Organic Fluorophores with Large Stokes Shift for the Visualization of Rapid Protein and Nucleic Acid Assays.

Organic small-molecule fluorophores, characterized by flexible chemical structure and adjustable optical performance, have shown tremendous potential in biosensing. However, classical organic fluorophore motifs feature large overlap between excitation and emission spectra, leading to the requirement of advanced optical set up to filter desired signal, which limits their application in scenarios with simple settings. Here, a series of wavelength-tunable small-molecule fluorescent dyes (PTs) bearing simple organic moieties have been developed, which exhibit Stokes shift up to 262 nm, molar extinction coefficients ranged 30,000-100,000 M-1 cm-1, with quantum yields up to 54.8 %. Furthermore, these dyes were formulated into fluorescent nanoparticles (PT-NPs), and applied in lateral flow assay (LFA). Consequently, limit of detection for SARS-CoV-2 nucleocapsid protein reached 20 fM with naked eye, a 100-fold improvement in sensitivity compared to the pM detection level for colloidal gold-based LFA. Besides, combined with loop-mediated isothermal amplification (LAMP), the LFA system achieved the visualization of single copy level nucleic acid detection for monkeypox (Mpox).

Efficacy of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in advanced NSCLC with different T790M statuses tested via digital droplet polymerase chain reaction ddPCR and next-generation sequencing.

OBJECTIVES: We hypothesize that digital droplet polymerase chain reaction (ddPCR) would optimize the treatment strategies in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) relapsed patients. In this study, we compared the efficacy of third-generation TKIs with various T790M statuses via ddPCR and next-generation sequencing (NGS). METHODS: NGS was performed on blood samples of patients progressed from previous EGFR-TKIs for resistance mechanism. T790M-negative patients received further liquid biopsy using ddPCR for T790M detection. RESULTS: A cohort of 40 patients were enrolled, with 30.0% (12/40) T790M-positive via NGS (Group A). In another 28 T790M-negative patients by NGS, 11 (39.3%) were T790M-positive (Group B) and 17 (60.7%) were T790M-negative (Group C) via ddPCR. A relatively longer progression-free survival (PFS) was observed in group A (NR) and group B (10.0 months, 95% CI 7.040-12.889) than in group C (7.0 months, 95% CI 0.000-15.219), with no significant difference across all three groups (p = 0.196), or between group B and C (p = 0.412). EGFR-sensitive mutation correlated with inferior PFS (p = 0.041) and ORR (p = 0.326), and a significantly lower DCR (p = 0.033) in T790M-negative patients via NGS (n = 28). CONCLUSION: This study indicates that ddPCR may contribute as a supplement to NGS in liquid biopsies for T790M detection in EGFR-TKIs relapsed patients and help to optimize the treatment strategies, especially for those without coexistence of EGFR-sensitive mutation. TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05458726.

A natural IgM hitchhiking strategy for delivery of cancer nanovaccines to splenic marginal zone B cells.

B cell-targeted cancer vaccines are receiving increasing attention in immunotherapy due to the combined antibody-secreting and antigen-presenting functions. In this study, we propose a natural IgM-hitchhiking delivery strategy to co-deliver tumor antigens and adjuvants to splenic marginal zone B (MZB) cells. We constructed nanovaccines (FA-sLip/OVA/MPLA) consisting of classical folic acid (FA)-conjugated liposomes co-loaded with ovalbumin (OVA) and toll-like receptor 4 agonists, MPLA. We found that natural IgM absorption could be manipulated at the bio-nano interface on FA-sLip/OVA/MPLA, enabling targeted delivery to splenic MZB cells. Systemic administration of FA-sLip/OVA/MPLA effectively activated splenic MZB cells via IgM-mediated multiplex pathways, eliciting antigen-specific humoral and cytotoxic T lymphocyte responses, and ultimately retarding E.G7-OVA tumor growth. In addition, combining FA-sLip/OVA/MPLA immunization with anti-PD-1 treatments showed improved antitumor efficiency. Overall, this natural IgM-hitchhiking delivery strategy holds great promise for efficient, splenic MZB cell-targeted delivery of cancer vaccines in future applications.

Unveiling the structural mechanisms of nonpeptide ligand recognition and activation in human chemokine receptor CCR8.

