Nanoarchitectonics of in Situ Antibiotic-Releasing Acicular Nanozymes for Targeting and Inducing Cuproptosis-like Death to Eliminate Drug-Resistant Bacteria.

A series of progress has been made in the field of antimicrobial use of nanozymes due to their superior stability and decreased susceptibility to drug resistance. However, catalytically generated reactive oxygen species (ROS) are insufficient for coping with multidrug-resistant organisms (MDROs) in complex wound environments due to their low targeting ability and insufficient catalytic activity. To address this problem, chemically stable copper-gallic acid-vancomycin (CuGA-VAN) nanoneedles were successfully constructed by a simple approach for targeting bacteria; these nanoneedles exhibit OXD-like and GSH-px-like dual enzyme activities to produce ROS and induce bacterial cuproptosis-like death, thereby eliminating MDRO infections. The results of in vitro experiments showed that the free carboxylic acid of GA could react with the free ammonia of teichoic acid in the methicillin-resistant Staphylococcus aureus (MRSA) cell wall skeleton. Thus, CuGA-VAN nanoneedles can rapidly "capture" MRSA in liquid environments, releasing ROS, VAN and Cu2+ on bacterial surfaces to break down the MRSA barrier, destroying the biofilm. In addition, CuGA-VAN effectively promoted wound repair cell proliferation and angiogenesis to facilitate wound healing while ensuring biosafety. According to transcriptome sequencing, highly internalized Cu2+ causes copper overload toxicity; downregulates genes related to the bacterial glyoxylate cycle, tricarboxylic acid cycle, and oxidative respiratory chain; and induces lipid peroxidation in the cytoplasm, leading to bacterial cuproptosis-like death. In this study, CuGA-VAN was cleverly designed to trigger a cascade reaction of targeting, drug release, ROS-catalyzed antibacterial activity and cuproptosis-like death. This provides an innovative idea for multidrug-resistant infections.

Chinese Health Insurance in the Digital Era: Bibliometric Study.

BACKGROUND: China has entered the era of digital health care after years of reforms in the health care system. The use of digital technologies in healthcare services is rapidly increasing, indicating the onset of a new period. The reform of health insurance has also entered a new phase. OBJECTIVE: This study aims to investigate the evolution of health care insurance within the context of telemedicine and Internet Plus Healthcare (IPHC) during the digital health care era by using scientometric methods to analyze publication patterns, influential keywords, and research hot spots. It seeks to understand how health care insurance has adapted to the growing integration of IPHC and telemedicine in health care services and the implications for policy and practice. METHODS: A total of 411 high-quality studies were curated from the China National Knowledge Infrastructure (CNKI) database in the Chinese language, scientometric analysis was conducted, and VOSviewer software was used to conduct a visualized analysis of keywords and hot spots in the literature. RESULTS: The number of articles in this field has increased notably from 2000 to 2022 and has increased annually based on a curve of y=0.332exp (0.4002x) with R2=0.6788. In total, 62 institutions and 811 authors have published research articles in the Chinese language in this field. This study included 290 keywords and formulated a total of 5 hot-topic clusters of "telemedicine," "IPHC," "internet hospital," "health insurance payments," and "health insurance system." CONCLUSIONS: Studies on the application of digital technologies in health care insurance has evolved from foundational studies to a broader scope. The emergence of internet hospitals has showcased the potential for integrating IPHC services into insurance payment systems. However, this development also highlights the necessity for enhanced interregional coordination mechanisms. The reform of health insurance payment is contingent upon ongoing advancements in digital technology and increased investment in electronic medical records and primary health care services. Future efforts should focus on integrating technology with administrative systems, advancing mobile health care solutions, and ensuring interoperability among various payment systems to improve efficiency and standardize health care services.

Nitrogen-Doped Carbon Quantum Dots with Photoactivation Properties for Ultraviolet Ray Detection.

Photoactivation is a phenomenon that could enhance the photoluminescence (PL) and photostability upon UV/vis light exposure, which is usually observed in CdSe/ZnS quantum dots (QDs). However, the photoactivation phenomenon has been scarcely reported in fluorescent carbon quantum dots (CQDs). Herein, the nitrogen-doped carbon quantum dots (N-CQDs) were prepared through a facile solvothermal approach with naphthalenetracarboxylic dianhydride and serine as precursors. Upon simple UV light irradiation for 10 min, the fluorescence quantum yield (QY) of N-CQDs could increase up to 10-fold. Based on this phenomenon, the N-CQDs were explored as an ultraviolet (UV) light sensor to assess the intensity of ultraviolet radiation in sunlight and indirectly evaluate the UV-blocking efficiency of various sunscreen products. Thus, this contribution not only provided an insight into developing a low-cost UV detector but also opened a door for the development of carbon quantum dots with converse-photobleaching properties.

