Apoptosis, a type of programmed cell death that plays a key role in both healthy and pathological conditions, releases extracellular vesicles such as apoptotic bodies and microvesicles, but exosome ...release due to apoptosis is not yet commonly accepted. Here, the reports demonstrating the presence of apoptotic exosomes and their roles in inflammation and immune responses are summarized, together with a general summary of apoptosis and extracellular vesicles. In conclusion, apoptosis is not just a 'silent' type of cell death but an active form of communication from dying cells to live cells through exosomes.
Cancer immunotherapy has emerged as a promising cancer treatment. However, the presence of immune-refractory tumor cells limits its clinical success by blocking amplification of anti-tumor immunity. ...Previously, we found that immune selection by immunotherapy drives the evolution of tumors toward multi-modal resistant and stem-like phenotypes via transcription induction of AKT co-activator TCL1A by NANOG. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and multi-aggressive properties of immune-edited tumor cells by identifying HSP90AA1 as a NANOG transcriptional target. Furthermore, we demonstrate that HSP90A potentiates AKT activation through TCL1A-stabilization, thereby contributing to the multi-aggressive properties in NANOG
tumor cells. Importantly, HSP90 inhibition sensitized immune-refractory tumor to adoptive T cell transfer as well as PD-1 blockade, and re-invigorated the immune cycle of tumor-reactive T cells. Our findings implicate that the HSP90A-TCL1A-AKT pathway ignited by NANOG is a central molecular axis and a potential target for immune-refractory tumor.
Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ...ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed.
In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete.
Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001).
Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction.
Hanmi Pharmaceutical.
Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated ...patterns (DAMPs). By inducing IL-1β from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called “apoptotic exosome-like vesicles” (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin–guided multivesicular endosomes mediated by Gβγ subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1β via NF-κB transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future.
Low-cost anion exchange membrane fuel cells have been investigated as a promising alternative to proton exchange membrane fuel cells for the last decade. The major barriers to the viability of anion ...exchange membrane fuel cells are their unsatisfactory key components-anion exchange ionomers and membranes. Here, we present a series of durable poly(fluorenyl aryl piperidinium) ionomers and membranes where the membranes possess high OH
conductivity of 208 mS cm
at 80 °C, low H
permeability, excellent mechanical properties (84.5 MPa TS), and 2000 h ex-situ durability in 1 M NaOH at 80 °C, while the ionomers have high water vapor permeability and low phenyl adsorption. Based on our rational design of poly(fluorenyl aryl piperidinium) membranes and ionomers, we demonstrate alkaline fuel cell performances of 2.34 W cm
in H
-O
and 1.25 W cm
in H
-air (CO
-free) at 80 °C. The present cells can be operated stably under a 0.2 A cm
current density for ~200 h.
Insects are the most abundant animals on Earth, and the microbiota within their guts play important roles by engaging in beneficial and pathological interactions with these hosts. In this study, we ...comprehensively characterized insect-associated gut bacteria of 305 individuals belonging to 218 species in 21 taxonomic orders, using 454 pyrosequencing of 16S rRNA genes. In total, 174,374 sequence reads were obtained, identifying 9,301 bacterial operational taxonomic units (OTUs) at the 3% distance level from all samples, with an average of 84.3 (± 97.7) OTUs per sample. The insect gut microbiota were dominated by Proteobacteria (62.1% of the total reads, including 14.1% Wolbachia sequences) and Firmicutes (20.7%). Significant differences were found in the relative abundances of anaerobes in insects and were classified according to the criteria of host environmental habitat, diet, developmental stage, and phylogeny. Gut bacterial diversity was significantly higher in omnivorous insects than in stenophagous (carnivorous and herbivorous) insects. This insect-order-spanning investigation of the gut microbiota provides insights into the relationships between insects and their gut bacterial communities.
The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. However, the mechanism and physiological significance by which ...post-translational modifications lead to PTEN suppression remain unclear. Here we demonstrate that PTEN destabilization is induced by EGFR- or oncogenic PI3K mutation-mediated AKT activation in cervical cancer. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. These processes require the stabilization of MKRN1 via AKT-mediated phosphorylation. In cervical cancer patients with high levels of pAKT and MKRN1 expression, PTEN protein levels are low and correlate with a low 5-year survival rate. Taken together, our results demonstrate that PI3K/AKT signals enforce positive-feedback regulation by suppressing PTEN function.
The performance of a cyclone is generally assessed using the pressure drop and the collection efficiency of the cyclone. In the present paper, a multi-objective optimization of a classic Stairmand ...cyclone separator is executed using the response surface methodology (RSM), combined with computational fluid dynamics (CFD) techniques for minimizing the pressure drop and maximizing the collection efficiency. Ten cyclone geometrical factors are considered in this work. Three of them are studied using the RSM according to the results of the preceding screening experiments. The second-order response surface models for each response are successfully carried out using the central composite design (CCD) in the RSM. The desirability function approach is used to optimize the geometrical factors of the cyclone. In comparison to the reference model, the optimal cyclone model decreases the pressure drop by 20.70% and the cut-off size by 75.38%. The accuracies of the response surface models are confirmed and the correctness of the optimal cyclone model is also validated using CFD; the results indicate excellent performance and reliability of the response surface model and the RSM optimization result. According to the analyses of the obtained flow fields, there are several reasons why decreases in the cut-off size with a lower pressure drop are found in the optimal model. The primary reasons for improvements are optimized values of relevant geometrical factors, the production of a distinct, undisturbed downward flow, an increase in the tangential velocity at the near wall region, and a decrease in the peak tangential velocity.
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•A multi-objective optimization of a Stairmand cyclone is executed.•Nine geometrical factors and two objective functions are considered.•Response surface methodology and computational fluid dynamics are utilized.•The reasons leading to improve the performance are explained in detail.
Not only are many Mycobacteria pathogens, but they can act as strong non‐specific immunopotentiators, generating beneficial effects on the pathogenesis of some diseases. However, there has been no ...direct evidence of the effect of mycobacterial species on colorectal cancer (CRC). Herein, we showed that there may be a meaningful inverse correlation between the incidence of tuberculosis and CRC based on global statistics and that heat‐killed Mycobacterial tuberculosis and live Mycobacterium bovis (Bacillus Calmette–Guérin strain) could ameliorate CRC development. In particular, using a faecal microbiota transplantation and a comparison between separate housing and cohousing, we demonstrated that the gut microbiota is involved in the protective effects. The microbial alterations can be elucidated by the modulation of antimicrobial activities including those of the Reg3 family genes. Furthermore, interleukin‐22 production by T helper cells contributed to the anti‐inflammatory activity of Mycobacteria. Our results revealed a novel role of Mycobacteria involving gut microbial alterations in dampening inflammation‐associated CRC and an immunological mechanism underlying the interaction between microbes and host immunity.
Subcutaneous injection of heat‐killed Mycobacterial tuberculosis or live Mycobacterium bovis Bacillus Calmette–Guérin strain ameliorates the development of colorectal cancer (CRC), in which the gut microbiota is involved. The mycobacteria can induce IL‐22 production from CD4+ T cells, which leads to the secretion of antimicrobial peptides, such as Reg3β and Reg3γ, from epithelial cells to the lumen. The increased antimicrobial peptides can elucidate the mycobacteria‐mediated gut microbial alteration. Collectively, mycobacteria have the potential to change the gut microbial structure to more beneficial members, thereby protecting from CRC.
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