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Yihong Tian,1,2,&ast; Yanyue Tan,3,&ast; Ming Yang,1 Xiayang Lv,3 Yunhao Zheng,1 Qiang Zhang,4 Yanyu Sun,1 Jun Wang,1,2 Xin Xiong1,2 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chengdu, Sichuan, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Nursing, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Orthodontics, Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Wang; Xin Xiong, West China Hospital of Stomatology, Sichuan University, No. 14 section 3, Renmin South Road, Chengdu, 610041, People’s Republic of China, Email wangjunv@scu.edu.cn; drxiongxin@scu.edu.cnObjective: This study aimed to thoroughly explore the relationship between individual oral behavior and the differing numbers of temporomandibular disorder (TMD) symptom in the general population.Methods: A total of 565 participants were recruited and completed a questionnaire containing demographic characteristics, eight specific oral behaviors, and five major TMD symptoms (5Ts) checklist. Multivariate linear regression analysis was performed to assess the relationship between individual oral behavior and the number of TMD symptoms, after controlling for confounders.Results: The prevalence of TMD symptoms was up to 38.2% in the general population, with 64.6% of the participants engaging in one or more oral behaviors. Female participants showed a stronger positive association with most oral behaviors than males. Moreover, wake oral behaviors exhibited a higher correlation coefficient value with TMD symptom number than sleep oral behaviors. Among the eight oral behaviors, bruxism in sleep exhibited no significant correlation with the of TMD symptom number (P> 0.05). Seven other specific oral behaviors were significantly correlated with the number of TMD symptoms by multivariate linear regression analysis (P< 0.01). The associations between the seven oral behaviors and TMD symptom number remained significant in sleep posture pressuring jaw (β: 0.165, 95% CI: 0.080– 0.250), bruxism in awake (β: 0.341, 95% CI: 0.132– 0.550), teeth clenching (β: 0.422, 95% CI: 0.264– 0.580), pressing, holding, or touching teeth together (β: 0.282, 95% CI: 0.169– 0.395), holding or tightening muscles without clenching (β: 0.447, 95% CI0.304– 0.589), holding jaw forward or to the side (β: 0.694, 95% CI0.526– 0.861), and holding jaw in rigid or tense position (β: 0.571, 95% CI0.418, 0.724) after adjustment for demographic factors (P< 0.01).Conclusion: There was a positive association between seven specific oral behaviors and TMD symptom number. Individuals with higher frequency of specific oral behaviors are more likely to suffer from more TMD symptoms. Sleep bruxism exhibited no association with TMD symptoms and symptom number.Keywords: oral behaviors, temporomandibular disorders, TMD symptom number, cross-sectional study

Shiya Zeng,1,&ast; Yanyue Tan,1,2,&ast; Zhiwei Cao,3 Yunhao Zheng,1 Tiqian Liu,1 Yifei Deng,1 Xin Xiong1 1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Nursing, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3School of Stomatology, Tianjin Medical University, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Xiong, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 15, West Section 3, Second Ring Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86 028 85501425, Email drxiongxin@scu.edu.cnObjective: Growing researches explore vitamin D’s role in temporomandibular disorders (TMDs), but the link between vitamin D and TMDs remains debated. To clarify the causal relationship, we conducted a Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS).Subjects and Methods: The GWAS dataset of vitamin D (GWAS ID: ukb-d-30890_irnt; sample size: 329247) was obtained from the IEU Open GWAS project. And that of TMDs (GWAS ID: finn-b-TEMPORO; sample size: 134280), initiated on August 25th, 2017 and publicly released on December 18th, 2023, was extracted from the FinnGen dataset, whose cases were diagnosed based on the revised International Classification of Diseases, 10th Edition (ICD-10) code K07.6. Both datasets were obtained from the European population. According to three assumptions of MR analysis, a bi-directional MR analysis was performed to measure the causal relationship, with Inverse variance weighted (IVW) as the primary method and MR Egger and Weighted median as supplement. Moreover, diverse sensitivity analyses, including Cochran’s Q test, MR Egger intercept, Mendelian randomized polymorphism RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis, were used to verify the stability of the findings.Results: The MR analysis supported causal effects of vitamin D levels on TMDs risks within the European population using IVW method [odds ratio = 1.316; 95% confidence interval = 1.086 to 1.595; P = 0.005], supported by MR Egger and Weighted median. While there was no indication that TMDs have a direct impact on vitamin D levels [β: − 0.00738, standard error = 0.00665; P = 0.568].Conclusion: The study revealed that within the European population higher levels of vitamin D led to higher risks of developing temporomandibular disorders, but found no obvious evidence that TMDs are causally associated with vitamin D. The conclusion should be cautiously interpreted, given the selection bias of TMDs patients sample.Keywords: Mendelian randomization analysis, temporomandibular joint disorders, vitamin D, 25-hydroxyvitamin D

Rongce Zhao,1,&ast; Jing Zhou,2,&ast; Zehao Zheng,1,&ast; Xinhao Xiong,1 Qiaoxuan Wang,3 Shaohua Li,1 Wei Wei,1 Rongping Guo1 1Department of Liver Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongping Guo; Wei Wei, Department of Liver Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China, Email guorp@sysucc.org.cn; weiwei@sysucc.org.cnBackground: For patients with large unresectable hepatocellular carcinoma (HCC), the effectiveness of conventional transarterial chemoembolization (TACE) remains suboptimal, which necessitates the administration of substantial volumes of chemotherapy drugs and lipiodol, thereby increasing the risk of liver failure and other chemotherapy-related complications. Therefore, we devised a strategy of initial hepatic arterial infusion chemotherapy (HAIC) followed by sequential drug-eluting bead TACE (DEB-TACE). In our treatment design, a lower tumor burden after HAIC facilitated complete embolization of tumor vasculature, and the use of less amount of embolic agents reduced the incidence of liver failure and embolization syndromes.Methods: This retrospective study evaluated consecutive patients with unresectable large HCC with a maximum tumor diameter of ≥ 7 cm who received FOLFOX-HAIC combined with sequential DEB-TACE from April 2019 to February 2024. Efficacy was evaluated using the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS); and safety was assessed using the frequency of key adverse events (AEs).Results: Among the 76 patients included, the median maximum tumor diameter was 12.4 cm (range, 7.0– 23.4 cm). The overall ORRs based on mRECIST and RECIST 1.1 criteria were 94.1% and 51.5%, respectively. The median OS was 28.1 months (95% CI, 22.7– 33.4), and the median PFS was 11.7 months (95% CI, 7.7– 15.8). All patients experienced AEs, but only 18.4% experienced grade 3 or 4 AEs, there was no treatment-related mortality.Conclusion: In this single-center, retrospective study, our results suggested that FOLFOX-HAIC with sequential DEB-TACE demonstrated promising efficacy and safety for patients with unresectable HCC with a maximum tumor diameter of ≥ 7 cm.Keywords: large unresectable hepatocellular carcinoma, hepatic arterial infusion chemotherapy, drug-eluting bead transarterial chemoembolization, sequential

Yi Zhou,1 Xinyu Xiong,1 Zhe Cheng,1 Zekai Chen,1 Shizhen Wu,2 Yan Yu,3 Yujin Liu,4 Guang Chen,1 Lingli Li5 1Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2College of Acupuncture and Bone Injury, Hubei University of Chinese Medicine, Wuhan, 430061, People’s Republic of China; 3Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 5Department of Traditional Chinese Medicine, Wuhan Fourth Hospital, Wuhan, 430033, People’s Republic of ChinaCorrespondence: Lingli Li, Department of Traditional Chinese Medicine, Wuhan Fourth Hospital, Wuhan, 430033, People’s Republic of China, Email 379994890@qq.com Guang Chen, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Email guangchen@tjh.tjmu.edu.cnPurpose: Ginseng (Panax ginseng Meyer) is an herbal medicine used in traditional Chinese medicine (TCM), has the effects of treating colitis and other diseases. Ginsenoside Rb1 (GRb1), a major component of ginseng, modulates autoimmunity and metabolism. However, the mechanism underlying GRb1 treatment of ulcerative colitis (UC) has not yet been elucidated. UC is a refractory inflammatory bowel disease (IBD) with a high recurrence rate, and researches on new drugs for UC have been in the spotlight for a long time.Methods: Mice with DSS-induced UC were treated with GRb1 or 0.9% saline for 10 days. Colon tissue of UC mice was collected to detect the levels of intestinal inflammatory cytokines and integrity of the intestinal barrier. RNA-seq and network pharmacology were used to predict the therapeutic targets of GRb1 during UC treatment.Results: GRb1 treatment alleviated intestinal inflammation and improved intestinal barrier dysfunction in UC mice. Specifically, GRb1 downregulated the levels of pro-inflammatory cytokines such as TNF-α and IL-6, while upregulating the level of the anti-inflammatory cytokine IL-10. Additionally, GRb1 treatment increased the levels of tight junction proteins including ZO-1, Occludin, and E-cadherin, which are crucial for maintaining intestinal barrier integrity. Further analyses using RNA-seq and network pharmacology suggested that these effects might involve the regulation of GRb1 in the signal transduction network of VDR, PPARγ, and NF-κB.Conclusion: The study demonstrated that GRb1 effectively alleviated UC by modulating intestinal inflammation and protecting the integrity of the intestinal barrier through the signal transduction network of VDR, PPARγ, and NF-κB.Keywords: ginsenoside Rb1, ulcerative colitis, intestinal barrier, vitamin D receptor, nuclear factor-kappa B

Jiaxuan Zheng,1,&ast; Xiaolong Xiong,2,&ast; Ke Li,2,&ast; Guangji Wang,2 Huiyuan Cao,2 Hui Huang2 1Department of Pathology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou City, Hainan Province, 570311, People’s Republic of China; 2Department of Sports Medicine, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou City, Hainan Province, 570311, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Huang, Department of Sports Medicine, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), No. 19 Xiuhua Road, Haikou City, Hainan Province, 570311, People’s Republic of China, Tel +86-15108938272, Email 120653927@hainmc.edu.cnObjective: Synovial inflammation is vital for the progression of osteoarthritis (OA). The objective of this study was to explore the effects and potential molecular mechanisms of sphingosine kinase 2 (SPHK2) on the proliferation and migration of fibroblast-like synoviocytes (FLS).Methods: A TNF-α-stimulated FLS model and a papain-induced OA rat model were constructed. The functions of SPHK2 knockdown in OA were explored by a series of in vivo and in vitro assays. Downstream target genes of SPHK2 were investigated using transcriptome sequencing and validated by reverse transcription quantitative PCR (RT-qPCR). The effects of the SPHK2/IL-17 signaling pathway on inflammation, proliferation, and migration of OA-FLS were investigated using the IL-17 pathway inhibitor (secukinumab) and the activator (rhIL-17A).Results: TNF-α stimulation promoted SPHK2 expression at mRNA and protein levels in OA-FLS. SPHK2 knockdown reduced IL-1β, IL-6, MMP-2, MMP-9, cyclinD1, and PCNA levels and suppressed proliferation and migration of OA-FLS. SPHK2 knockdown alleviated cartilage damage and synovial inflammation in the OA rat model. LRRIQ3, H4C8, CXCL1, CABP4, COL23A1, and PROK2 expression levels were regulated by SPHK2. SPHK2 knockdown inhibited the protein levels of IL-17A, IL-17RA, and Act1. The IL-17 pathway inhibitor secukinumab enhanced the inhibitory effect of SPHK2 knockdown on the proliferation and migration of OA-FLS, while the IL-17 pathway activator rhIL-17A exerted the opposite effect.Conclusion: SPHK2 knockdown inhibits proliferation and migration of OA-FLS by blocking the IL-17 pathway, which provides a novel approach to the OA treatment.Keywords: sphingosine kinase 2, fibroblast-like synoviocyte, IL-17 signaling pathway, proliferation, migration

