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Min Fang,1,2 Wei Yin,3 Chunyan Qiu,4 Tao Song,2 Baihua Lin,2 Ying Wang,2 Hanchu Xiong,2 Shixiu Wu1 1Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, People’s Republic of ChinaCorrespondence: Wei Yin, Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China, Email hzyinwei@live.cn Shixiu Wu, Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, People’s Republic of China, Email wushixiu@yeah.netObjective: Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer.Methods: We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people’s Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan–Meier method and further analyzed with multivariate analysis.Results: Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes.Conclusion: The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients.Keywords: triple negative breast cancer, B lymphocytes, T lymphocytes, tumor associated macrophages, multispectral immunofluorescence, prognosis

Xue Zhang,1,* Aili Zhang,2,* Hao Guan,1 Li Zhou,1 Jiao Zhang,3 Wenjie Yin1 1Department of Pharmacy, Kunming Yan’an Hospital, Yan’an Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650051, People’s Republic of China; 2Department of Scientific Research, Kunming Yan’an Hospital, Yan’an Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650051, People’s Republic of China; 3Department of Basic Medicine, Zhaotong Health Vocational College, Zhaotong, Yunnan, 657000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjie Yin; Xue Zhang, Department of Pharmacy, Kunming Yan’an Hospital, Yan’an Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650051, People’s Republic of China, Email yinwenjie0606@163.com; zxyougubaihe@163.comObjective: Low back pain is one of the main causes of disability in the world. Although regenerative medicine may represent breakthroughs in the management of low back pain, its use remains controversial. Therefore, we conducted a meta-analysis to evaluate the clinical efficacy of platelet-rich plasma (PRP) injection therapy versus different control groups for chronic low back pain during 4 weeks, 3 months, and 6 months.Methods: Different electronic databases were searched for randomized controlled trials up to August 2023. Mean changes from baseline in pain and Oswestry Disability Index (ODI) scores at 4 weeks, 3 months, and 6 months and standard deviations of outcome were recorded.Results: Four articles with 154 cases were finally included in this meta-analysis. After 4 weeks, corticosteroid (CS) was the optimal treatment option for chronic low back pain in terms of improvement in pain and disability index (surface under the cumulative ranking curve [SUCRA]=71.3%, SUCRA=57.8%, respectively). After 3 months, radiofrequency (RF) emerged as the best therapy in pain (SUCRA=100%) and disability index (SUCRA=98.5%), followed by PRP (SUCRA=62.3%, SUCRA=64.3%, respectively), CS (SUCRA=24.6%, SUCRA=25.9%, respectively) and lidocaine (SUCRA=13.1%, SUCRA=11.3%, respectively). At 6 months, RF was most likely to be the best treatment in pain (SUCRA=94.9%) and disability index (SUCRA=77.3%), followed by PRP (SUCRA=71.2%, SUCRA=79.6%, respectively). However, compared with the last follow-up, there was a slight downward trend in improvement pain and disability index with RF, while PRP was still an upward trend.Conclusion: This study demonstrated better short-term improvement of chronic low back pain with CS after 4 weeks. PRP and RF improvement effects matched, but follow-up of at least 6 months showed that PRP seemed to be more advantageous in improvement in disability indices. Considering the limitations of this study, these conclusions still need to be verified by more comparative RCTs and a longer follow-up period.Keywords: platelet-rich plasma, chronic low back pain, meta-analysis, randomized controlled trial, clinical efficacy

Li Che,1,2 Zhefan Xie,2,3 Guangshu Chen,4 Wei Zhang,2 Tingting Xia,2,3 Jiaxin Lin,2 Wenzhi Luo,2 Li Chen,2 Wenguang Yin,1 Xingdong Cai,2 Shengming Liu2 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Affiliated Dongguan People’s Hospital, Southern Medical University, Donguan, People’s Republic of China; 4Department of Endocrinology, Guangzhou Red Cross Hospital, The Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaCorrespondence: Shengming Liu; Xingdong Cai, The First Affiliated Hospital of Jinan University, Guangdong, People’s Republic of China, Email tlsm@jnu.edu.cn; cxd19790920@sina.comBackground: The role of irreversible airway inflammatory damage in chronic obstructive pulmonary disease (COPD) progression is evident. Autophagy is an essential process in the cellular material metabolic cycle, and a family of resistant vegetative molecules may be involved in the COPD autophagic process. In this study, we investigated the mechanism of resistin-like molecule β (RELMβ) in COPD smoking-induced autophagy.Methods: Firstly, the expression differences of RELMβ and autophagy markers between COPD and control groups were analyzed in the Gene Expression Omnibus (GEO) datasets and clinical specimens. Secondly, in vitro and in vivo experiments were conducted using immunoblotting, immunofluorescence, immunohistochemistry, and other methods to investigate the mechanism by which RELMβ promotes airway inflammation through autophagy in a cigarette smoke extract-induced 16HBE cell inflammation model and a cigarette smoke-induced COPD-like mouse model. In addition, immunoprecipitation was used to analyze the binding of RELMβ to the membrane protein TLR4.Results: The expression of RELMβ and autophagy genes p62 and LC3B in lung tissue of COPD patients was significantly increased. RELMβ can mediate the activation of autophagy in 16HBE cells, and through autophagy, it increases the expression of inflammatory cytokines in a cigarette smoke extract-induced 16HBE cell inflammation model. RELMβ promotes cigarette smoke-induced COPD-like mouse airway inflammation through autophagy, and RELMβ can mediate signal transduction through the cell membrane receptor TLR4.Conclusion: The RELMβ binds to TLR4 to encourage signal transduction and that RELMβ can promote inflammation in smoky COPD lungs through autophagy.Keywords: autophagy, COPD, airway inflammation, cigarette smoke extract

