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Haishui Sun,1,* Xiao Wang,2,3,* Zhaoyang Guo,4,* Zhenrong Hu,5 Yuanchen Yin,4 Shuhan Duan,6 Wenwen Jia,2 Wei Lu,2,3 Jingzhou Hu1,7 1Department of Oral and Maxillofacial - Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, People’s Republic of China; 2Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of D&A for Metal Functional Materials, School of Materials Science and Engineering, Tongji University, Shanghai, People’s Republic of China; 4School of Stomatology, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China; 5Department of Stomatology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 6Shanghai Key Laboratory of Stomatology, Department of Oral Surgery, Shanghai Ninth People’s Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Research Institute of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 7Department of Oral and Maxillofacial Surgery, Zhang Zhiyuan Academician Workstation, Hainan Western Central Hospital, Shanghai Ninth People’s Hospital, Danzhou, Hainan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingzhou Hu; Wei Lu, Email huyayi@shsmu.edu.cn; weilu@tongji.edu.cnIntroduction: Traditional surgical resection, radiotherapy, and chemotherapy have been the treatment options for patients with head and neck squamous cell carcinoma (HNSCC) over the past few decades. Nevertheless, the five-year survival rate for patients has remained essentially unchanged, and research into treatments has been relatively stagnant. The combined application of photothermal therapy (PTT) and immunotherapy for treating HNSCC has considerable potential.Methods: Live-dead cell staining and CCK-8 assays proved that Fe3O4 nanoparticles are biocompatible in vitro. In vitro, cellular experiments utilized flow cytometry and immunofluorescence staining to verify the effect of Fe3O4 nanoparticles on the polarisation of tumor-associated macrophages. In vivo, animal experiments were conducted to assess the inhibitory effect of Fe3O4 nanoparticles on tumor proliferation under the photothermal effect in conjunction with BMS-1. Tumour tissue sections were stained to observe the effects of apoptosis and the inhibition of tumor cell proliferation. The histological damage to animal organs was analyzed by hematoxylin and eosin (H&E) staining.Results: The stable photothermal properties of Fe3O4 nanoparticles were validated by in vitro cellular and in vivo animal experiments. Fe3O4 photothermal action not only directly triggered immunogenic cell death (ICD) and enhanced the immunogenicity of the tumor microenvironment but also regulated the expression of tumor-associated macrophages (TAMs), up-regulating CD86 and down-regulating CD206 to inhibit tumor growth. The PD-1/PD-L1 inhibitor promoted tumor suppression, and reduced tumor recurrence and metastasis. In vivo studies demonstrated that the photothermal action exhibited a synergistic effect when combined with immunotherapy, resulting in significant suppression of primary tumors and an extension of survival.Conclusion: In this study, we applied Fe3O4 photothermolysis in a biomedical context, combining photothermolysis with immunotherapy, exploring a novel pathway for treating HNSCC and providing a new strategy for effectively treating HNSCC.Keywords: photothermal therapy, immunotherapy, tumor-associated macrophages, head and neck squamous cell carcinoma

Lei Wang,1 Xinbao Li,2 Yan Li,2 Zhongying Bao,1 Shuhong Duan,1 Jie Zhang1 1Department of Infectious Diseases, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 2Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of ChinaCorrespondence: Lei Wang, Department of Infectious Diseases, Beijing Shijitan Hospital, Capital Medical University, NO. 10, Tie Yi Road, Yang Fang Dian, Haidian District, Beijing, 100038, People’s Republic of China, Tel + 86 10 63926121, Email wanglei2489@bjsjth.cnObjective: In this study we aimed to evaluate the postoperative safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal surface malignancies (PSM), and analyzed the risk factors and pathogen resistance associated with bloodstream infections.Methods: We retrospectively analyzed the incidence of postoperative bloodstream infections in 1500 patients undergoing CRS and HIPEC for PSM. We utilized univariate and multivariate analyses to screen for independent risk factors associated with postoperative bloodstream infections in CRS combined with HIPEC.Results: Among the 1500 cases of individuals undergoing CRS combined with HIPEC, 207 cases (13.8%) experienced bloodstream infections. A total of 233 strains of pathogens were isolated and cultured, consisting of 151 gram-positive cocci, 52 gram-negative bacilli, and 30 fungi. Coagulase-negative staphylococci (SCN) were the gram-positive cocci (54.94%), while Klebsiella pneumoniae subsp. Pneumoniae (7.30%) and Escherichia coli (5.58%) dominated the Gram-negative bacilli. Candida albicans was the predominant fungus. Staphylococci exhibited high sensitivity to tigecycline, linezolid, vancomycin, and quinupristin/dalfopristin. However, K. pneumoniae and E. coli were resistant to imipenem. Furthermore, five parameters were associated with the development of bloodstream infections: age (P = 0.040), surgical history (P = 0.033), prior tumor treatment (P < 0.001), tumor tissue type (P = 0.034), and completeness of cytoreduction (CC) score (P = 0.004). Among these, age (P = 0.013), prior tumor treatment (P = 0.001), tumor tissue type (P = 0.032), and CC score (P = 0.002) emerged as independent risk factors for postoperative bloodstream infections in patients undergoing CRS combined with HIPEC.Conclusion: Postoperative bloodstream infections in patients with PSM undergoing CRS combined with HIPEC are predominantly attributed to SCN, K. pneumoniae subsp. Pneumoniae, and C. albicans. Notably, Enterobacteriaceae exhibited resistance to carbapenem. Independent risk factors for postoperative infections in PSM include age, prior tumor treatment, tumor tissue type, and completeness of cytoreduction score.Keywords: bloodstream infections, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, pathogens drug resistance, pathogens

Zuohu Niu,1,&ast; Jialiang Chen,2,&ast; Huijing Wang,3,&ast; Rongrui Wang,3,4 Hongye Peng,3 Shaojie Duan,5 Shukun Yao4 1Department of Infections, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5Department of Geriatrics, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaojie Duan, Department of Geriatrics, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of China, Email 1782802171@qq.com Shukun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People’s Republic of China, Email shukunyao@126.comPurpose: It is unclear how the Chinese Visceral Adiposity Index (cVAI) relates to metabolic dysfunction-associated fatty liver disease (MAFLD) and alanine aminotransferase (ALT) in nonobese individuals. In this study, we evaluated the ability of the cVAI to predict MAFLD and elevated ALT in nonobese participants.Methods: This cross-sectional study recruited 541 nonobese subjects from March 2019 to January 2022 with the age range of 18– 80 years. Hepatic steatosis was diagnosed by ultrasound. Participants were divided into four groups according to cVAI quartiles. To assess the associations between cVAI and MAFLD and elevated ALT, multivariate logistic regression was used. Receiver operating characteristic (ROC) curves were generated to evaluate the ability of the cVAI to predict MAFLD and elevated ALT.Results: Compared to the group with the lowest cVAI, the group with the highest cVAI was positively associated with nonobese MAFLD [16.173 (4.082– 64.073), P < 0.001] and elevated ALT [8.463 (2.859– 25.049), P < 0.001]. The area under the ROC curve (AUC) of the cVAI was greater than that of WC, waist-to-height ratio, or BMI for predicting nonobese MAFLD in the male, female, > 38 and ≤ 38 years old subgroups (P < 0.05), respectively. In addition, the ability of the cVAI to predict MAFLD was better in females, young individuals, and individuals with a higher education level (P < 0.05). The cVAI also had good predictive ability for elevated ALT levels [0.655 (0.602– 0.708)], particularly in females, young people, and highly educated participants. Furthermore, the cVAI was strongly positively correlated with the liver fibrosis score (P < 0.05) and was also a strong indicator of concomitant metabolic syndrome in nonobese MAFLD patients [AUC = 0.688 (0.612– 0.763)].Conclusion: The cVAI was strongly related to nonobese MAFLD and elevated ALT. The cVAI may be a reliable and accessible predictor of nonobese MAFLD and elevated ALT.Keywords: Chinese visceral adiposity index, metabolic dysfunction-associated fatty liver disease, nonobese, Chinese, cross-sectional study