Yi Shao,&ast; Yunfu Chen,&ast; Xin Lan, Jun Lu, Guangling Tang, Sijie Tang, Ruixue Zhai, Chao Chen, Xinglong Xiong, Jing Shi Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Shi, Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, No. 28 Beijing Road, Guiyi Street, Yunyan District, Guiyang, Guizhou, 550001, People’s Republic of China, Tel +86-18685034016, Email shijing81@gmc.edu.cnBackground: Morin can alleviate vincristine-induced neuropathic pain via inhibiting neuroinflammation. Microglial cells play an important role in initiating and maintenance of pain and neuroinflammation. It remains unclear whether morin exerts antinociceptive properties through the regulation of microglial cells. This study aimed to elucidate the mechanisms of morin against neuropathic pain focusing on microglial cells.Methods: The thermal withdrawal latency and mechanical withdrawal threshold were used as measures of pain behaviours. Histological abnormalities of the sciatic nerve were observed with transmission electron microscopy. The sciatic functional index and the sciatic nerve conduction velocity were used as measures of the functional deficits of the sciatic nerve. Inflammatory factors were detected using ELISA. The expression of M1/M2 polarization markers of microglia and nuclear factor κB (NF-κB) p65 were measured by immunofluorescence, real-time quantitative PCR and Western blotting.Results: Morin alleviated vincristine-induced abnormal pain, sciatic nerve injury, and neuroinflammatory response in rats. Furthermore, morin decreased the expression of NF-κB P65 and M1 activation markers, increased the expression of M2 activation markers. Additionally, phorbol 12-myristate 13-acetate reversed the effects of morin on microglial polarization, the production of inflammatory factors and neuropathic pain, while ammonium pyrrolidine dithiocarbamate showed the opposite effects.Conclusion: Our results demonstrate that morin inhibits neuroinflammation to alleviate vincristine-induced neuropathic pain via inhibiting the NF-κB signalling pathway to regulate M1/M2 microglial polarization.Keywords: neuropathic pain, morin, microglia, NF-κB, neuroinflammation

Haijie Tan,1,&ast; Yi Chen,2,&ast; Yan Jiang,1 Xiaojing Sun,1 Wei Ye,1 Xuefang Zhu,1 Xiangsheng Xiong1 1Department of Anesthesiology, The Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China; 2Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangsheng Xiong, Department of Anesthesiology, The Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China, Email 158193942@qq.comBackground: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery.Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 μg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 μg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery.Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582– 0.628) and 0.054 (95% CI: 0.053– 0.056) μg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576– 1.226) and 0.055 (95% CI: 0.047– 0.109) μg/kg/min, respectively, with an efficacy ratio of 12.1:1.Conclusion: The administration of 0.6 μg/kg/min phenylephrine and 0.05 μg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.Keywords: ED90, phenylephrine, norepinephrine, spinal anesthesia-induced hypotension, preeclampsia, cesarean delivery

Yi Chen,1,&ast; Xiangsheng Xiong,2,&ast; Rui Qin,1 Lei Guo,1 Yongqiang Shi,1 Xinli Ni1 1Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 2Department of Anesthesiology, the Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinli Ni, Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China, Email xinlini6@nyfy.com.cnBackground: Fluid loading improves hemodynamic stability and reduces the incidence rate of post-spinal anesthesia hypotension when prophylactic vasopressors are administered. We investigated the impact of different crystalloid coload volumes on the 90% effective dose (ED) of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension in non-hypertensive patients undergoing cesarean section.Methods: Patients were randomly allocated to receive one of the different crystalloid coload volumes (0mL/kg [0mL/kg Group], 5mL kg [5mL/kg Group], and 10mL kg [10mL/kg Group]) in combination with prophylactic norepinephrine infusion immediately after the induction of spinal anesthesia. The prophylactic norepinephrine infusion doses were determined using the up-and-down sequential allocation methodology, with an initial dose of 0.025 μg/kg/min and a gradient of 0.005 μg/kg/min. The primary endpoint was the effective dose at which 90% (ED 90) of patients responded to prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension.Results: The estimated effective dose of norepinephrine infusion, at which 90% (ED 90) of patients responded, was found to be 0.084 (95% CI, 0.070 to 0.86), 0.074 (95% CI, 0.059 to 0.077), and 0.063 (95% CI, 0.053 to 0.064) μg/kg/min in the three groups, respectively.Conclusion: A crystalloid coload of 5 mL/kg or 10 mL/kg, as opposed to the groups receiving 0 mL/kg crystalloid coloads, resulted in a reduction of approximately 11.9% and 25.0%, respectively, in the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean section.Keywords: crystalloid, coload, norepinephrine, postspinal anesthesia hypotension, cesarean section

Sophie Lau Rui Han,1,&ast; Jie Xiang,1,&ast; Xiang-Xiang Zeng,2 Pei-Di Fan,1 Qiao-Yu Cheng,1 Xue-Man Zhou,1 Zheng Ye,2 Xin Xiong,1 Jun Wang1 1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Xiong; Jun Wang, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China, Tel +86-28-85503898 ; +86-28-85501425, Email drxiongxin@scu.edu.cn; wangjunv@scu.edu.cnPurpose: This study aimed to investigate the relationship between temporomandibular joint (TMJ) effusion and TMJ pain, as well as jaw function limitation in patients via two-dimensional (2D) and three-dimensional (3D) magnetic resonance imaging (MRI) evaluation.Patients and Methods: 121 patients diagnosed with temporomandibular disorder (TMD) were included. TMJ effusion was assessed qualitatively using MRI and quantified with 3D Slicer software, then graded accordingly. In addition, a visual analogue scale (VAS) was employed for pain reporting and an 8-item Jaw Functional Limitations Scale (JFLS-8) was utilized to evaluate jaw function limitation. Statistical analyses were performed appropriately for group comparisons and association determination. A probability of p< 0.05 was considered statistically significant.Results: 2D qualitative and 3D quantitative strategies were in high agreement for TMJ effusion grades (κ = 0.766). No significant associations were found between joint effusion and TMJ pain, nor with disc displacement and JLFS-8 scores. Moreover, the binary logistic regression analysis showed significant association between sex and the presence of TMJ effusion, exhibiting an Odds Ratio of 5.168 for females (p = 0.008).Conclusion: 2D qualitative evaluation was as effective as 3D quantitative assessment for TMJ effusion diagnosis. No significant associations were found between TMJ effusion and TMJ pain, disc displacement or jaw function limitation. However, it was suggested that female patients suffering from TMD may be at a risk for TMJ effusion. Further prospective research is needed for validation.Keywords: temporomandibular disorder, temporomandibular joint pain, three-dimensional analysis, 3D slicer

Ting Su, Wentong Wang, Xixi Xiong, Meihua Zhang, Yan Lu,&ast; Zhonglan Su&ast; Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Lu; Zhonglan Su, Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, People’s Republic of China, Email luyan6289@163.com; alice_su2595@126.comBackground: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL).Purpose: To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge.Material and Methods: Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022.Results: All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal.Conclusion: The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.Plain Language Summary: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, also may be present in hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma.The presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders and streptococcal infections. In addition, EBV-negative CHP has a better prognosis than previously thought and provides knowledge of its prognosis in the Chinese population.With changes in the disease pedigree supported by the development of medical technology, CHP may present as a reactive process of a combined primary disease.Keywords: Cytophagic histiocytic panniculitis, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, retrospective study

Ruonan Sun,1,&ast; Shuyuan Zhang,1,&ast; Jiarui Si,2 Liming Zhang,1 Haolun Yang,1 Zheng Ye,1 Xin Xiong2 1West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zheng Ye, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, People’s Republic of China, Email zheng_ye@scu.edu.cn Xin Xiong, West China Hospital of Stomatology, Sichuan University, No. 14 Section 3, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel/Fax +86-28-85503898, Email drxiongxin@scu.edu.cnBackground: Studies have reported correlations between various oral behaviors and painful temporomandibular disorders (TMD), yet comprehensive research on the independent effects of each oral behavior within the general population remains sparse.Objective: This cross-sectional study aimed to investigate the association between painful TMD (PT) and various oral behaviors in general population.Methods: A questionnaire survey was conducted with participants to collect data encompassing demographic characteristics, eight specific oral behaviors, and the 5 major TMD symptoms(5Ts) checklist. Participants were categorized into PT and non-PT (NPT) groups based on their responses to the 5Ts checklist. Those reporting TMJ/facial pain or headaches were assigned to the PT group, while all other participants constituted the NPT group. Both univariate and multivariate logistic regression analyses were employed to evaluate the association between individual oral behavior and the presence of PT, controlling for demographic confounders including age, sex, systemic diseases, and dental treatments history.Results: A total of 441 valid questionnaires were received, including 156 males and 285 females. The prevalence of PT was identified to be 33.33%, with 61.00% of participants engaging in one or more types of oral behaviors. Each oral behavior was more frequently reported in the PT group compared to the NPT group. The univariate logistic regression analysis identified positive correlations between all eight oral behaviors and PT. In the multivariate logistic regression analysis, these associations persisted after adjustment for demographic confounders including age, sex, history of systemic diseases and dental treatments (P< 0.01). The behaviors most strongly associated with PT were “Hold or jut jaw forward/to the side” (OR:4.478), “Hold, tighten or tense muscles without clench” (OR:3.343) and “Hold jaw in rigid or tense position” (OR:3.209).Conclusion: The presence of oral behaviors has significant association with PT. Individuals exhibiting multiple oral behaviors are more likely to experience PT. Additional studies are needed to clarify the effects of reducing oral behaviors on pain-related symptoms.Keywords: oral behaviors, painful temporomandibular disorders, Temporomandibular Joint, general population, cross-sectional study