Qi Zhang,* Yue-Xiang Ma,* Zheng Dai, Bin Zhang, Shan-Shou Liu, Wen-Xiu Li, Chuan-Qing Fu, Qian-Mei Wang, Wen Yin Department of Emergency, Xijing Hospital, Air Force Medical University, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Yin, Department of Emergency, Xijing Hospital, Air Force Medical University, No. 127 Changlexi Road, Xi’an, 710032, People’s Republic of China, Email xjyyyw@fmmu.edu.cnAbstract: Numerous studies on the formulation and clinical applications of novel hemoglobin-based oxygen carriers (HBOCs) are reported in the scientific literature. However, there are fewer scientometric analysis related to HBOCs. Here, we illustrate recent studies on HBOCs using both a scientometric analysis approach and a scope review method. We used the former to investigate research on HBOCs from 1991 to 2022, exploring the current hotspots and research trends, and then we comprehensively analyzed the relationship between concepts based on the keyword analysis. The evolution of research fields, knowledge structures, and research topics in which HBOCs located are revealed by scientometric analysis. The elucidation of type, acting mechanism, potential clinical practice, and adverse effects of HBOCs helps to clarify the prospects of this biological agent. Scientometrics analyzed 1034 publications in this research field, and these findings provide a promising roadmap for further study.Keywords: blood substitutes, trauma, hemorrhagic shock, organ preservation, anemia, risk management

Xuebin Tian,1,2,&ast; Yiwen Xie,1,2,&ast; Jingjing Chen,3,&ast; Wanpeng Yin,1,2 Yu Long Zhao,1 Peng Yao,4 Mingqing Dong,4 Changzhong Jin,1,2 Nanping Wu1,2 1Cell Biology Research Platform, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Hospital Office, Shandong Second Provincial General Hospital, Jinan, Shandong, People’s Republic of China; 4Department of Infectious Disease, Zhejiang Qingchun Hospital, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changzhong Jin; Nanping Wu, Email changzhongjin@163.com; flwnp2013@163.comBackground: Microbial translocation (MT) is a characteristic of human immunodeficiency virus (HIV) infection. Whether MT is also a biomarker of different immune responses to antiretroviral therapy (ART) received by people living with HIV (PLWH) is not known.Methods: We examined the presence of MT in a cohort of 33 HIV-infected immunological responders (IRs) and 28 immunological non-responders (INRs) (≥ 500 and < 200 cluster of differentiation (CD)4+ T-cell counts/μL after 2 years of HIV-1 suppression, respectively) with no comorbidities. Plasma samples were used to measure the circulating levels of MT markers. All enrolled study participants had received 2 years of viral-suppression therapy.Results: Levels of lipopolysaccharide (P = 0.0185), LPS-binding protein (P < 0.0001), soluble-CD14 (P < 0.0001), and endogenous endotoxin-core antibody (P < 0.0001) at baseline were significantly higher in INRs than in IRs and were associated with an increased risk of an immunological non-response, whereas the level of intestinal fatty acid-binding protein did not show this association. Analysis of receiver operating characteristic (ROC) curves demonstrated the utility of these individual microbial markers in discriminating INRs after ART in people living with HIV with high sensitivity, specificity, and area under the ROC curve.Conclusion: INRs in HIV infection are characterized by increased MT at baseline. These markers could be used as a rapid prognostic tool for predicting immune responses in people infected with the HIV.Keywords: HIV, immunological non-responders, microbial translocation

