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Junping Zhu,1– 3 Ziyan Wang,4,5 Chengxin Liu,4,5 Min Shi,1,5 Zhihua Guo,1,4,5 Ya Li,2 Rong Yu,1,3 Jiaming Wei1,5 1School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 3Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 4First Hospital and First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 5Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan Universities of Chinese Medicine, Changsha, 410208, People’s Republic of ChinaCorrespondence: Jiaming Wei; Rong Yu, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, 300 Xueshi Road, Science & Technology Industrial Park, Yuelu District, Changsha, Hunan, 410208, People’s Republic of China, Email 004916@hnucm.edu.cn; 002165@hnucm.edu.cnBackground: Xin-Tong-Tai Granule (XTTG), a Chinese medicine (CM) formula, has demonstrated significant therapeutic effects on atherosclerosis (AS) in both clinical and experimental settings. Nonetheless, the mechanisms underlying XTTG’s efficacy remain largely unexplored. This study aimed to elucidate the mechanisms through which XTTG acts against AS, employing network pharmacology, molecular docking, and experimental validation techniques.Methods: Initially, target identification for the main chemical components of XTTG was conducted using database, followed by determining the intersection targets between these compounds and disease. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were subsequently utilized to investigate the potential pathways through which XTTG exerts its effects on AS. Molecular docking was done to confirm the binding efficacy of XTTG’s active components. Additionally, the effects of XTTG were evaluated in vitro using oxidized low-density lipoprotein (ox-LDL) induced human aortic vascular smooth muscle cells (HAVSMCs) and in vivo in apolipoprotein E gene knockout (ApoE−/−) mice fed a high-fat diet (HFD).Results: 229 therapeutic targets were screened for PPI network and enrichment analysis. Notably, the nuclear factor kappa-B (NF-κB) signaling pathway, along with processes related to inflammation and autophagy, were significantly enriched, highlighting their importance. In vitro studies showed that XTTG repressed cell proliferation and lipid droplet aggregation in ox-LDL-induced HAVSMCs. It also decreased the ratio of phosphorylated NF-κB p65/ NF-κB p65, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, and elevated microtubule-associated protein light chain 3 (LC3) and decreased p62 protein expression. In vivo, XTTG ameliorated blood lipid profiles and aortic pathology in HFD-fed ApoE−/− mice, reduced NF-κB p65 expression and serum levels of TNF-α and IL-6, increased the ratio of LC3II/LC3I while decreasing p62 protein expression.Conclusion: XTTG mitigates AS primarily through anti-inflammatory and autophagy-modulating mechanisms, particularly via inhibition of NF-κB p65 expression. These findings underscore the potential of CM in treating AS and support its further clinical exploration. Keywords: Xin-Tong-Tai granule, atherosclerosis, network pharmacology, molecular docking, experimental verification

Min Shi,1,2,* Hui Yuan,2,3,* Ya Li,4 Zhihua Guo,2,3 Jiaming Wei1,2 1School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2Hunan Key Laboratory of Colleges and Universities of Intelligent TCM Diagnosis and Preventive Treatment of Chronic Diseases, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 3First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 41020, People’s Republic of China; 4School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Guo; Jiaming Wei, Hunan University of Chinese Medicine, 300 Xue Shi Road, Hanpu Science & Education Park, YueLu District, ChangSha, 410208, People’s Republic of China, Email 004294@hnucm.edu.cn; 004916@hnucm.edu.cnAbstract: Heart failure (HF) is a disease with high morbidity and mortality rates worldwide and significantly affects human health. Currently, the treatment options for HF are limited, and there is an urgent need to discover new therapeutic targets and strategies. Macrophages are innate immune cells involved in the development of HF. They play a crucial role in maintaining cardiac homeostasis and regulating cardiac stress. Recently, macrophages have received increasing attention as potential targets for treating HF. With the improvement of technological means, the study of macrophages in HF has made great progress. This article discusses the biological functions of macrophage phagocytosis, immune response, and tissue repair. The polarization, pyroptosis, autophagy, and apoptosis are of macrophages, deeply involved in the pathogenesis of HF. Modulation of the phenotypic changes of macrophages can improve immune-inflammation, myocardial fibrosis, energy metabolism, apoptosis, and angiogenesis in HF. Keywords: heart failure, macrophage, polarization, pyroptosis, apoptosis, autophagy

Peiling Zhou,1 Shiyu Peng,2 Sizhe Wen,1 Qinghui Lan,1 Yingyin Zhuang,1 Xuyan Li,1 Mengliang Shi,1,3 Changzheng Zhang1 1Guangdong Provincial Key Laboratory of Development and Education for Special Needs Children & School of Educational Sciences, Lingnan Normal University, Zhanjiang, 524048, People’s Republic of China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3School of Education, South China Normal University, Guangzhou, 510631, People’s Republic of ChinaCorrespondence: Changzheng Zhang, School of Educational Sciences, Lingnan Normal University, 29 Cunjin Road, Zhanjiang, Guangdong Province, 524048, People’s Republic of China, Email neurozhang@163.com Mengliang Shi, School of Education, South China Normal University, 55 West Zhongshan Avenue, Shipai Street, Guangzhou, Guangdong Province, 510631, People’s Republic of China, Email 20240169@m.scnu.edu.cnAbstract: The cerebellum has long been implicated in the etiopathogenesis of autism spectrum disorder (ASD), and emerging evidence suggests a significant contribution by reciprocal neural circuits between the cerebellum and ventral tegmental area (VTA) in symptom expression. This review provides a concise overview of morphological and functional alterations in the cerebellum and VTA associated with ASD symptoms, primarily focusing on human studies while also integrating mechanistic insights from animal models. We propose that cerebello–VTA circuit dysfunctional is a major contributor to ASD symptoms and that these circuits are promising targets for drugs and therapeutic brain stimulation methods.Keywords: autism spectrum disorder, cerebellum, ventral tegmental area, neural circuit

Mengyao Shi,1,&ast; Xueyu Mao,2,&ast; Xuechun Wu,2 Min Chu,2 Huicong Niu,2 Lulu Sun,1 Xinyue Chang,1 Yu He,1 Yi Liu,1 Daoxia Guo,3 Yonghong Zhang,1 Zhengbao Zhu,1 Jing Zhao2,4 1Department of Epidemiology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 2Department of neurology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China; 3School of Nursing, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 4Institute of Healthy Yangtze River Delta, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Zhao, Department of Neurology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China, Email zhao_jing@fudan.edu.cn Zhengbao Zhu, Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, Jiangsu Province, 215123, People’s Republic of China, Email zbzhu@suda.edu.cnBackground: Prealbumin is a symbol of protein nutrition and is involved in anti-inflammatory and neuron regeneration, but its association with the prognosis of ischemic stroke remains unclear. We aimed to prospectively explore the associations between serum prealbumin levels and adverse clinical outcomes after ischemic stroke in a large-scale cohort study.Methods: We measured serum prealbumin levels among 6609 ischemic stroke patients admitted at Minhang hospital. The primary outcome was composite of death and major disability (modified Rankin Scale [mRS] score ≥ 3) at 3 months after stroke onset, and secondary outcomes included death and the ordered 7-level categorical score of mRS.Results: During 3 months of follow-up, a total of 2118 patients developed the primary outcome. After multivariable adjustment, high prealbumin levels were associated with a decreased risk of primary outcome (odds ratio, 0.71; 95% CI, 0.59– 0.85; Ptrend< 0.0001) when 2 extreme quartiles were compared. Each unit increase of log-transformed prealbumin was associated with a 42% (95% CI, 28-53%) decreased risk of primary outcome. There was a better shift in the distribution of mRS score at 3 months with higher quartiles of serum prealbumin in ischemic stroke patients (Ptrend< 0.0001). Multivariable-adjusted spline regression model showed a linear relationship between prealbumin and the risk of primary outcome (P for linearity = 0.0036).Conclusion: High serum prealbumin level was independently associated with decreased risks of adverse clinical outcomes among ischemic stroke patients. Our findings suggested that prealbumin may be a valuable prognostic biomarker and indicated the importance of keeping nourished in the daily life.Keywords: prealbumin, ischemic stroke, prognosis, cohort study

Zhuying Zhang,1,2,&ast; Mai Shi,1,2,&ast; Jinghui Li,3 Dian Chen,1,2 Jie Ren,1,2 Zhenghui Li,1,2 Hsiaohan Tuan,1,2,&ast; Yi Zhao1,2,&ast; 1Department of Dermatology, Beijing Tsinghua Changgung Hospital, Beijing, People’s Republic of China; 2Photomedicine Laboratory, Institute of Precision Medicine, Tsinghua University, Beijing, People’s Republic of China; 3School of Medicine, Tsinghua University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Zhao; Hsiaohan Tuan, Department of Dermatology, Beijing Tsinghua Changgung Hospital, No. 168 Litang Road, Changping District, Beijing, 102218, People’s Republic of China, Tel +86-13718646181 ; +86-18610015166, Email zhaoyimd@tsinghua.edu.cn; dxha00337@btch.edu.cnIntroduction: The aging of the skin, which is affected by both external and internal causes, can reflect the external age and the internal health status. While the aging characteristics differ across ethnic groups, the specific changes in skin aging within the Chinese population have been underexplored. Moreover, investigating the similarity of aging skin characteristics between parent-offspring pairs remains uncharted territory. This study aims to fill these gaps by examining the skin aging features of Chinese women and assessing the similarity in aging skin characteristics between mother-daughter pairs.Methods: A total of 40 mother-daughter pairs were recruited and analyzed. The perceived ages of the participants were evaluated, and their aging skin traits were systematically graded. Statistical methods were employed to discern the trends of the aging skin characteristics. By introducing a novel similarity parameter, we compared whether various skin aging characteristics have similar patterns between mothers and daughters.Results: Our findings indicate that age 50 represents a pivotal point in skin aging. Beyond this age, the increase in rhytides and laxity scores accelerated noticeably, whereas the escalation in dyschromia scores became less marked. By introducing similar parameters between mother-daughter pairs and the radar map, we discovered that the skin aging characteristics are remarkably consistent between mother-daughter pairs.Conclusion: Understanding the main aging skin characteristics of different age groups can allow caregivers to devise treatments for preventing skin aging in women of various ages. The mother’s skin aging trend is also significant for the daughter’s skin aging prevention.Plain Language Summary: Skin aging, a complex process influenced by both internal and external factors, exhibits distinct patterns across ethnic groups. Despite this, the specific aging characteristics within the Chinese population and the hereditary similarities between parents and offspring have not been thoroughly investigated. To address this gap, our study focused on the skin aging features of Chinese women and explored the resemblance in these features between mother-daughter pairs. Eighty-seven women from the same community, including 40 mother-daughter pairs, participated in our study. We assessed how old each participant appeared to be and methodically evaluated their skin aging signs by a modified scale. With the introduction of a new similarity parameter, we further examined the extent to which skin aging traits showed parallel trends between mothers and their daughters.Our findings pinpoint age 50 as a pivotal moment in the skin aging trajectory, where the increase in wrinkles and skin laxity becomes more pronounced, contrasting with a deceleration in skin discoloration. Remarkably, a consistent pattern of aging characteristics was observed between mother-daughter pairs, suggesting a potential genetic influence. This study not only sheds light on the specific skin aging patterns among Chinese women but also underscores the significance of genetic factors in shaping these patterns. The insights gained pave the way for developing targeted interventions for skin aging prevention and treatment, emphasizing the importance of considering familial aging trends.Keywords: Chinese female, skin aging pattern, aging characteristics, intergenerational analysis

Bohai Du,1 Tianlan Li,1 Haoqi He,1 Xun Xu,2 Chunmei Zhang,1 Xianzhu Lu,1 Yuhan Wang,1 Jingyi Cao,1 Yinghan Lu,1 Yiwa Liu,1 Shanshan Hu,1 Juxiao Li,1 Li Li,1 Ming Shi1 1Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province, 523808, People’s Republic of China; 2Experimental Animal Center, Guangdong Medical University, Dongguan, Guangdong Province, 523808, People’s Republic of ChinaCorrespondence: Li Li; Ming Shi, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province, 523808, People’s Republic of China, Tel +86-15889530426 ; +86-769-22896568, Email lily2017@gdmu.edu.cn; shiming@gdmu.edu.cnIntroduction: Studies have shown that microplastics (MPs) and nanoplastics (NPs) could accumulate in the human body and pose a potential threat to human health. The purpose of this study is to evaluate the biodistribution and toxicity of MPs/NPs with different particle sizes comprehensively and thoroughly.Methods: The purpose of this study was to investigate the biodistribution and in vivo toxicity of polystyrene (PS) MPs/NPs with different sizes (50 nm, 100 nm, and 500 nm). The BALB/c mice were given 100 μL of PS50, PS100 and PS500 at the dosage of 1 mg/kg BW or 10 mg/kg BW, respectively, by gavage once a day. After 28 consecutive days of treatment, the biodistribution of differently sized PS MPs/NPs was determined through cryosection fluorescence microscopy and fluorescent microplate reader analysis, and the subsequent effects of differently sized PS MPs/NPs on histopathology, hematology and blood biochemistry were also evaluated.Results: The results showed that the three different sizes of PS MPs/NPs were distributed in the organs of mice, mainly in the liver, spleen, and intestine. At the same time, the smaller the particle size, the more they accumulate in the body and more easily penetrate the tissue. During the whole observation period, no abnormal behavior and weight change were observed. The results of H&E staining showed that no severe histopathological abnormalities were observed in the main organs in the low-dose exposure group, while. Exposure of three sizes of PS MPs/NPs could cause some changes in hematological parameters or biochemical parameters related to heart, liver, and kidney function; meanwhile, there were size- and dose-dependencies.Conclusion: The biological distribution and toxicity of plastic particles in mice were more obvious with the decrease of particle size and the increase of concentration of plastic particles. Compared with MPs, NPs were easier to enter the tissues and produce changes in liver, kidney, and heart functions. Therefore, more attention should be paid to the toxicity of NPs.Keywords: microplastics, nanoplastics, polystyrene, size, biodistribution, nanotoxicology

