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Yi-Fan Zhou,1,&ast; Shu-Han Chen,1,&ast; Wan-Da Wang,1 Jia-Le Chen,1 Ping-Yu Cai,1 Mei-Mei Li,1 Yue-Ling Lin,1 Wan-Qi Li,1 De-Hong Huang,1 Jun Li,1 Yue-Ting Li,2 Hui-Li Lin1 1Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, People’s Republic of China; 2Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui-Li Lin, Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, 362000, People’s Republic of China, Tel +86 18876598756, Email 1627974150@qq.com Yue-Ting Li, Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, Fujian Province, 362000, People’s Republic of China, Tel +86 15359593070, Email liyt163@126.comPurpose: The effect of metabolic factors on cardiovascular risk in obstructive sleep apnea (OSA) is unclear. This study aimed to investigate the effect of metabolic factors on the left ventricular diastolic function in patients with OSA.Patients and Methods: This cross-sectional study included a total of 478 patients with OSA from September 2018 to September 2023. After propensity score matching, wherein 193 patients with OSA with metabolic syndrome (MS) were 1:1 matched to patients with OSA without MS by sex and age, data from 386 patients were ultimately analyzed. Furthermore, all patients were divided into mild, moderate, and severe OSA groups according to their sleep apnea-hypopnea index (AHI). Measurements included nocturnal polysomnography, biochemical testing, and transthoracic echocardiography data.Results: The AHI in the MS group was higher (30.24± 21.69 vs 23.19± 17.65, p< 0.001) and the lowest oxygen saturation at night was lower (77.67± 9.23 vs 80.59± 9.26, p< 0.001) than those in the non-MS group. Additionally, the left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), end-diastolic ventricular septal thickness (IVST), left ventricular end-diastolic posterior wall thickness (LVPWT), left atrial internal diameter (LAD), and E peak to A peak velocity ratio (E/A) in the MS group were higher than those in the non-MS group (P< 0.05). The E peak to e’ peak velocity ratio (E/e’) in the MS group was higher than that in the non-MS group (12.02± 3.68 vs 11.13± 3.12, P=0.011) and was positively correlated with the diagnosis of MS and metabolic factors (r=0.115, p=0.024; r=0.131, p=0.010, respectively). Patients with five metabolic factors had a significantly higher risk of E/e’ elevation than patients in the non-MS group (odds ratio=4.238, p=0.007).Conclusion: MS may be related to OSA severity and left ventricular diastolic dysfunction. An increase in metabolic factors may increase the risk of diastolic dysfunction. Among metabolic factors, blood pressure may be the most important.Keywords: metabolic syndrome, obstructive sleep apnea, left ventricular dysfunction

Shao-Jie Wu,1,2,&ast; Dan-Dan Ruan,1,&ast; Qiu-Yan Wu,1,&ast; Yi Tang,1,2 Jian-Hui Zhang,1 Sen-Lin Cai,1,2 Yan-Feng Zhou,1,2 Jie-Wei Luo,1,3 Zhu-Ting Fang1,2 1Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Interventional Radiology, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 3Department of Traditional Chinese Medicine, Fujian provincial hospital, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie-Wei Luo; Zhu-Ting Fang, Email docluo0421@aliyun.com; 470389481@qq.comBackground: Drug-eluting bead transarterial chemoembolization (DEB-TACE) has good efficacy in the treatment of unresectable hepatocellular carcinoma (uHCC), with a relatively high objective response rate (ORR) compared to conventional transarterial chemoembolization (cTACE). This study aimed to evaluate the safety and medium-term clinical efficacy of DEB-TACE combined with lenvatinib (LEN) plus PD-1 inhibitors as a triple therapy for the treatment of uHCC.Methods: Data of patients with uHCC who received triple therapy of DEB-TACE combined with LEN plus PD-1 inhibitors from January 2019 to June 2021 were analyzed retrospectively. The study endpoints were ORR, progression-free survival (PFS), and treatment-related adverse events based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST).Results: Thirty-five patients were included in this study, with a median follow-up period of 15 months. The median cycle of DEB-TACE was 1, while that of all forms of TACE procedures per patient was 2. The median administration time of LEN was 7 months, and the median number of PD-1 inhibitor treatment was 4 cycles. The ORR based on mRECIST was 82.9%, disease control rate was 91.4%, and the median time to response was 7 weeks. Among these, the ORR of Barcelona Clinic Liver Cancer (BCLC) stage A reached 100%, while that of BCLC stages B and C reached 84.6% and 78.9%, respectively. The median PFS was 9 months; the mOS was not reached. Fourteen patients (40%) successfully underwent downstaging conversion and surgical resection, 32 patients (91.4%) experienced treatment-related adverse events, and no grade 5-related adverse reactions occurred.Conclusion: DEB-TACE combined with LEN and PD-1 inhibitors has a high ORR and surgical conversion rate in the treatment of uHCC tumors, and the toxicity and side effects were tolerable.Keywords: unresectable hepatocellular carcinoma, transarterial chemoembolization, drug-eluting bead, lenvatinib, PD-1 inhibitor, combined therapy

Xian Pan,1,2,&ast; Shao-Jie Wu,1,2,&ast; Yi Tang,1,2,&ast; Yan-Feng Zhou,1,2 Jie-Wei Luo,1,3 Zhu-Ting Fang1,2 1Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Interventional Radiology, Fujian Provincial Hospital, Fuzhou, People’s Republic of China; 3Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie-Wei Luo; Zhu-Ting Fang, Tel +86 59188217540, Email docluo0421@aliyun.com; 470389481@qq.comPurpose: In China, many patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage. Several studies have shown that triple therapy [transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)] is beneficial for patient survival. In this study, we aimed to evaluate the efficacy of triple therapy (TACE + TKIs + ICIs) for unresectable HCC (uHCC) and the conversion rate of surgical resection (SR). The primary endpoints were objective response rate (ORR) and disease control rate (DCR) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 and adverse events (AEs), while the secondary endpoint was the conversion rate of patients with uHCC treated with triple therapy followed by SR.Patients and Methods: Forty-nine patients with uHCC who received triple therapy at Fujian Provincial Hospital between January 2020 and June 2022 were retrospectively included. The treatment efficacy, SR conversion rate, and associated AEs were recorded.Results: Among the 49 patients enrolled, the ORRs assessed by mRECIST and RECIST v1.1 were 57.1% (24/42) and 14.3% (6/42), respectively, and the DCRs were 92.9% (39/42) and 88.1% (37/42), respectively. Seventeen (34.7%) patients met the criteria for resectable HCC and underwent resection. The median interval between the start of triple therapy and resection was 113.5 days (range 94.75 to 182 d), and the median number of TACE was 2 (range 1 to 2.5). The patients did not achieve median overall survival or median progression-free survival. Treatment-related AEs occurred in 48 (98%) patients, and 18 (36.7%) patients had grade ≥ 3 AEs.Conclusion: Triple combination therapy resulted in a relatively high ORR and conversion resection rate following uHCC treatment.Keywords: TACE, immune checkpoint inhibitors, tyrosine kinase inhibitor, surgical resection

