Flexible Supercapacitor with Wide Electrochemical Stable Window Based on Hydrogel Electrolyte.

Hydrogel electrolyte can endow supercapacitors with excellent flexibility, which has developed rapidly in recent years. However, the water-rich structures of hydrogel electrolyte are easy to freeze at subfreezing and dry at high temperatures, which will affect its energy storage characteristics. The low energy density of micro supercapacitors also hinders their development. Herein, a strategy is proposed to reduce the free water activity in the hydrogel to improve the operating voltage and the energy density of the device, which is achieved through the synergistic effect of the hydrogel skeleton, N, N'-dimethylformamide (DMF), NaClO4 and water. High concentrations of DMF and NaClO4 are introduced into sodium alginate/polyacrylamide (SA/PAAM) hydrogel through solvent exchange to obtain SA/PAAM/DMF/NaClO4 hydrogel electrolyte, which exhibited a high ionic conductivity of 82.1 mS cm-1, a high breaking strength of 563.2 kPa, and a wide voltage stability window of 3.5 V. The supercapacitor devices are assembled by the process of direct adhesion of the hydrogel electrolyte and  laser induced graphene (LIG). The micro-supercapacitor exhibited an operating voltage of 2.0 V, with a specific capacitance of 2.41 mF cm-2 and a high energy density of 1.34 µWh cm-2, and it also exhibit a high cycle stability, good flexibility, and integration performance.

Ecological and health risk assessments of heavy metals and their accumulation in a peanut-soil system.

Heavy metals pollution is a notable threat to environment and human health. This study evaluated the potential ecological and health risks of heavy metals (Cu, Cr, Cd, Pb, Zn, Ni, and As) and their accumulation in a peanut-soil system based on 34 soil and peanut kernel paired samples across China. Soil As and Cd posed the greatest pollution risk with 47.1% and 17.6% of soil samples exceeding the risk screen levels, respectively, with 26.5% and 20.6% of the soil sites at relatively strong potential ecological risk level, respectively, and with the geo-accumulation levels at several soil sites in the uncontaminated to moderately contaminated categories. About 35.29% and 2.94% of soil sites were moderately and severely polluted based on Nemerow comprehensive pollution index, respectively, and a total of 32.4% of samples were at moderate ecological hazard level based on comprehensive potential ecological risk index values. The Cd, Cr, Ni, and Cu contents exceeded the standard in 11.76, 8.82, 11.76 and 5.88% of the peanut kernel samples, respectively. Soil metals posed more health risks to children than adults in the order As > Ni > Cr > Cu > Pb > Zn > Cd for non-carcinogenic health risks and Ni > Cr â‰« Cd > As > Pb for carcinogenic health risks. The soil As non-cancer risk index for children was greater than the permitted limits at 14 sites, and soil Ni and Cr posed the greatest carcinogenic risk to adults and children at many soil sites. The metals in peanut did not pose a non-carcinogenic risk according to standard. Peanut kernels had strong enrichment ability for Cd with an average bio-concentration factor (BCF) of 1.62. Soil metals contents and significant soil properties accounted for 35-74% of the variation in the BCF values of metals based on empirical prediction models.

Different binding properties of odorant-binding protein 8 to insecticides in Orius sauteri.

Chemical sensing systems are vital in the growth and development of insects. Orius sauteri (Poppius) (Hemiptera: Anthocoridae) is an important natural enemy of many pests. The molecular mechanism of odorant binding proteins (OBPs) binding with common insecticides is still unknow in O. sauteri. In this study, we expressed in vitro OsauOBP8 and conducted fluorescence competition binding assay to investigate the function of OsauOBP8 to insecticides. The results showed that OsauOBP8 could bind with four common insecticides (phoxim, fenitrothion, chlorpyrifos, deltamethrin). Subsequently, we used molecular docking to predict and obtained candidate six amino acid residues (K4, K6, K13, R31, K49, K55) and then mutated. The result showed that three key residues (K4, K6, R31) play important role in OsauOBP8 bound to insecticides. Our study identified the key binding sites of OsauOBP8 to insecticides and help to better understand the molecular mechanism of OBPs to insecticides in O. sauteri.

Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases.

HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4-de]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

GlanceSeg: Real-time microaneurysm lesion segmentation with gaze-map-guided foundation model for early detection of diabetic retinopathy.

Early-stage diabetic retinopathy (DR) presents challenges in clinical diagnosis due to inconspicuous and minute microaneurysms (MAs), resulting in limited research in this area. Additionally, the potential of emerging foundation models, such as the segment anything model (SAM), in medical scenarios remains rarely explored. In this work, we propose a human-in-the-loop, label-free early DR diagnosis framework called GlanceSeg, based on SAM. GlanceSeg enables real-time segmentation of MA lesions as ophthalmologists review fundus images. Our human-in-the-loop framework integrates the ophthalmologist's gaze maps, allowing for rough localization of minute lesions in fundus images. Subsequently, a saliency map is generated based on the located region of interest, which provides prompt points to assist the foundation model in efficiently segmenting MAs. Finally, a domain knowledge filtering (DKF) module refines the segmentation of minute lesions. We conducted experiments on two newly-built public datasets, i.e., IDRiD and Retinal-Lesions, and validated the feasibility and superiority of GlanceSeg through visualized illustrations and quantitative measures. Additionally, we demonstrated that GlanceSeg improves annotation efficiency for clinicians and further enhances segmentation performance through fine-tuning using annotations. The clinician-friendly GlanceSeg is able to segment small lesions in real-time, showing potential for clinical applications.

Binding Properties of Odorant Binding Protein 37 in Plagiodera versicolora to Host Volatile, o-Cymene.

The chemosensory system plays an important role in the host plants location. Plagiodera versicolora (Coleoptera: Chrysomelidae) is a worldwide leaf-eating forest pest that feeds exclusively on salicaceous trees. There is no function study of odorant binding proteins (OBPs) in P. versicolora. In the current study, we found that PverOBP37 has a high expression in male and female antennae, heads, and legs by quantitative real-time PCR. The binding properties of PverOBP37 to 18 host plant volatiles were determined by fluorescence competition binding assays. The results showed that PverOBP37 could bind to the host plant volatile, o-cymene. Furthermore, four candidate key amino acid residues (F8, Y50, F103, and R107) of PverOBP37 to o-cymene were identified by molecular docking. The functional assay to confirm Y50, F103, and R107 mutations were key amino acid residues of PverOBP37 involved in the binding to o-cymene. Knockdown of PverOBP37 and Y-tube behavioral bioassays of mated females led to a significantly reduced attraction to o-cymene. This study not only revealed the molecular mechanism of PverOBP37 but also suggested that PverOBP37 is essential to detect host plant volatiles as cues to search for egg-laying sites in P. versicolora.

Metagenomic analysis reveals gene taxonomic and functional diversity response to microplastics and cadmium in an agricultural soil.

Both microplastics (MPs) and heavy metals are common soil pollutants and can interact to generate combined toxicity to soil ecosystems, but their impact on soil microbial communities (e.g., archaea and viruses) remains poorly studied. Here, metagenomic analysis was used to explore the response of soil microbiome in an agricultural soil exposed to MPs [i.e., polyethylene (PE), polystyrene (PS), and polylactic acid (PLA)] and/or Cd. Results showed that MPs had more profound effects on microbial community composition, diversity, and gene abundances when compared to Cd or their combination. Metagenomic analysis indicated that the gene taxonomic diversity and functional diversity of microbial communities varied with MPs type and dose. MPs affected the relative abundance of major microbial phyla and genera, while their coexistence with Cd influenced dominant fungi and viruses. Nitrogen-transforming and pathogenic genera, which were more sensitive to MPs variations, could serve as the indicative taxa for MPs contamination. High-dose PLA treatments (10%, w/w) not only elevated nitrogen metabolism and pathogenic genes, but also enriched copiotrophic microbes from the Proteobacteria phylum. Overall, MPs and Cd showed minimal interactions on soil microbial communities. This study highlights the microbial shifts due to co-occurring MPs and Cd, providing evidence for understanding their environmental risks.

