various immobilizing agents, applied in isolation and in combination, on Cd and Pb uptake by two medicinal plant species was examined.
Cadmium and Pb root concentrations in medicinal plants grown in the control soil varied between 0.5 and 2.6mgkg−1 for Cd and 3.2 and 36.4mgkg−1 for Pb. The highest accumulation occurred in Osterici Radix (Ostericum koreanum) and Ginger (Zingiber officinale) and the lowest in Yam (Dioscorea batatas). Application of immobilizing agents significantly reduced both Cd and Pb concentrations in all medicinal plants examined, where the most effective single immobilizing agent was lime fertilizer (LF). Application of combination treatments involving sorption agents such as compost together with lime further decreased Cd and Pb concentrations from 1.3 and 25.3mgkg−1 to 0.2 and 4.3mgkg−1, respectively, which was well below the corresponding WHO guidelines. Thus appropriate immobilizing agents in combination with species selection can be practically used for safer medicinal plant production.
•Plant selection was crucial for avoiding metal contamination of medicinal plants.•Application of soil immobilizing agents further decreased metal uptake.•Combinations of immobilizing agents were most effective.•Lime with compost decreased phytoavailability of Cd and Pb the most.•such as Gypsum (a dissolved organic carbon coagulator) was also effective.
Pathological changes in the epigenetic landscape of chromatin are hallmarks of cancer. Our previous study showed that global methylation of promoters may increase or decrease during the transition ...from gastric mucosa to intestinal metaplasia (IM) to gastric cancer (GC). Here, CpG hypomethylation of the serine/threonine kinase
promoter in IM and GC was detected in a reduced representation bisulfite sequencing database.
hypomethylation, which resulted in its upregulation in 120 cases of primary GC, was confirmed. Using public genome‑wide histone modification data, upregulation of
promoter activity was detected in primary GC but not in normal mucosae, suggesting that
may be repressed in gastric mucosa but activated in GC as a consequence of hypomethylation‑associated chromatin remodeling.
knockdown suppressed the proliferation, colony formation and migration activities of GC cells
, whereas stable overexpression of STK31 promoted the proliferation, colony formation, and migration activities of GC cells
and tumorigenesis in nude mice. Patients with GC in which
was upregulated exhibited significantly shorter survival times in a combined cohort. Thus, activation of
by chromatin remodeling may be associated with gastric carcinogenesis and also may help predict GC prognosis.
Previous studies have reported the association between myocardial infarction (MI) and air pollution (AP). However, limited information is available regarding the long-term effects of AP on the ...relative incidence rates of ST-elevation MI (STEMI) and Non-ST-elevation MI (NSTEMI). We investigated the association between long-term exposure to AP and the incidence of STEMI. Between January 2006 and December 2015, a total of 45,619 eligible patients with Acute Myocardial Infarction (AMI) were enrolled in the Korea Acute MI Registry (KAMIR) and KAMIR-National Institutes of Health. Mixed-effect regression models were used to examine the association between the annual average ambient AP before MI onset and the incidence of STEMI, and to evaluate the association of AP with the incidence of in-hospital cardiogenic shock. After mixed-effect regression model analysis, particulate matter (PM) 10 µm or less in diameter (PM
) was associated with increased incidence of STEMI compared with NSTEMI (odds ratio OR 1.009, 95% Confidence Interval CI 1.002-1.016; p = 0.012). For in-hospital cardiogenic shock complication, PM
and SO
were associated with increased risk, PM
(OR 1.033, 95% CI 1.018-1.050; p < 0.001), SO
(OR 1.104, 95% CI 1.006-1.212; p = 0.037), respectively. Policy-level strategies and clinical efforts to reduce AP exposure are necessary to prevent the incidence of STEMI and severe cardiovascular complications.
Background: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We ...aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. Methods: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received—placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0–2 at 12 weeks. Results: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 54.1%, 40/65 61.5%, and 36/57 63.2% patients; P =0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92–2.60) between the placebo and low-dose groups and 1.61 (0.94–2.76) between the placebo and high-dose groups. No serious adverse events were reported. Conclusions: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0–2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02831088.
Objective
This study aimed to investigate the impact of angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on 3-year clinical outcomes in elderly (≥ 65) ...acute myocardial infarction (AMI) patients without a history of hypertension who underwent successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES).
Methods
A total of 13,104 AMI patients who were registered in the Korea AMI registry (KAMIR)-National Institutes of Health (NIH) were included in the study. The primary endpoint was 3-year major adverse cardiac events (MACE), which was defined as the composite of all-cause death, recurrent myocardial infarction (MI), and any repeat revascularization. To adjust baseline potential confounders, an inverse probability weighting (IPTW) analysis was performed.
Results
The patients were divided into two groups: the ACEI group,
n
= 872 patients and the ARB group,
n
= 508 patients. After IPTW matching, baseline characteristics were balanced. During the 3-year clinical follow-up, the incidence of MACE was not different between the two groups. However, incidence of stroke (hazard ratio HR, 0.375; 95% confidence interval CI, 0.166–0.846;
p
= 0.018) and re-hospitalization due to heart failure (HF) (HR, 0.528; 95% CI, 0.289–0.965;
p
= 0.038) in the ACEI group were significantly lower than in the ARB group.
Conclusion
In elderly AMI patients who underwent PCI with DES without a history of hypertension, the use of ACEI was significantly associated with reduced incidences of stroke, and re-hospitalization due to HF than those with the use of ARB.
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