Effect of sternocleidomastoid flap repair and endoscopic injection of emulsified adipose tissue stromal vascular fraction in the treatment of refractory cervical anastomotic leak contaminating mediastinum.

Mediastinal infection caused by anastomotic leak is hard to cure, mainly because the poor drainage at the site of mediastinal infection leads to persistent cavity infection, which in turn becomes a refractory mediastinal abscess cavity after minimally invasive esophagectomy (MIE)-McKeown. Herein, we explored sternocleidomastoid (SCM) muscle flaps and emulsified adipose tissue stromal vascular fraction containing adipose-derived stem-cells to address this issue. We studied 10 patients with esophageal cancer who underwent MIE-McKeown + 2-field lymphadenectomy and developed anastomotic and mediastinal leak and received new technology treatment in the Affiliated Cancer Hospital of Zhengzhou University from June 2018 to March 2022. The clinical data and prognosis of the patients were collected and analyzed. A total of 5 patients received this surgery, and no other complications occurred during the perioperative period. Among the 5 patients, 1 patient was partially cured, and 4 patients were completely cured. During the follow-up 3 months postoperatively, all these 5 patients could eat regular food smoothly, and no relapse of leak and mediastinal infection occurred. The new surgical method has achieved good results in the treatment of anastomotic leak. Compared with the traditional thoracotomy, it is a less invasive and feasible surgical approach, which can be used as a supplement to the effective surgical treatment of cervical anastomotic leak contaminating the mediastinum.

Surface N Sites Mediate the Formation of Li Metal Cluster@N-Enriched Hierarchically Porous Carbon for Ultrahigh-Capacity Lithium Storage.

Graphite is the popular anode material of current lithium-ion batteries (LIBs). However, its low specific capacity and poor lithium intercalation potential hinder its use for high-power and large-scale energy storage. To meet the demand for energy storage, novel anode materials with high capacity, fast chargeable capability, and long cycle life are of great interest. Herein, we demonstrate an advanced nitrogen-enriched hierarchical porous carbon serving as a lithiophilic anode material for ultrahigh capacity and long-life LIBs. NHPC-700 (under optimal synthetic conditions), featuring a high surface area, rich N-doping, high porosity, and partially graphitized nanosheet structures, is successfully fabricated from a Schiff-base copolymer via a template-incipient wetness impregnation method. NHPC-700 exhibits an ultrahigh reversible lithium storage capacity of 2796 mA h g-1 at 0.1 A g-1 while still maintaining a high capacity of 526 mA h g-1 at 10 A g-1 after 1000 cycles. Theoretical and experimental studies reveal that this remarkable Li storage performance can be attributed to the large number of N lithiophilic sites on the inner surface of the small mesoporous pores. These sites guide Li metal nucleation in the initial period and control well the volume variation during charge/discharge cycles, thus exhibiting excellent cycle stability and great potential for practical application.

Theoretical investigation of distal charge separation in a perylenediimide trimer.

An exciton-phonon (ex-ph) model based on our recently developed block interaction product basis framework is introduced to simulate the distal charge separation (CS) process in aggregated perylenediimide (PDI) trimer incorporating the quantum dynamic method, i.e., the time-dependent density matrix renormalization group. The electronic Hamiltonian in the ex-ph model is represented by nine constructed diabatic states, which include three local excited (LE) states and six charge transfer (CT) states from both the neighboring and distal chromophores. These diabatic states are automatically generated from the direct products of the leading localized neutral or ionic states of each chromophore's reduced density matrix, which are obtained from ab initio quantum chemical calculation of the subsystem consisting of the targeted chromophore and its nearest neighbors, thus considering the interaction of the adjacent environment. In order to quantum-dynamically simulate the distal CS process with massive coupled vibrational modes in molecular aggregates, we used our recently proposed hierarchical mapping approach to renormalize these modes and truncate those vibrational modes that are not effectively coupled with electronic states accordingly. The simulation result demonstrates that the formation of the distal CS process undergoes an intermediate state of adjacent CT, i.e., starts from the LE states, passes through an adjacent CT state to generate the intermediates (∼200 fs), and then formalizes the targeted distal CS via further charge transference (∼1 ps). This finding agrees well with the results observed in the experiment, indicating that our scheme is capable of quantitatively investigating the CS process in a realistic aggregated PDI trimer and can also be potentially applied to exploring CS and other photoinduced processes in larger systems.