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic ß cells.

Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.

Global trends and hotspots of ulcerative colitis based on bibliometric and visual analysis from 1993 to 2022.

Ulcerative colitis (UC) has seen a significant increase over the past 3 decades. However, our understanding of its etiology, pathogenesis, and pharmacological treatment remains limited. This comprehensive review aims to address these gaps by analyzing trends, evaluating previous research, and providing insights for future investigations. We conducted a bibliometric analysis of UC-related papers indexed in the Web of Science from 1993 to 2022. The author, organization, country, and keyword networks in the field of UC were visualized. A total of 36,483 papers were included, showing a continuous upward trend. Most research on UC was conducted in universities, with hospitals leading in high-quality studies. The United States emerged as the primary contributor, followed by China and the United Kingdom. The overall quality of UC-related publications improved, indicating sustained interest in the field. The keywords related to UC was classified into 9 clusters. Keywords detection revealed that UC research focused mainly on the discovery of its etiology and exploration of treatment methods, with research directions evolving from initial treatment of UC and related diseases to clinical trials of UC and subsequently incorporating genomics and bioinformatics techniques to study UC and explore new therapeutic methods and drugs, including recent advances in gut microbiota. Our study identified gaps in understanding the etiology, pathogenesis, and treatment of UC. Future research in UC should focus on genomics, personalized treatment, microbial therapy and leveraging machine learning and artificial intelligence. These areas hold the potential for improving UC diagnosis, treatment, and management.

Chronic Low Back Pain and Sleep Disturbance in Adults in the US: The NHANES 2009-2010 Study.

BACKGROUND: Chronic low back pain (CLBP) is a significant health challenge with a high prevalence rate. Sleep disorders, which are prevalent among adults, have been linked with CLBP. However, the intricate relationship between sleep and pain adds complexity to our understanding of CLBP. OBJECTIVES: To investigate the association between CLBP and sleep disorders, with a focus on the potential role of sleep disorders as a risk factor for CLBP. STUDY DESIGN: Cross-sectional study based on publicly available data from the National Health and Nutrition Examination Survey (NHANES) for one cycle (2009-2010). SETTING: The NHANES employs a complex, multistage probability sampling design to select a nationally representative sample. METHODS: In this study, we included patients aged 20 to 69 years from the NHANES 2009-2010 cycle. After eliminating cases with missing data, a total of 863 patients remained. Baseline characteristics were analyzed by stratifying patients based on their CLBP status to assess initial inter-group disparities. Due to age imbalances between groups, we employed a 1:1 propensity score matching (PSM) method, reducing the sample to 508 patients. The association between CLBP and trouble sleeping was investigated following this calibration using a multivariate logistic regression analysis. RESULTS: Upon categorizing the baseline characteristics of 863 patients based on CLBP, we identified that those within the CLBP group tended to be older and had a greater prevalence of health conditions, including cancer, hypertension, and cardiovascular disease (CVD). Notably, the prevalence of sleep disorders was higher in the CLBP group than in the non-CLBP group (P < 0.001). After implementing an age-based PSM for the 2 groups, 508 patients were selected from the initial 863 patients. After adjusting for various confounders using multivariate logistic regression, our analysis revealed a strong association between sleep disorders and an increased risk of CLBP. LIMITATIONS: This is a cross-sectional study, and therefore causality cannot be established. CONCLUSIONS: This study underscores the significant association between sleep disorders and an elevated risk of CLBP, highlighting the need for comprehensive management strategies that consider the role of sleep disorders in CLBP.

Design, synthesis and biological evaluation of bakuchiol derivatives as multi-target agents for the treatment of Alzheimer's disease.