Stimuli-responsive AIEgens with an ultra acidochromic scope for self-reporting soft actuators.

This study develops a series of NBI-based acidochromic AIEgens engineered for ultra-wide acidochromic scope in self-reporting soft actuators, establishing the relationship between the photophysical properties and structural configurations of the AIEgens, further investigating their acidochromic behavior and fabricating acidity monitoring chips. The acidochromic behaviors were thoroughly investigated, and high-precision acidity monitoring chips were fabricated. We confirmed the protonation order of nitrogen atoms within the molecules and elucidated the acidochromic mechanisms through DFT and 1H NMR analyses. Utilizing these findings, we designed acid-driven hydrogel-based biomimetic actuators that can self-report and control the release of heavy loads under acidic conditions. These actuators hold significant potential for applications in targeted drug delivery within acidic biological environments, controlled release systems, and specialized transportation of heavy loads under acidic conditions.

Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein-Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy.

Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10, the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression (Kd = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 µg/mL) compared to S1g-10. It maintains comparable apoptosis induction capability with S1g-10 against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, 1H-15N TRSOY-NMR, and molecular docking, we revealed that Lys319 is a "hot spot" in the Hsp70-Bim PPI interface. Collectively, these results provide a novel chemical scaffold and structural insights for the rational design of Hsp70-Bim PPI inhibitors.

Application of metal-organic frameworks in infectious wound healing.

Metal-organic frameworks (MOFs) are metal-organic skeleton compounds composed of self-assembled metal ions or clusters and organic ligands. MOF materials often have porous structures, high specific surface areas, uniform and adjustable pores, high surface activity and easy modification and have a wide range of prospects for application. MOFs have been widely used. In recent years, with the continuous expansion of MOF materials, they have also achieved remarkable results in the field of antimicrobial agents. In this review, the structural composition and synthetic modification of MOF materials are introduced in detail, and the antimicrobial mechanisms and applications of these materials in the healing of infected wounds are described. Moreover, the opportunities and challenges encountered in the development of MOF materials are presented, and we expect that additional MOF materials with high biosafety and efficient antimicrobial capacity will be developed in the future.

Monodisperse Manganese-Vanadium-Oxo Clusters with Extraordinary Lithium Storage.

Although possessing well-defined nanostructures and excellent multi-electron redox properties, polyoxometalate clusters have poor intrinsic electrical conductivity and are prone to aggregation due to large surface energy, which makes them difficult to be fully utilized when applying as electrode materials for lithium-ion batteries. In this paper, monodisperse K7MnV13O38 (MnV13) clusters are achieved by rationally utilizing nano-sized high conductive carbon dots (CDs) as stabilizers. Benefiting from the fully exposed redox sites of MnV13 clusters (high utilization rate) and sufficient interfaces with carbon dots (extra interfacial energy storage), the optimized MnV13/10CDs anode delivers a high discharge capacity up to 1348 mAh g-1 at a current density of 0.1 A g-1 and exhibits superb rate/cycling capabilities. Density functional theory (DFT) calculations verify that ionic archway channels are formed between MnV13 and CDs, eliminating the bandgap and greatly improving the electron/ion conductivity of MnV13 and CDs. This paper paves a brand-new way for synthesis of monodisperse clusters and maximization of extra interfacial energy storage.

B, N co-doped carbon dots as efficient nanozymes for colorimetric and fluorometric dual-mode detection of cholesterol.

In this work, the B, N co-doped carbon dots (B, N-CDs) were synthesized via facile hydrothermal approach with 6-aminopyridine boronic acid as precursor. In addition to emitting intense blue luminescence when exposed to ultraviolet light, the prepared B, N-CDs displayed remarkable peroxidase-like activity, which could efficiently catalyze the oxidation of 3, 3', 5, 5' -tetramethylbenzidine (TMB) to blue ox-TMB in the presence of hydrogen peroxide (H2O2). Furthermore, the fluorescence intensity of B, N-CDs increased gradually upon the addition of H2O2. Since cholesterol oxidase (ChOx) can catalyze the oxidation of cholesterol to form H2O2, the as-prepared B, N-CDs was then used as both colorimetric and fluorometric sensors for the detection of cholesterol with detection limit of 0.87 and 2.31 µM, respectively. Finally, the dual-mode approach based on B, N-CDs was effectively utilized for detecting cholesterol levels in serum samples, proving the potential application of B, N-CDs in the field of biological assay.

