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Haoming Luo,1,2,* Miao Guo,3,4,* Mingxing Li,1 Yueshui Zhao,1 Jing Shen,1 Fukuan Du,1 Yu Chen,1 Shuai Deng,1 Yuhong Sun,1 Li Gu,1 Wanping Li,1 Xiaobing Li,1 Meijuan Chen,1 Zhangang Xiao,1,5,6 Shengpeng Wang,3,4 Xu Wu1,7 1Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China; 2Department of Pharmacy, Three Gorges University Hospital of Traditional Chinese Medicine & Yichang Hospital of Traditional Chinese Medicine, Yichang, Hubei, 443003, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China; 4Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China; 5Department of Pharmacy, Gulin County Hospital of Traditional Chinese Medicine, Luzhou, Sichuan, 646500, People’s Republic of China; 6School of Pharmacy, Sichuan College of Traditional Chinese Medicine, Mianyang, Sichuan, 621000, People’s Republic of China; 7Department of Paediatric Care, Luzhou People’s Hospital, Luzhou, Sichuan, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shengpeng Wang, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China, Email swang@um.edu.mo Xu Wu, Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China, Email wuxulz@swmu.edu.cnIntroduction: Rhodiola species have been utilized as functional foods in Asia and Europe for promoting health. Research has demonstrated that Rhodiola has the potential to alleviate inflammatory bowel disease (IBD) in animal models. However, the specific active components and the underlying mechanism for ameliorating intestinal damage remain unclear. This study aims to explore the relieving effect of Rosavin (Rov), a known active constituent of Rhodiola, in IBD and the regulatory mechanisms.Methods: The therapeutic effect of Rov was evaluated using a murine model of acute colitis induced by dextran sulfate sodium salt (DSS). Inflammatory cytokines and neutrophil activation markers were measured by corresponding kits. Immunohistochemistry, immunofluorescence, TUNEL, and EdU assays were applied to investigate the tight conjunction proteins expression, epithelial marker expression, number of apoptotic cells, and epithelial proliferation, respectively. The protection effect of Rov on gut epithelial injury was assessed using TNF-α-induced intestinal organoids. Additinally, RNA sequencing was applied to observe the genetic alteration profile in these intestinal organoids.Results: Oral administration of Rov significantly attenuated weight loss and restored colon length in mice. Notably, Rov treatment led to decreased levels of pro-inflammatory cytokines and neutrophil activation markers while increasing anti-inflammatory factors. Importantly, Rov restored intestinal despair by increasing the number of Lgr5+ stem cells, Lyz1+ Paneth cells and Muc2+ goblet cells in intestines of colitis mice, displaying reduced epithelial apoptosis and recovered barrier function. In TNF-α-induced intestinal organoids, Rov facilitated epithelial cell differentiation and protected against TNF-α-induced damage. RNA sequencing revealed upregulation in the gene expression associated with epithelial cells (including Lgr5+, Lyz1+ and Muc2+ cells) proliferation and defensin secretion, unveiling the protective mechanisms of Rov on the intestinal epithelial barrier.Discussion: Rov holds potential as a natural prophylactic agent against IBD, with its protective action on the intestinal epithelium being crucial for its therapeutic efficacy. Keywords: rosavin, colitis, inflammatory bowel disease, organoid, intestinal stem cell

Shulin Wei,1,2,* Mingxing Li,1,2,* Qin Wang,1,2,* Yueshui Zhao,1,2 Fukuan Du,1,2 Yu Chen,1,2 Shuai Deng,1,2 Jing Shen,1,2 Ke Wu,1,2 Jiayue Yang,1,2 Yuhong Sun,1 Li Gu,1 Xiaobing Li,1 Wanping Li,1 Meijuan Chen,1 Xiao Ling,3 Lei Yu,3 Zhangang Xiao,1,2 Lishu Dong,3 Xu Wu1,2 1Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China; 2South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China; 3Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lishu Dong, Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China, Email 1275607519@qq.com Xu Wu, Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China, Email wuxulz@126.comAbstract: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.Keywords: mesenchymal stem cells, immunomodulation, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, cell therapy

Mengtian Shan,1 Huimin Wan,1 Linyu Ran,1 Jihui Ye,1 Wang Xie,2 Jingjing Lu,1 Xueping Hu,1 Shengjie Deng,1 Wenyu Zhang,1 Miao Chen,3 Feilong Wang,1 Zhongliang Guo1,4 1Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Respiratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 3Department of Emergency, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, People’s Republic of China; 4Department of Respiratory Medicine, Ji’an Hospital, Shanghai East Hospital, Shanghai, Jiangxi, People’s Republic of ChinaCorrespondence: Zhongliang Guo; Feilong Wang, Shanghai East Hospital, School of Medicine, Tongji University, 150st Jimo Road, Pudong, Shanghai, 200092, People’s Republic of China, Tel +86-21-38804518, Fax +86-21-20334513, Email drguozhl@163.com; wang_feilong@tongji.edu.cnBackground: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo.Methods: Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence.Results: Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1β, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1β and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue.Conclusion: Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.Keywords: acute lung injury, acute respiratory distress syndrome, NLRP3 inflammasome, pyroptosis, dynasore, inflammation

Weijie Chen,1,2,* Simin Deng,3,* Huali Jiang,2,* Heng Li,2 Yu Zhao,2 Yiqiang Yuan4 1Department of Cardiology, The Second School of Clinical Medicine, Southern Medical University, Guangdong, People’s Republic of China; 2Department of Cardiology, Dongguan Tung Wah Hospital, Guangdong, People’s Republic of China; 3Research Center, Dongguan Eighth People’s Hospital, Guangdong, People’s Republic of China; 4Department of Cardiology, The Second School of Clinical Medicine, Southern Medical University, The Seventh People’s Hospital of Zhengzhou, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiqiang Yuan, Department of Cardiology, The Second School of Clinical Medicine, Southern Medical University, The Seventh People’s Hospital of Zhengzhou, No. 17 Jingnan 5th Road, Zhengzhou Economic and Technological Development Zone, Zhengzhou, Henan, People’s Republic of China, Tel +86-0371-61205666, Email zzqyyuanyiqiang@126.comPurpose: To explore the topology of the white matter network in individuals with essential hypertension by graph theory.Patients and Methods: T1-weighted image and diffusion tensor imaging (DTI) data from 43 patients diagnosed with essential hypertension (EHT) and 33 individuals with normotension (healthy controls, HCs) were incorporated in this cross-sectional study. Furthermore, structural networks were constructed by graph theory to calculate whole brain network characteristics and intracerebral node characteristics.Results: Both EHT and HC groups displayed small-worldness in their structural networks. The area under the curve (AUC) of the small-worldness coefficient (σ) was higher in the EHT group compared to the HC group, whereas the AUC of assortativity was lower in the EHT group in contrast to the HC group. The nodal clustering coefficient (CP) and local efficiency (Eloc) of the EHT group decreased in the right dorsolateral superior frontal gyrus and the left medial superior frontal gyrus. These values increased in the left anterior cingulate and paracingulate gyrus. Furthermore, weight and body mass index (BMI) were positively correlated with σ.Conclusion: The EHT group showed brain network separation and integration dysfunction. Weight and BMI were positively correlated with σ. The data acquired in this investigation implied that altered structural connectivity in the prefrontal region may be a potential neuroimaging marker in EHT patients.Keywords: DTI, EHT, graph theory, whole brain network characteristics, intracerebral node characteristics

Danyang Wang,1,2 Jianfeng Xing,2 Ying Zhang,2 Ziyang Guo,2 Shujing Deng,2 Zelin Guan,2 Binyang He,2 Ruirui Ma,2 Xue Leng,2 Kai Dong,2 Yalin Dong1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Kai Dong, School of Pharmacy, Xi’an Jiaotong University, 76 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of China, Tel/Fax +86-29-82655139, Email dongkai120@xjtu.edu.cn Yalin Dong, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China, Te1 +86-29-85323241, Fax +86-29-85323240, Email dongyalin@mail.xjtu.edu.cn; donglyalin@medmail.com.cnAbstract: Chronic wounds are recalcitrant complications of a variety of diseases, with pathologic features including bacterial infection, persistent inflammation, and proliferation of reactive oxygen species (ROS) levels in the wound microenvironment. Currently, the use of antimicrobial drugs, debridement, hyperbaric oxygen therapy, and other methods in clinical for chronic wound treatment is prone to problems such as bacterial resistance, wound expansion, and even exacerbation. In recent years, researchers have proposed many novel materials for the treatment of chronic wounds targeting the disease characteristics, among which metal–phenolic networks (MPNs) are supramolecular network structures that utilize multivalent metal ions and natural polyphenols complexed through ligand bonds. They have a flexible and versatile combination of structural forms and a variety of formations (nanoparticles, coatings, hydrogels, etc.) that can be constructed. Functionally, MPNs combine the chemocatalytic and bactericidal properties of metal ions as well as the anti-inflammatory and antioxidant properties of polyphenol compounds. Together with the excellent properties of rapid synthesis and negligible cytotoxicity, MPNs have attracted researchers’ great attention in biomedical fields such as anti-tumor, anti-bacterial, and anti-inflammatory. This paper will focus on the composition of MPNs, the mechanisms of MPNs for the treatment of chronic wounds, and the application of MPNs in novel chronic wound therapies.Keywords: metal–phenolic networks, chronic wounds, antimicrobial, antioxidant, reactive oxygen species scavenging, revascularization