The concept of multi-target-directed ligands offers fresh perspectives for the creation of brand-new Alzheimer's disease medications. To explore their potential as multi-targeted anti-Alzheimer's drugs, eighteen new bakuchiol derivatives were designed, synthesized, and evaluated. The structures of the new compounds were elucidated by IR, NMR, and HRMS. Eighteen compounds were assayed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in vitro using Ellman's method. It was shown that most of the compounds inhibited AChE and BuChE to varying degrees, but the inhibitory effect on AChE was relatively strong, with fourteen compounds showing inhibition of >50% at the concentration of 200 µM. Among them, compound 3g (IC50 = 32.07 ± 2.00 µM) and compound 3n (IC50 = 34.78 ± 0.34 µM) showed potent AChE inhibitory activities. Molecular docking studies and molecular dynamics simulation showed that compound 3g interacts with key amino acids at the catalytically active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and binds stably to acetylcholinesterase. On the other hand, compounds 3n and 3q significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 released from LPS-induced RAW 264.7 macrophages. Compound 3n possessed both anti-acetylcholinesterase activity and anti-inflammatory properties. Therefore, an in-depth study of compound 3n is expected to be a multi-targeted anti-AD drug.

Effects of Ca2+ and Mg2+ on Cu binding in hydrophilic and hydrophobic dissolved organic matter fractions extracted from agricultural soil.

Dissolved organic matter (DOM) has significant effects on soil copper (Cu) bioavailability. However, little is known about Cu interactions and major cation binding toward hydrophilic and hydrophobic DOM components extracted from soil solutions. In this study, we investigated the influence of major cations (Ca2+/Mg2+) on Cu complexing characteristics on different hydrophilic and hydrophobic DOM fractions using absorbance spectroscopy at different Cu2+ concentrations in the absence/presence of Ca2+/Mg2+. Different compositional hydrophobic and hydrophilic DOM fraction proportions occurred at three agricultural soil sites, with the hydrophobic acid (HOA) fraction accounting for the highest proportion. The addition of Cu2+ generated distinct ultraviolet (UV) bands/peaks (processed by differential linear and differential logarithmic transformation) of three hydrophilic DOM fractions, whereas Cu2+ induced less and weak specific peaks in the differential spectra and differential logarithmic of the HOA fractions, indicating hydrophilic DOM fractions tend to have a higher density of Cu2+ complexation sites. In the presence of either Ca2+/Mg2+, increased depression caused by Cu2+ binding on different DOM fractions was observed with increasing 10, 100, and 1000 µM Ca2+/Mg2+ levels, with more significant variations in peaks/banks for hydrophilic base (HIB) and HOA fractions, and less for hydrophilic acid (HIA) and hydrophilic neutral (HIN) fractions. In our study, the spectral parameters ΔS225-275 and ΔS275-325 were successfully used to quantify Cu amounts bonded to HIA and HIB, respectively. They exhibited strong linear relationships with correlation coefficients (R2) of 0.96 for HIA and 0.87 for HIB, respectively. Furthermore, Mg2+ exhibited stronger competition with Cu for HIA and HIB binding sites when compared with Ca2+.

A novel peroxisome-related gene signature predicts clinical prognosis and is associated with immune microenvironment in low-grade glioma.

Low-grade glioma (LGG), a common primary tumor, mainly originates from astrocytes and oligodendrocytes. Increasing evidence has shown that peroxisomes function in the regulation of tumorigenesis and development of cancer. However, the prognostic value of peroxisome-related genes (PRGs) in LGG has not been reported. Therefore, it is necessary to construct a prognostic risk model for LGG patients based on the expression profiles of peroxisome-related genes. Our study mainly concentrated on developing a peroxisome-related gene signature for overall survival (OS) prediction in LGG patients. First, according to these peroxisome-related genes, all LGG patients from The Cancer Genome Atlas (TCGA) database could be divided into two subtypes. Univariate Cox regression analysis was used to find prognostic peroxisome-related genes in TCGA_LGG dataset, and least absolute shrinkage and selection operator Cox regression analysis was employed to establish a 14-gene signature. The risk score based on the signature was positively associated with unfavorable prognosis. Then, multivariate Cox regression incorporating additional clinical characteristics showed that the 14-gene signature was an independent predictor of LGG. Time-dependent ROC curves revealed good performance of this prognostic signature in LGG patients. The performance about predicting OS of LGG was validated using the GSE107850 dataset derived from the Gene Expression Omnibus (GEO) database. Furethermore, we constructed a nomogram model based on the gene signature and age, which showed a better prognostic power. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses showed that neuroactive ligand-receptor interaction and phagosome were enriched and that the immune status was decreased in the high-risk group. Finally, cell counting kit-8 (CCK8) were used to detect cell proliferation of U251 and A172 cells. Inhibition of ATAD1 (ATPase family AAA domain-containing 1) and ACBD5 (Acyl-CoA binding-domain-containing-5) expression led to significant inhibition of U251 and A172 cell proliferation. Flow cytometry detection showed that ATAD1 and ACBD5 could induce apoptosis of U251 and A172 cells. Therefore, through bioinformatics methods and cell experiments, our study developed a new peroxisome-related gene signature that migh t help improve personalized OS prediction in LGG patients.

Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.

BACKGROUND: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy. METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting. RESULTS: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed. CONCLUSIONS: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.

Voltage activation induced MoO42- dissolution to enhance performance of iron doped nickel molybdate for oxygen evolution reaction.

Transition metal-based precatalysts are typically voltage-activated before electrochemical testing in the condition of alkaline oxygen evolution reaction. Nevertheless, the impact of voltage on the catalyst and the anion dissolution is frequently disregarded. In this study, Fe-doped NiMoO4 (Fe-NiMoO4) was synthesized as a precursor through a straightforward hydrothermal method, and MoFe-modified Ni (oxygen) hydroxide (MoFe-NiOxHy) was obtained via cyclic voltammetry (CV) activation. The effects of voltage on Fe-NiMoO4 and the dissolved inactive MoO42- ions in the process were examined in relation to OER performance. It has demonstrated that the crystallinity of the catalyst is reduced by voltage, thereby enhancing its electrocatalytic activity. The electron distribution state can be adjusted during the application of voltage, leading to the generation of additional active sites and an acceleration in the reaction rate. Additionally, MoO42- exhibits potential dependence during its dissolution. In the OER process, the dissolution of MoO42- enhances the reconstruction degree of Fe-NiMoO4 into the active substance and expedites the formation of active Ni(Fe)OOH. Hence, the optimized MoFe-NiOxHy exhibited exceptional electrocatalytic performance, with a current density of 100 mA cm-2 achieved at an overpotential of only 256 mV. This discovery contributes to a more comprehensive understanding of alkaline OER performance under the influence of applied voltage and the presence of inactive oxygen ions, offering a promising avenue for the development of efficient electrocatalysts.

Efficacy and safety of adamgammadex for reversing rocuronium-induced deep neuromuscular blockade: A multicenter, randomized, phase IIb study.

The rapid reversal of deep neuromuscular blockade (NMB) is important but remains challenging. This study aimed to evaluate the efficacy and safety of adamgammadex versus sugammadex in reversing deep rocuronium-induced NMB. This multicenter, randomized, phase IIb study included 80 patients aged 18-64 years, American Society of Anesthesiologists (ASA) grade 1-2, undergoing elective surgery under general anesthesia with rocuronium. Patients were randomized to the adamgammadex 7, 8, and 9 mg/kg group or the sugammadex 4 mg/kg group. The primary efficacy variable was the time to recovery of train-of-four ratio (TOFr) to 0.9. The secondary efficacy variables were the time to recovery of TOFr to 0.7, antagonistic success rate of the recovery of TOFr to 0.9 within 5 min, and incidence rate of recurarization within 30 min after drug administration. The explorative efficacy variable was the time to recovery of the corrected TOFr to 0.9 (actual/baseline TOF ratio). Adamgammadex 7, 8, and 9 mg/kg and sugammadex 4 mg/kg groups did not significantly differ in all efficacy variables. Importantly, adamgammadex 9 mg/kg permitted reversal within a geometric mean of 2.9 min. According to the safety profile, adamgammadex achieved good tolerance and low incidence of drug-related adverse events compared with the 4 mg/kg sugammadex. Adamgammadex 7, 8, and 9 mg/kg facilitated rapid reversal of deep rocuronium-induced NMB and had good tolerance and low incidence of drug-related adverse events. Therefore, adamgammadex is a potential and promising alternative to sugammadex.

Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722.

PURPOSE: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs). METHODS: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR). RESULTS: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively. CONCLUSION: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

Biodegradable, Bifunctional Electro-acoustic Transducers Based on Cellular Polylactic Acid Ferroelectrets for Sustainable Flexible Electronics.

Nowadays, humans rely increasingly on smart electronics to address grand challenges and to improve life conditions in the era of digitalization and big data. However, electronics often have a limited lifespan, and they may bring electronic waste problems after their service. To mitigate this problem, environmentally sustainable methods of electronic device production and disposal are highly recommended, where advanced functional materials should be redesigned with improved sensing performance over the entire operational life while also being naturally degradable at the end. Herein, a biodegradable and flexible bifunctional electroacoustic transducer was fabricated with the utilization of cellular polylactic acid (PLA) ferroelectret films, possessing a small acoustic impedance of ∼0.02 MRayl which is quite close to that of air and a high figure of merit (FOM: d33·g33) of ∼11 GPa-1. Such devices have a prominent signal-to-noise ratio (SNR) of ∼23.5 dB @1 kHz and can work either as a microphone by direct piezoelectric effect or a loudspeaker by reverse piezoelectric effect in air medium. When used as a microphone, the flexible device exhibits a prominent receiving sensitivity up to 4.2 mV/Pa (∼-47.5 dB/ref. 1 V/Pa) at 1 kHz. When served as a loudspeaker, it is capable of yielding high sound pressure levels (SPLs) ranging from 60 to 103 dB (ref. 20 µPa) in a broad frequency range of 1-80 kHz with an active area of 3.14 cm2. Additionally, the electrical response curve of the device is very flat in a wide frequency range from 300 to 3000 Hz. With the high-performance acoustic-electric conversion capacity, the PLA ferroelectret-based flexible and filmlike electroacoustic transducer was used to realize accurate speech recognition and control, providing a strong impetus for its advanced and eco-friendly applications in the era of the internet of things (IoT) and artificial intelligence.

Self-heating mitochondrion-induced free radical blast for immunogenic cell death stimulation and HCC immunotherapy.

Hepatocellular carcinoma (HCC) is an immunosuppressive tumor associated with high mortality. Photothermal and photodynamic therapies have been applied to induce immunogenic cell death (ICD) in HCC, successfully eliciting immune responses but facing limitations in penetration depth in clinical trials. Here, intrinsic mitochondrial hyperthermia was used to trigger thermosensitive drug release. The mitochondria were further self-heated through 2,4-dinitrophenol uncoupling, dramatically promoting free radical initiation and inducing tumor ICD. The synthesized mitochondrial-targeting TPP-HA-TDV nanoparticles specifically generated free radicals in the mitochondria without external stimulation, and obviously enhanced the release of ICD markers, subsequently evoking immune responses. The results showed that mitochondrial hyperthermia could be an endogenous target for thermosensitive drug release. Furthermore, self-heating mitochondria-induced free radical blast could be an efficient therapeutic for deep-seated tumor therapy.

Superhydrophilic and oleophobic sponges prepared based on Mussel-Inspired chemistry for efficient oil-water separation.

Superhydrophilic/oleophobic materials are considered to be the best materials for achieving oil-water separation, but their preparation is difficult and the existing methods are not universal. In this paper, a two-step modification strategy was used to prepare superhydrophilic/oleophobic sponges by adjusting the polar and nonpolar components of the materials using mussel-inspired chemistry. While remaining superhydrophilic, the modified sponge surface has a maximum contact angle of 135° with different oils in air. The modified sponge exhibited superoleophobicity in water, and the contact angle of oil could reach more than 150°. In addition, the modified sponges were also reusable, chemically stable, and mechanically durable. Its oil-water separation flux was up to 24900 Lm-2 h-1 bar-1 , and the separation efficiency was above 97 %. We believe that this method will provide an environmentally friendly and efficient way to prepare the superhydrophilic/oleophobic materials.