Microarray Chip-Based High-Throughput Screening of Neurofilament Light Chain Self-Assembling Peptide for Noninvasive Monitoring of Alzheimer's Disease.

Alzheimer's disease (AD) starts decades before cognitive symptoms develop. Easily accessible and cost-effective biomarkers that accurately reflect AD pathology are essential for both monitoring and therapeutics of AD. Neurofilament light chain (NfL) levels in blood and cerebrospinal fluid are increased in AD more than a decade before the expected onset, thus providing one of the most promising blood biomarkers for monitoring of AD. The clinical practice of employing single-molecule array (Simoa) technology for routine use in patient care is limited by the high costs. Herein, we developed a microarray chip-based high-throughput screening method and screened an attractive self-assembling peptide targeting NfL. Through directly "imprinting" and further analyzing the sequences, morphology, and affinity of the identified self-assembling peptides, the Pep-NfL peptide nanosheet with high binding affinity toward NfL (KD = 1.39 × 10-9 mol/L), high specificity, and low cost was characterized. The superior binding ability of Pep-NfL was confirmed in AD mouse models and cell lines. In the clinical setting, the Pep-NfL peptide nanosheets hold great potential for discriminating between patients with AD (P < 0.001, n = 37), mild cognitive impairment (P < 0.05, n = 26), and control groups (n = 30). This work provides a high-throughput, high-sensitivity, and economical system for noninvasive tracking of AD to monitor neurodegeneration at different stages of disease. The obtained Pep-NfL peptide nanosheet may be useful for assessing dynamic changes in plasma NfL concentrations to evaluate disease-modifying therapies as a surrogate end point of neurodegeneration in clinical trials.

A Proactive Intervention Study in Metabolic Syndrome High-Risk Populations Using Phenome-Based Actionable P4 Medicine Strategy.

The integration of predictive, preventive, personalized, and participatory (P4) healthcare advocates proactive intervention, including dietary supplements and lifestyle interventions for chronic disease. Personal profiles include deep phenotypic data and genetic information, which are associated with chronic diseases, can guide proactive intervention. However, little is known about how to design an appropriate intervention mode to precisely intervene with personalized phenome-based data. Here, we report the results of a 3-month study on 350 individuals with metabolic syndrome high-risk that we named the Pioneer 350 Wellness project (P350). We examined: (1) longitudinal (two times) phenotypes covering blood lipids, blood glucose, homocysteine (HCY), and vitamin D3 (VD3), and (2) polymorphism of genes related to folic acid metabolism. Based on personalized data and questionnaires including demographics, diet and exercise habits information, coaches identified 'actionable possibilities', which combined exercise, diet, and dietary supplements. After a 3-month proactive intervention, two-thirds of the phenotypic markers were significantly improved in the P350 cohort. Specifically, we found that dietary supplements and lifestyle interventions have different effects on phenotypic improvement. For example, dietary supplements can result in a rapid recovery of abnormal HCY and VD3 levels, while lifestyle interventions are more suitable for those with high body mass index (BMI), but almost do not help the recovery of HCY. Furthermore, although people who implemented only one of the exercise or diet interventions also benefited, the effect was not as good as the combined exercise and diet interventions. In a subgroup of 226 people, we examined the association between the polymorphism of genes related to folic acid metabolism and the benefits of folate supplementation to restore a normal HCY level. We found people with folic acid metabolism deficiency genes are more likely to benefit from folate supplementation to restore a normal HCY level. Overall, these results suggest: (1) phenome-based data can guide the formulation of more precise and comprehensive interventions, and (2) genetic polymorphism impacts clinical responses to interventions. Notably, we provide a proactive intervention example that is operable in daily life, allowing people with different phenome-based data to design the appropriate intervention protocol including dietary supplements and lifestyle interventions. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00115-z.

Morphological variation and expressed sequence tags-simple sequence repeats-based genetic diversity of Aspergillus cristatus in Chinese dark tea.