Han Yu,1– 4 Na Ning,1– 3 Fujin He,5 Jiao Xu,6 Han Zhao,5 Shaofeng Duan,5,7 Yunqi Zhao1– 4 1College of Science, Mathematics and Technology, Wenzhou-Kean University, Wenzhou, Zhejiang Province, 325060, People’s Republic of China; 2Wenzhou Municipal Key Laboratory for Applied Biomedical and Biopharmaceutical Informatics, Wenzhou-Kean University, Wenzhou, Zhejiang, 325060, People’s Republic of China; 3Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Wenzhou, Zhejiang, 325060, People’s Republic of China; 4Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, Union, NJ, 07083, USA; 5School of Pharmacy, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 6Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, People’s Republic of China; 7The First Affiliated Hospital of Henan University, Kaifeng, Henan, 475004, People’s Republic of ChinaCorrespondence: Yunqi Zhao, College of Science, Mathematics and Technology, Wenzhou-Kean University, Wenzhou, Zhejiang, 325060, People’s Republic of China, Tel +86 577 5587 0000, Fax +86 577 5587 0101, Email yuzhao@kean.edu Shaofeng Duan, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, People’s Republic of China, Fax +86 371 2286 5974, Email sduan@henu.edu.cnBackground: Targeted delivery systems have been developed to improve cancer treatment by reducing side effects and enhancing drug efficacy. Geraniol, a natural product, has demonstrated promising anti-cancer effects in various cancer types, including prostate cancer, which is the most commonly diagnosed cancer in men. Hyaluronic acid (HA), a natural carrier targeting CD44-positive prostate cancer cells, can be utilized in a targeted delivery system.Purpose: This study investigated the efficacy of a conjugate of HA and geraniol linked via a disulfide bond linker (HA-SS-Geraniol) in prostate cancer.Materials and Methods: The cytotoxicity of HA-SS-Geraniol was evaluated on human PC-3 prostate cancer cells. Flow cytometry was used to assess its effects on mitochondrial membrane potential, apoptosis, and cell cycle arrest. Additionally, proteomic analysis was conducted to explore the underlying mechanism of action induced by HA-SS-Geraniol treatment. A subcutaneous xenograft tumor model was established in nude mice to evaluate the toxicity and efficacy of HA-SS-Geraniol in vivo.Results: The results demonstrated that HA-SS-Geraniol exhibited potent cytotoxicity against PC-3 prostate cancer cells by inducing mitochondrial membrane potential loss and apoptosis in vitro. The proteomic analysis further supported the hypothesis that HA-SS-Geraniol induces cell death through mitochondria-mediated apoptosis, as evidenced by differential protein expression. The in vivo mouse model confirmed the safety of HA-SS-Geraniol and its ability to inhibit tumor growth.Conclusion: HA-SS-Geraniol holds promise as a biologically safe and potentially effective therapeutic agent for prostate cancer treatment. Its targeted delivery system utilizing HA as a carrier shows potential for improving the efficacy of geraniol in cancer therapy.Keywords: geraniol, hyaluronic acid, prostate cancer, nanoparticle, proteomics

Huanhuan Zhu, Chen Chen, Luhan Geng, Qing Li, Chengning Zhang, Lin Wu, Bo Zhang, Suyan Duan,&ast; Changying Xing,&ast; Yanggang Yuan&ast; Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanggang Yuan, Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel/Fax +86-25-6813-6462, Email ygyuan@njmu.edu.cnBackground: Mounting evidence suggests that mitochondrial dysfunction contributes to lupus nephritis (LN) pathogenesis. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) mediating pyruvate transport from the cytoplasm to the mitochondrial matrix, determines the cell survival and cellular energy supply. Here, we aimed to investigate the association of mitochondrial pyruvate carrier expression with the clinical and histological features in LN.Methods: Patients with biopsy-proven proliferative LN (class III and class IV, n=18) and membranous LN (class V, n=18) were included. Expression of MPC1 and MPC2 were examined by immunohistochemistry. MPC protein levels in the two groups were evaluated by the Student’s t-test. Correlation analysis between MPC levels and clinicopathological features was performed by Spearman’s rank correlation.Results: Both MPC1 and MPC2 were exclusively expressed in renal tubules of enrolled LN. Significantly lower MPC1 and MPC2 were observed in patients with proliferative LN compared to membranous LN. In addition, the MPC1 and MPC2 were negatively correlated with SLEDAI-2K score, renal function, and renal pathology activity index.Conclusion: Both MPC1 and MPC2 were localized in renal tubules, and decreased MPC content was more pronounced in proliferative LN than membranous LN. MPC levels were significantly correlated with renal functions and renal pathology activity.Keywords: lupus nephritis, mitochondrial pyruvate carrier, proliferative, membranous, tubulointerstitial lesions

Jiaqi Tian,1,&ast; Zhengpu Han,1,2,&ast; Dandan Song,1 Yanjie Peng,1 Min Xiong,3 Zhen Chen,2 Shuyin Duan,4 Lin Zhang1,5 1Clinical Medical Research Center for Women and Children Diseases, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, People’s Republic of China; 2School of Public Health, Weifang Medical University, Weifang, People’s Republic of China; 3School of Public Health, North China University of Science and Technology, Tangshan, People’s Republic of China; 4School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 5Key Laboratory of Birth Defect Prevention and Genetic Medicine of Shandong Health Commission, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Zhang, Clinical Medical Research Center for Women and Children Diseases, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250001, People’s Republic of China, Tel +86-531-68795046, Email zhanglin8901@163.com Shuyin Duan, School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250001, People’s Republic of China, Tel +86-13419581411, Email shuyinduan@126.comAbstract: Exosomes are nano-sized membrane vesicles that transfer bioactive molecules between cells and modulate various biological processes under physiological and pathological conditions. By applying bioengineering technologies, exosomes can be modified to express specific markers or carry therapeutic cargo and emerge as novel platforms for the treatment of cancer, neurological, cardiovascular, immune, and infectious diseases. However, there are many challenges and uncertainties in the clinical translation of exosomes. This review aims to provide an overview of the recent advances and challenges in the translation of engineered exosomes, with a special focus on the methods and strategies for loading drugs into exosomes, the pros and cons of different loading methods, and the optimization of exosome production based on the drugs to be encapsulated. Moreover, we also summarize the current clinical applications and prospects of engineered exosomes, as well as the potential risks and limitations that need to be addressed in exosome engineering, including the standardization of exosome preparation and engineering protocols, the quality and quantity of exosomes, the control of drug release, and the immunogenicity and cytotoxicity of exosomes. Overall, engineered exosomes represent an exciting frontier in nanomedicine, but they still face challenges in large-scale production, the maintenance of storage stability, and clinical translation. With continuous advances in this field, exosome-based drug formulation could offer great promise for the targeted treatment of human diseases.Keywords: engineered exosomes, drug delivery, clinical application, preparation strategy

Dong Zhang,1,2 Siwei Duan,3 Zhangyou He,4 Zeming Zhu,3 Zhiping Li,3 Qincheng Yi,4 Tiantian Cai,1,2 Juanjuan Li,1,2 Nan Chen,1,2 Shaoju Guo1,2 1Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China; 3Institute of Gastroenterology, Science and Technology Innovation Center of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Shaoju Guo, Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China, Tel +86-0755-82571384, Email gsj1080@163.comPurpose: This study was conducted to explore the mechanism of Sijunzi Decoction (SJZ) in the treatment of ulcerative colitis (UC).Methods: The study aimed to investigate the active components and targets of SJZ in the treatment of UC by screening databases such as TCMSP, GeneCards, OMIM, Distinct, TTD, and Drugbank. An online Venn tool, Cytoscape 3.7.2, and Autodock Tools were used to analyze the components and targets. The study also used a mouse model of UC to further investigate the effects of SJZ. HE staining, immunofluorescence, ELISA, qPCR, and Western blot were used to detect various indices.Results: Eighty-three active components and 112 action targets were identified from SJZ, including 67 targets for treating UC-related NETs. The five core targets identified were AKT1, JUN, IL1B, PTGS2, and TNF, and molecular docking studies indicated that the five targets were well-docked with ginsenoside Rh2, isoflavones, and formononetin. Animal experiments demonstrated that SJZ could alleviate various parameters such as weight, colon length, spleen index, disease activity index, and intestinal pathology of the UC mice. Immunofluorescence and Western blot showed that SJZ could reduce the expression of IL1B and TNF in intestinal neutrophils while increasing the expression of Occludin. Cellular immunofluorescence suggests that SJZ can reduce the expression of TNF and IL1B in NETs. The qPCR results also suggested that SJZ could inhibit TNF signal. Furthermore, ELISA results suggested that SJZ could inhibit the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while promoting the expression of anti-inflammatory cytokines (IL-10, IL-37, TGF-β).Conclusion: SJZ treats UC by reducing the content of intestinal NETs, with primary targets on the NETs being IL1B and TNFand suppress TNF signal. The practical components of SJZ may be ginsenoside Rh2, isoflavones, and formononetin.Graphical Abstract: Keywords: ulcerative colitis, Sijunzi decoction, network pharmacology, IL1B, TNF

