A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer.

BACKGROUND: Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer. RESULTS: An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies. CONCLUSION: We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer.

Mott-Schottky Effect in Core-Shell W@Wx C Heterostructure: Boosting Both Electronic/Ionic Kinetics for Lithium Storage.

The dynamics rate of traditional metal carbides (TMCs) is relatively slow, severely limiting its fast-charging capacity for lithium-ion batteries (LIBs). Herein, the core-shell W@Wx C heterostructure is developed to form Mott-Schottky heterostructure, thereby simultaneously accelerating the electronic and ionic transport kinetics during the charging/discharging process. The W nanoparticles are partially reduced into Wx C to form a particular core-shell structure with abundant heterogeneous interfaces. Benefiting from the Mott-Schottky effect, the electrons at the metal/semiconductor heterointerface can migrate spontaneously to realize an equal work function on both sides. In addition, the independent nanoparticle as well as the unique core-shell structure facilitate the ionic diffusion kinetics. As expected, the W@Wx C electrode exhibits excellent electrochemical stability for LIBs, whose capacity can be maintained at 173.8 mA h g-1 after 1600 cycles at a high current density of 5 A g-1 . When assembled into a full cell, it can achieve an energy density of 360.2 Wh kg-1 . This work presents a new avenue to promote the electronic and ionic kinetics for LIBs anodes by constructing the unique Mott-Schottky heterostructure.

Climbing the Apex of the ORR Volcano Plot via Binuclear Site Construction: Electronic and Geometric Engineering.

Great enthusiasm in single-atom catalysts (SACs) for the oxygen reduction reaction (ORR) has been aroused by the discovery of M-NX as a promising ORR catalysis center. However, the performance of SACs lags far behind that of state-of-the-art Pt due to the unsatisfactory adsorption-desorption behaviors of the reported catalytic centers. To address this issue, rational manipulation of the active site configuration toward a well-managed energy level and geometric structure is urgently desired, yet still remains a challenge. Herein, we report a novel strategy to accomplish this task through the construction of an Fe-Co dual-atom centered site. A spontaneously absorbed electron-withdrawing OH ligand was proposed to act proactively as an energy level modifier to empower easy intermediate desorption, while the triangular Fe-Co-OH coordination facilitates O-O bond scission. Benefiting from these attributes, the as-constructed FeCoN5-OH site enables an ORR onset potential and half-wave potential of up to 1.02 and 0.86 V (vs RHE), respectively, with an intrinsic activity over 20 times higher than the single-atom FeN4 site. Our finding not only opens up a novel strategy to tailor the electronic structure of an atomic site toward boosted activity but also provides new insights into the fundamental understanding of diatomic sites for ORR electrocatalysis.

Elevated Swelling-Activated Chloride Current Densities in Hypertrophied Ventricular Myocytes in a Rabbit Heart Failure Model.

BACKGROUND: The status of the swelling-activated chloride channel (ICl, swell) during heart failure remains unclear. This study aimed to investigate whether the ICl, swell activity is altered during heart failure and to determine how the ICl, swell influences atrial arrhythmias of the failing heart. METHODS: We established a heart failure rabbit model and analyzed the hemodynamic indicators 8 weeks after myocardial infarction, which include left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVDEP). Five untreated rabbits and 5 receiving a sham operation served as the control group. Left auricular appendage tissues were obtained and CLCN3 mRNA/CLCN3 protein expression levels were examined by using reverse transcription-polymerase chain reaction and Western blot, respectively. RESULTS: Compared to the control group, the heart failure group showed a significantly decreased LVSP (14.2 ± 0.27 versus 16.9 ± 0.86 kPa, P <.05)and elevated LVDEP (2.49 ± 0.30 versus 0.15 ± 0.03 kPa, P <.05), indicating that myocardial infarction leads to progressive heart failure of rabbits in the heart failure group. CLCN3 mRNA and CLCN3 protein expression were both significantly elevated in the heart failure group compared to the control group (P <.05). CONCLUSION: In sum, we propose that the dynamic nature of ICl, swell upregulation may contribute to the elevated expression of CLCN3 mRNA and CLCN3 protein, resulting in myocardial cell remodeling induced by heart failure. However, further study is needed to investigate the potential functions of ICl, swell, especially the relation between ICl, swell augmentation and arrhythmia after heart failure.