Introduction: Aspergillus cristatus is a homothallic fungus that is used in the natural fermentation process of Chinese Fuzhuan tea and has been linked to the production of bioactive components. However, not much is known about the variations present in the fungus. To understand the variation of the dominant microorganism, A. cristatus, within dark tea, the present study investigated the genetic and morphological diversity of 70 A. cristatus collected across six provinces of China. Methods: Expressed sequence tags-simple sequence repeats (EST-SSR) loci for A. cristatus were identified and corresponding primers were developed. Subsequently, 15 specimens were selected for PCR amplification. Results: The phylogenetic tree obtained revealed four distinct clusters with a genetic similarity coefficient of 0.983, corresponding to previously identified morphological groups. Five strains (A1, A11, B1, D1, and JH1805) with considerable differences in EST-SSR results were selected for further physiological variation investigation. Microstructural examinations revealed no apparent differentiation among the representative strains. However, colony morphology under a range of culture media varied substantially between strains, as did the extracellular enzymatic activity (cellulase, pectinase, protease, and polyphenol oxidase); the data indicate that there are differences in physiological metabolic capacity among A. cristatus strains. Discussion: Notably, JH1805, B1, and A11 exhibited higher enzymatic activity, indicating their potential application in the production of genetically improved strains. The findings provide valuable insights into species identification, genetic diversity determination, and marker-assisted breeding strategies for A. cristatus.

Dual targeting negative enrichment strategy for highly sensitive and purity detection of CTCs.

Circulating tumor cells (CTCs) have significant clinical value in early tumor detection, dynamic monitoring and immunotherapy. CTC detection stands out as a leading non-invasive approach for tumor diagnostics and therapeutics. However, the high heterogeneity of CTCs and the occurrence of epithelial-mesenchymal transition (EMT) during metastasis pose challenges to methods relying on EpCAM-positive enrichment. To address these limitations, a method based on negative enrichment of CTCs using specific leukocyte targets has been developed. In this study, aiming to overcome the low purity associated with immunomagnetic beads targeting solely the leukocyte common antigen CD45, we introduced CD66b-modified immunomagnetic beads. CD66b, a specific target for neutrophils with abundant residues, was chosen as a complementary approach. The process involved initial collection of nucleated cells from whole blood samples using density gradient centrifugation. Subsequently, magnetically labeled leukocytes were removed by magnetic field, enabling the capture of CTCs with higher sensitivity and purity while retaining their activity. Finally, we selected 20 clinical blood samples from patients with various cancers to validate the effectiveness of this strategy, providing a new generalized tool for the clinical detection of CTCs.

Nanozyme-Incorporated Microneedles for the Treatment of Chronic Wounds.

Acute wounds are converted to chronic wounds due to advanced age and diabetic complications. Nanozymes catalyze ROS production to kill bacteria without causing drug resistance, while microneedles (MNs) can break through the skin barrier to deliver drugs effectively. Nanozymes can be intergrateded into MNs delivery systems to improve painless drug delivery. It can also reduce the effective dose of drug sterilization while increasing delivery efficiency and effectively killing wounded bacteria while preventing drug resistance. This paper describes various types of metal nanozymes from previous studies and compares their mutual enhancement with nanozymes. The pooled results show that the MNs, through material innovation, are able to both penetrate the scab and deliver nanozymes and exert additional anti-inflammatory and bactericidal effects. The catalytic effect of some of the nanozymes can also accelerate the lysis of the MNs or create a cascade reaction against inflammation and infection. However, the issue of increased toxicity associated with skin penetration and clinical translation remains a challenge. This study reviews the latest published results and corresponding challenges associated with the use of MNs combined with nanozymes for the treatment of wounds, providing further information for future research.

Benzoselenadiazole-Functionalized H-Bonded Arylamide Foldamers: Solvent-Responsive Properties and Helix Self-Assembly Directed by Chalcogen Bonding in Solid State.

In this study, a series of H-bonded arylamide foldamers bearing benzoselenadiazole ends with solvent-responsive properties have been synthesized. In dichloromethane or dimethyl sulfoxide solvents, the molecules exhibit meniscus or linear structures, respectively, which can be attributed to the unique intramolecular hydrogen bonding behavior evidenced by 1D 1H NMR and 2D NOESY spectra. UV-vis spectroscopy experiments show that the absorption wavelength of H-bonded arylamide foldamers are significantly red-shifted due to the presence of benzoselenadiazole group. In addition, the crystal structures reveal that effective intermolecular dual Se ⋅ ⋅ ⋅ N interactions between benzoselenadiazole groups induce further assembly of the monomers. Remarkably, supramolecular linear and double helices structures are constructed under the synergistic induction of intramolecular hydrogen bonding and intermolecular chalcogen bonding. Additionally, 2D DOSY diffusion spectra and theoretical modelling based on density functional theory (DFT) are performed to explore the persistence of intermolecular Se ⋅ ⋅ ⋅ N interactions beyond the crystalline state.