Wen Yin,&ast; Si-Qi Zhang,&ast; Wen-Lin Pang,&ast; Xiao-Jiao Chen, Jing Wen, Jiong Hou, Cui Wang, Li-Yun Song, Zhen-Ming Qiu, Peng-Tao Liang, Jia-Li Yuan, Zhong-Shan Yang, Yao Bian Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhong-Shan Yang; Yao Bian, Yunnan University of Chinese Medicine, Kunming, Yunnan, People’s Republic of China, Tel +86-871-65919932, Email yangzhongshan@ynutcm.edu.cn; 1345538930@qq.comPurpose: Type 2 diabetes mellitus (T2DM) is a complex genetic disease associated with genetic and environmental factors. Previous studies have shown that changes in the gut microbiota may affect the development of host metabolic diseases and promote the progression of T2DM. Tang-ping-san (TPS) decoction can effectively treat T2DM. However, its specific mechanisms must be evaluated.Patients and Methods: In the present study, we established an animal model of T2DM using a high‑fat diet (HFD) with intraperitoneal injection streptozotocin injection.Results: The therapeutic effect of TPS decoction on T2DM in mice was initially evaluated. TPS decoction was found to improve hyperglycemia, hyperlipidemia, insulin resistance, and pathological liver, pancreatic, and colon changes. Moreover, it reduced the pro-inflammatory cytokine levels. Based on 16SrRNA sequencing, TPS decoction reduced the Firmicutes/Bacteroidetes ratio at the phylum level. At the genus level, it increased the relative abundances of Akkermansia, Muribaculaceae, and the Eubacterium coprostanoligenes group and decreased the relative abundance of Fusobacterium, Escherichia coli, Dubosiella, and Helicobacter.Conclusion: TPS decoction improves T2DM and liver function and reduces the risk of hyperglycemia, hyperlipidemia, insulin resistance, pathological organ changes, and inflammatory reactions. The mechanism of TPS decoction in T2DM can be correlated with the reversal of gut microbiota dysfunction and repair of the intestinal mucosal barrier.Keywords: type 2 diabetes mellitus, tang-ping-san decoction, gut microbiota, glycolipid metabolism, insulin resistance

Xiaoqi Huang,1,&ast; Weiling Yin,1,&ast; Min Shen,1 Xionghui Wang,1 Tao Ren,1 Lei Wang,1 Min Liu,2 Youmin Guo1 1Department of Radiology, Yan’an University Affiliated Hospital, Yan’an, People’s Republic of China; 2Department of Radiology, China-Japan Friendship Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Youmin Guo, Department of Radiology, Yan’an University Affiliated Hospital, Yan’an, People’s Republic of China, Tel +86-13909187113, Email cjr.guoyoumin@vip.163.comBackground: Previous studies have demonstrated that there is a certain correlation between emphysema and changes in pulmonary small blood vessels in patients with chronic obstructive pulmonary disease (COPD), but most of them were limited to the investigation of the inspiratory phase. The emphysema indicators need to be further optimized. Based on the parametric response mapping (PRM) method, this study aimed to investigate the effect of emphysema and functional small airway disease on intrapulmonary vascular volume (IPVV).Methods: This retrospective study enrolled 63 healthy subjects and 47 COPD patients, who underwent both inspiratory and expiratory CT scans of the chest and pulmonary function tests (PFTs). Inspiratory and expiratory IPVV were measured by using an automatic pulmonary vessels integration segmentation approach, the ratio of emphysema volume (Emph%), functional small airway disease volume (fsAD%), and normal areas volume (Normal%) were quantified by the PRM method for biphasic CT scans. The participants were grouped according to PFTs. Analysis of variance (ANOVA) and Kruskal–Wallis H-test were used to analyze the differences in indicators between different groups. Then, Spearman’s rank correlation coefficients were used to analyze the correlation between Emph%, fsAD%, Normal%, PFTs, and IPVV. Finally, multiple linear regression was applied to analyze the effects of Emph% and fsAD% on IPVV.Results: Differences were found in age, body mass index (BMI), smoking index, FEV1%, FEV1/forced vital capacity (FVC), expiratory IPVV, IPVV relative value, IPVV difference value, Emph%, fsAD%, and Normal% between the groups (P< 0.05). A strong correlation was established between the outcomes of PFTs and quantitative CT indexes. Finally, the effect of Emph% was more significant than that of fsAD% on expiratory IPVV, IPVV difference value, and IPVV relative value.Conclusion: IPVV may have a potential value in assessing COPD severity and is significantly affected by emphysema.Keywords: chronic obstructive pulmonary disease, intrapulmonary vascular volume, emphysema, functional small airway disease, parametric response mapping method