Zhongping Duan,1 Jinling Dong,1 Ying Liu,2 Haiyang Zhou,2 Shuli Duan,2 Weihong Liu,3 Rico Liang,3 Yue Ding3 1Fourth Department of Hepatology Center, Beijing You’an Hospital, Capital Medical University, Beijing, People’s Republic of China; 2iGandan, the Portal for All Liver Disease Caring, Beijing, People’s Republic of China; 3Brii Biosciences Inc., Beijing, People’s Republic of ChinaCorrespondence: Rico Liang, Brii Biosciences Inc, 3F, Building 7, Zhongguancun Dongsheng International Science Park, No. 1 North. Yongtaizhuang Road, Haidian District, Beijing, 100192, People’s Republic of China, Tel/Fax +86 10 6587 6121, Email Rico.Liang@briibio.comPurpose: HBV functional cure is an optimal treatment goal for chronic hepatitis B (CHB) at present and numerous new drugs aiming for HBV functional cure are in development. We carried out an internet-based survey to understand the treatment status, unmet needs, awareness of HBV functional cure and attitude toward related clinical trials among CHB patients in China.Patients and Methods: An internet-based anonymous survey was conducted on CHB patients who reside in mainland China. Determinants of awareness and attitude were identified by logistic regression models.Results: Of the 1220 CHB patients who completed the survey questionnaire, 11.1% (135/1220) were aware of HBV functional cure and 50.2% (612/1220) answered “definitely will” to participate in related clinical trials. Participants who knew their HBsAg level (HBsAg< 1500 IU/mL: OR=3.03, 95% CI: 1.87– 4.92; HBsAg≥ 1500 IU/mL: OR=2.57, 95% CI: 1.35– 4.88), who expected to achieve HBsAg loss with treatment (OR=1.63, 95% CI: 1.07– 2.50) and who were dissatisfied with current treatment due to the failure of achieving HBsAg loss (OR=1.67, 95% CI: 1.10– 2.53) had better awareness of HBV functional cure. Participants who had HBsAg level less than 1500 IU/mL (OR=1.45, 95% CI: 1.05– 1.99), treatment with pegylated interferon alpha with or without nucleos(t)ide (OR=1.68, 95% CI: 1.11– 2.53) and better awareness of HBV functional cure (OR=1.62, 95% CI: 1.01– 2.61) were more likely to say “definitely will” to participate in related clinical trials.Conclusion: Chinese CHB patients reported a low awareness of HBV functional cure. Although CHB patients in China reported a low rate of HBV functional cure awareness, they had a high acceptance of related clinical trials.Keywords: CHB, HBV functional cure, awareness, related clinical trials

Meng Zhou,&ast; Fang Lu,&ast; Ling Jiang, Chen Chen, Si Chen, Luhan Geng, Rui Sun, Qing Li, Suyan Duan, Bo Zhang, Huijuan Mao, Changying Xing, Yanggang Yuan Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanggang Yuan; Changying Xing, Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, Tel/Fax +86-25-6830-6462, Email ygyuan@njmu.edu.cn; cyxing62@126.comAim: Diabetic kidney disease (DKD) continues to be devastating complication of diabetes mellitus. Immune response and inflammatory reaction play essential roles in the progression of DKD. But the specific mechanism of immune cells, and their act on renal innate cells remains unclear. This article focused on immune cells and their communication with renal innate cells to provide bioinformatic evidence for further understanding the immune mechanism in DKD.Methods: Data were analyzed to evaluate the differentially expressed genes (DEGs) and their pathways in DKD patients and mice. Gene set enrichment analysis (GSEA) was used to explore the immune inflammation-related pathways. CIBERSORT was applied to evaluate the distribution of inflammatory cells in different states. Cell-type DEGs and their enrichment pathways were further explored in podocytes, proximal tubule cells and injured tubule cells. Cellchat was used to reveal the cellular communication between immune cells and renal innate cells in DKD.Results: GO and KEGG analysis showed that DEGs were mainly enriched in immune inflammation-related pathways. Monocytes, M2 macrophages and T cells were significantly increased in DKD samples, especially in renal tubule. ScRNA datasets showed that the immune cells number in DKD were significantly increased. Cell-type DEGs were involved in kidney growth and development. In DKD, the interaction numbers and strength between immune cells and innate cells were significantly increased. VISTANT, SPP1 and IGF signal flow were increased in DKD. SPP1-CD44, NRG1-ERBB4, NAMPT-INSR, and Igf1-Igf1r receptor ligand pairs were enhanced in DKD, which mediated the communication between immune-inflammatory cells and innate cells.Conclusion: Our study explored the pathogenesis of renal injury promoted by immunoinflammatory in DKD. VISTANT, SPP1, and IGF signaling pathways and SPP1-CD44, NRG1-ERBB4, NAMPT-INSR, and Igf1- Igf1r receptor ligand pairs might occupy essential place in the occurrence and progress of DKD.Keywords: diabetic kidney disease, immune cells, renal innate cells, bioinformatics

Shuo Duan,1,&ast; Weijie Dong,2,&ast; Yichun Hua,3 Yali Zheng,4 Zengsuonan Ren,5 Guanmei Cao,6 Fangfang Wu,4 Tianhua Rong,1 Baoge Liu1 1Department of Orthopaedic Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Orthopedics, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Medical Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Respiratory, Critical Care, and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 5Department of Orthopaedic Surgery, People’s Hospital of Hainan Tibetan Autonomous Prefecture, Hainan Tibetan Autonomous Prefecture, Qinghai Province, People’s Republic of China; 6Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baoge Liu, Department of Orthopaedic Surgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Tel +86 13581521066, Fax +010-59978702, Email baogeliu@hotmail.comPurpose: To explore the application of deep learning (DL) methods based on T2 sagittal MR images for discriminating between spinal tuberculosis (STB) and spinal metastases (SM).Patients and Methods: A total of 121 patients with histologically confirmed STB and SM across four institutions were retrospectively analyzed. Data from two institutions were used for developing deep learning models and internal validation, while the remaining institutions’ data were used for external testing. Utilizing MVITV2, EfficientNet-B3, ResNet101, and ResNet34 as backbone networks, we developed four distinct DL models and evaluated their diagnostic performance based on metrics such as accuracy (ACC), area under the receiver operating characteristic curve (AUC), F1 score, and confusion matrix. Furthermore, the external test images were blindly evaluated by two spine surgeons with different levels of experience. We also used Gradient-Class Activation Maps to visualize the high-dimensional features of different DL models.Results: For the internal validation set, MVITV2 outperformed other models with an accuracy of 98.7%, F1 score of 98.6%, and AUC of 0.98. Other models followed in this order: EfficientNet-B3 (ACC: 96.1%, F1 score: 95.9%, AUC: 0.99), ResNet101 (ACC: 85.5%, F1 score: 84.8%, AUC: 0.90), and ResNet34 (ACC: 81.6%, F1 score: 80.7%, AUC: 0.85). For the external test set, MVITV2 again performed excellently with an accuracy of 91.9%, F1 score of 91.5%, and an AUC of 0.95. EfficientNet-B3 came second (ACC: 85.9, F1 score: 91.5%, AUC: 0.91), followed by ResNet101 (ACC:80.8, F1 score: 80.0%, AUC: 0.87) and ResNet34 (ACC: 78.8, F1 score: 77.9%, AUC: 0.86). Additionally, the diagnostic accuracy of the less experienced spine surgeon was 73.7%, while that of the more experienced surgeon was 88.9%.Conclusion: Deep learning based on T2WI sagittal images can help discriminate between STB and SM, and can achieve a level of diagnostic performance comparable with that produced by experienced spine surgeons.Keywords: artificial intelligence, deep learning, spinal tuberculosis, spinal metastases, magnetic resonance imaging

IntroductionAn increasing emergence of novel animal pathogens has been observed over the last decade. Viruses are a major contributor to the increased emergence and therefore, veterinary surveillance and testing procedures are greatly needed to rapidly and accurately detect high-consequence animal diseases such as Foot and Mouth Disease, Highly Pathogenic Avian Influenza, Classical Swine Fever, and African Swine Fever. The major detection methods for such diseases include real-time PCR assays and pathogen-specific antibodies among others. However, due to genetic drift or -shift in virus genomes, failure to detect such pathogens is a risk with devastating consequences. Additionally, the emergence of novel pathogens with no prior knowledge requires non-biased detection methods for discovery.MethodsUtilizing enrichment techniques coupled with Oxford Nanopore Technologies MinION™ sequencing platform, we developed a sample processing and analysis pipeline to identify DNA and RNA viruses and bacterial pathogens from clinical samples.Results and discussionThe sample processing and analysis pipeline developed allows the identification of both DNA and RNA viruses and bacterial pathogens simultaneously from a single tissue sample and provides results in less than 12 h. Preliminary evaluation of this method using surrogate viruses in different matrices and using clinical samples from animals with unknown disease causality, we demonstrate that this method can be used to simultaneously detect pathogens from multiple domains of life simultaneously with high confidence.