The human CC chemokine receptor 8 (CCR8) is an emerging therapeutic target for cancer immunotherapy and autoimmune diseases. Understanding the molecular recognition of CCR8, particularly with nonpeptide ligands, is valuable for drug development. Here, we report three cryo-electron microscopy structures of human CCR8 complexed with Gi trimers in the ligand-free state or activated by nonpeptide agonists LMD-009 and ZK 756326. A conserved Y1.39Y3.32E7.39 motif in the orthosteric binding pocket is shown to play a crucial role in the chemokine and nonpeptide ligand recognition. Structural and functional analyses indicate that the lack of conservation in Y1143.33 and Y1724.64 among the CC chemokine receptors could potentially contribute to the selectivity of the nonpeptide ligand binding to CCR8. These findings present the characterization of the molecular interaction between a nonpeptide agonist and a chemokine receptor, aiding the development of therapeutics targeting related diseases through a structure-based approach.

Association of the Kiwi OmniCup system with maternal and neonatal morbidity: A retrospective cohort study.

OBJECTIVE: To discuss the effect of the Kiwi OmniCup system on reducing adverse maternal and neonatal outcomes and provide a reference for assisted vaginal delivery methods. METHODS: Women who gave birth to singleton term neonates in a cephalic presentation and underwent assisted vaginal delivery from 2017 to 2021 were eligible for inclusion in the study; they were divided into a Kiwi OmniCup system group and a forceps group. Binary logistic regression analysis was used to observe and compare maternal and neonatal outcomes. The primary outcomes were severe maternal and neonatal morbidity. Severe maternal morbidity was defined as the occurrence of at least one of the following outcomes: third- or fourth-degree perineal lacerations, refractory postpartum hemorrhage, thrombotic events, amniotic fluid embolism, admission to the intensive care unit, and maternal death. Severe neonatal morbidity was defined as the occurrence of at least one of the following outcomes: neonatal asphyxia requiring resuscitation or intubation, neonatal head and face injuries, neonatal fracture, and admission to the neonatal intensive care unit for longer than 24 h. RESULTS: The rate of severe neonatal morbidity in the forceps group was significantly higher than that in the Kiwi OmniCup system group, the differences between the two groups were significant (27.2% vs. 42.3%, P < 0.001), and there was no significant difference in the rate of severe maternal morbidity between the two groups (30% vs. 30%, P > 0.05). Binary logistic regression analysis showed that Kiwi OmniCup system-assisted delivery reduced severe neonatal morbidity (adjusted odds ratio 0.49; 95% confidence interval 0.33-0.73) and did not increase severe maternal morbidity compared with forceps-assisted delivery. CONCLUSION: The Kiwi OmniCup system, which can reduce the incidence of severe neonatal morbidity without increasing the incidence of serious adverse maternal outcomes, is worthy of clinical promotion.

Electronic structure optimizing of Ru nanoclusters via Co single atom and N, S co-doped reduced graphene oxide for accelerating water electrolysis.

The development of efficient and stable electrocatalysts for hydrogen evolution reaction (HER) is impending for the advancement of water-splitting. In this study, we developed a novel electrocatalyst consisting of highly dispersed Ru nanoclusters ameliorated by cobalt single atoms and N, S co-doped reduced graphene oxide (CoSARuNC@NSG). Benefitted from the optimized electronic structure of the Ru nanoclusters induced by the adjacent single atomic Co and N, S co-doped RGO support, the electrocatalyst exhibits exceptional HER performance with overpotentials of 15 mV and 74 mV for achieving a current density of 10 mA cm-2 in alkaline and acidic water. The catalyst outperforms most noble metal-based HER electrocatalysts. Furthermore, the electrolyzer assembled with CoSARuNC@NSG and RuO2 demonstrated an overall voltage of 1.56 V at 10 mA cm-2 and an excellent operational stability for over 25 h with almost no attenuation. Theoretical calculations also deduce its high HER activity demonstrated by the smaller reaction energy barrier due to the optimized electronic structure of Ru nanoclusters. This strategy involving the regulation of metal nanoparticles activity through flexible single atom and GO support could provide valuable insights into the design of high-performance and low-cost HER catalysts.

Calculation of carbon emissions in wastewater treatment and its neutralization measures: A review.