Luo-Gang Ding,1,&ast; Xiang Ji,2,&ast; Yue-Yue Liu,3,&ast; Min Shi,1 Jian-Da Li,1 Fei Liu,1 Yu-Yu Zhang,1 Jiang Yu,1 Jia-Qiang Wu1 1Shandong Key Laboratory of Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, 250100, People’s Republic of China; 2Key Laboratory of Shandong Microbial Engineering, College of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, People’s Republic of China; 3Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan, 250100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia-Qiang Wu; Jiang Yu, Shandong Academy of Agricultural Sciences, Jinan, 250100, People’s Republic of China, Email yujiang_2213@163.com; wujiaqiang2000@sina.comBackground: Influenza A (H1N1) virus is a highly contagious respiratory disease that causes severe illness and death. Vaccines and antiviral drugs are limited by viral variation and drug resistance, so developing efficient integrated theranostic options appears significant in anti-influenza virus infection.Methods: In this study, we designed and fabricated covalent organic framework (COF) based theranostic platforms (T705@DATA-COF-Pro), which was composed of an RNA polymerase inhibitor (favipiravir, T705), the carboxyl-enriched COF (DATA-COF) nano-carrier and Cy3-labeled single DNA (ssDNA) probe.Results: The multi-porosity COF core provided an excellent micro-environment and smooth delivery for T705. The ssDNA probe coating bound to the nucleic acids of H1N1 selectively, thus controlling drug release and allowing fluorescence imaging. The combination of COF and probe triggered the synergism, promoting drug further therapeutic outcomes. With the aid of T705@DATA-COF-Pro platforms, the H1N1-infected mouse models lightly achieved diagnosis and significantly prolonged survival.Conclusion: This research underscores the distinctive benefits and immense potential of COF materials in nano-preparations for virus infection, offering novel avenues for the detection and treatment of H1N1 virus infection.Keywords: crystal porous materials, microenvironment-responsive, controlled release, fluorescence imaging, diagnosis and therapy

Mengli Li,1,&ast; Tongtong Yin,1,&ast; Jiaying Qi,1 Minhao Shi,1 Fangfang Wang,1 Zhiyu Mao,1 Hui Zhang,1,2 Li Wang1 1School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2School of Nursing, Suzhou Vocational Health College, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Wang; Hui Zhang, Email li-wang-1@suda.edu.cn; zhanghuichange@sina.comObjective: To explore the cut-off values and health evaluations of upper arm circumference (AC) and calf circumference (CC) on sarcopenia in Chinese community-dwelling older people.Methods: In this cross-sectional study, AC, CC, handgrip strength, muscle mass and gait speed were measured in 1537 Chinese community-dwelling older people in Sub-study 1. Correlation analysis, receiver operator characteristic curve (ROC curve) analysis, and consistency analysis were used for determination of AC and CC cut-off values for sarcopenia diagnosis (sarcopenia-AC and CC). Thereafter, 269 participants accepted additional assessments on physical function, body composition and muscle strength in Sub-study 2. T-test or Mann-Whitney U-test was used to explore the differential effects of sarcopenia-AC and CC on health indicators between sarcopenic and non-sarcopenic participants.Results: In Sub-study 1, the Area Under ROC (AUC) of AC and CC for sarcopenia screening were greater than 0.700 (P< 0.05). The cut-off values, sensitivity and specificity of AC and CC on sarcopenia in males were 25.9 cm (86.0%, 83.6%) and 33.7 cm (90.7%, 81.4%) whereas in females were 26.5 cm (70.8%, 69.7%) and 33.0 cm (86.5%, 69.4%), respectively. In Sub-study 2, the participants with sarcopenia-AC or sarcopenia-CC showed lower muscle strength and lower fat and muscle mass than the ones without (P< 0.05). Additionally, males instead of females with sarcopenia-AC or sarcopenia-CC showed worse performance in time-up and go test and 6-Minute Walk Test (P< 0.05). However, the 30-second chair stand test was not different between participants with and without sarcopenia-AC or sarcopenia-CC in both sexes.Conclusion: We found accurate and Chinese population targeted cut-off values of AC and CC on sarcopenia diagnosis (25.9 cm and 33.7 cm in males; 26.5 cm and 33.0 cm in females) and a good evaluation effect of AC and CC on fat and muscle mass, muscle strength and physical functions in males, not females.Keywords: sarcopenia, upper arm circumference, calf circumference, health assessment

Honggang Guo,1,&ast; Yabin Cui,2,&ast; Yanliang Bai,1 Fan Yan,1 Wenhui Zhang,1 Yuqing Chen,1,&ast; Mingyue Shi1,&ast; 1Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Hematology, Henan University People’s Hospital, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuqing Chen; Mingyue Shi, Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, &num;7 Weiwu Road, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86-18697321863 ; +86-17839931733, Email henanblood@sina.com; shimingyue16@gmail.comBackground: Relapsed/refractory acute myeloid leukemia (R/R-AML) has dismal prognosis due to chemotherapy resistance. Circular RNAs (circRNAs) have shown emerging roles in chemotherapy resistance in various cancers including hematologic malignancies. However, the potential roles of circRNAs in AML progression and drug resistance remain largely undetermined.Methods: In this study, circulating circRNAs expression profiles were analyzed among R/R-AML, de novo AML and healthy controls (HC) using a human circRNA Array. Bioinformatic analysis was carried out to explore the differentially expressed circRNAs (DE-circRNAs). GO, KEGG pathway analysis, along with circRNA-miRNA-mRNA network analysis, were conducted to identify the potential biological pathways involved in R/R-AML. Finally, the UALCAN database was used to assess the prognosis of different target DE-circRNAs-related mRNAs.Results: Forty-eight DE-circRNAs were upregulated, whereas twenty-seven DE-circRNAs were downregulated in R/R-AML samples. Up-regulated DE-circRNAs in R/R-AML samples were mainly enrichment in the biological processes and pathways of cell migration, microRNAs in cancers, Rap1 and Ras signaling pathways. Six DE-circRNAs were randomly selected to further explore their relationships with R/R-AML. GO and KEGG pathway analyses of the six candidate DE-circRNAs-related target mRNAs were mainly involved in the regulation of signal transduction and Ras signaling pathway. By overlapping our RNA-sequencing results of differentially expressed genes (DEGs) in R/R-AML samples with the candidate DE-circRNAs-predicted target mRNAs, we identified sixty-eight overlapping targeted mRNAs. Using UALCAN database analysis, we identified that AML patients with six upregulated DE-circRNA-related genes (ECE1, PI4K2A, SLC9A6, CCND3, PPP1R16B, and TRIM32) and one downregulated gene DE-circRNA-related genes (ARHGAP10) might have a poor prognosis.Conclusion: This study revealed the overall alterations of circRNAs in R/R-AML. DE-circRNAs and their related genes might be used as potential early, sensitive and stable biomarkers for AML diagnosis, R/R-AML monitoring, and even as novel treatment targets for R/R-AML.Keywords: Relapsed/refractory, acute myeloid leukemia, circular RNAs, biomarkers, prognosis

Siyuan Wang,1,&ast; Beiyao Gao,1,&ast; Minghui Shi,2– 6 Shiwei Qumu,2– 5 Fen Dong,2– 5,7 Peijian Wang,1 Ting Yang,2– 5 Shan Jiang1 1Department of Rehabilitation Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Center for Respiratory Medicine, Beijing, People’s Republic of China; 3National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 4Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 6Capital Medical University, Beijing, People’s Republic of China; 7Department of Clinical Research and Data management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shan Jiang; Ting Yang, China-Japan Friendship Hospital, 2 Yinghuayuan East St. Hepingli, Chaoyang District, Beijing, 100029, People’s Republic of China, Email landjiang@126.com; dryangting@qq.comObjective: Given the established impact of exercise in reducing arterial stiffness and the potential for intermittent hypoxia to induce its elevation, this study aims to understand how oxygen desaturation during exercise affects arterial stiffness in individuals with COPD.Methods: We enrolled patients with stable COPD from China-Japan Friendship Hospital from November 2022 to June 2023. The 6-minute walk test (6-MWT) was performed with continuous blood oxygen saturation (SpO2) monitoring in these patients. The patients were classified into three groups: non-exercise induced desaturation (EID), mild-EID and severe-EID, according to the changes in SpO2 during the 6-MWT. The Cardio-Ankle Vascular Index (CAVI) and the change in CAVI (ΔCAVI, calculated as CAVI before 6MWT minus CAVI after the 6MWT) were measured before and immediately after the 6MWT to assess the acute effects of exercise on arterial stiffness. GOLD Stage, pulmonary function, and other functional outcomes were also measured in this study.Results: A total of 37 patients with stable COPD underwent evaluation for changes in CAVI (ΔCAVI) before and after the 6-MWT. Stratification based on revealed three subgroups: non-EID (n=12), mild-EID (n=15), and severe-EID (n=10). The ΔCAVI values was − 0.53 (− 0.95 to − 0.31) in non-EID group, − 0.20 (− 1.45 to 0.50) in mild-EID group, 0.6 (0.08 to 0.73) in severe-EID group. Parametric tests indicated significant differences in ΔCAVI among EID groups (p = 0.005). Pairwise comparisons demonstrated significant distinctions between mild-EID and severe-EID groups, as well as between non-EID and severe-EID groups (p = 0.048 and p = 0.003, respectively). Multivariable analysis, adjusting for age, sex, GOLD stage, diffusion capacity, and blood pressure, identified severe-EID as an independent factor associated with ΔCAVI (B = 1.118, p = 0.038).Conclusion: Patients with COPD and severe-EID may experience worsening arterial stiffness even during short periods of exercise.Keywords: COPD, arterial stiffness, exercise-induced oxygen desaturation, rehabilitation

Bin Zheng,1– 3,&ast; Fei Pan,1– 3,&ast; Minfei Shi,1– 3 Cuiping He,1– 3 Beibei He,1– 3 Rongrong Wang,1– 3 Guolian Ren,1– 3 Shuang Yang,4 Shuqiu Zhang1– 3 1School of Pharmacy, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 3Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 4School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang Yang, School of Basic Medical Sciences, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, 030001, People’s Republic of China, Email yangshuangzz@126.com Shuqiu Zhang, School of Pharmacy, Shanxi Medical University, No. 56, Xinjian South Road, Taiyuan, 030001, People’s Republic of China, Email shuqiu.zhang@sxmu.edu.cnPurpose: Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability.Methods: The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments.Results: DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively.Conclusion: SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism. Keywords: intestinal lymphatic transport, biomimetic liposomes, first-pass hepatic metabolism, oral delivery, dihydroartemisinin

