Preparation of Polyethylene/α-Zirconium Phosphate Nanocomposites via a Well-Controlled Polyethylene-Grafted Interface.

It is a daunting task to prepare polyolefin nanocomposites that contain well-exfoliated nanoplatelets due to the nonpolar and high crystallinity nature of polyolefins. In this research, a robust approach was developed to prepare polyethylene (PE) nanocomposites by grafting maleated polyethylene (MPE) onto pre-exfoliated α-zirconium phosphate (ZrP) nanoplatelets via a simple amine-anhydride reaction to form ZrP-g-MPE. Several variables, including maleic anhydride (MA) content, MPE graft density, MPE molecular weight, and PE matrix crystallinity, were investigated to determine how they influence ZrP-g-MPE dispersion in PE. It was found that grafted PE has a different morphology and that the long PE brushes with medium graft density on ZrP can achieve sufficient chain entanglement and cocrystallization with PE matrix to stabilize and maintain ZrP-g-MPE dispersion after solution or melt mixing. This leads to enhanced Young's modulus, yield stress, and ductility. The structure-property relationship of PE/ZrP-g-MPE nanocomposites and usefulness of this study for the preparation of high-performance polyolefin nanocomposites are discussed.

Long-Term Safety and Efficacy of Eltrombopag for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia: Results of the ASPIRE Extension Study.

ASPIRE, a three-part, international, phase 2 trial (ClinicalTrials.gov identifier: NCT01440374), investigated eltrombopag efficacy and safety in patients with advanced myelodysplastic syndrome or acute myeloid leukemia and grade 4 thrombocytopenia (<25 × 109 platelets/L). Approximately 30-65% of patients in this open-label extension phase experienced clinically relevant thrombocytopenic events; no conclusions could be made regarding long-term efficacy (non-randomized design, no placebo control), and survival rates may simply reflect advanced disease. Long-term safety was consistent with the double-blind phase and contrasted with earlier SUPPORT study findings in higher-risk patients, suggesting that eltrombopag may have a role in treating thrombocytopenia in patients with low-/intermediate-risk myelodysplastic syndrome.

Fracture Behavior of Polyrotaxane-Toughened Poly(Methyl Methacrylate).

The fracture behavior of polyrotaxane (PR)-modified poly(methyl methacrylate) (PMMA) was investigated. PR is a supramolecule with rings threaded onto a linear backbone chain, which is capped by bulky end groups to prevent the rings from de-threading. The ring structure is α-cyclodextrin (CD), and it can be functionalized to enhance its affinity with the hosting polymer matrix. Adding only 1 wt % of PR containing methacrylate functional groups (mPR) at the terminal of some of the polycaprolactone-grafted chains on CD promotes massive crazing, resulting in a significant improvement in fracture toughness while maintaining the modulus and transparency of the PMMA matrix. Dynamic mechanical analysis and atomic force microscopy studies reveal that mPR strongly interact with PMMA, leading to higher molecular mobility and enhanced molecular cooperativity during deformation. This molecular cooperativity may be responsible for the formation of massive crazing in a PMMA matrix, which leads to greatly improved fracture toughness.

Neutrophil-to-lymphocyte ratio is associated with carotid intraplaque neovascularization in asymptomatic carotid stenosis patients.

BACKGROUND AND PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) has been suggested as an available systemic inflammatory biomarker. This study aims to evaluate whether intraplaque neovascularization assessed by contrast-enhanced ultrasound (CEUS) is associated with NLR in asymptomatic carotid stenosis patients. MATERIALS AND METHODS: One hundred and forty-four asymptomatic patients with carotid luminal stenosis >30% were assessed using contrast-enhanced ultrasound imaging. The contrast enhancement within the plaque was classified on a visual semiquantitative grading scale. The data collected included the patient's risk factors, laboratory results, cardiovascular disease history, and drug use history. Univariate and multivariate analyses were assessed to identify independent factors related to intraplaque neovascularization with adjustment for potential confounders. RESULTS: Patients with CEUS grade 2 plaques had a higher level of LDL-C (p < .001), neutrophil count (p < .001), and blood glucose (p = .005), but lower level of lymphocyte count (p = .021). The presence of grade 2 plaques was significantly associated with high NLR values (OR 1.21, 95% CI 1.03-1.43, p = .017). Patients were divided into four groups according to the quartile of NLR values. Compared to the patients in the first quartile of NLR (<1.73), the patients in the fourth NLR quartile (≥3.38) were characterized by the most prevalence of CEUS grade 2 plaques (OR 4.55, 95% CI 1.69-12.25, p = .003). Multivariate logistic regression analysis after adjusting various variables demonstrated NLR remained an independent risk factor for the presence of CEUS grade 2 plaques. CONCLUSION: Intraplaque neovascularization is significantly associated with NLR in asymptomatic carotid stenosis patients.

