Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease.

BACKGROUND: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. METHODS: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). RESULTS: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased ß-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). CONCLUSIONS: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

Selective Arylation of RNA 2'-OH Groups via SNAr Reaction with Trialkylammonium Heterocycles.

Small-molecule reactions at the 2'-OH groups of RNA enable useful applications for transcriptome technology and biology. To date, all reactions have involved carbonyl acylation and mechanistically related sulfonylation, limiting the types of modifications and properties that can be achieved. Here we report that electron-deficient heteroaryl species selectively react with 2'-OH groups of RNA in water via SNAr chemistry. In particular, trialkyl-ammonium (TAA)-activated aromatic heterocycles, prepared in one step from aryl chloride precursors, give high conversions to aryl ether adducts with RNAs in aqueous buffer in ~2-3 h. Remarkably, a TAA triazine previously used only for reaction with carboxylic acids, shows unprecedented selectivity for RNA over water, reacting rapidly with 2'-OH groups while exhibiting a half-life in water of >10 days. We further show that a triazine aryl species can be used as a probe at trace-level yields to map RNA structure in vitro. Finally, we prepare a number of functionalized trialkylammonium triazine reagents and show that they can be used to covalently label RNA efficiently for use in vitro and in living cells. This direct arylation chemistry offers a simple and distinct structural scaffold for post-synthetic RNA modification, with potential utility in multiple applications in transcriptome research.

Enhanced surfactant remediation of diesel-contaminated soil using O3 nanobubbles.

Currently, nanobubbles are widely discussed in environmental research due to their unique properties, including significant specific surface area, transfer efficiency, and free radical generation. In this study, O2 and O3 nanobubbles (diameters ranging from 0 to 500 nm) were combined with conventional surfactant technology to investigate their enhanced efficacy in removing diesel contaminants from soil. The impact of various factors such as surfactant concentration, temperature, and soil aging duration on pollutant removal rates was examined across different experimental approaches (stirring/flushing). Soil samples subjected to different treatments were characterized using TG-DTG and FTIR analysis, while GC/MS was employed to assess the degradation products of diesel constituents in the soil. The results indicated that the elution efficiencies of the three surfactants (SDS, SDBS, and TX-100) for diesel in soil correlated positively with concentration (0.3-1.4 CMC) and temperature (18-60 °C), and inversely with aging time (10-300 days), with the elution capacity was SDS > SDBS > TX-100. Mechanical stirring (500 rpm) and temperature variations (18-60 °C) did not affect the stability of the nanobubbles. Upon the introduction of O3 nanobubbles to the surfactant solution, there was a consistent increase in both the removal (degraded and removed) efficiency and rate of diesel under varying experimental conditions, resulting in an enhancement of removal rates by approximately 8-15%. FTIR spectroscopy showed that surfactants containing O3 nanobubbles mitigated the impact on the primary functional groups of soil organic matter. GC/MS analyses indicated that residual pollutants were predominantly alkanes, with degradation difficulty ranking as: alkanes < alkenes < cycloalkanes < aromatic compounds. TG-DTG coupled with GC/MS analysis demonstrated that O3 nanobubbles contributed to a reduction in surfactant residues. This study significantly advances our understanding of how nanobubbles facilitate and optimize surfactant-assisted remediation of contaminated soil, thereby advancing the precise application of nanobubble technology in soil remediation.

Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Proline Henagliflozin in Chinese Subjects with Varying Degrees of Liver Dysfunction.

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (UCr) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.

Tricarboxylic Acid Cycle Regulation of Metabolic Program, Redox System, and Epigenetic Remodeling for Bone Health and Disease.