As the pursuit of "carbon neutrality" gains momentum, the emphasis on low-carbon solutions, emphasizing energy conservation and resource reuse, has introduced fresh challenges to conventional wastewater treatment approaches. Precisely evaluating carbon emissions in urban water supply and drainage systems, wastewater treatment plants, and establishing carbon-neutral operating models has become a pivotal concern in the future of wastewater treatment. Regrettably, limited research has been devoted to carbon accounting and the development of carbon-neutral strategies for wastewater treatment. In this review, to facilitate comprehensive carbon accounting, we initially recognizes direct and indirect carbon emission sources in the wastewater treatment process. We then provide an overview of several major carbon accounting methods and propose a carbon accounting framework. Furthermore, we advocate for a systemic perspective, highlighting that achieving carbon neutrality in wastewater treatment extends beyond the boundaries of wastewater treatment plants. We assess current technical measures both within and outside the plants that contribute to achieving carbon-neutral operations. Encouraging the application of intelligent algorithms for the multifaceted monitoring and control of wastewater treatment processes is paramount. Supporting resource and energy recycling is also essential, as is recognizing the benefits of synergistic wastewater treatment technologies. We advocate a systematic, multi-level planning approach that takes into account a wide range of factors. Our goal is to offer valuable insights and support for the practical implementation of water environment management within the framework of carbon neutrality, and to advance sustainable socio-economic development and contribute to a more environmentally responsible future.

Adjuvant and neo-adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC): Current status and perspectives.

Surgery followed by adjuvant chemotherapy is the standard of care for selected patients with early-stage or locally advanced non-small cell lung cancer (NSCLC). However, many of these patients still experience postoperative recurrence at 5 years. At present, peri-operative treatment methods are emerging to prevent early relapse, such as targeted therapy and immunotherapy. Investigation on predictive biomarkers of responses to adjuvant and neoadjuvant therapies is also continuously ongoing. Immunotherapy represented by immune checkpoint inhibitors (ICIs), either by monotherapy or in combination with chemotherapy, has shown benefit in promoting pathological responses and prolonging survival for patients with NSCLC without oncogenic mutations. Exploratory studies have also provided evidence regarding the selection of patients who benefit from ICI-based perioperative treatment. This review focuses on the existing data of current clinical trials of adjuvant and neoadjuvant strategies with ICIs in resectable NSCLC, the exploration of predictive biomarkers, and the perspectives and urgent challenges in the future.

Rapid and noninvasive cell assay by microfluidic-integrated intracavity evanescent field absorption in a fiber ring laser.

BACKGROUND: Highly sensitive and rapid detection of cell concentration and interfacial molecular events is of great value for biological, biomedical, and chemical research. Most traditional biosensors require large sample volumes and complicated functional modifications of the surface. It is of great significance to develop label-free biosensor platforms with minimal sample consumption for studying cell concentration changes and interfacial molecular events without labor-intensive procedures. RESULTS: Here, a fiber-optic biosensor based on intracavity evanescent field absorption sensing is designed for sensitive and label-free cell assays for the first time. The interaction between the cells and the evanescent field is enhanced by introducing microfluidic-integrated intracavity absorption in a fiber ring laser. This strategy extends the range of targeted analytes to include quantification of a large number of targets on a surface and improves the detection sensitivity of the fiber-optic biosensor. The level of sensing resolution could be improved from 10-4 RIU to 10-7 RIU using this strategy. The stem cells were studied over a wide concentration range (from 500 to 1.2 × 105 cells/ml) and were measured sequentially. By measuring the output power of the intracavity absorption sensing system, the cell concentration can be directly determined in a label-free manner. The results show that dozens of stem cells can be sensitively detected with a sample consumption of 72 µL. The response was fast (15 s) with a low temperature cross-sensitivity of 0.031 cells·ml-1/°C. SIGNIFICANCE: The proposed method suggests its capacity for true label-free and noninvasive cell assays with a low limit of detection and small sample consumption. This has the potential to be used as a universal tool for quantitative and qualitative characterization of various cells and other biochemical analytes.

Multiplexed discrimination of SARS-CoV-2 variants via plasmonic-enhanced fluorescence in a portable and automated device.

Portable assays for the rapid identification of lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to aid large-scale efforts in monitoring the evolution of the virus. Here we report a multiplexed assay in a microarray format for the detection, via isothermal amplification and plasmonic-gold-enhanced near-infrared fluorescence, of variants of SARS-CoV-2. The assay, which has single-nucleotide specificity for variant discrimination, single-RNA-copy sensitivity and does not require RNA extraction, discriminated 12 lineages of SARS-CoV-2 (in three mutational hotspots of the Spike protein) and detected the virus in nasopharyngeal swabs from 1,034 individuals at 98.8% sensitivity and 100% specificity, with 97.6% concordance with genome sequencing in variant discrimination. We also report a compact, portable and fully automated device integrating the entire swab-to-result workflow and amenable to the point-of-care detection of SARS-CoV-2 variants. Portable, rapid, accurate and multiplexed assays for the detection of SARS-CoV-2 variants and lineages may facilitate variant-surveillance efforts.