Wenting Tu,1,&ast; Taohu Zhou,1,2,&ast; Xiuxiu Zhou,1,&ast; Yanqing Ma,3 Shaofeng Duan,4 Yun Wang,1 Xiang Wang,1 Tian Liu,1 HanXiao Zhang,5 Yan Feng,1 Wenjun Huang,2 Xinang Jiang,1 Yi Xiao,1 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, People’s Republic of China; 2School of Medical Imaging, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China; 3Department of Radiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310000, People’s Republic of China; 4GE Healthcare, Precision Health Institution, Shanghai, 210000, People’s Republic of China; 5School of Medical Imaging, Xuzhou Medical University, Xuzhou, Jiangsu, 221018, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiyuan Liu; Li Fan, Department of Radiology, Second Affiliated Hospital, Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +86 21 81886012 ; +86 21 81886018, Fax +86 21 63587668, Email cjr.liushiyuan@vip.163.com; fanli0930@163.comPurpose: This study aimed to screen out computed tomography (CT) morphological features and clinical characteristics of patients with lung cancer to identify chronic obstructive pulmonary disease (COPD). Further, we aimed to develop and validate different diagnostic nomograms for predicting whether lung cancer is comorbid with COPD.Patients and Methods: This retrospective study examined data from 498 patients with lung cancer (280 with COPD, 218 without COPD; 349 in training cohort, 149 in validation cohort) from two centers. Five clinical characteristics and 20 CT morphological features were evaluated. Differences in all variables were assessed between COPD and non-COPD groups. Models were developed using multivariable logistic regression to identify COPD, including clinical, imaging, and combined nomograms. Receiver operating characteristic curves were used to evaluate and compare the performance of nomograms.Results: Age, sex, interface, bronchus cutoff sign, spine-like process, and spiculation sign were independent predictors of COPD in patients with lung cancer. In the training and validation cohorts, the clinical nomogram showed good performance to predict COPD in lung cancer patients (areas under the curves [AUCs] of 0.807 [95% CI, 0.761– 0.854] and 0.753 [95% CI, 0.674– 0.832]); while the imaging nomogram showed slightly better performance (AUCs of 0.814 [95% CI, 0.770– 0.858] and 0.780 [95% CI, 0.705– 0.856]). For the combined nomogram generated with clinical and imaging features, the performance was further improved (AUC=0.863 [95% CI, 0.824– 0.903], 0.811 [95% CI, 0.742– 0.880] in the training and validation cohort). At 60% risk threshold, there were more true negative predictions (48 vs 44) and higher accuracy (73.15% vs 71.14%) for the combined nomogram compared with the clinical nomogram in the validation cohort.Conclusion: The combined nomogram developed with clinical and imaging features outperformed clinical and imaging nomograms; this provides a convenient method to detect COPD in patients with lung cancer using one-stop CT scanning.Keywords: chronic obstructive pulmonary disease, lung cancer, computed tomography, chest imaging, nomogram

Li Li,1 Rongjin Sun,1 Joseph Zenga,2 Heather Himburg,3 Lu Wang,1 Shengnan Duan,1 Jingwen Liu,1 Dinh Bui,1 Zuoxu Xie,1 Ting Du,4 Lijun Xie,1 Taijun Yin,1 Stu Wong,2 Song Gao,4 Ming Hu1 1Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA; 2Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA; 3Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USACorrespondence: Ming Hu, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA, Email mhu@uh.edu Song Gao, Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA, Email Song.Gao@tsu.eduObjective: We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production.Methods: An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2.Results: A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11– 17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells.Conclusion: In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.Graphical Abstract: Keywords: cyclooxygenase-1, cyclooxygenase-2, turnover number, inflammation, absolute quantification, liquid chromatography with tandem mass spectrometry

Shaobo Duan,1 Ye Zhang,1 Shuang Xu,1 Pei Jiang,1 Qinghua Qi2 1Department of Health Management, Henan Provincial People’s Hospital Zhengzhou University People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Qinghua Qi, Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China, Email qiqinghua333@sina.comObjective: To investigate the predictive role of contrast-enhanced ultrasonography (CEUS) plus D-dimer levels in the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).Methods: CEUS was applied to assess lymph nodes in 186 patients with confirmed DLBCL. The clinical data and laboratory indicators were collected from these patients, and a retrospective analysis was conducted on the relationship between the quantitative parameters of CEUS (TTP, PI, AUC, WOT), D-dimer levels, and clinical features of the DLBCL patients. The Cox regression model was used for univariate and multivariate analyses for the risk factors associated with the prognosis.Results: There was an increase of D-dimer levels in advanced DLBCL patients, who were combined with a significant reduction in TTP and WOT and a significant increase in PI and AUC. D-dimer levels and quantitative parameters of CEUS were strongly correlated with the Ann Arbor, B symptoms, International Prognostic Index (IPI), LDH and CRP levels. The results of the Cox regression model indicated that D-dimer levels, TTP and PI, the quantitative parameters of CEUS, were important prognostic factors for DLBCL.Conclusion: CEUS results and D-dimer levels can be used as independent prognostic factors for DLBCL.Keywords: diffuse large B-cell lymphoma, contrast-enhanced ultrasonography, D-dimer, prognosis

Shasha Duan,1– 3,&ast; Chao Wang,1,2,&ast; Xiangli Xu,4 Xiaoshan Zhang,3 Gaofeng Su,1,2 You Li,1,2 Shuai Fu,1,2 Ping Sun,1,2 Jiawei Tian1 1Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 2The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, People’s Republic of China; 3Department of Ultrasound, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, People’s Republic of China; 4Department of Ultrasound, the Second Hospital of Harbin city, Harbin, Heilongjiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiawei Tian; Ping Sun, Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin, Heilongjiang Province, 150086, People’s Republic of China, Tel +86 451-86605811, Fax +86 451-86605745, Email jwtian2004@163.com; sunpinghmu@163.comPurpose: Angiogenesis is required for improving myocardial function and is a key factor in long-term prognosis after an acute myocardial infarction (AMI). Although exosomes are known to play a crucial role in angiogenesis, the role of peripheral exosomes in angiogenic signal transduction in patients with AMI remains unclear. Here, we explored the effect of exosomes extracted from the peripheral serum of AMI patients on angiogenesis and elucidated the downstream pathways.Patients and Methods: Serum exosomes were obtained from patients with AMI (AMI-Exo) and healthy individuals (Con-Exo). The exosomes were cocultured with human umbilical vein endothelial cells (HUVECs) in vitro, with aortic rings ex vivo, and were used to treat mouse hind-limb ischemia and mouse AMI model in vivo.Results: AMI-Exo raised HUVEC proliferation, tube formation, and migration, and enhanced microvessel sprouting from aortic rings compared to Con-Exo, both in vitro and ex vivo. Quantitative reverse transcription-polymerase chain reaction revealed that the abundance of miR-126-3p, a crucial regulator of angiogenesis, was increased in AMI-Exo. The inhibition of miR-126-3p decreased the benefits of AMI-Exo treatment, and miR-126-3p upregulation enhanced the benefits of Con-Exo treatment in HUVECs, aortic rings, the mouse hind-limb ischemia model, and the mouse AMI model. Knockdown and overexpression analyses revealed that miR-126-3p regulated angiogenesis in HUVECs by directly targeting tuberous sclerosis complex 1 (TSC1). Moreover, we found that miR-126-3p could inhibit TSC1 expression, which further activated mTORC1 signaling and increased HIF-1α and VEGFA expression, ultimately promoting angiogenesis.Conclusion: Collectively, our results provide a novel understanding of the function of exosomes in angiogenesis post AMI. We demonstrated that exosomes from the peripheral serum of AMI patients promote angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α signaling pathway.Keywords: acute myocardial infarction, angiogenesis, exosomes, miR-126-3p, tuberous sclerosis complex 1