Imbalanced osteogenic cell-mediated bone gain and osteoclastic remodeling accelerates the development of osteoporosis, which is the leading risk factor of disability in the elderly. Harmonizing the metabolic actions of bone-making cells and bone resorbing cells to the mineralized matrix network is required to maintain bone mass homeostasis. The tricarboxylic acid (TCA) cycle in mitochondria is a crucial process for cellular energy production and redox homeostasis. The canonical actions of TCA cycle enzymes and intermediates are indispensable in oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis for osteogenic differentiation and osteoclast formation. Knockout mouse models identify these enzymes' roles in bone mass and microarchitecture. In the noncanonical processes, the metabolites as a co-factor or a substrate involve epigenetic modification, including histone acetyltransferases, DNA demethylases, RNA m6A demethylases, and histone demethylases, which affect genomic stability or chromatin accessibility for cell metabolism and bone formation and resorption. The genetic manipulation of these epigenetic regulators or TCA cycle intermediate supplementation compromises age, estrogen deficiency, or inflammation-induced bone mass loss and microstructure deterioration. This review sheds light on the metabolic functions of the TCA cycle in terms of bone integrity and highlights the crosstalk of the TCA cycle and redox and epigenetic pathways in skeletal tissue metabolism and the intermediates as treatment options for delaying osteoporosis.

Ribonucleic Acid Sequencing Reveals the Upregulation and Resolution of Inflammation and Extracellular Matrix Remodeling in Lidocaine-Treated Human Acute Monocytic Leukemia Cell Line THP-1.

Lidocaine, a local anesthetic widely used in dentistry, is esteemed for its efficacy and safety. Recent research reveals its additional role in modulating the immune system, and particularly in reducing inflammation crucial for protecting tooth-supporting tissues. Notably, monocytes and macrophages, essential cellular components overseeing various physiological and pathological processes, stand as potential mediators of lidocaine's effects. Therefore, this study aimed to investigate how lidocaine influences cell behavior using RNA sequencing. To investigate the effect of lidocaine on THP-1 cells' behavior, we performed an MTT assay and RNA-Seq along with qPCR analyses to evaluate the transcriptomic and proteomic changes in THP-1 cells. Our results showed that a high dose of lidocaine (>1 mM) had a significant cytotoxic effect on THP-1 cells. However, a lidocaine dose lower than 0.5 mM induced a mixed anti-inflammatory profile by significantly upregulating tissue remodeling (GDF15, FGF7, HGF, COL4A3, COL8A2, LAMB2, LAMC2, PDGFRA, and VEGFA) and through the resolution of inflammation (Cpeb4, Socs1, Socs2, Socs3, Dusp1, Tnfaip3, and Gata3) gene cassettes. This study explores the effect of lidocaine on the THP-1 in the M2-like healing phenotype and provides potential applications of lidocaine's therapeutic effectiveness in dental tissue repair.

[Distribution Characteristics of Near Surface Ozone Volume Fraction in Shanxi Province Based on Atmospheric Composition Observation Network].

Based on the continuous data of O3， NO， NO2， and NOx and the meteorological data from March 2019 to February 2020 at six atmospheric composition observation stations in Shanxi Province， the characteristics and influence factors of O3 volume fractions were studied using statistical analysis and backward trajectory analysis. The results showed that O3 volume fractions were generally higher from April to September and lower from October to the following March. During the study period， O3 pollution represented by φ（MDA8O3）， i.e.， the maximum daily 8-h average of O3 volume fractions， was the most serious at the Jincheng and Linfen stations in the south of Shanxi， followed by that in the Wutaishan， Shuozhou， and Datong stations in the north， with the least pollution occurring at the Taiyuan station in the middle. There were differences between the urban and alpine stations， although their seasonal O3 volume fractions were both summer > spring > autumn > winter. O3 volume fractions at the urban station were usually lower than those at the alpine station； O3 at the urban station might have been influenced by photochemical reactions with precursor NOx； however， this was not the main source of high O3 at the alpine station. The peak and valley values appeared at 15：00 and 06：00， respectively， at the urban station， whereas they appeared at 20：00 and 10：00， respectively， at the alpine station， representing diametrically opposite diurnal variation patterns. Further， the daily amplitude of O3 at the urban station was much larger than that at the alpine station. For urban stations specifically， temperature was the most important meteorological factor affecting O3 volume fraction， compared with sunlight hours， precipitation， and total cloud cover. The NO2 volume fraction in the daytime affected the daily amplitude of O3； although the photochemical generation potential of O3 at the Taiyuan station was good， the O3 volume fractions were the lowest among urban stations due to strong NO titration. The higher O3 corresponded to lower NOx in which NO2 was dominant， and the higher NOx was largely composed of NO， under which conditions O3 would be depleted completely. The surface wind that affected O3 volume fractions of all stations primarily came from the southeast， south， and southwest， and specific wind speed led to the increase in O3 volume fraction. The geographical situation of the station would cause the difference in the transport of atmospheric pollutants， whereas the horizontal transmissions of high O3 from the North China Plain and Fenwei Plain were likely to be the common reason for the increase in O3 volume fraction in Shanxi.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Generation of the stable propagation Bessel beam and the axial multifoci beam with pure phase elements.