Nan Sun,1 Dan Dai,1 Shihang Deng,2 Xun Cai,3 Ping Song1 1Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Dermatology, Shenzhen Bao’an Authentic TCM Therapy Hospital, Shenzhen, 518126, People’s Republic of China; 3Department of Dermatology, The Fifth People’s Hospital of Suzhou, Suzhou, 215131, People’s Republic of ChinaCorrespondence: Nan Sun; Ping Song, Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China, Email dr-sue@foxmail.com; songping@vip.126.comBackground: Atopic dermatitis (AD) is an allergic inflammatory skin disease caused by aberrant and over-reactive immune response. Although circadian rhythm disruption is implicated in multiple immunoinflammatory conditions, including AD, the mechanisms at the molecular level underlying AD and circadian rhythms remain elusive.Methods: Bulk and single-cell RNA-sequencing data of AD patients were acquired from the Gene Expression Omnibus, including GSE121212, GSE120721, and GSE153760 datasets. A single-sample gene set enrichment analysis was performed to estimate circadian rhythm gene expression levels. A differential expression analysis was utilized to identify the key candidate genes in AD. CIBERSORT was used to quantify the proportions of immune cells, and the R package “Seurat” was utilized to investigate single-cell RNA-sequencing data.Results: Circadian rhythm gene expression levels were lower in AD skin samples than in normal skin samples. Dendritic cells were significantly upregulated and negatively correlated with circadian rhythm gene expression levels in AD patients. Compared with circadian rhythm-related genes in the control samples, ARNTL2, NOCT, and RORC were differentially expressed in AD; ARNTL2 and NOCT were significantly upregulated, whereas RORC was significantly downregulated in AD. ARNTL2, NOCT, and RORC also showed robust abilities to diagnose AD. We validated that the abundance of the dendritic cell was positively correlated with the ARNTL2 and NOCT expression levels using bulk RNA-sequencing data of the GSE121212 and single-cell RNA-sequencing data of the GSE153760. Moreover, the functional enrichment analysis showed that the IL-17 and NF-κB signaling pathways, Th1 and Th2 cell differentiations, and primary immunodeficiency, were enriched in AD patients.Conclusion: The findings of this study suggested that the circadian rhythm is involved in the progression of AD, and RNTL2, NOCT, and RORC as well as dendritic cells are differentially expressed in AD. These findings could be used to introduce diagnostic and chronotherapeutic modalities for AD.Keywords: atopic dermatitis, circadian rhythms, dendritic cells, ARNTL2, NOCT, RORC

Luying Qiu,1 Yaxuan Wang,2 Yuye Wang,1,3 Fang Liu,1 Shumin Deng,1 Weishuang Xue,1 Yanzhe Wang1 1Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Neurology, China-Japan Friendship Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yanzhe Wang, Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, Liaoning Province, 110001, People’s Republic of China, Tel +86-15040289417, Email yanzhewangcmu@126.comPurpose: The oxygen and glucose deprivation-reoxygenation (OGDR) model is widely used to evaluate ischemic stroke and cerebral ischemia-reperfusion (I/R) injury in vitro. Excessively activated microglia produce pro-inflammatory mediators such as matrix metalloproteinases [MMPs] and their specific inhibitors, tissue inhibitors of metalloproteinases [TIMPs], causing neuronal damage. Ursolic acid (UA) acts as a neuroprotective agent in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model keeping the MMP/TIMP balance with underlying mechanisms unclear. Our study used OGDR model to determine whether and how UA reduces neuronal damage by reversing MMP/TIMP imbalance caused by microglia in I/R injury in vitro.Methods: SH-SY5Y cells were first cultured with 95% N2 and 5% CO2 and then cultivated regularly for OGDR model. Cell viability was tested for a proper UA dose. We established a co-culture system with SH-SY5Y cells and microglia-conditioned medium (MCM) stimulated by lipopolysaccharide (LPS) and interferon-gamma (IFNγ). MMP9 and TIMP1 levels were measured with ELISA assay to confirm the UA effect. We added recombinant MMP9 (rMMP9) and TIMP1 neutralizing antibody (anti-TIMP1) for reconfirmation. Transmission electron microscopy was used to observe cell morphology, and flow cytometry and Annexin V-FITC and PI labeling for apoptotic conditions. We further measured the calcium fluorescence intensity in SH-SY5Y cells.Results: The MCM significantly reduced cell viability of SH-SY5Y cells after OGDR (p

Huilin Su,1– 3,* Weiwei Jiang,4,* Paul E Verweij,3,5 Li Li,2 Junhao Zhu,2 Jiande Han,1 Min Zhu,2 Shuwen Deng6 1Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Medical Microbiology and Center of Expertise in Mycology, Radboud University Medical Center, Nijmegen, the Netherlands; 4Department of Dermatology, Hospital affiliated to the 72nd Army of Chinese PLA, Huzhou, People’s Republic of China; 5Department of Medical Microbiology and Center of Expertise in Mycology, CWZ Hospital, Nijmegen, the Netherlands; 6Department of Medical Microbiology, The People’s Hospital of SND, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuwen Deng, Department of Medical Microbiology, The People’s Hospital of SND, Suzhou, People’s Republic of China, Email shuwen.deng@gmail.com Min Zhu, Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China, Email juneminmyco@126.comIntroduction: The emergence of resistance in Trichophyton rubrum to azoles and terbinafine has become increasingly evident in recent years, necessitating the development of novel antifungal drugs and the exploration of new indications for existing agents.Methods: In this study, we retrospectively evaluated the in vitro antifungal activity of 3 echinocandins (anidulafungin, caspofungin, and micafungin) against 73 clinical isolates of T. rubrum collected from a teaching hospital in Shanghai, China, using EUCAST E.DEF 9.3.1 with minor modification. We also reviewed the susceptibility of T. rubrum to echinocandins globally by literature searching.Results: Our findings revealed that micafungin exhibited the lowest modal minimum effective concentration (MEC) value (0.08 mg/L, n = 28) and the lowest geometric mean (GM) MEC value (0.014 mg/L) among the 73 isolates of T. rubrum tested, followed by anidulafungin with a modal MEC value of 0.016 mg/L (n = 67) and a GM of 0.018 mg/L. Caspofungin displayed a higher modal MEC value of 0.5 mg/L (n = 35) and a GM of 0.308 mg/L. Despite variations in methodologies, similar results were obtained from the review of five relevant studies included in our analysis.Discussion: Echinocandins exhibited excellent in vitro activity against T. rubrum isolates, with micafungin and anidulafungin demonstrating greater potency than caspofungin. These findings suggest that echinocandins could be considered as potential treatment options for managing recalcitrant dermatophytoses resulting from the emergence of resistance. However, it is important to note that the clinical efficacy of these in vitro findings has yet to be established and warrants further investigation.Keywords: echinocandins, Trichophyton rubrum, antifungal activity, review

Song Deng,1,* Kaiwei Cai,1,* Chaoying Pei,1 Xingyuan Zhang,1 Xiaoyi Xiao,1 Ye Chen,1 Ying Chen,1 Rongyao Liang,1 Yanlong Chen,1 Pei Li,1 Zhiyong Xie,2 Qiongfeng Liao1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiongfeng Liao, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China, Tel/Fax +86 02039358081, Email zyfxliao@gzucm.edu.cn Zhiyong Xie, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, 510006, People’s Republic of China, Tel/Fax +86 075523260207, Email xiezhy@mail.sysu.edu.cnPurpose: This study aimed to investigate the underlying treatment mechanism of Radix Astragali (RA) in hyperuricemia from the perspective of microbiota and metabolomics.Methods: We used potassium oxyazinate (PO) to induce hyperuricemia mice, and we determined serum alanine aminotransferase/aspartate aminotransferase (ALT/AST), xanthine oxidase (XOD), creatinine (CRE), uric acid (UA), blood urea nitrogen (BUN) levels, liver XOD levels and assessed the kidney tissue histopathology. The therapeutic mechanism of RA in hyperuricemic mice was studied by 16S rRNA, metagenomic sequencing and metabolomics.Results: Our research showed that RA has therapeutic effect in hyperuricemia mice, such as slow the weight loss, repair kidney damage, and downregulate serum UA, XOD, CRE, ALT/AST, BUN, and liver XOD levels. RA restored the disturbance structure of the microbiota in hyperuricemia mice by increasing the relative abundances of beneficial bacteria (Lactobacillaceae and Lactobacillus murine) but decreasing the relative abundances of pathogenic bacteria (Prevotellaceae, Rikenellaceae and Bacteroidaceae). Meanwhile, we found that RA directly regulated the metabolic pathway (such as linoleic acid metabolism and glycerophospholipid metabolism) and indirectly regulated bile acid metabolism by mediating microbiota to ameliorate metabolic disorders. Subsequently, there was a robust correlation between specific microbiota, metabolites and the disease index.Conclusion: The ability of RA to protect mice against hyperuricemia is strongly linked to the microbiome-metabolite axis, which would provide evidence for RA as a medicine to prevent or treat hyperuricemia.Graphical Abstract: Keywords: Radix Astragali, hyperuricemia, microbiota, metabolism, bile acid