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer's Disease.

The association between dysfunctional microglia and amyloid-ß (Aß) is a fundamental pathological event and increases the speed of Alzheimer's disease (AD). Additionally, the pathogenesis of AD is intricate and a single drug may not be enough to achieve a satisfactory therapeutic outcome. Herein, we reported a facile and effective gene therapy strategy for the modulation of microglia function and intervention of Aß anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). The biomimetic nanovesicles codelivery ß-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) and TREM2 plasmid (pTREM2) gene drug efficiently penetrate the blood-brain barrier and enhance the drug accumulation at AD lesions with the help of exosomes homing ability and angiopep-2 peptides. Specifically, an upregulation of TREM2 expression can reprogram microglia from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype while also restoring its capacity to phagocytose Aß and its nerve repair function. In addition, siRNA reduces the production of Aß plaques at the source by knocking out the BACE1 gene, which is expected to further enhance the therapeutic effect of AD. The in vivo study suggests that TSEL through the synergistic effect of two gene drugs can ameliorate APP/PS1 mice cognitive impairment by regulating the activated microglial phenotype, reducing the accumulation of Aß, and preventing the retriggering of neuroinflammation. This strategy employs biomimetic nanovesicles for the delivery of dual nucleic acids, achieving synergistic gene therapy for AD, thus offering more options for the treatment of AD.

Yeast Bxi1/Ybh3 mediates conserved mitophagy and apoptosis in yeast and mammalian cells: convergence in Bcl-2 family.

The process of degrading unwanted or damaged mitochondria by autophagy, called mitophagy, is essential for mitochondrial quality control together with mitochondrial apoptosis. In mammalian cells, pan-Bcl-2 family members including conical Bcl-2 members and non-conical ones are involved in and govern the two processes. We have illustrated recently the BH3 receptor Hsp70 interacts with Bim to mediate both apoptosis and mitophagy. However, whether similar pathways exist in lower eukaryotes where conical Bcl-2 members are absent remained unclear. Here, a specific inhibitor of the Hsp70-Bim PPI, S1g-10 and its analogs were used as chemical tools to explore the role of yeast Bxi1/Ybh3 in regulating mitophagy and apoptosis. Using Om45-GFP processing assay, we illustrated that yeast Ybh3 mediates a ubiquitin-related mitophagy pathway in both yeast and mammalian cells through association with Hsp70, which is in the same manner with Bim. Moreover, by using Bax/Bak double knockout MEF cells, Ybh3 was identified to induce apoptosis through forming oligomerization to trigger mitochondrial outer membrane permeabilization (MOMP) like Bax. We not only illustrated a conserved ubiquitin-related mitophagy pathway in yeast but also revealed the multi-function of Ybh3 which combines the function of BH3-only protein and multi-domain Bax protein as one.

Role of Altitude in Influencing the Spray Combustion Characteristics of a Heavy-Duty Diesel Engine in a Constant Volume Combustion Chamber. Part II: Impinging Diesel Jet.

Wall impingement, particularly liquid-wall impingement, has been demonstrated to be one of the critical causes of combustion deterioration in plateau diesel engines. Obviously, the complexity of wall impingement is exacerbated by the plateau scenario. However, fundamental studies specifically dedicated to this phenomenon are still inconclusive and insufficiently detailed, obviating the feasibility of the targeted design and optimization of diesel engines operating in regions with different altitudes. Consequently, the second part of this investigation, presented in this work, focused on the detailed physical and chemical processes of impinging spray combustion under different altitude conditions. A wall impingement system was designed to generate an impinging spray flame. The impingement distance was varied from 77 to 37 mm to cover different situations of wall impingement. The liquid spray, ignition, and combustion processes were visualized in detail by using different optical diagnostics. The results showed that the variation of the liquid length with the impingement distance was mainly dependent on the liquid impingement under the same altitude condition. The effect of the impingement distance on the ignition distance was more sensitive to the altitude. The quantitative analysis of the flame natural luminosity confirmed the decisive effect of the impinging flame morphology on the ambient entrainment and fuel-air mixing under different altitude conditions, and it also revealed that there was an optimal impingement distance under identical altitude conditions to achieve minimum soot emissions. And interestingly, the optimal impingement distance increased with altitude. Finally, the spray combustion processes of an impinging diesel jet were determined to occur in four typical regions, upon which a schematic diagram depicting the flame structure of an impinging diesel jet was proposed to phenomenologically describe the role of altitude in impinging spray combustion processes. Based on this, an attempt was made to explore some new perspectives beyond the popular solutions to recover and improve the performance of plateau diesel engines.