Yun Hong,1,&ast; Da-Peng Dai,2,&ast; Jian-Ping Cai,2 Shuang-Hu Wang,3 Yi-Ran Wang,1,4 Fang-Ling Zhao,2,4 Shan Zhou,2 Quan Zhou,3 Pei-Wu Geng,3 Yun-Fang Zhou,3 Xue Xu,1 Ji-Hua Shi,1 Qing-Feng Luo1 1Department of Gastroenterology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China; 2The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, People’s Republic of China; 3Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, 323020, People’s Republic of China; 4Peking University Fifth School of Clinical Medicine, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing-Feng Luo, Department of Gastroenterology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China, Tel + 86 138 1151 9095, Email luoqf2000@126.comPurpose: To study the potential drug–drug interactions between simvastatin and vonoprazan and to provide the scientific basis for rational use of them in clinical practice.Methods: An incubation system was established with rat liver microsomes, and the main metabolite of vonoprazan M-I was detected by UPLC-MS/MS. The IC50 value of simvastatin was then calculated and its inhibitory mechanism against vonoprazan was also analyzed. Twelve SD rats were randomly divided into 2 groups, then they were given simvastatin or saline for 2 weeks continuously. On the day of the experiment, both groups were intragastrically administered with vonoprazan once, followed by the collection of blood at different time points. Then the plasma concentration of vonoprazan and M-I in rats were detected by UPLC-MS/MS.Results: In vitro experiments revealed that simvastatin could inhibit the metabolism of vonoprazan, and its inhibition type belonged to the mixed non-competitive and competitive inhibition model. In vivo experiments in rats demonstrated that the area under concentration time curve (AUC) of vonoprazan was decreased but the clearance (CLz/F) of it was increased in the simvastatin administrated group, as compared to those of the control group. However, M-I in simvastatin treated group exhibited the higher AUC and lower CLz/F values compared to those in the control group. These data indicated that multiple doses of simvastatin administration could reduce the plasma concentration of vonoprazan and accelerate its metabolic rate in rats.Conclusion: Simvastatin could inhibit the metabolism of vonoprazan in vitro but multiple doses of simvastatin exhibited the opposite effect In vivo. Altogether, our data indicated that an interaction existed between simvastatin and vonoprazan and additional cares might be taken when they were co-administrated in clinic.Keywords: vonoprazan, simvastatin, drug–drug interactions, liquid chromatography-tandem mass spectrometry, rat liver microsomes

Fang Peng,1 Hao Yuan,1 Yi-Feng Zhou,2 Si-Xian Wu,1 Zhen-Yi Long,1 Ya-Meng Peng1 1Department of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China; 2Operating Room, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of ChinaCorrespondence: Hao Yuan, Department of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China, Tel +8613677366519, Email yuanhao666@hunnu.edu.cnPurpose: We aimed to explore the clinical diagnostic value of combined detection via protein induced by vitamin K absence or antagonist II (PIVKA-II), alpha-fetoprotein (AFP), and D-dimer (D-D) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).Materials and Methods: We analyzed PIVKA-II, AFP, and D-D levels in 291 subjects comprising liver cirrhosis (LC) patients (n = 143) and HCC patients (n = 148). Receiver operating characteristic (ROC) curves were used to analyze and compare the clinical diagnostic value of the three biomarkers for HBV-related HCC alone and in combination.Results: The levels of PIVKA-II, AFP, and D-D were positively correlated with tumor size in HCC patients. The levels of PIVKA-II and AFP in early-stage HCC, advanced HCC, HBV DNA+ HCC, and HBV DNA- HCC patients were higher than those in LC patients, while the levels of D-D were lower. The area under the curve for combined detection was greater than that for single-index detection in early-stage HCC, advanced HCC, HBV DNA+ HCC, and HBV DNA- HCC patients.Conclusion: D-D may be a useful biomarker for the diagnosis of HBV-related HCC. The combined detection of PIVKA-II, AFP, and D-D had better diagnostic value for different types of HCC than the detection of individual biomarkers.Keywords: PIVKA-II, alpha-fetoprotein, D-dimer, biomarker, hepatocellular carcinoma, hepatitis B virus

Zhen-Yi Long,1,&ast; Yi-Feng Zhou,2,&ast; Hao Yuan,1 Ya-Meng Peng,1 Si-Xian Wu,1 Fang Peng1 1Department of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China; 2Operating Room, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao YuanDepartment of Clinical Laboratory, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, People’s Republic of ChinaTel +86-13677366519Fax +86-731-82278012Email yuanhao666@hunnu.edu.cnPurpose: We explored the expression levels of IgG4 and interleukin (IL)-21 in the serum and ankle joints of collagen-induced arthritis (CIA) rats at different disease stages.Materials and Methods: Wistar rats were randomly divided into normal and model groups, and the latter group was administered bovine type II collagen to induce arthritis. Enzyme-linked immunosorbent assay was performed at 21, 28, 35, and 42 days to detect IgG4 and IL-21 in the serum, followed by histological and immunohistochemical analyses of IgG4 and IL-21r in the ankle joint of rats.Results: The contents of IgG4 and IL-21 in the serum of the CIA model group were positively correlated and increased with disease progression. The expression of IgG4 and IL-21 receptors in the ankle joint of the CIA model group was significantly higher than that in the control group. These proteins were closely related to the pathological score. The serum IL-21 level in the model group was closely related to the level of IL-21 receptor in the ankle joint.Conclusion: IL-21 may promote the occurrence and development of rheumatoid arthritis by combining with IL-21r to regulate the content of IgG4.Keywords: rheumatoid arthritis, immunoglobulin, interleukin, interleukin receptor

Meng-Xin Tian,1,2,* Liu-Ping Luo,3,4,* Wei-Ren Liu,1,2,* Wei Deng,5 Jia-Cheng Yin,1,2 Lei Jin,1,2 Xi-Fei Jiang,1,2 Yu-Fu Zhou,1,2 Wei-Feng Qu,1,2 Zheng Tang,1,2 Han Wang,1,2 Chen-Yang Tao,1,2 Yuan Fang,1,2 Shuang-Jian Qiu,1,2 Jian Zhou,1–2,6 Jing-Feng Liu,3,4 Jia Fan,1–2,6 Ying-Hong Shi1,21Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, People’s Republic of China; 3Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Department of Health Statistics and Social Medicine, Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai, People‘s Republic of China; 6Institutes of Biomedical Sciences, Fudan University, Shanghai, People‘s Republic of China*These authors contributed equally to this work Purpose: To develop and validate a decision aid to help make individualized estimates of tumor recurrence for patients with resected combined hepatocellular cholangiocarcinoma (CHC).Patients and methods: Risk factors of recurrence were identified in the derivation cohort of 208 patients who underwent liver resection between 1995 and 2014 at Zhongshan Hospital to develop a prediction score. The model was subsequently validated in an external cohort of 101 CHC patients using the C concordance statistic and net reclassification index (NRI).Results: On multivariate analysis, five independent predictors associated with tumor recurrence were identified, including sex, γ-glutamyl transferase, macrovascular invasion, hilar lymphoid metastasis and adjuvant transcatheter arterial chemoembolization. The prediction score was constructed using these 5 variables, with scores ranging from 0 to 5. A patient with a score of 0 had a predicted 1- and 5-year recurrence risk of 11.1% and 22.2%, respectively. In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th, TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090–0.279, P