Simultaneous Intra- and Intermolecular Singlet Fission in Bipentacene Macrocycle Aggregates.

Singlet fission (SF) is a process where a singlet state splits into two triplet states, which is essential for enhancing optoelectronic devices. Macrocyclic structures allow for precise control of chromophore orientation and facilitate singlet fission in solutions. However, the behavior of these structures in thin films, crucial for solid-state device optimization, remains underexplored. This study examines the aggregation and singlet fission processes of bipentacene macrocycles (BPc) in thin films using molecular dynamics simulations and electronic structure calculations. Findings indicate that BPc aggregates more rapidly with less chloroform, aligning parallel to the substrate. Intramolecular singlet fission (iSF) rates are rarely changed during evaporation, but the efficiency of intermolecular singlet fission (xSF) improves due to the increase in packing domains, suggesting that orderly crystal domains are not necessary for device efficiency. This opens avenues for varied device designs and traditional solution-based methods for optimal device development.

A new, potential and safe neoadjuvant therapy strategy in epidermal growth factor receptor mutation-positive resectable non-small-cell lung cancer-targeted therapy: a retrospective study.

Background: Studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resectable non-small-cell lung cancer (NSCLC) have been conducted. The purpose of our study was to evaluate the benefits of osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC. Method: This retrospective study evaluated patients with EGFR mutations in exon 19 or 21 who received targeted therapy with osimertinib (80 mg per day) before surgery between January 2019 and October 2023 in Henan Cancer Hospital. Results: Twenty patients were evaluated, all of whom underwent surgery. The rate of R0 resection was 100% (20/20). The objective response rate was 80% (16/20), and the disease control rate was 95% (19/20). Postoperative pathological analysis showed a 25% (5/20) major pathological response rate and 15% (3/20) pathological complete response rate. In total, 25% (5/20) developed adverse events (AEs), and the rate of grades 3-4 AEs was 10% (2/20). One patient experienced a grade 3 skin rash, and 1 patient experienced grade 3 diarrhea. Conclusion: Osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC is safe and well tolerated. Osimertinib has the potential to improve the radical resection rate and prognosis.

Renormalized-Residue-Based Multireference Configuration Interaction Method for Strongly Correlated Systems.

The implementation of multireference configuration interaction (MRCI) methods in quantum systems with large active spaces is hindered by the expansion of configuration bases or the intricate handling of reduced density matrices (RDMs). In this work, we present a spin-adapted renormalized-residue-based MRCI (RR-MRCI) approach that leverages renormalized residues to effectively capture the entanglement between active and inactive orbitals. This approach is reinforced by a novel efficient algorithm, which also facilitates an efficient deployment of spin-adapted matrix product state MRCI (MPS-MRCI). The RR-MRCI framework possesses several advantages: (1) It considers the orbital entanglement and utilizes highly compressed MPS structure, improving computational accuracy and efficiency compared with internally contracted (ic) MRCI. (2) Utilizing small-sized buffer environments of a few external orbitals as probes based on quantum information theory, it enhances computational efficiency over MPS-MRCI and offers potential application to large molecular systems. (3) The RR framework can be implemented in conjunction with ic-MRCI, eliminating the need for high-rank RDMs, by using distinct renormalized residues. We evaluated this method across nine diverse molecular systems, including Cu2O22+ with an active space of (24e,24o) and two complexes of lanthanide and actinide with active space (38e,36o), demonstrating the method's versatility and efficacy.