Small molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance.

INTRODUCTION: Estrogen receptor (ER) positive patients compromise about 70% of breast cancers. Tamoxifen, an antagonist of ERα66 (the classic ER), is the most effective and the standard first-line drug. However, its efficacy is limited by the development of acquired resistance. METHODS: A specific inhibitor of Hsp70-Bim protein-protein interaction (PPI), S1g-2, together with an inhibitor of Hsp70-Bag3 PPI, MKT-077 and an ATP-competitive inhibitor VER155008, were used as chemical tools. Cell viability assays, co-immunoprecipitation and gene knockdown were used to investigate the role of Hsp70 in tamoxifen resistance. A xenograft model was established in which tamoxifen-resistant breast cancer (MCF-7/TAM-R) cells maintained in the presence of 5 µM tamoxifen were subcutaneously inoculated. The anti-tumor efficiency of S1g-2 was measured after a daily injection of 0.8 mg/kg for 14 days. RESULTS: It was revealed that Hsp70-Bim PPI protects ERα-positive breast cancer from tamoxifen-induced apoptosis through binding and stabilizing ERα36, rather than ERα66, resulting in sustained EGFR mRNA and protein expression. Disruption of Hsp70-Bim PPI and downregulation of ERα36 expression in tumor samples are consistent with the in vitro functions of S1g-2, resulting in about a three-fold reduction in tumor volume. CONCLUSIONS: The in vivo activity and safety of S1g-2 illustrated that it is a potential strategy for Hsp70-Bim disruption to overcome tamoxifen-resistant ER-positive breast cancer.

Apatinib Plus Toripalimab (Anti-PD1 Therapy) as Second-Line Therapy in Patients With Advanced Gastric or Esophagogastric Junction Cancer: Results From a Randomized, Open-Label Phase II Study.

BACKGROUND: This study aimed to assess the activity of apatinib plus toripalimab in the second line for patients with advanced gastric or esophagogastric junction cancer (GC/EGJC). METHODS: In this open-label, phase II, randomized trial, patients with advanced GC/EGJC who progressed after first-line chemotherapy were enrolled and received 250 mg apatinib per day plus 240 mg toripalimab on day 1 per 3 weeks (arm A) or physician's choice of chemotherapy (PC, arm B). The primary endpoint of this study was the 1-year survival rate. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed as secondary endpoints. RESULTS: Twenty-five patients received apatinib plus toripalimab while 26 were enrolled in arm B. The 1-year survival rates of the 2 groups were 43.3% and 42.3%, respectively (P = .903). The PFS was 2.77 versus 2.33 months (P = .660). The OS was 8.30 versus 9.88 months (P = .539). An objective response was reported in 20.0% of patients in arm A compared to 26.9% in arm B (P = .368), respectively. A total of 6 (24.0%) patients experienced adverse events of grade ≥ 3 in arm A, while 9 (34.6%) patients suffered from adverse events of grade ≥ 3 in arm B. No drug-related deaths occurred in either group. CONCLUSION: Toripalimab plus apatinib treatment in second-line therapy of advanced GC/EGJC showed manageable toxicity but did not improve clinical outcomes relative to PC treatment (ClinicalTrials.gov Identifier: NCT04190745).

Controlled Sequential Doping of Metal Nanocluster.

Atomically precise doping of metal nanoclusters provides excellent opportunities not only for subtly tailoring their properties but also for in-depth understanding of composition (structure)-property correlation of metal nanoclusters and has attracted increasing interest partly due to its significance for fundamental research and practical applications. Although single and multiple metal atom doping of metal nanoclusters (NCs) has been achieved, sequential single-to-multiple metal atom doping is still a big challenge and has not yet been reported. Herein, by introducing a second ligand, a novel multistep synthesis method was developed, controlled sequential single-to-multiple metal atom doping was successfully achieved for the first time, and three doped NCs Au25Cd1(p-MBT)17(PPh3)2, Au18Cd2(p-MBT)14(PPh3)2, and [Au19Cd3(p-MBT)18]- (p-MBTH: para-methylbenzenethiol) were obtained, including two novel NCs that were precisely characterized via mass spectrometry, single-crystal X-ray crystallography, and so forth. Furthermore, sequential doping-induced evolutions in the atomic and crystallographic structures and optical and catalytic properties of NCs were revealed.