Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is ...critical for identifying novel therapeutic targets in gastric cancer.
A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays.
circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy.
Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.
Abstract
A more common and noninvasive predicting biomarker for programmed cell death 1 (PD-1) antibody remains to be explored. We assessed 46 patients with advanced gastric cancer who received PD-1 ...antibody immunotherapy and 425-genes next-generation sequencing (NGS) testing. Patients who had a > 25% decline in maximal somatic variant allelic frequency (maxVAF) had a longer progression free survival (PFS) and higher response rate than those who did not (7.3 months vs 3.6 months,
p
= 0.0011; 53.3% vs 13.3%,
p
= 0.06). The median PFS of patients with undetectable and detectable post-treatment circulating tumor DNA (ctDNA) was 7.4 months vs. 4.9 months (
p
= 0.025). Mutation status of TGFBR2, RHOA, and PREX2 in baseline ctDNA influenced the PFS of immunotherapy (
p
< 0.05). Patients with alterations in CEBPA, FGFR4, MET or KMT2B (
p
= 0.09) gene had greater likelihood of immune-related adverse events (irAEs). ctDNA can serve as a potential biomarker of the response to immunotherapy in advanced gastric cancers, and its potential role in predicting irAEs worth further exploration.
As one of the fascinating high capacity cathodes, O3‐type layered oxides usually suffer from their intrinsic air sensitivity and sluggish kinetics originating from the spontaneous lattice Na ...extraction during air exposure and high tetrahedral site energy of Na+ diffusion transition state. What is worse, the improvement on the two handicaps is hard to simultaneously realize because of the contradiction between Na containment suggested in air stability mechanism and enhanced Na diffusion mentioned in kinetics strategy. Herein, it is shown that a simple strategy of introducing proper Na vacancies into lattice can simultaneously realize a dual performance improvement. Na vacancies decrease the charge density on transitional metal ions and enhance the antioxidative capability of material, ensuring a stable lattice Na containment for Na0.93Li0.12Ni0.25Fe0.15Mn0.48O2 when exposed to air. Additionally, more Na+ diffusional sites and enlarged Na layer spacing are obtained and result in a significantly decreased energy barrier from ≈1000 to 300 meV and a high rate capability of 70.8% retention at 2000 mA g−1. Remarkably, such a strategy can be easily realized by either pre‐ or post‐treating, which exhibits excellent universality for various O3 materials, implying its enormous potential to promote the commercial application of O3‐type cathodes.
A universal strategy of introducing proper Na vacancies into a crystal lattice is proposed to simultaneously improve air‐stability and kinetics of O3‐type layered oxide cathodes. The dual improvement benefits from the multiple effects of Na vacancies on crystalline and electronic structure, namely, decreased charge density on transition metal ions, enhanced antioxidative capability, decreased Na+ diffusion barrier, and optimized migration path.
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
The uncontrollable dendrite growth and unstable solid electrolyte interphase have long plagued the practical application of Li metal batteries. Herein, a dual‐layered artificial interphase ...LiF/LiBO–Ag is demonstrated that is simultaneously reconfigured via an electrochemical process to stabilize the lithium anode. This dual‐layered interphase consists of a heterogeneous LiF/LiBO glassy top layer with ultrafast Li‐ion conductivity and lithiophilic Li–Ag alloy bottom layer, which synergistically regulates the dendrite‐free Li deposition, even at high current densities. As a result, Li||Li symmetric cells with LiF/LiBO–Ag interphase achieve an ultralong lifespan (4500 h) at an ultrahigh current density and area capacity (20 mA cm−2, 20 mAh cm−2). LiF/LiBO–Ag@Li anodes are successfully applied in quasi‐solid‐state batteries, showing excellent cycling performances in symmetric cells (8 mA cm−2, 8 mAh cm−2, 5000 h) and full cells. Furthermore, a practical quasi‐solid‐state pouch cell coupling with a high‐nickel cathode exhibits stable cycling with a capacity retention of over 91% after 60 cycles at 0.5 C, which is comparable or even better than that in liquid‐state pouch cells. Additionally, a high‐energy‐density quasi‐solid‐state pouch cell (10.75 Ah, 448.7 Wh kg−1) is successfully accomplished. This well‐orchestrated interphase design provides new guidance in engineering highly stable interphase toward practical high‐energy‐density lithium metal batteries.