Tritrichomonas foetus (TF) is a significant reproductive pathogen of cattle, and sample collection, handling, transport, and testing are significant hurdles to surveillance programs. Recent methods have been developed that allow for the direct detection of TF using a reverse transcription real-time PCR (direct RT-qPCR) approach. To evaluate these methods, a comparative analysis was conducted to assess the technical performance of this assay with a commercially available real-time PCR (qPCR) assay. In addition, the evaluation of two types of collection media (PBS and TF transport tube) was conducted that evaluated sample stability from 0 to 3 days when stored at 4°C or 25°C. Extended incubation times for PBS media were also evaluated (5, 7, and 14 days) at both refrigeration and frozen temperatures to evaluate the effect of extended transport time on samples. Limits of detection (LODs), dynamic range, and RNA stability were assessed using lab-cultured TF spiked into samples of normal bovine smegma collected in PBS or TF transport media, and performance was assessed on field samples collected in parallel. 100% agreement was found between direct RT-qPCR and qPCR at 10 parasites/extraction and a LOD of 1 parasite/extraction. Differences in detection were not observed in either collection media when incubated at either temperatures for up to 3 days of incubation. In addition, the extended incubation experiments indicate that samples containing 10 parasites/extraction can be detected at 4°C for 5 days with a mean Cq 26.34 (95% CI: 23.11–29.58) and detected at −20°C for 7 or 14 days, with a mean Cq 29.55 (95% CI: 27.73–31.37). A significant decrease in detectable RNA was observed in samples containing

Hui Zhang,1,&ast; Peiyao Jia,1,2,&ast; Ying Zhu,1,2,&ast; Ge Zhang,1 Jingjia Zhang,1 Wei Kang,1 Simeng Duan,1 Weijuan Zhang,3 Qiwen Yang,1 Yingchun Xu1 1Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People’s Republic of China; 3MRL Global Medical Affairs, MSD China, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiwen Yang; Yingchun XuDepartment of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +86-18600100521; Tel/Fax +86-010-69159766Email yangqiwen81@vip.163.com; xycpumch@139.comPurpose: In recent years, less options are available for treating carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa. The present study investigates the susceptibility rates to imipenem/relebactam for the treatment of intra-abdominal infections (IAIs), respiratory tract infections (RTIs) and urinary tract infections (UTIs) caused by A. baumannii and P. aeruginosa in China.Patients and Methods: A total of 1886 P. aeruginosa and 1889 A. baumannii isolates were collected in 21 centers (7 regions) as a part of the global SMART surveillance program between 2015 and 2018. Antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) recommendations using the broth microdilution methodology at Peking Union Medical College Hospital.Results: For P. aeruginosa, overall susceptibility rates to imipenem/relebactam were 84.2% at a CLSI breakpoint of ≤ 2 mg/L compared to 55.7% for imipenem. Susceptibility rates of imipenem-non-susceptible P. aeruginosa to imipenem/relebactam were 64.4% and for multidrug-resistance (MDR) P. aeruginosa susceptibility rates were increased from 25.2% for imipenem to 65.8% for imipenem/relebactam. The susceptibilities of imipenem-non-susceptible and MDR P. aeruginosa strains were similarly restored by imipenem/relebactam in non-ICU and ICU wards. The rate of imipenem-non-susceptibilities A. baumannii isolates was 79.0%, whereas the MDR rate was 81.9%. Relebactam did not change the susceptibilities of imipenem-non susceptible or MDR A. baumannii isolates.Conclusion: Imipenem/relebactam provides a therapy option to treat infections caused by MDR or imipenem-non-susceptible P. aeruginosa but not A. baumannii infections in China.Keywords: carbapenem-resistance, extended-spectrum β-lactamase, multidrug-resistance, β-lactamase inhibitor, carbapenemase

Shenxia Xie,1,2,&ast; Xiaoqiong Hou,1,3,&ast; Wei Yang,1,3,&ast; Wei Shi,1,3 Xiaomei Yang,1,3 Siliang Duan,3 Fengzhen Mo,3 Aiqun Liu,3 Wu Wang,1,4 Xiaoling Lu1,3,5 1School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 3International Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 4Laboratory of Tropical Biomedicine and Biotechnology, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan, 571101, People’s Republic of China; 5College of Stomatology, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoling LuCollege of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaEmail luxiaoling@gxmu.edu.cnWu WangLaboratory of Tropical Biomedicine and Biotechnology, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan, 571101, People’s Republic of ChinaEmail lxd8860@163.comBackground: The broader application of adoptive cell therapy (ACT) in cancer immunotherapies (particularly for solid tumors) has always been limited by the immunosuppressive tumor microenvironment (TME) and the insufficient targetability of effector T cells, resulting in unsatisfied therapeutic outcome. Here, we designed a new strategy by using aptamer-based immunoliposomes to modify PD-1-silencing T cells, which were activated by dendritic cell (DC)/tumor fusion cells (FCs) to improve the antitumor potency of cytotoxic T lymphocytes (CTLs/CD8+ T cells).Methods: PD-1 gene was knocked out from CD8+ T cells using CRISPR/Cas9 system to liberate T cell activity from immunosuppression. The PD-1− T cells were stimulated with DC/tumor FCs, followed by further functional modification of tumor-specific nanoliposomes (hEnd-Apt/CD3-Lipo) to generate FC/PD-1− CTLs. The activation and proliferation and specificity of the modified FC/PD-1− CTLs were measured. The antitumor activity of these CTLs against HepG2-tumors was evaluated in xenograft NOD/SCID mice, and the antitumor mechanism was investigated based on tissue immunohistochemistry and serum ELISA.Results: Our results indicated that the modification of hEnd-Apt/CD3-Lipo nanocomposites on the FC/PD-1− CTLs had a more substantial synergetic effect in inhibiting tumor growth and prolonging animal survival, rather than other control liposomes. Furthermore, the hEnd-Apt/CD3-Lipo-modified FC/PD-1− CTLs showed a stronger antitumor outcome in the tumor-bearing mouse model, through the mechanisms of suppressing tumor cell proliferation, promoting tumor apoptosis, reducing angiogenesis but increasing the infiltration of the FC/PD-1− CTLs in the tumor tissue, as well as upregulating the systemic levels of IFN-γ, IL-2, TNF-α and IL-6 cytokines, by comparison of the control settings.Conclusion: In sum, our investigation suggests an enhancement of antitumor effect by the surface modification of endoglin-targeting nanoliposomes upon DC/tumor FC-activated PD-1− CTLs, therefore, provides a new tumoral endoglin-targeted approach as a promising strategy to reduce immunosuppression of tumor microenvironment and improve the immunotherapeutic outcome of anticancer ACT.Keywords: nanoliposome, PD-1, CRISPR/Cas9, endoglin, aptamer, antitumor immunotherapy

Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep.

Ziqiang Ding,1,2,* Dujin Wang,1,2,* Wei Shi,2,3,* Xiaomei Yang,2,3 Siliang Duan,2 Fengzhen Mo,2 Xiaoqiong Hou,2,3 Aiqun Liu,2 Xiaoling Lu2,4 1National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 2International Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 3School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 4College of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoling LuInternational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaTel/Fax +86 771-2387 518Email luxiaoling@gxmu.edu.cnPurpose: Cancer tissue-specific and nuclei-targeted drug delivery is ideal for the delivery of chemotherapy. However, it has only been achieved in in vitro studies mainly due to low efficiency in vivo. In this study, we aimed to establish an efficient dual-targeted system that targets liver cancer tissue as well as the nuclei of cancer cells in vivo.Methods: We first synthesized TAT peptide (TATp)-mesoporous silica nanoparticle (MSN) complex (TATp-MSN) and generated liposomes that carried liver cancer-specific aptamer TLS11a (TLS11a-LB). We then generated the drug TLS11a-LB@TATp-MSN/doxorubicin (DOX) by mixing TLS11a-LB and DOX-loaded TATp-MSN. After physical and chemical characterization of the nanoparticles, DOX release from these formulations was evaluated at pH 5.0 and 7.4. Furthermore, we also evaluated nuclear localization and cytotoxicity of the drug in H22 cells in vitro and investigated the liver cancer targeting and antitumor activities of the nano-drug in vivo using a H22 tumor-bearing mice model.Results: TLS11a-LB@TATp-MSN/DOX and its controls were confirmed as nano-drugs (< 100 nm) using transmission electron microscopy (TEM). The DOX release rate of TLS11a-LB@TATp-MSN/DOX was significantly faster at pH 5.0 than at pH 7.4. TLS11a-LB@TATp-MSN/DOX effectively targeted the nuclei of H22 cells and released DOX with a higher efficiency than that of the control groups. In addition, TLS11a-LB@TATp-MSN/DOX exhibited slight cytotoxicity, but not significantly more than controls. In vivo studies showed that TLS11a-LB@TATp-MSN accumulated in subcutaneous H22 tumors in the right axilla of BALB/c mice, reaching peak levels at 48 h after intravenous injection, respectively, and demonstrated that TLS11a-LB@TATp-MSN/DOX group enhanced tumor treatment efficacy while reducing systemic side effects.Conclusion: TLS11a-LB@TATp-MSN/DOX can efficiently deliver DOX to the nuclei of liver cancer cells by dual targeting liver cancer tissue and the nuclei of the cancer cells in mice. Thus, it is a promising nano-drug for the treatment of liver cancer.Keywords: targeted drug delivery, liver cancer treatment, MSN-based vehicles, doxorubicin, tissue- and nuclei-specific targeting