Yu Liu, Xiaoliang Xiong, Nan Cao, Yinlong Zhao Nuclear Medicine Department, Jilin University Second Hospital, Changchun, Jilin Province, People’s Republic of ChinaCorrespondence: Yinlong Zhao, Email yinlong@jlu.edu.cnAbstract: Keloid is a prevalent skin disorder characterized by the abnormal growth of keloid tissue, which usually occurs following wound healing or surgical incisions. It typically progresses through several stages: the inflammatory stage, the proliferative stage, collagen remodeling, and ultimately the formation of keloid. This review aims to summarize the diagnostic and therapeutic methods for keloid, and evaluate their effectiveness. The diagnosis of keloid is usually based on medical history and clinical manifestations such as pain, itching, erythema, and induration. Other commonly used diagnostic methods include tissue biopsy and ultrasound examination. Various treatment options for keloid exist, including physical therapy, medication, surgical treatment, and radiation therapy. Physical therapy includes pressure therapy, laser therapy, such as silicone sheets, elastic bandages, and laser irradiation. Medication treatment mainly involves the application of topical medications or intralesional injections, such as topical corticosteroids, 5-fluorouracil, and others. Radiation therapy can be administered using applicators and superficial radiation therapy, among other methods. The treatment outcomes of keloid vary from person to person and recurrence is common. Therefore, a comprehensive treatment approach may be the most effective strategy. Individualized treatment plans should consider factors such as the patient’s age, gender, medical history, and the severity of the condition. In conclusion, the diagnosis and treatment of keloid require consideration of multiple factors and the implementation of individualized treatment plans. Future research should focus on identifying the molecular mechanisms underlying the occurrence and progression of keloid in order to develop more effective treatment methods.Keywords: keloid, pathogenesis, clinical treatment

Xianrui Song,1,&ast; Danyang Li,1,&ast; Lingling Gan,2,&ast; Xiyu Xiong,1 Aobo Nie,1 Huanhuan Zhao,3 Yunfeng Hu,1 Guangming Li,4 Jun Guo1 1Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 2Experiment Center for Science and Technology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 3Basic Medical Experiment Center, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 4Department of Anesthesiology, Huaian First People’s Hospital, Nanjing Medical University, Huaian, Jiangsu, 223001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Guo, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China, Tel +86 13813909055, Email guoj@njucm.edu.cn Guangming Li, Department of Anesthesiology, Huaian First People’s Hospital, Nanjing Medical University, Huaian, Jiangsu, 223001, People’s Republic of China, Email ligm7681@163.comIntroduction: Extracellular protein nanoparticles (PNs) and ions perform synergistical functions in the control of transmembrane osmotic pressure (OP) under isotonic conditions. Intravenous injection may disrupt the ion balance and alter PN levels in blood plasma, changing transmembrane OP and damaging vascular endothelial cells.Methods: Na ions were injected into AngII–induced HUVECs to simulate cell injury in vitro, and tail vein infusion of Na ions into hypertensive rats was performed to assess vascular damage. Optical measurements using an intermediate filament (IF) tension probe were conducted to detect indicators related to transmembrane OP. Immunofluorescence, Western blotting and small interfering RNA (siRNA) transfection were employed to investigate inflammasomes and the relationship between Abl2 and inflammation.Results: Electrolyte injections with sodium ions (but not glucose and hydroxyethyl starch) induced the production of ASC and NLRP3 inflammasomes in Ang II–induced HUVECs; this in turn resulted in the disorder of calcium signals, and changes in transmembrane OP and cell permeability. Moreover, injection of Na ions into Ang II–induced HUVECs activated the mechanosensitive protein Abl2, involved in inflammation-induced transmembrane OP changes. A drug combination was identified that could induce OP recovery and block hyperpermeability induced by cytoplasmic inflammatory corpuscles in vivo and in vitro.Conclusion: Changes in extracellular PNs and ions following chemical stimuli (Ang II) participate in the regulation of transmembrane OP. Furthermore, injection of Na ions causes vascular endothelial injury in Ang II-induced cells in vitro and hypertension rats in vivo, suggesting it is not safe for hypertensive patients, and we propose a new drug combination as a solution. Keywords: Na ion injection, vimentin tension probe, protein-nanoparticles, transmembrane OP, Ang II-induced vascular endothelial injury, Abl2

Dan Pu, Shiyong Zhang, Shoushan Hu, Yuyao Zhang, Xin Xiong, Shufang Du State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Shufang Du; Xin Xiong, Email dushufang@scu.edu.cn; drxiongxin@scu.edu.cnObjective: This study aims to investigate the relationship between oral health-related quality of life (OHRQoL) and emotional distress (ED), including anxiety and depression, in orthodontic patients.Methods: A cross-sectional study was conducted involving 603 orthodontic patients, consisting of 401 females (66.5%) with a mean age of 24.15 ± 7.72 and 202 males (33.5%) with a mean age of 24.16 ± 7.72. A questionnaire containing questions of demographic information, the Oral Health Impact Profile (OHIP-14) and the Huaxi emotional-distress index (HEI) was employed to assess OHRQoL and ED. According to the HEI score, the respondents were divided into ED group (HEI > 8) and non-ED group (HEI ≤ 8). Data were analyzed using Kolmogorov–Smirnov test, Mann–Whitney test and logistic regression analysis with the significance level set at p < 0.05.Results: The prevalence of poor OHRQoL and ED of the study sample was 28.4% and 19.57%, respectively. There was a significantly higher prevalence of ED among poor OHRQoL patients (35.67%) compared to those with good OHRQoL (13.19%) (p < 0.001). Poor OHRQoL and risky drinking behavior addressed higher significant correlation with ED patients than non-ED patients (p < 0.05). There were no statistical differences in other factors such as gender, age, and appliance type (p > 0.05). Poor OHRQoL orthodontic patients were at a higher risk of suffering from anxiety and depression compared to those with good OHRQoL (age-risky drinking behavior-sex-adjusted: OR = 4.00; all p < 0.001).Conclusion: Oral health-related quality of life (OHRQoL) is related to emotional stress. Namely, patients with poor OHRQoL are more likely to experience anxiety and depression. As a result, orthodontists should consistently assess the emotional well-being and OHROoL of patients over the treatment course for better treatment outcomes.Keywords: orthodontic patients, oral health-related quality of life, emotional distress, anxiety, depression, cross-sectional study

Xingran Shao, Yaqi Dong, Han Liu, Jiao Wei, Xiao Xiong Department of Dermatology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of ChinaCorrespondence: Jiao Wei; Xiao Xiong, Department of Dermatology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, 442008, People’s Republic of China, Tel +86 15872706796 ; +86 13636169342, Email Dr_weijiao2023@163.com; xiongx2016@163.comAbstract: Eccrine poroma (EP) is a benign skin appendicular tumor that differentiates into the terminal sweat duct and is often differentiated from basal cell carcinoma (BCC) and seborrheic keratosis. This report describes a 58-year-old woman who presented with left occipital plaque. Histopathological analysis showed that the tumor cells were located in the lower part of the epidermis. The tumor cells were cuboidal or circular basal-like cells of the same size. The surrounding cells were not arranged in a palisade shape. Scattered tumor clusters composed of basal-like cells were also seen in the dermis, staining basophilic, and the surrounding cells were arranged in a palisade pattern. Immunohistochemistry showed that BerEP4, epithelial membrane antigen EMA, carcinoembryonic antigen CEA, Bcl-2, CD10, CK7 were positive, AR, PAS were negative. According to the pathological examination and immunohistochemical results, a case of eccrine poroma with concurrent basal cell carcinoma was diagnosed.Keywords: eccrine poroma, basal cell carcinoma, immunohistochemistry, carcinoembryonic antigen, CEA, epithelial membrane antigens, EMA, BerEP4

Yicheng Guo,1 Huiqun Gan,1 Shigui Xu,1 Guosheng Zeng,2 Lili Xiao,2 Zhijun Ding,2 Jie Zhu,3 Xinglong Xiong,3 Zhiyuan Fu1 1Department of Pharmacy, Dermatology Hospital of Jiangxi Province, Nanchang, People’s Republic of China; 2Jiangxi Provincial Clinical Research Center for Skin Diseases, Nanchang, People’s Republic of China; 3Candidate Branch of National Clinical Research Center for Skin Diseases, Nanchang, People’s Republic of ChinaCorrespondence: Zhiyuan Fu, Department of Pharmacy, Dermatology Hospital of Jiangxi Province, 388, Yinbing Road, Nanchang, Jiangxi, People’s Republic of China, Tel +86 13970827820, Email fuzhiyuan0774@yeah.netPurpose: This study aims to confirm the efficacy of Xijiao Dihuang decoction (XJDHT), a classic prescription, in treating psoriasis and to explore the potential therapeutic mechanism.Methods: For pharmacodynamic analysis, a mouse model of imiquimod cream (IMQ)-induced psoriasis was constructed. Active ingredients and genes of XJDHT, as well as psoriasis-related targets, were obtained from public databases. Intersecting genes (IGEs) of XJDHT and psoriasis were collected by Venn Diagram. A protein–protein interaction (PPI) network of IGEs is constructed through the STRING database. The Molecular Complex Detection (MCODE) and Cytohubba plug-ins of Cytoscape software were used to identified hub genes. In addition, we conducted enrichment analysis of IGEs using the R package clusterProfiler. Hub genes were validated via external GEO databases. The influence of XJDHT on Hub gene expression was examined by qPCR and ELISA, and molecular docking was used to evaluate the binding efficacy between active ingredients and hub genes.Results: The results revealed that XJDHT possesses 92 potential genes for psoriasis, and 8 Hub genes were screened. Enrichment analysis suggested that XJDHT ameliorate psoriasis through multiple pathways, including AGE-RAGE, HIF-1, IL-17 and TNF signaling pathway. Validation data confirmed the differential expression of IL6, VEGFA, TNF, MMP9, STAT3, and TLR4. Molecular docking revealed a strong affinity between active ingredients and Hub genes. The efficacy of XJDHT in improving psoriatic lesions in model mice was demonstrated by PASI score and HE staining, potentially attributed to the down-regulation of VEGFA, MMP9, STAT3, TNF, and IL-17A, as evidenced by ELISA and qPCR.Conclusion: This study employed network pharmacology and in vitro experiments to identify the potential mechanisms underlying the therapeutic effects of XJDHT on psoriasis, providing a new theoretical basis for its clinical application in the treatment of psoriasis.Keywords: psoriasis, Xijiao Dihuang decoction, network pharmacology, molecular docking, angiogenesis

