Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary ...mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.
Long-distance entanglement distribution is essential for both foundational tests of quantum physics and scalable quantum networks. Owing to channel loss, however, the previously achieved distance was ...limited to ~100 kilometers. Here we demonstrate satellite-based distribution of entangled photon pairs to two locations separated by 1203 kilometers on Earth, through two satellite-to-ground downlinks with a summed length varying from 1600 to 2400 kilometers. We observed a survival of two-photon entanglement and a violation of Bell inequality by 2.37 ± 0.09 under strict Einstein locality conditions. The obtained effective link efficiency is orders of magnitude higher than that of the direct bidirectional transmission of the two photons through telecommunication fibers.
Background and Aim
Remimazolam tosilate (RT) is a new short‐acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy ...and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy.
Methods
This positive‐controlled, non‐inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety.
Results
The success rate of sedation in the RT group was non‐inferior to that in the propofol group (97.34% vs 100.00%; difference in rate −2.66%, 95% CI −4.96 to −0.36, meeting criteria for non‐inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment‐related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001).
Conclusion
This trial established non‐inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.
Conjugated polymers (CPs) have recently gained increasing attention as photocatalysts for sunlight-driven hydrogen evolution. However, they suffer from insufficient electron output sites and poor ...solubility in organic solvents, severely limiting their photocatalytic performance and applicability. Herein, solution-processable all-acceptor (A
-A
)-type CPs based on sulfide-oxidized ladder-type heteroarene are synthesized. A
-A
-type CPs showed upsurging efficiency improvements by two to three orders of magnitude, compared to their donor-acceptor -type CP counterparts. Furthermore, by seawater splitting, PBDTTTSOS exhibited an apparent quantum yield of 18.9% to 14.8% at 500 to 550 nm. More importantly, PBDTTTSOS achieved an excellent hydrogen evolution rate of 35.7 mmol h
g
and 150.7 mmol h
m
in the thin-film state, which is among the highest efficiencies in thin film polymer photocatalysts to date. This work provides a novel strategy for designing polymer photocatalysts with high efficiency and broad applicability.
Lung carcinoma is the primary reason for cancer-associated mortality, and it exhibits the highest mortality and incidence in developed and developing countries. Non-small cell lung cancer (NSCLC) and ...SCLC are the 2 main types of lung cancer, with NSCLC contributing to 85% of all lung carcinoma cases. Conventional treatment mainly involves surgery, chemoradiotherapy, and immunotherapy, but has a dismal prognosis for many patients. Therefore, identifying an effective adjuvant therapy is urgent. Historically, traditional herbal medicine has been an essential part of complementary and alternative medicine, due to its numerous targets, few side effects and substantial therapeutic benefits. In China and other East Asian countries, traditional herbal medicine is increasingly popular, and is highly accepted by patients as a clinical adjuvant therapy. Numerous studies have reported that herbal extracts and prescription medications are effective at combating tumors. It emphasizes that, by mainly regulating the P13K/AKT signaling pathway, the Wnt signaling pathway, and the NF-κB signaling pathway, herbal medicine induces apoptosis and inhibits the proliferation and migration of tumor cells. The present review discusses the anti-NSCLC mechanisms of herbal medicines and provides options for future adjuvant therapy in patients with NSCLC.
Solid/liquid interfaces are ubiquitous in nature and knowledge of their atomic-level structure is essential in elucidating many phenomena in chemistry, physics, materials science and Earth science
. ...In electrochemistry, in particular, the detailed structure of interfacial water, such as the orientation and hydrogen-bonding network in electric double layers under bias potentials, has a significant impact on the electrochemical performances of electrode materials
. To elucidate the structures of electric double layers at electrochemical interfaces, we combine in situ Raman spectroscopy and ab initio molecular dynamics and distinguish two structural transitions of interfacial water at electrified Au single-crystal electrode surfaces. Towards negative potentials, the interfacial water molecules evolve from structurally 'parallel' to 'one-H-down' and then to 'two-H-down'. Concurrently, the number of hydrogen bonds in the interfacial water also undergoes two transitions. Our findings shed light on the fundamental understanding of electric double layers and electrochemical processes at the interfaces.
Aim
Abnormally activated vascular smooth muscle cells are key factors in pulmonary artery remodelling (PAR) and pulmonary artery hypertension (PAH). Keratin 1 is involved in inflammatory diseases; ...however, its role in PAH is unknown. We speculated that keratin 1 could regulate PASMCs and prevent PAH.
Methods
Rats were exposed to hypoxia (10% O2) or MCT (50 mg/kg, intraperitoneal injection) or treated with AAV6 virus. PAR was measured through HE and Masson staining. PASMC activities were measured using MTS assay, EdU and Western blot analyses after cell knockdown with siRNAs or overexpression with Krt1 vectors.
Results
1. Hypoxic PAR was associated with a decrease in keratin 1, especially in PASMCs. 2. Keratin 1 knockdown led to cell proliferation, migration and contraction to synthetic transformation, while keratin 1 overexpression attenuated hypoxia‐induced changes in PASMCs. 3. Decreased keratin 1 induced TLR7 upregulation and mediated increases in the inflammatory factors S100a8 and S100a9. 4. Keratin 1 overexpression reduced the inflammatory factor expression induced by TLR7 activation. 5. Further studies demonstrated that keratin 1 expression was negatively correlated with pulmonary vascular pressure following prolonged hypoxia. 6. Pre‐treatment with keratin 1 decreased pulmonary artery pressure and the right heart hypertrophy index and alleviated PAR in two model rats. 7. Keratin 1 exhibited a hypermethylation status in hypoxic pulmonary arteries in the sequencing. Hypoxia‐induced decrease in keratin 1 expression was associated with Dnmt1 upregulation induced by YY1 downregulation in PASMCs.
Conclusion
This study suggests that keratin 1 regulates PASMC expansion and has a preventive effect on PAH.
We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). ...Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.
Driven by the persisting poor understanding of the sluggish kinetics of the hydrogen evolution reaction (HER) on Pt in alkaline media, a direct correlation of the interfacial water structure and ...activity is still yet to be established. Herein, using Pt and Pt–Ni nanoparticles we first demonstrate a strong dependence of the proton donor structure on the HER activity and pH. The structure of the first layer changes from the proton acceptors to the donors with increasing pH. In the base, the reactivity of the interfacial water varied its structure, and the activation energies of water dissociation increased in the sequence: the dangling O−H bonds < the trihedrally coordinated water < the tetrahedrally coordinated water. Moreover, optimizing the adsorption of H and OH intermediates can re‐orientate the interfacial water molecules with their H atoms pointing towards the electrode surface, thereby enhancing the kinetics of HER. Our results clarified the dynamic role of the water structure at the electrode–electrolyte interface during HER and the design of highly efficient HER catalysts.
On nickel–platinum alloy nanoparticles under alkaline conditions, the reactivity of interfacial water varies with its structure and the order of water dissociation. The inclusion of nickel re‐orientates interfacial water molecules with their hydrogen atoms pointing towards the electrode surface, thereby enhancing the kinetics of the hydrogen evolution reaction (HER).
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