[Deep eutectic solvents synergistic with carboxymethyl -ß-cyclodextrin on the improvement of chiral separation of metoprolol by capillary electrophoresis].

The physical and chemical properties of chiral drugs are very similar. However, their pharmacological and toxicological effects vary significantly. For example, one enantiomer may have favorable properties whereas the other may be ineffective or even have toxic side effects. Hence, exploring innovative strategies to improve enantiomeric resolution is of great importance. Metoprolol (MET) is a ß-receptor blocker used to treat hypertension, stable angina pectoris, and supraventricular tachyarrhythmia. Establishing chiral separation and analysis methods of MET enantiomers is important for enhancing the quality of chiral drugs. Capillary electrophoresis (CE) has the advantages of a small sample size, simple operation, high separation efficiency, and many alternative modes; therefore it is widely used in the field of chiral drug separation. The chiral selectors commonly used for CE-based chiral separation include cyclodextrin (CD) and its derivatives, polysaccharides, proteins, and macrocyclic antibiotics. CD is one of the most commonly used and effective chiral selectors for CE. The relatively hydrophobic structure inside the cavity and the relatively hydrophilic structure outside the cavity of CD enable it and chiral molecules to form inclusion compounds with different binding constants, thus achieving chiral separation. However, the use of CD alone as a chiral selector does not always yield satisfactory separation results. Hence, the addition of other additives, such as ionic liquids and deep eutectic solvents (DESs) to assist CD-based chiral separation systems has received extensive attention. Previous studies on the enantiomeric separation of MET by CE have focused on the addition of CD and its derivatives alone for separation. Few studies have been conducted on the synergistic addition of auxiliary additives to CD to improve the enantiomeric resolution of MET. In this study, three DESs, namely, choline chloride-D-glucose, choline chloride-D-fructose, and lactate-D-glucose, were used for the CE-based chiral separation of MET for the first time, and the synergistic effect of the DESs on the separation of MET enantiomers by CD-based capillary zone electrophoresis was speculated. For this purpose, an uncoated fused silica capillary with inner diameter of 50 µm, total length of 50 cm and effective length of 41.5 cm was used as the separation column. First, the effects of CD type, CD concentration, buffer pH, and buffer concentration on MET separation were investigated, and the optimal conditions (15 mmol/L carboxymethyl-ß-cyclodextrin (CM-ß-CD), pH=3.0, and 40 mmol/L phosphate buffer) were obtained. Other CE conditions were as follows: UV detection at 230 nm, applied voltage of 25 kV. All operations were carried out at 20 ℃. Next, three types of DESs were prepared as auxiliary additives via a mixed-heating method. The DESs were mixed in a 50 mL round-bottomed flask at a certain molar ratio and then heated in a water bath at 80 ℃ for 3 h until a clear and transparent liquid was obtained. The effects of different DESs and their mass fraction on chiral separation were subsequently studied. The optimal choline chloride-D-fructose mass fraction was ultimately determined to be 1.5%. The resolution of MET increased from 1.30 without DES to 2.61 with 1.5% choline chloride-D-fructose, thereby achieving baseline separation. Finally, the separation effect and mechanism were speculated. The MET chiral separation method established in this study is of great significance for improving the quality of chiral compounds and ensuring the safety and effectiveness of clinical drugs. Furthermore, it may be useful in the research and development of CE-based chiral separation techniques using CD derivatives with DESs.

Elevated microRNA-214-3p level ameliorates neuroinflammation after spinal cord ischemia-reperfusion injury by inhibiting Nmb/Cav3.2 pathway.