Preparation of Well-Exfoliated Poly(ethylene-co-vinyl acetate)/α-Zirconium Phosphate Nanocomposites.

Poly(ethylene-co-vinyl acetate) (PEVAc) nanocomposites containing exfoliated α-zirconium phosphate (ZrP) have been prepared using a simple solution mixing method to improve their barrier and mechanical properties. ZrP was pre-exfoliated with a surfactant, followed by additional targeted surface functionalization and surfactant exchange to allow for hydrogen bonding of ZrP with the acetate functionality on PEVAc and to improve ZrP surface hydrophobicity. The solvent is found to play an important role in stabilizing ZrP exfoliation in the presence of PEVAc to retain full exfoliation and homogeneous dispersion upon the removal of the solvent. The PEVAc/ZrP nanocomposite exhibits greatly improved oxygen barrier, melt strength, and mechanical properties. The usefulness of the present study for the preparation of olefinic polymer nanocomposites is discussed.

α-Zirconium Phosphate Nanoplatelets with Covalent Modifiers for Exfoliation in Organic Media.

Nanocomposites with exfoliated 2D materials are highly sought after due to resulting material enhancement of barrier and increased modulus among others. In the past, this was achieved by using polyols that were effective but caused a significant drop in the glass transition temperature of the nanocomposite. In this contribution, α-zirconium phosphate (ZrP) nanoplatelets were covalently modified to allow for dispersion in solvents with varying hydrophobicity and poly(methyl methacrylate) (PMMA) for the first time. The nanoplatelets were prepared by using a polyetheramine surfactant to achieve exfoliation, followed by modification with epoxides. Combinations of different epoxides were shown capable of tuning the functionality and hydrophobicity of the exfoliated ZrP in organic media. After grafting glycidyl methacrylate and cyclohexene oxide to the surface of ZrP, an in situ free radical polymerization of MMA allowed for high concentrations of self-assembled exfoliated ZrP in a PMMA matrix.

Manipulation of Fracture Behavior of Poly(methyl methacrylate) Nanocomposites by Interfacial Design of a Metal-Organic-Framework Nanoparticle Toughener.

The interfacial region between nanoparticles and polymer matrix plays a critical role in influencing the mechanical behavior of polymer nanocomposites. In this work, a set of model systems based on poly(methyl methacrylate) (PMMA) matrix containing poly(alkyl glycidyl ether) brushes grafted on 50 nm metal-organic-framework (MOF) nanoparticles were synthesized and investigated. By systematically increasing the polymer brush length and graft density on the MOF nanoparticles, the fracture behavior of PMMA/MOF nanocomposite changes from forming only a few large crazes to generating massive crazing and to undergoing shear banding, which results in significant improvement in fracture toughness. The implication of the present finding for the interfacial design of the nanoparticles for the development of high-performance, multifunctional polymer nanocomposites is discussed.

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.

Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions.

Non-transfusion-dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with ß thalassaemia intermedia (n = 95), haemoglobin (Hb) E/ß thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non-transferrin-bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non-splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor-15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra-hepatic iron distribution are more likely in previously transfused, splenectomised and iron-overloaded NTDT patients with TfSat >70%.

Optimising iron chelation therapy with deferasirox for non-transfusion-dependent thalassaemia patients: 1-year results from the THETIS study.