Ya-Zhen Zhu,1 Xi-Wen Liao,2 Wu Yin,1 Hai-Ming Wei1 1Department of Pathology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 2Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of ChinaCorrespondence: Hai-Ming WeiDepartment of Pathology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Email ming9753@sina.comPurpose: This study aimed to determine the potential application of the protein phosphatase 1 regulatory subunit 3 (PPP1R3B) gene as a prognostic marker in stomach adenocarcinoma (STAD), as well as its potential mediating biological processes and pathways.Materials and Methods: Differential expression analyses were performed using the TIMER2.0 and UALCAN databases. Complete RNA-seq data and other relevant clinical and survival data were acquired from The Cancer Genome Atlas (TCGA). Univariate survival analyses, Cox regression modelling, and Kaplan–Meier curves were implemented to investigate the associations between PPP1R3B gene expression and clinical pathologic features. A genome wide gene set enrichment analysis (GSEA) was conducted to define the underlying molecular mechanisms mediating the observed associations between the PPP1R3B gene and STAD development.Results: We found that PPP1R3B was overexpressed in STAD tissues, and that higher PPP1R3B expression correlated with worse prognoses in patients with STAD. Comprehensive survival analyses suggested that PPP1R3B might be an independent predictive factor for survival time in patients with STAD. The prognostic relationship between PPP1R3B and STAD was also verified using Kaplan–Meier curves. Patients with higher PPP1R3B levels had a shorter clinical survival time on average. Additionally, a GSEA demonstrated that PPP1R3B might be involved in multiple biological processes and pathways.Conclusion: Our findings demonstrate that the PPP1R3B gene has utility as a potential molecular marker for STAD prognoses.Keywords: PPP1R3B, mRNA, stomach adenocarcinoma, prognosis, prognostic biomarkers

Ting Wang,1,2 Wei Yin,3 Yonghan Huang,2 Qingxue Zhang1 1Department of Reproductive Medicine Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Reproductive Medicine Center, The First People’s Hospital of Foshan(Affiliated FoShan Hospital of Sun Yat-sen University), Foshan, People’s Republic of China; 3Department of Obstetrics, Guangzhou Women and Children’s Center, Guangzhou, People’s Republic of ChinaCorrespondence: Qingxue Zhang Email qingxuezhang.sysu@outlook.comBackground: Gestational diabetes mellitus (GDM) during pregnancy can greatly increase the risk for a number of adverse prenatal and postpartum consequences, including postpartum impaired glucose tolerance (IGT). Determining the need for insulin therapy is critical for controlling the glycemic level in GDM patients. The study contains two major purposes: 1) to identify the potential predictors for the need of insulin therapy in GDM patients; 2) to identify the factors that are related to the onset of postpartum IGT.Materials and Methods: Here, we performed a retrospective study on 112 GDM patients in China to identify the significant predictors for the need of insulin therapy and onset of postpartum IGT in patients with GDM.Results: Age and gestational weeks at GDM diagnosis, pregestational BMI, family history of diabetes mellitus (DM), plasma glucose levels assessed by 75-g OGTT at both the 1-hour and 2-hour time points (PG-1h and PG-2h) and HbA1c level were all significantly different between the patients that received insulin therapy and those did not. During postpartum, family history of DM, PG-1h PG-2h and HbA1c level were found to be significantly different between the patients with normal glucose tolerance and those with IGT.Conclusion: Our results reveal a number of factors that are closely associated with the need of insulin therapy and onset of postpartum IGT, especially the PG-1h and PG-2h levels. These findings will provide valuable indications on selection of treatment strategy for GDM and GDM-induced postpartum IGT.Keywords: insulin, glucose, diabetes, pregnancy, postpartum

Siling Ren,1,* Jingxian Wu,2,* Wanchun Yin,1 Qianqian Liao,1 Sailan Gong,1 Beibei Xuan,1 Xiaoling Mu1 1Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 2Department of Pathology, Chongqing Medical University, Chongqing 400016, People’s Republic of China*These authors contributed equally to this work.Correspondence: Xiaoling MuDepartment of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaEmail mxl@hospital.cqmu.edu.cnObjective: In this study, 345 patients with endometrial carcinoma (EC) were selected to investigate the correlation between ER/PR status and the EC disease-free survival (DFS) rate.Methods: The intensity and proportion of tumor cell expression of estrogen receptors and progesterone receptors (ER/PR) status of 345 postoperative tumor specimens in ECs were independently assessed semi-quantitatively by two pathologists using immunohistochemistry, the summed score ranged from 0 to 8 points was worked out by adding proportion score and intensity score based on the breast cancer hormone receptor immunohistochemical Allred scoring system. The association between DFS in ECs and ER/PR expression (intensity, proportion and summed score) was assessed using Cox regression analysis. Gene expression data were obtained from The Cancer Genome Atlas research network (TCGA).Results: According to inclusion criteria, 201 type I and 144 type II EC patients were enrolled in this study. In the univariate analysis of type I endometrial carcinoma, the intensity, proportion and summed score of ER/PR status were significantly correlated with DFS. After adjusting for factors known to significantly impact survival, the influence of ER/PR status on DFS is generally decreased but the correlation is still significant. In the univariate analysis of type II endometrial carcinoma, the intensity, proportion and summed score of ER/PR status were significantly correlated with DFS. After adjusting for factors known to significantly impact survival, the influence of ER status on DFS is generally decreased, but the correlation is still significant, the effect of PR expression on DFS is not statistically significant.Conclusion: Higher ER/PR expression status was associated with better DFS in patients with type I endometrial cancer after adjusting for known factors that significantly affect survival. In patients with type II endometrial cancer, patients with positive ER expression were significantly associated with better DFS. However, the effect of PR expression on DFS was not statistically significant.Keywords: endometrial cancer, endometrioid carcinoma, disease-free survival rate, hormone receptor status, ER, PR

