TACE plus lenvatinib and tislelizumab for intermediate-stage hepatocellular carcinoma beyond up-to-11 criteria: a multicenter cohort study.

Background: Intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) beyond the up-to-11 criteria represent a significant therapeutic challenge due to high and heterogeneous tumor burden. This study evaluated the effectiveness and safety of transarterial chemoembolization (TACE) in combination with lenvatinib and tislelizumab for these patients. Methods: In this retrospective cohort study, patients with unresectable intermediate-stage HCC beyond the up-to-11 criteria were enrolled and divided into TACE monotherapy (T), TACE combined with lenvatinib (TL), or TACE plus lenvatinib and tislelizumab (TLT) group based on the first-line treatment, respectively. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to RESIST1.1 and modified RECIST, and adverse events (AEs). Results: There were 38, 45, and 66 patients in the T, TL, and TLT groups, respectively. The TLT group exhibited significantly higher ORR and DCR than the other two groups, as assessed by either mRECIST or RECIST 1.1 (all P<0.05). Median PFS and OS were significantly longer in the TLT group compared with the T group (PFS: 8.5 vs. 4.4 months; OS: 31.5 vs. 18.5 months; all P<0.001) and TL group (PFS: 8.5 vs. 5.5 months; OS: 31.5 vs. 20.5 months; all P<0.05). The incidence of TRAEs was slightly higher in the TLT and TL groups than in the T group, while all the toxicities were tolerable. No treatment-related death occurred in all groups. Conclusions: TACE combined with lenvatinib and tislelizumab significantly improved the survival benefit compared with TACE monotherapy and TACE plus lenvatinib in patients with intermediate-stage HCC beyond the up-to-11 criteria, with an acceptable safety profile.

Deubiquitinase UCHL1 regulates estradiol synthesis by stabilizing voltage-dependent anion channel 2.

Lack of estradiol production by granulosa cells blocks follicle development, causes failure of estrous initiation, and results in an inability to ovulate. The ubiquitin-proteasome system plays a critical role in maintaining protein homeostasis and stability of the estrous cycle, but knowledge of deubiquitination enzyme function in estradiol synthesis is limited. Here, we observe that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is more significant in estrous sows and high litter-size sows than in nonestrous sows and low-yielding sows. Overexpression of UCHL1 promotes estradiol synthesis in granulosa cells, and interference with UCHL1 has the opposite effect. UCHL1 binds, deubiquitinates, and stabilizes voltage-dependent anion channel 2 (VDAC2), promoting the synthesis of the estradiol precursor pregnenolone. Cysteine 90 (C90) of UCHL1 is necessary for its deubiquitination activity, and Lys45 and Lys64 in VDAC2 are essential for its ubiquitination and degradation. In vivo, compared with WT and sh-NC-AAV groups, the estrus cycle of female mice is disturbed, estradiol level is decreased, and the number of antral follicles is decreased after the injection of sh-UCHL1-AAV into ovarian tissue. These findings suggest that UCHL1 promotes estradiol synthesis by stabilizing VDAC2 and identify UCHL1 as a candidate gene affecting reproductive performance.

Hepatic Arterial Infusion Chemotherapy Plus Lenvatinib and Tislelizumab with or Without Transhepatic Arterial Embolization for Unresectable Hepatocellular Carcinoma with Portal Vein Tumor Thrombus and High Tumor Burden: A Multicenter Retrospective Study.

Purpose: The current therapeutic strategies for high-risk, unresectable hepatocellular carcinoma (HCC) patients demonstrate suboptimal outcomes. This study aimed to assess the clinical efficacy of the combined approach of hepatic arterial infusion chemotherapy (HAIC), lenvatinib, and tislelizumab, either with or without transhepatic arterial embolization (TAE), in managing HCC patients with portal vein tumor thrombus (PVTT) and significant tumor load. Patients and Methods: In this multicenter retrospective study, we analyzed patients diagnosed with primary, unresectable HCC presenting with PVTT and substantial tumor load who had undergone treatment with HAIC, lenvatinib, and tislelizumab, with or without TAE (referred to as the THLP or HLP group), between January 2019 and February 2022 across four medical centers in China. The outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). Results: The study cohort comprised 100 patients, 50 each in the THLP and HLP groups. The THLP group demonstrated a significantly superior ORR (72% vs 52%, P=0.039). However, both groups exhibited comparable DCR (88% vs 76%, P=0.118), as assessed by the modified response evaluation criteria in solid tumors. The median OS and PFS for the entire cohort were 12.5 months (95% CI, 10.9-14.8) and 5.0 months (95% CI, 4.2-5.4), respectively. The THLP group exhibited a significantly extended OS (median, 14.1 vs 11.3 months, P=0.041) and PFS (median, 5.6 vs 4.4 months, P=0.037) in comparison to the HLP group. The most frequently reported treatment-related adverse events included abdominal pain and nausea, both reported by 59% of patients. Conclusion: The combination of HAIC, lenvatinib, tislelizumab, and TAE was feasible in HCC patients with PVTT and high tumor burden, with tolerable safety.