Qin Li,1,2,* Qin Xiao,2,3,* Jianwei Li,3,4 Shaofeng Duan,5 He Wang,6 Yajia Gu2,3 1Shanghai Institute of Medical Imaging, Shanghai, China; 2Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China; 3Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 4Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; 5PDx, GE Healthcare, Shanghai, China; 6Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China*These authors contributed equally to this workCorrespondence: Yajia GuDepartment of Radiology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Shanghai 200032, China, Tel +8618017312040Fax +862164174774Email guyajia@126.comPurpose: To identify MRI-based radiomics signature (Rad-score) as a biomarker of risk stratification for disease-free survival (DFS) in patients with HER2-positive invasive breast cancer treated with trastuzumab-based neoadjuvant chemotherapy (NAC) and establish a radiomics-clinicoradiologic-based nomogram that combines Rad-score, MRI findings, and clinicopathological variables for DFS estimation.Patients and Methods: A total of 127 patients were divided into a training set and testing set according to the ratio of 7:3. Radiomic features were extracted from multiphase CE-MRI (CEm). Rad-score was calculated using the LASSO (least absolute shrinkage and selection operator) regression analysis. The cutoff point of Rad-score to divide the patients into high- and low-risk groups was determined by receiver operating characteristic curve analysis. A Kaplan–Meier survival curves and the Log rank test were used to investigate the association of the Rad-score with DFS. Univariate and multivariate Cox proportional hazards model were used to determine the association of Rad-score, MRI features, and clinicopathological variables with DFS. A radiomics-clinicoradiologic-based nomogram combining the Rad-score, MRI features, and clinicopathological findings was plotted to validate the radiomic signatures for DFS estimation.Results: The Rad-score stratified patients into high- and low-risk groups for DFS in the training set (P< 0.0001) and was validated in the testing set (P=0.002). The radiomics-clinicoradiologic-based nomogram estimated DFS (training set: C-index=0.974, 95% confidence interval (CI)= 0.954– 0.994; testing set: C-index=0.917, 95% CI= 0.842– 0.991) better than the clinicoradiologic-based nomogram (training set: C-index=0.855, 95% CI= 0.739– 0.971; testing set: C-index=0.831, 95% CI=0.643– 0.999).Conclusion: The Rad-score is an independent biomarker for the estimation of DFS in invasive HER2-positive breast cancer with NAC and the radiomics-clinicoradiologic-based nomogram improved individualized DFS estimation.Keywords: radiomics, breast cancer, prognosis, magnetic resonance imaging

Shurong Duan, Fei Wang, Jingwei Cao, Chunyan Wang Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People’s Republic of ChinaCorrespondence: Chunyan Wang Department of NeurologyThe First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, People’s Republic of ChinaTel/ Fax +86-451-85555130Email wxqsjnk1@163.comIntroduction: Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality, and the effective therapies for ICH remain to be explored. Exosomes (Exos) have been found to play important roles in cell communication by transferring molecules, including microRNAs (miRNAs/miRs). MiRNAs are critical regulators of genes involved in many various biological processes and have been demonstrated to aggravate or alleviate brain damages induced by ICH. The aim of the present study was to investigate the effect of Exos derived from miR-146a-5p-enriched bone marrow mesenchymal stem cells (BMSCs-miR-146a-5p-Exos) on experimental ICH.Methods: ICH was induced in adult male Sprague-Dawley rats by an intrastriatal injection of collagenase type IV. At 24 h after surgery, Exos were administrated. For detecting apoptotic cells, TUNEL staining was performed using an in situ Cell Death Detection Kit. Fluoro-Jade B staining was performed to detect degenerating neurons. Immunofluorescence assay was performed to detect the expression of myeloperoxidase (MPO) and OX-42. The binding of miR-146a-5p and its target genes was confirmed by luciferase reporter assay.Results: At 24 h after surgery, BMSCs-miR-146a-5p-Exos administration significantly improved neurological function, reduced apoptotic and degenerative neurons, and inhibited inflammatory response. Furthermore, miR-146a-5p-enriched Exos obviously inhibited the M1 polarization of microglia after ICH in rats, accompanied by the reduced expression of pro-inflammatory mediators releasing by M1 microglia including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1). Finally, we observed that miR-146a-5p directly targeted interleukin-1 receptor-associated kinase1 (IRAK1) and nuclear factor of activated T cells 5 (NFAT5), which contributed to the inflammation response and the polarization of M1 microglia/macrophages.Conclusion: We demonstrated that miR-146a-5p-riched BMSCs-Exos could offer neuroprotection and functional improvements after ICH through reducing neuronal apoptosis, and inflammation associated with the inhibition of microglial M1 polarization by downregulating the expression of IRAK1 and NFAT5.Keywords: intracerebral hemorrhage, microRNA-146a-5p, exosomes, apoptosis, microglial M1 polarization

Chengning Zhang,1,* Suyan Duan,1,* Miao Guo,2 Yanggang Yuan,1 Zhimin Huang,1 Jingfeng Zhu,1 Bin Sun,1 Bo Zhang,1 Changying Xing1 1Departments of Nephrology; 2Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changying XingDepartment of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, People’s Republic of ChinaTel/Fax +86-25-6830-6462Email cyxing62@126.comBackground: Tacrolimus (TAC) is beneficial for patients with idiopathic membranous nephropathy (IMN). It has a narrow therapeutic concentration range and many factors influence TAC blood concentration. CYP3A5 is the most important enzyme in TAC metabolism. The aim of this study was to analyze the effects of CYP3A5 gene polymorphisms on the efficacy and safety of TAC in IMN patients.Patients and Methods: Patients with IMN who received oral TAC (0.05– 0.075mg/kg/day) combined with prednisone (0.5mg/kg/day) from March 2016 to October 2018 were included. The data of clinical characteristics, therapeutic drugs and adverse reactions of patients were collected at baseline and during 24 weeks of treatment. Patients were divided into two groups according to different CYP3A5 genetic polymorphisms. The significant differences in the efficacy and side effects between the two groups were analyzed.Results: A total of 76 patients who completed follow-up were divided into CYP3A5 nonexpresser (CYP3A5*3/*3) group and CYP3A5 expresser (CYP3A5 *1/*3) group. The significant association between the CYP3A5 phenotype and TAC metabolism was observed. A total of 43 case-times patients exhibited adverse effects. The infection rate in CYP3A5 nonexpresser group (21.95%) was remarkably higher than the rate in CYP3A5 expresser group (5.71%). Blood concentration and C0/D levels were risk factors for adverse events through logistic regression analysis. There was no statistical difference between the study groups with respect to the efficacy.Conclusion: Our results demonstrated that CYP3A5 polymorphisms had important guiding roles in the treatment of IMN with tacrolimus. CYP3A5 expressers required higher daily doses of TAC to achieve the target drug concentration, but with fewer side effects. CYP3A5 genetic polymorphism might be used for TAC dosing adjustment to optimize the treatment for patients with IMN.Keywords: CYP3A5 polymorphisms, idiopathic membranous nephropathy, tacrolimus, side effects