Efficacy and safety of iron chelation therapy with deferasirox in iron-overloaded non-transfusion-dependent thalassaemia (NTDT) patients were established in the THALASSA study. THETIS, an open-label, single-arm, multicentre, Phase IV study, added to this evidence by investigating earlier dose escalation by baseline liver iron concentration (LIC) (week 4: escalation according to baseline LIC; week 24: adjustment according to LIC response, maximum 30mg/kg/day). The primary efficacy endpoint was absolute change in LIC from baseline to week 52. 134 iron-overloaded non-transfusion-dependent anaemia patients were enrolled and received deferasirox starting at 10mg/kg/day. Mean actual dose±SD over 1year was 14.70±5.48mg/kg/day. At week 52, mean LIC±SD decreased significantly from 15.13±10.72mg Fe/g dw at baseline to 8.46±6.25mg Fe/g dw (absolute change from baseline, -6.68±7.02mg Fe/g dw [95% CI: -7.91, -5.45]; P<0.0001). Most common drug-related adverse events were gastrointestinal: abdominal discomfort, diarrhoea and nausea (n=6 each). There was one death (pneumonia, not considered drug related). With significant and clinically relevant reductions in iron burden alongside a safety profile similar to that in THALASSA, these data support earlier escalation with higher deferasirox doses in iron-overloaded non-transfusion-dependent anaemia patients.

Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia.

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 µg/l), as well as thresholds to guide chelator dose interruption (<300 µg/l) and dose escalation (>2000 µg/l). (clinicaltrials.gov identifier: NCT00873041).

Approaching low liver iron burden in chelated patients with non-transfusion-dependent thalassemia: the safety profile of deferasirox.

OBJECTIVE: Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3. METHODS: THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10 mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6 months before reaching LIC<3 (Period 1), and the 6 months immediately before achieving LIC<3 (Period 2). RESULTS: Mean ± SD deferasirox treatment duration up to reaching LIC<3 was 476 ± 207 d, and deferasirox dose was 9.7 ± 3.0 mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LIC<3 compared with measurements near the previous LIC assessment. CONCLUSIONS: The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation.

Revealing chemical release from plastic debris in animals' digestive systems using nontarget and suspect screening and simulating digestive fluids.

Plastic debris in the environment are not only pollutants but may also be important sources of a variety of contaminants. This work simulated kinetics and potential of chemical leaching from plastic debris in animals' digestive systems by incubating polyvinyl chloride (PVC) cord particles in artificial digestive fluids combined with nontarget and suspect screening based on UHPLC-Orbitrap HRMS. Impacts of particle size, aging, and digestive fluid were investigated to elucidate mechanisms of chemical leaching. Thousands of chemical features were screened in the leachates of PVC cord particles in the artificial digestive fluids, among which >60% were unknown. Bisphenol A (BPA) and bis(2-ethylhexyl) phthalate (DEHP) were the dominant identified CL1 compounds. Finer size and aging of the PVC particles and prolonged incubation time enhanced chemical release, resulting in greater numbers, higher levels, and more complexity in components of the released chemicals. The gastrointestinal fluid was more favorable for chemical leaching than the gastric fluid, with greater numbers and higher levels. Hundreds to thousands of chemical features were screened and filtered in the leachates of consumer plastic products, including food contact products (FCPs) in the artificial bird gastrointestinal fluid. In addition to BPA and DEHP, several novel bisphenol analogues were identified in the leachate of at least one FCP. The results revealed that once plastic debris are ingested by animals, hundreds to thousands of chemicals may be released into animals' digestive tracts in hours, posing potential synergistic risks of plastic debris and chemicals to plastic-ingesting animals. Future research should pay more attentions to identification, ecotoxicities, and environmental fate of vast amounts of unknown chemicals potentially released from plastics in order to gain full pictures of plastic pollution in the environment.

P4HA2 hydroxylates SUFU to regulate the paracrine Hedgehog signaling and promote B-cell lymphoma progression.

Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma.

Synergistic Assembly of Charged Oligomers and Amino Acids at the Air-Water Interface: An Avenue toward Surface-Directed CO2 Capture.