A monofluoride ether-based electrolyte solution for fast-charging and low-temperature non-aqueous lithium metal batteries.

The electrochemical stability window of the electrolyte solution limits the energy content of non-aqueous lithium metal batteries. In particular, although electrolytes comprising fluorinated solvents show good oxidation stability against high-voltage positive electrode active materials such as LiNi0.8Co0.1Mn0.1O2 (NCM811), the ionic conductivity is adversely affected and, thus, the battery cycling performance at high current rates and low temperatures. To address these issues, here we report the design and synthesis of a monofluoride ether as an electrolyte solvent with Li-F and Li-O tridentate coordination chemistries. The monofluoro substituent (-CH2F) in the solvent molecule, differently from the difluoro (-CHF2) and trifluoro (-CF3) counterparts, improves the electrolyte ionic conductivity without narrowing the oxidation stability. Indeed, the electrolyte solution with the monofluoride ether solvent demonstrates good compatibility with positive and negative electrodes in a wide range of temperatures (i.e., from -60 °C to +60 °C) and at high charge/discharge rates (e.g., at 17.5 mA cm-2). Using this electrolyte solution, we assemble and test a 320 mAh Li||NCM811 multi-layer pouch cell, which delivers a specific energy of 426 Wh kg-1 (based on the weight of the entire cell) and capacity retention of 80% after 200 cycles at 0.8/8 mA cm-2 charge/discharge rate and 30 °C.

Accelerated Transfer and Spillover of Carbon Monoxide through Tandem Catalysis for Kinetics-boosted Ethylene Electrosynthesis.

Cu-based catalysts have been widely applied in electroreduction of carbon dioxide (CO2 ER) to produce multicarbon (C2+ ) feedstocks (e.g., C2 H4 ). However, the high energy barriers for CO2 activation on the Cu surface is a challenge for a high catalytic efficiency and product selectivity. Herein, we developed an in situ *CO generation and spillover strategy by engineering single Ni atoms on a pyridinic N-enriched carbon support with a sodalite (SOD) topology (Ni-SOD/NC) that acted as a donor to feed adjacent Cu nanoparticles (NPs) with *CO intermediate. As a result, a high C2 H4 selectivity of 62.5 % and an industrial-level current density of 160 mA cm-2 at a low potential of -0.72 V were achieved. Our studies revealed that the isolated NiN3 active sites with adjacent pyridinic N species facilitated the *CO desorption and the massive *CO intermediate released from Ni-SOD/NC then overflowed to Cu NPs surface to enrich the *CO coverage for improving the selectivity of CO2 ER to C2 H4 .

Regulating Surface Oxygen Activity by Perovskite-Coating-Stabilized Ultrahigh-Nickel Layered Oxide Cathodes.

Ultrahigh-Ni layered oxides are proposed as promising cathodes to fulfill the range demand of electric vehicles; yet, they are still haunted by compromised cyclability and thermal robustness. State-of-the-art surface coating has been applied to solve the instability via blocking the physical contact between the electrolyte and the highly active Ni4+ ions on the cathode surface, but it falls short in handling the chemo-physical mobility of the oxidized lattice oxygen ions in the cathode. Herein, a direct regulation strategy is proposed to accommodate the highly active anionic redox within the solid phase. By leveraging the stable oxygen vacancies/interstitials in a lithium and oxygen dual-ion conductor (layered perovskite La4 NiLiO8 ) coating layer, the reactivity of the surface lattice oxygen ion is dramatically restrained. As a result, the oxygen release from the lattice is suppressed, as well as the undesired irreversible phase transition and intergranular mechanical cracking. Meanwhile, the introduced dual-ion conductor can also facilitate lithium-ion diffusion kinetics and electronic conductivity on the particle surface. This work demonstrates that accommodating the anionic redox chemistry by dual-ion conductors is an effective strategy for capacity versus stability juggling of the high-energy cathodes.