Xiaodong Wang,1 Paride Abliz,1 Shuwen Deng2 1Department of Dermatology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Department of Medical Microbiology, People’s Hospital of Suzhou New District, Suzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Shuwen Deng, Department of Medical Microbiology, People’s Hospital of Suzhou New District, No. 95, Huashan Road, Suzhou, Jiangsu, People’s Republic of China, Email shuwen.deng@gmail.com Paride Abliz, Department of Dermatology, the First Affiliated Hospital of Xinjiang Medical University, No. 393, Xinyi Road, Urumqi, Xinjiang, People’s Republic of China, Email palidae@aliyun.comBackground: Macrolide resistance in Treponema pallidum (T. pallidum) has been increasing in recent years worldwide. However, few data are available on macrolide resistance in T. pallidum from Xinjiang province, located in the western part of China, which is an area with a high incidence of syphilis. In this study, we investigated the molecular characteristics of macrolide resistance in T. pallidum from patients with latent syphilis in Xinjiang, China.Methods: In total, 204 whole blood samples were collected from patients with latent syphilis during 2016 to 2017, in the First Hospital of Xinjiang Medical University. Genomic DNA of blood samples was extracted using a QIAamp DNA Mini Kit and T. pallidum was detected by PCR with the specific polA gene of T. pallidum. The 23S rRNA gene of T. pallidum was amplified among the T. pallidum-positive samples by nested PCR, and macrolide resistance-associated mutation sites A2058G and A2059G in the 23S rRNA gene were identified using restriction enzymes MboII and BsaI.Results: The specific polA gene of T. pallidum (T. pallidum positive) was detected in 27 blood samples (13.2%) from 204 patients with latent syphilis. The 23S rRNA gene was then amplified in all 27 T. pallidum-positive samples, among which 24/27 samples (88.9%) harbored the A2058G mutation in the 23S rRNA gene and 3/27 (11.1%) had the A2059G mutation.Conclusion: Our results indicated that T. pallidum macrolide resistance should not be ignored in Xinjiang, China, and that A2058G was the predominant macrolide resistance mechanism. Blood may be a suitable specimen for the detection of resistant mutations of T. pallidum in patients with latent syphilis who do not show any clinical symptoms.Keywords: macrolide resistance, Treponema pallidum, latent syphilis, 23S rRNA

Zhiqiang Liu,1,&ast; Xiaoli Gao,1,&ast; Lirong Liang,2 Xuan Zhou,1 Xiaozhe Han,3 Ting Yang,4– 7 Kewu Huang,8 Yingxiang Lin,8 Shu Deng,9 Zuomin Wang,1 Chen Wang4– 7,10 1Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Oral Science and Translational Research, Nova Southeastern University College of Dental Medicine, Fort Lauderdale, FL, USA; 4Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 6Institute of Respiratory Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 7Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 8Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China; 9Department of Immunology and Infectious Diseases, The Forsyth Institute, Harvard School of Dental Medicine Affiliate, Cambridge, MA, USA; 10WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zuomin Wang, Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 10 85231492, Email wzuomin@sina.cn Chen Wang, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Chaoyang District, Beijing, 100029, People’s Republic of China, Tel +86 10 65105565, Email wangchen@pumc.edu.cnPurpose: There is insufficient information about the prevalence and risk factors of gastroesophageal reflux disease (GERD) in the Chinese adult population. We aimed to assess the prevalence and identify the risk factors of GERD in China.Methods: We collected data from a nationally representative sample (50,991 subjects) of Chinese adults from a large nation-wide cross-sectional survey. GERD was diagnosed by a standardized Chinese-language GERD questionnaire with a score of ≥ 8. The demographic characteristics, comorbidities and periodontal factors of all participants were collected.Results: Fifty-thousands-one-hundred-eighty-three participants were finally included in this study. The overall prevalence of GERD was 5.6% (95% CI, 5.4– 5.8%) among the general Chinese population aged 20 years or older. Women, smokers, and people with older age, BMI ≥ 25.0 kg/m2, urban residence, lower education level or comorbidities were more prevalent with GERD (p < 0.001). Symptoms of severe periodontitis (OR = 1.40, 95% CI 1.28– 1.52, p < 0.001) and lower frequency of tooth brushing (OR = 2.01, 95% CI 1.76– 2.29, p < 0.001) were significantly associated with risk of GERD.Conclusion: Symptom-based GERD is highly prevalent in the Chinese population. Overweight and smoking are major preventable risk factors for GERD. Periodontal factors are novel potential risk factors for GERD and should be given more attention in GERD prevention.Keywords: gastroesophageal reflux disease, prevalence, risk factor, periodontitis, epidemiology

Chenlu Xiao,1,2,&ast; Dan Qiao,1,&ast; Lijuan Xiong,3,&ast; Wenjie Tian,4 Dongjiang Wang,4 Shuwen Deng,5 Jian Guo4 1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Clinical Microbiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Laboratory Medicine, Second Affiliated Hospital of Traditional Chinese Medicine of Guizhou University, Guizhou, People’s Republic of China; 4Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 5Department of Medical Microbiology, People’s Hospital of Suzhou New District, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Guo; Shuwen Deng, Email guojian1110@126.com; shuwen.deng@gmail.comBackground: Aspergillus spp. infection in immunocompromised patients results in increasing morbidity and mortality. This study investigated clinical and microbiological characteristics of aspergillosis in a Chinese tertiary teaching hospital.Methods: A total of 114 patients with aspergillosis were included over a 5-year period at Ruijin Hospital. In sum, 114 Aspergillus strains were isolated and identified at species level using matrix-assisted laser desorption ionization time-of-flight mass spectrometry, confirmed by ITS gene region and β-tubulin (BenA) gene sequencing. Sensititre YeastOne was used in vitro to test susceptibility to antifungal drugs: amphotericin B, itraconazole, voriconazole, posaconazole, isavuconazole, micafungin, anidulafungin, and caspofungin.Results: The median age of the patients was 61 (19) years, men accounted for 53.5% (n=61) of the sample, about 64% were immunocompromised, and 36% had underlying diseases. Pulmonary diseases accounted for 27.2%. Aspergillus isolates were mainly isolated from sputum (n=42, 36.8%). Antifungal therapy was administered to 106 (93.0%) patients and voriconazole (n=76, 66.7%) was the most frequently used as empirical therapy. Aspergillus fumigatus (n=69, 60.5%) was the most common species. There was a 73.7% concordance between MALDI-TOF MS and molecular identification. All Aspergillus isolates showed good susceptibility to anidulafungin and caspofungin.Conclusion: Immunocompromised patients are an at-risk population for aspergillosis, and voriconazole was used as empirical therapy in Ruijin Hospital, China. A. fumigatus was the predominant Aspergillus species causing aspergillosis, and A. flavus — as non–A. fumigatus species are increasing — the second-leading cause of aspergillosis. Anidulafungin and caspofungin were the most active in vitro against the Aspergillus isolates tested. The MALDI-TOF MS method showed good accuracy for identification of common Aspergillus spp. In vitro antifungal-susceptibility testing is crucially important for decisions on effective therapy with aspergillosis.Keywords: aspergillosis, epidemiology, Aspergillus spp., MALDI-TOF MS, molecular identification, antifungal susceptibility

Qin Hu,1– 4,&ast; Jinglan Chen,1,2,5,&ast; Shusen Sun,1,6 Sheng Deng1,2,5 1Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Hospital Institute Administration, Central South University, Changsha, People’s Republic of China; 4Xiangya Health Development Research Center, Changsha, People’s Republic of China; 5The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, People’s Republic of China; 6Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Western New England University, Springfeld, MA, USA&ast;These authors contributed equally to this workCorrespondence: Sheng Deng, Email dengsxy@sina.comObjective: Carbapenem-resistant Enterobacteriaceae (CRE) has become a significant public health problem in the last decade. We aimed to explore the risk factors of mortality in patients with CRE infections and to focus on the current evidence on antimicrobial regimens for CRE infections, particularly from the perspective of mortality.Methods: A systematic literature review was performed by searching the databases of EMBASE, PubMed, and the Cochrane Library to identify studies that evaluated mortality-related risk factors and antimicrobial regimens for CRE infections published from 2012 to 2022.Results: In total, 33 and 28 studies were included to analyze risk factors and antibiotic treatment, respectively. The risk factors most frequently reported as significantly associated with CRE mortality were antibiotic use (92.9%; 26/28 studies), comorbidities (88.7%; 23/26 studies), and hospital-related factors (82.8%; 24/29 studies). In 10 studies that did not contain ceftazidime/avibactam (CAZ-AVI) therapy, seven demonstrated significantly lower mortality in combination therapy than in monotherapy. However, 5 of 6 studies identified no substantial difference between CAZ-AVI monotherapy and CAZ-AVI combination therapy. Six studies reported substantially lower mortality in CAZ-AVI regimens than in other regimens.Conclusion: Several risk factors, particularly antibiotic use and patients’ comorbidities, are strong risk factors for CRE mortality. The optimal regimen for CRE infections remains controversial. Combination therapy should be considered when carbapenems, colistin, tigecycline, or aminoglycosides are administered. CAZ-AVI appears to be a promising antibiotic for CRE infections. Most importantly, treatment should be individualized according to the source and severity of the disease or other highly related risk factors.Keywords: carbapenem resistant Enterobacteriaceae, CRE, mortality, risk factors, antimicrobial, treatment