Ziyan Wang,1,2,&ast; Chengxin Liu,1,2,&ast; Jiaming Wei,2,3 Hui Yuan,1,2 Min Shi,2,3 Fei Zhang,2,3 Qinghua Zeng,2,3 Aisi Huang,2,3 Lixin Du,4 Ya Li,4 Zhihua Guo2,3 1First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan Universities of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 3School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 4School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ya Li; Zhihua Guo, Email 003872@hnucm.edu.cn; 004294@hnucm.edu.cnObjective: This study aims to explore the mechanism of action of Yixintai in treating chronic ischemic heart failure by combining bioinformatics and experimental validation.Materials and Methods: Five potential drugs for treating heart failure were obtained from Yixintai (YXT) through early mass spectrometry detection. The targets of YXT for treating heart failure were obtained by a search of online databases. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted on the common targets using the DAVID database. A rat heart failure model was established by ligating the anterior descending branch of the left coronary artery. A small animal color Doppler ultrasound imaging system detected cardiac function indicators. Hematoxylin-eosin (HE), Masson’s, and electron microscopy were used to observe the pathological morphology of the myocardium in rats with heart failure. The network pharmacology analysis results were validated by ELISA, qPCR, and Western blotting.Results: A total of 107 effective targets were obtained by combining compound targets and eliminating duplicate values. PPI analysis showed that inflammation-related proteins (TNF and IL1B) were key targets for treating heart failure, and KEGG enrichment suggested that NF-κB signaling pathway was a key pathway for YXT treatment of heart failure. Animal model validation results indicated the following: YXT can significantly reduce the content of intestinal microbiota metabolites such as trimethylamine oxide (TMAO) and improve heart failure by improving the EF and FS values of heart ultrasound in rats and reducing the levels of serum NT-proBNP, ANP, and BNP to improve heart failure. Together, YXT can inhibit cardiac muscle hypertrophy and fibrosis in rats and improve myocardial ultrastructure and serum IL-1β, IL-6, and TNF-α levels. These effects are achieved by inhibiting the expressions of NF-κB and PKC.Conclusion: YXT regulates the TMAO/PKC/NF-κB signaling pathway in heart failure.Keywords: heart failure, yixintai, TMAO, PKC/NF-κB pathway, traditional Chinese medicine, network pharmacology

Lve Cheng,&ast; Junwei Niu,&ast; Yao Cheng,&ast; Jie Liu, Mengjia Shi, Shijia Huang, Xiong Ding, Shengwei Li Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiong Ding; Shengwei Li, Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong, Chongqing, 400010, People’s Republic of China, Tel +86-13677662766 ; +86-13508312245, Email dingxiong@hospital.cqmu.edu.cn; lishengwei@hospital.cqmu.edu.cnBackground: There is a lack of validated predictive models for the occurrence of systemic inflammatory response syndrome (SIRS) after percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) for the treatment of hepatolithiasis. This is the first study to estimate the incidence of SIRS after PTCSL.Methods: A retrospective analysis of 284 PTCSL sessions for the treatment of hepatolithiasis at our institution between January 2019 and January 2023 was performed. The development of SIRS after PTCSL was the primary study endpoint. Independent risk factors for SIRS after PTCSL were identified using univariate and multivariate logistic regression analyses. A nomogram prediction model was constructed using these independent risk factors, and the predictive value was assessed using receiver operating characteristic (ROC) curves.Results: The incidence of SIRS after PTCSL was 20.77%. According to multivariate analysis, the number of PTCSL sessions (odds ratio [OR]=0.399, 95% confidence interval [CI]=0.202– 0.786, p=0.008), stone location (OR=2.194, 95% CI=1.107– 4.347, p=0.024), intraoperative use of norepinephrine (OR=0.301, 95% CI=0.131– 0.689, p=0.004), intraoperative puncture (OR=3.476, 95% CI=1.749– 6.906, P< 0.001), preoperative gamma-glutamyltransferase (OR=1.002, 95% CI=1.001– 1.004, p=0.009), and preoperative total lymphocyte count (OR=1.820, 95% CI=1.110– 2.985, p=0.018) were found to be independent risk factors for the development of SIRS after PTCSL. These six independent risk factors were used to construct a nomogram prediction model, which showed satisfactory accuracy with an area under the ROC curve of 0.776 (95% CI: 0.702– 0.850).Conclusion: The number of PTCSL sessions, stone location, intraoperative use of norepinephrine, intraoperative puncture, preoperative gamma-glutamyltransferase, and preoperative total lymphocyte count may predict the occurrence of SIRS after PTCSL. This prediction model may help clinicians identify high-risk patients in advance.Keywords: percutaneous transhepatic cholangioscopic lithotripsy, hepatolithiasis, systemic inflammatory response syndrome, risk factors, nomogram

Mingjie Shi,1,2 Yue Wei,3 Runmin Guo,1,2 Fei Luo1,2 1Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, Guangdong, People’s Republic of China; 2Matenal and Child Research Institute, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, People’s Republic of China; 3Department of Ultrasound, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, People’s Republic of ChinaCorrespondence: Fei Luo, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, People’s Republic of China, Email luofei_00@163.comBackground: Sepsis is a major contributor to morbidity and mortality among hospitalized patients. This study aims to identify markers associated with the severity and prognosis of sepsis, providing new approaches for its management and treatment.Methods: Data were mined from the Gene Expression Omnibus (GEO) databases and were analyzed by multiple statistical methods like the Spearman correlation coefficient, Kaplan-Meier analysis, Cox regression analysis, and functional enrichment analysis. Candidate indicator’ associations with immune infiltration and roles in sepsis development were evaluated. Additionally, we employed techniques such as flow cytometry and neutral red staining to evaluate its impact on macrophage functions like polarization and phagocytosis.Results: Twenty-eight genes were identified as being closely linked to the severity of sepsis, among which transforming growth factor beta induced (TGFBI) emerged as a distinct marker for predicting clinical outcomes. Notably, reductions in TGFBI expression during sepsis correlate with poor prognosis and rapid disease progression. Elevated expression of TGFBI has been observed to mitigate abnormalities in sepsis-related immune cell infiltration that are critical to the pathogenesis and prognosis of the disease, including but not limited to type 17 T helper cells and activated CD8 T cells. Moreover, the protein-protein interaction network revealed the top ten genes that interact with TGFBI, showing significant involvement in the regulation of the actin cytoskeleton, extracellular matrix-receptor interactions, and phagosomes. These are pivotal elements in the formation of phagocytic cups by macrophages, squaring the findings of the Human Protein Atlas. Additionally, we discovered that TGFBI expression was significantly higher in M2-like macrophages, and its upregulation was found to inhibit lipopolysaccharide-induced polarization and phagocytosis in M1-like macrophages, thereby playing a role in preventing the onset of inflammation.Conclusion: TGFBI warrants additional exploration as a promising biomarker for assessing illness severity and prognosis in patients with sepsis, considering its significant association with immunological and inflammatory responses in this condition.Keywords: sepsis, septic shock, TGFBI, prognosis, biomarker

Guiyuan He,1,&ast; Xi Wang,1,&ast; Beiqing Li,1 Lei Wang,1 Jing Zhang,2 Yang Shi,1 Wenxiu Zhu,1 Ming Shi1,3 1Centre for Reproductive and Genetic Medicine, Dalian Women and Children’s Medical Group, Dalian, People’s Republic of China; 2Department of Clinical Laboratory, Central Hospital of Dalian University of Technology, Dalian Municipal Central Hospital, Dalian, People’s Republic of China; 3Department of Clinical Laboratory, Dalian Women and Children’s Medical Group, Dalian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Shi, Centre for Reproductive and Genetic Medicine & Department of Clinical Laboratory, Dalian Women and Children’s Medical Group, Dalian, 116037, People’s Republic of China, Email zhsh6655@sohu.comPurpose: Fragile sites are specific chromosomal regions showing gaps, poor staining, contractions, or even breaks in the chromosomes. These spontaneous and heritable fragile sites are prone to structural variations which can lead to adverse reproductive outcomes. This paper aims to present a specific case study of a female patient, with a mosaic karyotype involving chromosome 16q22 fragile site which is very rare in clinic and her experience of infertility.Case Presentation: A 37-year-old woman is diagnosed with ten-year primary infertility. She worked in a factory, and she was occasionally exposed to paint. She underwent two cycles of follicular monitoring with intrauterine insemination (IUI) using her husband’s sperm six years ago but failed. Most of her prepregnancy tests were normal, except a not smooth right fallopian tube. Her G-band karyotype of peripheral blood lymphocytes was mos 46, XX, del(16)(q22)[40]/46, XX, fra(16)(q22)[29]/46, XX, fra(16)tr(16)(q22)[3]/46, XX[28] which inherited from her mother. The SCE assay detected a significantly higher frequency of SCEs in the 16q region of the patient’s chromosomes compared to her mother and a healthy control. However, the average SCEs per chromosome were quite close. Moreover, copy number variation (CNV) sequencing showed no deletion nor duplication at 16q22.Conclusion: Infertility cannot be completely attributed to the fragile site on chromosome 16q22. Assisted reproductive technology combined with preimplantation genetic testing may help in achieving a healthy live birth.Keywords: fragile sites, infertility, fra(16)(q22), del(16)(q22), SCE, CNV

Hao Guo,1,&ast; Li-Heng Li,2,&ast; Xiao-Hong Lv,1,&ast; Feng-Zhi Su,1,&ast; Jie Chen,1,&ast; Fei Xiao,1,3 Min Shi,1 Yu-Bo Xie1,3 1Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Anesthesiology, The Guilin Municipal Hospital of Traditional Chinese Medicine, Guangxi, People’s Republic of China; 3Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu-Bo Xie, Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, No. 22 Shuangyong Road, Nanning, 530000, People’s Republic of China, Tel +86 13977121557, Email xybdoctor@163.comPurpose: Postoperative sleep disturbance, characterized by diminished postoperative sleep quality, is a risk factor for postoperative delirium (POD); however, the association between pre-existing sleep disturbance and POD remains unclear. This study aimed to evaluate the association between preoperative sleep disturbance and POD in elderly patients after non-cardiac surgery.Patients and methods: This retrospective cohort study was conducted at a single center and enrolled 489 elderly patients who underwent surgery between May 1, 2020, and March 31, 2021. Patients were divided into the sleep disorder (SD) and non-sleep disorder (NSD) groups according to the occurrence of one or more symptoms of insomnia within one month or sleep- Numerical Rating Scale (NRS)≥ 6 before surgery. The primary outcome was the incidence of POD. Propensity score matching analysis was performed between the two groups. Multiple logistic regression analysis was performed to identify the risk factors for POD.Results: In both the unmatched cohort (16.0% vs 6.7%, P=0.003) and the matched cohort (17.0% vs 6.2%, P=0.023), the incidence of POD was higher in the SD group than in the NSD group. In addition, the postoperative sleep quality and the VAS score at postoperative 24 h were significantly lower in the SD group than in the NSD group. Multivariate logistic regression analysis indicated that age (Odds Ratio, 1.13 [95% CI: 1.04– 1.23], P=0.003) and preoperative sleep disturbance (Odds Ratio, 3.03 [95% CI: 1.09– 9.52], P=0.034) were independent risk factors for the development of POD.Conclusion: The incidence of POD was higher in patients with pre-existing sleep disturbance than those without it. Whether improving sleep quality for preoperative sleep disturbance may help prevent POD remains to be determined.Keywords: sleep disturbances, postoperative delirium, postoperative sleep quality, postoperative pain, anesthesia

Chenhui Wang,1 Lei Han,2 Yuru Li,2 Xibin Mi,3 Mengwei Yan,4 Xinxiu Yu,2 Yu Lu,2 Meihong Shi,2 Pengfei Liu,2 Liang Han,2 Baoguo Wang1 1Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Infirmary, Taikang Yanyuan Continuing Care Retirement Community, Beijing, People’s Republic of China; 3Department of Pain Management, Yanyuan Rehabilitation Hospital, Beijing, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Baoguo Wang, Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, No. 50 Yikesong Street, Haidian District, Beijing, 100095, People’s Republic of China, Tel/Fax +86 10 6285 6766, Email wangbg@ccmu.edu.cnPurpose: To identify the prevalence of exacerbation of pre-existing chronic pain after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and investigate the impact of exacerbated previous chronic pain on quality of life, sleep quality, anxiety and depression levels and risk factors associated with exacerbated chronic pain among elderly coronavirus disease of 2019 (COVID-19) survivors.Patients and Methods: In this cross-sectional study, elderly COVID-19 survivors with chronic pain residing in Continuing Care Retirement Community (CCRC) were recruited from April 2023 to June 2023. Eligible individuals were divided into exacerbation and non-exacerbation groups based on the patient-reported worsening symptoms of previous chronic pain after SARS-CoV-2 infection. Baseline information, COVID-19 symptoms, laboratory parameters, characteristics of exacerbated chronic pain, quality of life, anxiety and depression levels were systematically collected.Results: Ninety-five (95/441, 21.5%) older adults suffered from exacerbated chronic pain with a median numerical rating scale (NRS) score of 6 (4– 7) on a median duration of 4.9 (4.3– 5.6) months after SARS-CoV-2 infection. More participants were not vaccinated against COVID-19 (46.5%, 40/86 vs 26.1%, 86/330, P < 0.001) in exacerbation group. Exacerbation group exhibited poor quality of life (EQ5D index: 0.734 [0.536– 0.862] vs 0.837 [0.716– 0.942], P < 0.001), more severe anxiety (GAD-7: 2 [0– 5] vs 0 [0– 3], P < 0.001) and depression (PHQ-9: 4 [2– 7] vs 2.5 [0– 5], P < 0.001) than non-exacerbation group. Risk factors significantly associated with exacerbation of pre-existing chronic pain were neuropathic pain (aOR 4.81, 95% CI 1.73– 13.32, P = 0.003), lymphocyte count (aOR 0.31, 95% CI 0.12– 0.78, P = 0.013) and D-dimer levels (aOR 6.46, 95% CI 1.92– 21.74, P = 0.003).Conclusion: Our study observed a prevalence of 21.5% exacerbation of pre-existing chronic pain after SARS-CoV-2 infection, with a consequence of poor quality of life, more severe anxiety and depression. Previous chronic neuropathic pain, lower lymphocyte count and higher D-dimer levels were risk factors associated with the development of exacerbated previous chronic pain.Keywords: post-COVID-19, older adults, chronic pain, exacerbated symptoms