Acetylcholine (ACh) enhances Cd tolerance through transporting ACh in vesicles and modifying Cd absorption in duckweed (Lemna turionifera 5511).

Acetylcholine (ACh), an important neurotransmitter, plays a role in resistance to abiotic stress. However, the role of ACh during cadmium (Cd) resistance in duckweed (Lemna turionifera 5511) remains uncharacterized. In this study, the changes of endogenous ACh in duckweed under Cd stress has been investigated. Also, how exogenous ACh affects duckweed's ability to withstand Cd stress was studied. The ACh sensor transgenic duckweed (ACh 3.0) showed the ACh signal response under Cd stress. And ACh was wrapped and released in vesicles. Cd stress promoted ACh content in duckweed. The gene expression analysis showed an improved fatty acid metabolism and choline transport. Moreover, exogenous ACh addition enhanced Cd tolerance and decreased Cd accumulation in duckweed. ACh supplement reduced the root abscission rate, alleviated leaf etiolation, and improved chlorophyll fluorescence parameters under Cd stress. A modified calcium (Ca2+) flux and improved Cd2+ absorption were present in conjunction with it. Thus, we speculate that ACh could improve Cd resistance by promoting the uptake and accumulation of Cd, as well as the response of the Ca2+ signaling pathway. Also, plant-derived extracellular vesicles (PDEVs) were extracted during Cd stress. Therefore, these results provide new insights into the response of ACh during Cd stress.

Glycyrrhizic Acid-Lipid Framework Nanovehicle Loading Triptolide for Combined Immunochemotherapy.

Despite the acknowledged advantages of combined immunochemotherapy for tumor treatment, the high efficiency of co-delivery of these combined agents into the targeted tumor tissue is still challenging. Herein, based on a "three-birds-with-one-stone" strategy, a facile glycyrrhizic acid (GL)-lipid hybrid nanoplatform loading triptolide (TP/GLLNP) is designed to better address the dilemma. Differing from the traditional liposomes with dual-drug co-delivery NPs, GL with a cholesterol-like structure is primarily employed to construct the lipid membrane skeleton of the GL-based lipid nanoparticle (GLLNP), and then triptolide (TP) is readily loaded in the lipid bilayer of GLLNP. The fabricated GLLNP possessed similar drug loading efficacy, particle size, and storage stability; none of the hemolysis; even higher membrane fluidity; and lower absorbed opsonin proteins compared with the conventional liposomes. Compared to TP-loaded traditional liposomes (TP/Lipo), TP/GLLNP exhibits significantly enhanced cellular uptake, cytotoxicity, and apoptosis of HepG2 cells. In addition, GLLNP could ameliorate tumor immunosuppression by promoting tumor-associated macrophage polarization from M2 to M1 phenotype. Furthermore, enhanced retention and accumulation in the tumor area of GLLNP could be found. As expected, TP/GLLNP displayed synergistic anti-hepatocellular carcinoma efficacy in vivo. In conclusion, this study provides an inspirational strategy to combine the anti-HCC benefits of GL and TP using a novel dual-drug co-delivery nanosystem.

Polyelectrolyte elastomer-based ionotronic sensors with multi-mode sensing capabilities via multi-material 3D printing.

Stretchable ionotronics have drawn increasing attention during the past decade, enabling myriad applications in engineering and biomedicine. However, existing ionotronic sensors suffer from limited sensing capabilities due to simple device structures and poor stability due to the leakage of ingredients. In this study, we rationally design and fabricate a plethora of architected leakage-free ionotronic sensors with multi-mode sensing capabilities, using DLP-based 3D printing and a polyelectrolyte elastomer. We synthesize a photo-polymerizable ionic monomer for the polyelectrolyte elastomer, which is stretchable, transparent, ionically conductive, thermally stable, and leakage-resistant. The printed sensors possess robust interfaces and extraordinary long-term stability. The multi-material 3D printing allows high flexibility in structural design, enabling the sensing of tension, compression, shear, and torsion, with on-demand tailorable sensitivities through elaborate programming of device architectures. Furthermore, we fabricate integrated ionotronic sensors that can perceive different mechanical stimuli simultaneously without mutual signal interferences. We demonstrate a sensing kit consisting of four shear sensors and one compressive sensor, and connect it to a remote-control system that is programmed to wirelessly control the flight of a drone. Multi-material 3D printing of leakage-free polyelectrolyte elastomers paves new avenues for manufacturing stretchable ionotronics by resolving the deficiencies of stability and functionalities simultaneously.

