Among the most promising therapeutic modalities for cancer treatment is the blockade of immune checkpoint pathways, which are frequently co-opted by tumors as a major mechanism of immune escape. ...CTLA-4 and PD-1 are the representative examples, and their blockade by therapeutic antibodies leads to enhanced anti-tumor immunity with durable clinical responses, but only in a minority of patients. This has highlighted the need to identify and target additional immune checkpoints that can be exploited to further enhance immune responses to refractory cancers. These emerging targets include natural killer (NK) cell-directed checkpoint receptors (KIR and CD94/NKG2A) as well as the NK- and T cell-expressed checkpoints TIM-3, TIGIT, CD96, and LAG-3. Interestingly, the potentiation of anti-tumor immunity by checkpoint blockade relies not only on T cells but also on other components of the innate immune system, including NK cells. NK cells are innate lymphoid cells that efficiently kill tumor cells without MHC specificity, which is complementary to the MHC-restricted tumor lysis mediated by cytotoxic T cells. However, the role of these immune checkpoints in modulating the function of NK cells remains unclear and somewhat controversial. Unraveling the mechanisms by which these immune checkpoints function in NK cells and other immune cells will pave the way to developing new therapeutic strategies to optimize anti-tumor immunity while limiting cancer immune escape. Here, we focus on recent findings regarding the roles of immune checkpoints in regulating NK cell function and their potential application in cancer immunotherapy.
Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some ...underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.
•Phytoncide essential oil was applied for the control of browning of freshcut lettuce.•EP showed lower levels for all the parameters related to browning, except L* value.•Anti-browning effects of ...each treatment, decreasing strength were EP>EE>WP>WW.
Phytoncide essential oil derived from pine leaves was applied for the control of enzymatic browning of fresh-cut lettuce. Changes in the browning characteristics of cut lettuce treated with phytoncide in an water or ethanol solution (1%, v/v) at 10°C were investigated for 12days at 4°C. Other samples dipped in distilled water or 95% ethanol were used as the controls. The samples treated with phytoncide in an ethanol solution showed significantly higher L* values and lower a* values, ΔE values, browning index, phenolic compounds, and enzyme activities (PPO, POD, PAL) related to browning. The samples dipped in distilled water showed the opposite tendency. On the basis of changes in the browning characteristics, anti-browning effects of each treatment, phytoncide in an ethanol solution was the most effective treatment applied. These results suggest that phytoncide treatment could be used as an effective method for controlling enzymatic browning in fresh-cut lettuce.
Accumulation of β-amyloid (Aβ) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular ...Aβ fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in Aβ degradation by microglia and its effects on AD are unknown. Here we demonstrate a novel role for autophagy in the clearance of extracellular Aβ fibrils by microglia and in the regulation of the Aβ-induced NLRP3 (NLR family, pyrin domain containing 3) inflammasome using microglia specific atg7 knockout mice and cell cultures. We found in microglial cultures that Aβ interacts with MAP1LC3B-II via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for AD.
The risks and benefits of long-term dual antiplatelet therapy remain unclear.
This prospective, multicenter, open-label, randomized comparison trial was conducted in 24 clinical centers in Korea. In ...total, 5045 patients who received drug-eluting stents and were free of major adverse cardiovascular events and major bleeding for at least 12 months after stent placement were enrolled between July 2007 and July 2011. Patients were randomized to receive aspirin alone (n=2514) or clopidogrel plus aspirin (n=2531). The primary end point was a composite of death resulting from cardiac causes, myocardial infarction, or stroke 24 months after randomization. At 24 months, the primary end point occurred in 57 aspirin-alone group patients (2.4%) and 61 dual-therapy group patients (2.6%; hazard ratio, 0.94; 95% confidence interval, 0.66-1.35; P=0.75). The 2 groups did not differ significantly in terms of the individual risks of death resulting from any cause, myocardial infarction, stent thrombosis, or stroke. Major bleeding occurred in 24 (1.1%) and 34 (1.4%) of the aspirin-alone group and dual-therapy group patients, respectively (hazard ratio, 0.71; 95% confidence interval, 0.42-1.20; P=0.20).
Among patients who were on 12-month dual antiplatelet therapy without complications, an additional 24 months of dual antiplatelet therapy versus aspirin alone did not reduce the risk of the composite end point of death from cardiac causes, myocardial infarction, or stroke.
http://www.clinicaltrials.gov. Unique identifier: NCT01186146.