Highly stable, antiviral, antibacterial cotton textiles via molecular engineering.

Cotton textiles are ubiquitous in daily life and are also one of the primary mediums for transmitting viruses and bacteria. Conventional approaches to fabricating antiviral and antibacterial textiles generally load functional additives onto the surface of the fabric and/or their microfibres. However, such modifications are susceptible to deterioration after long-term use due to leaching of the additives. Here we show a different method to impregnate copper ions into the cellulose matrix to form a copper ion-textile (Cu-IT), in which the copper ions strongly coordinate with the oxygen-containing polar functional groups (for example, hydroxyl) of the cellulose chains. The Cu-IT displays high antiviral and antibacterial performance against tobacco mosaic virus and influenza A virus, and Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa and Bacillus subtilis bacteria due to the antimicrobial properties of copper. Furthermore, the strong coordination bonding of copper ions with the hydroxyl functionalities endows the Cu-IT with excellent air/water retainability and superior mechanical stability, which can meet daily use and resist repeated washing. This method to fabricate Cu-IT is cost-effective, ecofriendly and highly scalable, and this textile appears very promising for use in household products, public facilities and medical settings.

Effects of High-Temperature Annealing Atmosphere on the Secondary Recrystallization Behavior and Magnetic Properties of Fe-3.2%Si-0.055%Nb Grain-Oriented Silicon Steel.

High-temperature annealing is a key step for the secondary recrystallization of grain-oriented silicon steel, which has an important effect on the final sharp Goss texture. In this work, the effects of three different annealing atmospheres during high-temperature annealing (100%H2, 25%N2 + 75%H2 and 50%N2 + 50%H2) on the secondary recrystallization microstructure and texture of Fe-3.2%Si-0.055%Nb low temperature grain-oriented silicon steel were analyzed by optical microscopy (OM) and electron back-scattered diffraction (EBSD) techniques, and the magnetic properties of the samples were compared. The results show that when the high-temperature annealing atmosphere is 100%H2, the texture of the grains with secondary recrystallization is mainly <110>//ND orientation, but the grains without secondary recrystallization have a disordered orientation. When the high-temperature annealing atmosphere is 50%H2 + 50%N2, the secondary recrystallization grains present a Goss texture and brass texture. After high-temperature annealing in the 25%N2 + 75%H2 atmosphere, the sample can be fully recrystallized to obtain secondary recrystallization grains; the grain size is relatively uniform and the texture is mainly a Goss texture with a sharp edge. The content of this reaches 93.1%, the magnetic induction B800 is the highest, reaching 1.89 T, and the iron loss P1.7/50 is the lowest, reaching 1.33 W/kg.

Fibroblast growth factor 21 (FGF21) promotes porcine granulosa cell estradiol production and proliferation via PI3K/AKT/mTOR signaling.

The proliferation and steroidogenesis of mammalian ovarian granulosa cells (GCs) are related to follicular development. Previous studies found that fibroblast growth factor 21 (FGF21) regulated female fertility through the hypothalamic-pituitary-gonad axis. However, FGF21 receptors are expressed on GCs, so we speculate that it might affect female reproduction by regulating their physiological activities. Here, we showed that FGF21, fibroblast growth factor receptor-1(FGFR1), and beta-klotho (KLB) were expressed in porcine GCs. ELISA assays showed that estradiol (E2) production was increased significantly when treating GCs with recombinant FGF21 (rFGF21). In addition, rFGF21 upregulated the mRNA and protein levels of E2 synthesis-related genes including StAR, CYP11A1, and CYP19A1 in porcine GCs. Correspondingly, FGF21 siRNA inhibited E2 levels and its synthesis-related gene expression. After rFGF21 treatment, CCK8 showed increased cell viability, and flow cytometry showed that the number of S phase increased, and cycle-related genes also increased. However, treatment with FGF21 siRNA to porcine GCs suppressed the cell cycle, viability, and EdU positive cell number. Consequently, FGF21/FGFR1/KLB forms a complex to activate the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway and further promote the proliferation and E2 synthesis in porcine GCs. Collectively, these findings suggests that FGF21 regulates porcine ovarian folliculogenesis.