Yunfang Zhou,1,* Shuanghu Wang,1,* Xuhua Ying,2 Yifan Wang,2 Peiwu Geng,1 Aiping Deng,3 Zhihong Yu3 1The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, 2Cancer Institute of Integrative Medicine, Zhejiang Academy of Chinese Medicine, Hangzhou, 3Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy. Keywords: multidrug resistance, doxorubicin, indomethacin, redox-responsive, micelles, breast cancer

Yanfang Zhou,1,* Jiemei Li,1,* Fang Lu,1 Junjie Deng,2 Jiahua Zhang,1 Peijie Fang,1 Xinsheng Peng,1 Shu-Feng Zhou3 1Guangdong Medical Universtity, Dongguan, Guangdong, People’s Republic of China; 2Department of Materials Science and Engineering, Drexel University, Philadelphia, PA, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA *These authors contributed equally to this work Abstract: Dendrimers are hyperbranched macromolecules with well-defined topological structures and multivalent functionalization sites, but they may cause cytotoxicity due to the presence of cationic charge. Recently, we have introduced alkyne-terminated poly(amidoamine) (PAMAM) dendrons of different generations (G=2,3) into chitosan to obtain dendronized chitosan derivatives [Cs-g-PAMAM (G=2,3)], which exhibited a better water solubility and enhanced plasmid DNA transfection efficiency. In this study, we attempted to examine the impact of Cs-g-PAMAM (G=2,3) at different concentrations (25 µg/mL, 50 µg/mL, and 100 µg/mL) on the morphology, surface structure, and viability of rat red blood cells (RBCs). The results showed that treatment of RBCs with Cs-g-PAMAM (G=2,3) at 50 µg/mL and 100 µg/mL induced a slightly higher hemolysis than Cs, and Cs-g-PAMAM (G=3) caused a slightly higher hemolysis than Cs-g-PAMAM (G=2), but all values were 0.05). Furthermore, Cs-g-PAMAM (G=2,3) exhibited a lower cytotoxicity in human kidney 293T cells. These results indicate that Cs-g-PAMAM (G=2,3) are hemocompatible but may disturb membrane and lipid structures at higher concentrations. Further safety and biocompatibility evaluations are warranted for Cs-g-PAMAM. Our findings prove helpful for a better understanding of the advantages of combining PAMAM dendrimers and chitosan to design and develop new, safe, and effective drug delivery vehicles. Keywords: dendronized chitosan derivative, PAMAM, RBC, hemolysis, hemocompatibility

Hongliang Sun,1 Linfeng Xu,1 Tianyuan Fan,2 Hongzhi Zhan,3 Xiaodong Wang,3 Yanfei Zhou,2 Ren-jie Yang3 1Department of Interventional Therapy, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 2Pharmacy School of Beijing University, Beijing, 3Department of Interventional Therapy, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China Background: The purpose of this study was to observe the effect and feasibility of hyperthermia and the influence of heat on surrounding organs in a VX2 rabbit liver model exposed to an alternating magnetic field after embolization with ferromagnetic nanoparticles. Methods: Forty rabbits containing implanted hepatic VX2 carcinomas were divided into four groups, each containing ten rabbits. Fourteen days after tumor transplantation, we opened the abdomen to observe the size and shape of the tumor. A transfemoral retrograde approach was then used for hepatic arterial catheterization in groups B, C, and D to perform angiography and embolization. The next day, three rabbits in group B and all rabbits in group D were exposed to an alternating magnetic field, and the temperature was recorded simultaneously in the center of the tumor, at the edge of the tumor, and in the normal liver parenchyma. On day 28, all animals was euthanized to observe changes in the implanted liver tumor and the condition of the abdomen. A pathologic examination was also done. Results: Before surgery, there was no significant difference in tumor volume between the four groups. Three different temperature points (center of the tumor, edge of the tumor, and in the normal liver parenchyma) of group B under an alternating magnetic field were 37.2°C ± 1.1°C, 36.8°C ± 1.2°C, and 36.9°C ± 2.1°C, none of which were significantly different from pretreatment values. Three points basal temperature in group D showed no significant difference (F = 1.038, P = 0.413). Seven to 26 minutes after hyperthermia, the temperature at the center of the tumor and at the edge of the tumor in group D was significantly different from the corresponding points in group B and from normal liver tissue in group D (FB–D center = 5.431, PB–D center = 0.041, FB–D edge = 9.744, PB–D edge = 0.011; FD = 8.379, PD = 0.002). The highest temperature recorded at the rim of the tumor was 46°C in group D. Fourteen days later, the tumor volume in the four groups was group A 31.4 ± 20.6 cm3, group B 26.7 ± 18.2 cm3, group C 28.7 ± 9.1 cm3, and group D 25.8 ± 13.9 cm3, with no significant difference found between the groups (F = 0.218, P = 0.883). The increase in tumor volume was greatest in group A and least in group D, while that in groups B and D was similar. Conclusion: It is feasible to treat a VX2 tumor in an alternating magnetic field after embolization with magnetic nanoparticles without a significant effect on the surrounding normal liver parenchyma. Keywords: hyperthermia, ferromagnetic nanoparticles, Lipiodol®, hepatocellular carcinoma, animal model

Jifu Hao1, Xinsheng Fang2, Yanfang Zhou3, Jianzhu Wang1, Fengguang Guo1, Fei Li1, Xinsheng Peng31College of Pharmacy, Taishan Medical University, Taian, PR China; 2Agronomy Department of Shandong Agriculture University, Taian, PR China; 3School of pharmaceutical Sciences, Guangdong Medical College, Dongguan, PR ChinaAbstract: The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X1), surfactant (X2), and drug/lipid ratio (X3) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 ± 0.058 and zeta potential was -8.74 mV. The EE (%) and DL (%) could reach up to 83.29% ± 1.23% and 10.11% ± 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas–Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release.Keywords: chloramphenicol, solid lipid nanoparticle, Box-Behnken design, melt-emulsion ultrasonication and low temperature-solidification technique

Quasi-one-dimensional (1D) materials provide a superior platform for characterizing and tuning topological phases for two reasons: (i) existence for multiple cleavable surfaces that enables better experimental identification of topological classification and (ii) stronger response to perturbations such as strain for tuning topological phases compared to higher dimensional crystal structures. In this paper, we present experimental evidence for a room-temperature topological phase transition in the quasi-1D material Bi4I4, mediated via a first-order structural transition between two distinct stacking orders of the weakly coupled chains. Using high-resolution angle-resolved photoemission spectroscopy on the two natural cleavable surfaces, we identify the high-temperature β phase to be the first weak topological insulator with two gapless Dirac cones on the (100) surface and no Dirac crossing on the (001) surface, while in the low-temperature α phase, the topological surface state on the (100) surface opens a gap, consistent with a recent theoretical prediction of a higher-order topological insulator beyond the scope of the established topological materials databases that hosts gapless hinge states. Our results not only identify a rare topological phase transition between first-order and second-order topological insulators but also establish a novel quasi-1D material platform for exploring unprecedented physics.