Saiyue Deng,1 Quan Wang,2 Jingjing Fan,3 Xiaoyun Yang,3 Junhua Mei,4 Jiajia Lu,5 Guohua Chen,4 Yuan Yang,1 Wenhua Liu,6 Runsen Wang,7 Yujia Han,7 Rong Sheng,7 Wei Wang,1 Li Ba,1 Fengfei Ding1,8 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 3Cardiac Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Department of Neurology, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 5Cardiac Unit, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 6Department of Clinical Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 7Huawei Technologies Co, Shenzhen, People’s Republic of China; 8Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of ChinaCorrespondence: Fengfei Ding, Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China, Tel +86 134 7625 5813, Email fengfei_ding@fudan.edu.cn Li Ba, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Tel +86 136 0764 1809, Email bali2015@126.comPurpose: Heart rate variability (HRV) indices have been used as stress indicators. Rare studies investigated the associations of circadian rhythms of the HRV indices with the stress, mood, and sleep conditions in populations under stress.Methods: In total 257 female participants (203 shift workers and 54 non-shift workers) were included. All the participants completed a structured questionnaire to assess the stress, mood, and sleep conditions and performed 24-hour Holter electrocardiogram monitoring on the day away from shifts. Using epochs of 1-min or 5-min beat-to-beat intervals, the HRV indices (SDNN, RMSSD, LF, HF, LF/HF, and LFnu, SD1, SD2, SD1/SD2) were plotted as a function of time and fitted into cosine periodic curves, respectively. Three mathematical parameters based on the cosine periodic curves were extracted, MESOR (M, overall averages of the cosine curve), amplitude (A, amplitude of the peak of the cosine curve), and acrophase (θ, latency to the peak) to quantify the circadian rhythms of the HRV indices. Multivariable linear regression models were used to reveal the associations of these parameters with the clinical assessments of stress, mood, or sleep conditions, as well as with the 24-h averages of the HRV indices.Results: The parameters M and A of SDNN, RMSSD, LF, and HF, and θ of LF/HF and LFnu significantly differ between shift and non-shift workers. The parameter θ of LF/HF positively correlates with the severity of stress and anxiety. The parameter A of LF/HF and LFnu also positively correlates with daytime sleepiness and sleep fragmentation. In addition, the parameters M and A instead of θ of SDNN, RMSSD, LF, LF/HF, and LFnu significantly correlate with the 24-h averages of HRV indices.Conclusion: The circadian rhythms of the HRV indices over 24 hours can, to some extent, predict the severity of stress, emotion and sleep conditions in female populations under stress.Keywords: circadian rhythms, HRV indices, mental health, stress, sleepiness, fatigue, sleep fragmentation

Wenjun Wu,1 Qunyan Zhou,2 Peng Yuan,3 Dan Qiao,2 Shukun Deng,3 Haiyan Cheng,1 Ye Ren1 1Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 2Department of Clinical Nutrition, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 3Department of Rehabilitation Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of ChinaCorrespondence: Wenjun Wu, Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, People’s Republic of China, 214023, Tel +86 510 85351181, Fax +86 510 85737592, Email cxlwwj@163.com Qunyan Zhou, Department of Clinical Nutrition, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, No. 299 Qingyang Road, Wuxi, People’s Republic of China, 214023, Tel +86 510 85350757, Fax +86 510 85737592, Email qunyan224@163.comPurpose: The aim of the present study was to investigate the effect and safety of a multiphase modified ketogenic diet (MMKD) compared to beinaglutide treatment or lifestyle modification (LM) alone on weight loss in obese patients in China.Patients and Methods: The present study was conducted in adults with obesity who did not have diabetes with two phases as follows: a 4-week run-in phase to guide diet and exercise, followed by a 12-week intervention phase aiming to lose weight. All participants performed aerobic and resistance exercise, and they were free to select any one of three weight-loss strategies as follows: LM group, 12 weeks of hypocaloric balanced diet (HBD); MMKD group, two cycles of a multiphase diet with each cycle comprised of 2 weeks of ketogenic diet (KD), 2 weeks of transition diet and 2 weeks of HBD; and beinaglutide group, 12 weeks of HBD plus daily injection of beinaglutide (0.4 mg per day). Body weight, body composition and metabolic variables were measured before and after the 12 weeks of treatment.Results: All intervention strategies had significant weight loss, and the MMKD led to greater weight loss than LM (difference, − 3.7 kg; 95% confidence interval [CI], − 6.1 to − 1.4; P = 0.001) but not beinaglutide (difference, − 1.5 kg; 95% CI, − 4.3 to 1.3; P = 0.587). Waist circumference (WC), fat mass, body fat percentage (BFP) and visceral fat area (VFA) were also significantly decreased, and the MMKD had a greater effect on these parameters than LM or beinaglutide. In addition, significant reductions in blood pressure and homoeostatic model assessment of insulin resistance (HOMA-IR) were observed in all three groups, but the MMKD resulted in the most significant improvement in insulin resistance. Almost no adverse events, except for two cases of dizziness, were observed in the MMKD group, which was significantly fewer events than the other two groups.Conclusion: These findings demonstrated that the MMKD is an effective and safe treatment for weight loss, thus providing an additional option for obese Chinese patients.Keywords: dietary therapy, obesity, beinaglutide, lifestyle modification

Xudong Hu,1,&ast; Bing Luo,2,&ast; Lei Qiu,2 Shaosen Chen,3 Qing Wu,2 Qingbiao Chen,2 Xingqing Liu,1 Chen Ling,1 Shuping Deng,4 Manjuan Yuan,3 Peicun Hu3 1Department of Anesthesiology, The Second People’s Hospital of Foshan, Foshan, 528000, People’s Republic of China; 2Department of Surgery, The Second People’s Hospital of Foshan, Foshan, 528000, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Foshan, Foshan, 528000, People’s Republic of China; 4Department of Internal Medicine, Huanshi Hospital, People’s Hospital of Chancheng District, Foshan, 528000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peicun Hu, Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Foshan, No. 78 of Weiguo Road, Foshan, Guangdong, 528000, People’s Republic of China, Tel +86 13902845621, Fax +86 757-88032008, Email hpcun@163.comAbstract: Cancer is the second leading cause of death following ischemic heart disease in the world and the primary clinical, social and economic burden. Surgical resection is the main measure for the treatment of the vast majority of solid tumors. However, the recurrence and metastasis of tumors occur at different periods after surgery in many cases undergoing radical tumor surgery, which is the main cause of death of tumor patients. Moreover, tumor patients are prone to suffer from mental depression, which may increase the morbidity and mortality of tumors. Tumors have a series of clinical biological signs with the following five main features: postoperative pain and cancerous pain; suppression of antitumor immunity; angiogenesis in tumors; proliferation, growth and metastasis of tumors; and mental depression. Surgery is the first treatment in the majority of cancer patients with solid tumors. Opioids are required for anesthesia and postoperative analgesia. For cancerous pain control, patients undergo surgery, and their quality of life of is improved. However, traditional opioids, such as morphine, may inhibit antitumor immunity, induce vascular growth of tumors and promote the proliferation, invasion and migration of cancer cells, and traditional opioids can induce a risk of somatic dependence. However, studies have found that not all opioids share the effects of immunosuppression, tumor proliferation promotion and angiogenesis induction. Dezocine, a novel opioid with specific pharmacological mechanisms, has been demonstrated to regulate the five clinical and biological features of tumors. We reviewed the preclinical and clinical studies of dezocine on postoperative pain and cancer pain in tumor patients as well as the immune system, tumor angiogenesis, tumor proliferation, tumor growth, tumor metastasis and mental depression. We proposed that dezocine may be the best choice of opioids for anesthesia and analgesia in cancer patients.Keywords: dezocine, cancer, anesthesia, postoperative analgesia, cancerous pain, immune, angiogenesis, proliferation, growth and metastasis, mental depression

Baohong Yuan, Danyan Liu, Zunyan Zhu, Yonggang Hao, Kaihua He, Shiyun Deng Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Danyan Liu, Tel/Fax +86 23 8901 1069, Email liudanyan0418@163.comPurpose: Ultrasound-guided thoracic paravertebral block (TPVB) has become increasingly popular for postoperative analgesia after thoracic surgery. We designed this prospective, randomized, double-blind, placebo-controlled trial to investigate the effect of TPVB on blood coagulation in patients after thoracoscopic lobectomy.Patients and Methods: Sixty patients scheduled for thoracoscopic lobectomy were randomly allocated to two groups. Patients underwent ultrasound-guided TPVB with 0.33% ropivacaine (T group) or 0.9% saline (C group) at the end of the surgery under general anesthesia. Patient-controlled intravenous analgesia (PCIA) was administered for both group after the surgery. The primary outcome was the thromboelastogram (TEG) parameters before anesthesia (T0), at the end of operation (T1) and in 1 day (T2) and 2 days (T3) after the operation, the second outcomes were the analgesic effect and the amount of intraoperative opioid consumption, operation time, infusion volume, blood loss and urine volume.Results: The visual analog scale (VAS) scores in group T were lower than group C (P < 0.05). In group T, compared with T0, the R value at T1 and T2 is significantly reduced, and the K value at T1 were significantly shortened, the α-angle and MA value at T1 were significantly increased (P < 0.05). In group C, compared with T0, the R value and K value were significantly shortened, the α-angle and MA value were significantly increased at all postoperative time points (P < 0.05). Compared with group C at the same time point, the R and K values of group T were significantly longer, and the α-angle and MA values were significantly reduced at T2 and T3 points, with statistically significant differences (P< 0.05).Conclusion: TPVB is beneficial to improve postoperative hypercoagulability and promote postoperative rehabilitation of patients after thoracoscopic lobectomy.Keywords: paravertebral nerve block, thoracoscopic lobectomy, thrombelastogram, blood coagulation