Oleic acid reduces steroidogenesis by changing the lipid type stored in lipid droplets of ovarian granulosa cells.

BACKGROUND: Oleic acid is an abundant free fatty acid present in livestock that are in a negative energy-balance state, and it may have detrimental effects on female reproduction and fertility. Oleic acid induces lipid accumulation in bovine granulosa cells, which leads to a foam cell-like morphology and reduced steroidogenesis. However, why oleic acid increases lipid accumulation but decreases steroidogenesis remains unclear. This study focused on oleic acid's effects on lipid type and steroidogenesis. RESULTS: Oleic acid increased the lipid accumulation in a concentration-dependent manner and mainly increased the triglyceride level and decreased the cholesterol ester level. Oleic acid also led to a decline in estradiol and progesterone production in porcine granulosa cells in vitro. In addition, oleic acid up-regulated the expression of CD36 and diacylglycerol acyltransferase 2, but down-regulated the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, scavenger receptor class B member 1 and acetyl-Coenzyme A acetyltransferase 2, as well as steroidogenesis-related genes, including cytochrome P450 family 11 subfamily A member 1, cytochrome P450 family 19 subfamily A member 1 and 3 as well as steroidogenic acute regulatory protein at the mRNA and protein levels. An oleic acid-rich diet also enhanced the triglyceride levels and reduced the cholesterol levels in ovarian tissues of female mice, which resulted in lower estradiol levels than in control-fed mice. Compared with the control, decreases in estrus days and the numbers of antral follicles and corpora lutea, as well as an increase in the numbers of the atretic follicles, were found in the oleic acid-fed female mice. CONCLUSIONS: Oleic acid changed the lipid type stored in lipid droplets of ovarian granulosa cells, and led to a decrease in steroidogenesis. These results improve our understanding of fertility decline in livestock that are in a negative energy-balance state.

Lenvatinib plus TACE with or without pembrolizumab for the treatment of initially unresectable hepatocellular carcinoma harbouring PD-L1 expression: a retrospective study.

PURPOSE: The aim of this retrospective study was to compare the clinical outcomes of pembrolizumab-lenvatinib-transarterial chemoembolization (TACE) versus lenvatinib-TACE sequential therapy in selected populations of Chinese patients with initially unresectable hepatocellular carcinoma (uHCC) harbouring programmed cell death ligand-1 (PD-L1) expression. METHODS: Consecutive patients with initial PD-L1-positive uHCC who received pembrolizumab-lenvatinib-TACE or lenvatinib-TACE sequential therapy were retrospectively identified from three medical institutions during 2016-2020. The primary endpoints included the rate of conversion therapy, defined as converting initially uHCC to hepatectomy, overall survival (OS), and progression-free survival (PFS); secondary endpoint was the frequency of key adverse events (AEs). RESULTS: In total, 220 consecutively recruited patients were retrospectively reviewed, 78 of whom were ineligible according to the current criteria, leaving 142 patients [pembrolizumab-lenvatinib-TACE: n = 70, median age 58 years (range 36-69) and lenvatinib-TACE: n = 72, 57 years (35-68)] who were eligible for the study. The median duration of follow-up was 27 months [95% confidence interval (CI), 26.3-28.7 months]. At the last follow-up, the rate of conversion therapy was 25.7% in the pembrolizumab-lenvatinib-TACE group and 11.1% in the lenvatinib-TACE group (p = 0.025). The median OS was 18.1 months (95% CI 16.5-20.7) in the pembrolizumab-lenvatinib-TACE group versus 14.1 months (95% CI 12.2-16.9) in the lenvatinib-TACE group [hazard ratio (HR) 0.56, 95% CI 0.38-0.83; p = 0.004]. A distinct difference in the median PFS interval between the groups was detected [9.2 months (95% CI 7.1-10.4) in the pembrolizumab-lenvatinib-TACE group vs. 5.5 months (95% CI 3.9-6.6) in the lenvatinib-TACE group (HR 0.60; 95% CI 0.39-0.91; p = 0.006)]. The rates of the key AEs assessed, which were hypertension, nausea, and rash, were higher in the pembrolizumab-lenvatinib-TACE group than in the lenvatinib-TACE group (all p < 0.05). CONCLUSION: Among the selected populations of patients with initial PD-L1-positive uHCC, pembrolizumab-lenvatinib-TACE sequential therapy may have promising antitumour activity, with an acceptable conversion rate and a well-characterized safety profile.