Wang Z, Wang P, Cao L, et al. Cancer Manag Res. 2019;11:10859-10870 The authors have advised due to an error at the time of figure assembly, Figure 8B on page 4543 is incorrect. The correct Figure 8 is shown in Download Article. Figure 8 miR-150-5p knockdown significantly attenuated the repressive effects of LINC01121 down-regulation on the migration and invasion of breast cancer cells Migration and invasion of MCF-7 and MDA-MB-231 cells were measured by transwell after co-transfected miR-150-5p inhibitor and si-LINC01121 or co-transfected with an NC inhibitor and si-LINC01121 at 48 h (***p < 0.001). The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Zhuolu Wang,1 Pinghu Wang,1 Lin Cao,1 Fucheng Li,1 Shenjia Duan,1 Guorong Yuan,1 Lixin Xiao,1 Lin Guo,1 Hong Yin,1 Duying Xie,1 Jing Zhu,1 Xingchu Chen,1 Mengqi Zhang2 1Department of Breast Surgery, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, People’s Republic of China; 2Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of ChinaCorrespondence: Xingchu ChenDepartment of Breast Surgery, Hunan Provincial Maternal and Child Health Care Hospital, No. 53, Xiangchun Road, Kaifu District, Changsha 410008, People’s Republic of ChinaTel +86-13974900511Email hncc88@163.comMengqi ZhangDepartment of Neurology, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha 410008, People’s Republic of ChinaTel +86-13548614858Email zhangmengqi8912@126.comPurpose: Long intergenic noncoding RNA 01121 (LINC01121) has been reported to be aberrantly expressed and acts as an oncogene in pancreatic cancer. However, the detailed molecular mechanism of LINC01121 in breast cancer remains largely unclear. In this study, we aimed to investigate the expression and biological function of LINC01121 in breast cancer.Methods: LINC01121 and miR-150-5p expression were measured in breast cancer cell lines using quantitative reverse transcription PCR. MTS and flow cytometry assays were performed to determine cell proliferation, the cell cycle, and apoptosis. Cell migration and invasion were assessed by transwell assay. The protein expression of HMGA2 in breast cancer cell lines was measured by Western blotting. A luciferase reporter assay was used to assess the binding of LINC01121 and miR-150-5p.Results: We found that LINC01121 was markedly up-regulated in breast cancer cell lines compared with normal breast epithelial cells. LINC01121 down-regulation markedly suppressed cell proliferation, cell cycle progression, migration, and invasion and promoted apoptosis in breast cancer cells. Further investigation showed that LINC01121 could serve as a molecular sponge for miR-150-5p and indirectly modulate the expression of its target, HMGA2. Moreover, miR-150-5p knockdown rescued the effects of LINC01121 down-regulation on HMGA2 protein expression, cell proliferation, cell cycle progression, apoptosis, migration, and invasion in breast cancer cells.Conclusion: Knockdown LINC01121 inhibited breast cancer cell proliferation, migration, and invasion via the miR-150-5p/HMGA2 axis.Keywords: breast cancer, LINC01121, growth, migration, invasion, miR-150-5p

Bin Yang,1,* Lili Guo,2,* Guangming Lu,1,* Wenli Shan,2 Lizhen Duan,2 Shaofeng Duan31Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People’s Republic of China; 2Department of Radiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an 223300, People’s Republic of China; 3GE Healthcare China, Shanghai 210000, People’s Republic of ChinaCorrespondence: Lili GuoDepartment of Radiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an 223300, People’s Republic of ChinaEmail guolili163@163.comGuangming LuDepartment of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, People’s Republic of ChinaTel +86 13 95 160 8346Fax +86 2 58 480 4659Email cjr.luguangming@vip.163.com*These authors contributed equally to this workPurpose: We aimed to assess the classification performance of a computed tomography (CT)-based radiomic signature for discriminating invasive and non-invasive lung adenocarcinoma.Patients and Methods: A total of 192 patients (training cohort, n=116; validation cohort, n=76) with pathologically confirmed lung adenocarcinoma were retrospectively enrolled in the present study. Radiomic features were extracted from preoperative unenhanced chest CT images to build a radiomic signature. Predictive performance of the radiomic signature were evaluated using an intra-cross validation cohort. Diagnostic performance of the radiomic signature was assessed via receiver operating characteristic (ROC) analysis.Results: The radiomic signature consisted of 14 selected features and demonstrated good discrimination performance between invasive and non-invasive adenocarcinoma. The area under the ROC curve (AUC) for the training cohort was 0.83 (sensitivity, 0.84 ; specificity, 0.78; accuracy, 0.82), while that for the validation cohort was 0.77 (sensitivity, 0.94; specificity, 0.52 ; accuracy, 0.82).Conclusion: The CT-based radiomic signature exhibited good classification performance for discriminating invasive and non-invasive lung adenocarcinoma, and may represent a valuable biomarker for determining therapeutic strategies in this patient population.Keywords: lung adenocarcinoma, radiomics, biomarker, computed tomography

Hui Zhang,1 Dawei Tong,1 Aaron Johnson,2 Ge Zhang,1 Zhipeng Xu,1 Yang Yang,1 Jingjia Zhang,1 Dongxue Li,1 Simeng Duan,1 Yao Wang,1 Qiwen Yang,1 Yingchun Xu11Department of Microbiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, People’s Republic of China; 2Department of Microbiology, International Health Management Associates, Schaumburg, IL 60173-3817, USABackground: To explore the susceptibility trends of antimicrobials and resistance increase to antibiotics of Enterobacteriaceae isolated from patients in China with intra-abdominal infections (IAI) from 2011 to 2015.Methods: MIC90 and MIC50 values of 12 commonly used antibiotics from Escherichia coli and Klebsiella pneumoniae isolated from IAI samples were determined.Results: A total of 8,477 Gram-negative bacterial pathogens were collected from 21 medical centers in China. The majority of IAI isolate-derived pathogens were E. coli (3,854, 45.5%) and K. pneumoniae (1,670, 19.7%) of which 1,990 (23.5%) were consecutively collected from community acquired (CA) and 6,186 (73.0%) from hospital acquired (HA) IAIs. The drugs with the highest efficacy against E. coli and K. pneumoniae isolates derived from IAI samples were imipenem, ertapenem, amikacin and piperacillin-tazobactam. MIC90 values for piperacillin-tazobactam were 64 μg/mL in 2015 with fluctuations from 16–64 μg/mL through the years for E. coli, but were stable at ≥64 μg/mL from 2011 to 2015 for K. pneumoniae isolates. Susceptibilities to ertapenem, imipenem and amikacin were high for E. coli isolates throughout the study, but K. pneumoniae isolated from abscesses, colon and peritoneal fluid collected from medical and surgical ICUs showed an increasing trend of carbapenem resistance in 2015.Conclusion: In 2015 there was a trend of enhanced carbapenem resistance, particularly for K. pneumoniae isolated from IAI samples obtained from patients in ICUs.Keywords: MIC, Enterobacteriaceae, intra-abdominal infection, carbapenems, cefepime, piperacillin-tazobactam

Hui Zhang,1 Aaron Johnson,2 Ge Zhang,1 Yang Yang,1 Jingjia Zhang,1 Dongxue Li,1 Simeng Duan,1 Qiwen Yang,1 Yingchun Xu11Division of Microbiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China; 2Division of Microbiology, International Health Management Associates, Schaumburg, IL 60173-3817, USAObjectives: To update the epidemiology and susceptibility of hospital-acquired (HA) and community-acquired (CA), as well as intensive care unit (ICU) vs non-ICU-derived intra-abdominal infection (IAI) and urinary tract infection (UTI) pathogens in Chinese hospitals.Methods: A total of 2,546 Gram-negative isolates from IAIs and 1,947 isolates from UTIs collected in 16 hospitals and 7 regions of China from 2016 to 2017 were analyzed.Results: E. coli and K. pneumoniae were the most common pathogens identified in HA (40.7%, 21.9%) and CA (49.2%, 21.3%) IAIs and in HA (59.0%, 17.3%) and CA (64.3%, 12.7%) UTIs, respectively. The overall rates of extended-spectrum β-lactamase (ESBL)-positive strains were 48.2% for E. coli and 26.4% for K. pneumoniae. The rates of ESBL-positive E. coli and K. pneumoniae strains were significantly higher in HA than in CA IAIs (51.7% vs 42.4%, P=0.016 and 22.0% vs 20.6%, P