Jianv Wang,1,&ast; Hongye Liao,1,&ast; Jieming Ban,2 Sen Li,2 Xia Xiong,1 Qingqing He,1 Xinyu Shi,2 Hongping Shen,2 Sijin Yang,2 Changzhen Sun,2 Li Liu1 1Department of Dermatology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Drug Research Center of Integrated Traditional Chinese and Western Medicine, National Traditional Chinese Medicine Clinical Research Base, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changzhen Sun, Drug Research Center of Integrated Traditional Chinese and Western Medicine, National Traditional Chinese Medicine Clinical Research Base, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86-136-9949-2406, Email sunchangzhen@swmu.edu.cn Li Liu, Department of Dermatology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86-193-3860-9127, Email liuli@swmu.edu.cnBackground: Near-infrared cyanine dyes have high sensitivity and spatial resolution imaging capabilities, but they also have unavoidable drawbacks such as photobleaching, low water solubility, fluorescence quenching, and toxic side effects. As an effective biologic drug carrier, albumin combines with cyanine dyes to form albumin@dye nanoparticles. These nanoparticles can alleviate the aforementioned issues and are widely used in tumor imaging and photothermal therapy.Methods: Herein, a newly synthesized near-infrared dye IR-817 was combined with bovine serum albumin (BSA) to create BSA@IR-817 nanoparticles. Through the detection of fluorescence emission and absorption, the optimal concentration and ratio of BSA and IR-817 were determined. Subsequently, dynamic light scattering (DLS) measurements and scanning electron microscopy (SEM) were used for the physical characterization of the BSA@IR-817 nanoparticles. Finally, in vitro and in vivo experiments were conducted to assess the fluorescence imaging and photothermal therapeutic potential of BSA@IR-817 nanoparticles.Results: IR-817 was adsorbed onto the BSA carrier by covalent conjugation and supramolecular encapsulation, resulting in the formation of dispersed, homogeneous, and stable nanoparticles with a particle size range of 120– 220 nm. BSA@IR-817 not only improved the poor water solubility, fluorescence quenching, and toxic side effects of IR-817 but also enhanced the absorption and fluorescence emission peaks in the near-infrared region, as well as the fluorescence in the visible spectrum. In addition, BSA@IR-817 combined with laser 808 irradiation was able to convert light energy into heat energy with temperatures exceeding 50 °C. By creating a mouse model of subcutaneous melanoma, it was discovered that the tumor inhibition rate of BSA@IR-817 was greater than 99% after laser irradiation and that it achieved nearly complete tumor ablation without causing significant toxicity.Conclusion: Our research, therefore, proposes the use of safe and effective photothermal nanoparticles for the imaging, diagnosis, and treatment of melanoma, and offers a promising strategy for future biomedical applications.Keywords: albumin, cyanine dyes, near-infrared imaging, photothermal therapy, melanoma

Xin Xiong,1,2,&ast; Xinlin Gao,1,&ast; Jiawei Zhong,1 Shoushan Hu,1 Yijun Li,1 Yunhao Zheng,1 Yang Liu2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China; 2State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Liu, State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel +86 028-85503898, Fax +86 018-85503898, Email liu@scu.edu.cnPurpose: This study conducted a bibliometric analysis that comprehensively described publications on temporomandibular joint and occlusion from 1 January 2000 to 31 October 2022, aiming to reveal hotspots and predict future research trends.Methods: A total of 2985 articles and reviews were retrieved from Web of Science Core Collection (WoSCC). Excel 2019, VOSviewer and CiteSpace software were used for visualizing analysis of research trends, authors, journals, institutions, countries, keywords and cited references.Results: Both the annual publication counts and citation times increased significantly. Wang MQ was the most active author. Moreover, Manfredini D and Okeson JP were the most influential two. Journal of Oral Rehabilitation was the core journal. University of Sao Paulo was the most productive institutions. “Temporomandibular disorders” (TMDs), “temporomandibular joint” and “occlusion” were the top 3 keywords with the most frequencies. Keywords and references with burst showed that the causes of TMDs, diagnosis and treatments for TMDs as well as bruxism may be hotspots currently and in the future.Conclusion: In this study, the research trends, the most productive and influential authors, journals, institutions, countries, in addition to keywords and cited references with burst in the field of temporomandibular joint and occlusion were revealed by a bibliometric analysis, which could help scholars to understand recent hotspots and future trends.Keywords: bibliometric analysis, temporomandibular joint, occlusion, keywords analysis

Jiasi Wu, Xin Xiong, Xiumin Hu Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Jiasi Wu, Email wujiasi@cdutcm.edu.cnPurpose: Cytokine storm secondary lung injury (CSSLI) is the leading death cause in COVID-19 virus infection, and CD39-dominated purinergic brake drives NLRP3 inflammasome activation and pyroptosis, which plays a crucial role in the pathogenesis of CSSLI. Though electroacupuncture (EA) can alleviate lung injury caused by a variety of inducers, its effect on CSSLI and the underlying mechanism needs further investigation.Methods: We established a widely recognized CSSLI mice model with CpG1826 (CpG), a TLR-9 agonist agent. Luminex liquid chip was employed to detect serum levels of 12 cytokines/chemokines to evaluate cytokine storm formation. H+E staining and transmission electron microscope were applied to examine pulmonary pathological injury and alveolar macrophage structure, respectively. IL-1β, IL-18, IL-1α, and HMGB-1 in BAL fluid were determined by ELISA kits. mRNA and protein levels of lung CD39 and NLRP3 were assessed by qRT-PCR and Western blotting. An in vitro model was also established by incubating PMA-differentiated THP-1 cells with serum samples obtained from relevant group of mice.Results: Repeated CpG induced CSSLI together with the elevation of 11 cytokines/chemokines including GM-CSF, IL-16, IL-1α, MCP-1, IL-2, IL-10, CCL3, IL-1β, TNF-α, IL-6, and IL-17A, though not IFN-γ, which was reduced by EA pretreatment to a different extent. EA also alleviated lung injury and recovered lung macrophage structure. Moreover, CpG enhanced IL-1β and IL-18 level in BAL fluid, promoted NLRP3, while suppressing CD39 expression in lung, all of which were reversed by EA pretreatment. Of note, EA failed to further decrease BAL fluid IL-1β, IL-18, IL-1α, and HMGB-1 levels when A438079, a selective inhibitor of P2X7, was administered. However, both CD39 and NLRP3 are dispensable for EA decreasing multi-cytokine secretion in serum-incubated and CpG-stimulated THP-1 cells. Taken together, EA alleviated CSSLI in CpG-challenged mice by regulating the CD39-NLRP3 pathway in a P2X7-dependent way.Conclusion: EA demonstrated potential to be applied in COVID-19 treatment.Keywords: electroacupuncture, cytokine storm, CD39, NLRP3 inflammasome, lung injury, CpG1826

Yunhao Zheng,1 Rui Zhu,2 Chuqiao Xiao,3 Qiaoyu Cheng,3 Yifei Long,3 Xueman Zhou,3 Shilong Zhang,4 Jun Wang,3 Xin Xiong1,3 1Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 2Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 3Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 4Department of Orthodontics, School and Hospital of Stomatology, Hebei Medical University & Hebei Key Laboratory of Stomatology, Shijiazhuang, People’s Republic of ChinaCorrespondence: Xin Xiong, National Clinical Research Center for Oral Diseases, State Key Laboratory of Oral Diseases, Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +86-28-85503898, Email drxiongxin@scu.edu.cnPurpose: This study aims to explore the association of pressure pain thresholds (PPTs) with age, gender, and pain in patients with temporomandibular disorders (TMD).Patients and Methods: A total of 301 TMD patients (248 female and 53 male) were recruited and classified into the high and low age groups according to their median age of 26 years. Patients’ demographics, pain-related variables, TMD-related variables, and PPTs of both left and right temporomandibular joints (TMJs), masseter, and temporalis were collected.Results: Pain duration and visual analog scale of pain (VAS) showed no significant correlations with PPTs (P> 0.05). Multiple linear regression analysis revealed a significant positive association of PPTs of all six sites with males (β=0.41– 0.72 kg·cm− 2, 95% CI (0.19– 0.38, 0.74– 0.99), P< 0.001), as well as with the high age group [β=0.28– 0.36 kg·cm− 2, 95% CI (0.07– 0.20, 0.47– 0.53), P< 0.020]. Furthermore, PPTs of the left TMJ showed a significant negative association with left pain-related TMD (PT) [β=− 0.21 kg·cm− 2, 95% CI (− 0.38, − 0.04), P=0.026], but PPTs of the remaining sites did not show a significant association with PT (P> 0.05). Stratified analysis showed that PPTs in females were associated with the high age group [β=0.25– 0.37 kg·cm− 2, 95% CI (0.04– 0.20, 0.45– 0.56), P< 0.020] and that PPT of the left TMJ was associated with left PT [β=− 0.21 kg·cm− 2, 95% CI (− 0.39, − 0.03), P=0.043]. The remaining PPTs did not show a significant association with PT (P> 0.05). In males, PPTs did not show significant correlations with age, PT and VAS (P> 0.05).Conclusion: PPTs in the orofacial region are associated with gender and age in TMD patients. Pain duration and intensity show no significant correlations with PPTs in TMD patients. Researchers and dentists should take age and gender into account when using PPTs as auxiliary diagnostic indicators for PT.Keywords: pain sensitivity, temporomandibular disorders, pressure pain threshold, age, gender

Jiangxia Huang,1 Qianru Yang,1 Pan Lv,1 Xiaoyan Xiong,2 Ougen Liu1 1Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Ougen Liu, Department of Dermatology, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Email 13576296646@163.comAbstract: Cutaneous pili migrans is a rare condition caused by embedded hair shafts or fragments which presents as a mobile black linear rash and is easily confused with cutaneous larva migrans. “Ingrowing hair”, in which the hair shaft grows inside the skin and burrows into the uppermost dermis rather than exiting the skin, is much rarer, and only 8 cases have been reported thus far, all in Asian men. We report a case of a 22-year-old Chinese male with a 4 cm-long black linear rash that migrated from the anterior abdomen to the left lower abdomen. The black lines represented hair shafts with follicular structures. The lesion disappeared immediately after hair removal. No recurrence occurred in 4 weeks of follow-up. To our knowledge, this is the first description of ingrowing hair occurring in the abdomen.Keywords: cutaneous pili migrans, ingrowing hair, creeping hair

Zheng Y, Zhu R, Xiao C, et al. J Pain Res. 2023;16:2205–2216. The authors have advised that they neglected to include a funding statement on page 2215 of the published paper. The funding statement should read as follows. Funding This work was supported by the Technology Innovation Project of Science and Technology Bureau of Chengdu (2022-YF05-01691-SN) and Clinical Research Project of West China Hospital of Stomatology, Sichuan University (LCYJ-2023-YY-2). The authors apologize for this error.