Shanyu Liu,1,2,&ast; Xiaolin Hou,3,&ast; Min Shi,1 Yuling Shen,1,2 Zhaoying Li,1,2 Zhenzhu Hu,1,2 Dongdong Yang1 1Department of Neurology, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Department of Neurosurgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongdong Yang, Department of Neurology, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No. 39, Twelve Bridges Road, Chengdu, Sichuan Province, 610075, People’s Republic of China, Tel/Fax +86 028-87783481, Email dongdongyang2020@163.comPurpose: Previous studies have reported mixed results regarding the importance of cortical abnormalities in patients with migraines. However, cortical sulci, as a component of the cerebral cortex, have not been specifically investigated in migraine patients. Therefore, we aim to evaluate alterations in cortical sulcal morphology among patients with chronic migraine (CM), episodic migraine (EM), and healthy controls (HCs).Patients and Methods: In this cross-sectional study, structural magnetic resonance images were acquired from 35 patients with CM, 35 with EM, and 35 HCs. Cortical sulci were identified and reconstructed using the BrainVisa 5.0.4 software. We focused on regions involved in pain processing in which abnormal cortical structure were identified in previous neuroimaging studies. Morphometric analysis was performed to calculate sulcal parameters including mean depth, cortical thickness, and opening width. Partial correlation analyses of clinical characteristics and sulcal parameters were performed for CM, EM and the combined migraine (CM + EM) groups.Results: In comparison with HCs, both CM and EM groups showed increased opening width in bilateral insula. In comparison with HC and EM groups, CM patients showed increased cortical thickness in bilateral superior postcentral sulcus, bilateral median frontal sulcus and left superior parietal sulcus, as well as increased mean depth in the left anterior callosomarginal fissure and decreased mean depth in bilateral superior frontal sulcus and left median frontal sulcus. Migraine frequency and disease duration were both correlated with cortical thickness in bilateral superior postcentral sulcus.Conclusion: Abnormal sulcal morphometry primarily affected areas associated with pain processing in patients with migraine, with CM exhibiting more extensive abnormalities in areas related to sensory and affective processing. These changes may contribute to understanding the pathology of EM and CM.Keywords: sulcal morphometry, mean depth, cortical thickness, opening width, chronic migraine, episodic migraine

Yinzheng Li,1 Shulin Ma,1 Zheng Wang,1 Mengxia Shi,1 Rui Zeng,1– 4,&ast; Ying Yao1,5,&ast; 1Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, People’s Republic of China; 3NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, People’s Republic of China; 4Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, People’s Republic of China; 5Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Yao; Rui Zeng, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Tel +86 13720379867 ; +86 15002726366, Email yaoyingkk@126.com; zengrui@tjh.tjmu.edu.cnPurpose: The distal nephron of kidney plays a pivotal role in advancing acute kidney injury (AKI). Understanding the role of distal nephrons in AKI and identifying markers of injured distal nephrons are critical to comprehending the mechanism of renal injury and identifying novel therapeutic targets.Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data from mice with AKI induced by ischemia-reperfusion (IR), unilateral ureteral obstruction (UUO), cisplatin (CP), sodium oxalate (SO) and lipopolysaccharide (LPS). Additionally, we analyzed renal transcriptomics samples for AKI. Subsequently, we validated the effectiveness of targeting the biomarker Gclc in vitro and in vivo through metabolomics and immunofluorescence.Results: The LOH-Inj and DCT-Inj subtypes were identified through scRNA-seq. Compared to normal distal nephrons, the injured distal nephrons exhibited higher levels of ferroptosis, pro-inflammation, and fibrosis. The expression of ferroptosis-related gene Gclc were high in various AKI models. Furthermore, Gclc was exclusively expressed in the distal nephron and upregulated in the injury subtype. To confirm our findings, we suppressed GCLC expression in the kidneys, resulting to aggravated IR-induced AKI. Inhibition of Gclc promoted damage to primarily renal tubular epithelial cells by promoting inflammatory infiltration, inhibiting glutathione metabolism and exacerbating oxidative stress.Conclusion: Our research findings suggest that Gclc is a potential marker for injured distal nephron.Keywords: Gclc, distal nephron, acute kidney injury, single-cell sequencing

Le Xu, Minkang Shi Department of Pediatrics, Liyang People’s Hospital, Liyang, JiangSu, 213300, People’s Republic of ChinaCorrespondence: Minkang Shi, Department of Pediatrics, Liyang People’s Hospital, No. 70 Jianshe West Road, Liyang, JiangSu, 213300, People’s Republic of China, Email smk198403231411@163.comPurpose: Asthma substantially affects the quality of life and health of children. Lipocalin 2 (LCN2) is an immune-related protein, which is predicted to be highly expressed in asthma. Here, we investigated the role of LCN2 in ovalbumin (OVA)-induced asthma mouse model.Methods: We knocked down LCN2 in an asthma mouse model and performed histopathological analysis using hematoxylin and eosin (H&E) staining assay. Differentiated cells were assessed using Diff-Quick staining assay. We investigated the regulatory T (Treg) cell/ T helper 17 (Th17) cell balance using flow cytometry and enzyme-linked immunosorbent assay (ELISA). Inflammatory factors were measured using quantitative real-time reverse transcription PCR (qRT-PCR). The involved pathways were assessed using Western blotting.Results: LCN2 was upregulated in patients with asthma. OVA promoted pathological deterioration in the lungs, increased IgE levels in the plasma, and elevated the number of differentiated inflammatory cells, whereas LCN2 knockdown abrogated the OVA-induced effects. Additionally, the Treg/Th17 imbalance and increased inflammatory cytokine levels were improved by LCN2 knockdown in OVA-treated mice. Moreover, LCN2 knockdown reversed the activation of the janus kinase (JNK) pathway.Conclusion: LCN2 knockdown improved the Treg/Th17 balance, alleviated inflammation, and inactivated the JNK pathway in OVA-induced asthma mouse model, suggesting that LCN2 may be a novel therapeutic target for asthma in children.Keywords: innate immunity, T lymphocyte differentiation, peripheral blood, JNK pathway, inflammation

Li Wang,1,&ast; Fei Quan,2,&ast; Zhen Guo,3 Zhongyu Lu,2 Duoxia Yang,2 Meiqi Shi1 1Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The Medical Department, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, People’s Republic of China; 3Radiology Department, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meiqi Shi, Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, No. 42, Baiziting, Xuanwu District, Nanjing, Jiangsu, 210009, People’s Republic of China, Tel/Fax +86 25 83283568, Email shimeiqi1963@163.comAbstract: Approximately 10– 20% of patients demonstrate primary resistance to EGFR-TKIs, and different EGFR mutations vary in sensitivity to EGFR-TKIs. We report a case of a 78-year-old male with lung adenocarcinoma that EGFR L858R (AF = 1.32%) coexisting with EGFR S645C (AF = 7.13%) in his diagnosed tissues analyzed by NGS. The patient was primarily resistant to first-line osimertinib and rapidly progressed after pembrolizumab in combination with pemetrexed and bevacizumab, as demonstrated by persistently elevated CEA levels during treatment. ctDNA-based NGS analysis revealed loss of EGFR L858R while persistence of highly abundant EGFR S645C in the pleural fluid and plasma after treatment, suggesting that EGFR L858R may be a subclone. We provide the first clinical evidence of the primary resistance of EGFR S645C to osimertinib and emphasize the importance of identifying clones and subclones. Our patient did not respond to immunotherapy either, and preclinical studies have shown that EGFR S645C activates the MEK signaling pathway, the combination of EGFR-TKIs and MEK inhibitors may be effective.Keywords: EGFR S645C, osimertinib, primary resistance, NSCLC, subclone

Jin Sun,1– 3 Yingnan Li,1– 3 Mengjiao Shi,1,2 Hongwei Tian,1– 3 Jun Li,1– 3 Kai Zhu,1– 3 Ying Guo,1– 3 Yanhua Mu,1– 3 Jing Geng,1– 3 Zongfang Li1– 4 1National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Center for Tumor and Immunology, the Precision Medical Institute, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 4Department of Geriatric General Surgery, the Second Affiliated Hospital of Xi’ an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Jing Geng; Zongfang Li, National & Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the second affiliated hospital, Xi’an Jiaotong University, No. 157 West 5th Road, Xi’an, 710004, People’s Republic of China, Tel +86-29-87679700 ; Tel/Fax +86-29-87679508, Email jgeng18@xjtu.edu.cn; lzf2568@xjtu.edu.cnPurpose: HOX cluster-embedded long noncoding RNAs (HOX-lncRNAs) have been shown to be tightly related to hepatocellular carcinoma (HCC). However, the potential biological roles and underlying molecular mechanism of HOX-lncRNAs in HCC largely remains to be elucidated.Methods: The expression signature of eighteen HOX-lncRNAs in HCC cell lines were measured by qRT-PCR. HOXD-AS2 expression and its clinical significance in HCC was investigated by bioinformatics analysis utilizing the TCGA data. Subcellular localization of HOXD‐AS2 in HCC cells was observed by RNA-FISH. Loss‑of‑function experiments in vitro and in vivo were conducted to probe the roles of HOXD-AS2 in HCC. Potential HOXD-AS2-controlled genes and signaling pathways were revealed by RNA-seq. Rescue experiments were performed to validate that SMYD3 mediates HOXD-AS2 promoting HCC progression. The positive feedback loop of HOXD-AS2 and SMYD3 was identified by luciferase reporter assay and ChIP-qPCR.Results: HOXD-AS2 was dramatically elevated in HCC, and its up-regulation exhibited a positive association with aggressive clinical features (T stage, pathologic stage, histologic grade, AFP level, and vascular invasion) and unfavorable prognosis of HCC patients. HOXD-AS2 was distributed both in the nucleus and the cytoplasm of HCC cells. Knockdown of HOXD-AS2 restrained the proliferation, migration, invasion of HCC cells in vitro, as well as tumor growth in subcutaneous mouse model. Transcriptome analysis demonstrated that SMYD3 expression and activity of MEK/ERK pathway were impaired by silencing HOXD-AS2 in HCC cells. Rescue experiments revealed that SMYD3 as downstream target mediated oncogenic functions of HOXD-AS2 in HCC cells through altering the expression of cyclin B1, cyclin E1, MMP2 as well as the activity of MEK/ERK pathway. Additionally, HOXD-AS2 was uncovered to be positively regulated at transcriptional level by its downstream gene of SMYD3.Conclusion: HOXD-AS2, a novel oncogenic HOX-lncRNA, facilitates HCC progression by forming a positive feedback loop with SMYD3 and activating the MEK/ERK pathway.Keywords: hepatocellular carcinoma, HOXD-AS2, SMYD3, MEK/ERK signaling

Chunmei Yan,1 Qiuxia Li,1 Qiang Sun,2 Lu Yang,3 Xing Liu,1 Yuxin Zhao,1 Mingyi Shi,4 Xiaofang Li,1 Kaipei Luo1 1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 4School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Xiaofang Li; Kaipei Luo, Department of Pharmaceutics of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, 611130, People’s Republic of China, Email lixiaofang@cdutcm.edu.cn; luokaipei@126.comAbstract: Malignant tumor, the leading cause of death worldwide, poses a serious threat to human health. For decades, natural product has been proven to be an essential source for novel anticancer drug discovery. Shikonin (SHK), a natural molecule separated from the root of Lithospermum erythrorhizon, shows great potential in anticancer therapy. However, its further clinical application is significantly restricted by poor bioavailability, adverse effects, and non-selective toxicity. With the development of nanotechnology, nano drug delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. To overcome the shortcoming of SHK, various nano drug delivery systems such as liposomes, polymeric micelles, nanoparticles, nanogels, and nanoemulsions, were developed to achieve efficient delivery for enhanced antitumor effects. Herein, this review summarizes the anticancer pharmacological activities and pharmacokinetics of SHK. Additionally, the latest progress of SHK nanomedicines in cancer therapy is outlined, focusing on long circulation, tumor targeting ability, tumor microenvironment responsive drug release, and nanosystem-mediated combination therapy. Finally, the challenges and prospects of SHK nanomedicines in the future clinical application are spotlighted.Graphical Abstract: Keywords: shikonin, cancer therapy, pharmacokinetics, nanomedicine, drug delivery