Chuan-gen Guo,1,* Shuai Ren,2,* Xiao Chen,2 Qi-dong Wang,1 Wen-bo Xiao,1 Jing-feng Zhang,1 Shao-feng Duan,3 Zhong-qiu Wang2 1Department of Radiology, The First Affiliated Hospital, College of Medicine Zhejiang University, Hangzhou 310003, China; 2Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; 3GE Healthcare, Shanghai 201203, China *These authors contributed equally to this work Purpose: The purpose of this study was to evaluate the performance of magnetic resonance imaging (MRI) findings and texture parameters for prediction of the histopathologic grade of pancreatic neuroendocrine tumors (PNETs) with 3-T magnetic resonance.Patients and methods: PNETs are classified into Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3) tumors based on the Ki-67 proliferation index and the mitotic activity. A total of 77 patients with pathologically confirmed PNETs met the inclusion criteria. Texture analysis (TA) was applied to T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) maps. Patient demographics, MRI findings, and texture parameters were compared among three different histopathologic subtypes by using Fisher’s exact tests or Kruskal–Wallis test. Then, logistic regression analysis was adopted to predict tumor grades. ROC curves and AUCs were calculated to assess the diagnostic performance of MRI findings and texture parameters in prediction of tumor grades.Results: There were 31 G1, 29 G2, and 17 G3 patients. Compared with G1, G2/G3 tumors showed higher frequencies of an ill-defined margin, a predominantly solid tumor type, local invasion or metastases, hypo-enhancement at the arterial phase, and restriction diffusion. Four T2-based (inverse difference moment, energy, correlation, and differenceEntropy) and five DWI-based (correlation, contrast, inverse difference moment, maxintensity, and entropy) TA parameters exhibited statistical significance among PNETs (P

Background: The Chinese government has provided health services to those infected by the human immunodeficiency virus (HIV) under the acquired immunodeficiency syndrome (AIDS) care policy since 2003. Detailed research on the actual expenditures and costs for providing care to patients with AIDS is needed for future financial planning of AIDS health care services and possible reform of HIV/AIDS-related policy. The purpose of the current study was to determine the actual expenditures and factors influencing costs for untreated AIDS patients in a rural area of China after initiating highly active antiretroviral therapy (HAART) under the national Free Care Program (China CARES).Methods: A retrospective cohort study was conducted in Yunnan and Shanxi Provinces, where HAART and all medical care are provided free to HIV-positive patients. Health expenditures and costs in the first treatment year were collected from medical records and prescriptions at local hospitals between January and June 2007. Multivariate linear regression was used to determine the factors associated with the actual expenditures in the first antiretroviral (ARV) treatment year.Results: Five ARV regimens are commonly used in China CARES: zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP), stavudine (D4T) + 3TC + efavirenz (EFV), D4T + 3TC + NVP, didanosine (DDI) + 3TC + NVP and combivir + EFV. The mean annual expenditure per person for ARV medications was US$2,242 (US$1 = 7 Chinese Yuan (CNY)) among 276 participants. The total costs for treating all adverse drug events (ADEs) and opportunistic infections (OIs) were US$29,703 and US$23,031, respectively. The expenses for treatment of peripheral neuritis and cytomegalovirus (CMV) infections were the highest among those patients with ADEs and OIs, respectively. On the basis of multivariate linear regression, CD4 cell counts (100-199 cells/μL versus

Yuanjun Cheng,1,* Donglai Chen,2,* Li Shi,1 Wentao Yang,1 Yonghua Sang,1 Shanzhou Duan,1 Yongbing Chen1 1Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, China; 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China *These authors contributed equally to this work Abstract: Esophageal bronchogenic cysts are extremely rare. Here we report a case of massive upper digestive tract hematoma and bronchogenic cyst mimicking aortic dissection that was safely removed without esophagectomy. A 30-year-old man was referred to our hospital for the treatment of a mediastinal cystic tumor located in the submucosa of the distal esophagus. His chief complaints were dysphagia > 1 week and severe persistent upper abdominal pain mimicking aortic dissection with constant vomiting for 1 day after gastroscopy examination. The serum level of carbohydrate antigen (CA)199 was > 1,000 U/mL and CA125 was 4,816 U/mL. Hemoglobin levels decreased from 122 g/L to 85 g/L in 5 days. Imaging examinations detected a huge hematoma of the gastric wall. Preoperative diagnosis was difficult. Although the pain indicated a possible aortic dissection, the abnormal levels of tumor biomarkers suggested malignancy. The patient underwent left thoracotomy. The cyst showed an exophytic lesion connected to the esophageal wall at the level of the gastroesophageal junction. Muddy brown contents were obtained by aspiration of the mass intraoperatively. Because enucleation could not be performed, esophageal myotomy in the distal esophagus and partial resection of the cyst were selected. Histopathological examination indicated a bronchogenic cyst of the esophagus. At a follow-up visit 3 months later, the patient had no signs of disease recurrence or any complaints. Postoperative tumor biomarkers returned to normal range. The present report summarizes the clinical details of the case and reviews the literature in order to improve the accuracy of diagnosis. Keywords: esophagus, bronchogenic cyst, thoracotomy, tumor biomarkers, hematoma

Change of land use and agricultural management, combined with severe droughts during the last two decades, are the main reasons for a strong decrease of water quality and quantity in the Miyun reservoir (China). Due to semi-arid monsoon climate, episodic water fluxes have to be considered adequately in an integrated water resources management in the total catchment area. To get insight into runoff generation processes, sediment and nutrient source areas and transfer dynamics, a monitoring approach was established in the Miyun catchment area spanning from plot measurements with weighable gravitation lysimeters and in situ measurements to a subcatchment scale of approx. 10 km2. One of these subcatchments (Sheyuchuan) was selected to adapt the methodologies to the regional runoff pattern using the web GIS-based modeling tool STOFFBILANZ. Calibration of the daily runoff modeling is based on the lysimeter observations from Shixia station and runoff observations in Sheyuchuan subcatchment for the reference year 2011. Despite the fact that the climatic water balance in the region is negative, the precipitation event on 24 July 2011 with a rainfall of 107 mm caused a significant leachate at the lysimeter. The daily modeling for the lysimeter core by the FAO-ETc-adj approach showed a similar deep percolation and a similar distribution of evapotranspiration for the year considered. In the next step, the calibrated model was applied to the subcatchment Sheyuchuan to compare the results of direct runoff and groundwater runoff (deep percolation) with the runoff observations at the weir. Deep percolation was extremely small (1.7 mm yr-1), and direct runoff was 26.9 mm yr-1 in 2011. In comparison to the monitoring results at the weir, a disagreement in the quantity of runoff was found between the observation on the one hand and the simulation on the other hand, which can be explained by water storage in reservoirs for irrigation purposes. Additionally, the water fluxes in the total catchment area were simulated at meso-scale, obtaining a good correlation with observed values.

Shi-Yue Duan, Xue-Mei Ge, Nan Lu, Fei Wu, Weien Yuan, Tuo JinSchool of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of ChinaAbstract: A chemically dynamic spermine-based polymer: polyspermine imidazole-4, 5-amide (PSIA, Mw > 7 kDa) was designed, synthesized, and evaluated in terms of its ability to deliver nucleic acids. This polymer was made from an endogenous monomer professionally condensing genes in sperms, spermine, and a known safety drug metabolite, imidazole-4, 5-dicarboxylic acid, through a bis-amide bond conjugated with the imidazole ring. This polymer can condense pDNA at a W/W ratio above 10 to form polyplexes (100–200 nm in diameter), which is consistent with the observation by transmission electron microscopy (TEM), and the zeta potential was in the range of 10–20 mV. The pDNA packaged polymer was stable in phosphate buffer solution (PBS) at pH 7.4 (simulated body fluid) while the polyplexes were releasing pDNA into the solution at pH 5.8 (simulated endo-lysosomes) due to the degradation of the bis-amide linkages in response to changes in pH values. PSIA-polyplexes were able to achieve efficient cellular uptake and luciferase gene silencing by co-transfection of pDNA and siRNA in COS-7 cells and HepG2 cells with negligible cytotoxicity. Biodistribution of Rhodamine B-labeled PSIA-polyplexes after being systemically injected in BALB/c nude-mice showed that the polyplexes circulated throughout the body, accumulated mainly in the kidney at 4 hours of sample administration, and moved to the liver and spleen after 24 hours. All the results suggested that PSIA offered a promising example to balance the transfection efficiency and toxicity of a synthetic carrier system for the delivery of therapeutic nucleic acids.Keywords: gene delivery, polyspermine, cytotoxicity, transfection efficiency, biodistribution