Zhishu Li,1 Jiayue Chen,1 Jia Zeng,2 Ping Shi,2 Xiaomin Xiong,2 Meng Wang,1 Dong Zheng,1 Rui Zhao,1 Lixia Dong1 1Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Guangyuan Central Hospital, Guangyuan, People’s Republic of ChinaCorrespondence: Lixia Dong, Email luckydonglixia@163.comBackground: In patients with tuberculous pleural effusion (TPE) of various ages, the diagnostic accuracy of pleural biomarkers varies, and there are insufficient studies specifically in different age groups. Therefore, we investigated the adenosine deaminase cut-off value and its combination with the gamma interferon release assay for the diagnosis of TPE among patients aged ≥ 40 years.Methods: A retrospective analysis of 198 patients who underwent medical thoracoscopy and were admitted to the hospital between 2015 and 2020 with exudative pleural effusion and either fever, night sweats, fatigue, cough, or other clinical manifestations was performed. The medical thoracoscopy, ADA, and T-SPOT results were analysed in the pleural fluid. The patients were divided into groups based on age: 18– 39, 40– 59, and 60– 87.Results: The best cut-off values of ADA were 29.5, 31.5 and 19.5 U/L, respectively, for the aged 18– 39, aged 40– 87 and aged 60– 87 groups. The accuracy of 31.5 U/L was higher than 40 U/L for aged ≥ 40 years (86 vs 83%). The ADA diagnostic accuracy was higher than that of people under 40 years (83 vs 77%) when cut-off value of ADA was 40 U/L, but the IGRA accuracy was lower than that of people under 40 (87 vs 91%). The sensitivity of ADA or IGRA detection in patients over 40 years was 99%, and the specificity was 78%. The ADA specificity combined with IGRA for TPE was the highest (100%) in the ≥ 40 age group, and the sensitivity was 69%.Conclusion: Our study revealed the best cut-off values of ADA for TBE in different age groups. Combining ADA and IGRA in pleural fluid improves the detection rate of TPE in patients over 40 years of age with exudative pleural effusion. ADA combined with IGRA increases specificity, and ADA or IGRA increases sensitivity substantially.Keywords: adenosine deaminase, interferon gamma releasing assays, aged, diagnosis, pleural effusion, tuberculosis

Qinqin Tang, Yanjun Zhou, Yujuan Chen, Jie Chen, Xincai Xiong Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of ChinaCorrespondence: Xincai Xiong, Department of Dermatology, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan South Road, Shunqing District, Nanchong City, Sichuan Province, 637000, People’s Republic of China, Tel +86 13551686620, Email xiongxincai@163.comAbstract: Sporotrichosis is a deep fungus infection caused by the Sporothrix. In China, the most common species is Sporothrix globosa which is difficult to treat with most antifungal drugs. Atypical clinical forms of sporotrichosis can be a hinder to clinicians for an early diagnosis and treatment. We report a case of fixed cutaneous sporotrichosis of the face caused by S. globosa in a healthy adult that was initially misdiagnosed as rosacea due to its unusual clinical features. We made an effort to dermoscopically track changes in skin lesions both before and after treatment, confirming that itraconazole was effective in the treatment of sporotrichosis.Keywords: skin disease, dermatology, sporotrichosis, fixed cutaneous sporotrichosis, dermoscopy, Sporothrix globosa, fungus infection

Xin Xiong,1,&ast; Rong Rong,2,&ast; Li-Ying Tang,3,&ast; Tie Sun,1 Yi-Cong Pan,1 Hui-Ye Shu,1 Li-Juan Zhang,1 Qian-Min Ge,1 Rong-Bin Liang,1 Yi Shao1 1Department of Pathology and Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Centre of Natural Ocular Disease Clinical Research Center, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Department of Ophthalmology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, 361004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Shao, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Wai Zheng Street, Dong Hu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel/Fax +86 791-88692520, Email freebee99@163.comObjective: To explore the risk factors of ocular metastasis (OM) in patients with hepatocellular carcinoma (HCC) by analyzing the demographic characteristics and serum markers.Methods: From July 2002 to December 2012, 1064 HCC patients were included in our study. The chi-squared test and Student’s t-test were used to assess the difference between OM and any other metastasis (NOM). Receiver operating curve (ROC) was used to analyze the diagnostic value of serum biomarkers in HCC patients with OM.Results: The incidence of OM in HCC patients was 1.88% in our research. There are no significant differences in age, gender, or histopathology in the OM group and the group without any metastasis. Binary logistic regression analysis presented that compared with the patients without cancer metastasis, carbohydrate antigen 125 (CA-125) and hemoglobin (Hb) were risk factors in hepatocellular carcinoma patients with OM (P < 0.05). The ROC curve analysis showed that the areas under the CA-125, Hb, and CA125+Hb curves were 0.877, 0.554, and 0.431, and the cutoff values of CA-125 and Hb each were 115.78 u/mL and 120.50 g/L.Conclusion: Our data suggest that CA-125 and Hb are risk indicators in hepatocellular carcinoma patients with OM, and that CA-125+Hb has potentially greater utility in diagnosing hepatocellular carcinoma.Keywords: hepatocellular carcinoma, ocular metastases, CA-125, Hb, risk factors

Guangmin Wei,1 Yinghao Pan,2 Jingying Wang,2 Xia Xiong,2 Yuanmin He,2 Jixiang Xu2 1Department of Dermatology, Medical Center Hospital of Qionglai City, Qionglai, Sichuan, People’s Republic of China; 2Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Jixiang Xu, Department of Dermatology, The Affiliated Hospital of Southwest Medical University, No. 25 of Taiping Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email xujx888@163.comAbstract: Vitiligo is a chronic depigmenting disorder of the skin and mucosa caused by the destruction of epidermal melanocytes. Although the exact mechanism has not been elucidated, studies have shown that oxidative stress plays an important role in the pathogenesis of vitiligo. High mobility group box protein B1 (HMGB1) is a major nonhistone protein and an extracellular proinflammatory or chemotactic molecule that is actively secreted or passively released by necrotic cells. Recent data showed that HMGB1 is overexpressed in both blood and lesional specimens from vitiligo patients. Moreover, oxidative stress triggers the release of HMGB1 from keratinocytes and melanocytes, indicating that HMGB1 may participate in the pathological process of vitiligo. Overall, this review mainly focuses on the role of HMGB1 in the potential mechanisms underlying vitiligo depigmentation under oxidative stress. In this review, we hope to provide new insights into vitiligo pathogenesis and treatment strategies.Keywords: vitiligo, HMGB1, oxidative stress, melanocytes

Jin Gao,1,2 Tingting Liu,1 Xingyu Xiong,1 Mei Zhao,1 Kun Du,1,2 Jiwei Li2,3 1Department of Neonates; 2Yunnan Province Clinical Research Center for Children’s Health and Disease, Kunming, People’s Republic of China; 3Department of Pathology, Kunming Children’s Hospital, The Affiliated Children’s Hospital of Kunming Medical University, Kunming, People’s Republic of ChinaCorrespondence: Kun Du; Jiwei Li, Email Dukun@etyy.cn; 360623155@qq.comAbstract: Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi, which is transmitted by larval trombiculid mites. Due to nonspecific clinical presentation, scrub typhus is grossly underdiagnosed in pregnant women, fetuses and neonates. Here, we present a congenital infection case and hope to provide more insight into this disease.Keywords: neonatal scrub typhus, vertical transmission, congenital infection, Orientia tsutsugamushi, meningitis

Lin Zhou,1 Xueping Liu,1 Xulin Li,1 Xiangyan He,1 Xia Xiong,1,&ast; Jingdong Lai2,&ast; 1Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Department of Dermatology & STD, Suining First People’s Hospital, Suining, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingdong Lai; Xia Xiong, Tel +86-13679670608 ; +86-13608282035, Fax +86-08303165651 ; +86-08303165232, Email 987047361@qq.com; xiongxia789@126.comBackground: Although the changed lipid environment of the pilosebaceous unit and the growth of lipophilic Cutibacterium acnes (C. acnes) during puberty has long been considered as the trigger of acne vulgaris, the involvement of the interaction between the epidermal barrier integrity and the skin microbiome in this disease has not been fully elucidated.Objective: The aim of this study was to analyze the differences in the epidermal barrier and skin microbiota in patients with acne vulgaris and their correlation.Methods: The skin microbial samples and epidermal barrier data from 74 acne patients and 19 healthy subjects were collected in this cross-sectional study. The microbial diversity was analyzed based on a high-throughput sequencing approach that targets the V3-V4 region of the bacteria 16S ribosomal RNA genes.Results: Compared with healthy controls, acne patients had significantly increased transepidermal water loss (TEWL), pH levels, sebum, porphyrins, and red areas, and reduced skin microbiome diversity according to the goods coverage diversity index (p = 0.021), Shannon diversity index (p = 0.037), and Simpson diversity index (p = 0.023). Moreover, the diversity gradually decreased with the increase in acne grading. Based on the principal coordinate analysis (PCoA) analysis plot, the skin microbiota of acne patients and healthy controls could be divided into two different sets, which could not be used to separate acne patients with different disease severity. Finally, this study found that both TEWL and sebum were negatively associated with the Shannon and Simpson diversity index. Meanwhile, the taxa Enhydrobacter and Stenotrophomonas were positively associated with TEWL, stratum corneum hydration, respectively.Conclusion: This study demonstrated that acne vulgaris exists in patients with both damaged epithelial barriers and associated microbiota dysbiosis; the findings will help improve the understanding of the disease and may contribute to the development of better treatment options.Keywords: epidermal barrier, skin microbiome

Zhenyu Hao &ast;, Yongqiong Deng &ast;, Yuanmin He, Xia Xiong Department of Dermatology STD, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongqiong Deng, Department of Dermatology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, People’s Republic of China, Tel +8613679670608, Email dengyongqiong1@126.comAbstract: Signet-ring cell (SRC) is a histologic type in which cells show unique features under the microscope. We mainly found signet-ring cells (SRCs) in gastrointestinal and breast tumors. Cutaneous metastasis from internal carcinomas was an uncommon presentation. The cases of signet-ring cell carcinoma (SRCC) metastasis to the skin were rarely reported. Cutaneous metastasis indicated a poor prognosis for a patient. Here, we report a female who had huge grape-like nodules arising from gastrointestinal SRCC in her trunk and thigh.Keywords: signet-ring cutaneous metastasis, SRCC, signet-ring cell carcinoma, unknown primary tumors, gastrointestinal tumors