Spin-Adapted Externally Contracted Multireference Configuration Interaction Method Based on Selected Reference Configurations.

As one kind of approximation of the full configuration interaction solution, the selected configuration interaction (sCI) methods have been shown to be valuable for large active spaces. However, the inclusion of dynamic correlation beyond large active spaces is necessary for more quantitative results. Since the sCI wave function can provide a compact reference for multireference methods, previously, we proposed an externally contracted multireference configuration interaction method using the sCI reference reconstructed from the density matrix renormalization group wave function [J. Chem. Theory Comput. 2018, 14, 4747-4755]. The DMRG2sCI-EC-MRCI method is promising for dealing with more than 30 active orbitals and large basis sets. However, it suffers from two drawbacks: spin contamination and low efficiency when using Slater determinant bases. To solve these problems, in this work, we adopt configuration state function bases and introduce a new algorithm based on the hybrid of tree structure for convenient configuration space management and the graphical unitary group approach for efficient matrix element calculation. The test calculation of naphthalene shows that the spin-adapted version could achieve a speed-up of 6.0 compared with the previous version based on the Slater determinant. Examples of dinuclear copper(II) compound as well as Ln(III) and An(III) complexes show that the sCI-EC-MRCI can give quantitatively accurate results by including dynamic correlation over sCI for systems with large active spaces and basis sets.

Associations between resting heart rate and cognitive decline in Chinese oldest old individuals: a longitudinal cohort study.

BACKGROUND: The trajectories of cognitive function in the oldest old individuals is unclear, and the relationship between resting heart rate (RHR) and cognitive decline is controversial. METHODS: 3300 participants who had cognitive function repeatedly measured 4 ~ 8 times were included, and latent class growth mixed models were used to identified the cognitive function trajectories. Cognitive decline was defined by the trajectory shapes, considering level and slope. After excluding individuals with sinus rhythm abnormal, 3109 subjects were remained and were divided into five groups by their RHR. Logistic regression models were used to estimate the relationship between RHR and cognitive decline. RESULTS: Three distinct cognitive function trajectory groups were identified: high-stable (n = 1226), medium-decreasing (n = 1526), and rapid-decreasing (n = 357). Individuals of medium/rapid-decreasing group were defined as cognitive decline. Adjusting for covariates, the odds ratios (95% confidence intervals) of RHR sub-groups were 1.19 (0.69, 2.05), 1.27 (1.03, 1.56), 1.30 (1.01, 1.67) and 1.62 (1.07, 2.47) for those RHR < 60 bpm, 70 ~ 79 bpm, 80 ~ 89 bpm and > 90 bpm respectively, compared with those RHR 60 ~ 69 bpm. The interaction effect between RHR and physical activity (PA) on cognitive decline was found, and stratification analysis was presented that higher RHR would only show risk effects on cognitive decline in those with physical inactivity (P < 0.05 for all). CONCLUSIONS: Our study demonstrates RHR more than 70 bpm present significant risk effect on cognitive decline, and this relationship is modified by PA. Elder population with physical inactivity and higher RHR should be paid more attention to prevent cognitive decline.

The influence of emerging atmospheric organophosphorus flame retardants from land source emissions on the East China Sea.

Organophosphate flame retardants (OPFRs) pose a new challenge to the marine environment due to their toxicity and persistence. This study explores the contributions of OPFR emissions from different land sources and sectors to its contamination of the East China Sea (ECS) using a novel atmospheric transport model（ChnMETOP）for POPs and a marine food web model. The results show that the major land sources causing OPFR pollution in the ECS were situated in Yangtze River Delta (YRD) and middle reach areas of China's Yangtze River, confirming that source proximity made most significant contributions to OPFR pollution in the ECS. Among those OPFR emission sectors, industrial emissions accounted for the highest modeled OPFR levels in the seawaters, followed by the OPFR usage process in textile, plastic, and rubber products. Assessment of bioaccumulation of OPFR in the marine food web of the ECS and the potential risk in commercial fish consumers reveals lower exposure risk via dietary fish ingestion. However, the risk might increase if OPFRs are continuously bioaccumulated in the biotic and released into the abiotic marine environment. This study simultaneously identified both the source locations and emission sectors, thereby providing important policy implications in mitigating OPFR pollution in the ECS marine environment.