Jie Ren,1,&ast; Jingzhou Wang,2,&ast; Xingchen Yao,1 Yue Wu,1 Ming Shi,1 Xiangjun Shi,3 Xinru Du1 1Department of Orthopaedics, Beijing Chao-yang Hospital, Beijing, 100020, People’s Republic of China; 2Department of Orthopaedics, Beijing Daxing District People’s Hospital, Beijing, 102600, People’s Republic of China; 3Department of Hematology, Beijing Chao-yang Hospital, Beijing, 100020, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinru Du, Department of orthopaedics, Beijing Chao-yang Hospital, No. 8 of Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 13683156652, Email duxinru@163.comObjective: To explore the role of sclerosteosis (SOST) gene expression in the occurrence and development of multiple myeloma (MM) complicated with sarcopenia.Methods: Analysis of the SOST expression in skeletal muscle tissue of patients with MM using high-throughput sequencing combined with transcriptomics; observation of morphological changes of the mouse C2C12 myoblasts co-cultured with SP2/0 myeloma cells in Transwell; observation of the SOST expression in the C2C12 myoblasts using the immunofluorescence labeling method; and assessment of the changes in exercise capacity of mice with MM using ethology; and the measurement of the SOST expression in muscles of mice using immunohistochemistry.Results: The transcription level of the SOST gene in the muscle tissue was significantly higher in patients with MM and sarcopenia than in patients with MM without sarcopenia and elderly patients with sarcopenia; the area of C2C12 mouse myoblasts co-cultured with SP2/0 myeloma cells was 167,904 ± 8653.7 pix; this was significantly lower than the area of 402,994 ± 13,575.0 pix in the control group (CG); the fluorescence intensity of SOST in the cells of the experimental group (EG) was 159,389 ± 10,534 AU; this was significantly higher than the intensity of 26,338 ± 6059 AU in the CG; the differences in results of the coat-hanger test, the tail suspension test, the weight-bearing forced swimming test, and the grip strength test between the tumor-bearing mice in the EG and the CG were statistically significant; and the quantitative result of SOST expression in the muscle tissue of the EG mice was 11,515 ± 1573 pix; this was significantly higher than the result of 3399 ± 798.8 pix in the CG.Conclusion: The SOST gene expression was significantly higher in muscle of mice in EG than in CG; and increased SOST gene expression might be a pathogenesis of MM complicated with sarcopenia.Keywords: multiple myeloma, SOST, multiple myeloma mouse model, ethology, sarcopenia, myoblast differentiation

Mengxia Shi,1 Bin Hu,1 Yu Hong,1 Meng Wang,1,&ast; Ying Yao1,2,&ast; 1Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Yao, Department of Nephrology and Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, People’s Republic of China, Tel +86-13720379867, Email yaoyingkk@126.com Meng Wang, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, People’s Republic of China, Tel +86-15927407065, Email nishuihan2003@163.comPurpose: Deep sea water (DSW) is a natural resource rich in minerals, which participates in biological processes such as energy metabolism, regulates serum glucose and lipids levels, and has a certain protective effect on endocrine and metabolism-related diseases. Studies have shown that the improvement of glucose tolerance in diabetic mice by DSW may be associated with the protective effect on the structure and function of pancreatic islets, and the specific mechanism is still unclear. Other studies have shown that long-term exposure to high concentrations of fatty acids can lead to apoptosis and dysfunction of pancreatic β-cell, increasing the risk of type 2 diabetes mellitus (T2DM). Down-regulation of plasma fatty acid levels may reduce pancreatic β-cell dysfunction, thereby improving glucose homeostasis. Understanding the specific mechanism of DSW regulating blood glucose is of great significance for its clinical application.Methods: In the present study we used db/db mice as a T2DM model and treated mice with deep ocean mineral concentration (DOMC, a commercial product of DSW) for 4 and 12 weeks. Basic information, serum biochemical indicators, and pathological tissues were gathered for exploration.Results: The db/db mice treated with 4 weeks’ DOMC (db/db+DOMC) showed decreased plasma cholesterol and triglyceride levels. Tests implied that in adipose tissues, the db/db+DOMC group’s lipolysis process was inhibited, and the β-fatty acid oxidation process was promoted. Besides, DOMC reduced lipogenesis and encouraged β-oxidation in the liver, as a result, improved fatty liver in db/db mice. Further measurements showed DOMC improved glucose homeostasis slightly in db/db animals after a 12-week treatment by preventing pancreatic β-cell apoptosis.Conclusion: DOMC inhibited pancreatic β-cell apoptosis and regulated glucose homeostasis in db/db mice by lowering the lipid levels via regulation of fatty acid β-oxidation, lipolysis, and lipogenesis processes.Keywords: deep sea water, type 2 diabetes mellitus, lipid metabolism, glucose homeostasis, pancreatic β-cell apoptosis

XiaoXiao Jia,1,2,&ast; Ming Shi,3,&ast; Qifei Wang,1,2 Jessica Hui,4 Joshua Hui Shofaro,1,2 Ryenchindorj Erkhembayar,5 Mizhou Hui,1,2 Chenzhe Gao,1 Munkh-Amgalan Gantumur1 1College of Life Science, Northeast Agricultural University, Harbin, People’s Republic of China; 2College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, People’s Republic of China; 3School of Life Science and Technology, Harbin Institute of Technology, Harbin, People’s Republic of China; 4Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; 5Department of International Cyber Education, Graduate School, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia&ast;These authors contributed equally to this workCorrespondence: Mizhou Hui; Munkh-Amgalan Gantumur, Email huimizhou@163.com; mnkh.calm@gmail.comBackground: Hyaluronic acid (HA) and HA fragments interact with a variety of human body receptors and are involved in the regulation of various physiological functions and leukocyte trafficking in the body. Accordingly, the development of an injectable HA fragment with good tissue permeability, the identification of its indications, and molecular mechanisms are of great significance for its clinical application. The previous studies showed that the clinical effects of injectable 35kDa B-HA result from B-HA binding to multiple receptors in different cells, tissues, and organs. This study lays the foundation for further studies on the comprehensive clinical effects of injectable B-HA.Methods: We elaborated on the production process, bioactivity assay, efficacy analyses, and safety evaluation of an injectable novel HA fragment with an average molecular weight of 35 kDa (35 kDa B-HA), produced by recombinant human hyaluronidase PH20 digestion.Results: The results showed that 35 kDa B-HA induced human erythrocyte aggregation (rouleaux formation) and accelerated erythrocyte sedimentation rates through the CD44 receptor. B-HA application and injection treatment significantly promoted the removal of mononuclear cells from the site of inflammation and into the lymphatic circulation. At a low concentration, 35 kDa B-HA inhibited production of reactive oxygen species and tumor necrosis factor by neutrophils; at a higher concentration, 35 kDa B-HA promoted the migration of monocytes. Furthermore, 35 kDa B-HA significantly inhibited the migration of neutrophils with or without lipopolysaccharide treatment, suggesting that in local tissues, higher concentrations of 35 kDa B-HA have antiinflammatory effects. After 99mTc radiolabeled 35 kDa B-HA was intravenously injected into mice, it quickly entered into the spleen, liver, lungs, kidneys and other organs through the blood circulation.Conclusion: This study demonstrated that the HA fragment B-HA has good tissue permeability and antiinflammatory effects, laying a theoretical foundation for further clinical studies.Keywords: hyaluronic acid, 35kDa hyaluronic acid fragment, B-HA/HA35, molecular weight, inflammation, inflammatory cells, reactive oxygen species, injection safety

Mizhou Hui,1 Xiaoxiao Jia,1 Xinrong Li,2 Rayko Lazcano-Silveira,1 Ming Shi3 1College of Life Sciences, Northeast Agricultural University, Harbin, Heilongjiang, People’s Republic of China; 2College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, Shandong, People’s Republic of China; 3Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of ChinaCorrespondence: Ming Shi, Harbin Institute of Technology, 2 Yikuang Street, Nangang District, Harbin, Heilongjiang, 150001, People’s Republic of China, Tel +86 13654537645, Email shiming@hit.edu.cnIntroduction: Liposoluble carbon-60 (C60) has potential applications in many fields, including cosmetics, medical devices, and medicine, but its specific mechanism of action remains unclear. This study explored whether liposoluble C60 could be delivered to human organs, tissues, and cells through blood, extracellular fluid, and cell culture fluid and whether it exerts anti-inflammatory and antioxidant effects at the molecular, cellular, and whole-animal levels.Methods: At the cellular level, we mixed C60 dissolved in grape seed oil with cell culture medium containing 10% serum and investigated its effects on tumor necrosis factor-α (TNF-α) release, migration, phagocytosis, respiratory burst, and apoptosis in freshly isolated human neutrophils. At the molecular level, we mixed a trace amount of C60 dissolved in grape seed oil with aqueous and ethanolic solutions and studied its antioxidant effect. At the animal level, we investigated the inhibitory effect of C60 on the serum inflammatory marker C-reactive protein (CRP) in beagle dogs after oral administration of C60 dissolved in grape seed oil.Results: The results showed that the trace amount of C60 dissolved in grape seed oil significantly inhibited TNF-α release, cell migration, phagocytosis, and respiratory burst in freshly isolated human neutrophils. In addition, the trace amount of C60 dissolved in grape seed oil had a significant scavenging effect on superoxide free radicals and 1,1-diphenyl-2-trinitrophenylhydrazine free radicals. Oral administration of C60 dissolved in grape seed oil markedly reduced the level of the serum inflammatory marker CRP in beagle dogs.Conclusion: In summary, a trace amount of hydrophobic C60 in hydrophilic media effectively produced anti-inflammatory and antioxidant effects in cells and animals. C60 dissolved in grape seed oil is a novel anti-inflammatory and antioxidant drug candidate.Keywords: Carbon 60, anti-inflammation, anti-oxidation, C-reactive protein

Jian Li,1– 3 Qing Zhang,1– 3 Jiahui Cai,1– 3 Yibo Yang,1– 3 Jia Zhang,1– 3 Yanting Gao,1– 3 Shihe Liu,1– 3 Kun Li,1– 3 Ming Shi,1– 3 Zhiwei Liu,1– 3 Liming Gao4 1College of Environmental & Chemical Engineering, Yanshan University, Qinhuangdao, People’s Republic of China; 2Applied Chemistry Key Laboratory of Hebei Province, Yanshan University, Qinhuangdao, People’s Republic of China; 3Key Laboratory of Nanobiotechnology of Hebei Province, Yanshan University, Qinhuangdao, People’s Republic of China; 4Oncology Department, the First Hospital of Qinhuangdao, Qinhuangdao, People’s Republic of ChinaCorrespondence: Jian Li, College of Environment & Chemical Engineering, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, People’s Republic of China, Tel +86-335-8061569, Fax +86-335-8061569, Email Lijianbio@ysu.edu.cnIntroduction: During the combined treatment of tumors, the non-interfering transportation of drugs with different solubilities and the controllable sequential release are the main challenges. Here, we reported a double-chamber “Dandelion” -like sequential drug delivery system to realize the sequential release of different drugs for treating malignant tumors synergistically.Methods: After synthesizing mesoporous silica nanoparticles (MSN) by template method, a hydrophilic chemotherapy drug doxorubicin (DOX) was loaded into the channels of mesoporous silica (MSN) and locked with polydopamine (PDA) coating. Next, β-cyclodextrin (β-CDs) was decorated on PDA by Michael addition reaction, and the hydrophobic photosensitizer chlorin e6 (Ce6) was encapsulated into the hydrophobic chambers of β-CDs. Finally, AS1411 was modified on the surface of PDA and obtained DOX@MSN@PDA-β-CD/Ce6-AS1411 nanoparticles (DMPCCA) through which orthogonal loading and effective controlled release of different drugs were realized.Results: Under the sequential irradiations of 808 nm and 660 nm near-infrared (NIR) laser, PDA promoted the extensive release of Ce6 firstly while playing the effect of photothermal therapy (PTT), further to achieve the effect of photodynamic therapy (PDT) of Ce6. Meanwhile, the rapid release of DOX loaded in MSN channels showed a time lag of about 5 h after Ce6 release, through which it maximized the chemotherapeutic effect. Besides, the present drug loading nano-platform combined passive tumor-targeting effect given by EPR and active tumor-targeting effect endowed by AS1411 realized PTT-PDT-chemotherapy triple mode synergistic combination.Conclusion: We offer a general solution to address the key limitations for the delivery and sequential release of different drugs with different solubilities.Graphical Abstract: Keywords: sequential release, mesoporous silica, chemotherapy, tumor-targeting, PTT-PDT-chemotherapy combination

