Biodegradable Nanoparticles Mediated Co-delivery of Erlotinib (ELTN) and Fedratinib (FDTN) Toward the Treatment of ELTN-Resistant Non-small Cell Lung Cancer (NSCLC) via Suppression of the JAK2/STAT3 Signaling Pathway

Background: Erlotinib (ELTN)-based targeted therapy as first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung cancers suffers from insufficient selectivity, side effects, and drug resistance, which poses critical challenges in the clinical setting. Acquired resistance of ELTN results in extremely poor prognoses of non-small cell lung cancer (NSCLC) patients, wherein activation of the JAK2/STAT3 signaling pathway has been proven to induce acquired ELTN resistance.Methods: In this study, we developed a nanoparticle (NP) delivery system based on Food and Drug Administration (FDA)-approved poly(ethylene glycol) (PEG)-poly(lactic acid) (PLA) for the co-delivery of ELTN and fedratinib (FDTN, a small-molecular, highly selective JAK2 inhibitor). Both ELTN and FDTN could be encapsulated into the PEG-PLA NPs via optimization of the encapsulation method. The effect of NPs on NSCLC cells was evaluated by MTT assay. Western blotting was performed to study the molecular mechanisms of NPs inhibiting the downstream pathways of EGFR in vitro. The histological analysis and protein expression in vivo were assessed by hematoxylin/eosin (H&E) staining and immunohistochemistry, respectively.Results: The drug cargoes exhibited great stability, and could be released more efficiently in the acidic tumorous condition. Mechanistic study showed that FDTN notably down-regulated the expression levels of proteins in the JAK2/STAT3 signaling pathway, including p-EGFR, p-JAK2, p-STAT3 and Survivin, therefore reversing the ELTN resistance. As a result, synergistic anti-cancer effect was achieved by PEG-PLA NPs encapsulating both ELTN and FDTN in ELTN-resistant NSCLC tumors both in vitro and in vivo, and lower systemic side effect was noted for the co-delivery NPs compared to free drugs.Conclusion: This study provides a promising approach to overcome the ELTN resistance in the treatment of NSCLC, and the use of FDA-approved materials with clinically applied/investigated chemical drugs may facilitate the translation of the current delivery system

Magnetic Texture in Insulating Single Crystal High Entropy Oxide Spinel Films

Magnetic insulators are important materials for a range of next generation memory and spintronic applications. Structural constraints in this class of devices generally require a clean heterointerface that allows effective magnetic coupling between the insulating layer and the conducting layer. However, there are relatively few examples of magnetic insulators which can be synthesized with surface qualities that would allow these smooth interfaces and precisely tuned interfacial magnetic exchange coupling which might be applicable at room temperature. In this work, we demonstrate an example of how the configurational complexity in the magnetic insulator layer can be used to realize these properties. The entropy-assisted synthesis is used to create single crystal (Mg0.2Ni0.2Fe0.2Co0.2Cu0.2)Fe2O4 films on substrates spanning a range of strain states. These films show smooth surfaces, high resistivity, and strong magnetic responses at room temperature. Local and global magnetic measurements further demonstrate how strain can be used to manipulate magnetic texture and anisotropy. These findings provide insight into how precise magnetic responses can be designed using compositionally complex materials that may find application in next generation magnetic devices

Roles of AP-2 in clathrin-mediated endocytosis.

The notion that AP-2 clathrin adaptor is an essential component of an endocytic clathrin coat appears to conflict with recent observations that substantial AP-2 depletion, using RNA interference with synthesis of AP-2 subunits, fails to block uptake of certain ligands known to internalize through a clathrin-based pathway

Chemical Composition and Transgenerational Effects on Caenorhabditis elegans of Seasonal Fine Particulate Matter

While numerous studies have demonstrated the adverse effects of fine particulate matter (PM) on human health, little attention has been paid to its impact on offspring health. The multigenerational toxic effects on Caenorhabditis elegans (C. elegans) were investigated by acute exposure. PM2.5 and PM1 samples were collected and analysed for their chemical composition (inorganic ions, metals, OM, PAHs) in different seasons from April 2019 to January 2020 in Lin’an, China. A higher proportion of organic carbon components (34.3%, 35.9%) and PAHs (0.0144%, 0.0200%) occupied the PM2.5 and PM1 samples in winter, respectively. PM1 in summer was enriched with some metal elements (2.7%). Exposure to fine PM caused developmental slowing and increased germ cell apoptosis, as well as inducing intestinal autofluorescence and reactive oxygen species (ROS) production. PM1 caused stronger toxic effects than PM2.5. The correlation between PM component and F0 generation toxicity index was analysed. Body length, germ cell apoptosis and intestinal autofluorescence were all highly correlated with Cu, As, Pb, OC and PAHs, most strongly with PAHs. The highest correlation coefficients between ROS and each component are SO42− (R = 0.743), Cd (R = 0.816) and OC (R = 0.716). The results imply that OC, PAHs and some transition metals play an important role in the toxicity of fine PM to C. elegans, where the organic fraction may be the key toxicogenic component. The multigenerational studies show that PM toxicity can be passed from parent to offspring, and gradually returns to control levels in the F3–F4 generation with germ cell apoptosis being restored in the F4 generation. Therefore, the adverse effects of PM on reproductive damage are more profound

