Explore the vast range of titles available.

Acute liver injury is commonly caused by bacterial endotoxin/lipopolysaccharide (LPS), and by drug overdose such as acetaminophen (APAP). The exact role of epigenetic modification in acute liver injury remains elusive. Here, we investigated the role of histone methyltransferase G9a in LPS- or APAP overdose-induced acute liver injury. Under d-galactosamine sensitization, liver-specific G9a-deficient mice (L-G9a−/−) exhibited 100% mortality after LPS injection, while the control and L-G9a+/− littermates showed very mild mortality. Moreover, abrogation of hepatic G9a or inhibiting the methyltransferase activity of G9a aggravated LPS-induced liver damage. Similarly, under sublethal APAP overdose, L-G9a−/− mice displayed more severe liver injury. Mechanistically, ablation of G9a inhibited H3K9me1 levels at the promoters of Gstp1/2, two liver detoxifying enzymes, and consequently suppressed their transcription. Notably, treating L-G9a−/− mice with recombinant mouse GSTP1 reversed the LPS- or APAP overdose-induced liver damage. Taken together, we identify a novel beneficial role of G9a-GSTP1 axis in protecting against acute liver injury.

Natural killer/T-cell lymphoma (NKTCL) is a highly invasive subtype of non-Hodgkin lymphoma, typically positive for cytoplasmicCD3, CD56, cytotoxic markers, including granzyme B and TIA1, and Epstein-Barr virus (EBV). The current treatment methodsfor NKTCL are associated with several drawbacks. For example, chemotherapy can lead to drug resistance, while treatment withradiotherapy alone is inadequate and results in frequent relapses. Moreover, hematopoietic stem cell transplantation exhibits limitedefficacy and is not well recognized by domestic and foreign experts. In recent years, immunotherapy has shown good clinical resultsand has become a hot spot in cancer research. Clinical activity of targeted antibodies, such as daratumumab (anti-CD38 antibody)and brentuximab vedotin (anti-CD30 antibody), have been reported in NKTCL. Additionally, dacetuzumab and Campath-1H havedemonstrated promising results. Further encouraging data have been obtained using checkpoint inhibitors. The success of theseimmunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL. Furthermore, anti-CCR4monoclonal antibodies (mAbs) exert cytotoxic actions on both CCR4+ tumor cells and regulatory T cells. Depletion of these cellsand the long half-life of anti-CCR4 mAbs result in enhanced induction of antitumor effector T cells. The role of IL10 in NKTCL hasalso been investigated. It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies.Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promisingresults and sustained remission. Cellular immunotherapy may be used either as maintenance therapy following initial inductionchemotherapy or in cases of relapsed/refractory disease. The present review outlines the known immunotherapy targets for thetreatment of NKTCL.

Astaxanthin has 550 times more antioxidant activity than vitamin E, so it can scavenge free radicals in vivo and improve body immunity. However, the poor stability of astaxanthin becomes a bottleneck problem that limits its application. Herein, Haematococcus pluvialis (H. pluvialis) as a raw material was used to extract astaxanthin, and the optimal extraction conditions included the extraction solvent (EA:EtOH = 1:6, v/v), extraction temperature (60 °C), and extraction time (70 min). The extracted astaxanthin was then loaded using lecithin to form corresponding liposomes via the ethanol injection method. The results showed that the particle size and zeta potential of the prepared liposomes were 105.8 ± 1.2 nm and −38.0 ± 1.7 mV, respectively, and the encapsulation efficiency of astaxanthin in liposomes was 88.83%. More importantly, the stability of astaxanthin was significantly improved after being embedded in the prepared liposomes.

Excessive nuclear factor-κB (NF-κB) activation mediated by tumor necrosis factor α (TNFα) plays a critical role in inflammation. Here we demonstrate that angiopoietin-like 8 (ANGPTL8) functions as a negative feedback regulator in TNFα-triggered NF-κB activation intracellularly. Inflammatory stimuli induce ANGPTL8 expression, and knockdown or knockout of ANGPTL8 potentiates TNFα-induced NF-κB activation in vitro. Mechanistically, upon TNFα stimulation, ANGPTL8 facilitates the interaction of IKKγ with p62 via forming a complex, thus promoting the selective autophagic degradation of IKKγ. Furthermore, the N-terminal domain mediated self-oligomerization of ANGPTL8 is essential for IKKγ degradation and NF-κB activation. In vivo, circulating ANGPTL8 level is high in patients diagnosed with infectious diseases, and the ANGPTL8/p62-IKKγ axis is responsive to inflammatory stimuli in the liver of LPS-injected mice. Altogether, our study suggests the ANGPTL8/p62-IKKγ axis as a negative feedback loop that regulates NF-κB activation, and extends the role of selective autophagy in fine-tuned inflammatory responses. NF-κB activation mediated by TNFα has a critical role in inflammation; however, the underlying mechanisms await further investigation. Here the authors show that selective autophagy regulates NF-κB activation via an ANGPTL8/p62-IKKγ signaling axis.