BACKGROUND: Neuromedin B (Nmb) plays a pivotal role in the transmission of neuroinflammation, particularly during spinal cord ischemia-reperfusion injury (SCII). However, the detailed molecular mechanisms underlying this process remain elusive. METHODS: The SCII model was established by clamping the abdominal aorta of male Sprague-Dawley (SD) rats for 60 min. The protein expression levels of Nmb, Cav3.2, and IL-1ß were detected by Western blotting, while miR-214-3p expression was quantified by qRT-PCR. The targeted regulation between miR-214-3p and Nmb was investigated using a dual-luciferase reporter gene assay. The cellular localization of Nmb and Cav3.2 with cell-specific markers was visualized by immunofluorescence staining. The specific roles of miR-214-3p on the Nmb/Cav3.2 interactions in SCII-injured rats were explored by intrathecal injection of Cav3.2-siRNA, PD168368 (a specific NmbR inhibitor) and synthetic miR-214-3p agomir and antagomir in separate experiments. Additionally, hind-limb motor function was evaluated using the modified Tarlov scores. RESULTS: Compared to the Sham group, the protein expression levels of Nmb, Cav3.2, and the proinflammatory factor Interleukin(IL)-1ß were significantly elevated at 24 h post-SCII. Intrathecal injection of PD168368 and Cav3.2-siRNA significantly suppressed the expression of Cav3.2 and IL-1ß compared to the SCII group. The miRDB database and dual-luciferase reporter gene assay identified Nmb as a direct target of miR-214-3p. As expected, in vivo overexpression of miR-214-3p by agomir-214-3p pretreatment significantly inhibited the increases in Nmb, Cav3.2 and IL-1ß expression and improved lower limb motor function in SCII-injured rats, while antagomiR-214-3p pretreatment reversed these effects. CONCLUSIONS: Nmb protein levels positively correlated with Cav3.2 expression in SCII rats. Upregulating miR-214-3p ameliorated hind-limb motor function and protected against neuroinflammation via inhibiting the aberrant Nmb/Cav3.2 interactions and downstream IL-1ß release. These findings provide novel therapeutic targets for clinical prevention and treatment of SCII.

Knowledge mapping and global trends of drug hypersensitivity from 2013 to 2023: A bibliometric analysis.

BACKGROUND: Drug hypersensitivity is a major global public health issue with a significant increase in prevalence in populations. Here, we provide a deep insight into the frontier hotspot and future direction in the field of drug hypersensitivity. METHODS: A knowledge map is portrayed based on publications related to drug hypersensitivity from Web of Science Core Collection using CiteSpace. Co-occurrence relationships of countries, institutes, authors, journals, references, and keywords are constructed. According to the co-occurrence relationships, hotspots and future trends are overviewed. RESULTS: The United States ranked first in the world and China with the second highest publications was the only developing country. Torres, Mayorga, and Blanca were highly productive authors. Harvard University was the institution with the most research publications. Keywords co-occurrence analysis suggested applications in emerging causes, potential mechanisms, and clinical diagnosis as the research hotspots and development frontiers. CONCLUSION: Research on drug hypersensitivity is in a rapid development stage and an emerging trend in reports of anaphylaxis to polyethylene glycols is identified. Developing algorithms for understanding the standardization process of culprit drugs, clinical manifestations, and diagnostic methods will be the focus of future direction. In addition, a better understanding of the mechanisms to culprit drugs with immunological precise phenotypic definitions and high-throughput platforms is needed.

Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), characterized by low survival rates and a high recurrence rate, is a major cause of cancer-related mortality. Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common driver of NSCLC. Within this study, the inhibitory activity of (+)-anthrabenzoxocinone ((+)-ABX), an oxygenated anthrabenzoxocinone compound derived from Streptomyces, against NSCLC is demonstrated for the first time both in vitro and in vivo. Mechanistically, it is confirmed that the PI3K/AKT/mTOR signaling pathway is targeted and suppressed by (+)-ABX, resulting in the induction of S and G2/M phase arrest, apoptosis, and autophagy in NSCLC cells. Additionally, the augmentation of intracellular ROS levels by (+)-ABX is revealed, further contributing to the inhibition of the signaling pathway and exerting inhibitory effects on tumor growth. The findings presented in this study suggest that (+)-ABX possesses the potential to serve as a lead compound for the treatment of NSCLC.

Visualization Analysis of Artificial Intelligence Literature in Forensic Research.