XAF1 Inhibits Cell Proliferation and Induces Apoptosis in Human Lung Adenocarcinoma Cell Line A549 In Vitro

Background and objective XAF1 is a factor necessary to inhibit tumor cell growth. Low XAF1 expression is associated with various tumor cells. The aim of this study is to investigate the effect and the mechanism of adenovirus vector Ad5/F35 mediated X-linked inhibitor of apoptosis protein associated factor-1 (XAF1) on the inhibition of cell proliferation and the induction of apoptosis of human lung adenocarcinoma cell A549. Methods Recombinant virus Ad5/F35-XAF1 and controlled virus Ad5/F35-NULL exhibited different multiplicities of infection (MOI) at the same time. mRNA and protein expressions of XAF1 were determined by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. Cell proliferation was observed by methyl thiazolyl tetrazolium (MTT) assay, and cell apoptosis was analyzed by FACS with Annexin V-FITC/PI double staining. The expressions of apoptosis-associated proteins, such as PARP, Caspase-3, and Caspase-8, were also determined by Western blot. Results mRNA and protein expressions of XAF1 were significantly increased in human lung adenocarcinoma cell A549 after this cell was transfected with Ad5/F35-XAF1 for 48 h; these expressions were higher than those of the controlled group Ad5/F35-NULL. Cell proliferation was inhibited and apoptosis was induced in a dose-dependent manner in the Ad5/F35-XAF1 group. After Ad5/F35-XAF1 transfection was performed, the cleavage of apoptosis-associated proteins, such as PARP, Caspase-3, and Caspase-8, was activated. Conclusion Restored XAF1 expression inhibits cell proliferation and induces cell apoptosis in human lung adenocarcinoma cell line A549. Furthermore, XAF1 may activate associated apoptotic signaling pathways in A549 cell line

Surface deformation and damage of 2022 (M 6.8) Luding earthquake in China and its tectonic implications

The 2022 (M 6.8) Luding earthquake on the Xianshuihe Fault Zone (XFZ) caused severe casualties and property losses, and surface deformation and damage of which is crucial for studying the earthquake hazard assessment. However, few intensive scientific understanding has obtained to date because of widespread coronavirus transmission, strong vegetation coverage, and post-earthquake paralyzed traffic. By integrating high-resolution satellite images, large-scale geomorphic mapping, and UAV surveys, we constrain coseismic fractures and ruptures along an NW-SE-trending surface deformation zone, with discontinuous geomorphic scarps, en echelon cracks, and bulges concentrated in the areas of Yanzigou, Moxi, Menghugang, and Xingfu villages near the epicenter. Field observation also shows that the zone extends nearly parallel to the pre-existing XFZ with a length of ∼35 km with variable widths and a maximum vertical displacement of ∼100 ± 10 cm. The earthquake-induced surface coseismic effects, such as landslides, rock falls, and collapses, caused damage to the area. The amplification effect of the topography and the improper aseismic design and poor constructions may be responsible for the spatial distribution of MM Intensity IX, which is larger than other previous earthquakes that occurred in the surrounding area with a similar tectonic setting

Progress in Single-cell RNA Sequencing of Lung Adenocarcinoma

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and one of the main causes of cancer-related deaths. In the past decade, with the widespread use of computed tomography (CT) in routine screening for lung cancer, the incidence of LUAD presenting as small pulmonary nodules radiologically, has increased remarkably. The mechanisms of the occurrence and progression of LUADs are complex, and the prognoses of patients with LUAD vary significantly. Although significant progress has been made in targeted therapy and immunotherapy for LUADs in recent years, the drug resistance of tumor cells has not been effectively overcome, which limits the benefits of patients. With the accomplishment of the Human Genome Project, sequencing-based genomic and transcriptomics have come into the field of clinical and scientific researches. Single-cell sequencing, as a new type of sequencing method that has captured increasing attention recently, can perform specific analysis of cell populations at single-cell level, which can reveal the unique changes of each cell type. Single-cell sequencing can also provide accurate assessment on heterogeneous stromal cells and cancer cells, which is helpful to reveal the complexity of molecular compositions and differences between non- and malignant tissues. To sum up, it is an urgent need for clinicians and basic scientists to deeply understand the pathogenesis and development of LUAD, the heterogeneity of tumor microenvironment (TME) and the mechanism of drug resistance formation through single-cell sequencing, so as to discover new therapeutic targets. In this paper, we reviewed and summarized the application and progress in single-cell sequencing of LUADs