Autosomal-dominant spinocerebellar ataxias constitute a large, heterogeneous group of progressive neurodegenerative diseases with multiple types. To date, classical genetic studies have revealed 31 distinct genetic forms of spinocerebellar ataxias and identified 19 causative genes. Traditional positional cloning strategies, however, have limitations for finding causative genes of rare Mendelian disorders. Here, we used a combined strategy of exome sequencing and linkage analysis to identify a novel spinocerebellar ataxia causative gene, TGM6. We sequenced the whole exome of four patients in a Chinese four-generation spinocerebellar ataxia family and identified a missense mutation, c.1550T-G transition (L517W), in exon 10 of TGM6. This change is at a highly conserved position, is predicted to have a functional impact, and completely cosegregated with the phenotype. The exome results were validated using linkage analysis. The mutation we identified using exome sequencing was located in the same region (20p13-12.2) as that identified by linkage analysis, which cross-validated TGM6 as the causative spinocerebellar ataxia gene in this family. We also showed that the causative gene could be mapped by a combined method of linkage analysis and sequencing of one sample from the family. We further confirmed our finding by identifying another missense mutation c.980A-G transition (D327G) in exon seven of TGM6 in an additional spinocerebellar ataxia family, which also cosegregated with the phenotype. Both mutations were absent in 500 normal unaffected individuals of matched geographical ancestry. The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family as an effective and cost efficient method for mapping genes of rare Mendelian disorders and the use of linkage analysis and exome sequencing for further improving efficiency. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and is particularly prevalent in China. China is also a hyperendemic area for hepatitis B virus (HBV) infection. Although a strong association between HBV infection and HCC has been established previously, the role of hepatitis C virus (HCV) infection and the interaction between HBV and HCV in the development of HCC has not been adequately explored. The major objective of this study is to determine the relationship between HBV or HCV infection and HCC by use of case-control study in Henan, China.Method: In all, 152 HCC patients and 115 control patients were collected from four hospitals in Henan, China between January 1994 and October 1995. The demographic characteristics of the two groups were comparable. In further analysis, a 1:1 pair-matched case-control study was performed. Of 152 HCC patients, 113 were randomly selected to be pair-matched by sex and age (+/-5 years) to controls with non-hepatic disease. All the cases and controls were interviewed during hospitalization by two specially trained interviewers using a standard questionnaire. All sera were tested for HBV and HCV markers. Odds ratios (OR) and 95% CI for HCC risk factors were calculated by logistic regression model controlling for possible confounding factors such as sex and age. The multivariate analysis was done on the basis of the univariate analysis.Results: The results of this study indicated that the prevalence of hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) were much higher in HCC patients (63.2% and 11.2% respectively) than in the control patients (5.2%, 3.5%). The difference between two groups was significant (P < 0.05). Risk factor analysis revealed that both HBV and HCV infection were important factors for HCC in Henan, China and HBV appeared to have a key role in the development of HCC. Odds ratios of HBsAg and HBV infection were 28.82 (95% CI: 11.18-78.78) and 31.22 (95% CI: 13.86-72.15), respectively. Moreover, the risk of developing HCC increased significantly and showed an additive effect when both viral markers of HBV and HCV infection were considered (OR = 42.85). Results from the 1:1 pair-matched case-control study also showed that HBV infection was an important risk factor for HCC, which was consistent with the results from the group-matched case-control study.Conclusion: This is the first reported case-control study of HCC in Henan, China. This study provides further evidence that chronic HBV infection is strongly associated with the development of HCC among this population. Our results have demonstrated that HCV and HBV infection are independent and probably additive risk factors for HCC. [ABSTRACT FROM AUTHOR]

Background: Preoperative diagnosis of malignancy in patients with pancreatic cystic lesions (PCLs) remains challenging. The aim of this study was to assess the sensitivity, specificity, and positive and negative likelihood ratios (LRs) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA)-based cytology in differentiating malignant PCLs from benign PCLs., Methods: A comprehensive search was performed in multiple databases in November 2023. Studies differentiating benign and malignant PCLs via EUS-FNA-based cytology, in which the results were compared with those of surgical excision histopathology, were included in this meta-analysis. Data from the selected studies were pooled to summarize the sensitivity, specificity, positive and negative LRs, diagnostic odds ratios and summary receiver operating characteristic (SROC) curves., Results: We included 755 patients from 15 distinct studies who underwent EUS-FNA-based cytology and had a histopathological diagnosis. The pooled sensitivity and specificity in diagnosing malignant PCLs were 0.62 (95% CI, 0.42-0.78) and 0.96 (95% CI, 0.91-0.98), respectively. The positive and negative LRs for diagnosing malignant PCLs were 16.3 (95% CI, 7.2-37.0) and 0.40 (95% CI, 0.25-0.64), respectively. The area under the curve (AUC) was 0.94 (95% CI, 0.91-0.95)., Conclusions: EUS-FNA-based cytology has overall high specificity, medium sensitivity and good diagnostic accuracy in differentiating malignant from benign PCLs. Further research is needed to improve the overall sensitivity of EUS-FNA-based cytology for the diagnosis of malignant PCLs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Ding et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Thyroid-associated ophthalmopathy (TAO) is the most common orbital disease in adults. Ocular surface diseases are the most common cause of ocular discomfort in patients with TAO, seriously affecting the quality of life of patients. The manifestations of ocular surface damage include dry eye, conjunctival congestion, edema, exposure keratitis, superficial punctate keratopathy and superior limbal keratoconjunctivitis, among which the incidence of dry eye is the highest. The pathogenesis of dry eye in TAO is rather complex. In addition to the exposure of the ocular surface caused by anatomical changes such as proptosis and eyelid retraction, in recent years, an increasing number of studies have indicated that ocular surface microenvironmental damages such as immune injury of the lacrimal gland, abnormal structure and function of meibomian glands, and chronic ocular surface inflammation are also involved in its pathogenesis. This article reviews the latest research progress on the ocular surface changes in patients with TAO and the pathogenesis of its dry eye, hoping to provide assistance for the clinical treatment of dry eye in TAO.