Ultrafast Self-Limited Growth of Strictly Monolayer WSe2 Crystals.

The controllable synthesis of uniform tungsten diselenide (WSe2 ) is crucial for its emerging applications due to the high sensitivity of its extraordinary physicochemical properties to its layer numbers. However, undesirable multilayer regions inevitably form during the fabrication of WSe2 via the traditional chemical vapor deposition process resulted from the lack of significantly energetically favorable competition between layer accumulation and size expansion. This work innovatively introduces Cu to occupy the hexagonal site positioned at the center of the six membered ring of the WSe2 surface, thus filtrates the undesired reaction path through precisely thermodynamical control and achieves self-limited growth WSe2 crystals. The as-obtained WSe2 crystals are characterized as strictly single-layer over the entire wafer. Furthermore, the strictly self-limited growth behavior can achieve the "win-win" cooperation with the synthesis efficiency. The fastest growth (≈15 times of the growth rate in the previous work) of strictly monolayer WSe2 crystals thus far is realized due to the high-efficiency simultaneous selenization process. The as-proposed ultrafast Cu-assisted self-limited growth method opens a new avenue to fabricate strictly monolayer transition metal dichalcogenides crystals and further promotes their practical applications in the future industrial applications.

Analysis and Validation of the Prognosis ability of the M7GRelated miRNAs in Lung Adenocarcinoma.

BACKGROUND: N7-methylguanosine (m7G) modification plays a crucial role in the development and progression of lung cancers. MicroRNAs (miRNAs) are closely involved in programmed cell death and the mechanism of tumor growth. The m7G-associated miRNAs genes in lung adenocarcinoma (LUAD), and their prognosis prediction ability of LUAD, however, had not been investigated. METHODS: The RNA transcriptomes, clinical indices, and immune scores of LUAD patients were searched and downloaded from The Cancer Genome Atlas (TCGA) and the ESTIMATE database. The miRNAs targeting METTL1 and WDR4 were extracted from the TargetScan database. Differentially expressed m7G-related miRNAs were identified and their prediction power of LUAD prognosis was systematically investigated. RESULTS: Among 40 the differentially expressed m7G-related miRNAs in LUAD, five (hsa-miR-31-5p, hsa-miR-5571-3p, hsa-miR-4697-3p, hsa-miR-6858-5p, and hsa-miR-873-3p) demonstrate significant predictive value for prognosis. The risk score constructed by these five miRNAs was an independent prognostic factor (univariate Cox regression results: hazard ratio (HR) = 1.6619, 95% confidential interval (CI) = 1.2103-2.2819, p = 0.0017; multivariate Cox regression results: HR = 1.6004, 95% CI = 1.1633-2.2017, p = 0.0039). The survival curves showed that patients with high-risk scores had a poor prognosis. Calibration curves indicated good predictability in a nomogram constructed combining the miRNA and the clinical indices of age, sex, chemotherapy, radiotherapy, stage, and risk score. GO and KEGG analysis of the overlapping genes showed that the prognostic miRNAs were closely associated with the neuropeptide signaling pathway. Besides, the immune infiltration analysis showed that the expression of the AMPD1 gene was strongly associated with immune cells and immunology functions in LUAD. CONCLUSION: This study identified DE m7G-related miRNAs and demonstrated their prediction ability in the prognosis of LUAD patients. The risk signature based on these miRNAs demonstrates high accuracy in predicting the prognosis of LUAD patients.

Multi-sites synergistic modulation in oxygen reduction electrocatalysis.

Revealing the types of and interplays among multiple active-sites in iron-nitrogen-carbon (FeNC) materials is of great significance for developing high-performance, Fe-based non-precious metal catalysts for oxygen reduction reaction (ORR). In this paper, a single-atom FeNC catalyst is prepared through high-temperature pyrolyzing of melamine foam (MF), iron phthalocyanine (FePc), phthalocyanine (Pc), and zinc (Zn)-salts composite. The catalyst is found to contain a variety of active-sites, including carbon atom next to pyridinic-N (pyridinicNC), Fe-N4 and pore defect. It is shown that MF with high N-content is responsible for the formation of the main pyridinicNC sites and in the meantime acts as the self-sacrificed template for framework of the catalyst. The presence of Pc can facilitate the formation of the predominant Fe-N4 sites, since the interplay between Pc and FePc results in a confinement of Fe-N4. Zn-salts serve as the pore-forming additives to create sufficient pore defects which can also anchor pyridinicNC and Fe-N4 structures. The results of density functional theory (DFT) calculations suggest that the multiple active-sites function synergistically to enable high-efficiency ORR electrocatalysis. The optimal FeNC catalyst shows superior ORR activity with a half-wave potential of ∼0.88 V (vs. RHE), as well as high methanol tolerance and electrochemical stability compared to the commercial carbon-supported platinum (Pt/C) catalyst.