HM Adnan Hameed1– 4&ast;, Cuiting Fang1– 4&ast;, Zhiyong Liu,1– 3 Yanan Ju,1– 3 Xingli Han,1– 4 Yamin Gao,1– 4 Shuai Wang,1– 3,5 Gift Chiwala,1– 4 Yaoju Tan,6 Ping Guan,6 Jinxing Hu,6 Xiaoli Xiong,1– 3 Jiacong Peng,3,7 Yongping Lin,3,7 Muzammal Hussain,4 Nanshan Zhong,3,7,8 Dmitry A Maslov,9 Gregory M Cook,10,11 Jianxiong Liu,6 Tianyu Zhang1– 4 1State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, People’s Republic of China; 2China-New Zealand Joint Laboratory of Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory of Respiratory Infectious Diseases, Guangzhou, People’s Republic of China; 4University of Chinese Academy of Sciences (UCAS), Beijing, People’s Republic of China; 5National Clinical Research Center for Infectious Diseases, Guangdong Provincial Clinical Research Center for Tuberculosis, Shenzhen Third People’s Hospital, Shenzhen, People’s Republic of China; 6State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China; 7State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 8Guangzhou National Laboratory, Guangzhou, People’s Republic of China; 9Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia; 10Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; 11Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand&ast;These authors contributed equally to this workCorrespondence: Tianyu Zhang, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Room A207, 190 Kaiyuan Ave, Science Park, Huangpu District, Guangzhou, 510530, People’s Republic of China, Tel +86-2032015270, Email zhang_tianyu@gibh.ac.cn Jianxiong Liu, Guangzhou Chest Hospital, 62 Hengzhigang Road, Yuexiu District, Guangzhou, People’s Republic of China, Tel +86-2083595977, Email ljxer64@qq.comObjective: Rifampicin (RIF)-resistance, a surrogate marker for multidrug-resistant tuberculosis (TB), is mediated by mutations in the rpoB gene. We aimed to investigate the prevalence of mutations pattern in the entire rpoB gene of Mycobacterium tuberculosis clinical isolates and their association with resistance level to RIF.Methods: Among 465 clinical isolates collected from the Guangzhou Chest Hospital, drug-susceptibility of 175 confirmed Mtb strains was performed via the proportion method and Bactec MGIT 960 system. GeneXpert MTB/RIF and sanger sequencing facilitated in genetic characterization, whereas the MICs of RIF were determined by Alamar blue assay.Results: We found 150/175 (85.71%) RIF-resistant strains (MIC: 4 to > 64 μg/mL) of which 57 were MDR and 81 pre-XDR TB. Genetic analysis identified 17 types of mutations 146/150 (97.33%) within RRDR (codons 426– 452) of rpoB, mainly at L430 (P), D435 (V, E, G, N), H445 (N, D, Y, R, L), S450 (L, F) and L452 (P). D435V 12/146 (8.2%), H445N 16/146 (10.9%), and S450L 70/146 (47.94%) were the most frequently encountered mutations. Mutations Q432K, M434V, and N437D are rarely identified in RRDR. Deletions at (1284– 1289 CCAGCT), (1295– 1303 AATTCATGG), and insertion at (1300– 1302 TTC) were detected within RRDR of three RIFR strains for the first time. We detected 47 types of mutations and insertions/deletions (indels) outside the RRDR. Four RIFR strains were detected with only novel mutations/indels outside the RRDR. Two of the four had (K274Q + C897 del + I491M) and (A286V + L494P), respectively. The other two had (G1687del + P454L) and (TT1835-6 ins + I491L) individually. Compared with phenotypic characterization, diagnostic sensitivities of GeneXpert MTB/RIF and sequencing analysis were 95.33% (143/150), and 100% (150/150) respectively.Conclusion: Our findings underscore the key role of RRDR mutations and the contribution of non-RRDR mutations in rapid molecular diagnosis of RIFR clinical isolates. Such insights will support early detection of disease and recommend the appropriate anti-TB regimens in high-burden settings.Keywords: rifampicin-resistance, Mycobacterium tuberculosis, rpoB, GeneXpert MTB/RIF, resistance-determining region

Felicia Forma,1 Tyler G Knight,2 Frances P Thorndike,1 Xiaorui Xiong,1 Rebecca Baik,2 Fulton F Velez,1 Yuri A Maricich,1 Daniel C Malone3 1Pear Therapeutics, Inc., Medical Affairs Department, Boston, MA, USA; 2Labcorp Drug Development, Market Access Consulting Department, Gaithersburg, MD, USA; 3Strategic Therapeutics, LLC, Oro Valley, AZ, USACorrespondence: Felicia Forma, Pear Therapeutics, Medical Affairs Department, 200 State St, Boston, MA, 02109, USA, Email felicia.forma@peartherapeutics.comBackground and Objectives: This analysis evaluated insomnia severity and long-term impact on healthcare resource utilization (HCRU) and costs after treatment with Somryst® (previously called SHUTi), a digital therapeutic delivering cognitive behavioral therapy for insomnia (CBT-I).Methods: Change from baseline in insomnia severity index (ISI) score was assessed using last observed ISI score. A pre/post analysis of claims data was conducted, comparing HCRU in patients with self-identified sleep problems who successfully initiated the therapeutic (index date) between June 1, 2016 and December 31, 2018.Results: A total of 248 patients were analyzed (median age 56.5 years, 57.3% female, mean ISI score 19.13, 52.4% treated with sleep aid medications pre-index). After 9 weeks, mean ISI score declined by 37.2% from baseline (19.1 vs 12.0), 58.8% of patients achieved ISI responder status (ISI score improved by => 7; NNT: 1.7), and 26.6% of patients achieved insomnia remission (ISI score < 8; NNT for remission: 3.8). After two-year follow-up, post-index events were reduced (compared to 2 years pre-index) for emergency department visits (− 53%; IRR: 0.47; 95% CI 0.27, 0.82; P=0.008), hospiatizations (-21%; IRR: 0.79; 95% CI 0.46, 1.35; P=0.389) and hospital outpatient visits (− 13%; IRR: 0.87; 95% CI 0.66, 1.14; P=0.315). Slightly increased rates were observed for ambulatory surgical center visits (2%; IRR: 1.02; 95% CI 0.73, 1.44; P=0.903) and office visits (2%; IRR: 1.02; 95% CI 0.92, 1.14; P=0.672). The number of patients treated with sleep aid medications dropped 18.5% (52.4% pre-index vs 42.7% post-index). Average number of prescriptions decreased from 3.98 pre-index to 3.73 post-index (P= 0.552). Total two-year cost reduction post-index vs pre-index was $510,678, or -$2059 per patient.Conclusion: In a real-world cohort of patients with chronic insomnia, treatment with a digital therapeutic delivering CBT-I was associated with reductions in insomnia severity, emergency department visits, and net costs.Keywords: CBT-I, cognitive behavioral therapy for insomnia, chronic insomnia, prescription digital therapeutic, SHUTi, Somryst

Xiaoqi Tan,1,&ast; Yuxin He,1,&ast; Yongliang Ou,2 Xia Xiong,1 Yongqiong Deng1 1Department of Dermatology STD, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Health Management Center, Luzhou People’s Hospital, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongqiong Deng; Xia Xiong, Department of Dermatology STD, the Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People’s Republic of China, Email dengyongqiong1@126.com; xiongxia789@126.comPurpose: Taohong Siwu decoction (THSWD) is traditionally used to treat androgenic alopecia (AGA) in clinical practice of traditional Chinese medicine. This study used a network pharmacology approach to elucidate the molecular mechanism governing the effect of THSWD on AGA.Materials and Methods: The major active components and their corresponding targets of THSWD were screened. AGA-related targets were obtained by analyzing the differentially expressed genes between AGA patients and healthy individuals. The protein–protein interaction networks of putative targets of THSWD and AGA-related targets were visualized and merged to identify the candidate targets for THSWD against AGA. Gene ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for core targets were performed. Finally, the key effective components and core targets screened were verified by molecular docking.Results: In this study, 69 compounds and 202 compound targets of THSWD, as well as 1158 disease targets, were screened. Forty-five interactive targets were identified for constructing the “ingredient-targets” network. The functional annotations of target genes were found to be related to oxidative stress, reactive oxygen species, and hydrogen peroxide. Pathways involved in the treatment of AGA included apoptosis and PI3K-AKT signaling pathways. The luteolin, quercetin, kaempferol, baicalein, and beta-carotene were identified as the vital active compounds, and AKT1, TP53, JUN, CASP3 and MYC were considered as the core targets. Assessment of molecular docking revealed that these active compounds and targets had good-binding interactions.Conclusion: The results indicated that the effects of THSWD against AGA may be related to anti-inflammation and anti-oxidation properties of the compounds through the specific biological processes and the related pathways.Keywords: Taohong Siwu decoction, network pharmacology, mechanism prediction, androgenetic alopecia

Wenjun Xu,1,2 Hui Tu,1 Xiaoyun Xiong,1 Ying Peng,1,2 Ting Cheng1,2 1Department of Nursing, the Second Affiliated Hospital of Nanchang University, NanChang, Jiangxi, 330000, People’s Republic of China; 2School of Nursing, Nanchang University, NanChang, Jiangxi, 330000, People’s Republic of ChinaCorrespondence: Hui Tu, Department of Nursing, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, NanChang, Jiangxi, 330000, People’s Republic of China, Tel +86 135-76095925, Email 12674789@qq.comObjective: This study aimed to develop and validate a risk prediction model that can be used to identify percutaneous coronary intervention (PCI) patients at high risk for 30-day unplanned readmission.Patients and Methods: We developed a prediction model based on a training dataset of 1348 patients after PCI. The data were collected from January 2020 to December 2020. Clinical characteristics, laboratory data and risk factors were collected using the hospital database. The LASSO regression method was applied to filter variables and select predictors, and feature selection for a 30-day readmission risk model was optimized using least absolute shrinkage. Multivariate logistic regression was used to construct a nomogram. The performance and clinical utility of the nomogram were evaluated with a receiver operating characteristic (ROC) curve, a calibration curve, and decision curve analysis (DCA). Internal validation of the predictive accuracy was performed using bootstrapping validation.Results: The predictors included in the prediction nomogram were medical insurance, length of stay, left ventricular ejection fraction on admission, history of hypertension, the presence of chronic lung disease, the presence of anemia, and serum creatinine level on admission. The area under the receiver operating characteristic curve for the predictive model was 0.735 (95% CI: 0.711– 0.759). The P value of the Hosmer–Lemeshow goodness of fit test was 0.326, indicating good calibration, and the calibration curves showed good agreement between the classifications and actual observations. DCA also demonstrated that the nomogram was clinically useful. A high c-index value of 0.723 was obtained during the internal validation.Conclusion: We developed an easy-to-use nomogram model to predict the risk of readmission 30 days after discharge for PCI patients. This risk prediction model may serve as a guide for screening high-risk patients and allocating resources for PCI patients at the time of hospital discharge and may provide a reference for preventive care interventions.Keywords: percutaneous coronary intervention, 30-day readmission, nomogram, prediction model

