Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G ...protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed.
Purpose
This study aims to evaluate the perioperative outcomes of aortic valve replacement (AVR) via right anterior minithoracotomy (RAT) during the learning curve.
Methods
It was a retrospective, ...observational, cohort study of patients who underwent RAT AVR from June 2015 to April 2022. Primary outcomes measured were 30-day morbidity and mortality.
Results
A total of 107 consecutive patients underwent elective RAT AVR. Our patients were mostly male (78.5%), elderly (mean 68.7 years), and obese (34.6%). A majority of the patients (93.5%) were of low operative risk. Median cross-clamp and bypass times were 95 and 123 minutes respectively. There was a statistically significant correlation between increase in number of cases and decrease in operative time. All patients had no paravalvular leak at discharge. There were no operative cardiovascular mortality or major morbidity including stroke, myocardial infarction, renal failure requiring dialysis, or vascular complication. No patient required intraoperative conversion to full sternotomy for completion of AVR.
Conclusion
Our study demonstrated that RAT AVR can be safely introduced. The learning curve required in performing RAT AVR can be safely negotiated through training, previous experience in minimally invasive surgery, careful patient selection including use of preoperative computed tomography of the aorta, and introduction of sutureless/rapid deployment valves.
Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the ...DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.
Abstract
Previous studies have shown that each edible oil type has its own characteristic fatty acid profile; however, no method has yet been described allowing the identification of oil types simply ...based on this characteristic. Moreover, the fatty acid profile of a specific oil type can be mimicked by a mixture of 2 or more oil types. This has led to fraudulent oil adulteration and intentional mislabeling of edible oils threatening food safety and endangering public health. Here, we present a machine learning method to uncover fatty acid patterns discriminative for ten different plant oil types and their intra-variability. We also describe a supervised end-to-end learning method that can be generalized to oil composition of any given mixtures. Trained on a large number of simulated oil mixtures, independent test dataset validation demonstrates that the model has a 50
th
percentile absolute error between 1.4–1.8% and a 90
th
percentile error of 4–5.4% for any 3-way mixtures of the ten oil types. The deep learning model can also be further refined with on-line training. Because oil-producing plants have diverse geographical origins and hence slightly varying fatty acid profiles, an online-training method provides also a way to capture useful knowledge presently unavailable. Our method allows the ability to control product quality, determining the fair price of purchased oils and in-turn allowing health-conscious consumers the future of accurate labeling.
The efficient and simple separation of oil–water mixtures has been a global challenge due to the growing problem of oily wastewater. To address this issue, various materials with special wetting ...properties and functionality have been developed in the past decades for oil–water separation. In this study, a superhydrophobic cellulose acetate (CA) functional coating was prepared by electrostatic spraying of CA and chemical vapor deposition of methyltrichlorosilane (MTCS) on a stainless steel mesh (SSM). Water contact angle in air (WCA) of the resulting coating is154° or more, and oil under water contact angle (UWOCA) is 0°. Simultaneously, the separation flux of the resulting coating for oil–water mixtures is as high as 23977.77 L·m−2·h−1, with separation efficiencies exceeding 99%. Due to its excellent water repellency, the CA functional coating can effectively separate oil and water, and can be easily dried for continuous use. Furthermore, the CA functional coating exhibits good stability in salt solutions and acidic environments, making it an ideal material for addressing oily wastewater challenges.
Highlights
The coating obtained by electrostatic spraying and CVD was superhydrophobic.
The separation flux and separation efficiencies of coatings is 23977.77 L·m−2·h−1 and 99%.
Coatings remain stable under polar environment conditions (pH = 2–12 and NaCl = 1–3 mol/L).
Preparation of superhydrophobic stainless steel mesh coatings by electrostatic spraying of cellulose acetate(CA) and chemical vapour deposition of methyltrichlorosilane(MTCS).