Single-Atom and Hierarchical-Pore Aerogel Confinement Strategy for Low-Platinum Fuel Cells.

Achieving high catalytic performance through the lowest possible content of platinum (Pt) is the key to cost reduction of proton-exchange-membrane fuel cells (PEMFCs). However, lowering the Pt loading in PEMFCs leads to the high mass-transport resistance of oxygen originating from the limited active sites, and causes less stability of the catalysts due to Pt size growth after long-time operation. Herein, Pt-metal/metal-N-C aerogel catalysts are designed that substantially reduce oxygen-related mass transport resistance and have long-term durability. The tailoring of the Fe-N-C aerogel support with hierarchical and interconnecting pores enable a low local oxygen transport resistance (0.18 s cm-1 ) for PEMFCs with ultralow Pt loading (50 ± 5 µgPt cm- 2 ). Chemical confinement of Fe─N sites ensures high stability of the loaded-Pt both in the processes of synthesis up to 1000 °C and practical application in PEMFCs. The ultralow Pt PEMFC displays a low voltage loss of 8 mV at 0.80 A cm- 2 and unchanged electrochemical surface area after 60 000 cycles of accelerated durability testing. The allying of the hierarchical pores, the aerogel, and the single atoms can fully reflect their structural advantages and expand the understanding for the synthesis of advanced fuel cell PEMFCs catalysts.

Two-Dimensional Ordered Double-Transition Metal Carbides for the Electrochemical Nitrogen Reduction Reaction.

The electrochemical nitrogen reduction reaction (NRR) provides a green and sustainable strategy as an alternative to the Haber-Bosch process. The development of electrocatalysts with low overpotential, high selectivity, and fast reaction kinetics remains a significant challenge. Here, density functional theory computations are carried out to systematically predict the prospect of 18 two-dimensional (2D) ordered double-transition metal carbides (MXenes) as NRR electrocatalysts. Our results revealed that the basal plane of Mo2Nb2C3 MXene exhibited the most outstanding catalytic activity while effectively suppressed the hydrogen evolution reaction with an overpotential of 0.48 V. The exposed Mo3 moiety moderately regulating the electron transfer between reaction intermediates is answerable for the high activity. Finally, our finding broadens the horizon of 2D materials as NRR electrocatalysts.

Highly efficient and selectivity removal of heavy metal ions using single-layer NaxKyMnO2 nanosheet: A combination of experimental and theoretical study.

Manganese oxides (MnO2) are widely applied in heavy metal ions removal due to their low-cost, environmental-friendly and biocompatibility. However, the adsorption capacity of MnO2 need to be further improved to satisfy the demand of practical application. Herein, a highly dispersed single layer NaxKyMnO2 nanosheet was synthesized by a facile wet-chemical method with sodium dodecyl sulfonate as surfactant. The high surface specific area, excellent dispersibility and abundant oxygen vacancies endowed NaxKyMnO2 nanosheets with potential in heavy metal ions adsorption. The adsorption experiments results showed that NaxKyMnO2 nanosheets possessed high efficiency and selectivity towards lead ion (Pb2+) with a high adsorption capacity of 2091.8 µmol g-1. The NaxKyMnO2 also showed an excellent reusability with the removal rate of 95.4% for Pb2+ even after five cycles. Moreover, both the theoretical calculation and experimental data illustrated that the single layer NaxKyMnO2 nanosheets possess high selectivity to Pb2+ adsorption.

Derivatization assisted LC-p-MRM-MS with high CID voltage for rapid analysis of brassinosteroids.