A spontaneously reconfigured, dual‐layered artificial interphase of LiF/LiBO–Ag is proposed to stabilize Li anode at high current densities. The LiF/LiBO top layer guarantees fast Li‐ion transition, and the lithiophilic Li–Ag bottom layer enables uniform Li deposition. Benefiting from the well‐orchestrated interphase design, the quasi‐solid‐state lithium metal batteries demonstrate a high practical specific energy (448.7 Wh kg−1), superior high‐rate performances, and high safety.
An electrochemical difluoromethylation triggered lactonization of alkenes was developed for the first time. This protocol employs readily prepared CF
HSO
Na as the difluoromethylating reagent, ...affording unprecedented CF
H-containing lactones in moderate yields. Moreover, with CF
SO
Na as the trifluoromethylating reagent, a wide array of CF
-containing lactones were obtained under additional supporting electrolyte- and catalyst-free conditions.
Ether solvents with superior reductive stability promise excellent interphasial stability with high‐capacity anodes while the limited oxidative resistance hinders their high‐voltage operation. ...Extending the intrinsic electrochemical stability of ether‐based electrolytes to construct stable‐cycling high‐energy‐density lithium‐ion batteries is challenging but rewarding. Herein, the anion‐solvent interactions were concerned as the key point to optimize the anodic stability of the ether‐based electrolytes and an optimized interphase was realized on both pure‐SiOx anodes and LiNi0.8Mn0.1Co0.1O2 cathodes. Specifically, the small‐anion‐size LiNO3 and tetrahydrofuran with high dipole moment to dielectric constant ratio realized strengthened anion‐solvent interactions, which enhance the oxidative stability of the electrolyte. The designed ether‐based electrolyte enabled a stable cycling performance over 500 cycles in pure‐SiOx||LiNi0.8Mn0.1Co0.1O2 full cell, demonstrating its superior practical prospects. This work provides new insight into the design of new electrolytes for emerging high‐energy density lithium‐ion batteries through the regulation of interactions between species in electrolytes.
The anion‐solvent interactions in Li‐ion batteries were promoted in ether‐based electrolyte by applying the small‐anion‐size LiNO3 and tetrahydrofuran with a high ratio of dipole moment to dielectric constant. The designed ether‐based electrolyte showed optimized interphasial stability on the pure‐SiOx anode and NMC811 cathode, thus enabling stable cycling performance of the pure‐SiOx||NMC811 full cell over 500 cycles.
Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored ...the potential role of Au in an H
O
-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model.
In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml, or 200 μg/ml) were added in culture medium at 0 h and 6 h after neurons stimulated by H
O
(100 μM). After exposed for 12 h, neurons were collected for western blot (WB), immunofluorescence, and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits, and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR.
Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS), and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages, and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1 (HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au.
Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.
A novel coronavirus pneumonia, first identified in Wuhan City and referred to as COVID‐19 by the World Health Organization, has been quickly spreading to other cities and countries. To control the ...epidemic, the Chinese government mandated a quarantine of the Wuhan city on January 23, 2020. To explore the effectiveness of the quarantine of the Wuhan city against this epidemic, transmission dynamics of COVID‐19 have been estimated. A well‐mixed “susceptible exposed infectious recovered” (SEIR) compartmental model was employed to describe the dynamics of the COVID‐19 epidemic based on epidemiological characteristics of individuals, clinical progression of COVID‐19, and quarantine intervention measures of the authority. Considering infected individuals as contagious during the latency period, the well‐mixed SEIR model fitting results based on the assumed contact rate of latent individuals are within 6–18, which represented the possible impact of quarantine and isolation interventions on disease infections, whereas other parameter were suppose as unchanged under the current intervention. The present study shows that, by reducing the contact rate of latent individuals, interventions such as quarantine and isolation can effectively reduce the potential peak number of COVID‐19 infections and delay the time of peak infection.
Highlights
A novel coronavirus pneumonia (COVID‐19) has been quickly spreading to other cities and countries.
We aim to explore the effectiveness of the quarantine of the Wuhan city against this epidemic by using a well‐mixed “susceptible exposed infectious recovered” (SEIR) compartmental model.
Interventions such as quarantine and isolation can effectively reduce the potential peak number of COVID‐19 infections and delay the time of peak infection.
Long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown.
Real-time PCR ...analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells.
lncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted.
lncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.
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