OBJECTIVES: To analyze the literature on artificial intelligence in forensic research from 2012 to 2022 in the Web of Science Core Collection Database, to explore research hotspots and developmental trends. METHODS: A total of 736 articles on artificial intelligence in forensic medicine in the Web of Science Core Collection Database from 2012 to 2022 were visualized and analyzed through the literature measuring tool CiteSpace. The authors, institution, country (region), title, journal, keywords, cited references and other information of relevant literatures were analyzed. RESULTS: A total of 736 articles published in 220 journals by 355 authors from 289 institutions in 69 countries (regions) were identified, with the number of articles published showing an increasing trend year by year. Among them, the United States had the highest number of publications and China ranked the second. Academy of Forensic Science had the highest number of publications among the institutions. Forensic Science International, Journal of Forensic Sciences, International Journal of Legal Medicine ranked high in publication and citation frequency. Through the analysis of keywords, it was found that the research hotspots of artificial intelligence in the forensic field mainly focused on the use of artificial intelligence technology for sex and age estimation, cause of death analysis, postmortem interval estimation, individual identification and so on. CONCLUSIONS: It is necessary to pay attention to international and institutional cooperation and to strengthen the cross-disciplinary research. Exploring the combination of advanced artificial intelligence technologies with forensic research will be a hotspot and direction for future research.

Evaluating the Role of Postbiotics in the Modulation of Human Oral Microbiota: A Randomized Controlled Clinical Trial.

There is a lack of clinical data to support the effectiveness and safety of postbiotics in the modulation of human oral microbiota and oral health care. Here, volunteers were recruited and randomly assigned to two cohorts: a placebo group (n = 15) and a postbiotic group (n = 16). The placebo group used toothpaste that did not contain postbiotics, while the postbiotic group used toothpaste with postbiotics (3 × 1010 CFU inactivated Lactobacillus salivarius LS97, L. paracasei LC86, and L. acidophilus LA85). Saliva samples were collected at different time points and the immunoglobulin A (IgA) and short-chain fatty acid (SCFA) levels were determined, while the salivary microbiota was analyzed by 16S rRNA amplicon sequencing. The results showed that salivary IgA levels and acetic and propionic acid levels were notably higher in the postbiotic group (P < 0.05), accompanied by an increase in the level of alpha diversity of the salivary microbiota, and these indexes remained high 1 month after discontinuing the use of toothpaste with or without postbiotics. A notable decrease in the relative abundance of the unclassified_Enterobacteriaceae, Klebsiella, Escherichia, etc. in the postbiotic group was accompanied by a notable increase in Ruminofilibacter and Lactobacillus. However, both groups did not cause significant changes in the overall structure of the host salivary microbiota. In conclusion, postbiotics dramatically and consistently improved oral immunity levels and SCFA content in the host. In addition, postbiotics were able to increase the level of microbial alpha diversity and down-regulate the abundance of some harmful microbes without significantly altering the structure of the host salivary microbiota. Chinese Clinical Trial Registry (ChiCTR) ( www.chictr.org.cn ) under the registration number ChiCTR2300074088.

Biodegradable and flame-retardant cellulose-based wearable triboelectric nanogenerator for mechanical energy harvesting in firefighting clothing.

Integrating flexible triboelectric nanogenerators (TENGs) into firefighting clothing offers exciting opportunities for wearable portable electronics in personal protective technology. However, it is still a grand challenge to produce eco-friendly TENGs from biodegradable and low-cost natural polymers for mechanical-energy harvesting and self-powered sensing. Herein, conductive polypyrrole (PPy) and natural chitosan (CS)/phytic acid (PA) tribonegative materials were employed onto the Lycra fabric (LC) in turn to assemble the biodegradable and flame-retardant single-electrode mode LC/PPy/CS/PA TENG (abbreviated as LPCP-TENG). The resultant LPCP-TENG exhibits truly wearable breathability (1378.6 mm/s), elasticity (breaking elongation 291 %), and shape adaptivity performance that can produce an open circuit voltage of 0.3 V with 2 N contact pressure at a working frequency of 5 Hz with a limiting oxygen index of 35.2 %. Furthermore, facile monitoring for human motion of firefighters on fireground is verified by LPCP-TENG when used as self-powered flexible tactile sensor. In addition, degradation experiments have shown that waste LPCP-TENG can be fully degraded in soil within 120 days. This work broadens the applicational range of wearable TENG to reduce the environmental effects of abandoned TENG, exhibiting prosperous applications prospects in the field of wearable power source and self-powered motion detection sensor for personal protection application on fireground.