Hao Wang,1,2,* Xuhui Ge,1,3,* Huiheng Qu,1,2,* Ning Wang,1,2 Jiawen Zhou,4 Wenjing Xu,1,2 Jingjing Xie,1,2 Yongping Zhou,1,2 Liqing Shi,1 Zhongke Qin,1 Zhuang Jiang,1,2 Wenjie Yin,1 Jiazeng Xia1,2 1Department of General Surgery and Translational Medicine Center, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi 214002, Jiangsu, People’s Republic of China; 2Department of General Surgery, Wuxi Clinical College Affiliated to Nantong University, Wuxi 214002, Jiangsu, People’s Republic of China; 3Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of China; 4The State Key Laboratory of Reproductive Medicine; Key Laboratory for Aging & Disease, Research Centre for Bone and Stem Cells, Department of Human Anatomy, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiazeng XiaDepartment of General Surgery and Translational Medicine Center, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, 68, Zhong Shan Road, Wuxi 214002, Jiangsu, People’s Republic of ChinaEmail jiazengxia@yahoo.comPurpose: Glycyrrhizic acid (GA) is the main active ingredient extracted from Chinese herb licorice root, and it shows anti-tumor effects in many cancer types, while its role in gastric cancer (GC) is still unknown. In this study, we evaluated the effects of GA on GC cells and explored the underlying mechanisms.Methods: The anti-proliferation effect of GA on GC cells was assessed by CCK-8, colony formation, and EdU assay. The effects of GA on cell cycle and apoptosis were detected by flow cytometer. Western blotting was performed to explore the underlying mechanisms.Results: Our results showed that GA had a time- and dose-dependent inhibitory effect on proliferation of GC cells. Flow cytometer analysis demonstrated that GA would lead to G1/S-phase arrest and apoptosis. GA treatment down-regulated the levels of G1 phase-related proteins, including cyclin D1, D2, D3, E1, and E2. In terms of apoptosis, GA treatment up-regulated the levels of Bax, cleaved PARP, and pro-caspase-3, -8, -9, but did not influence their cleavage patterns. The expression of Bcl-2, survivin and p65 was attenuated after treatment. Besides, GA would down-regulate the phosphorylation of PI3K/AKT pathway.Conclusion: This study focused on inhibitory effect of GA on GC cells by inducing cell cycle arrest and apoptosis. Several important cyclins- and apoptosis-related proteins were involved in the regulation of GA to GC cells, and phosphorylated PI3K and AKT were attenuated. The results of this study indicated that GA is a potential and promising anti-cancer drug for GC.Keywords: glycyrrhizic acid, gastric cancer, cell cycle, apoptosis, PI3K/AKT pathway

Xuejuan Gao,1,* Yanfeng Zhao,2,* Yi Bao,2,* Wei Yin,3 Liyu Liu,4 Ruchuan Liu,4 Zhengquan Yu,5 Xiao Zhou,2 Jianwei Shuai1,6 1Department of Physics, Xiamen University, Xiamen, People’s Republic of China; 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China; 3Key Laboratory of Oral Biomedical Engineering of Education, Hospital of Stomatology, Wuhan University, Wuhan, People’s Republic of China; 4College of Physics, Chongqing University, Chongqing, People’s Republic of China; 5State Key Laboratories for Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, People’s Republic of China; 6State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianwei ShuaiDepartment of Physics, Xiamen University, Siming South Road 422-19, Xiamen 361005, People’s Republic of ChinaTel +86 13959287814Email jianweishuai@xmu.edu.cnXiao ZhouDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital affiliated to Tongji University, 507 Zhengmin Road, Wu Jiao Chang, Yangpu, Shanghai 200433, People’s Republic of ChinaTel +86 13916118590Email zhouxiaosph@163.comPurpose: Previous studies have shown that the presence of EGFR T790M mutation may reduce the treatment efficacy of tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer. However, little is known about the clinical features and outcomes of EGFR T790M mutation in pretreated patients with NSCLC.Patients and methods: The clinical features of EGFR-activating and T790M mutations were assessed in a large cohort of patients with EGFR-TKI-naïve NSCLC (all/EGFR mutations, n=16,347/7,687). The correlation between the pretreatment T790M mutation status and clinical outcomes was evaluated using univariate and multivariate analyses.Results: Pretreatment T790M mutation was reported in 1.39% of the patients and coexisted with an EGFR-activating or uncommon mutation. The dual EGFR T790M and common EGFR-activating mutations were more likely to be detected in lung adenocarcinoma, whereas single T790M mutation was more prevalent in non-adenocarcinomas. The presence of de novo T790M mutation correlated with reduced recurrence-free survival (RFS) in patients with NSCLC (odds ratio [OR] 3.37, 95% confidence interval [CI] 1.67–6.79, P = 0.001). After molecular stratification, T790M mutation was shown to exert adverse effects on the RFS of EGFR 19-del group (OR 2.89, 95% CI 1.10–7.91, P = 0.028) and EGFR L858R group (OR 3.43, 95% CI 1.33–8.88, P = 0.013). Furthermore, pretreatment T790M mutation promoted tumor metastasis to different sites.Conclusion: T790M-positive tumors presented special clinical features, and the coexistence of T790M and common EGFR-activating mutations was associated with poor prognosis in patients with NSCLC.Keywords: pretreatment T790M mutation, dual EGFR mutations, recurrence-free survival, non-small cell lung cancer