NR1D1 targeting CYP19A1 inhibits estrogen synthesis in ovarian granulosa cells.

The circadian system performs an important role in mammalian reproduction with significant effects on hormone secretion. Nuclear receptor subfamily 1 group D member 1 (NR1D1) functions as a transcriptional repressor in the circadian system and affects granulosa cells (GCs), but how it regulates estrogen synthesis has not been clarified. We investigated the effect of NR1D1 on estrogen synthesis and found that NR1D1 was highly expressed in GCs, mainly in cell nuclei. Additionally, the expression of NR1D1 and estrogen synthesis key genes CYP19A1, CYP11A1 and StAR showed rhythmic changes in porcine ovarian GCs. Activation of NR1D1 enhances its ability to inhibit the transcriptional activity of CYP19A1 by binding to the RORE on the CYP19A1 promoter, resulting in a decrease in estradiol content. Interference with NR1D1 can eliminate the transcriptional inhibition of CYP19A1 and promote the synthesis of estradiol. The results suggest that the hormone secretion of the ovary itself is also regulated by the biological clock, and any factors that affect the circadian rhythm can affect the endocrine and reproductive performance of sows, so the natural rhythm of sows should be maintained in production.

Platelet-to-lymphocyte ratio and C-reactive protein as markers for colorectal polyp histological type.

BACKGROUND: The platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) level are markers that have been reported to predict the histological type of various tumors, and here, we evaluated their utility in predicting colorectal polyp histological types. METHODS: We retrospectively reviewed 172 patients with colorectal polyps who underwent endoscopic polypectomy. The associations between histological type and clinicopathologic parameters were assessed by multivariate analysis. RESULTS: The optimal PLR and CRP cut-off values were 113.32 and 0.39, respectively. The PLR (P = 0.002) and CRP (P = 0.009) values were associated with the histological type according to the univariate analysis, whereas low PLR (P ≤ 0.001) and CRP (P = 0.017) values were independent risk factors in the multivariate analysis together with maximum tumor diameter (P ≤ 0.001) and tumor number (P = 0.0014). CONCLUSIONS: Preoperative PLR and CRP are correlated with the colorectal polyp histological type.

Alloying Nickel with Molybdenum Significantly Accelerates Alkaline Hydrogen Electrocatalysis.

Bifunctional hydrogen electrocatalysis (hydrogen-oxidation and hydrogen-evolution reactions) in alkaline solution is desirable but challenging. Among all available electrocatalysts, Ni-based materials are the only non-precious-metal-based candidates for alkaline hydrogen oxidation, but they generally suffer from low activity. Here, we demonstrate that properly alloying Ni with Mo could significantly promote its electrocatalytic performance. Ni4 Mo alloy nanoparticles are prepared from the reduction of molybdate-intercalated Ni(OH)2 nanosheets. The final product exhibits an apparent hydrogen-oxidation activity exceeding that of the Pt benchmark and a record-high mass-specific kinetic current of 79 A g-1 at an overpotential of 50 mV. A superior hydrogen-evolution performance is also measured in alkaline solution. These experimental data are rationalized by our theoretical simulations, which show that alloying Ni with Mo significantly weakens its hydrogen adsorption, improves the hydroxyl adsorption and decreases the reaction barrier for water formation.

Boosted Oxygen Evolution Reactivity via Atomic Iron Doping in Cobalt Carbonate Hydroxide Hydrate.

Cobalt carbonate hydroxide hydrate (CCHH) has long been functioning merely as a precursor to prepare compound catalysts; however, its intrinsic potential for the oxygen evolution reaction (OER) is quite limited due to its poor catalytic activity. Herein, a concept has been proposed to solve this issue by doping Fe into CCHH nanowires grown on nickel foam (denoted as Fe-CCHH/NF) for achieving efficient OER catalysis by electrochemical transformation. The obtained Fe-CCHH/NF-30 exhibits OER catalytic performance with an overpotential of only 200 mV versus the reversible hydrogen electrode (vs. RHE) at a current density of 10 mA cm-2 and small Tafel slope of 50 mV dec-1 in 1 M KOH. Moreover, it displays stability for over 130 h at a large current density of 55 mA cm-2, and no activity decline is observed after the 3000 cycle test. The performance of Fe-CCHH/NF-30 renders it one of the most promising OER catalysts. The density functional theory calculation reveals that the doped Fe can greatly enhance the OER activity by lowering the reactive energy barrier.