Vector-guided Fourier single-pixel imaging.

The Fourier single-pixel imaging technique exhibits great potential for compressive imaging. However, the utilization of low sampling ratio can introduce unwanted ringing artifacts, thereby compromising the fidelity of reconstructed image detail. To address this issue, Vector guided Fourier single-pixel imaging (V-FSI) has been proposed. We analyze the statistical properties in the edge vector field derived from images with low sampling ratio. Based on this information, a tailored sampling map is designed to acquire the significant high-frequency components for image reconstruction. Experimental results demonstrate the remarkable effectiveness of the proposed V-FSI method in enhancing image quality. Notably, V-FSI exhibits exceptional capabilities in perceiving and preserving the details of the objects, particularly for objects characterized by pronounced periodicity and directionality.

Grid1 regulates the onset of puberty in female rats.

The study aimed to investigate the effect of Grid1, encoding the glutamate ionotropic receptor delta type subunit 1(GluD1), on puberty onset in female rats. Grid1 mRNA and protein expression was detected in the hypothalamus of female rats at prepuberty and puberty. Additionally, the expression of Grid1 was suppressed in primary hypothalamus cells and prepubertal rat. Finally, investigated the effect of Grid1 knockdown on puberty onset and reproductive performance. The levels of Grid1 mRNA in the hypothalamus, the fluorescence intensity in the arcuate nucleus and paraventricular nucleus of the prepubertal rats was significantly lower than pubertal. Treatment of hypothalamic neurons with LV-Grid1 decreased the level of Grid1 and Rfrp-3 (encoding RFamide-related peptide 3) mRNA expression, but increased the Gnrh (encoding gonadotropin-releasing hormone) mRNA levels. After an ICV injection, the time for the rat vaginal opening occurred earlier. Moreover, Gnrh mRNA expression was increased, whereas Rfrp-3 mRNA expression was decreased in the hypothalamus. The concentration of progesterone(P4) in the serum was significantly decreased compare with control group. Ovary hematoxylin-eosin staining revealed that the LV-Grid1 group mainly contained primary and secondary follicles. The reproductive performance of the rats was not affected by the Grid1 knockdown. Therefore, Grid1 may affect the onset of puberty in female rats by regulating the levels of Gnrh, and Rfrp-3 in the hypothalamus, as well as the concentrations of P4, but not reproduction performance.

Transcription suppression of GABARAP mediated by lncRNA XIST-EZH2 interaction triggers caspase-11-dependent inflammatory injury in ulcerative colitis.

BACKGROUND: We have previously found that enhancer of zeste homolog 2 (EZH2) is correlated with inflammatory infiltration and mucosal cell injury in ulcerative colitis (UC). This study aims to analyze the role of X-inactive specific transcript (XIST), a possible interactive long non-coding RNA of EZH2, in UC and to explore the mechanisms. METHODS: C57BL/6N mice were treated with dextran sulfate sodium (DSS), and mouse colonic mucosal epithelial cells were treated with DSS and lipopolysaccharide (LPS) for UC modeling. The UC-related symptoms in mice, and the viability and apoptosis of mucosal epithelial cells were determined. Inflammatory injury in animal and cellular models were assessed through the levels of ACS, occludin, IL-1ß, IL-18, TNF-α, caspase-1, and caspase-11. Molecular interactions between XIST, EZH2, and GABA type A receptor-associated protein (GABARAP) were verified by immunoprecipitation assays, and their functions in inflammatory injury were determined by gain- or loss-of-function assays. RESULTS: XIST was highly expressed in DSS-treated mice and in DSS + LPS-treated mucosal epithelial cells. It recruited EZH2, which mediated gene silencing of GABARAP through H3K27me3 modification. Silencing of XIST alleviated body weight loss, colon shortening, and disease active index of mice and reduced inflammatory injuries in their colon tissues. Meanwhile, it reduced apoptosis and inflammation in mucosal epithelial cells. However, these alleviating effects were blocked by either EZH2 overexpression or GABARAP knockdown. Rescue experiments identified caspase-11 as a key effector mediating the inflammatory injury following GABARAP loss. CONCLUSION: This study suggests that the XIST-EZH2 interaction-mediated GABARAP inhibition activates caspase-11-dependent inflammatory injury in UC.