Simin Deng,1,&ast; Lingyu Sun,2,&ast; Weijie Chen,1,&ast; Xiaorong Liu,2 Shangjie Chen3 1The Second School of Clinical Medicine, Southern Medical University, Dongguan Tung Wah Hospital, Guangdong, People’s Republic of China; 2Department of Rehabilitation Medicine, Dongguan Tung Wah Hospital, Guangdong, People’s Republic of China; 3Department of Rehabilitation Medicine, Affiliated Baoan Hospital of Shenzhen, Southern Medical University, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shangjie ChenDepartment of Rehabilitation Medicine, Affiliated Baoan Hospital of Shenzhen, Southern Medical University, No. 118 Longjing Second Road, Baoan District, Shenzhen, Guangdong, People’s Republic of ChinaTel +86-755-27788311Fax +86-755-29791989Email csjme@163.comPurpose: Subjective cognitive decline (SCD) is the earliest symptom stage of Alzheimer’s disease (AD), and the APOE&epsiv;4 allele is the strongest genetic risk factor for sporadic AD. Based on graph theory, the resting state functional connectivity (rsFC) in SCD patients with APOE&epsiv;4 was studied to explore the effect of APOE&epsiv;4 on the rsFC network properties of SCD patients.Patients and Methods: This cross-sectional study included MRI image data from 19 SCD patients with APOE&epsiv;4 (SCD+), 29 SCD patients without APOE&epsiv;4 (SCD−), and 30 normal control (NC−) individuals without APOE&epsiv;4. We generated a binary matrix based on anatomical automatic labeling (AAL) 90 atlas to construct the functional network. We then calculated the whole brain network characteristics and intracerebral node characteristics by graph theory.Results: For the whole brain network characteristics, all three groups showed small-worldness. The SCD+ group had increased compensatory information transfer speed and enhanced integration capability. This group also had high heterogeneity for intracerebral node characteristics, mainly in the default mode network, left superior occipital gyrus, and bilateral putamen.Conclusion: APOE&epsiv;4 effects the functional brain network in patients with SCD and may be a potential indicator for the identification of SCD.Keywords: SCD, APOE&epsiv;4 allele, graph theory, whole brain network characteristics, intracerebral node characteristics

Heming Lu,1,&ast; Yuying Wu,2,&ast; Xu Liu,1 Huixian Huang,1 Hailan Jiang,1 Chaohua Zhu,1 Yuping Man,3 Pei Liu,4 Xianglong Li,1 Zhaohong Chen,1 Xianfeng Long,1 Qiang Pang,1 Shan Deng,1 Junzhao Gu1 1Department of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 2Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 3Department of Radiology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, People’s Republic of China; 4Department of Oncology, Youjiang Medical University for Nationalities, Baise, 533000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heming LuDepartment of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, No. 6 Taoyuan Road, Nanning, 530021, People’s Republic of ChinaTel +86-771-218-6806Email luhming3632@163.comPurpose: To evaluate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting early treatment response.Materials and Methods: Patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT) were enrolled. Pelvic DCE-MRI scans were performed before RT (pre-RT), in the middle of RT (mid-RT), and at the end of RT (post-RT), separately. Parameters (ie, Ktrans, Kep, and Ve) were measured. Pre-, mid-, and post-RT Ktrans were denoted as Ktrans-preTx, Ktrans-midTx, and Ktrans-postTx, respectively. And the same denoting rule also went for Kep and Ve. Difference for the same parameter such as Ktrans measured between two consecutive time points was calculated as second Ktrans value minus first Ktrans value. The differences in Ktrans between pre-RT and post-RT, between pre-RT and mid-RT, and between mid-RT and post-RT were denoted as ΔKtrans-post-preTx, ΔKtrans-mid-preTx, and ΔKtrans-post-midTx, respectively, and the same denoting rule was also applied to Kep and Ve.Results: A total of 57 patients were enrolled. After the treatment, 31 patients had complete response (CR group). The remaining 26 patients had partial response (NCR group). Significant differences were found in Ktrans-postTx, Kep-postTx, Ve-midTx, ΔKtrans-post-preTx, ΔKtrans-post-midTx, ΔKep-post-preTx, ΔKep-mid-preTx and ΔKep-post-midTx between the two groups. Receiver operating characteristic (ROC) analysis for their performances in predicting treatment response showed an area under curve (AUC) of 0.656– 0.849, sensitivity of 61.3– 93.5%, specificity of 46.1– 73.1%, and maximal Youden Index of 36.5– 66.6. Among those parameters, Kep-postTx was the best, and its AUC, sensitivity, specificity, maximal Youden Index, and cutoff value were 0.849, 87.1%, 73.1%, 60.2, and 0.341, respectively. These combined parameters showed an AUC of 0.952, with sensitivity of 87.1%, specificity of 96.1%, and maximal Youden Index of 83.2.Conclusion: DCE-MRI parameters can predict early treatment outcome. Among those parameters, Kep-postTx is the best predictor. The combination of multi-parameters can increase the predictive potency.Keywords: cervical cancer, locally advanced disease, dynamic contrast-enhanced magnetic resonance imaging, concurrent chemoradiotherapy, prognosis prediction

Jiaying Tan,1,* Mi Tian,1,* Feng Zhao,1 Shuixiang Deng,1 Peng Jin,1 Yao Wang,1 Huimei Wen,1 Xiaohua Qin,2,3 Ye Gong1,4 1Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 2Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 3Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, 200040, People’s Republic of China; 4Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohua QinInstitute of Antibiotics, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of ChinaEmail 0456240@fudan.edu.cnYe GongDepartment of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of ChinaEmail gong_ye@fudan.edu.cnBackground: Male genitourinary abscess is one of the serious complications of urinary tract infections (UTIs). There were few researches on the clinical and pathogenic characteristics of male genitourinary abscess.Patients and Methods: A retrospective observational study was conducted between January 2004 and April 2019. Male patients with genitourinary abscess originated from urinary tract, including sites of scrotum, testis, epididymis, spermatic cord, and prostate, were enrolled. Clinical and microbial records were collected and analyzed, and antimicrobial susceptibility testings were performed according to CLSI standard. Whole-genome sequencing was applied to detect the β-lactamase genes and virulence genes, as well as to determine the multilocus-sequence typing (MLST) of the collected Klebsiella pneumoniae (K. pneumoniae) isolates.Results: A total of 22 male patients were included. The main clinical symptoms were fever (86.4%), scrotal swelling (68.2%), local skin warmth (59.1%) and ulceration (45.5%). Urinary irritation was often presented in prostate involved abscess. Ultrasound features had a 94.7% positive rate. Surgical treatment, including abscess drainage, was helpful to the prognosis. No matter where the specimens obtained from, including blood, urine or pus, multidrug-resistant K. pneumoniae was the dominant (11 cases, 50.0%) microorganism in positive cultures. Nine of eleven K. pneumoniae isolates had been preserved and recovered. As for MLST typing, all the nine available isolates of K. pneumoniae belonged to the ST11 type and characterized with blaKPC-2 carbapenemase gene. Virulence genes rmpA2, ybtS, kfuC, wzi, aerobactin genes (iucABCD and iutA) and type 3 fimbriae genes (mrkAD) were identified in all the K. pneumoniae isolates.Conclusion: It seemed that more patients under 35 years old were vulnerable to genitourinary abscess. There was an increasing trend that multidrug-resistant K. pneumoniae isolates with multiple virulence genes were involved in male genitourinary abscess. Prompt and proper antibiotic use, combined with adequate drainage of the abscess, was important to prognosis.Keywords: male genitourinary abscess, carbapenem-resistant Klebsiella pneumoniae, virulence genes, MLST type

Siyao Deng,1 Wenjing Ye,1 Shichuan Zhang,2,3 Guiquan Zhu,4 Peng Zhang,2 Yanqiong Song,2 Fanglei Duan,3 Jinyi Lang,2,3 Shun Lu2,3 1School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Radiation Oncology Key Laboratory of Sichuan Province, Chengdu, People’s Republic of China; 4State Key Laboratory of Oral Diseases, National Clinical Research Centre for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Shun LuDepartment of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Renmin South Road 55#, Chengdu, 610041, People’s Republic of ChinaTel +86 28 85420897Fax +86 28 85420110Email lushun1982@live.cnPurpose: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital anomalies, progressive bone marrow failure and high susceptibility to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Management of FA patients with head and neck cancer is a challenge due to increased risk of surgery, poor tolerance of chemotherapy, and severe myelotoxicity of radiotherapy.Patients and Methods: We present a case of a 33-year-old man with carcinoma of oral tongue (T1N2M0), who experienced prolonged and profound bone marrow failure as a consequence of concurrent cisplatin/radiation. The young patient who developed HNSCC without risk factors, the myelotoxicity after exposure to platinum-based agent cisplatin and the further evaluation of phenotypic characteristics raised suspicion of FA. Whole exome sequencing performed for the patient and parents ultimately established the diagnosis of FA.Results: Genetic testing in 23 FANC genes revealed two novel heterozygous mutations, c.367C>T and c.3971_3972delCGinsTT in FANCA gene of the patient, which were inherited from his father and mother, respectively. Radiotherapy with reduced dose has successfully alleviated the symptoms of tumor invasion and progression, and the radiation-related side effects were acceptable. Unfortunately, the patient eventually died of locoregional disease progression.Conclusion: This case highlights the importance of considering the diagnosis of FA in young patients who develop HNSCC in the absence of risk factors, thus permitting more effective oncological treatment strategies and improved outcomes. In conclusion, any decision on different modalities of management in such patients should be based on a balance between locoregional control and therapeutic toxicity.Keywords: fanconi anemia, radiotherapy, cisplatin, head and neck squamous cell carcinoma, toxicity