Vitality of Intralayer Vibration in hBN for Effective Long-Range Interlayer Hole Transfer across High Barriers in MoSe2/hBN/WSe2 Heterostructures.

Introducing the two-dimensional (2D) hexagonal boron nitride (hBN) between 2D transition metal dichalcogenide (TMD) layers promises convenient manipulation of the interlayer exciton (IX) and interlayer charge transfer in TMD/hBN/TMD heterostructures, while the role of inserted hBN layers during IX formation is controversial. Employing ab initio nonadiabatic molecular dynamics (NAMD) simulations and the electron-phonon coupling model, we systematically investigate interlayer hole transfer in MoSe2/WSe2 bilayers intercalated by hBN layers with various thicknesses. The conventional direct hole transfer from MoSe2 to WSe2 is decelerated by 2-3 orders of magnitude after the hBN insertion. Meanwhile, a novel channel intermediated by a deeper hole of WSe2 becomes dominant, where the intralayer shear mode of hBN plays a crucial role by reducing the energy barriers for this new channel. The unique role of hBN layers is revealed for the first time, enriching the knowledge of the underlying microscopic mechanisms and providing instructive guidance to practical van der Waals optoelectronic devices.

Deca-BDE emissions, validation, and environmental fate in China.

Decabromodiphenyl ether (Deca-BDE) was officially listed in Annex A of the Stockholm Convention for persistent organic pollutants (POPs). It is necessary to establish its emission inventory to help reduce Deca-BDE contamination in the environment. We established a comprehensive Deca-BDE emission inventory in China. The results reveal that, from 2015 to 2017, the Deca-BDE emissions in its production source (source I) were less altered but increased annually in flame retarded plastics processing (source II), Deca-BDE-containing products usage (source III), and electronic waste (e-waste) treatment (source IV). We show that Deca-BDE emissions declined significantly in sources I and II but grew in source III and source IV from 2017 to 2018. We set up the provincial emission inventory to a gridded map on a spatial resolution of 0.25°× 0.25° latitude/longitude. The gridded inventory was incorporated into ChnMETOP model to simulate Deca-BDE concentrations in air and soil, and the modeled concentrations were compared to field-sampling data. The results show that the Deca-BDE emission inventory developed in this study agreed well with observed data, demonstrating that the Deca-BDE inventory in China developed in the present study is reliable. The inventory provides a support for quantifying human exposure risk to Deca-BDE and developing effective mitigation measures to mitigate Deca-BDE emissions.

Ester Bond: Chemically Labile Yet Mechanically Stable.

Due to the dynamic nature of ester linkages, ester-bond-containing materials are well known for their outstanding degradability and stimuli responsiveness. However, whether ester hydrolysis is affected by mechanical forces remains unclear. Here, we develop a single-molecule assay to quantitatively study the force-dependent ester hydrolysis using an engineered circular permutant protein with a caged ester bond as a model. Our single-molecule force spectroscopy results show that the ester hydrolysis rate is surprisingly insensitive to forces, with a ∼7 s-1 dissociation rate that remains almost unchanged in the force range of 80 to 200 pN. Quantum calculations reveal that the ester hydrolysis involves an intermediate state formed by either H3O+- or OH--bonded tetrahedral intermediates. The measured ester-hydrolysis kinetics at the single-molecule level may primarily correspond to the rupture of these intermediate states. However, the rate-limiting step appears to be the formation of the tetrahedral intermediates, which cannot be quantitatively characterized in our experiments. Nonetheless, based on the quantum calculations, this step is also insensitive to applied forces. Altogether, our study suggests that the ester bond is chemically labile yet mechanically stable, serving as the basis for the design of responsive materials using ester bonds as mechanically inert units.