A DNAzymes-in-droplets assay for Burkholderia gladioli pathovar cocovenenans with single-bacterium sensitivity.

Foodborne pathogens pose a serious risk to human health, and the simple and rapid detection of such bacteria in complex food matrices remains challenging. Herein, we present the selection and characterization of a novel RNA-cleaving fluorogenic DNAzyme, named RFD-BC1, with exceptional specificity for Burkholderia gladioli pv. cocovenenans (B. cocovenenans), a pathogen strongly associated with fatal food poisoning cases. RFD-BC1 was activated by a protein secreted specifically by whole viable B. cocovenenans and displayed an optimum pH distinct from the selection pH, with a rate constant of approximately 0.01 min-1 at pH 5.0. Leveraging this newly discovered DNAzyme, we developed a novel system, termed DNAzymes-in-droplets (DID), that integrates droplet microfluidics to achieve the rapid and selective detection of live B. cocovenenans with single-cell sensitivity. We believe that the approach described herein holds promise for combating specific bacterial pathogens in food samples, offering significant potential for broader applications in food safety and public health.

Brain gray matter morphometry relates to onset age of bilingualism and theory of mind in young and older adults.

Lifelong bilingualism may result in neural reserve against decline not only in the general cognitive domain, but also in social cognitive functioning. In this study, we show the brain structural correlates that are associated with second language age of acquisition (L2AoA) and theory of mind (the ability to reason about mental states) in normal aging. Participants were bilingual adults (46 young, 50 older) who completed a theory-of-mind task battery, a language background questionnaire, and an anatomical MRI scan to obtain cortical morphometric features (i.e., gray matter volume, thickness, and surface area). Findings indicated a theory-of-mind decline in older adults compared to young adults, controlling for education and general cognition. Importantly, earlier L2AoA and better theory-of-mind performance were associated with larger volume, higher thickness, and larger surface area in the bilateral temporal, medial temporal, superior parietal, and prefrontal brain regions. These regions are likely to be involved in mental representations, language, and cognitive control. The morphometric association with L2AoA in young and older adults were comparable, but its association with theory of mind was stronger in older adults than young adults. The results demonstrate that early bilingual acquisition may provide protective benefits to intact theory-of-mind abilities against normal age-related declines.

Effects of postoperative antioxidants on the salivary glands in patients with thyroid cancer undergoing radioactive iodine-131 treatment.

OBJECTIVE: This study aimed to evaluate the effects of three antioxidants, selenium yeast capsule, vitamin E and vitamin C, alone or in combination, on the salivary glands of patients with differentiated thyroid cancer (DTC) treated with iodine-131 ( 131 I). METHODS: A total of 69 postoperative DTC patients were randomly divided into three groups: vitamin E combined with vitamin C group (21 cases); selenium yeast group (23 cases); and selenium yeast combined with vitamin C group (25 cases). Salivary gland functional changes were assessed by salivary gland dynamic imaging functional parameters in the enrolled patients before and 1 month after 131 I treatment. RESULTS: Comparison of salivary gland function parameters before and after 131 I treatment in the three groups were evaluated. In the vitamin E combined with the vitamin C group, the left parotid gland excretion fraction (EF) value was significantly higher than that before treatment. In the selenium yeast group, the left parotid gland excretion part, bilateral parotid gland excretion ratio (ER), left submandibular gland maximum uptake ratio within 20 min (UR20), and the right submandibular gland ER values were significantly higher than that before treatment, while in the selenium yeast combined with vitamin C group, the bilateral parotid gland EF, bilateral submandibular gland UR20, EF, and left submandibular gland ER values were significantly higher than that before treatment (all P < 0.05). CONCLUSION: During high-dose 131 I treatment, vitamin E combined with vitamin C improved the excretory function of parotid glands in DTC patients; selenium supplementation had a protective effect on salivary glands; and the combination of selenium and vitamin C had a better effect.