A recently proposed method is upgraded to convert two amplitude phase modulation systems (APMSs) to pure phase elements (PPEs), for generating the stable propagation Bessel beam and the axial multifoci beam, respectively. Phase functions of the PPEs are presented analytically. Numerical simulations by the complete Rayleigh-Sommerfeld method demonstrate that the converted PPE has implemented the same optical functionalities as the corresponding APMS, in either the longitudinal or the transverse direction. Compared with the traditional APMS, the converted PPE possesses many advantages such as fabrication process simplification, system complexity reduction, production cost conservation, alignment error avoidance, and experimental precision enhancement. These inherent advantages position the PPE as an ideal choice and driving force behind further advancements in optical system technology.

Miro1 improves the exogenous engraftment efficiency and therapeutic potential of mitochondria transfer using Wharton's jelly mesenchymal stem cells.

Mitochondria are important for maintaining cellular energy metabolism and regulating cellular senescence. Mitochondrial DNA (mtDNA) encodes subunits of the OXPHOS complexes which are essential for cellular respiration and energy production. Meanwhile, mtDNA variants have been associated with the pathogenesis of neurodegenerative diseases, including MELAS, for which no effective treatment has been developed. To alleviate the pathological conditions involved in mitochondrial disorders, mitochondria transfer therapy has shown promise. Wharton's jelly mesenchymal stem cells (WJMSCs) have been identified as suitable mitochondria donors for mitochondria-defective cells, wherein mitochondrial functions can be rescued. Miro1 participates in mitochondria trafficking by anchoring mitochondria to microtubules. In this study, we identified Miro1 over-expression as a factor that could help to enhance the efficiency of mitochondrial delivery. More specifically, we reveal that Miro1 over-expressed WJMSCs significantly improved intercellular communications, cell proliferation rates, and mitochondrial membrane potential, while restoring mitochondrial bioenergetics in mitochondria-defective fibroblasts. Furthermore, Miro1 over-expressed WJMSCs decreased rates of induced apoptosis and ROS production in MELAS fibroblasts; although, Miro1 over-expression did not rescue mtDNA mutation ratios nor mitochondrial biogenesis. This study presents a potentially novel therapeutic strategy for treating mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and other diseases associated with dysfunctional mitochondria, while the pathophysiological relevance of our results should be further verified by animal models and clinical studies.

Micromechanism for Copper-Deficiency Enhanced Stability: A Quasi In Situ TEM Study of Electric-Induced Structural Evolution in Cu2-x(S, Se) Liquid-Like Thermoelectric Materials.

Cu-based liquid-like thermoelectric materials have garnered tremendous attention due to their inherent ultralow lattice thermal conductivity. However, their practical application is hampered by stability issues under a large current or temperature gradient. It has been reported that introduction of copper vacancies can enhance the chemical stability, whereas the micromechanism behind this macroscopic improvement still remains unknown. Here, we have established a quasi in situ TEM method to examine and compare the structural evolution of Cu2-xS0.2Se0.8 (x = 0, 0.05) under external electric fields. It is then found that the preset Cu vacancies could favor the electric-induced formation of a more stable intermediate phase, i.e., the hexagonal CuSe-type structure in the form of either lamellar defects (majorly) or long-range order (minorly), in which ordering of S and Se also occurred. Thereby, copper and chalcogen atoms could largely be solidified into the matrix, and the elemental deposition and evaporation process is mitigated under an electric field.