Interfaces are considered a major bottleneck in the capture of CO2 from air. Efforts to design surfaces to enhance CO2 capture probabilities are challenging due to the remarkably poor understanding of chemistry and self-assembly taking place at these interfaces. Here, we leverage surface-specific vibrational spectroscopy, Langmuir trough techniques, and simulations to mechanistically elucidate how cationic oligomers can drive surface localization of amino acids (AAs) that serve as CO2 capture agents speeding up the apparent rate of absorption. We demonstrate how tuning these interfaces provides a means to facilitate CO2 capture chemistry to occur at the interface, while lowering surface tension and improving transport/reaction probabilities. We show that in the presence of interfacial AA-rich aggregates, one can improve capture probabilities vs that of a bare interface, which holds promise in addressing climate change through the removal of CO2 via tailored interfaces and associated chemistries.

Canakinumab in combination with docetaxel compared with docetaxel alone for the treatment of advanced non-small cell lung cancer following platinum-based doublet chemotherapy and immunotherapy (CANOPY-2): A multicenter, randomized, double-blind, phase 3 trial.

OBJECTIVES: Canakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy. MATERIALS AND METHODS: CANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel. RESULTS: A total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2-12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5-13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76-1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3-4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm. CONCLUSION: Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy. CLINICAL REGISTRATION: NCT03626545.

Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study.

Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was -7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of -6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.

Profile, Tissue Distribution, and Time Trend of Bisphenol Plastic Additives in Freshwater Wildlife of the Pearl River Ecosystem, China.

Plastic-related contaminants in the environment have attracted increasing attention, with plastic pollution becoming a serious issue globally. The present study investigated the potential bioaccumulation and biotransfer of bisphenol (BP) compounds that are widely added in various products such as plastics and other products in a freshwater ecosystem, China. Among commonly applied 14 BP analogues, bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) were predominant, representing 64%-100% of the total concentrations of BPs (ΣBPs) in freshwater wildlife. Both the concentrations and analogue profiles in the fish showed seasonal differences and species dependence. Higher BP concentrations were observed in fish collected during the dry season than the wet season. Higher percentages of non-BPA analogues (e.g., BPS and BPF) were observed in fish collected during the wet season. Pelagic species accumulated notably higher levels of BPs than midwater and bottom species. The liver generally contained the highest ΣBPs, followed successively by the swim bladder, belly fat, and dorsal muscle. The analogue profile also showed some differences among tissues, varying by species and season. Lower ΣBPs but higher percentages of non-BPA analogues were observed in female than male common carp. Time trends of the BPA concentration in fish varied by species, probably related to habitats and diets of the fish. Habitats, feeding behaviors, and trophic transfer may have significant impacts on exposure of wildlife to BPs in natural ecosystems. The BPs did not demonstrate strong potential for bioaccumulation. More research is warranted about metabolism and transgenerational transfer of BPs in wildlife to fully reveal the bioaccumulation and consequently ecological risks of these chemicals in the environment. Environ Toxicol Chem 2023;42:2130-2142. © 2023 SETAC.

Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.

Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-κB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors.

Multi-residue determination of bisphenol analogues in organism tissues by ultra-high performance liquid chromatography-tandem mass spectrometry.

A reliable and sensitive analyzing method was developed and validated for determination of 13 novel bisphenol analogues (BPs) along with bisphenol A (BPA) in organism tissues. The complex organism tissues were treated by ultrasonic-assisted extraction using acetonitrile/formic acid (99:1, v/v), followed by successive purification using enhanced matrix removal-lipid sorbents and primary secondary amine sorbents. The BPs were finally determined by ultra-high performance liquid chromatography-tandem mass spectrometry after derivatization using pyridine-3-sulfonyl chloride. Satisfactory recoveries of 75 - 118% were obtained for the BPs, with good repeatability (RSD < 20%). Matrix interferences were efficiently diminished. The method quantification limits (MQLs) reached 0.003 - 0.1 ng g-1 dry weight (dw). The validated method was successfully applied to a preliminary investigation of the BPs in wild marine organisms collected from the nearshore waters along the coast of Guangdong, China. Besides BPA, novel BPs such as bisphenol F, bisphenol AF, and tetrabromobisphenol A were also detected at < MDL - 15.5 ng g-1 dw. This work laid a strong basis for further in-depth research on bioaccumulation of the novel BPs in the environment.