International trends in pulmonary hypertension mortality between 2001 and 2019: Retrospective analysis of the WHO mortality database.

Background: There are limited published data on mortality trends in pulmonary hypertension (PH) worldwide. The objective of this study was to assess the PH-related mortality and time trends in the general population over the past 20 years. Material and methods: We used country-level PH mortality data from the World Health Organization (WHO) mortality database (2000-19), using the International Classification of Diseases, tenth revision (ICD-10) codes (I27.0, I27.2, I27.8, or I27.9). The average annual percentage changes (AAPCs) were calculated to describe mortality trends. Results: Fifty-four countries were included in this study. Between 2017 and 2019, the average age-standardized death rates (per 100,000) were 0.80 and 0.87 for males and females, respectively. Joinpoint analyses revealed a decreasing PH mortality trend for the overall population from 2000 to 2019 (AAPC -3.2 [95% confidence interval (CI) -4.1 to -2.4]), which was consistent between males and females (males: AAPC -5.3 [95% CI -6.2 to -4.4], females: AAPC -1.7 [95% CI -2.4 to -0.9]). When the estimates were stratified by etiology, we found that the mortality rates from idiopathic pulmonary arterial hypertension (I27.0) and pulmonary heart disease (unspecified, I27.9) had decreased significantly, while the mortality rates in other secondary PH (I27.2) and other specified pulmonary heart diseases (I27.8) had significantly increased. In addition, there were substantial differences in mortality rates and time trends across countries. Conclusion: Although an overall decrease in PH mortality trends over the past two decades, there were substantial differences across countries. For countries with high or rising mortality rates, more efforts are needed to reduce the mortality.

Single and mixture toxicity of cadmium and copper to swim bladder in early life stages of Japanese medaka (Oryzias latipes).

Toxicity observed in aquatic ecosystems often cannot be explained by the action of a single pollutant. Likewise, evaluation standards formulated by a single effect cannot truly reflect the environmental quality requirements. The study of mixtures is needed to provide environmental relevance and knowledge of combined toxicity. In this study, the embryos of Japanese medaka (Oryzias latipes) were treated with individual and binary mixture of copper (Cu) and cadmium (Cd) until 12 days post-fertilization (dpf). Hatching, mortality, development, histology and gene expression were assessed. Our results showed that the highest concentration mixture of Cd (10 mg/L) and Cu (1 mg/L) affected survival, hatching time and hatching success. Occurrence of uninflated swim bladder was the highest (value) with exposure to 10 mg/L Cd. Swim bladder was commonly over-inflated in a mixture (0.1 mg/L Cd + 1.0 mg/L Cu) exposure. Individuals exposed to the mixture (0.1 Cd + 1.0 Cu mg/L) showed up to a 7.69% increase in swim bladder area compared to the control group. The mixtures containing 0.1 or 10 mg/L Cd, each with 1.0 mg/L Cu resulted in significantly increased of Pbx1b expression, higher than any Cd or Cu alone (p < 0.01). In the co-exposure group (0.1/10 Cd + 1.0 Cu mg/L), Pbx1b expression was found at 12 dpf but not 7 dpf in controls. Higher concentrations of Cd may progressively reduce Pbx1b expression, potentially explaining why 75% of individuals in the 10 mg/L Cd group failed to inflate their swim bladders. Additionally, the swim bladder proved to be a valuable bio-indicator for biological evaluation.

Preparation of tough and stiff ionogels via phase separation.