The oregano essential oil (OEO) nanoemulsion was prepared, and the effects of different added amounts of OEO nanoemulsion on the mechanical and antibacterial properties of PSE-like chicken protein isolate (PPI) film were investigated. Results revealed that the nanoemulsion containing 12 % Tween 80 and 6 % OEO had the smallest particle size (82.46 nm) and the best stability. Compared to the control group, the film of the PPI/OEO-2.5 % treatment group demonstrated superior mechanical properties. With the increase of the concentration of OEO nanoemulsion, the UV transmittance and water contact angle of the films decreased gradually (more hydrophilic), the opacity and water vapor permeability significantly increased, while the thermal stability, antioxidant properties (DPPH scavenging activity, 17.07 % ∼ 56.00 %), and antibacterial properties were markedly enhanced. The PPI/OEO-2.5 % treated film was applied to the preservation of pork, extending the shelf life by 2-4 days. These findings suggested that PPI had great application potential in bioactive packaging materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a kind of pulmonary vascular lesion characterized by vasoconstriction and reshaping of small pulmonary arteries, ultimately resulting in increased pulmonary artery pressure and pulmonary vascular resistance, and eventually leading to right ventricular failure and death. This study was aimed to construct a platelet-derived growth factor BB (PDGF-BB)-induced rat pulmonary artery smooth muscle cells (PASMCs) model and conduct a combined transcriptomic and metabolomic analysis to identify proliferation-related targets, thereby enhancing understanding of the pathogenesis underlying PAH., Methods: Rat PASMCs were isolated and cultured in the presence or absence of PDGF-BB for 24 hours. Cells were collected for transcriptomics and metabolomics investigations., Results: A total of 1288 differentially expressed genes (572 up-regulated and 716 down-regulated) were identified in PDGF-BB-treated rat PASMCs compared to control cells. Subsequently, Gene ontology (GO) enrichment analysis revealed that 791 enriched GO terms were significantly enriched in PDGF-BB treated cells. Similarly, 294 differential metabolic pathways were enriched in PDGF-BB treated cells according to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA) were performed on the differentially expressed genes (DEGs). It turned out that 7219 gene sets were more enriched in PDGF-BB treated cells. In addition, a total of 28 secondary differential metabolites were identified in PDGF-BB-treated rat PASMCs compared to control cells (p-value < 0.05 and VIP > 1)., Conclusions: We speculate that Mylk, Pla2g4a, Gucy1b1, Adcy8, Adcy4, Gucy1a2, Col3a1, and Plcb4 are potential targets for the treatment of PAH., (© The Author(s) 2025. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pediatric septic shock is a critical condition associated with high mortality rates, largely due to sepsis-induced immunosuppression. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been explored as a therapeutic intervention to counteract this immunosuppression. Despite its potential, the efficacy of GM-CSF in pediatric septic shock has not been clearly established. This study aims to investigate the impact of GM-CSF administration on survival rates and to identify key predictors of treatment outcomes in pediatric septic shock patients., Methods: We conducted a retrospective cohort study at the Pediatric Intensive Care Unit (PICU) of Children's Hospital of Fudan University, Shanghai, from January 1, 2019, to December 31, 2023. The study included pediatric patients diagnosed with septic shock, analyzing their demographic data, GM-CSF and adjunctive therapies, laboratory results, and clinical outcomes. We employed univariate and multivariate logistic regression models to assess the influence of GM-CSF on 28-day mortality and identify significant predictors of treatment outcomes., Results: The study included 200 pediatric patients, with 66 receiving GM-CSF treatment and 134 not treated with GM-CSF. The initial comparison showed a higher 28-day mortality in the GM-CSF group (59.1%) compared to the non-GM-CSF group (35.1%, P = 0.001). Notably, after adjustment for confounding factors, multivariate analysis revealed that the effect of GM-CSF treatment on 28-day mortality among pediatric septic shock patients did not reach statistical significance, with an odds ratio (OR) of 0.472 and a 95% confidence interval (CI) ranging from 0.153 to 1.457 (P = 0.192). However, the analysis indicated a potential trend suggesting that GM-CSF treatment may contribute to a reduction in 28-day mortality. In addition, significant predictors of treatment outcomes included hematopoietic stem cell transplantation (HSCT), lactic acid (LAC) levels, hospital-acquired septic shock (HASS), red blood cell (RBC) count, and platelet (PLT) count., Conclusions: GM-CSF treatment may benefit pediatric septic shock patients, especially those with higher lactic acid, and lower RBC and platelet counts. These factors, which are significant predictors of outcomes, should be monitored during therapy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study protocol was approved by the Medical Ethics Committee of the Children’s Hospital of Fudan University [No.97 (2024)] and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The patient’s informed consent has been obtained from the patient’s legal guardian. Consent for publication: Informed consent was obtained from legal guardians of all patients who participated in the study for publication of anonymous patients’ data, (© 2025. The Author(s).)

Objective: To explore the construction method of a resistant multiple myeloma (MM) patient-derived xenotransplantation (PDX) model., Methods: 1.0×10 7 MM patient-derived mononuclear cells (MNCs), 2.0×10 6 MM.1S cells and 2.0×10 6 NCI-H929 cells were respectively subcutaneously inoculated into NOD.CB17-Prkdc scid Il2rg tm1 / Bcgen (B-NDG) mice with a volume of 100 μl per mouse to establish mouse model. The morphologic, phenotypic, proliferative and genetic characteristics of PDX tumor were studied by hematoxylin-eosin staining, immunohistochemical staining (IHC), cell cycle analysis, flow cytometry and fluorescence in situ hybridization (FISH). The sensitivity of PDX tumor to bortezomib and anlotinib monotherapy or in combination was investigated through cell proliferation, apoptosis and in vitro and in vivo experiments. The effects of anlotinib therapy on tumor blood vessel and cell apoptosis were analyzed by IHC, TUNEL staining and confocal fluorescence microscope., Results: MM PDX model was successfully established by subcutaneously inoculating primary MNCs. The morphologic features of tumor cells from MM PDX model were similar to those of mature plasma cells. MM PDX tumor cells positively expressed CD138 and CD38, which presented 1q21 amplification, deletion of Rb1 and IgH rearrangement, and had a lower proliferative activity than MM cell lines. in vitro , PDX, MM.1S and NCI-H929 cells were treated by bortezomib and anlotinib for 24 hours, respectively. Cell viability assay showed that the IC 50 value of bortezomib were 5 716.486, 1.025 and 2.775 nmol/L, and IC 50 value of anlotinib were 5 5107.337, 0.706 and 5.13 μmol/L, respectively. Anlotinib treatment increased the apoptosis of MM.1S cells ( P < 0.01), but did not affect PDX tumor cells ( P >0.05). in vivo , there was no significant difference in PDX tumor growth between bortezomib monotherapy group and control group ( P >0.05), while both anlotinib monotherapy and anlotinib combined with bortezomib effectively inhibited PDX tumor growth (both P < 0.05). The vascular perfusion and vascular density of PDX tumor were decreased in anlotinib treatment group (both P < 0.01). The apoptotic cells in anlotinib treatment group were increased compared with those in control group ( P < 0.05)., Conclusion: Bortezomib-resistant MM PDX model can be successfully established by subcutaneous inoculation of MNCs from MM patients in B-NDG mice. This PDX model, which retains the basic biological characteristics of MM cells, can be used to study the novel therapies.