Predicting hidden bulk phases from surface phases in bilayered Sr3Ru2O7

Abstract The ability to predict hidden phases under extreme conditions is not only crucial to understanding and manipulating materials but it could also lead to insight into new phenomena and novel routes to synthesize new phases. This is especially true for Ruddlesden-Popper perovskite phases that possess interesting properties ranging from superconductivity and colossal magnetoresistance to photovoltaic and catalytic activities. In particular, the physical properties of the bilayer perovskite Sr3Ru2O7 at the surface are intimately tied to the rotation and tilt of the RuO6 octahedra. To take advantage of the extra degree of freedom associated with tilting we have performed first principles hybrid density functional simulations of uniaxial pressure applied along the c-axis of bulk Sr3Ru2O7 where we find that the octahedra become tilted, leading to two phase transitions. One is a structural transition at $$\simeq$$ ≃ 1.5 GPa, and the other is from a ferromagnetic (FM) metal to an antiferromagnetic (AFM) insulator at $$\simeq$$ ≃ 21 GPa whose AFM spin configuration is different from the AFM state near the FM ground state

Anomalous surface lattice dynamics in the low-temperature phase of Ba(Fe1-xCox)2As2

In complex materials, how correlation between charge, spin, and lattice affects the emergent phenomena remains unclear. The newly discovered iron-based high-temperature superconductors and related compounds present to the community a prototype family of materials, where interplay between charge, spin, and lattice degrees of freedom can be explored. With the occurrence of structural, magnetic, and superconducting transitions in the bulk of these materials, creating a surface will change the delicate balance between these phases, resulting in new behavior. A surface lattice dynamics study on (001) Ba(Fe(1-x)Co(x))(2)As(2), through electron energy loss spectroscopy measurements, reveals unusual temperature dependence of both the phonon frequency and line width in the low-temperature orthorhombic phase. The rate of change of phonon frequency with temperature is gigantic, two orders of magnitude larger than in the bulk. This behavior cannot be explained using conventional models of anharmonicity or electron-phonon coupling; instead, it requires that a large surface-spin-charge-lattice coupling be included. Furthermore, the higher surface-phase-transition temperature driven by surface stabilization of the low-temperature orthorhombic phase seems to turn the first-order transition (bulk) into the second-order type, equivalent to what is observed in the bulk by applying a uniaxial pressure. Such equivalence indicates that the surface mirrors the bulk under extreme conditions

Surgical Treatment of Refractory Chest Tumors Assisted by Cardiopulmonary Bypass

Background and objective A retrospective review of the surgical treatment of refractory chest tumors involving the heart or large vessels with cardiopulmonary bypass (CPB). Methods To summarize 11 cases of chest tumor patients who had undergone cardiopulmonary bypass surgery from January 2008 to May 2017 in our hospital, and analyze the general condition, clinical characteristics, treatment methods, postoperative hospitalization time, complications and follow-up results of all patients. Results All 11 patients were operated with cardiopulmonary bypass. Total resection of tumors in 8 cases and most of the excision in 3 cases. 1 case of left atrial metastatic leiomyosarcoma were excised in the left atrium, and then the right lung resection was performed. 1 case of left lung central lung cancer resection through the median sternum incision. 2 cases underwent pulmonary artery repair at the same time, 3 cases underwent partial pericardiectomy and 3 cases underwent pulmonary wedge resection at the same time. All the patients were effectively relieved after the operation. No death rate in hospital and 30 days after operation. 3 cases of postoperative pulmonary infection were recovered after the treatment of antibiotics. 1 case of lymphoma relapsed 6 months after surgery and died one year later. 1 case of pericardial fibrosarcoma had local recurrence and extensive metastasis at 13 months after operation, and died after 15 months. 1 case of pulmonary leiomyosarcoma were found to have local recurrence 15 months after the operation and were relieved after chemotherapy. The remaining 8 patients survived, and no obvious recurrence and distant metastasis were found in the computed tomography (CT) examination. Conclusion The CPB assisted surgical treatment can be performed for patient of refractory chest tumors involving the heart or large vessels. It can improve the surgical resection rate of refractory chest tumors, effectively alleviate the effects on respiratory and circulatory functions, and significantly prolong the survival period of these patients