Ionogels have the advantages of thermal stability, non-volatility, ionic conductivity and environmental friendliness, and they can be used in the field of flexible electronics and soft robotics. However, their poor mechanical strength and complex preparation methods limit their practical application. Herein, we propose a simple strategy to improve the performance of ionogels by adjusting their phase separation behavior. In a polymer-ionic liquid (IL) binary system with an upper critical solution temperature (UCST) and Berghmans' point, the phase separation behavior will be frozen below the temperature corresponding to the Berghmans' point, and thus, the degree of phase separation can be adjusted by controlling the cooling rate. We found that a polyacrylamide (PAM)-IL binary system possessed a UCST and Berghmans' point and the resulting ionogels had excellent mechanical properties. Their tensile strength, tensile modulus, compressive strength and compressive modulus reached 31.1 MPa, 319.8 MPa, 122 MPa and 1.7 GPa, respectively, while these properties of the other ionogels were generally less than 10 MPa. Furthermore, they were highly transparent, stretchable, stable and multifunctional.

Efficacy and safety of sintilimab combined with apatinib as third-line or above therapy for patients with advanced or metastatic gastric cancer.

This study aimed to evaluate the efficacy and safety of the combination of sintilimab and apatinib for the treatment of patients with advanced or metastatic gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. This retrospective study analyzed data from 34 patients who had advanced or metastatic GC/GEJ cancer and received the combination therapy of sintilimab and apatinib as a third-line or above treatment. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Among the 34 patients, none achieved a complete response (CR), 3 patients (8.8%) achieved a partial response, 23 patients (67.6%) had stable disease, and 8 patients (23.5%) experienced progressive disease. The ORR and DCR were 8.8% and 76.5%, respectively. The median PFS was 6.0 months (95% CI: 3.6-8.4), and the median OS was 11.6 months (95% CI: 8.1-15.1). Subgroup analysis revealed significant differences in OS between patients with high and low Eastern Cooperative Oncology Group Performance Status scores and between patients with and without a history of gastrectomy. Common adverse events (AEs) during treatment included fatigue (52.9%), anemia (47.1%), leukopenia (26.5%), hypothyroidism (23.5%), nausea and vomiting (20.6%), neutropenia (20.6%), and thrombocytopenia (17.6%), most of which were grade 1 and 2 AEs. No deaths occurred due to AEs. These findings indicate that the combination of sintilimab and apatinib has a favorable therapeutic effect in patients with advanced GC. Moreover, the AEs associated with this therapy are generally manageable.

Noninvasive Monitoring of Immunotherapy in Lung Cancer by Lymphocyte Activation Gene 3 PET Imaging of Tumor-Infiltrating Lymphocytes.

Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3+) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [68Ga]Ga-NOTA-C25 and performed a series of in vitro and in vivo assays to test its specificity. Next, [68Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [68Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3+ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [68Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [68Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [68Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3+ TILs in lung cancer. [68Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.

Study of hispidulin in the treatment of uric acid nephropathy based on NF-κB signaling pathway.

Uric acid nephropathy (UAN) is caused by purine metabolism disorders. UAN rat models were established in SD rats. The modeling rats received different doses of hispidulin (10, 20, 50 mg/mL). Febuxostat was applied as the positive drug. Serum creatinine, uric acid (UA), and cystatin-C (cys-C), neutrophil gelatinase-associated lipocalin (NGAL), IL-1ß, IL-8, TNF-α, and IL-6 in rats were detected. HE staining was done to assess kidney injury. UAN rats possessed prominent levels of serum creatinine, UA, cys-C, and NGAL, which all reduced after hispidulin treatment in a dose-dependent manner. HE staining determined the improvement of kidney injury after treatment, which was comparable to the efficacy of febuxostat. Hispidulin inhibited the release of IL-1ß, IL-8, TNF-α, and IL-6 in UAN rats. Hispidulin enhanced autophagy in UAN rats, presenting as ascending LC3II/I ratio and downregulated P62. The increasing trend of inflammasome-related proteins of NLRP3 and Caspase-1 was changeovered by hispidulin. The activation of NF-kB signaling was intercepted by hispidulin in UAN rats. Hispidulin can effectively improve renal function injury caused by UAN in rats. The mechanism may be related to the inhibition of inflammatory response induced by autophagy and activation of NF-κB pathway.