Atherosclerosis and its associated cardio-cerebrovascular complications remain the leading causes of mortality worldwide. Current lipid-lowering therapies reduce only approximately one-third of the cardiovascular risk. Furthermore, vascular restenosis and thrombotic events following surgical interventions for severe vascular stenosis significantly contribute to treatment failure. This highlights the urgent need for novel therapeutic targets to manage atherosclerosis and prevent restenosis and thrombosis after vascular injury. This study identifies TTK protein kinase (TTK) as a key regulator of vascular smooth muscle cell (VSMC) phenotypic switching in the context of postinjury neointimal formation and atherosclerosis. Mechanistically, TTK upregulation in VSMCs phosphorylates p120-catenin, leading to β-catenin nuclear accumulation and dissociation of the myocardin (MYOCD)/serum response factor (SRF) complex. Deletion of TTK specifically in VSMCs reduces postinjury neointimal formation in vascular injury models and attenuates atherosclerotic lesions in ApoE -/- mice. Notably, oral administration of the TTK inhibitor CFI-402257 mitigated neointimal formation without impairing reendothelialization and reduced atherosclerotic lesions in ApoE -/- mice without altering lipid levels. These findings suggest that targeting TTK, through inhibitors or alternative strategies, represents a promising approach to simultaneously prevent postinjury restenosis and treat atherosclerosis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Purpose: This study compared the efficacy and acceptability of a ready-to-use intranasal dexmedetomidine spray (DS) versus traditional drops administered by syringe (DD) in pediatric patients undergoing elective surgery., Patients and Methods: Eighty-six preschool children were enrolled in a prospective, randomized, controlled study. Children were randomly assigned to receive either DS or DD. For children weighing between 10.5 and 18.5 kg, a dexmedetomidine dosage of 30 μg (two sprays) was administered, while those weighing between 18.5 and 25.5 kg received 45 μg (three sprays). In the DD group, dexmedetomidine was administered at a dose of 2 μg/kg based on body weight. The primary outcome was the proportion of children achieving a Ramsay sedation scale (RSS) score of ≥3 within 30 min. Secondary outcomes included acceptance of intranasal medication, anxiety at parental separation and prior to induction, and compliance with induction., Results: A total of 83 cases were analyzed. The proportion of children achieving an RSS score of ≥3 within 30 min was similar between the DS and DD groups (90.7% vs. 77.5%, respectively). However, the acceptance score was significantly better in the DS group (mean difference [95%]: -0.9 [-1.267 to -0.5325], P < 0.001). No significant differences were observed between the groups in terms of successful child-parent separation (88.4% vs. 85%) or satisfactory anxiolytic effect prior to induction (95.3% vs. 92.5%). Compliance with induction was comparable, with 53.5% in the DS group and 40.0% in the DD group demonstrating "optimal" compliance., Conclusion: Both intranasal spray and syringe drop methods were highly effective in providing sedation and anxiolysis, but the ready-to-use intranasal dexmedetomidine spray was more acceptable to children, offering a viable alternative to the syringe method., Clinical Trial Registration: ChiCTR.org.cn, identifier ChiCTR2400089374., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Jin, Cai, Zhou, Zhang, Chen, Xu, Li and Yuan.)

Background: The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC., Methods: Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (-4A) MAF1, or short-hairpin MAF1 (shMAF1). Liver tissues and tumors were harvested and analyzed using histology, immunohistochemistry, immunoblotting, quantitative reverse-transcription PCR, and flow cytometry. MAF1 was overexpressed or knocked down in HCC cells via lentiviral transfection. Cell lines were analyzed using RNA sequencing, immunoblotting, dual luciferase reporter, and chromatin precipitation assays., Results: Both MAF1-WT and MAF1-4A proteins significantly inhibit hepatocarcinogenesis in mice, with the mutant form exhibiting a stronger suppressive effect. Although MAF1 knockdown alone does not induce abnormalities in the mouse liver, it accelerates c-Myc-induced carcinogenesis. Our results provide the first in vivo evidence that MAF1 plays a tumor suppressor role by activating PTEN to suppress the AKT-mammalian target of rapamycin signaling pathway during hepatocarcinogenesis in physiologically relevant tumor models. More importantly, we found that MAF1 not only enhances the intratumoral infiltration of CD8 + T cells by increasing CXCL10 secretion but also enhances their functional activity by inhibiting PDL1 transcription in mouse liver cancer, which were confirmed in human HCC or in vitro experiments. Furthermore, PDL1 overexpression accelerates mouse hepatocarcinogenesis by antagonizing the tumor-suppressive role of MAF1., Conclusions: Our study uncovers a novel anti-tumor immunity of MAF1 in hepatocarcinogenesis and human HCC. These findings suggest that the stimulated MAF1 could potentially improve immunotherapy in combination with immune checkpoint inhibitors in HCC patients, especially in those with an absence of T cells in HCC tissues., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Rice bacterial blight is a devastating disease worldwide, causing significant yield losses. Understanding how plants defend against microbial infection is critical for sustainable crop production. In this study, we show that ALEX1, a previously identified pathogen-induced long noncoding RNA, localizes to the nucleus and directly binds AUXIN RESPONSE FACTOR 3 (ARF3). We showed that ARF3 forms the condensates in the nucleus via its intrinsically disordered middle region (MR), and that these ARF3 condensates display solid-like properties. We further revealed that ALEX1 directly binds the MR of ARF3 to regulate ARF3 condensate dynamics and promote ARF3 homodimerization. The dispersed, dimeric form of ARF3, referred to as its functional phase state, enhances its ability to transcriptionally repress the expression of downstream target genes such as JAZ13, thereby modulating the jasmonic acid signaling pathway and enhancing pathogen resistance in rice. Collectively, this study reveals the role of a long noncoding RNA in regulating protein condensation and complex assembly, thus contributing to plant pathogen resistance., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Protein lysine crotonylation has been found to be closely related to the occurrence and development of various diseases. Currently, site identification of crotonylation is mainly dependent on antibody enrichment; however, due to the cost, heterogeneity, and specificity of antibodies, it is desired to develop an alternative chemical tool to detect crotonylation. Herein, we report an alkynyl-functionalized bioorthogonal chemical probe, Cr-alkyne, for the detection and identification of protein lysine crotonylation in mammalian cells. Our in-gel fluorescence and chemical proteomic analyses demonstrated that Cr-alkyne can be metabolically incorporated into lysine of histones and directly label known crotonylated proteins. We further applied Cr-alkyne to the proteome-wide profiling of crotonylation and revealed a large number of previously unreported modification sites, some of which could be validated by co-elution with synthetic peptides. Moreover, by integrating Cr-alkyne with quantitative chemical proteomics, we also explored the crotonylation sites regulated by HDACs, unveiling new HDAC regulated sites. Our study thus provides an enabling chemical tool for characterizing protein crotonylation and greatly expands our understanding of substrate proteins and functions of this important modification., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Glucose transporter 1 deficiency syndrome (Glut1DS) was initially reported by De Vivo and colleagues in 1991. This disease arises from mutations in the SLC2A1 and presents with a broad clinical spectrum. It is a treatable neuro-metabolic condition, where prompt diagnosis and initiation of ketogenic dietary therapy can markedly enhance the prognosis. However, due to its rarity, Glut1DS is susceptible to misdiagnosis or missed diagnosis, which can lead to delayed treatment and irreversible dysfunction of the central nervous system. To promote diagnostic awareness and effective treatments, the recommendations for diagnosis and treatment have been developed., Methods: The panel on Glut1DS included 28 participants from the members of the Ketogenic Diet Professional Committee of the Chinese Epilepsy Association and Chinese experts with extensive experience in managing Glut1DS. All authors extensively reviewed the literature, and the survey results were discussed in detail over several online meetings. Following multiple deliberative sessions, all participants approved the final manuscript for submission., Results: Early diagnosis and timely treatment of Glut1DS are crucial for improving prognosis. Physicians should be alert to suspiction of this disease if the following clinical manifestations appear: seizures, episodic or persistent movement disorders (often triggered by fasting, fatigue, or exercise), delayed motor and cognitive development. Characteristic clinical presentations may include seizures combined with movement disorders, episodic eye-head movements, and paroxysmal exercise-induced dyskinesia (PED). In these cases, genetic testing should be promptly completed, and a lumbar puncture should be performed if necessary. The ketogenic diet is internationally recognized as the first-line treatment; the earlier it is started, the better the prognosis. It can effectively control seizures and improve motor disorders. Antiepileptic drug treatment is generally ineffective or provides limited symptom improvement before starting the ketogenic diet., Conclusion: The recommendations provide clinicians with a relatively systematic guide for the rapid identification, diagnosis, and timely treatment of Glut1DS., Competing Interests: Declarations. Conflict of interest: No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Ethical approval: Not required., (© 2024. The Author(s).)