Bin Wang,1 Yuanwei Guo,2 Xiaofeng Chen,3 Chao Zeng,1 Qikang Hu,1 Wei Yin,1 Wei Li,1 Hui Xie,1 Bingyu Zhang,1 Xingchun Huang,1 Fenglei Yu1 1Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, People’s Republic of China; 2Center for Clinical Pathology, Affiliated to The First People’s Hospital of Chenzhou, University of South China, Chenzhou 432000, People’s Republic of China; 3Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha 410011, People’s Republic of China Background: Stromal cell-derived factor 1 (SDF-1) is an important chemokine for stem cell mobilization, and plays a critical role in mobilization of mesenchymal stem cells (MSCs). Bone morphogenetic protein 2 (BMP-2) plays a critical role in osteogenesis of MSCs. However, the use of SDF-1 and BMP-2 in bone tissue engineering is limited by their short half-lives and rapid degradation in vitro and in vivo. Methods: The chitosan oligosaccharide/ heparin nanoparticles (CSO/H NPs) were first prepared via self-assembly. Chitosan-agarose-gelatin (CAG) Scaffolds were then synthesized via gelation technology using cross-linked chitosan, agarose, and gelatin, and were modified by CSO/H NPs. The encapsulation efficiency and release kinetics of SDF-1 and BMP-2 were quantified using an enzyme-linked immunosorbent assay. A CCK-8 assays were used to evaluate biocompatibility of NP-modified scaffolds. The biological activity of the loaded SDF-1 and BMP-2 was evaluated using the transwell migration assay and osteogenic induction assay. An animal MSC recruitment model was used to study the ability of SDF-1 released from NP-modified scaffolds to induce migration of MSCs. Results: In this study, we developed a novel nanoparticle-modified CAG scaffold for the delivery of SDF-1 and BMP-2. CCK-8 assays demonstrated excellent biocompatibility of NP-modified scaffolds. In addition, we investigated the release of SDF-1 and BMP-2 from NP-modified scaffolds, and evaluated the effect of released SDF-1 on MSC migration. The effect of released BMP-2 on MSC osteogenesis was also examined. In vitro cell migration assays showed that SDF-1 released from NP-modified scaffolds retained its migration activity; osteogenesis studies demonstrated that released BMP-2 exhibited a strong ability to induce differentiation towards osteoblasts. Our in vivo recruitment assays showed continuous chemotactic response of MSCs to SDF-1 released from the NP-modified scaffold.Conclusion: The simplicity of synthesizing CSO/H NP-modified CAG scaffolds, combined with its high cytokine loading capacity and sustained release effect, renders NP-modified CAG scaffold an attractive candidate for sustained release of SDF-1 and BMP-2 to promote bone repair and regeneration. Keywords: cytokine delivery system, nanoparticles, chitosan-agarose-gelatin scaffold, stromal cell-derived factor-1, bone morphogenetic protein-2

Yueyao Du,* Tingting Yan,* Liheng Zhou, Wenjin Yin, Jinsong Lu Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China *These authors contributed equally to this work Background: Germline genetic polymorphisms in certain genes are associated with the response to anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer (BC). This translational study aims to evaluate the potential role of rs1042713 in the beta 2-adrenergic receptor (ADRB2) gene in predicting pathological complete responses (pCRs) to taxane- and platinum-based neoadjuvant chemotherapy in locally advanced breast cancer (LABC).Materials and methods: The distribution frequencies of rs1042713 were genotyped in LABC patients who received taxane- and platinum-based neoadjuvant chemotherapy. Associations between tumor-relevant biomarkers, genotypes and pCRs were evaluated using Student’s t-test for continuous variables and Chi-square or Fisher’s exact test for categorical variables. For univariate analysis, the relationship between the rs1042713 polymorphism and pCR was analyzed by Chi-square or Fisher’s exact test. The modified ORs with their 95% CIs were calculated by a multivariate logistic regression analysis to explore the association between genotype and pCR.Results: There was a significant correlation of the rs1042713 genotype with estrogen receptor (ER) status (P=0.008). Significant differences were detected in the rs1042713 genotypes of pCR and non-pCR patients (P=0.046). The pCR rate was 18.2% in patients with ADRB2 rs1042713 AA genotypes and 38.7% in AG+GG genotypes. Women carrying the AG+GG (OR=2.91, 95% CI: 1.02–8.29, P=0.046) genotype had a higher pCR rate than those with the AA genotype.Conclusion: rs1042713, which is located in the ADRB2 gene, could predict pCR to taxane- and platinum-based neoadjuvant chemotherapy in LABC. This finding suggests that rs1042713 could play a potential role as a predictive marker in clinical settings. Keywords: beta 2-adrenergic receptor gene, locally advanced breast cancer, neoadjuvant chemotherapy, pathological complete response, polymorphism

