The Influence of Drug-Eluting Beads Transarterial Chemoembolization on Serum Levels of Soluble Programmed Cell Death Protein-1 in Advanced Hepatocellular Carcinoma Patients.

Aim: This study aims to explore the role of soluble programmed cell death protein 1 (sPD-1) in individuals with hepatocellular carcinoma (HCC) undergoing treatment with drug-eluting beads transarterial chemoembolization (D-TACE). Additionally, we aim to assess the potential utility of sPD-1 for determining the optimal timing for combining D-TACE with immune checkpoint inhibitors (ICIs). Materials and Methods: A total of 44 HCC patients eligible for D-TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood from the patients were collected on the day before D-TACE and 3, 7, and 30 days after D-TACE, respectively, for the assay of sPD-1. The relationships between sPD-1 levels, clinical features, outcomes, and the fluctuation of sPD-1 during treatment were analyzed. Results: The initial sPD-1 levels in patients were found to be significantly higher than those in the control group. Although the initial sPD-1 levels displayed a decreasing trend with an increase in BCLC stage, no significant differences were observed among patients at different BCLC stages. The sPD-1 level on day 3 after D-TACE was similar to that on day 7 after D-TACE and significantly lower than the initial level. The sPD-1 level on day 30 after D-TACE was significantly higher than that on day 3 and day 7 after D-TACE and nearly returned to the initial level before D-TACE. Conclusion: The level of sPD-1 was found to be significantly elevated in patients with HCC. However, further research is deemed necessary to fully understand the role of sPD-1 as a potential biomarker in the initiation, progression, and prognosis of HCC. The decrease in sPD-1 following D-TACE suggests that immune effector cells might potentially be reduced, as well as immune function weakened, highlighting the need to avoid the prompt administration of ICIs after D-TACE.

Enhancing Kinetics in Sodium Super Ion Conductor Na3MnTi(PO4)3 through Microbe-Assisted and Structural Optimization.

Sodium (Na) super ion conductor (NASICON) structure Na3MnTi(PO4)3 (NMTP) is considered a promising cathode for sodium-ion batteries due to its reversible three-electron reaction. However, the inferior electronic conductivity and sluggish reaction kinetics limit its practical applications. Herein, we successfully constructed a three-dimensional cross-linked porous architecture NMTP material (AsN@NMTP/C) by a natural microbe of Aspergillus niger (AsN), and the structure of different NMTP cathodes was optimized by adjusting different transition metal Mn/Ti ratios. Both approaches effectively altered the three-dimensional NMTP structure, not only improving electronic conductivity and controlling Na+ diffusion pathways but also enhancing the electrochemical kinetics of the material. The resultant AsN@NMTP/C-650, sintered at 650 °C, exhibits better electrochemical performance with higher reversible three-electron reactions corresponding to the voltage platforms of Ti4+/3+, Mn3+/2+, and Mn4+/3+ around 2.1, 3.6, and 4.1 V (vs Na+/Na), respectively. The capacity retention rate is up to 89.3% after 1000 cycles at a 2C rate. Moreover, a series of results confirms that the Na3.4Mn1.2Ti0.8(PO4)3 cathode has the most excellent electrochemical performance when the Mn/Ti ratio is 1.2/0.8, with a high capacity of 96.59 mAh g-1 and 97.1% capacity retention after 500 cycles.

Characteristics of beta parapapillary atrophy in primary angle-closure suspect.