Oxidative stress is a major contributor to the difficulties in chronic wound healing. Although antioxidant hydrogels have been developed, they are still insufficient for addressing the entire chronic wound healing process. In this study, a lutein-loaded multifunctional hydrogel dressing (Lutein/CMC/PVP/TA, Lutein/CPT) with synergistic antioxidation properties was developed by hydrogen bonding and electrostatic crosslinking of tannic acid (TA) with carboxymethyl chitosan (CMC) and polyvinylpyrrolidone (PVP). When loaded with 5 mg/mL of lutein, the 5Lutein/CPT hydrogel showed suitable swelling ratio, degradation rate, stability and biocompatibility. The hydrogel dressing demonstrates excellent self-healing behavior (≤20 s) and effectively extends the service life of the dressing. Importantly, this hydrogel displays pH-responsive drug release characteristics to meet the needs of the wound healing process. Specifically, under alkaline conditions (the initial stage of wound healing), TA and lutein are simultaneously released for synergistic antioxidant use in scavenging reactive oxygen species (ROS) and resolving inflammation. Under acidic conditions (late stage of wound healing), lutein is released to facilitate collagen formation. Additionally, the hydrogels demonstrated excellent antimicrobial (E. coli, S. aureus, and MRSA) activity and anti-biofilm ability. Animal experiments have shown that the 5Lutein/CPT hydrogel can promote wound closure, collagen fiber generation, angiogenesis and anti-inflammation. In conclusion, 5Lutein/CPT hydrogel dressings hold potential as candidate materials for promoting diabetic wound healing. Moreover, this study provides novel insights into the combined use of natural plant antioxidants in CMC-based hydrogel dressings to treat chronic wounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Bauxite processing residue produced at an Alumina refinery was used to produce manufactured soil. The residue was first acidified and then leached to remove excess salts. Green waste compost was added at rates of 5 and 10 % w/w, with or without the addition of 20 % w/w dune sand. The products were dried, crushed and sieved and the chemical, physical and microbial properties of the materials characterized. Products had an electrical conductivity and pH of 1.0-1.1 dS m -1 and 8.0-8.1 respectively in 1:5 soil:water extracts and corresponding values in saturation paste extracts were 5.4-5.7 dS m -1 and 7.4-7.5. The effective cation exchange capacity was 202-351 mmol c  kg -1 , exchangeable Na percentage was 41-46 %, Colwell-extractable P was 108-119 mg kg -1 and the Toxicity Characteristic Leaching Procedure showed that extractable metal concentrations were an order of magnitude below regulatory limits so the material can be considered as non-hazardous. Diethylenetriaminepentaacetic acid-extractable Cu, Zn and Mn were below reported critical levels. Addition of compost lowered concentrations of extractable Cr, As and V and drying the material further reduced extractable levels. When the material was dried it shrunk and solidified and the aggregates produced had a low macroporosity and high microporosity and water holding capacity compared with dune sand. Aggregates were very stable as measured by wet sieving. Compost addition increased organic C content, and the size (microbial biomass C) and activity (basal respiration and the activity of enzymes involved in C, N, S and P mineralization) of the soil microbial community. It was concluded that the materials produced had soil-like chemical, physical and microbial properties and could potentially be used as a soil substitute., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To investigate the levels of β-amyloid 1-42 (Aβ1-42) and total bilirubin (TBIL) in serum of patients with Alzheimer 's disease (AD) and the relationship between them. Methods: A case-control study was conducted to select 73 patients with AD who were hospitalized in Beijing Huilongguan Hospital from November 2023 to February 2024 as AD group, and 70 healthy controls (HC) were selected as HC group. The basic information of all subjects and the clinical information of AD patients were collected, and the levels of Aβ1-42 and TBIL were detected and compared between the two groups. The effects of Aβ1-42 and TBIL on AD were analyzed by binary logistic regression. Correlation analysis was used to analyze the relationship between TBIL and Aβ1-42 in AD group and HC group. According to the level of Aβ1-42 in AD patients, they were divided into Aβ1-42 elevated group and Aβ1-42 normal group. The differences of clinical data and TBIL levels between the two groups were compared. According to the quartile of TBIL in AD patients, they were divided into Q1 group, Q2 group, Q3 group and Q4 group. The correlation between TBIL and the risk of Aβ1-42 elevation was analyzed by binary logistic regression. The receiver operating characteristic (ROC) curve was drawn to analyze the ability of TBIL level to predict the increase of Aβ1-42 in AD patients. Results: There was no significant difference in gender, marital status, education level, smoking and drinking between AD group and HC group ( P> 0.05), while the levels of Aβ1-42 and TBIL and age in AD group were significantly higher than those in HC group [101.10(71.20, 128.60) pg/ml/22.40(10.00, 39.60) pg/ml , Z =-8.714, P <0.001;(11.00±3.22/8.07±3.00) μmol/L , t =5.621, P <0.001;(77.14±8.20/68.30±10.27) years, t =5.672, P <0.001]. For AD patients, the TBIL level in the Aβ1-42 elevated group was lower than that in the Aβ1-42 normal group [(10.05±2.94/11.66±3.28) μmol/L , t =-2.148, P =0.035], while there was no significant difference in other demographic and clinical data between the two groups ( P >0.05). Binary logistic regression analysis showed that higher levels of Aβ1-42 ( OR =1.021, 95% CI ：1.010-1.032) and TBIL ( OR =1.505, 95% CI ：1.249-1.814), older age ( OR =1.083, 95% CI ：1.020-1.150) and female ( OR =4.348, 95% CI ：1.253-15.094) were risk factors for AD. Correlation analysis showed that TBIL was negatively correlated with Aβ1-42 in AD patients ( r= -0.322, P =0.006). After adjusting the relevant covariates, binary logistic regression showed that compared with AD patients in Q1 group, the risk of Aβ1-42 elevation in AD patients in Q4 group was lower ( OR =0.052, 95% CI ：0.005-0.535, P <0.05), and TBIL was negatively correlated with the risk of Aβ1-42 elevation ( P trend<0.05). ROC curve showed that the area under the curve (AUC) of TBIL in predicting the increase of Aβ1-42 in AD patients was 0.642. Conclusion: The levels of Aβ1-42 and TBIL in AD patients were higher, and the level of TBIL was negatively correlated with the risk of Aβ1-42 elevation.