Jing Zhang,1 Xiuchao He,1 Wenying Yu,2 Fuming Ying,3 Jun Cai,4 Shengde Deng1 1Department of Imaging Center, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, 315000, People’s Republic of China; 2Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang Province, 315000, People’s Republic of China; 3Department of Hepatobiliary Surgery, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang Province, 315000, People’s Republic of China; 4Department of PET-CT Diagnosis Center, Mingzhou Hospital of Zhejiang University, Ningbo, Zhejiang Province, 315000, People’s Republic of ChinaCorrespondence: Shengde DengDepartment of Imaging Center, The Affiliated Hospital of Medical School of Ningbo University, No. 247 of Renmin Street, Jiangbei District, Ningbo, Zhejiang Province, 315000, People’s Republic of ChinaTel/Fax +86 574 55873876Email demgshemgde@163.comIntroduction: Primary hepatic extraskeletal osteosarcoma (ESOS) is a rare tumor with no specific clinical manifestations, and little is known about it. Here, we describe an elderly patient with primary hepatic osteosarcoma confirmed by pathology results to raise awareness.Case Report: We report an unusual case of a 62-year-old man who presented with right upper quadrant pain. The inflammatory indicators were elevated, and alkaline phosphatase (AKP), carbohydrate antigen (CA-199 and CA-125) were slightly increased. Computed tomography images and magnetic resonance images discovered a 7.8 × 7.4 × 6.6 cm mass with irregular radiated and cotton-like tumor bone between the liver and right kidney space. Pathology revealed the mass to be primary exophytic ESOS of the liver. The patient underwent a surgical operation and standard chemotherapy and is still alive with no recurrence and metastasis to date.Conclusion: Owing to the rarity of the tumor and the lack of clinical characteristics and specific laboratory indexes, it is difficult to make a correct diagnosis. Medical imaging features mainly behave soft tissue entity with tumor bone composition. Surgical resection combined with adjuvant chemotherapy is the main treatment for ESOS.Keywords: extraskeletal, osteosarcoma, hepatic, tumor bone, primary

Ji-sheng Wang,1,2,* Xue-feng Gong,3,4,* Jun-long Feng,1,2,* Hai-song Li,2 Xiao Li,5 Sheng Deng,1,2 Pei-zhong Ren,3,4 Jia-mei Wang,3,4 Ming-sheng Lv,3,4 Rui-feng Jin,3,4 Qiu-yi Chen,3,4 Bin Wang,2 Hong-sheng Cui4 1First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Andrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of China; 3The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Pneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Department of Andrology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450046, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin WangAndrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, People’s Republic of ChinaEmail dayiwangbln@sina.comHong-sheng CuiPneumology Department, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaEmail Hshcui@sina.comBackground: Jiawei Shengjiang Powder (JWSJP) is a classical Chinese medicinal formula, which has been widely applied in the treatment of asthma and complications for many years due to its curative effect.Aim: To verify the effect of JWSJP in improving abnormal sperm motility caused by asthma and to explore its potential mechanism.Materials and Methods: The active compounds of JWSJP were obtained from high performance liquid chromatography tandem mass spectrometry and the Traditional Chinese Medicine System Pharmacology. The key active components and targets of JWSJP were predicted based on network pharmacological analysis and bioinformatics research. Rats were randomly divided into normal, model and treatment groups. The rat model of allergic asthma was induced by intraperitoneal injection of ovalbumin solution. The experiment judged improvement of semen quality by evaluating sperm motility, and detected the expression of related proteins in testicular tissue of Sprague-Dawley rats by RT-qPCR and Western blot methods. Hematoxylin and eosin (HE) staining was used to observe the changes in testicular tissue structure in rats.Results: Through the analysis of network pharmacology and bioinformatics, it was found that beta-sitosterol, quercetin, gallic acid, pelargonidin and kaempferol were the key active components of Jiawei Shengjiang Powder. Tumor necrosis factor (TNF), interleukin-6 (IL-6) and insulin (INS) genes are crucial targets of JWSJP in the treatment of spermatogenic dysfunction caused by acute asthma. After 8 weeks of intervention, compared with the model group, the treatment group had significantly improved sperm motility (P < 0.05). There were significant differences in TNF, IL6, and INS proteins in the treatment group, and the HE staining of testicular tissue structure in the treatment group was significantly improved.Conclusion: JWSJP can improve the abnormal sperm motility induced by asthma, and its mechanism may be related to the expression of related proteins and mRNA of TNF, IL6, and INS.Keywords: Jiawei Shengjiang Powder, asthmatic attack, asthenospermia, network pharmacology

Shengming Deng,1– 4,* Zhiyao Fan,1– 4,* Huanyu Xia,1– 4,* Yitao Gong,1– 4 Yunzhen Qian,1– 4 Qiuyi Huang,1– 4 He Cheng,1– 4 Kaizhou Jin,1– 4 Zhiwen Xiao,1– 4 Guopei Luo,1– 4 Xianjun Yu,1– 4 Chen Liu1– 4 1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Pancreatic Cancer Institute, Shanghai, People’s Republic of China; 4Pancreatic Cancer Institute, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen Liu; Xianjun YuShanghai Pancreatic Cancer Institute, 270 Dong an Road, Shanghai 200032, People’s Republic of ChinaTel/Fax +86-21-6403-1446Email liuchen@fudanpci.org; yuxianjun@fudanpci.orgBackground: The fibrinogen/albumin ratio (FAR) has been widely reported to be a possible biomarker for predicting prognosis in several types of tumors, but the prognostic value of the FAR in pancreatic neuroendocrine neoplasms (Pan-NENs) has not been systematically studied.Patients and Methods: In total, 324 patients with Pan-NENs were recruited. The patients were divided into 2 subgroups according to the FAR cutoff value, and clinicopathological characteristics of the 2 subgroups were compared. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The prognostic value of the FAR was analyzed in univariate and multivariate analyses.Results: The optimal cutoff value for the FAR was calculated to be 0.08 for OS. The patients with a FAR ≥ 0.08 had higher proportions of nonfunctioning tumors, Pan-NECs, grade 3 tumors, and stage IV tumors than those with a FAR < 0.08. In the univariate analysis, a FAR ≥ 0.08 was associated with poor OS (hazard ratio (HR) = 2.37, P < 0.001) and PFS (HR = 2.37, P < 0.001). In the multivariate analysis, a FAR ≥ 0.08 was an independent risk factor for poor OS (HR = 4.70, P < 0.001) and PFS (HR = 1.80, P = 0.006).Conclusion: The pretreatment FAR, which includes fibrinogen and albumin, was a feasible and predictive biomarker for prognosis in patients with Pan-NENs. An elevated FAR, based on a cutoff value of 0.08, was an independent risk factor for poor OS and PFS.Keywords: pancreatic neuroendocrine neoplasms, survival, fibrinogen/albumin ratio

The study on the surface morphology and crystal orientation of the Zn-0.5Sn coating could offer some guidance to improve the surface performance of the hot-dip galvanizing coating. In this paper, a scanning electron microscope (SEM) and an energy dispersive spectrometer (EDS) were used to analyze the typical morphology and the element distribution of spangles. The surface texture of the coating was analyzed by X-ray diffraction (XRD). Electron backscatter diffraction (EBSD) was used to analyze the crystal orientation of spangles. The results show that Sn segregates among the spangle dendrites while a metastable divorced eutectic structure can be maintained in the tin-rich phase, where the composition tends to be very similar. The crystal orientation of spangles affects their morphology, leading to the formation of feathery, ridged, and orthogonal dendrite arm spangles. When the angle among the orientation of the spangle crystal and the normal of the steel base surface changes from 0° to 90°, feathery spangles change to orthogonal dendrite arms spangles. The misorientation within a spangle is small while that among spangles is quite large. The orientation changes in the direction of the dendrite arm are relatively smooth and low, while the orientation changes which are perpendicular to the dendrite arm have a saltatory and irregular fluctuation.