A Novel Cell Membrane-Associated RNA Extraction Method and Its Application in the Discovery of Breast Cancer Markers.

Cell membrane-associated RNA (mem-RNA) has been demonstrated to be cell-specific and disease-related and are considered as potential biomarkers for disease diagnostics, drug delivery, and cell screening. However, there is still a lack of methods specifically designed to extract mem-RNA from cells, limiting the discovery and applications of mem-RNA. In this study, we propose the first all-in-one solution for high-purity mem-RNA isolation based on two types of magnetic nanoparticles, named MREMB (Membrane-associated RNA Extraction based on Magnetic Beads), which achieved ten times enrichment of cell membrane components and over 90% recovery rate of RNA extraction. To demonstrate MREMB's potential in clinical research, we extracted and sequenced mem-RNA of typical breast cancer MCF-7, MDA-MB-231, and SKBR-3 cell lines and non-neoplastic breast epithelial cell MCF-10A. Compared to total RNA, sequencing results revealed that membrane/secreted protein-encoding mRNAs and long noncoding RNAs (lncRNAs) were enriched in the mem-RNA, some of which were significantly overexpressed in the three cancer cell lines, including extracellular matrix-related genes COL5A1 and lncRNA TALAM1. The results indicated that MREMB could enrich membrane/secreted protein-coding RNA and amplify the expression differences of related RNAs between cancer and non-neoplastic cells, promising for cancer biomarker discovery.

Application of the wholebrain calculation interactive framework to map whole-brain neural connectivity networks.

The aim of this work was to develop a simple and feasible method of mapping the neural network topology of the mouse brain. Wild-type C57BL/6 J mice (n = 10) aged 8-10 weeks were injected with the cholera toxin subunit B (CTB) tracer in the anterior (NAcCA) and posterior (NAcCP) parts of the nucleus accumbens (NAc) core and in the medial (NAcSM) and lateral (NAcSL) parts of the NAc shell. The labeled neurons were reconstructed using the WholeBrain Calculation Interactive Framework. The NAcCA receives neuronal projections from the olfactory areas (OLF) and isocortex; the thalamus and isocortex project more fibers to the NAcSL, and the hypothalamus send more fiber projections to the NAcSM. Cell resolution can be automatically annotated, analyzed, and visualized using the WholeBrain Calculation Interactive Framework, making large-scale mapping of mouse brains at cellular and subcellular resolutions easier and more accurate.

Analysis of organic acid metabolism reveals citric acid and malic acid play major roles in determining acid quality during the development of kiwifruit (Actinidia eriantha).

BACKGROUND: Actinidia eriantha is one of the most important kiwifruit species in Actinidia. The relative high accumulation of organic acids in fruit of A. eriantha is an unfavorable factor for organoleptic quality. To identify key metabolic enzymes and genes involved in organic acids accumulation during fruit development, physiological, biochemical, and molecular experiments were conducted for the dynamic fruit samples of a new kiwifruit cultivar, A. eriantha 'Ganlv 1'. RESULTS: The contents of citric acid and malic acid increased greatly during fruit development, while quinic acid content decreased obviously. Significant positive correlations were observed between fruit titratable acidity and the contents of both citric acid and malic acid, and a significant negative correlation was found between fruit titratable acidity and the quinic acid content. The high accumulation of citric acid was found to be caused by the increased activity of citrate synthase (CS), and the decreased activities of two degradation-related enzymes, mitochondrial aconitase and nicotinamide adenine dinucleotide (NAD)-dependent isocitrate dehydrogenase. In addition, the accumulation of malic acid depended mainly on the increased synthesis catalyzed by NAD-dependent malate dehydrogenase (NAD-MDH) and phosphoenolpyruvate carboxylase. Further analysis suggested that AeCS2 and AeMDH2 played pivotal roles in controlling the activities of CS and NAD-MDH respectively. CONCLUSION: The high accumulation level of citric acid relied on both the strong synthesis ability and the weak degradation ability. The accumulation level of malic acid was mainly affected by the synthesis. The novel information would be helpful for our understanding of the formation of fruit acidity quality. © 2023 Society of Chemical Industry.

Front-line therapy for brain metastases and non-brain metastases in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: a network meta-analysis.

BACKGROUND: The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR -mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR -mutated NSCLC patients with different BM statuses. METHODS: Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR -mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework. RESULTS: This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.20, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For patients without BM, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 47.1%. For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively. CONCLUSION: Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR -mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.