OBJECTIVE: To investigate the characteristics of beta parapapillary atrophy (ß-PPA) in patients with primary angle-closure suspect (PACS). METHODS AND ANALYSIS: In total, 215 and 259 eyes with PACS and non-PACS (NPACS), respectively, were enrolled in this observational, cross-sectional study. Stereoscopic fundus and optical coherence tomography images were used to characterise ß-PPA; the former was also used to measure the major ß-PPA parameters. Univariate and multiple logistic regression analyses were used to identify the factors correlated with the presence of ß-PPA and with ß-PPA parameters. RESULTS: The ß-PPA occurrence rates were 48.80% and 44.40% in the PACS and NPACS groups, respectively, with no significant difference between groups. Compared with that in the NPACS group, the ß-PPA area was significantly larger (p=0.005) in the PACS group, but the angular extent and maximum radial length did not differ between groups (p=0.110 and 0.657, respectively) after adjusting for age and axial length. The presence of ß-PPA was associated with older age (OR 1.057, 95% CI 1.028 to 1.088, p<0.001) and larger disc area (OR 1.716, 95% CI 1.170 to 2.517, p=0.006). A larger ß-PPA area was associated with older age (p=0.014), greater vertical cup-to-disc ratio (p=0.028), larger disc area (p<0.001) and PACS diagnosis (p=0.035). CONCLUSION: 48.80% of participants with PACS had ß-PPA, which is slightly larger than NPACS. The area of ß-PPA was larger in PACS, while the angular extent and maximum radial length did not differ between groups.

Investigation of the drug-drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear. AIM OF THE STUDY: This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. MATERIALS AND METHODS: Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. RESULTS: BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. CONCLUSIONS: BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

Development and validation of a scale for the assessment of the knowledge-attitude-practice of parents towards children snoring.

BACKGROUND: Children Snoring is a common childhood disorder that affects the growth and development of children and is detrimental to their health. Increasing awareness of Children Snoring among parents is important. AIM: To develop the Knowledge-Attitude-Practice of Parents towards Children Snoring Scale and test the reliability and validity of the scale. METHODS: The development of the tool was divided into two phases involving 1257 parents from China. In the first phase, an initial project bank was created through a literature review. This was followed by a Delphi expert consultation, group discussion and pre-survey. The second stage screened the items and conducted an exploratory factor analysis, then conducted a confirmatory factor analysis and tested for reliability and validity. RESULTS: Support was found for the 25-item Knowledge-Attitude-Practice toward Children Snoring scale. Exploratory and confirmatory factor analyses provide support for four subscales: (parental basic cognition toward Children Snoring; parents' perception of complications of Children Snoring; parents' attitude towards Children Snoring; parents' concern and prevention of Children Snoring). Internal consistency for the total scale was high (Cronbach's α = 0.93). The intraclass correlation coefficient of test-retest reliability was 0.92 (95%CI: 0.85 to 0.95), which provided support for the stability of the scale. CONCLUSION: The Knowledge-Attitude-Practice of Parents towards Children Snoring scale shows promise as a measure that may be used by medical workers and community children's health managers.

Cell-free DNA methylation profiles enable early detection of colorectal and gastric cancer.

Colorectal cancer (CRC) and gastric cancer (GC) rank the top five common and lethal cancers worldwide. Early detection can significantly reduce the mortality of CRC and GC. However, current clinical screening methods including invasive endoscopic techniques and noninvasive fecal occult blood test screening tests/fecal immunochemical test have shown low sensitivity or unsatisfactory patient's compliance. Aberrant DNA methylation occurs frequently in tumorigenesis and cell-free DNA (cfDNA) methylation has shown the potential in multi-cancer detection. Herein, we aimed to explore the value of cfDNA methylation in the gastrointestinal cancer detection and develop a noninvasive method for CRC and GC detection. We applied targeted methylation sequencing on a total of 407 plasma samples from patients diagnosed with CRC, GC, and noncancerous gastrointestinal benign diseases (Non-Ca). By analyzing the methylation profiles of 34 CRC, 62 GC and 107 Non-Ca plasma samples in the training set (n=203), we identified 40,110 gastrointestinal cancer-specific markers and 63 tissue of origin (TOO) prediction markers. A new integrated model composed of gastrointestinal cancer detection and TOO prediction for three types of classification of CRC, GC and Non-Ca patients was further developed through logistic regression algorithm and validated in an independent validation set (n=103). The model achieved overall sensitivities of 83% and 81.3% at specificities of 81.5% and 80% for identifying gastrointestinal cancers in the test set and validation set, respectively. The detection sensitivities for GC and CRC were respectively 81.4% and 83.3% in the cohort of the test and validation sets. Among these true positive cancer samples, further TOO prediction showed accuracies of 95.8% and 95.8% for GC patients and accuracies of 86.7% and 93.3% for CRC patients, in test set and validation set, respectively. Collectively, we have identified novel cfDNA methylation biomarkers for CRC and GC detection and shown the promising potential of cfDNA as a noninvasive gastrointestinal cancer detection tool.