NF-κB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-κB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target ...cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-κB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-κB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-κB activation. Vav1 controls downstream p65 phosphorylation and NF-κB activation. Synergistic signalling is defective in X-linked lymphoproliferative disease (XLP1) NK cells entailing 2B4 dysfunction and required for p65 phosphorylation by PI3K-Akt signal, suggesting stepwise signalling checkpoint for NF-κB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-κB activation and NK cell responses.
A cohort of patients who underwent stent implantation for unprotected left main coronary artery disease was compared with a propensity-matched cohort of patients who underwent coronary-artery bypass ...grafting. The risk of death and the composite outcome of death, Q-wave myocardial infarction, or stroke did not differ significantly between the two groups. The risk of target-vessel revascularization was higher in the group that received stents.
The risk of death and the composite outcome of death, Q-wave myocardial infarction, or stroke did not differ significantly between the two groups. The risk of target-vessel revascularization was higher in the group that received stents.
Significant narrowing of the left main coronary artery puts a patient at high risk, since it can jeopardize the entire myocardium of the left ventricle, and it has the worst prognosis of any form of coronary artery disease.
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On the basis of clinical trials that show a survival benefit with bypass surgery as compared with medical treatment,
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coronary-artery bypass grafting (CABG) has been considered standard therapy for patients with left main coronary artery disease and is recommended by current practice guidelines.
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Because of concern about procedural risk and long-term durability, percutaneous coronary intervention (PCI) usually has been restricted . . .
Poly(L-lactide) (PLA) was melt-mixed with micrometer-sized and nanosized calcium carbonate (CaCO₃) particles before and after modification with calcium stearate. Adhesion between the CaCO₃ particles ...and the PLA matrix was assessed qualitatively by scanning electron microscopy observation of the fractured surface morphology of the composites. The effect of the incorporation of the CaCO₃ particles on the thermal stability of the PLA-based composites was quantified by the temperatures corresponding to 5 and 50% of weight loss and the activation energy determined through thermogravimetric analyses of the composites. The tensile strength and modulus values of the composite were improved greatly without a significant loss in the elongation at break when the nanosized CaCO₃ was incorporated up to 30 wt %.
Multiwalled carbon nanotubes (MWNT) were functionalized with amine groups using a ‘grafting to’ technique. The oxidized MWNT (MWNT–COOH) were converted to the acyl chloride functionalized MWNT ...(MWNT–COCl) by treating them with thionyl chloride (SOCl2), and then MWNT–COCl was reacted with hexamethylenediamine to prepare MWNT–NH2. The formation of MWNT–NH2 was confirmed through the FTIR observation. MWNT–NH2/nylon 6 composites with different MWNT loadings were prepared by the simple melt compounding approach. A fine dispersion of MWNTs throughout nylon 6 matrix was observed by SEM and TEM. The fractured surface of the composites showed not only a uniform dispersion of MWNTs but also a strong interfacial adhesion with the matrix, as evidenced by the presence of many broken but strongly embedded MWNTs in the matrix in the absence of debonding of MWNTs from the matrix. Incorporation of MWNTs improved the mechanical properties significantly. Higher thermal stability was obtained for the composites with better dispersed MWNTs.
•Warm-water deastringency pretreatment inhibited browning of fresh-cut persimmons.•Warm-water deastringency pretreatment retarded softening of fresh-cut persimmons.•Deastringency treatment reduced ...antioxidant activity of fresh-cut persimmons.
The changes in the quality characteristics of the fresh-cut products prepared from intact ‘Cheongdobansi’ persimmons treated with different deastringency methods (nontreated, carbon dioxide gas, warm water, ethanol vapour) have been investigated for 6days at 10°C. Flesh firmness of the persimmons decreased after ethanol vapour treatment. The decrease in L∗ value and flesh firmness in the slices prepared from persimmons treated with warm water was retarded. Soluble solids content and titratable acidity of the persimmons decreased after all deastringency treatments. Soluble tannins and radical scavenging activity of the slices from untreated persimmons were maintained at higher concentrations, unlike slices from astringency-removed persimmons. These results suggest that pre-slicing deastringency treatments affect the characteristics of fresh-cut persimmons, and that warm-water treatment could be a useful method to control the browning and softening of fresh-cut persimmons.
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