Gegen Qinlian standard decoction alleviated irinotecan-induced diarrhea via PI3K/AKT/NF-κB axis by network pharmacology prediction and experimental validation combination.

BACKGROUND: The frequently occurred chemotherapy-induced diarrhea (CID) caused by irinotecan (CPT-11) administration has been the most representative side-effects of CPT-11, resulting in the chemotherapy suspension or failure. Our previous studies indicated that Gegen Qinlian formula exhibited a significant alleviation effect on CPT-11-induced diarrhea. However, referencing to Japanese Kampo medicine, the TCM standard decoction would supply the gap between ancient preparation application and modern industrial production. METHODS: The LC-MS technology combined with network pharmacology was employed to identify the active ingredients and mechanisms of GQD standard decoction for CPT-11-induced diarrhea. The anti-inflammatory activities associated with intestinal barrier function of GQD standard decoction were studied by SN-38 activated NCM460 cells in vitro and CPT-11-induced diarrhea in vivo. Proteins involved in inflammation, mRNA levels, disease severity scores, and histology involved in intestinal inflammation were analysed. RESULTS: There were 37 active compounds were identified in GQD standard decoction. Network pharmacology analyses indicated that PI3K-AKT signaling pathway were probably the main pathway of GQD standard decoction in CPT-11-induced diarrhea treatment, and PIK3R1, AKT1, NF-κB1 were the core proteins. Moreover, we found that the key proteins and pathway predicted above was verified in vivo and in vitro experiments, and the GQD standard decoction could protect the cellular proliferation in vitro and ameliorate CPT-11-induced diarrhea in mice model. CONCLUSIONS: This study demonstrated the molecular mechanism of 37 active ingredients in GQD standard decoction against CPT-11-induced diarrhea. And the core proteins and pathway were validated by experiment. This data establishes the groundwork for particular molecular mechanism of GQD standard decoction active components, and this research can provide a scientific reference for the TCM therapy of CID.

Targeting the RhoA-GEF-H1 pathway of mast cells attenuates experimental airway allergy.

Mast cells are the major effector cells in allergic diseases. RhoA and its downstream pathway is associated with the pathogenesis of airway allergy. The objective of this study is to test a hypothesis that modulating the RhoA-GEF-H1 axis in mast cells can attenuate airway allergy. An airway allergic disorder (AAD) mouse model was employed. Mast cells were isolated from AAD mouse airway tissues to be analyzed by RNA sequencing. We observed that mast cells isolated from the respiratory tract of AAD mice were resistant to apoptosis. Mast cell mediator levels in nasal lavage fluid were correlated with apoptosis resistance in AAD mice. Activation of RhoA in AAD mast cells was related to resistance to apoptosis. Mast cells isolated from the airway tissues in AAD mouse exhibited strong RhoA-GEF-H1 expression. The RhoA-GEF-H1 axis was associated with the lower FasL expression in AAD mast cells. Activation of the RhoA-GEF-H1 axis promoted the production of mediators in mast cells. Inhibition of GEF-H1 facilitated the SIT-induced mast cell apoptosis and enhanced the therapeutic efficacy of AAD. In conclusion, RhoA-GEF-H1 activities are associated with resistance to apoptosis in mast cells isolated from sites of allergic lesions. The state of apoptosis resistance in mast cells is associated with the state of AAD disease. Inhibition of GEF-H1 restores the sensitivity of mast cells to apoptosis inducers, and alleviates experimental AAD in mice.

Progress of Hydrophobic Ionogels: A Review.

The emergence of hydrophobic ionogels composed of hydrophobic polymer matrices and hydrophobic ionic liquids has drastically broadened the applications of ionic devices, especially for underwater explorations. Compared with traditional ionogels, hydrophobic ones are capable of achieving long-term stability in ambient and aqueous environments. In this review, the latest research developments of intrinsically hydrophobic ionogels are summarized, with particular emphases placed on the materials, mechanisms and applications. The basic issues about hydrophobic ionogels, including the material systems, dynamic gelation bonds and network structures are elucidated. The up-to-date advent of the ambient/underwater applications of hydrophobic ionogels concerning adhesion, self-healing, and sensing are comprehensively summarized. Special attention is paid to underwater scenarios considering the rapid development of marine explorations and the intrinsic properties of hydrophobic ionogels. Finally, the current challenges and immediate opportunities of this emerging yet fast-developing research field are discussed.