Renhui Huang,1,2,&ast; Qi Shi,1,&ast; Shutian Zhang,1,2 Hong Lin,1,2 Chengzhi Han,1,2 Xinyi Qian,1 Yijun Huang,1 Xiaorong Ren,1 Jiayuan Sun,3 Nana Feng,4 Chunmei Xia,1 Meng Shi5 1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Respiratory Endoscopy, Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of China; 4Department of Respiratory and Critical Medicine, Shanghai Eighth People’s Hospital Affiliated to Jiangsu University, Shanghai, People’s Republic of China; 5Department of Thoracic and Cardiovascular Surgery, Huashan Hospital, Affiliated with Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meng Shi, Department of Thoracic and Cardiovascular Surgery, Huashan Hospital, Affiliated with Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, People’s Republic of China, Tel +86 15921527577, Email huashan_heart@sina.cn Chunmei Xia, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86 13917406439, Email cmxia@fudan.edu.cnPurpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.Graphical Abstract: Keywords: cGAS-STING, endoplasmic reticulum stress, alveolar epithelial type II cells, lung ischemia/reperfusion injury

Shanshan Peng,1 Na Liu,1 Kai Wei,1 Gang Li,2 Zheng Zou,3 Tao Liu,3 Meifang Shi,3 Yuan Lv,1 Yong Lin1 1Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Baoshan Renhe Hospital, Shanghai, People’s Republic of China; 3Youyi Road Community Health Service Centre for Baoshan District, Shanghai, People’s Republic of ChinaCorrespondence: Yong Lin, Department of Laboratory Medicine, Huashan Hospital, Fudan University, No. 12 the Middle of Urumqi Road, Shanghai, People’s Republic of China, Tel +86 13916553198, Email linyong7007@163.comPurpose: Recent studies have focused on whether kidney injury molecule-1 (KIM-1) might serve as a marker of acute kidney tubular injury. Our study analyzed the levels of KIM-1 in the healthy population of different ages to explore the correlation between KIM-1 and age. Moreover, we constructed a model to predict kidney age.Methods: A cross-sectional study was conducted by Huashan Hospital, Shanghai, China, between April 2020 and December 2020. KIM-1 and other kidney biomarkers were measured in 176 healthy individuals ranging from 26 to 91 years old. Statistical correlated analyses for urinary KIM-1, creatinine (uCREA), potassium (K), sodium (Na) and chlorine (Cl), plasmic renin, angiotensin-2 (AngII) and aldosterone (ALD), and serum microalbuminuria (MALB), β 2-microglobulin (B2MG), cystatin C (CYSC), urea nitrogen (BUN), creatinine (CREA), and glucose (GLU) were performed to assess the correlation between age and kidney biomarkers. All variables were selected as independent variables for the prediction of age by multiple linear regression.Results: KIM-1 positively correlated with age in kidney healthy people (r = 0.41, p < 0.05), whether among females (r = 0.51, p < 0.05) or males (r = 0.27, p < 0.05). It was much related to K (r = 0.34), B2MG (r = 0.28), and CL (r = 0.23). The predicted model was constructed with eGFR, Cl, ALD, CYSC, KIM-1, BUN, GLU and AngII, reaching an adjusted R2 of 69.5% and a standard error of the estimated 7.84 years.Conclusion: The level of urinary KIM-1 increases with age in healthy people. The model constructed by KIM-1 and the other 7 biomarkers can predict kidney age in healthy people.Keywords: aging, kidney biomarkers, KIM-1, healthy

Mingming Shi,1,&ast; Xiao Zhang,2,&ast; Hui Wang1 1Center for Disease Control and Prevetion of Shangcheng District, Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingming Shi, Email shimingming1213@126.comObjective: Little information is available on the prevalence and associated risk factors of diabetes and prediabetes in the community located in Hangzhou city, Zhejiang Province, southeast China. This study aims to investigate the prevalence of adult diabetes and prediabetes and their associated risk factors among a community population in Hangzhou.Methods: A multistage sampling method was used in this study. Ten communities located in Shangcheng district of Hangzhou city were selected, and 3096 permanent residents (resident for ≥ 6 months) aged 18 years and above were enrolled into this study. Finally, a total of 2986 participants were included. A questionnaire interview and physical examination were conducted for all participants by trained investigators in a local medical center. Anthropometric measurements covered height, weight, waist circumference (WC) and blood pressure, while the blood tests included fasting blood glucose, an oral glucose tolerance test and fasting lipid profiles. The American Diabetes Association diabetes diagnosis criteria were used to discriminate among normal blood glucose, diabetes and prediabetes. The Rao–Scott adjusted χ2 test and complex sampling design-based unconditional multivariate logistic regression analysis were used to evaluate factors associated with diabetes and prediabetes. Descriptive and inferential statistics were calculated in Stata version 15. P-values < 0.05 indicate statistical significance.Results: The overall prevalence of diabetes was 13.97%, of which 81.54% had prediagnosed diabetes and 18.46% were newly diagnosed with diabetes in the present study. The prevalence of prediabetes was 18.89%. Multivariable logistic regression analysis showed that age, education, once smoking, family history of diabetes, obesity, central obesity and hypertension were factors associated with diabetes, while age, smoking, drinking, central obesity and hypertension were significant factors related to prediabetes.Conclusion: The prevalence of diabetes and prediabetes in adults in Hangzhou city remains high. Interventions aiming to modify risk factors such as drinking, obesity, central obesity and hypertension are urgently required.Keywords: diabetes, prediabetes, prevalence, associated factors

Kun Yang,1 Mengdong Shi,1 Cong Fu,2,&ast; Ran Huo1,2,&ast; 1Department of Plastic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cong Fu; Ran Huo, Tel +86 15154101889 ; +86 15168889001, Fax +860531-68778153, Email cong3399@outlook.com; huoran@medmail.com.cnAbstract: Follicular occlusion triad (FOT) is a chronic inflammatory skin disease that comprises hidradenitis suppurativa, acne conglobata, and perifolliculitis capitis abscedens et suffodiens and can seriously affect a patient’s quality of life. Currently, there is no consensus on the treatment plan for FOT. There are also only a few reports on the treatment of severe FOT. In July 2020, a male patient who was diagnosed with severe FOT was treated in our hospital and received comprehensive surgical treatment for 2 months. This treatment strategy was effective and the patient had no recurrence during a follow-up period of > 1 year. By retrospectively analyzing the clinical data of the patient, recording the patient’s condition during postoperative recovery, and reviewing relevant literatures, the clinical manifestations, diagnosis, choice of treatment methods, and prognosis of FOT were evaluated.Keywords: chronic inflammatory skin disease, comprehensive treatment, surgical management

Min Shi,&ast; Jing Chen,&ast; Tianxiao Liu,&ast; Weixin Dai, Zhan Zhou, Lifei Chen, Yubo Xie Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yubo Xie, Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuang-yong Road, Nanning, 530021, People’s Republic of China, Tel +86 186 7795 8208, Email xybdoctor@163.comIntroduction: Remimazolam is a novel benzodiazepine γ-aminobutyric acid A (GABAa) receptor agonist used for sedation and the induction as well as maintenance of general anesthesia. Previous research proved that anesthetic agents acting on GABAa receptor, such as thiopentone, propofol and midazolam, have protective actions for cerebral ischemia/reperfusion (I/R) injury. We here probed into remimazolam for its protective effect and potential mechanism of action against cerebral I/R injury.Material and Methods: A rat model of middle cerebral artery occlusion (MCAO) with focal transient cerebral I/R injury was established and was given tail vein injection of gradient remimazolam (5, 10, 20 mg/kg) after 2 h of ischemia. Following 24 h of reperfusion, neurological function, brain infarct volume, morphology of cerebral cortical neurons, and expressions of corticocerebral NLRP3, ASC, caspase-1, GSDMD, IL-1β and IL-18 were evaluated.Results: The results showed that remimazolam could effectively improve the neurological dysfunction, reduce the infarct volume and alleviate the damage of cortical neurons after I/R injury. Notably, the expression of NLRP3 inflammasome pathway was down-regulated, suggesting that remimazolam exerted protective actions on I/R injury by suppressing pyroptosis with decreased expression and release of inflammatory factors, and the involvement of the NLRP3 inflammasome pathway might be the core during that process. Overall, our results indicate that NLRP3 inflammation is a promising target.Conclusion: Based on this mechanism, remimazolam may be one of the ideal anesthetic drugs for patients with ischemic stroke.Keywords: remimazolam, NLRP3 inflammasome, ischemia/reperfusion injury, I/R, pyroptosis, inflammation

Liurui Dou, Mingyue Shi, Juanjuan Song, Xiaona Niu, Junwei Niu, Shengjie Wei, Dan Li, Yanliang Bai, Kai Sun Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Henan, People’s Republic of ChinaCorrespondence: Kai Sun; Yanliang BaiDepartment of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, No. 7 Weiwu Road, Jinshui District Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86-18237110038; +86-13783605211, Email sunkai@cellscience.org; yanliangbai@126.comBackground: The ratio of C-reactive protein to albumin (CAR) is an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in several solid tumours and chronic lymphocytic leukaemia (CLL). However, no studies have investigated the prognostic value of the CAR in patients with acute myeloid leukaemia (AML).Objectives and Methods: We retrospectively analysed 212 newly diagnosed non-M3 AML patients. Using the receiver operating characteristic curve (ROC) method, the optimal cut-off value for CAR was determined. We investigated the correlations of the pretreatment CAR levels with clinical characteristics, treatment response of induction chemotherapy, overall survival (OS) and event-free survival (EFS). We also assessed the prognostic value of the CAR compared with other inflammation-based prognostic parameters by the area under the curve (AUC).Results: According to the ROC curve, the optimal cut-off value of CAR was 1.015. CAR was associated with age, C-reactive protein (CRP) levels, albumin levels, ferritin levels, bone marrow blast percentage, French-American-British (FAB) classification, immunophenotype and 2017 European Leukemia Net (2017 ELN) risk stratification. Importantly, we found that high CAR was a powerful indicator of a lower complete remission (CR) rate (p< 0.001), worse OS (p< 0.001) and worse EFS (p< 0.001). Subgroup analysis showed that a high CAR was associated with shorter OS and EFS in patients with intermediate risk stratification or those aged ≤ 65 years or those without haematopoietic stem cell transplantation (HSCT). In the multivariate analysis, the CAR was an independent prognostic factor for OS and EFS. Furthermore, the predictive value of CAR for OS is superior to that of CRP, albumin and GPS in de novo AML patients aged ≤ 65 years old.Conclusion: CAR is a simple and effective prognostic marker in patients with AML. It could be an additional prognostic factor that help further precise the current risk stratification of non-M3 AML, particularly for patients in intermediate risk stratification and those aged ≤ 65 years and those who did not undergo HSCT.Keywords: acute myeloid leukaemia, C-reactive protein to albumin ratio, prognosis

Liang Li,1 Xue Yu,2 Guanqiang Ma,1 Zhiqi Ji,1 Shihao Bao,1 Xiaopeng He,1,3 Liang Song,1,3 Yang Yu,1,3 Mo Shi,1,3 Xiangyan Liu1,3 1Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Pediatrics, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 420100, People’s Republic of China; 3Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of ChinaCorrespondence: Mo Shi; Xiangyan LiuDepartment of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People’s Republic of ChinaEmail legendsm01@163.com; liuxiangyan1@163.comBackground: Early-stage lung squamous cell carcinoma (LUSC) progression is accompanied by changes in immune microenvironments and the expression of immune-related genes (IRGs). Identifying innate IRGs associated with prognosis may improve treatment and reveal new immunotherapeutic targets.Methods: Gene expression profiles and clinical data of early-stage LUSC patients were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases and IRGs from the InnateDB database. Univariate and multivariate Cox regression and LASSO regression analyses were performed to identify an innate IRG signature model prognostic in patients with early-stage LUSC. The predictive ability of this model was assessed by time-dependent receiver operator characteristic curve analysis, with the independence of the model-determined risk score assessed by univariate and multivariate Cox regression analyses. Overall survival (OS) in early-stage LUSC patients was assessed using a nomogram and decision curve analysis (DCA). Functional and biological pathways were determined by gene set enrichment analysis, and differences in biological functions and immune microenvironments between the high- and low-risk groups were assessed by ESTIMATE and the CIBERSORT algorithm.Results: A signature involving six IRGs (SREBF2, GP2, BMX, NR1H4, DDX41, and GOPC) was prognostic of OS. Samples were divided into high- and low-risk groups based on median risk scores. OS was significantly shorter in the high-risk than in the low-risk group in the training (P < 0.001), GEO validation (P = 0.00021) and TCGA validation (P = 0.034) cohorts. Multivariate Cox regression analysis showed that risk score was an independent risk factor for OS, with the combination of risk score and T stage being optimally predictive of clinical benefit. GSEA, ESTIMATE, and the CIBERSORT algorithm showed that immune cell infiltration was higher and immune-related pathways were more strongly expressed in the low-risk group.Conclusion: A signature that includes these six innate IRGs may predict prognosis in patients with early-stage LUSC.Keywords: early-stage lung squamous cell carcinoma, prognosis, risk score, gene signature, innate immune-related genes, immune cell infiltration