Albumin-to-Alkaline Phosphatase Ratio Associates with Good Prognosis of Hepatitis B Virus-Positive HCC Patients.

PURPOSE: The aim of this study was to investigate the prognostic significance of preoperative AAPR in hepatitis B virus-related hepatocellular carcinoma patients after curative hepatectomy. PATIENTS AND METHODS: A total of 221 patients with hepatitis B virus-related HCC patients who received curative liver resection were included. After propensity matching analysis, 188 patients were enrolled in the final analysis. COX regression analyses were used to analyze the prognosis value of AAPR and other prognostic factors. The overall survival (OS) and recurrence-free survival (RFS) curves were constructed and compared between different groups. RESULTS: The optimal cutoff of AAPR was defined as 0.40 with X-tile software. According to cutoff value, patients were divided into low-AAPR group (≤0.40) and high-AAPR group (>0.40). The cumulative 1-, 3-, and 5-year OS rates were 97.1%, 78.2%, and 67.3% in patients with AAPR>0.40 group, respectively, which were significantly higher than those in the AAPR≤0.40 group (80.2%, 54.4%, and 40.1%, respectively) (P <0.001). In the multivariate COX regression analysis, AAPR, tumor number, ascites, and portal vein tumor thrombus (PVTT) were independent risk factors for OS and RFS. CONCLUSION: AAPR shows promise as a reliable prognostic factor in patients with hepatitis B virus-related HCC after curative hepatectomy, which could be used as a routine inspection of HCC patients before surgery.

Broadband Tunable Mid-infrared Plasmon Resonances in Cadmium Oxide Nanocrystals Induced by Size-Dependent Nonstoichiometry.

A central theme of nanocrystal (NC) research involves synthesis of dimension-controlled NCs and studyof size-dependent scaling laws governing their optical, electrical, magnetic, and thermodynamic properties. Here, we describe the synthesis of monodisperse CdO NCs that exhibit high quality-factor (up to 5.5) mid-infrared (MIR) localized surface plasmon resonances (LSPR) and elucidate the inverse scaling relationship between carrier concentration and NC size. The LSPR wavelength is readily tunable between 2.4 and ∼6.0 µm by controlling the size of CdO NCs. Structural and spectroscopic characterization provide strong evidence that free electrons primarily originate from self-doping due to NC surface-induced nonstoichiometry. The ability to probe and to control NC stoichiometry and intrinsic defects will pave the way toward predictive synthesis of doped NCs with desirable LSPR characteristics.

Understanding the Structural Evolution and Lattice Water Movement for Rhombohedral Nickel Hexacyanoferrate upon Sodium Migration.

Prussian blue analogues (PBAs) have been regarded as prospective cathode materials for sodium-ion batteries due to tunable chemical composition and structure. Herein, a high-performance rhombohedral nickel hexacyanoferrate is synthesized via a controllable low-temperature reaction process. It can deliver impressive capacity retention of 87.8% after 10 000 cycles at 10C and high rate discharge capacity of 53 mAh g-1 at 40C. According to the structural evolution and lattice water movement, superior electrochemical performance is ascribed to small lattice alteration and high reversibility of rhombohedral-cubic transition upon Na+ insertion/extraction. The environment information of local- and long-range structure evolution is revealed by ex situ X-ray absorption spectroscopy (XAS) and in situ X-ray diffraction (XRD). Importantly, lattice water movement during cycling by Fourier transform infrared (FTIR) measurements offers an experimental validation about Na+ nonlinear migration path, as well as the accumulative lattice distortion effect from large-size Na(OH2)+ unit. The revealed mechanism points out the modified path for PBAs.

Primary tumor-secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway.

Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor-bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO-1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO-1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF-induced hyperpermeability. Further investigations revealed that VEGF-induced occludin phosphorylation at Ser-490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin-proteasome system. In conclusion, primary tumor-secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF-induced vascular hyperpermeability in the lung premetastatic niche.