Historic wooden buildings are a symbol of China’s “culture of wood” and require extraction of forest resources for their renovation. In the 21st century, natural resources are limited globally, and sustainable solutions are needed. In this study, we established a new method to connect building and forest sites for efficient utilization of limited forest resources for the renovation of historic buildings. We obtained measurements of large wooden components from Shenyang Imperial Palace. We also performed morphometric analyses on 47 thinned, old-growth larch trees to determine the relative taper curve, and selected 108 standing trees for simulation of the tree-height curve in the Mt. Changbai area, Jinlin Province, Northeast China. On the basis of forest metrology, we established an upper tree prediction method. By measuring the diameter at breast height (DBH) alone, we could compare size information (e.g., diameter, length) for standing trees and wooden building components. This method was then applied to estimate the required DBH class of standing trees for the renovation of Shenyang Imperial Palace.

A major challenge in the identification of material properties is handling different sources of uncertainty in the experiment and the modelling of the experiment for estimating the resulting uncertainty in the identified properties. Numerous improvements in identification methods have provided increasingly accurate estimates of various material properties. However, characterizing the uncertainty in the identified properties is still relatively crude. Different material properties obtained from a single test are not obtained with the same confidence. Typically the highest uncertainty is associated with respect to properties to which the experiment is the most insensitive. In addition, the uncertainty in different properties can be strongly correlated, so that obtaining only variance estimates may be misleading. A possible approach for handling the different sources of uncertainty and estimating the uncertainty in the identified properties is the Bayesian method. This method was introduced in the late 1970s in the context of identification [1] and has been applied since to different problems, notably identification of elastic constants from plate vibration experiments [2]-[4]. The applications of the method to these classical pointwise tests involved only a small number of measurements (typically ten natural frequencies in the previously cited vibration test) which facilitated the application of the Bayesian approach. For identifying elastic constants, full field strain or displacement measurements provide a high number of measured quantities (one measurement per image pixel) and hence a promise of smaller uncertainties in the properties. However, the high number of measurements represents also a major computational challenge in applying the Bayesian approach to full field measurements. To address this challenge we propose an approach based on the proper orthogonal decomposition (POD) of the full fields in order to drastically reduce their dimensionality. POD is based on projecting the full field images on a modal basis, constructed from sample simulations, and which can account for the variations of the full field as the elastic constants and other parameters of interest are varied. The fidelity of the decomposition depends on the number of basis vectors used. Typically even complex fields can be accurately represented with no more than a few dozen modes and for our problem we showed that only four or five modes are sufficient [5]. To further reduce the computational cost of the Bayesian approach we use response surface approximations of the POD coefficients of the fields. We show that 3rd degree polynomial response surface approximations provide a satisfying accuracy. The combination of POD decomposition and response surface methodology allows to bring down the computational time of the Bayesian identification to a few days. The proposed approach is applied to Moiré interferometry full field displacement measurements from a traction experiment on a plate with a hole. The laminate with a layup of [45,- 45,0]s is made out of a Toray® T800/3631 graphite/epoxy prepreg. The measured displacement maps are provided in Figure 1. The mean values of the identified properties joint probability density function are in agreement with previous identifications carried out on the same material. Furthermore the probability density function also provides the coefficient of variation with which the properties are identified as well as the correlations between the various properties. We find that while the longitudinal Young’s modulus is identified with good accuracy (low standard deviation), the Poisson’s ration is identified with much higher uncertainty. Several of the properties are also found to be correlated. The identified uncertainty structure of the elastic constants (i.e. variance co-variance matrix) has potential benefits to reliability analyses, by allowing a more accurate description of the input uncertainty. An additional advantage of the Bayesian approach is that it provides a natural way (in the form of the prior probability density function) for accounting for prior information that may be available on the material properties thought. This is of great interest for reducing the uncertainty on properties that can only be determined with low confidence from the plate with a hole experiment, such as Poisson’s ratio or transverse Young’s modulus in our case.