Yongfeng Pang, Mingfei Shi Department of Rehabilitation, Tiantai People’s Hospital of Zhejiang Province, Zhengjiang, 317200, People’s Republic of ChinaCorrespondence: Mingfei ShiDepartment of Rehabilitation, Tiantai People’s Hospital of Zhejiang Province, No. 1 Kangning Middle Road, Tiantai County, Zhengjiang, 317200, People’s Republic of ChinaTel +86-13516877456Email ming_fly141@yeah.netBackground: Mild cognitive impairment (MCI) is a typical symptom of early Alzheimer’s disease (AD) and is driven by the dysfunction of microRNAs (miRs). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique for handling neuropsychiatric disorders and has universally effects on the functions of miRs. In the current study, the improvement effects of rTMS on MCI associated with AD were explored by focusing on miR-567/NEUROD2/PSD95 axis.Methods: MCI was induced in mice using scopolamine and was treated with rTMS of two frequencies (1 Hz and 10 Hz). The changes in cognitive function, brain structure, neurotrophic factor levels, and activity of miR-567/NEUROD2/PSD95 axis were assessed. The interaction between rTMS and miR-567 was further verified by inducing the level of miR-567 in AD mice.Results: The administrations of rTMS improved the cognitive function of AD mice and attenuated brain tissue destruction, which were associated with the restored production of BDNF and NGF. Additionally, rTMS administrations suppressed the expression of miR-567 and up-regulated the expressions of NEUROD2 and PSD95, which contributed to the improved condition in central nerve system. With the induced level of miR-567, the effects of rTMS were counteracted: the learning and memorizing abilities of mice were impaired, the brain neuron viability was suppressed, and the production of neurotrophic factors was suppressed even under the administration of rTMS. The changes in brain function and tissues were associated with the inhibited expressions of NEUROD2 and PSD95.Conclusion: The findings outlined in the current study demonstrated that rTMS treatment could protect brain against AD-induced MCI without significant side effects, and the function depended on the inhibition of miR-567.Keywords: Alzheimer’s disease, mild cognitive impairment, miR-567, NEUROD2, repetitive transcranial magnetic stimulation

Yingke He,1 Monica Tan,1 Michelle Shi,2 Xiu Ling Jacqueline Sim,1 Elaine Lum,3 Sungwon Yoon,3 Hairil Rizal Abdullah1 1Department of Anaesthesiology, Singapore General Hospital, 169608, Singapore; 2Department of Psychology, Singapore General Hospital, 169608, Singapore; 3Health Services and Systems Research, Duke-NUS Graduate Medical School, 169857, SingaporeCorrespondence: Hairil Rizal AbdullahDepartment of Anaesthesiology, Singapore General Hospital, Outram Road, 169608, SingaporeEmail Hairil.rizal.abdullah@singhealth.com.sgBackground: Perioperative smoking is associated with an increased incidence of general postoperative morbidity and mortality. The perioperative period is recognized as an important “teachable moment” that can motivate patients to adopt health changing behaviors.Objective: In this study, we aimed to determine the prevalence of smokers among elective surgical patients in an Asian tertiary hospital. We also investigated their smoking characteristics, previous quitting attempts, readiness-to-quit status as well as knowledge of smoking-related postoperative complications.Methods: We conducted a single-center prospective cohort study among all patients who attended a preoperative assessment clinic within a 2-month period (August to September 2020) using a preoperative smoking questionnaire.Results: A total of 3362 patients participated in the study, of which 348 (10.4%) were current smokers. More than half (65.6%) of the smokers had previously attempted to quit smoking, with most (78%) having made more than one attempt. Forty-nine percent of current smokers were in the pre-contemplation stage of quitting and thirty-one percent were in the contemplation stage. Only twenty-one percent were in the preparation stage of quitting. Thirty-eight percent of patients recognized the importance of smoking cessation perioperatively but only twenty-eight percent were confident of quitting perioperatively. Less than sixty percent of smokers were aware of at least one type of smoking-related postoperative complication. Less than half of the patients (45%) had ever received advice on perioperative smoking cessation from the surgeons.Conclusion: A thorough understanding of smokers’ smoking characteristics, barriers to quit and readiness-to-quit status are crucial to establishing a successful multidisciplinary perioperative smoking cessation program. Counselling should address knowledge deficits and be tailored to a patient’s stage-of-change in order to seize this precious perioperative “teachable moment”.Keywords: perioperative smoking cessation, readiness-to-quit status, barriers to quit perioperatively

Li J, You J, Wu C, et al. Int J Nanomedicine. 2018;13:4607-4625. An error during the preparation of Figure S1 for publishing led to the inadvertent creation of a duplicate region in figure part S1B on page 4622. The journal wishes to apologise for this error. The correct version of Figure S1 is as follows. Figure S1 Transmission electron microscopy characterizations of Fe3O4 nanoparticles (NPs) (A) and Fe3O4@mSiO2 NPs (B). The insert in (A) is the distribution of Fe3O4 NP size.

Yanru Pei,* Mingyue Shi,* Juanjuan Song, Xiaona Niu, Shengjie Wei, Liurui Dou, Mengyu Xiao, Dan Li, Fangfang Xu, Yanliang Bai, Kai Sun Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai Sun; Yanliang BaiDepartment of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of ChinaTel +86-18237110038; +86-13783605211Email sunkai@cellscience.org; yanliangbai@126.comBackground: Hemorrhagic complications are the most common cause of early death in patients with APL and remain a major challenge in the management of APL. Early fatal bleeding events occur not only in high-risk but also in non-high-risk acute promyelocytic leukemia (APL) patients with normal or low WBC counts.Objectives and Methods: To demonstrate the role of the absolute number of circulating leukemic cells in early bleeding events in APL patients. Clinical and laboratory characteristics of 149 patients newly diagnosed with APL were obtained from medical records and retrospectively investigated.Results: In this study, circulating absolute leukemic cells were positively correlated with the WBC count (r=0.9813, p< 0.001) in all patients with APL, and importantly, they were strongly associated with significant bleeding events in non-high-risk patients. Multivariate logistic regression analysis showed that the absolute number of leukemia cells was an independent risk factor for significant bleeding events in APL patients. A cut-off value of 2.59× 109/L for circulating leukemic cells to predict significant bleeding events in APL patients was obtained by ROC curve analysis. We further confirmed that the significant bleeding rate of patients with non-high-risk APL was statistically increased when the absolute number of circulating leukemic cells was ≥ 2.59× 109/L.Conclusion: Circulating leukemic cell content has great clinical value for predicting early bleeding events in APL patients, especially in non-high-risk APL.Keywords: circulating leukemic cells, early fatal bleeding events, non-high-risk acute promyelocytic leukemia

Yuhan Chen,1,* Yuanyuan Chen,1,* Xueze Jiang,1 Mengkun Shi,2 Zhenwei Yang,1 Zhiyong Chen,1 Xuesheng Hua,1 Jie Chen,1 Yuepeng Wang1 1Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Cardio-Thoracic Surgery, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuepeng Wang; Jie ChenDepartment of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of ChinaTel +86 18217267289; +86 15280380968Email wangyuepeng@xinhuamed.com.cn; jieyuepeng@msn.comBackground: Activation of vascular adventitial fibroblasts (VAFs) upon vascular injury contributes greatly to the medial vascular smooth muscle cells (VSMCs) proliferation, migration and the subsequent neointima formation. A number of factors including fibroblast growth factors (FGFs) have been shown to control VSMC growth, proliferation and phenotypic switching, suggesting that they may function as paracrine signals for VAFs to modulate VSMCs functions. However, little is known about the signaling molecule(s) and its mechanism of action. This study is set to identify which and how FGF family members are involved in VAFs mediated vascular remodeling.Methods: We used qPCR, Western blot and Immunohistochemistry to observe the spatiotemporal expression of FGF10 and FGFR2 in injured vascular tissue. The proliferation and migration assays of VSMCs were performed in a co-culture system. The activation of signaling pathway was detected by Western blot, immunohistochemistry and immunofluorescence. Hematoxylin-eosin and immunofluorescence were used to assess the effects of exogenous FGF10 and siFGF10 on the neointima formation.Results: The expression of FGF10 and FGFR2 were increased from day 3 through day 14 post injury. FGF10 was significantly upregulated in adventitia, and FGFR2 was detected in both media and neointima after injury. In vitro, FGF10 was most prominently expressed in VAFs and FGFR2 was significantly expressed in VSMCs. Both were regulated by PDGF. Co-culture of VAFs and VSMCs in vitro showed that VAF-derived FGF10 promoted the proliferation and migration of VSMCs. PDGF could synergistically enhance the process. VAF-derived FGF10 can significantly activate the FGFR2 in VSMCs and furthermore significantly activate the downstream MAPK/PI3K-AKT signaling pathways. Delivery of exogenous FGF10 potentiated the neointima formation, while siFGF10 attenuated the neointima formation.Conclusion: VAFs-derived FGF10 promoted the proliferation and migration of VSMCs and neointima formation, and FGF10-FGFR2 signaling triggered the activation of MAPK/PI3K-AKT pathways in VSMCs and PDGF synergistically amplified FGF10 signaling.Keywords: vascular adventitial fibroblasts, vascular smooth muscle cells, FGF10, proliferation, migration, neointima formation

Yong-Fa Zhang,1,2,* Ming Shi,3,* Liang-He Lu,3 Lu Wang,1,2 Rong-Ping Guo3 1Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 3The Department of Hepatobiliary Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lu WangDepartment of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of ChinaTel/Fax +8620-64175590Email cms024mm@163.comRong-Ping GuoDepartment of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of ChinaTel/Fax +8620-87342266Email guorp@sysucc.org.cnPurpose: It remains unknown which staging system is best in predicting the survival of patients with intermediate stage hepatocellular carcinoma (HCC). We aimed to investigate the performance of nine currently used HCC staging systems.Patients and Methods: Between 2005 and 2014, a large cohort of 880 consecutive patients with intermediate stage HCC and sufficient data for utilization in all staging systems were enrolled. The prognostic performance of each staging system was compared. Independent prognostic variables were also identified.Results: Multivariate analysis revealed that alkaline phosphatase (ALP), aspartate aminotransferase (AST), etiology, alpha-fetoprotein (AFP), Child-Pugh stage, tumor size, and tumor number were independent prognostic factors for survival. In the entire cohort, the Hong Kong Liver Cancer (HKLC) staging system was associated with the highest Harrell’s c-index and lowest Akaike information criterion value in comparison with other systems. In subgroup analysis according to treatment strategy, the HKLC staging system remained the best prognostic model in patients undergoing hepatic resection (n=222) or transarterial chemoembolization (n=658). Additional prognostic factors of AST, ALP, etiology, and AFP improved the discriminatory ability of HKLC.Conclusion: The HKLC staging system is stable and consistently the best prognostic model in all patients with intermediate-stage HCC and in patients subjected to different treatment strategies. Selecting an optimal staging system is helpful in improving the design of future clinical trials in intermediate stage HCC.Keywords: hepatocellular carcinoma, intermediate-stage, staging system, prognosis, overall survival, hepatic resection, transarterial chemoembolization

Jie Mei,1,2,* Shao-Hua Li,1,2,* Qi-Jiong Li,1,2,* Xu-Qi Sun,1,2 Liang-He Lu,1,2 Wen-Ping Lin,1,2 Lie Zheng,1,3 Min-Shan Chen,1,2 Ming Shi,1,2 Wei Wei,1,2 Rong-Ping Guo1,2 1Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 2Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Medical Imaging, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong-Ping Guo; Wei Wei Email guorp@sysucc.org.cn; weiwei@sysucc.org.cnBackground: Hepatic artery infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) immunotherapy have shown promising outcomes in patients with advanced hepatocellular carcinoma (HCC), respectively. However, the combination of the two treatments has not been reported. In this study, we compared the efficacy of HAIC combined with anti-PD-1 immunotherapy (HAICAP) and HAIC in patients with advanced HCC.Methods: Between November 2018 and December 2019, advanced HCC patients that were treated with either HAICAP or HAIC were retrospectively recruited and reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.Results: As a result, 229 patients were included in this study. Patients were divided into HAICAP group (n = 81) and HAIC group (n = 148) accordingly. The follow-up time ranged from 1.0 to 21.6 months, with a median of 11.0 months. The median overall survival was 18.0 months in the HAICAP group and 14.6 months in the HAIC group (p = 0.018; HR = 0.62; 95% CI 0.34– 0.91). The median progression-free survival was 10.0 months in the HAICAP group and 5.6 months in the HAIC group (p = 0.006; HR = 0.65; 95% CI 0.43– 0.87). The disease control rate in overall response (83% vs 66%; p = 0.006) and intrahepatic response (85% vs 74%, respectively; p = 0.045) were higher in the HAICAP group than in the HAIC group.Conclusion: In comparison to HAIC, HAICAP was associated with a better treatment response and survival benefits for patients with advanced HCC.Keywords: hepatocellular carcinoma, hepatic artery infusion chemotherapy, programmed cell death protein-1, FOLFOX, combination therapy