In this study, a derivatization-assisted pseudo-multiple reaction monitoring with high CID voltage (HV-p-MRM) strategy was proposed for the analysis of brassinosteroids (BRs) by liquid chromatography-triple quadrupole mass spectrometry (LC-QqQ MS). The concept of the HV-p-MRM strategy was proposed on the basis of an assumption that the precursor ion of analyte is stable in collision cell and less prone to fragmentation at high CID voltage, while co-existing ions (impurity) of easy fragmentation can break down into smaller fragment ions. In such case, by increasing the CID voltage, the co-existing ions that are introduced due to the low resolution of the quadrupole 1 (Q1) can be filtered out by quadrupole 3 (Q3), while the stable precursor ion of analyte will pass through Q3, thereby that the signal-to-noise ratio (S/N) of the analysis can be improved. As a proof-of-concept study, BRs were derivatized with rhodamine B-boronic acid (RhB-BA) and then the derivatives were used to investigate their variations in MS signal, background noise, and S/N upon the CID voltage and MS scanning resolution. The results showed that S/N of these derivatives can be improved in HV-p-MRM mode. To further demonstrate the feasibility of HV-p-MRM strategy, a RhB-BA derivatization assisted LC-HV-p-MRM-MS method was developed for the analysis of BRs. Using this method, rapid and sensitive determination of BRs in different organs of rape flower was achieved. It can be expected that HV-p-MRM may be suitable for the analytes that are stable or can be converted into compounds of high stability in collision cell at high CID voltage.

Boosting the Performance of Iron-Phthalocyanine as Cathode Electrocatalyst for Alkaline Polymer Fuel Cells Through Edge-Closed Conjugation.

Recent progress in anion-exchange membranes has evoked increasing interests in alkaline polymer fuel cells (APFCs). A large body of recent research has demonstrated attractive activity of Fe-N macrocycle complexes as electrocatalysts for the oxygen reduction reaction (ORR) in alkaline media. To be a substitute for Pt in APFCs, however, most of the macrocycle molecules remain largely unsatisfactory in both of the catalytic activity and durability. Herein, we show that a one-pot microwave conjugation results in a polymerized iron-phthalocyanine (pFePc) which exhibits extremely high ORR performance, showing activity much better than that of the FePc monomer and 20 wt % Pt/C, and similar to that of the 60 wt % Pt/C under the same catalyst loading. Furthermore, we proposed an edge-closing strategy to significantly enhance the stability of the pFePc catalyst in alkaline media by eliminating the edge anhydride groups. Using the edge-closed pFePc as the cathode catalyst in APFC, a power density as high as 452 mW·cm-2 is achieved, which is among the best performance of non-noble metal catalyst-based APFCs so far reported.

Extremely Weak van der Waals Coupling in Vertical ReS2 Nanowalls for High-Current-Density Lithium-Ion Batteries.

The synthesis of vertical ReS2 nanowalls on 3D graphene foam (V-ReS2 /3DGF) is demonstrated by a chemical vapor deposition route. The vertical nanowall structure leads to an effective exposure of active sites and enhances the lithium interaction with all of the layers. When serving as the anode material for lithium-ion batteries, the V-ReS2 /3DGF composite demonstrates excellent cycling stability at high-current-density.

JNK3 couples the neuronal stress response to inhibition of secretory trafficking.

Secretory trafficking through the Golgi complex is critical for neuronal development, function, and stress response. Altered secretion is associated with the pathogenesis of various neurological diseases. We found that c-Jun amino-terminal kinase 3 (JNK3) inhibited secretory trafficking by promoting the depletion of phosphatidylinositol 4-phosphate (PI4P) in the Golgi complex of COS7 cells and primary rat neurons. Exposure of cultured primary rat neurons to excitotoxic concentrations of NMDA (N-methyl-d-aspartate), an agonist of a class of ionotropic glutamate receptors, or overexpression of zD17 (a palmitoyl transferase) resulted in JNK3 palmitoylation and association with the Golgi complex. Analysis of mutant constructs of JNK3 indicated that Golgi association was independent of its kinase activity but depended on its palmitoylation. The association of JNK3 with the Golgi in cultured neurons decreased the secretory trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 (glutamate receptor subunit 1), a component of ionotropic glutamate receptors found at glutamatergic synapses. Palmitoylated JNK3 bound to the phosphatase Sac1, increasing its abundance at the Golgi and thereby decreasing the abundance of PI4P, a lipid necessary for post-Golgi trafficking. Disrupting the JNK3-Sac1 interaction with two synthetic peptides prevented the loss of surface GluR1 and preserved synaptic integrity in cultured neurons exposed to NMDA. Together, our results suggest that JNK3 participates in an adaptive response to neuronal hyperexcitation by impeding secretory trafficking at the Golgi complex.