New Density Matrix Renormalization Group Approaches for Strongly Correlated Systems Coupled with Large Environments.

Thanks to the high compression of the matrix product state (MPS) form of the wave function and the efficient site-by-site iterative sweeping optimization algorithm, the density matrix normalization group (DMRG) and its time-dependent variant (TD-DMRG) have been established as powerful computational tools in accurately simulating the electronic structure and quantum dynamics of strongly correlated molecules with a large number (101-2) of quantum degrees of freedom (active orbitals or vibrational modes). However, the quantitative characterization of the quantum many-body behaviors of realistic strongly correlated systems requires a further consideration of the interaction between the embedded active subsystem and the remaining correlated environment, e.g., a larger number (102-3) of external orbitals in electronic structure or infinite condensed-phase phononic modes in nucleus dynamics. To this end, we introduced three new post-DMRG and TD-DMRG approaches, namely (1) DMRG2sCI-MRCI and DMRG2sCI-ENPT by the reconstruction of selected configuration interaction (sCI) type of compact reference function from DMRG coefficients and the use of externally contracted MRCI (multireference configuration interaction) and Epstein-Nesbet perturbation theory (ENPT), without recourse to the expensive high order n-electron reduced density matrices (n-RDMs). (2) DMRG combined with RR-MRCI (renormalized residue-based MRCI), which improves the computational accuracy and efficiency of internally contracted (ic) MRCI by renormalizing the contracted bases with small-sized buffer environment(s) of a few external orbitals as probes based on quantum information theory. (3) HM (hierarchical mapping)-TD-DMRG in which a large environment is reduced to a small number of renormalized environmental modes (which accounts for the most vital system-environment interactions) through stepwise mapping transformation. These advances extend the efficacy of highly accurate DMRG/TD-DMRG computations to the quantitative characterization of the electronic structure and quantum dynamics in realistic strongly correlated systems coupled with large environments and are reviewed in this paper.

Kylin 1.0: An ab-initio density matrix renormalization group quantum chemistry program.

The accurate evaluation of electron correlations is highly necessary for the proper descriptions of the electronic structures in strongly correlated molecules, ranging from bond-dissociating molecules, polyradicals, to large conjugated molecules and transition metal complexes. For this purpose, in this paper, a new ab-initio quantum chemistry program Kylin 1.0 for electron correlation calculations at various quantum many-body levels, including configuration interaction (CI), perturbation theory (PT), and density matrix renormalization group (DMRG), is presented. Furthermore, fundamental quantum chemistry methods such as Hartree-Fock self-consistent field (HF-SCF) and the complete active space SCF (CASSCF) are also implemented. The Kylin 1.0 program possesses the following features: (1) a matrix product operator (MPO) formulation-based efficient DMRG implementation for describing static electron correlation within a large active space composed of more than 100 orbitals, supporting both U 1 n × U 1 S z and U 1 n × SU 2 S symmetries; (2) an efficient second-order DMRG-self-consistent field (SCF) implementation; (3) an externally contracted multi-reference CI (MRCI) and Epstein-Nesbet PT with DMRG reference wave functions for including the remaining dynamic electron correlation outside the large active spaces. In this paper, we introduce the capabilities and numerical benchmark examples of the Kylin 1.0 program.

Atmospheric deposition contributed mostly to organophosphorus flame retardant entering into the Bohai Sea, China.