The ground-state electronic order in doped manganites is frequently associated with a lattice modulation, contributing to their many interesting properties. However, measuring the thermal evolution of the lattice superstructure with reciprocal-space probes alone can lead to ambiguous results with competing interpretations. Here we provide direct observations of the evolution of the superstructure in La1/3Ca2/3MnO3 in real space, as well as reciprocal space, using transmission electron microscopic (TEM) techniques. We show that the transitions are the consequence of a proliferation of dislocations plus electronic phase separation. The resulting states are well described by the symmetries associated with electronic-liquid-crystal (ELC) phases. Moreover, our results resolve the long-standing controversy over the origin of the incommensurate superstructure and suggest a new structural model that is consistent with recent theoretical calculations.

Abstract Numerous studies have reported that long-term sports training can affect inhibitory control and induce brain functional alterations. However, the influence of environmental dynamics in sports training on inter-cortical connectivity has not been well studied. In the current study, we used twin-coil transcranial magnetic stimulation to investigate the functional connectivity between dorsolateral prefrontal cortex (DLPFC) and ipsilateral primary motor cortex (M1) during proactive and reactive inhibition in participants with sports skills in dynamic environment (open-skill experts), stable environment (closed-skill experts), and no sports skills (controls). Using a modified stop signal task, proactive inhibition was measured by the response delay effect (RDE), and reactive inhibition was measured by the stop-signal reaction time (SSRT). Intra-hemispheric DLPFC-M1 interactions and single pulse motor-evoked potentials (MEPs) were measured during the task. A stronger inhibitory effect of the DLPFC over M1 was observed during early reactive control stages compared to baseline levels. In addition, this inhibitory effect was pronounced when comparing open-skill experts to non-athlete controls, a relationship that was significantly correlated with superior reactive control performance. Furthermore, DLPFC to M1 influencing direction shifted from late proactive control to reactive control. Behavioral results also demonstrated enhanced proactive control abilities in open-skill experts relative to controls. Such enhancement may be due to the combination of environmental complexity and physical fitness in long-term skill training.

Abstract The engineered TadA variants used in cytosine base editors (CBEs) present distinctive advantages, including a smaller size and fewer off-target effects compared to cytosine base editors that rely on natural deaminases. However, the current TadA variants demonstrate a preference for base editing in DNA with specific motif sequences and possess dual deaminase activity, acting on both cytosine and adenosine in adjacent positions, limiting their application scope. To address these issues, we employ TadA orthologs screening and multi sequence alignment (MSA)-guided protein engineering techniques to create a highly effective cytosine base editor (aTdCBE) without motif and adenosine deaminase activity limitations. Notably, the delivery of aTdCBE to a humanized mouse model of Duchenne muscular dystrophy (DMD) mice achieves robust exon 55 skipping and restoration of dystrophin expression. Our advancement in engineering TadA ortholog for cytosine editing enriches the base editing toolkits for gene-editing therapy and other potential applications.

Abstract Background Lymph node (LN) metastasis is a significant prognostic factor for esophageal squamous cell carcinoma (ESCC), and there are no satisfactory methods for accurately predicting metastatic LNs. The present study aimed to assess the efficacy of 99mTc‐3PRGD2 single‐photon emission computed tomography (SPECT)/computed tomography (CT) for diagnosing metastatic LNs in ESCC. Methods A total of 15 enrolled patients with ESCC underwent 99mTc‐3PRGD2 SPECT/CT and 18F‐fluorodeoxyglucose positron emission tomography‐computed tomography (18F‐FDG PET/CT) examinations preoperatively. High‐definition bone carving reconstruction technology (HD‐xSPECT Bone) was applied to quantitatively assess the LN's SUVmax via SPECT/CT. The two methods were compared for diagnosing metastatic LNs with pathology as the gold standard. Results Among 15 patients, 23 metastatic lymph node stations (mLNSs) were predicted by SPECT/CT, with a mean SUVmax of 2.71 ± 1.34, of which 15 were pathologically confirmed; 32 mLNSs were predicted by PET/CT with a mean SUVmax of 4.41 ± 4.02, of which 17 were pathologically confirmed. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SPECT/CT for diagnosing metastatic LNs were 62.50%, 91.30%, 85.34%, 65.22%, and 90.32%, respectively, and those of PET/CT were 70.83%, 83.70%, 81.03%, 53.13%, and 91.67%, respectively. There was no significant difference in sensitivity (p = 0.061) or specificity (p = 0.058) between the two methods. The AUCSPECT/CT was 0.816 and the SUVmax threshold was 2.5. Conclusion 99mTc‐3PRGD2 SPECT/CT might be an effective method for diagnosing metastatic LNs in ESCC, especially in combination with HD‐xSPECT Bone. The diagnostic efficiency of this method was noninferior to that of 18F‐FDG PET/CT. The SUVmax threshold of 2.5 showed the highest agreement with the pathology findings.