A developmental validation of the Quick TargSeq 1.0 integrated system for automated DNA genotyping in forensic science for reference samples.

Analysis of short tandem repeats (STRs) is a global standard method for human identification. Insertion/Deletion polymorphisms (DIPs) can be used for biogeographical ancestry inference. Current DNA typing involves a trained forensic worker operating several specialized instruments in a controlled laboratory environment, which takes 6-8 h. We developed the Quick TargSeq 1.0 integrated system (hereinafter abbreviated to Quick TargSeq) for automated generation of STR and DIP profiles from buccal swab samples and blood stains. The system fully integrates the processes of DNA extraction, polymerase chain reaction (PCR) amplification, and electrophoresis separation using microfluidic biochip technology. Internal validation studies were performed using RTyper 21 or DIP 38 chip cartridges with single-source reference samples according to the Scientific Working Group for DNA Analysis Methods guidelines. These results indicated that the Quick TargSeq system can process reference samples and generate STR or DIP profiles in approximately 2 h, and the profiles were concordant with those determined using traditional STR or DIP analysis methods. Thus, reproducible and concordant DNA profiles were obtained from reference samples. Throughout the study, no lane-to-lane or run-to-run contamination was observed. The Quick TargSeq system produced full profiles from buccal swabs with at least eight swipes, dried blood spot cards with two 2-mm disks, or 10 ng of purified DNA. Potential PCR inhibitors (i.e., coffee, smoking tobacco, and chewing tobacco) did not appear to affect the amplification reactions of the instrument. The overall success rate and concordance rate of 153 samples were 94.12% and 93.44%, respectively, which is comparable to other commercially available rapid DNA instruments. A blind test initiated by a DNA expert group showed that the system can correctly produce DNA profiles with 97.29% genotype concordance with standard bench-processing methods, and the profiles can be uploaded into the national DNA database. These results demonstrated that the Quick TargSeq system can rapidly generate reliable DNA profiles in an automated manner and has the potential for use in the field and forensic laboratories.

[Spatial and Temporal Distribution and Risk Assessment of Heavy Metals in Surface Water of Changshou Lake Reservoir, Chongqing].

To understand the water pollution status and environmental risks of Changshou Lake, the concentrations of heavy metals (Cr, Cu, Zn, As, Cd, and Pb) in the water were collected and analyzed during different seasons. The study investigated temporal and spatial variations, distribution characteristics, pollution levels, and health risks associated with heavy metals in Changshou Lake. The results showed that all six heavy metals were below than the Class Ⅰ standard of the Surface Water Environmental Quality Standard (GB 3838-2002), but recent years have witnessed an increasing trend, with Cu, As, and Pb showing a significant increase (P<0.05). The temporal and spatial distributions of these heavy metals were different. Temporally, Cr and Cd concentrations in surface water were higher in summer, As and Zn were higher in spring, and Pb and Cu were higher in autumn and winter. Spatially, the concentrations of Cr, As, Cu, Zn, and Pb showed higher concentrations in the southern outlet of the reservoir, the northwestern Longxi River inlet, and the central part of the reservoir, whereas Cd was higher in the northern stagnant area. The overall levels of heavy metals in the water body of Changshou Lake were low, with Cr and Cu slightly polluted, while other heavy metals were identified as having an insignificant pollution level. Drinking water was the primary exposure pathway to carcinogenic and non-carcinogenic heavy metals in surface water bodies. The health risk values of Cr and As in water bodies were high, ranging from 6.2×10-10 to 3.0×10-4 and 5.1×10-8 to 3.9×10-5, respectively. The corresponding contribution rates for children and adults to the total health risk were high, with Cr accounting for 87.18% and 87.20%, respectively, while As accounted for 12.73% and 12.71%, respectively. Therefore, it is crucial to prioritize environmental risks associated with Cr and Cu, as well as the health risks associated with Cr and As in Changshou Lake These findings provide a scientific foundation for water pollution control and environmental quality improvement in Changshou Lake, and rational development and utilization of water resources.