Hua Feng,1,2 Xiujuan Xiong,3 Zhuo Chen,1 Nan Luo,2 Yongning Wu1,4,5 1State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330000, People’s Republic of China; 2School of Public Health, Nanchang University, Nanchang, 330006, People’s Republic of China; 3Department of Pathology, Basic Medical College of Nanchang University, Nanchang, 330006, People’s Republic of China; 4China National Center for Food Safety Risk Assessment, Beijing, 100022, People’s Republic of China; 5Chinese Academy of Medical Science Research Unit, Beijing, 100730, People’s Republic of ChinaCorrespondence: Yongning Wu, State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330000, People’s Republic of China, Tel +86-10-52165589, Email wuyongning@cfsa.net.cnBackground: Dendritic cells (DCs) comprise a valuable target for immune-modulation in food allergy (FA). Long noncoding RNA (lncRNA), metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has immunomodulatory capacities and may influence the outcome of DC antigen presentation. However, the precise molecular mechanisms underlying the implication of MALAT1 in FA remain unclear.Methods: BALB/c mice were sensitized to ovalbumin in accordance with a model of FA protocol and injected with adenovirus. After modeling, immunohistochemistry was performed to analyze the jejunal tissues of FA mice and hematoxylin-eosin staining and toluidine blue staining were performed to detect inflammation and mast cell numbers. Ovalbumin-sensitized mice were monitored for symptoms of diarrhea and rectal temperature. Immature DCs were stimulated by oxidized low density lipoprotein to trigger their maturation.Results: MALAT1 was found highly expressed in mice with FA, and its silencing relieved allergic reactions with reduction in intestinal inflammatory cells and mast cells in FA mice. MALAT1 aggravated symptoms by downregulating zinc finger protein 36 (ZFP36). MALAT1 also downregulated ZFP36 expression to promote interleukin-6 (IL-6) secretion by DCs and maturation of DCs, with increased serum-specific immunoglobulin E (IgE) and IgG1 levels.Conclusion: Together, these data suggested that therapeutically blocking MALAT1 in FA could reduce the severity of FA by decreasing secretion of IL-6 by DCs and suppressing the immunomodulation of Tregs.Keywords: food allergy, metastasis associated in lung adenocarcinoma transcript 1, zinc finger protein 36, dendritic cells, interleukin 6, Tregs, immunomodulation

Xinlin Xiong,1– 3 Zhenhua Luo,4,5 Haiyan Zhou,3 Zonggang Duan,1 Li Niu,3 Kai Zhang,1 Guangwei Huang,1 Wei Li1,3 1Clinical College, Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of China; 2Department of Cardiology, Chengdu University Affiliated Hospital, Chengdu City, Sichuan Province, People’s Republic of China; 3Department of Cardiology, Guizhou Medical University Affiliated Hospital, Guiyang City, Guizhou Province, People’s Republic of China; 4NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People’s Hospital, Guiyang City, Guizhou Province, People’s Republic of China; 5Department of Central Lab, Guizhou Provincial People’s Hospital, Guiyang City, Guizhou Province, People’s Republic of ChinaCorrespondence: Wei Li, Email liwei249188@sina.comObjective: Little is currently known on the role of T-cell immunoglobulin and ITIM domain (TIGIT) expression in Foxp3+ regulatory T cells (TIGIT+Tregs) in acute coronary syndrome (ACS) patients. The aim of this study was to investigate the role and alterations of TIGIT+Tregs in ACS patients.Methods: We enrolled 117 subjects, including 61 ACS patients, 26 chronic coronary syndrome (CCS) patients, and 30 control subjects without coronary artery disease. The quantification of TIGIT+Tregs was determined by flow cytometry; serum interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) were also measured.Results: TIGIT+Tregs expression was significantly lower in ACS patients compared with CCS and control patients (P< 0.05). The expression of TIGIT+Tregs was comparable in patients with and without traditional risk factors (P> 0.05). Logistic regression analysis revealed that TIGIT+Tregs levels are independent predictors of ACS (P< 0.01). Receiver-operating characteristic (ROC) curve analysis showed the expression levels of TIGIT+Tregs had a discriminative power for ACS (P< 0.01). IL-6 levels were increased (P< 0.01), while TGF-β was decreased in ACS patients compared with CCS and control patients (P< 0.01). Meanwhile, an inverse correlation between IL-6 and TIGIT+Tregs was observed (P< 0.01), while a positive correlation between TGF-β and TIGIT+Tregs was found (P< 0.05).Conclusion: TIGIT+Tregs levels are significantly reduced in ACS, accompanied by upregulated IL-6 and downregulated TGF-β expression. The downregulated TIGIT+Tregs are independent predictors of ACS. These findings suggest that TIGIT+Tregs may have an anti-inflammatory and protective effect on ACS, and its decreased expression may be associated with atherosclerotic plaque destabilization.Keywords: T-cell immunoglobulin and ITIM domain, regulatory T cell, acute coronary syndrome, inflammation

Shiyu Jiang, Jixiang Xu, Xia Xiong, Yongqiong Deng Department of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Yongqiong DengDepartment of Dermatology & STD, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People’s Republic of ChinaTel +86-13679670608Fax +86-8303165651Email dengyongqiong1@126.comAbstract: The common causes for melanonychia include melanoma, repetitive trauma, underlying systemic diseases, onychomycosis, pseudomonas infection and drugs. Drug-induced melanonychia usually affects numerous nails and appears as light brown to black pigmentation on the deck or nail bed with longitudinal, transverse or diffuse distribution. In previous cases, a number of chemotherapeutic agents such as azathioprine, bleomycin sulfate, cyclophosphamide, hydroxyurea and methotrexate were usually linked to melanonychia. Citri reticulatae pericarpium (CRP) is a traditional Chinese herb which is widely used in many foods and health care products in China. Up till now, there were no adverse reactions of CRP reported throughout the literature. Herein, we firstly reported a case of melanonychia in a 67-year-old man caused by CRP for external use.Keywords: traditional Chinese herb, citri reticulatae pericarpium, melanonychia

Jingying Wang, Yinghao Pan, Guangmin Wei, Hanxiao Mao, Rulan Liu, Xia Xiong, Jixiang Xu, Yuanmin He Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Yuanmin He, Department of Dermatology, The Affiliated Hospital of Southwest Medical University, No. 25 of Taiping Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email heym88@163.comAbstract: Most patients are anxious about the skin lesions on the penis. This study reports a case of lichen nitidus on the penis and reviews related literature. A 40-year-old male has presented with small papules with skin color on the penis for one year. The patient was diagnosed with lichen nitidus, and tacrolimus cream and humectant were topically administered after diagnosis. The symptoms were alleviated after treatment. We first report a series of the cases with lichen nitidus on the penis, knowing the clinical and pathological manifestations of this disease can reduce misdiagnosis and unnecessary treatment.Keywords: Lichen nitidus, penis, pathological feature, treatment, prognosis

Yang H, Xiong X, Zhang L, Wu C, Liu Y. Int J Nanomedicine. 2011;6:2043–2051. An error during the preparation and figure assembly of Figure 7A on page 2049 led to the non-specific IgG group being inadvertently duplicated from the Control group. The correct version of Figure 7 is shown below. Figure 7 Continued. Figure 7 Adhesion of control microbubbles, VCAM-1-targeted microbubbles, and isotype control IgG microbubbles under low shear stress exposure of 6.3 dynes/cm2 for 3 minutes. (A) Representative bright field micrographs of microbubbles adhered to LPS-activated HUVEC-CS cells (magnification 40×). The insets are the high-magnification fields of the white dotted windows. (B) The adhered microbubble numbers on the HUVEC-CS cell monolayer were quantified by microbubble counting from six random microscopic fields (magnification 40×) for each group.Abbreviations: VCAM-1, vascular cell adhesion molecule 1; HUVEC-CS, human umbilical vein endothelial cells, subline.Notes: *P < 0.05 vs control (non-targeted microbubbles); **P < 0.01 vs control (non-targeted microbubbles) or non-specific IgG conjugated microbubbles. This correction has no impact to the findings of the study, and does not change any description, results or conclusions of the original paper. The authors apologize for this error.

Jing Yu,1,* Xi Zhang,1,2,* Qiyue Huang,1 Sirui Tan,1 Xianze Xiong,3 Hongfeng Gou1 1Department of Abdominal Cancer, West China Medical School, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Radiotherapy, The Affiliated Hospital of Hebei University, Baoding, 07100, People’s Republic of China; 3Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongfeng GouDepartment of Abdominal Cancer, West China Medical School, Cancer Center, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, People’s Republic of ChinaTel +86-28-85422589Fax +86-28-85423609Email gouhongfeng1977@wchscu.cnXianze XiongDepartment of Bile Duct Surgery, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, People’s Republic of ChinaEmail xianzexiong123@163.comPurpose: The patients with advanced mismatch repair deficiency (dMMR) cancers can benefit from programmed cell death 1 (PD-1) pathway blockade, regardless of the tumor type. Little is known about the prevalence of dMMR in intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC). This study aimed to assess the mismatch repair (MMR)-related protein expression in patients with ICC and cHCC-CC.Patients and Methods: Formalin-fixed, paraffin-embedded tumor specimens were obtained from patients undergoing surgery at the West china Hospital between 2009 and 2017. The immunoreactions for MLH1, MSH2, MSH6, and PMS2 were investigated to determine the MMR status.Results: A total of 97 patients were evaluated, including 73 ICC patients and 24 cHCC-CC patients. The prevalence of dMMR was only found in two cases of 97 patients (2.06%). Both patients are ICC. In 24 cHCC-CC patients, no dMMR was observed. They did not receive an adjuvant chemotherapy after surgery. At the end of the follow-up, one patient was in a tumor-free state, and the other patient had local recurrence and metastasis. After receiving sintilimumab (an immune checkpoint inhibitor [ICI] for PD- 1), the patient had a partial response.Conclusion: DMMR was detected in few patients with ICC and cHCC-CC. Thus, it is not recommended to routinely evaluate the MMR status of patients with ICC or cHCC-CC after surgery, but that of patients with advanced ICC or cHCC-CC should be assessed.Keywords: mismatch-repair deficiency, intrahepatic cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma, immune checkpoint inhibitors, prognosis