Interface Ionic/Electronic Redistribution Driven by Conversion-Alloy Reaction for High-Performance Solid-State Sodium Batteries.

NASICON-type Na+ conductors show a great potential to realize high performance and safety for solid-state sodium metal batteries (SSSMBs) owing to their superior ionic conductivity, high chemical stability, and low cost. However, the interfacial incompatibility and sodium dendrite hazards still hinder its applications. Herein, a conversion-alloy reaction-induced interface ionic/electronic redistribution strategy, constructing a gradient sodiophilic and electron-blocking interphase consisting of sodium-tin (Na-Sn) alloy and sodium fluoride (NaF) between NASICON ceramic electrolyte and Na anode is proposed. The Nax Sny alloy-rich layer near the side of the sodium electrode acts as a superior conductor to enhance the anodic sodium-ion transport dynamics while the NaF-rich layer near the side of the ceramic electrolyte serves as an electron insulator to confine the interfacial electron turning ability, achieving uniform and dendrite-free Na deposition during the cycling. Profiting from the synergistic effect of the gradient interphase, the critical current density (CCD) of the assembled Na symmetric cell is significantly increased to 1.7 mA cm-2 and the cycling stability of that is as high as 1200 h at 0.5 mA cm-2 . Moreover, quasi-solid-state sodium batteries with both Na3 V2 (PO4 )3 and NaNi1/3 Fe1/3 Mn1/3 O2 cathode display outstanding electrochemical performance.

Osseointegration Potential Assessment of Bone Graft Materials Loaded with Mesenchymal Stem Cells in Peri-Implant Bone Defects.

Many studies have been exploring the use of bone graft materials (BGMs) and mesenchymal stem cells in bone defect reconstruction. However, the regeneration potential of Algipore (highly purified hydroxyapatite) and Biphasic (hydroxyapatite/beta-tricalcium phosphate) BGMs combined with bone marrow-derived mesenchymal stem cells (BMSCs) remains unclear. Therefore, we evaluated their osseointegration capacities in reconstructing peri-implant bone defects. The cellular characteristics of BMSCs and the material properties of Algipore and Biphasic were assessed in vitro. Four experimental groups-Algipore, Biphasic, Algipore+BMSCs, and Biphasic+BMSCs-were designed in a rabbit tibia peri-implant defect model. Implant stability parameters were measured. After 4 and 8 weeks of healing, all samples were evaluated using micro-CT, histological, and histomorphometric analysis. In the energy-dispersive X-ray spectroscopy experiment, the Ca/P ratio was higher for Algipore (1.67) than for Biphasic (1.44). The ISQ values continuously increased, and the PTV values gradually decreased for all groups during the healing period. Both Algipore and Biphasic BGM promoted new bone regeneration. Higher implant stability and bone volume density were observed when Algipore and Biphasic BGMs were combined with BMSCs. Biphasic BGM exhibited a faster degradation rate than Algipore BGM. Notably, after eight weeks of healing, Algipore with BSMCs showed more bone-implant contact than Biphasic alone (p < 0.05). Both Algipore and Biphasic are efficient in reconstructing peri-implant bone defects. In addition, Algipore BGM incorporation with BSMCs displayed the best performance in enhancing implant stability and osseointegration potential.

Electroencephalographic spectrogram-guided total intravenous anesthesia using dexmedetomidine and propofol prevents unnecessary anesthetic dosing during craniotomy: a propensity score-matched analysis.