Association of altitude and frailty in Chinese older adults: using a cumulative frailty index model.

Objective: The population is aging exponentially and the resulting frailty is becoming increasingly evident. We aimed to explore the association between altitude and frailty, and to identify associated factors for frailty. Methods: This is a community-based cross-sectional survey. 1,298 participants aged ≥60 years from three different altitudes were included in the study. To quantify frailty, we constructed a frailty index (FI) and a frailty score (FS). The FI was divided into non-frailty, prefrailty, and frailty. The Odds Ratios and confidence intervals (ORs, 95%CIs) were used to evaluate the association between altitude and FI and FS in multivariate ordinal logistic regression and linear regression. Results: There were 560 (53.1%) participants in the prefrailty and 488 (37.6%) in the frailty group. The FS increased with higher altitude (P for trend <0.001). Multivariate ordinal logistic regression analysis revealed an association between altitude and frailty, OR = 1.91 (95% CI: 1.38-2.64) in mid-high altitude and 2.49 (95% CI:1.40-4.45) in high altitude. The same trend of association was found in the univariate analysis. The FS increased by 1.69 (95% CI: 0.78-2.60) at mid-high altitude and 3.24 (95%CI:1.66-4.81) at high altitude compared to medium altitude. Conclusion: The study indicates that high altitude exposure is an associated factor for frailty in older adults. This association become stronger with higher altitudes. As a result, it is essential to conduct early frailty screening for residents living at high altitudes.

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F-mediated phosphatidylserine exposure.

Oxidized low-density lipoprotein (oxLDL), a key component in atherosclerosis and hyperlipidemia, is a risk factor for atherothrombosis in dyslipidemia, yet its mechanism is poorly understood. In this study, we used oxLDL-induced human aortic endothelial cells (HAECs) and high-fat diet (HFD)-fed mice as a hyperlipidemia model. Phosphatidylserine (PS) exposure, cytosolic Ca2+ , reactive oxygen species (ROS), and lipid peroxidation were measured by flow cytometer. TMEM16F expression was detected by immunofluorescence, western blot, and reverse transcription polymerase chain reaction. Procoagulant activity (PCA) was measured by coagulation time, intrinsic/extrinsic factor Xase, and thrombin generation. We found that oxLDL-induced PS exposure and the corresponding PCA of HAECs were increased significantly compared with control, which could be inhibited over 90% by lactadherin. Importantly, TMEM16F expression in oxLDL-induced HAECs was upregulated by enhanced intracellular Ca2+ concentration, ROS, and lipid peroxidation, which led to PS exposure. Meanwhile, the knockdown of TMEM16F by short hairpin RNA significantly inhibited PS exposure in oxLDL-induced HAECs. Moreover, we observed that HFD-fed mice dramatically increased the progress of thrombus formation and accompanied upregulated TMEM16F expression by thromboelastography analysis, FeCl3 -induced carotid artery thrombosis model, and western blot. Collectively, these results demonstrate that TMEM16F-mediated PS exposure may contribute to prothrombotic status under hyperlipidemic conditions, which may serve as a novel therapeutic target for the prevention of thrombosis in hyperlipidemia.