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

Shu-Yu Long, Qiong Yang, Rui Chi, Li Luo, Xi Xiong, Zheng-Qiong Chen Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaCorrespondence: Zheng-Qiong Chen Email chenzhengqiong75@163.comPurpose: Antepartum hemorrhage (APH) in women with placenta previa (PP) has been associated with increased perinatal complications. The present study aims to evaluate the maternal and neonatal outcomes, and risk factors related to this condition.Methods: This retrospective study was conducted in the Obstetrics and Gynecology Department of the Second Affiliated Hospital of Army Military Medical University from January 2016 to September 2019, which included all women with PP. The clinical and ultrasound features in patients with or without APH were compared.Results: There were 233 women with APH and 302 women without APH in the cohort. Most of the women with APH were prone to adverse maternal and neonatal outcomes. In the logistic regression analysis, cervical length was inversely correlated to APH (OR: 0.972, 95% CI: 0.952∼ 0.993), while complete PP increased the risk for APH (OR: 2.121, 95% CI: 1.208∼ 3.732). Furthermore, the anterior placenta increased the risk for APH (OR: 1.664, 95% CI: 1.139∼ 2.430), the partial absence of the over lying myometrium increased the risk for APH (OR: 2.015, 95% CI: 1.293∼ 3.141), and the previous history of uterine artery embolization (UAE) increased the highest risk for APH (OR: 11.706, 95% CI: 1.424∼ 96.195).Conclusion: Obstetricians should be aware of the increased risk of adverse pregnancy outcomes related to APH in women with complete PP, short cervical length, anterior placenta, and partially absent over lying myometrium. Prior UAE is a novel risk factor associated with increased prevalence of APH.Keywords: placenta previa, antepartum hemorrhage, bleeding, pregnancy complications, risk factor

Ting-Ting Tan, Qiu-Lei Sun, Li Luo, Zhu Chen, Xi Xiong, Jin-Hong Xiang, Ping Yan, Chun-Yan Gao, Zheng-Qiong Chen Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaCorrespondence: Zheng-Qiong ChenDepartment of Obstetrics and Gynecology, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaTel +86-23-6877-4012Email chenzhengqiong75@163.comPurpose: To validate a 10-point scoring system for the prediction of successful treatment modality in patients with cesarean scar pregnancy (CSP).Patients and Methods: Data were collected from women seen between April 1, 2018, and June 30, 2019, at the Second Affiliated Hospital of Army Medical University of China who were diagnosed with CSP and underwent evacuation, followed by uterine artery embolization (UAE) and successive laparoscopic local resection as salvage treatment if necessary. A score was computed based on clinical and ultrasonographic parameters included in a previously developed scoring system. Treatment indicated by the scoring system was compared with actual treatment received. Receiver operating characteristic (ROC) curves were used to identify cut-off scores for salvage treatment.Results: Of 183 women, 108 were successfully treated by evacuation, 57 required UAE, and 18 eventually underwent laparoscopic surgery. Among 97 women scoring 0– 4, 89 (91.8%) were treated by evacuation only. Of 69 women scoring between 5 and 7, 44 (63.8%) needed UAE following evacuation. Of 17 women scoring 8– 10, 10 women (58.8%) underwent laparoscopic surgery. A cut-off of 4.145 was obtained by ROC curve for prediction of any salvage treatment; this was comparable to the scale’s conventional cut-off of 4. The cut-off score for women requiring laparoscopic surgery was 6.580, which was lower than 8 obtained in the scale’s initial validation.Conclusion: The overall performance of the 10-point scoring system was moderate for predicting successful treatment modalities of women with CSP, but the scale showed good predictive ability in recognizing women needing only evacuation before recovery.Keywords: cesarean scar pregnancy, 10-point scoring system, validation, evacuation

Feng Li,1,2,* Qingshui Wang,3,* Xiaoxue Xiong,3 Chenyi Wang,3 Xiaohua Liu,4 Ziqiang Liao,3 Ke Li,3 Bifeng Xie,5 Yao Lin3 1Department of Pathology, Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 2Department of Pathology, Fujian Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; 3Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, People’s Republic of China; 4Department of Obstetrics, Anxi County Hospital, Anxi, Fujian Province, People’s Republic of China; 5College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, People’s Republic of China *These authors contributed equally to this work Background: Eukaryotic translation initiation factor 4E (eIF4E) is a key regulator of protein synthesis. Changes in eIF4E activity disproportionally affect the translation of a subset of oncogenic mRNAs in some cancers. Materials and methods: We have assessed the expression levels of vascular endothelial growth factor C (VEGFC), eIF4E, eIF4E-binding proteins (4E-BPs) and phospho-4E-BP1 in clear cell renal carcinoma (ccRCC; n=101) using immunohistochemistry and analyzed the relevant mRNA levels and survival using online databases. Results: The protein levels of VEGFC, an eIF4E-regulated gene, were upregulated in ccRCC tissues compared with adjacent normal renal tissues, indicating an enhanced eIF4E activity in ccRCC. The expression of eIF4E had no significant changes in ccRCC tissues. However, 4E-BP1 and phospho-4E-BP1 were found to be overexpressed in ccRCC tissues (P

Chao Zhang,1 Haiyan Li,2 Xin Xiong,1 Suodi Zhai,1 Yudong Wei,2 Shuang Zhang,2 Yuanyuan Zhang,1 Lin Xu,2 Li Liu1 1Department of Pharmacy, 2Institute of Clinical Trial, Peking University Third Hospital, Beijing, People’s Republic of China Abstract: We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet®) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax), extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration–time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations. Keywords: pharmacokinetics, safety, ethinylestradiol/gestodene, transdermal contraceptive patch

Xiaozhou Fan,1 Yanli Guo,1 Luofu Wang,2 Xingyu Xiong,1 Lianhua Zhu,1 Kejing Fang1 1Department of Ultrasound, Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China; 2Department of Urology, Daping Hospital, Institute of Surgery Research, Third Military Medical University, Chongqing, People’s Republic of China Abstract: In this study, the lipid targeted nanobubble carrying the A10-3.2 aptamer against prostate specific membrane antigen was fabricated, and its effect in the ultrasound imaging of prostate cancer was investigated. Materials including 2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and polyethyleneglycol-2000 were for mechanical oscillation, and nanobubbles were obtained through the centrifugal flotation method. After mice were injected with nanobubbles, abdominal color Doppler blood flow imaging significantly improved. Through left ventricular perfusion with normal saline to empty the circulating nanobubbles, nanobubbles still existed in tumor tissue sections, which demonstrated that nanobubbles could enter tissue spaces via the permeability and retention effect. Fluorinated A10-3.2 aptamers obtained by chemical synthesis had good specificity for PSMA-positive cells, and were linked with carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid molecules from the outer shell of nanobubbles via amide reaction to construct targeted nanobubbles. Gel electrophoresis and immunofluorescence confirmed that targeted nanobubbles were fabricated successfully. Next, targeted nanobubbles could bind with PSMA-positive cells (C4-2 cells), while not with PSMA-negative cells (PC-3 cells), using in vitro binding experiments and flow cytometry at the cellular level. Finally, C4-2 and PC-3 xenografts in mice were used to observe changes in parameters of targeted and non-targeted nanobubbles in the contrast-enhanced ultrasound mode, and the distribution of Cy5.5-labeled targeted nanobubbles in fluorescent imaging of live small animals. Comparison of ultrasound indicators between targeted and non-targeted nanobubbles in C4-2 xenografts showed that they had similar peak times (P>0.05), while the peak intensity, half time of peak intensity, and area under the curve of ½ peak intensity were significantly different (P

Xiaozhou Fan,1,* Luofu Wang,2,* Yanli Guo,1 Xingyu Xiong,1 Lianhua Zhu,1 Kejing Fang1 1Department of Ultrasound, Southwest Hospital, 2Department of Urology, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China *These authors contributed equally to this work Abstract: Ultrasound (US)-targeted microbubble destruction has been widely used as an effective drug-delivery system. However, nanobubbles (NBs) have better stability and stronger penetration than microbubbles, and drug delivery assisted by US-targeted NB destruction (UTND) still needs to be investigated. Our aim was to investigate the effect of doxorubicin (DOX) on the inhibition of prostate cancer growth under UTND. Contrast-enhanced US imaging of transplanted PC3 prostate cancer in mice showed that under a combination of 1 W/cm2 US power and a 100 Hz intermittent pulse with a “5 seconds on, 5 seconds off” mode, NBs with an average size of (485.7±33) nm were effectively destroyed within 15 minutes in the tumor location. PC3 cells and 20 tumor-bearing mice were divided into four groups: a DOX group, a DOX + NB group, a DOX + US group, and a DOX + NB + US group. The cell growth-inhibition rate and DOX concentration of xenografts in the DOX + NB + US group were highest. Based on another control group and these four groups, another 25 tumor-bearing mice were used to observe the treatment effect of nine DOX injections under UTND. The xenografts in the DOX + NB + US group decreased more obviously and had more cellular apoptosis than other groups. Finally, electron microscopy was used to estimate the cavitation effect of NBs under US irradiation in the control group, NB group, US group, and NB + US group. The results of scanning electron microscopy showed that PC3 cells in the DOX + NB + US group had more holes and significantly increased cell-surface folds. Meanwhile, transmission electric microscopy confirmed that more lanthanum nitrate particles entered the parenchymal cells in xenografts in the NB + US group compared with the other groups. This study suggested that UTND technology could be an effective method to promote drugs to function in US-irradiated sites, and the underlying mechanism may be associated with a cavitation effect. Keywords: ultrasound therapy, nanobubble, cavitation effect, prostate cancer

Hong Yang, Xiaoyan Xiong, Lie Zhang, Chunhui Wu, Yiyao LiuDepartment of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of ChinaAbstract: The expression of certain endothelial cell adhesion molecules is increased during endothelial dysfunction or inflammatory activation. This has led to the concept of using microbubbles for targeted molecular imaging or drug delivery. In this approach, microbubbles with a specific ligand to receptors expressed at the site of specific diseases are constructed. The present study aimed to engineer a novel type of bio-functionalized microbubbles (vascular cell adhesion molecule 1 [VCAM-1]-targeted microbubbles), and determine whether VCAM-1-targeted microbubbles exhibit specific adhesion to lipopolysaccharide (LPS)-activated endothelial cells. Our data showed that VCAM-1expression was significantly upregulated in both LPS-activated endothelial cells in vitro and endothelium in a rat atherosclerosis model in vivo. Targeted microbubbles were designed by conjugating anti-VCAM-1 monoclonal antibodies to the shell of microbubbles using biotin–avidin bridging chemistry methods. Microbubble adhesion to endothelial cells was assessed in a flow chamber at two shear stress conditions (6.3 and 10.4 dynes/cm2). Our data showed that microbubble adhesion depends on both the surface anti-VCAM-1 antibody densities and the exposed shear stresses. Adhesion of VCAM-1-targeted microbubbles onto LPS-activated endothelial cells increased with the surface antibody densities, and decreased with the exposed shear stresses. These findings showed that the specific ligand-carrying microbubbles have considerable potential in targeted ultrasound molecular imaging or ultrasound-assisted drug/gene delivery applications.Keywords: targeted microbubbles, VCAM-1, adhesion, HUVEC-CS, shear flow