Aims: Methicillin-resistant Staphylococcus aureus (MRSA) is an important zoonotic pathogen with multidrug-resistant phenotypes increasingly prevalent in both human and veterinary clinics. This study evaluated the potential of auranofin (AF) as an antibiotic adjuvant to enhance the anti-MRSA activity of florfenicol (FFC) and established a pharmacokinetic/pharmacodynamic (PK/PD) model to compare the efficacy of FFC alone or in combination with AF against MRSA., Methods and Results: We observed an increased susceptibility and significant synergistic effects of MRSA to FFC in the presence of AF. The combination treatment of FFC and AF significantly inhibited MRSA biofilm formation and decreased the metabolic activity of mature biofilms. Importantly, AF fully restored the efficacy of FFC in both Galleria mellonella larvae and murine models. PK/PD studies demonstrated that the AUC24h/MIC targets required to achieve the bacteriostatic and bactericidal effects were significantly lower with the combination therapy compared to florfenicol monotherapy., Conclusions: These results reveal the potential of AF as a novel adjuvant to improve the efficacy of FFC in treating MRSA invasive infections and provide valuable PK/PD insights for designing effective combination therapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

The increasing antibiotic resistance poses a significant global health challenge, threatening our ability to combat infectious diseases. The phenomenon of collateral sensitivity, whereby resistance to one antibiotic is accompanied by increased sensitivity to another, offers potential avenues for novel therapeutic interventions against infections unresponsive to classical treatments. In this study, we elucidate the emergence of tobramycin (TOB)-resistant small colony variants (SCVs) due to mutations in the hemL gene, which render S . Typhimurium more susceptible to nitrofurantoin (NIT). Mechanistic studies demonstrate that the collateral sensitivity in TOB-resistant S . Typhimurium SCVs primarily stems from disruptions in haem biosynthesis. This leads to dysfunction in the electron transport chain (ETC) and redox imbalance, ultimately inducing lethal accumulation of reactive oxygen species (ROS). Additionally, the upregulation of nfsA/B expressions facilitates the conversion of NIT prodrug into its active form, promoting ROS-mediated bacterial killing and contributing to this collateral sensitivity pattern. Importantly, alternative NIT therapy demonstrates a significant reduction of bacterial load by more than 2.24-log 10 cfu/g in the murine thigh infection and colitis models. Our findings corroborate the collateral sensitivity of S . Typhimurium to nitrofurans as a consequence of evolving resistance to aminoglycosides. This provides a promising approach for treating infections due to aminoglycoside-resistant strains.

Background: The liver plays a crucial role in detoxification and metabolism. When its capacity to metabolize foreign substances is exceeded, it can lead to acute liver injury (ALI). Therefore, preventing liver disease and maintaining daily liver health are of utmost importance. Xiaobugan Decoction (XBGD), a traditional Chinese medicine (TCM) formula, is recorded in 'Fuxingjue', is used in folk practice to promote liver health and regulate respiration. However, the hepatoprotective mechanisms of XBGD remained unclear., Purpose: We investigated the prophylactic and hepatoprotective effects of XBGD and explored its related molecular mechanisms using a mouse model of carbon tetrachloride (CCl 4 )-induced ALI., Study Design and Methods: XBGD composition was determined using analytical methods, and the main compounds were identified using ultra-high-performance liquid chromatography coupled with Q-Exactive focus mass spectrum (UHPLC-QE-MS) and high-performance liquid chromatography (HPLC). A CCl 4 -induced L02 cell injury model was employed to explore the protective effects of XBGD on liver cells, and a CCl 4 -induced ALI mouse model was used to investigate the hepatoprotective effects of XBGD., Results: Cellular experiments demonstrated that XBGD had a protective function against L02 cell damage by increasing cell viability, restoring alanine aminotransferase (ALT), aspartate aminotransferase (AST), and superoxide dismutase (SOD) levels, reducing malondialdehyde (MDA) content, and improving mitochondrial membrane potential (ΔΨm). In the mouse ALI model, XBGD prevented ALI by reducing ALT, AST, and alkaline phosphatase (ALP) levels and inhibiting oxidative stress. Quantitative real-time polymerase chain reaction (qPCR), immumohistochemical staining and western blotting results revealed that XBGD exerted hepatoprotective effects by reducing inflammatory responses and inhibiting cell apoptosis. Furthermore, 1 H-NMR metabolomics indicated that XBGD regulates hepatic and intestinal metabolism, whereas 16S rDNA sequencing demonstrated the regulatory effects of XBGD on the gut microbiota. Correlation analysis highlighted the close relationship among gut microbiota, metabolites, and ALI indicators., Conclusions: XBGD is a promising TCM for the prevention of CCl 4 -induced ALI via regulation of microbiota and metabolism. This study provides a new perspective on the development of hepatoprotective measures and the prevention of liver disease in daily life., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Abstract: Objective: The study investigated the effects of air pollutants on the incidence of acute angle-closure glaucoma (AACG) in Hefei, China.Methods: A combination of generalized additive models (GAM) and distributed lag non-linear models (DLNM) was used to explore the relationship between air pollutants and the incidence of AACG.Results: Exposure-response curves showed that exposure to PM 2.5 , PM 10 , NO 2 , SO 2 , CO, and O 3 were all positively correlated with the onset of AACG. Among them, NO 2 , and CO having higher relative risk values for AACG onset.Conclusions: This study highlighted the potential risks of these pollutants and expanded the knowledge of the environmental role in AACG incidence, which will encourage local governments to adopt policy measures and guidance to improve public health., Competing Interests: Conflict of Interest for All Authors NONE DECLARED, (Copyright © 2024 American College of Occupational and Environmental Medicine.)