Defeng Qing,1,* Yuying Wu,2,* Xu Liu,1,* Hailan Jiang,1,* Chaohua Zhu,1,* Pei Liu,3 Junming Dang,4 Xianglong Li,1 Zhaohong Chen,1 Xianfeng Long,1 Qiang Pang,1 Luxing Peng,1 Shan Deng,1 Junzhao Gu,1 Renfeng Zhao,2 Changyi Chen,2 Heming Lu1 1Department of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China; 2Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China; 3Department of Radiation Oncology, Youjiang Medical University for Nationalities, Baise 533000, People’s Republic of China; 4Department of Oncology, Guangxi University of Chinese Medicine, Nanning 530001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heming LuDepartment of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning City 530021, People’s Republic of ChinaTel +86-771-218-6504Email luhming3632@163.comPurpose: We aimed to evaluate the long-term survival outcomes of concurrent chemoradiotherapy (CCRT) combined with nimotuzumab followed by surgery in patients with locally advanced cervical cancer (LACC).Patients and Methods: Patients received whole pelvic intensity-modulated radiation therapy (IMRT) and concomitantly with weekly cisplatin (40 mg/m2) or nedaplatin (30 mg/m2) and weekly nimotuzumab (200 mg). After assessment of the treatment response, patients then underwent radical surgery.Results: Between June 2013 and July 2016, 33 patients with FIGO IB2–IIIB cervical cancer were recruited. Clinical complete response and partial response were observed in 8 (24.3%) and 23 patients (69.7%), respectively. Twenty-seven patients (81.8%) were successfully treated with radical hysterectomy and pelvic lymphadenectomy: 9 (33.3%) showed pathological complete response; 10 (37.1%) showed partial response and 8 (29.6%) presented with persistent macroscopic/microscopic residual carcinoma. For the intention-to-treat population, the median follow-up time was 53.7 months. Locoregional recurrence and distant metastases were observed in three and seven patients, respectively. The 5-year overall survival, progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival were 81.5%, 72.7%, 90.9%, and 78.3%, respectively. Both acute and late toxicities were manageable and mainly limited to grade 1 or 2.Conclusion: Concurrent chemoradiotherapy combined with nimotuzumab followed by surgery for patients with LACC is safe and results in excellent long-term treatment outcomes. Further randomized controlled studies are warranted to confirm the findings.Keywords: locally advanced cervical cancer, neoadjuvant chemotherapy, intensity-modulated radiotherapy, anti-EGFR monoclonal antibody, radical surgery

Xinrui Qiao, Jie Yang, Yuli Shang, Shu Deng, Shiyu Yao, Zhe Wang, Yi Guo, Cheng Peng Department of Stomatology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Cheng Peng Department of StomotologyThe Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin 300211, People’s Republic of ChinaTel +86 139 2007 9346Email peng_cheng2013@163.comBackground: Next generation of coating materials on the surface of implants is designed with a paradigm shift from an inert material to an osteoimmunomodulatory material. Regulating immune response to biomedical implants through influencing the polarization of macrophage has been proven to be an effective strategy.Methods: Through anodization and hydrothermal treatment, magnesium ion incorporated TiO2 nanotube array (MgN) coating was fabricated on the surface of titanium and it is hypothesized that it has osteoimmunomodulatory properties. To verify this assumption, systematic studies were carried out by in vitro and in vivo experiments.Results: Mg ion release behavior results showed that MgN coating was successfully fabricated on the surface of titanium using anodization and hydrothermal technology. Scanning electron microscopy (SEM) images showed the morphology of the MgN coating on the titanium. The expression of inflammation-related genes (IL-6, IL-1β, TNF-α) was downregulated in MgN group compared with TiO2 nanotube (NT) and blank Ti groups, but anti-inflammatory genes (IL-10 and IL-1ra) were remarkably upregulated in the MgN group. The in vitro and in vivo results demonstrated that MgN coating influenced macrophage polarization toward the M2 phenotype compared with NT and blank-Ti groups, which enhanced osteogenic differentiation of rat bone mesenchymal stem cells rBMSCs in conditioned media (CM) generated by macrophages.Conclusion: MgN coating on the titanium endowed the surface with immune-regulatory features and exerted an advantageous effect on osteogenesis, thereby providing excellent strategies for the surface modification of biomedical implants.Keywords: TiO2 nanotube, magnesium ions, osteoimmunomodulation, macrophage

Ganhua You, 1, 2 Xiangshu Long, 3, 4 Fang Song, 3, 4 Jing Huang, 3, 4 Maobo Tian, 3, 4 Yan Xiao, 3, 4 Shiyan Deng, 3, 4 Qiang Wu 3, 4 1Guizhou University School of Medicine, Guiyang 550025, People’s Republic of China; 2Guizhou Institute for Food and Drug Control, Guiyang 550004, People’s Republic of China; 3Department of Cardiology, Guizhou Provincial People’s Hospital, Guiyang 550002, People’s Republic of China; 4Department of Cardiology, People’s Hospital of Guizhou University, Guiyang 550002, People’s Republic of ChinaCorrespondence: Qiang WuDepartment of Cardiology, Guizhou Provincial People’s Hospital, 83 Zhongshan East Road, Guiyang, Guizhou, People’s Republic of ChinaTel +86-0851-85937194Fax +86-0851-85924943Email wqgz0851@126.comBackground: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS.Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS.Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS.Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.Keywords: metformin, taurine up-regulated gene 1, AMPK/mTOR, autophagy, atherosclerosis

Xingbing Huang, 1, 2,* Wenhua Ding, 2,* Fengchun Wu, 2 Sumiao Zhou, 2 Shuhua Deng, 2 Yuping Ning 1– 3 1First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, People’s Republic of China; 3Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuping Ning 36 Mingxin Road, Liwan District, Guangzhou, People’s Republic of ChinaTel +86 20 8189 1425Fax +86 20 8189 1391Email ningjeny@126.comObjective: Preclinical studies have reported that abnormal kynurenic acid (KYNA) may play a role in cognitive deficits. Schizophrenia (SCZ) is characterized by a wide range of cognitive deficits that may evolve from abnormal KYNA. This study aimed to explore the relationship between KYNA and cognitive impairment in SCZ, which has not yet been reported.Methods: We recruited 30 SCZ patients and 34 healthy controls, measured clinical symptoms by using the Positive and Negative Syndrome Scale and performed cognitive tests using the MATRICS Consensus Cognitive Battery (MCCB). Plasma levels of tryptophan, kynurenine, and KYNA were determined by high-performance liquid chromatography–tandem mass spectrometry.Results: We found that plasma KYNA levels were significantly higher in patients than in healthy controls (p=0.009). The cognitive performance of patients in the total MCCB scores and the scores of all subscales were significantly lower than those in healthy controls (all P < 0.01). Correlation analysis showed that KYNA levels were negatively correlated with attention/vigilance (r=– 0.457, p=0.019) and social cognition (r=– 0.481, p=0.013) only in SCZ patients.Conclusion: Our results indicate that elevated plasma KYNA levels may serve as a biomarker of cognitive impairment in SCZ patients.Keywords: schizophrenia, kynurenic acid, cognitive impairment, symptom

Yike Huang,* Suya Deng,* Xinxin Luo, Yi Liu, Wanjun Xu, Jingmiao Pan, Min Wang, Zhining Xia School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, Chongqing 401331, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhining XiaSchool of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, Huxi Campus, No.55 Daxuecheng South Road, Shapingba, Chongqing 401331, People’s Republic of ChinaTel +86-13883077188Email znxia@cqu.edu.cnBackground: Most of the oral drugs have the properties of weak intestinal absorption and low bioavailability, which leads to little treatment to diseases. By nanotechnology, these drugs can be efficiently delivered to pass biological barriers and promote the cell uptake ability for the enhancement of the oral bioavailability.Methods: The present work chose the prepared curcumin-loaded galactosylated albumin nanoparticles (Gal-BSA NPs) as the nano-drug samples to study the intestinal capacity and the oral bioavailability.Results: The cell uptake assay showed that the Gal-BSA NPs could promote the internalization of more curcumin into the Caco-2 cells. Moreover, the cell uptake mechanism of Gal-BSA-Cur NPs depended on the clathrin-mediated endocytosis transport. The intestinal permeation assay using one Ussing chamber exhibited that the absorptive amounts of curcumin in Gal-BSA-Cur NPs group were 1.5-fold of pure curcumin group. Meanwhile, the permeation mechanism of Gal-BSA-Cur NPs across the intestine mainly depended on the passive transport. The pharmacokinetics study in vivo suggested that the oral bioavailability of Gal-BSA-Cur NPs was improved by 1.4-fold compared with pure curcumin.Conclusion: All results demonstrated that Gal-BSA NPs could improve the intestinal absorption capacity and oral bioavailability of curcumin through the double absorption mechanisms of the clathrin-mediated endocytosis and the passive transport.Keywords: intestinal absorption, galactosylated nanoparticles, oral bioavailability, absorption mechanism, curcumin

Jin Li1,*, Weiwei Hu2,*, Min Li1, Shaoli Deng1, Qing Huang1, Weiping Lu1 1Department of Clinical Laboratory Medicine, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiping LuDepartment of Clinical Laboratory Medicine, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, People’s Republic of ChinaTel +86 236 875 7607Fax +86 236 871 6530Email luweiping19710416@163.comBackground: Metallo-β-lactamase-producing Pseudomonas aeruginosa (MBL-PA) are important causative agents of nosocomial infections and are associated with significant mortality rates, especially in intensive care units. The timely detection and typing of these strains is essential for surveillance, outbreak prevention and antibiotic therapy optimization. In this study, fifteen VIM-type and fifteen SPM-type MBL-PA strains were selected as strains to establish MALDI-TOF MS SuperSpectra.Methods: This study was undertaken to evaluate the utility of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with the VITEK MS plus system in the detection of VIM- and SPM-type MBL-PA isolates. For each species, we increased the reference spectra, and then, a SuperSpectrum was created based on the selection of 39 specific masses. In a second step, we validated the SuperSpectra with the remaining 50 isolates (25 isolates of VIM-type and 25 isolates of SPM-type).Results: Fifty MBL-PA strains were used as the validation strains, including twenty-five VIM-type and twenty-five SPM-type MBL-PA strains. Complete antimicrobial susceptibility testing and genotypic characterizations were performed for all isolates, which were subsequently identified using the newly created SuperSpectra databases following a previously reported method. The results showed that there was 92% agreement between the MBL profile generated by MALDI-TOF MS and that obtained using gene sequencing analysis methods.Conclusion: MALDI-TOF MS is a promising, rapid and economical method for detecting VIM- or SPM-type MBL-PA that could be successfully introduced into the routine diagnostic workflow of clinical microbiology laboratories.Keywords: VIM, SPM, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, SuperSpectra, VITEK MS plus system