Atmospheric emission sources of persistent organic pollutants (POPs) in China's eastern seaboard regions cause heavy POP contamination in the Bohai Sea (BS), China. Because many rivers are emptying into the BS, terrestrial runoff has been considered a dominant pathway of POPs onto the BS. Here, we explored the contribution of atmospheric transport and terrestrial runoff to organophosphorus flame retardants (OPFRs) to the BS by using an atmospheric transport model and a terrestrial runoff model. We examined the sensitivity and response of OPFR in the BS seawater to its atmospheric transport, deposition, and riverine discharge via terrestrial runoff. Both terrestrial runoff and atmospheric transport model simulations reveal that the atmospheric transport and deposition, including dry, wet, and diffusive gaseous deposition, dominate OPFR input into the BS. The total OPFR fluxes entering the BS via the atmospheric pathway and riverine input were 70.4 and 2.8 t/yr in 2013, respectively.

Hierarchical Mapping for Efficient Simulation of Strong System-Environment Interactions.

Quantum dynamics (QD) simulation is a powerful tool for interpreting ultrafast spectroscopy experiments and unraveling their microscopic mechanism in out-of-equilibrium excited state behaviors in various chemical, biological, and material systems. Although state-of-the-art numerical QD approaches such as the time-dependent density matrix renormalization group (TD-DMRG) already greatly extended the solvable system size of general linearly coupled exciton-phonon models with up to a few hundred phonon modes, the accurate simulation of larger system sizes or strong system-environment interactions is still computationally highly challenging. Based on quantum information theory (QIT), in this work, we realize that only a small number of effective phonon modes couple to the excitonic system directly regardless of a large or even infinite number of modes in the condensed phase environment. On top of the identified small number of direct effective modes, we propose a hierarchical mapping (HM) approach through performing block Lanczos transformations on the remaining indirect modes, which transforms the Hamiltonian matrix to a nearly block-tridiagonal form and eliminates the long-range interactions. Numerical tests on model spin-boson systems and realistic singlet fission models in a rubrene crystal environment with up to 7000 modes and strong system-environment interactions indicate HM can reduce the system size by 1-2 orders of magnitude and accelerate the calculation by ∼80% without losing accuracy.

Tumor-suppressive E3 ubiquitin ligase CHIP inhibits the PBK/ERK axis to repress stem cell properties and radioresistance in non-small cell lung cancer.

Recently, radioresistant cancer cells surviving radiotherapy have been suggested to show more aggressive phenotypes than parental cells, and the underlying mechanisms may be associated with cancer stem cells. This study provided novel mechanistic insights for E3 ubiquitin ligase CHIP in stem cell properties and radioresistance of non-small cell lung cancer (NSCLC). After bioinformatic prediction for key genes involved, NSCLC tissues and cells were collected to measure the expression of CHIP and PBK. E3 ubiquitin ligase CHIP was poorly expressed, while PBK was highly expressed in NSCLC tissues and cells. CHIP reduced the protein stability of PBK through the ubiquitin-protease pathway to repress the activation of ERK pathway. Based on the gain- or loss-of-function experiments, it was noted that restoration of CHIP curtailed stem cell properties and radioresistance in NSCLC, as manifested by inhibited sphere formation and cell proliferation, decreased number of CD133+CD44+ cells and expression of OCT4, SOX2, and NANOG, as well as facilitated apoptosis of NSCLC cells. Besides, in vivo animal experiments further confirmed that CHIP restrained tumorigenic ability and improved radiosensitivity of NSCLC cells by inhibiting PBK/ERK axis. Collectively, CHIP suppressed stem cell properties and radioresistance of NSCLC cells by inhibiting PBK/ERK axis, therefore offering a potential therapeutic target for enhancing efficacy of radiotherapy.

CircSCN8A suppresses malignant progression and induces ferroptosis in non-small cell lung cancer by regulating miR-1290/ACSL4 axis.