BACKGROUND: The bispectral index (BIS) may be unreliable to gauge anesthetic depth when dexmedetomidine is administered. By comparison, the electroencephalogram (EEG) spectrogram enables the visualization of the brain response during anesthesia and may prevent unnecessary anesthetic consumption. METHODS: This retrospective study included 140 adult patients undergoing elective craniotomy who received total intravenous anesthesia using a combination of propofol and dexmedetomidine infusions. Patients were equally matched to the spectrogram group (maintaining the robust EEG alpha power during surgery) or the index group (maintaining the BIS score between 40 and 60 during surgery) based on the propensity score of age and surgical type. The primary outcome was the propofol dose. Secondary outcome was the postoperative neurological profile. RESULTS: Patients in the spectrogram group received significantly less propofol (1585 ± 581 vs. 2314 ± 810 mg, P < 0.001). Fewer patients in the spectrogram group exhibited delayed emergence (1.4% vs. 11.4%, P = 0.033). The postoperative delirium profile was similar between the groups (profile P = 0.227). Patients in the spectrogram group exhibited better in-hospital Barthel's index scores changes (admission state: 83.6 ± 27.6 vs. 91.6 ± 17.1; discharge state: 86.4 ± 24.3 vs. 85.1 ± 21.5; group-time interaction P = 0.008). However, the incidence of postoperative neurological complications was similar between the groups. CONCLUSIONS: EEG spectrogram-guided anesthesia prevents unnecessary anesthetic consumption during elective craniotomy. This may also prevent delayed emergence and improve postoperative Barthel index scores.

Effects of various functional monomers' reaction on the surface characteristics and bonding performance of polyetheretherketone.

PURPOSE: Polyetheretherketone (PEEK) is a new polymeric material that has received significant attention in dentistry because of its mechanical properties, biocompatibility, and aesthetics. However, the bonding performance of PEEK to other materials is not preferable. This study aimed to analyze the variations in the surface characteristics of PEEK under the chemical action of primers containing different functional monomers or polymers and to evaluate the bonding performance of PEEK and dental cement. METHODS: Disk-shaped PEEK samples were prepared by dental milling, blasting with alumina oxide, and covering with primers containing functional monomers or polymers. The surface characteristics of the samples were analyzed by microscopy and spectroscopy. The shear bond strength (SBS) between PEEK and dental cement, with and without thermocycling, was tested using a universal testing machine. Finally, the data were statistically analyzed and compared. RESULTS: Functional monomers or polymers were successfully bonded to the surface of PEEK. This treatment significantly improved its hydrophilicity and surface free energy (P < 0.05). The primer containing pentaerythritol triacrylate had the highest SBS without thermocycling (13.89 MPa). Meanwhile, the primers containing urethane dimethacrylate (UDMA) and methyl methacrylate (MMA) (abbreviated as the HC group) showed the highest SBS and lowest reduction (25.51%) after thermocycling. Notably, all the testing groups achieved the ISO10477 standard of 5 MPa. After thermocycling, adhesive failure accounted for the largest proportion of failures in all the groups except the HC group. CONCLUSIONS: The chemical priming treatment can significantly improve the SBS of PEEK and dental cement. Moreover, a primer containing both UDMA and MMA can provide improved bonding for PEEK materials.

Magnetic Prussian blue nanoshells are controllable anchored on the surface of molybdenum disulfide nanosheets for efficient separation of radioactive cesium from water.

The rapid development of nuclear energy in China has led to increased attention to the treatment of radioactive wastewaters. Herein, a novel magnetic adsorbent, magnetic Prussian blue­molybdenum disulfide (PB/Fe3O4/MoS2) nanocomposite, was prepared by a simple in-situ fixation of ferric oxide nanoparticles (Fe3O4 NPs) and Prussian Blue (PB) shell layers on the surface of molybdenum disulfide (MoS2) nanosheets carrier. The prepared PB/Fe3O4/MoS2 nanocomposites adsorbent displayed excellent fast magnetic separation and adsorption capacity of Cs+ (Qm = 80.51 mg/g) from water. The adsorption behavior of Cs+ by PB/Fe3O4/MoS2 conformed to Langmuir isothermal and second-order kinetic model, which belonged to chemical adsorption and endothermic reaction. The equilibrium adsorption capacity of PB/Fe3O4/MoS2 to Cs+ has reached 90 % in less than 110 min. Moreover, the adsorption properties of PB/Fe3O4/MoS2 remained good in the pH range of 2-7. Based on this, PB/Fe3O4/MoS2 complex was a fast and high selectivity adsorption material for Cs+, which was expected to be used in the practical treatment of cesium-containing radioactive wastewater.

Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

AIM: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. MATERIALS AND METHODS: This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. RESULTS: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. CONCLUSIONS: HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world.

BACKGROUND: Pembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease. AIM: To analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the real world. METHODS: Patients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study. Clinical staging of the patients was based on the 8th edition of the American Joint Committee on Cancer TNM staging system. The patients received different treatments based on clinical stage. In brief, patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery. For those who were not candidates for resection, radical concurrent chemoradiotherapy plus pembrolizumab was more preferable. Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab. Long-term survival outcomes such as overall survival (OS), progression-free survival, disease-free survival, long-term adverse effects (AEs), immune maintenance therapy and predictors of immune checkpoint inhibitors (ICIs) efficacy were evaluated. RESULTS: A total of 55 patients with advanced ESCC were enrolled in this retrospective, observational study. The median age was 61 years (range 44-74), with 47.3% (26/55) of the patients in stage IV and 45.5% of the patients had the tumor (25/55) located in the middle third of the esophagus. The median OS in all patients was not reached. The 12-mo OS rate among all patients was 78.8% and the 18-mo OS rate was 72.7%. 9 patients died due to tumor progression and 7 patients died due to treatment-related complications. The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome. Patients with complete response or partial response in all patients (P = 0.005) and in the chemoradiotherapy plus pembrolizumab group (P = 0.007) obtained a better prognosis than non-responders. A total of 20 patients (20/55, 36%) received immune maintenance therapy. Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-to-(leukocyte-neutrophil) ratio did not predict the efficacy of ICIs. CONCLUSION: Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC, with safe and manageable long-term AEs.

π-Sticked Metal-Organic Monolayers for Single-Metal-Site Dependent CO2 Photoreduction and Hydrogen Evolution Reaction.

Hierarchical self-assembly of 2D metal-organic layers (MOLs) for the construction of advanced functional materials have witnessed considerable interest, due to the increasing atomic utilizations and well-defined atom-property relationship. However, the construction of atomically precise MOLs with mono-/few-layered thickness through hierarchical self-assembly process remains a challenge, mostly because the elaborate long-range order is difficult to control via conventional noncovalent interaction. Herein, a quadruple π-sticked metal-organic layer (πMOL) is reported with checkerboard-like lattice in ≈1.0 nanometre thickness, on which the catalytic selectivity can be manipulated for highly efficient CO2 reduction reaction (CO2 RR) and hydrogen evolution reaction (HER) over a single metal site. In saturated CO2 aqueous acetonitrile, Fe-πMOL achieves a highly effective CO2 RR with the yield of ≈3.98 mmol g-1  h-1 and 91.7% selectivity. In contrast, the isostructural Co-πMOL as well as mixed metallic FeCo-πMOL exhibits a high activity toward HER under similar conditions. DFT calculations reveal that single metal site exhibits the significant difference in CO2 adsorption energy and activation barrier, which triggers highly selective CO2 RR for Fe site and HER for Co site, respectively. This work highlights the potential of supramolecular π… π interaction for constructing monolayer MOL materials to uniformly distribute the single metal sites for artificial photosynthesis.

Patient delay in chronic kidney disease: A qualitative study.

This study aimed to investigate the reasons for patient delay in chronic kidney disease (CKD) and provide a scientific basis for implementing effective interventions. With the adoption of the phenomenological method in qualitative research, semi-structured, face-to-face interviews were conducted with 14 cases, and the Colaizzi seven-step analysis method was used to analyze the interview data and refine the themes. A total of 4 themes were obtained, namely, a cognitive explanation of illness, negative psychological emotions, socioeconomic levels, and limited medical resources. The current status of patient delay in chronic kidney disease is serious, and there are various reasons for it. Health management departments and healthcare providers at all levels should pay attention to this situation and provide targeted supportive interventions and health education to help patients establish the correct awareness of medical consultation and effectively improve their quality of survival.