[Pollution Source Apportionment of Heavy Metals in Cultivated Soil Around a Red Mud Yard Based on APCS-MLR and PMF Models].

In order to explore the characteristics and sources of heavy metal pollution in cultivated soil around a red mud yard in Chongqing， the content and spatial distribution characteristics of eight heavy metal elements （Cd， Cr， Hg， Ni， Pb， As， Cu， and Zn） in the soil were analyzed， and the single factor pollution index method and Nemerow comprehensive pollution index method were used to evaluate the characteristics of heavy metal pollution in soil. On the basis of correlation analysis， the APCS-MLR and PMF models were used to quantitatively analyze the sources of heavy metals. The results showed that the average contents of the other seven heavy metal elements were higher than the background values of Chongqing soil， except for that of Cr. The heavy metals Cd， Hg， and As were moderately polluted， and Pb， Cu， Ni， and Zn were mildly polluted. The spatial distribution pattern of Cr， Ni， Pb， Cu， and Zn in the soil was similar， and there was a very significant positive correlation between them （P < 0.01）. The spatial distribution characteristics of Cd， Hg， and As were significantly different， and there was no significant correlation between them （P > 0.05）. The source apportionment showed that the sources of heavy metals in the soil in the study area were relatively complex， and the APCS-MLR and PMF models could identify the same four pollution sources， namely red mud yard percolation emission and natural sources， thermal power generation emission sources， agricultural activities and natural sources， and non-ferrous metal smelting emission sources. There was little difference in the results of source apportionment between the two models. The contribution rates of the four pollution sources in the APCS-MLR model were 51.8%， 18.0%， 15.9%， and 14.3%， respectively， whereas those in the PMF model were 45.9%， 12.8%， 21.5%， and 19.8%， respectively.

Heavy metal pollution in agricultural soils from surrounding industries with low emissions: Assessing contamination levels and sources.

The potential for heavy metal (HM) pollution in agricultural soils adjacent to industries with elevated HM emissions has long been recognized. However, industries with relatively lower levels of HM emissions, such as alumina smelting and glass production, may still contribute to the pollution of surrounding agricultural soils through continuous, albeit low-level, emissions. Despite this, this issue has not garnered adequate attention thus far. Therefore, this study aimed to assess the extent of HM pollution in agricultural soils adjacent to an alumina smelting and a glass production factory, identifying contamination levels and potential sources through the analysis of input fluxes, isotope fingerprints, and receptor models. Results showed moderate cadmium (Cd) contamination in surface soil, exceeding standards at a rate of 86.36 %. Further analysis revealed that atmospheric deposition was the primary route for Cd input in both paddy fields (89.20 %) and dryland soils (91.61 %). Additionally, the δ114/110Cd values in surface soils indicated that dust played a role in influencing Cd levels in distant surface soils, while raw materials and slags were identified as primary sources near the factory. Industrial sources were considered the primary contributors of Cd in soil accounting for approximately 73.38 % and 82.67 %, respectively, according to the positive matrix factorization model (PMF) and absolute principal component scores-multiple linear regression model (APCS-MLR). Overall, this study underscores the importance of monitoring HMs from industries with relatively low emissions and provides a scientific basis for effectively managing HMs pollution in agricultural soils, ensuring the preservation of agricultural soil quality.

Fractional CO2 Laser for Vulvar Tissue Rejuvenation: A Prospective Study.