[Clinical analysis of plasma cell granuloma occurred in head and neck].

OBJECTIVE: To discuss the diagnosis and treatment of plasma cell granuloma in the head and neck region. METHOD: Retrospective analysis of 3 cases of plasma cell granuloma occurred in head and neck. One case treated with endoscopic surgery and nasal and oral steroids after operation. Two cases treated with Caldwell-Luc style resection, followed by oral steroids and radiotherapy, one of the two cases combined with chemotherapy simultaneously. RESULT: The patient done with endoscopic surgery followed up for 5 years, there was no tumor recurrence in the nasal cavity and maxillary sinus openings and sinus lining. Paranasal sinus CT was examed on the patient done with partial resection and radiotherapy 2 years after operation, no residual tumor proliferation. The third patient underwent paranasal sinus CT examination 3 years after operation, and no limitation of mouth opening was found. CONCLUSION: The incidence rate of Plasma cell granuloma occured in head and neck is low. It is an inflammatory disease, but its physical signs and imaging findings are similar to malignant tumors. Because of the invasion feature, surgical resection should be the first choice, and if combined with radiotherapy and chemotherapy, the prognosis could be better.

[Mastoid surgery for secretory otitis media with mixed hearing loss].

OBJECTIVE: To analyze the therapeutic effect of mastoid surgery for secretory otitis media with mixed hearing loss. METHODS: A retrospective analysis was conducted of the data from 26 cases (43 ears) of secretory otitis media with bone conduction hearing loss collected from 2001 to 2008. Thirty-two ears were treated with mastoid surgery and myringotomy with insertion of ventilation tubes. All the patients received medications after the operation. RESULTS: All the patients showed obvious improvement after mastoid surgery. The average pure tone of air conduction hearing threshold was about 25 dB after the surgery, with the average pure tone of bone conduction hearing threshold of about 15 dB. The patients were followed up for 1-2 years during which no significant change in hearing was recorded, and no middle ear effusion in the tympanic cavity was found after removal of the ventilation tubes. CONCLUSION: Persistent secretory otitis media can be associated with mixed hearing loss, and mastoid surgery can significantly enhance the hearing level to produce positive therapeutic effects.

[The reparation of tissular defect and reconstruction of laryngeal function in subtotal laryngectomy with pedicled cutaneous and musculocutaneous flaps].

OBJECTIVE: To explore the recovery of wounded surface and reconstruction of laryngeal function after subtotal laryngectomy. METHOD: Thirty-three cases of subtotal laryngectomy were reviewed for analysis. The hyoid bone, most part of thyroid cartilage and the gap before epiglottis exsected while arytenoids cartilage of one side, 1/3 thyroid cartilage and 1/3 true vocal cord were reserved in the subtotal laryngectomy operation. And pedicled cutaneous flap of one side and pedicled musculocutaneous flap of the other side were used to rehabilitate the wounded surface and reconstruct the laryngeal function. RESULT: The function of respiration and swallowing resumed in all cases, 93.9% patients got normal pronunciation function after windpipe casing pulled out. Three-year survival rate was 89.3% and five-year survival rate was 78.6%. CONCLUSION: The results demonstrated our method has such advantages as follows: being easy to get material, having good vascular circle, laryngeal narrow seldom happened, shortening the time with windpipe casing and improving the quality of life.

[Determination of platelet activating factor in middle ear effusion of patients with secretory oitits media].

OBJECTIVE: To study the role of platelet activating factor (PAF) in the pathogenesis of secretory otitis media (SOM). METHOD: The content of PAF in blood plasma and middle ear effusion(MEE) were measured in 56(68years) patients with secretory otitis media and in 40 normal subjects respectively by RP-HPLC. RESULT: The concentration of PAF in MEE was remarkably higher than those in blood plasma (P < 0.01). The concentration of PAF in blood plasma in the SOM group was higher than those in the normal control group(P < 0.05). The concentration of PAF of MEE in the mucous fluid group was higher than those in the serous fluid group(P < 0.01). CONCLUSION: PAF might be an important mediator in MEE of SOM, it might be closely related to the persistence of SOM, and might play an important role in the pathogenesis of SOM.