Haoran Lei, Ming Shi, Hang Xu, Shengjiang Bai, Xingyu Xiong, Qiang Wei, Lu Yang Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Lu YangDepartment of Urology, West China Hospital, Sichuan University, Chengdu, 37 Guoxue Alley, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86-18980606829Fax +86-028-85422451Email wycleflue@163.comAbstract: Although it has always been believed that radiation has immunosuppressive effects, more and more preclinical and clinical trials have shown that the combination of radiotherapy and immunotherapy has a potential synergistic effect to treat cancers including urological malignancies. When radiotherapy is combined with immunotherapy, improved prognosis has been observed in different urinary tumors. However, there is no standard treatment, such as the optimal dose/fractionation and the sequence of immunotherapy and radiotherapy. In this review, we discussed the effects of radiotherapy on the cancer immune system and emphasized the synergy of radiotherapy combined with immunotherapy. Although it has significantly improved the prognosis of tumors, there are still some unresolved questions about how to best use this combination in clinical practice. Ongoing trials will provide further information on the interaction of radiotherapy combined with immunotherapy, and are expected to guide clinical practice and improve clinical outcomes.Keywords: radiotherapy, immunotherapy, urological malignancies, abscopal effect

Yang Zhao, MinKe He, RunBin Liang, QiJiong Li, Ming Shi Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Ming ShiDepartment of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of ChinaTel/Fax +86-020-87343938Email shiming@sysu.edu.cnPurpose: Our aim was to compare the antiemetic efficacy of the triple combination of aprepitant, dolasetron and dexamethasone with the combination of dolasetron and dexamethasone for chemotherapy-induced nausea and vomiting (CINV) in hepatocellular carcinoma (HCC) patients receiving hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil and leucovorin (FOLFOX).Patients and Methods: This was a retrospective study. In the dolasetron plus dexamethasone group (D group), the patients received dolasetron (100 mg, i.v., on day 1) and dexamethasone (10 mg, i.v., on day 1) 30 min before starting administration of chemotherapeutic drugs. In the aprepitant plus dolasetron and dexamethasone group (AD group), the patients received dolasetron and dexamethasone as described above, and aprepitant (125 mg, p.o.) on day 1 followed by 80 mg on days 2 and 3. The primary endpoint was the complete response rate (CR, defined as no emetic episodes and no rescue medication use) during the first cycle of hepatic arterial infusion chemotherapy.Results: Between January 2018 and August 2019, 302 eligible patients were included: 197 in AD group and 105 in D group. Patients in AD group had significantly higher complete response rates than those in D group during the first cycle (85.8% vs 71.4%, P = 0.003) and all cycles (73.6% vs 49.5%, P< 0.001). Patients in AD group had lower rescue therapy (1.5% vs 26.7%, P< 0.001) and lower incidence of disruption related to chemotherapy-induced nausea and vomiting (0.5% vs 6.7%, P = 0.002) than patients in D group.Conclusion: Aprepitant, dolasetron plus dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients treated with FOLFOX-HAIC therapy than dolasetron plus dexamethasone.Keywords: aprepitant, chemotherapy-induced nausea and vomiting, hepatocellular carcinoma, hepatic arterial infusion chemotherapy

Xiawan Yang, 1,* Yanliang Bai, 1,* Mingyue Shi, 1 Wanjun Zhang, 1 Junwei Niu, 1 Chengye Wu, 2 Lei Zhang, 2 Zhiwei Xu, 3 Xiang Liu, 4 Yuqing Chen, 1 Kai Sun 1 1Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Henan, People’s Republic of China; 2Institute of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Henan, People’s Republic of China; 3Department of Clinical Research Service Center, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Henan, People’s Republic of China; 4Department of Geriatric Medicine, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai Sun; Yuqing ChenDepartment of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, No. 7 Weiwu Road, Jinshui District Zhengzhou, Henan 450003, People’s Republic of ChinaTel +86-18237110038; +86-18697321863Email sunkai@cellscience.org; henanblood@sina.comPurpose: To validate the clinical efficacy of the recently developed EUTOS long-term survival (ELTS) score in a real-world setting.Patients and Methods: A total of 479 chronic myeloid leukemia (CML) patients treated with frontline imatinib between January 2010 and December 2017 were enrolled in this retrospective study. The ELTS score was evaluated on the end-points including complete cytogenetic response (CCyR), progression-free survival (PFS), overall survival (OS) and CML-related death, and the efficiency of the ELTS score was further compared with the historical Sokal, Hasford, EUTOS scores.Results: With a median follow-up of 69 months (range, 9– 112 months), 462 evaluable patients were stratified into the ELTS low-risk (n = 230), ELTS intermediate-risk (n = 168) and ELTS high-risk (n = 64) groups. For the regular assessment indicators like CCyR, PFS and OS, the ELTS scoring system could effectively identify the corresponding risk groups, similarly with the results provided by previous scoring systems. With respect to the CML-related death, the ELTS score could accurately identify a high-risk group with a significantly higher risk of dying of CML, and the 5-year cumulative incidence occurred in the ELTS high-, intermediate-, and low-risk groups was 11% (95% CI: 3– 19%), 5% (95% CI: 1– 9%) and 2% (95% CI: 0– 4%), respectively. Most notably, the ELTS score outperformed the Sokal, Hasford and EUTOS scores without statistical difference among different risk groups.Conclusion: The ELTS score could effectively predict the prognosis of imatinib-treated CML patients in real-life settings.Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, Sokal, Hasford, EUTOS, EUTOS long-term survival score

Mengkun Shi,1 Cheng Zhan,2 Jialun Shi,3 Qun Wang2 1Department of Oncology, The Affiliated Heping Hospital of Changzhi Medical College, Changzhi City, Shanxi Province, People’s Republic of China; 2Department of Thoracic Surgery, ZhongShan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Thoracic Surgery, The Affiliated Heping Hospital of Changzhi Medical College, Changzhi City, Shanxi Province, People’s Republic of ChinaCorrespondence: Jialun ShiDepartment of Thoracic Surgery, The Affiliated Heping Hospital of Changzhi Medical College, 110 Yan’an South Road, Changzhi City, Shanxi Province 046000, People’s Republic of ChinaTel +86-13122625627Email hepingdoctor@126.comPurpose: Risk stratification of patients with non-small cell lung cancer (NSCLC) is crucial to select the appropriate treatments, but available models for patients with complete resection are unsatisfactory. The purpose of this study was to determine a prediction model based on clinical information, routine physical and blood tests, and molecular markers.Patients and Methods: This was a retrospective cohort study of patients who underwent surgical resection for lung cancer between 2009 to 2013. Potential prognostic factors were used to build a full prediction model based on a multivariable Cox regression analysis. A nomogram was constructed. The risk stratification cutoffs for clinical use were determined based on the model.Results: A total of 368 NSCLC patients with R0 resection were included. The final multivariable model indicated that low diffusing capacity of the lung for carbon monoxide (HR=1.66, 95% CI: 1.18–2.34), high platelet-to-lymphocyte ratio (HR=1.42, 95% CI: 1.04–1.95), histology type of squamous cell carcinoma and others (squamous cell carcinoma vs adenocarcinoma, HR=1.40, 95% CI: 1.01–1.96; others vs adenocarcinoma, HR=2.36, 95% CI: 1.15–4.84; P trend=0.001), N>0 status (HR=1.96, 95% CI: 1.42–2.70), high serum carcinoembryonic antigen levels (HR=1.61, 95% CI: 1.13–2.27), and postoperative chemotherapy (HR=0.53, 95% CI: 0.33–0.87) were independently associated with poor OS. The patients were classified into four risk groups according to the nomogram, and the OS was different among the four groups (P

Mingyue Shi,1–3 Fangfang Xu,4 Xiawan Yang,2 Yanliang Bai,2 Junwei Niu,2 Emmanuel Kwateng Drokow,2 Mingyi Chen,3 Yuqing Chen,2 Kai Sun2 1Division of Graduate, Department of Hematology, The Second Clinical Medical School and the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 3Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA; 4Department of Research and Discipline Development, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of ChinaCorrespondence: Kai Sun; Yuqing ChenDepartment of Hematology, Zhengzhou University People’s Hospital and Henan Provincial People’s Hospital, #7 Weiwu Road, Zhengzhou 450003, Henan, People’s Republic of ChinaTel +86 182 3711 0038Email sunkai@cellscience.org henanblood@sina.comBackground: Hypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined.Purpose: To explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines.Methods: In our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels.Results: Our results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death.Conclusion: Our study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.Keywords: eltrombopag, decitabine, myeloid leukemia, reactive oxygen species, ROS

CongXiao Zhang,*,1,2 XinWang Zhu,*,1 LuLu Li,1 TianKui Ma,1 Mai Shi,1 Ying Yang,1 QiuLing Fan11Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Blood Purification Center, Shenyang the 4th Hospital of People, Shenyang 110031, People’s Republic of China*These authors contributed equally to this workBackground: Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation.Methods: To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic db/db mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1β expression in the renal cortices of db/db mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1β expression in the glomerular mesangial cells were measured.Results: The NLRP3 inflammasome was activated in db/db mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1β pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1β in db/db mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in db/db mice. MCC950 increased the expression of podocin in db/db mice, and decreased the expression of TGF-β1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of db/db mice and HG-induced mesangial cells.Conclusion: MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in db/db mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1β pathway, which may be a potential therapeutic strategy to prevent the progression of DN.Keywords: diabetic nephropathy, MCC950, NLRP3 inflammasome, db/db mice, mesangial cells

Jiandong Liu,1,* Jinge Zhao,1,*, Mengni Zhang,2 Ni Chen,2 Guangxi Sun,1 Yaojing Yang,1 Xingming Zhang,1 Junru Chen,1 Pengfei Shen,1 Ming Shi,1 Hao Zeng11Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workIntroduction: Since the new 2014 grading system was recommended by the International Society of Urological Pathology (ISUP), it has been validated in patients with localized prostate cancer (PCa) and it has shown excellent prognostic value. However, its predictive power in high-risk PCa remains unclear.Methods: A total of 420 patients with high-risk PCa who underwent radical prostatectomy (RP) were included in this study. Biochemical recurrence-free survival (BRFS) was set as the endpoint.Results: Biochemical recurrence occurred in 84/420 (20.0%) patients at the end of follow-up. Compared to the three-tier grouping system, the five-tier grouping system could more effectively distinguish the BRFS of patients with higher predictive accuracy (C-index: 0.599 vs 0.646). The BRFS of patients with grade group (GG) 1 and GG 2 was similar (P=0.593). Also, the prognosis between those with GG 2 and GG 3 could be clearly distinguished (P=0.001). However, the discrimination capacity between patients with GG 3 and GG 4 was limited (P=0.681). When tertiary Gleason pattern (TGP5) and intraductal carcinoma of the prostate (IDC-P) were excluded, the HR value of the GG 4 group vs the GG 3 group increased from 1.15 (95% CI: 0.59–2.22) to 1.49 (95% CI: 0.72–3.10) and 1.36 (95% CI:0.65–2.83), respectively.Conclusions: This study is the first to validate the new 2014 ISUP grading system in patients with high-risk PCa who underwent RP. The 2014 system could effectively classify patients into five groups with high predictive accuracy. Notably, the existence of TGP5 and IDC-P needs to be routinely reported in clinical practice, which could help to support the predictive value of the new grading system.Keywords: biochemical recurrence-free survival, ISUP grading system, high-risk, prostate cancer, radical prostatectomy

Emmanuel Kwateng Drokow,1 Hafiz Abdul Waqas Ahmed,1 Cecilia Amponsem-Boateng,2 Gloria Selorm Akpabla,3 Juanjuan Song,1 Mingyue Shi,1 Kai Sun11Department of Hematology, Zhengzhou University People‘s Hospital & Henan Provincial People‘s Hospital Henan, Zhengzhou, People’s Republic of China; 2Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, People’s Republic of China; 3Department of Internal Medicine, Tianjin Medical University, Tianjin, People’s Republic of ChinaPurpose: Chimeric Antigen Receptor T(CAR-T) cell therapy is an immunotherapy approach used in treating cancer which has seen rapid development over the decades. It becomes the preferred treatment choice after patients have failed conventional chemotherapy.Methods: We conducted a meta-analysis in 320 patients from 14 studies to estimate the survival outcome, response rate and toxicity of autologous CD19 CAR-T cell therapy and predict other factors associated with a better prognosis.Results: The overall response rate was 71.88% (95% CI: 61.34–80.46%, p