Objective: Aging and changes in hormone levels influence the appearance of the vulva, including the texture, pigmentation, and other manifestations, all of which may largely affect the physical and mental health of women. This study aimed to evaluate the efficacy and safety of fractional carbon dioxide (CO2) laser treatment for vulvar rejuvenation in Chinese women. Background: The limited options currently available for vulvar rejuvenation raise concerns. There is insufficient evidence to determine whether the fractional CO2 laser can safely and effectively rejuvenate the vulvar area for women of various ages and races. Methods: The study included 17 patients (mean age = 36.4 years) treated three times by continuous fractional CO2 laser with an interval of 1 month between each session. The primary outcomes were changes in vulva texture and pigmentation. Treatment was evaluated using images of the patients. Baseline and posttreatment images were collected and evaluated using a scoring system from 0 to 3 to grade the vulvar texture and pigmentation changes. In addition, patients rated their degree of vaginal rejuvenation after the treatment using a scoring system from 0 to 3. Results: Fractional CO2 laser treatment effectively and significantly increased vulvar texture and decreased vulvar pigmentation after three sessions (p < 0.05). Patients also self-reported noticeable improvement. There were no adverse reactions during the treatment and follow-up. Conclusions: Fractional CO2 laser treatment is a safe and effective method for vulvar rejuvenation in women.

Formation of halogenated forms of bisphenol A (BPA) in water: Resolving isomers with ion mobility - mass spectrometry and the role of halogenation position in cellular toxicity.

Halogenated BPA (XBPA) forms resulting from water chlorination can lead to increased toxicity and different biological effects. While previous studies have reported the occurrence of different XBPAs, analytical limitation have hindered the analysis and differentiation of the many potential isomeric forms. Using online solid-phase extraction - liquid chromatography - ion-mobility - high-resolution mass spectrometry (OSPE-LC-IM-HRMS), we demonstrated a rapid analysis method for the analysis of XBPA forms after water chlorination, with a total analysis time of less than 10 min including extraction and concentration and low detection limits (∼5-80 ng/L range). A multi in-vitro bioassay testing approach for the identified products revealed that cytotoxicity and bioenergetics impacts were largely associated with the presence of halogen atoms at positions 2 or 2' and the overall number of halogens incorporated into the BPA molecule. Different XBPA also showed distinct impacts on oxidative stress, peroxisome proliferator-activated receptor gamma - PPARγ, and inflammatory response. While increased DNA damage was observed for chlorinated water samples (4.14 ± 1.21-fold change), the additive effect of the selected 20 XBPA studied could not explain the increased DNA damage observed, indicating that additional species or synergistic effects might be at play.

Microstress for metal halide perovskite solar cells: from source to influence and management.

The power conversion efficiency of metal halide perovskite solar cells (PSCs) has increased dramatically in recent years, but there are still major bottlenecks in the commercial application of such materials, including intrinsic instability caused by external stimuli such as water, oxygen, and radiation, as well as local stress generated inside the perovskite and external stress caused by poor interlayer contact. However, some crucial sources of instability cannot be overcome by conventional encapsulation engineering. Among them, the tensile strain can weaken the chemical bonds in the perovskite lattice, thereby reducing the defects formation energy and activation energy of ion migration and accelerating the degradation rate of the perovskite crystal. This review expounds the latest in-depth understanding of microstrain in perovskite film from the thermodynamic sources and influences on the perovskite physicochemical structure and photoelectric performance. Furthermore, it also summarizes the effective strategies for strain regulation and interlayer contact performance improvement, which are conducive to the improvement of photovoltaic performance and internal stability of PSCs. Finally, we present a prospective outlook on how to achieve more stable and higher efficiency PSCs through strain engineering.

Outcomes of allogeneic hematopoietic stem cell transplantation in R/R DLBCL patients with failure of CAR-T therapy.

From October 2017 to June 2022, we retrospectively report outcomes of R/R DLBCL patients with failure of CAR-T therapy, then receiving allo-HSCT. Among 10 patients, 5 were males and 5 females, with a median age of 43.5 (27-52) years. All patients were diagnosed refractory/relapsed diffuse large B cell lymphoma. The median time from CAR-T treatment to transplantation was 84.5 (31-370) days. The median follow-up was 21 (3-69) months. 5/10 patients attained CR and 1/10 patient attained PR during the follow up. The objective response rate (ORR) was 60%. The 1-year overall survival (OS) and progression-free survival (PFS) were 70% and 40%, respectively. At the time of the analysis, 6 patients were still living. During the follow up, four patients have died and the causes were disease relapses and progressions (2 patients), acute renal failure (1 patient), severe pulmonary infection (1 patient). Non-relapse was 20.0%.

Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with antitumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/refractory mature Bcell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase 2 dose (RP2D). Overall, 134 Chinese patients were enrolled (dose escalation, n=27; dose expansion, n=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% CI, 37.5-64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the doseexpansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased doseproportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Scutellaria Baicalensis Georgi Stem and Leaf Flavonoids Ameliorate the Learning and Memory Impairment in Rats Induced by Okadaic Acid.

AIM: The objective of this study is to explore the impact and underlying mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on cognitive impairment caused by intracerebroventricular injection of okadaic acid (OA) in rats. METHODS: An experimental model of Alzheimer's disease (AD) was induced in rats by intracerebroventricular injection of OA, resulting in memory impairment. The Morris water maze test was employed to confirm the successful establishment of the memory impairment model. The rats that exhibited significant memory impairment were randomly divided into different groups, including a model group, three SSFs dose groups (25, 50, and 100 mg/kg), and a positive control group treated with Ginkgo biloba tablets (GLT) at a dose of 200 mg/kg. To evaluate the learning and memory abilities of the rats, the Morris water maze test was conducted. Hematoxylin-eosin (HE) staining was used to observe any morphological changes in neurons. Immunohistochemistry (IHC) was performed to measure the expression of choline acetyltransferase (ChAT) protein. Western blotting (WB) was utilized to assess the phosphorylation levels of tau protein at Ser262 and Ser396. The activities of inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS) were quantified using ultraviolet spectrophotometry. The levels of inflammatory factors, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were measured using ELISA. RESULTS: In rats, the administration of OA via intracerebroventricular injection resulted in cognitive impairment, neuropathological changes, and alterations in protein expression and activity levels. Specifically, the protein expression of ChAT was significantly reduced (P<0.01), while the phosphorylation levels of tau protein at Ser262 and Ser396 were significantly increased (P<0.01). Moreover, iNOS activity in the hippocampus and cerebral cortex exhibited a significant increase (P<0.01), whereas cNOS activity showed a decrease (P<0.05). Furthermore, the levels of IL-1ß and TNF-α in the cerebral cortex were elevated (P<0.01), while the level of IL-6 was decreased (P<0.05). The administration of three doses of SSFs and GLT to rats exhibited varying degrees of improvement in the aforementioned pathological alterations induced by OA. CONCLUSION: SSFs demonstrated the ability to enhance cognitive function and mitigate memory deficits in rats following intracerebroventricular injection of OA. This beneficial effect may be attributed to the modulation of ChAT protein expression, tau hyperphosphorylation, NOS activity, and inflammatory cytokine levels by SSFs.

Quercetin targets SarA of methicillin-resistant Staphylococcus aureus to mitigate biofilm formation.

IMPORTANCE: Anti-biofilm is an important strategy against Staphylococcus aureus chronic infection. SarA is a positive regulator of biofilm formation in S. aureus. In this study, we identified the SarA inhibitor quercetin using computer simulation screening. Previous studies have shown that quercetin inhibits biofilm; however, the underlying mechanism remains unknown. This study revealed the inhibitory effect of quercetin on the SarA protein. We also isolated the SarA protein and confirmed its interaction with quercetin in vitro. Besides, the inhibitory effect of quercetin on the transcription and translation levels of the SarA protein was also determined. The effects of quercetin on S. aureus biofilm inhibition and biofilm components were consistent with the changes in the transcription level of biofilm-related genes regulated by SarA. In summary, our study revealed the mechanism by which quercetin affects biofilm formation by inhibiting the transcriptional regulator SarA of S. aureus.