Extranodal natural killer (NK)/T cell lymphoma (ENKTL-NT or NKTCL), with its aggressive nature and poor prognosis, has been widely studied to discover more effective treatment options. Various somatic gene alterations have been identified by traditional Sanger sequencing. However, recently, novel gene mutations in NKTCL have been revealed by next-generation sequencing (NGS) technology, suggesting the potential for novel targeted therapies. This review discusses recurrent aberrations in NKTCL detected by NGS, which can be categorized into three main groups, specifically, tumor suppressors (TP53, DDX3X, and MGA), the JAK/STAT cascade, and epigenetic modifiers (KMT2D, BCOR, ARID1A, and EP300). Some epigenetic dysregulation and DDX3X mutation, which have been rarely identified by traditional sequencing technology, were recently uncovered with high frequencies by NGS. In this review, we summarize the mutational frequencies of various genes in NKTCL. In general, based on our analysis, BCOR is the most frequently mutated gene (16.9%), followed by TP53 (14.7%), and DDX3X (13.6%). The characterization of such genes provides new insight into the pathogenesis of this disease and indicates new biomarkers or therapeutic targets.

Background Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive subtype of lymphoma characterized by a poor prognosis. While immune checkpoint blockade (ICB) therapy has emerged as an effective treatment modality for various cancers, its efficacy among individuals is inconsistent and remains suboptimal for the majority of NKTCL patients. Faecalibacterium prausnitzii , recognized as a next-generation probiotic with immunomodulatory capabilities, has not yet been fully explored for its potential to influence the outcomes of ICB therapy. Methods We established syngeneic tumor-bearing mouse models of NKTCL and treated the mice with an anti-PD-L1 monoclonal antibody (mAb) and F. prausnitzii . Metabolomics analysis was performed to quantify butyrate concentrations in fecal, plasma, and tumor samples from the mice. Furthermore, we used flow cytometry, multiplex immunohistochemistry, and enzyme-linked immunosorbent assays to assess the effects of butyrate supplementation on antitumor immune responses in mice receiving anti-PD-L1 therapy. Additionally, an antibiotic-pretreated mouse model was utilized to further investigate the influence of F. prausnitzii on the efficacy of ICB therapy. Results The combination of F. prausnitzii and an anti-PD-L1 mAb effectively inhibited tumor growth, primarily through the action of its metabolite butyrate. Notably, F. prausnitzii -derived butyrate played a crucial role in enhancing the efficacy of ICB therapy by augmenting antitumor immune responses, as evidenced by reduced PD-L1 expression and increased levels of cytotoxic CD8+ T cells within the tumor microenvironment. Moreover, prior administration of antibiotics significantly compromised the efficacy of the anti-PD-L1 mAb. However, supplementation with F. prausnitzii mitigated the negative effects of antibiotics and restored the altered gut microbiota in tumor-bearing mice. Conclusions This study highlights the potential of F. prausnitzii in augmenting ICB therapy and presents a novel gut probiotic-centered therapeutic strategy for the treatment of NKTCL.

Products such as cattles and pigs can be processed into several types of products (parts) targeting different segments of customers, which belong to the so called coproducts. Mismatch risk is a significant issue in such coproduct supply chains. Under the Stackelberg game setting, we consider a coproduct supply chain consisting of one producer acting as the leader and one retailer being the follower and establish a stylized model to study how the mismatch risk should be allocated. Two supply chain modes are considered, i.e., the P-chain mode under which the producer is responsible for the processing activity and hence holds the mismatch risk, and the R-chain under which the retailer is responsible for the processing activity. We use the unbalanced ratio to reflect the degree of mismatch between supply and demand among different parts of the coproduct and study how the tradeoff between the bargaining power and the mismatch cost, by different mismatch risk allocations, influences the optimal decisions and the performances of the two parties as well as the whole supply chain. Our main findings include: (1) P-chain dominates R-chain from the perspective of the chain performance; and (2) the upstream producer is not always better off in the P-chain under which he bears more mismatch risk. Numerical study shows the robustness of our main results and further studies the effect of demand uncertainty and the processing cost on the performance of P-chain as compared to R-chain.

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice ( Ncr1-Cre-Gnaq fl/fl ), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies. Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive disease. Here, the authors identify recurrent somatic mutations of GNAQ in NKTCL, and model how this mutation contributes to NKTCL pathogenesis.

Crowdfunding provides a novel and potential way for innovative but risky new ventures to fund their new product development (NPD) projects. To help potential investors evaluate the projects and enhance the credibility of disclosure, founders are struggling with how to phrase the project description. The rapidly growing cleantech crowdfunding projects provide an ideal context to study this issue. We collected information on cleantech crowdfunding projects and matched non-cleantech crowdfunding projects from Kickstarter. The sample period extends from January 2013 to October 2018. Using signaling research as a theoretical lens and a dictionary-based, computerized text mining method, we found that founders of high-quality cleantech crowdfunding projects could create a reliable signal of quality by providing a project description with a less ambiguous tone and thus boost the success of crowdfunding. Moreover, the signaling effectiveness of a less ambiguous tone is more pronounced in cleantech crowdfunding than in matched non-cleantech crowdfunding, suggesting that the marginal benefit of using a less ambiguous tone is larger when the industry information environment is noisier. Further evidence shows that the signaling effectiveness of a less ambiguous tone in cleantech crowdfunding could be strengthened by backers’ endorsements. Our findings imply that tone ambiguity in project descriptions is related to founders’ information-concealing behavior. Potential investors could search ambiguous words in project descriptions and just allocate their limited attention into projects with a low percentage of ambiguous words to avoid information overload. Founders of high-quality projects could boost crowdfunding success by using a less ambiguous tone to describe their projects. The marginal effect is larger when there is greater uncertainty about project prospects.