Microplastic (MP) pollution is an emerging contaminant in aquatic environments worldwide. Nonetheless, the developmental toxicity of MPs in the early life stages of fish and the mechanisms involved ...are not yet fully understood. The present study investigated the effects of different concentrations of polystyrene (PS) MPs on the early development of the marine model fish the medaka Oryzias melastigma. Our results showed that waterborne exposure to PS MPs significantly delayed the hatching time, altered the heartbeat and decreased the hatching rate of embryos. Furthermore, the genes involved in cardiac development, encoding for embryo-hatching enzymes, as well as inflammatory responses were significantly upregulated. The transcriptome results showed that mainly the pathways involved in metabolism, immune response, genetic information processing and diseases were significantly enriched. These results demonstrate that PS MPs negatively impact embryogenesis and the immune response of O. melastigma.
•MPs significantly changed the hatching time and hatching rate of medaka embryos.•MPs appeared to impair the heart development of embryos.•MPs induced inflammatory and immune genes of embryos.•Toxicity of MPs is size- and time-dependent.
An efficient diastereo- and enantioselective Mannich-type/cyclization cascade reaction of α-substituted isocyanoacetates and cyclic trifluoromethyl ketimines cooperatively catalyzed by cinchona ...alkaloid-derived multi-hydrogen-bonding donor squaramide and AgOAc has been investigated, affording the optically active trifluoromethyl-substituted tetrahydroimidazo1,5-cquinazoline derivatives in excellent yields (up to 99%) and good to excellent stereoselectivities (up to >15:1 dr, up to 98% ee) under mild conditions.
Interleukin (IL)‐33, a member of the IL‐1 cytokine family, is an important modulator of the immune system associated with several immune‐mediated disorders. High levels of IL‐33 are expressed by the ...central nervous system (CNS) suggesting a potential role of IL‐33 in autoimmune CNS diseases. We have investigated the expression and function of IL‐33 in the development of experimental autoimmune encephalomyelitis (EAE) in mice. We report here that IL‐33 and its receptor ST2 (IL‐33Rα) are highly expressed in spinal cord tissue, and ST2 expression is markedly increased in the spinal cords of mice with EAE. Furthermore, ST2‐deficient (ST2−/−) mice developed exacerbated EAE compared with wild‐type (WT) mice while WT, but not ST2−/− EAE mice treated with IL‐33 developed significantly attenuated disease. IL‐33‐treated mice had reduced levels of IL‐17 and IFN‐γ but produced increased amounts of IL‐5 and IL‐13. Lymph node and splenic macrophages of IL‐33‐treated mice showed polarization toward an alternatively activated macrophage (M2) phenotype with significantly increased frequency of MR+PD‐L2+ cells. Importantly, adoptive transfer of these IL‐33‐treated macrophages attenuated EAE development. Our data therefore demonstrate that IL‐33 plays a therapeutic role in autoimmune CNS disease by switching a predominantly pathogenic Th17/Th1 response to Th2 activity, and by polarization of anti‐inflammatory M2 macrophages.
Natural nanoparticles have been extensively studied due to their diverse properties and easy accessibility. Here, the nanoparticles extracted from cuttlefish ink (CINPs) with significant antitumor ...efficacy are explored. These CINPs, with spherical morphology, good dispersibility, and biocompatibility, are rich in melanin and contain a variety of amino acids and monosaccharides. Through the activation of mitogen-activated protein kinase (MAPK) signaling pathway, CINPs can efficiently reprogram tumor-associated macrophages (TAMs) from immune-suppressive M2-like phenotype to antitumor M1-like phenotype. Besides, under near-infrared (NIR) irradiation, CINPs exhibit high photothermal effect and tumor cell killing ability, which make them a potential candidate in photothermal therapy (PTT) of tumor. In vivo, CINPs can increase the proportion of M1 macrophages and foster the recruitment of cytotoxic T lymphocytes (CTLs) to tumors, leading to reduced primary tumor growth and lung metastasis. In combination with their photothermal effect, which can induce tumor-specific antigens release, CINPs could almost completely inhibit tumor growth accompanied by more active immune responses. Collectively, these CINPs described here can provide both tumor immunotherapy and PTT, implying that CINPs are promising for tumor treatment.
Abstract
Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three ...cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%–24.3%) and 95% (95% CI: 85.4%–100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.
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