Liwan Fu,1 Ya-nan Li,1 Dongmei Luo,1,2 Shufang Deng,1 Yue-Qing Hu1,31State Key Laboratory of Genetic Engineering, Institute of Biostatistics, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China; 2Department of Information and Computing Science, School of Mathematics and Physics, Anhui University of Technology, Maanshan, Anhui, People’s Republic of China; 3Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, People’s Republic of ChinaObjective: Numerous studies have explored the role of methylenetetrahydrofolate reductase gene (MTHFR) C677T polymorphism and homocysteine (Hcy) concentration in obesity, but the results are inconsistent. Hence, we performed a meta-analysis implementing Mendelian randomization approach to test the assumption that the increased Hcy concentration is plausibly related to the elevated risk of obesity.Methods: Eligible studies were selected based on several inclusion and exclusion criteria. Correlations between MTHFR C677T and obesity risk, MTHFR C677T and Hcy concentration in obesity, Hcy concentration, and obesity were estimated by ORs, effect size and standard mean difference with their corresponding 95% CIs, respectively. Furthermore, Mendelian randomization analysis was performed to estimate the relationship between Hcy level and obesity.Results: Consequently, this meta-analysis implemented with Mendelian randomization approach was conducted among 8,622 cases and 29,695 controls. The results indicated that MTHFR C677T is associated with an increased risk of obesity (for T vs C: OR=1.06, 95% CI=1.02–1.10; for TT vs CC: OR=1.13, 95% CI=1.03–1.24). Moreover, in obese subjects, the pooled Hcy concentration in individuals of TT genotype was 2.91 mmol/L (95% CI: 0.27–5.55) higher than that in individuals of CC genotype. Furthermore, the pooled Hcy concentration in subjects with obesity was 0.74 mmol/L (95% CI: 0.36–1.12) higher than that in controls. The evaluated plausible OR associated with obesity was 1.23 for 5 μmol/L Hcy level increase.Conclusions: Through this meta-analysis, we emphasize a strong relationship between Hcy level and obesity by virtue of MTHFR C677T polymorphism.Keywords: homocysteine, MTHFR, obesity, polymorphism

Yeye Zhou,* Zixuan Zhao,* Jihui Li, Bin Zhang, Shibiao Sang, Yiwei Wu,* Shengming DengDepartment of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workPurpose: In the present study, we aimed to investigate the role of baseline, interim and end-of treatment positron emission tomography/computed tomography (PET/CT) in assessing the prognosis of follicular lymphoma (FL).Methods: A total of 84 FL patients were retrospectively analyzed in this study. Baseline (n=59), interim (n=24, after 2–4 cycles) and end-of treatment (n=43) PET/CT images were re-evaluated, and baseline maximum standardized uptake value (SUVmax), total metabolic tumor volume (tMTV) and total lesion glycolysis (TLG) were recorded. Interim (I-PET) and end-of treatment (E-PET) PET/CT responses were interpreted by Deauville five-point scale (D-5PS) and International Harmonization Project criteria (IHP). Survival curves were calculated by Kaplan-Meier curves, and differences between groups were compared by log-rank test.Results: The 2-year progression-free survival (PFS) of the high- and low-TLG groups was 57.14% and 95.56%, respectively (p=0.0001). The 2-year overall survival (OS) of the high- and low-TLG groups was 62.50% and 100%, respectively (p0.05). However, E-PET results using D-5PS and IHP criteria were statistically significant (p=0.0001 and p=0.006). The D-5PS showed stronger prognostic value compared with IHP criteria. The optimal cutoff value of ΔSUVmax% was 66.95% according to I-PET and 68.97% according to E-PET. However, only the ΔSUVmax% from the baseline to the end-of therapy yielded statistically significant results in the prediction of PFS (p=0.0002).Conclusion: Our findings indicated that the baseline TLG and E-PET results were significantly associated with prognosis in patients with FL.Keywords: follicular lymphoma, PET/CT, MTV, TLG, D-5PS, IHP

Moli Wu,1,2,* Danyang Song,1,* Hui Li,1 Yang Yang,1 Xiaodong Ma,1 Sa Deng,1 Changle Ren,3 Xiaohong Shu11College of Pharmacy, Dalian Medical University, Dalian 116044, People’s Republic of China; 2College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, People’s Republic of China; 3Surgery Department of Dalian Municipal Central Hospital, Dalian Medical University, Dalian 116033, People’s Republic of China *These authors contributed equally to this workAbstract: STAT3 is the most ubiquitous member of the STAT family and involved in many biological processes, such as cell proliferation, differentiation, and apoptosis. Mounting evidence has revealed that STAT3 is aberrantly activated in many malignant tumors and plays a critical role in cancer progression. STAT3 is usually regarded as an effective molecular target for cancer treatment, and abolishing the STAT3 activity may diminish tumor growth and metastasis. Recent studies have shown that negative regulators of STAT3 signaling such as PIAS, SOCS, and PTP, can effectively retard tumor progression. However, PIAS, SOCS, and PTP have also been reported to correlate with tumor malignancy, and their biological function in tumorigenesis and antitumor therapy are somewhat controversial. In this review, we summarize actual knowledge on the negative regulators of STAT3 in tumors, and focus on the potential role of PIAS, SOCS, and PTP in cancer treatment. Furthermore, we also outline the STAT3 inhibitors that have entered clinical trials. Targeting STAT3 seems to be a promising strategy in cancer therapy.Keywords: cancer, STAT3 signaling, PIAS, SOCS, PTP, negative regulators

Xiang Wang,1 Yuanqi Hua,1 Guangya Xu,1 Senyi Deng,1 Daoke Yang,2 Xiang Gao1 1Department of Neurosurgery, Institute of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; 2Tumor Hospital of First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China Background: For the past few years, gene-therapy has recently shown considerable clinical benefit in cancer therapy, and the applications of gene therapies in cancer treatments continue to increase perennially. EZH2, an ideal candidate for tumor gene therapy, plays an important role in the tumorigenesis. Methods: In this study, we developed a novel gene delivery system with a self-assembly method by Methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) and DOTAP(DMC). And EZH2si-DMC was used to research anti-glioma both in vitro and in vivo. Results: DMC with zeta-potential value of 36.7 mV and size of 35.6 nm showed good performance in the delivery siRNA to glioma cell in vitro with high 98% transfection efficiency. EZH2si-DMC showed good anti-glioma effect in vitro through inducing cell apoptosis and inhibiting cell growth. What’s more, treatment of tumor-bearing mice with DMC-EZH2si complex had significantly inhibited tumor growth at the subcutaneous model in vivo by inhibiting EZH2 protein expression, promoting apoptosis and reducing proliferation. Conclusion: The EZH2 siRNA and DMC complex may be used to treat the glioma in clinical as a new drug. Keywords: glioma, gene therapy, EZH2, MPEG-PCL, DOTAP, tumorigenesis

A measurement of the diffuse astrophysical neutrino spectrum is presented using IceCube data collected from 2011-2022 (10.3 years). We developed novel detection techniques to search for events with a contained vertex and exiting track induced by muon neutrinos undergoing a charged-current interaction. Searching for these starting track events allows us to not only more effectively reject atmospheric muons but also atmospheric neutrino backgrounds in the southern sky, opening a new window to the sub-100 TeV astrophysical neutrino sky. The event selection is constructed using a dynamic starting track veto and machine learning algorithms. We use this data to measure the astrophysical diffuse flux as a single power law flux (SPL) with a best-fit spectral index of γ=2.58-0.09+0.10 and per-flavor normalization of φper-flavorAstro=1.68-0.22+0.19×10-18×GeV-1 cm-2 s-1 sr-1 (at 100 TeV). The sensitive energy range for this dataset is 3-550 TeV under the SPL assumption. This data was also used to measure the flux under a broken power law, however we did not find any evidence of a low energy cutoff.

The IceCube Neutrino Observatory relies on an array of photomultiplier tubes to detect Cherenkov light produced by charged particles in the South Pole ice. IceCube data analyses depend on an in-depth characterization of the glacial ice, and on novel approaches in event reconstruction that utilize fast approximations of photoelectron yields. Here, a more accurate model is derived for event reconstruction that better captures our current knowledge of ice optical properties. When evaluated on a Monte Carlo simulation set, the median angular resolution for in-ice particle showers improves by over a factor of three compared to a reconstruction based on a simplified model of the ice. The most substantial improvement is obtained when including effects of birefringence due to the polycrystalline structure of the ice. When evaluated on data classified as particle showers in the high-energy starting events sample, a significantly improved description of the events is observed.

Hu Meng,1,2,* Shuai Deng,1,2,* Yajing You,3 Hon Fai Chan1,2 1Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China; 2School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; 3Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, China *These authors contributed equally to this work Abstract: Protein-based therapies hold great promise for treating many diseases. Nevertheless, the challenges of producing therapies with targeted attributes via standardized processes may hinder the development of protein formulations and clinical translation of the advanced therapies. Microfluidics represents a promising technology to develop protein formulations with pre-programmed functional characteristics, including size, morphology, and controlled drug release property. In this review, we discuss some examples of adopting microfluidics for fabricating particle- and fiber/tube-based formulations and highlight the advantages of microfluidics-assisted fabrication. Keywords: protein therapy, microfluidics, biofabrication, controlled release

Wang Y, He Z, Deng S. Drug Des Devel Ther. 2016;10:1663– 1674. The authors have advised due to an error at the time of figure assembly, Figure 4A on page 1670 is incorrect. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article