Circular RNAs (CircRNAs) are reported to exert vital regulatory roles in the occurrence and development of various human malignancies, including non-small cell lung cancer (NSCLC). Bioinformatics methods identified the down-regulation of circSCN8A (circBase ID: hsa_circ_0026337) in NSCLC tissues. However, its biological functions and molecular mechanisms in NSCLC remain unknown. In this study, we found that circSCN8A expression was down-regulated in NSCLC tissues and cells. Low circSCN8A expression was positively associated with aggressive clinicopathological characteristics and poor prognosis in NSCLC patients. CircSCN8A suppressed cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and blocked tumor growth in vivo. Moreover, circSCN8A promoted cell ferroptosis in NSCLC. Mechanistically, circSCN8A acted as a competing endogenous RNA (ceRNA) by sponging miR-1290 to enhance the expression of long-chain acyl-CoA synthetase-4 (ACSL4). Furthermore, the knockdown of ACSL4 or overexpression of miR-1290 reversed the effect of circSCN8A on facilitating ferroptosis and inhibiting cell proliferation and metastasis. In summary, circSCN8A represses cell proliferation and metastasis in NSCLC by regulating the miR-1290/ACSL4 axis to induce ferroptosis. Thus, circSCN8A may represent a promising therapeutic target against NSCLC.

Mixed-Precision Implementation of the Density Matrix Renormalization Group.

The mixed-precision optimization is an effective emerging technique for quantum chemistry methods to obtain better computational performance and maintain the chemical accuracy. Here, we developed a two-level mixed-precision implementation for the density matrix renormalization group (DMRG) method. This implementation is based on the idea that the DMRG process is an iterative process. Therefore, the first several iteration steps can be executed in single precision. A feasible single-precision DMRG may generate moderate accuracy, and when a few double-precision cleanup sweeps are added, the double-precision accuracy will be recovered. In the double-precision sweeps, we developed a mixed-precision diagonalization method that can run the most time-consuming step in single precision and maintain the double-precision accuracy. By combining these two mixed-precision schemes, we implemented our mixed-precision DMRG method. The benchmark result shows that our mixed-precision implementation achieved a good performance. A speed-up of up to 2.31 is achieved, and the accuracy is preserved within 0.01 kcal/mol.

E3 Ubiquitin Ligase CHIP Inhibits the Interaction between Hsp90ß and MAST1 to Repress Radiation Resistance in Non-Small-Cell Lung Cancer Stem Cells.

The radiation resistance of cancer stem cells poses a critical obstacle for management of non-small-cell lung cancer (NSCLC). It is interesting to note that E3 ubiquitin ligase CHIP is involved in radiation resistance and stemness phenotypes in NSCLC, while the downstream mechanisms remain elusive. Therefore, this study is aimed at exploring the possible molecular mechanism of E3 ubiquitin ligase CHIP in radiation resistance of NSCLC stem cells. Cancer and adjacent normal tissues of NSCLC patients were collected to determine expression of CHIP, Hsp90ß, and MAST1. CD133+ cells were isolated from the NSCLC tissues and the lung cancer cell line A549 by flow cytometric sorting. Accordingly, downregulated CHIP and upregulated Hsp90ß and MAST1 were observed in cancer tissues from NSCLC patients and in NSCLC stem cells. Sphere formation assay, colony formation assay, and flow cytometry were performed to examine self-renewal ability, survival, and apoptosis of NSCLC stem cells. An animal model of tumor xenograft was developed in nude mice to observe the tumorigenic ability and radiation resistance of NSCLC stem cells. CHIP overexpression was demonstrated to inhibit the NSCLC stem cell properties and radiation resistance in vitro and in vivo. Mechanistically, CHIP promoted MAST1 ubiquitination by blocking Hsp90ß interaction with MAST1, thus inhibiting MAST1 protein stability. Furthermore, CHIP-mediated downregulation of MAST1 protein stability inhibited the NSCLC stem cell properties and radiation resistance. Collectively, CHIP promotes the ubiquitination of MAST1 by blocking the interaction of Hsp90ß with MAST1, leading to decreased MAST1 protein stability, which suppressed NSCLC stem cell properties and radiation resistance.