Search

Ying Yang,1– 3,* Bixia Zhou,1,2,* Min Li,4 Yishuai Sun,1,2 Xulei Jiang,1,2 Xinxin Zhou,1,2 Chengjun Hu,1,2 Dou Zhang,3 Hang Luo,3 Wuyuan Tan,1,2 Xinghua Yang,1,2 Shaorong Lei1,2 1Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, People’s Republic of China; 3State Key Laboratory of Powder Metallurgy, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Oncology, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaorong Lei, Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 73189753014, Email leishaorong@csu.edu.cn Xinghua Yang, Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 73189753014, Email yxhua8805@sina.comPurpose: The treatment of craniofacial bone defects caused by trauma, tumors, and infectious and degenerative diseases is a significant issue in current clinical practice. Following the rapid development of bone tissue engineering (BTE) in the last decade, bioactive scaffolds coupled with multifunctional properties are in high demand with regard to effective therapy for bone defects. Herein, an innovative bone scaffold consisting of GO/Cu nanoderivatives and GelMA-based organic-inorganic hybrids was reported for repairing full-thickness calvarial bone defect.Methods: In this study, motivated by the versatile biological functions of nanomaterials and synthetic hydrogels, copper nanoparticle (CuNP)-decorated graphene oxide (GO) nanosheets (GO/Cu) were combined with methacrylated gelatin (GelMA)-based organic-inorganic hybrids to construct porous bone scaffolds that mimic the extracellular matrix (ECM) of bone tissues by photocrosslinking. The material characterizations, in vitro cytocompatibility, macrophage polarization and osteogenesis of the biohybrid hydrogel scaffolds were investigated, and two different animal models (BALB/c mice and SD rats) were established to further confirm the in vivo neovascularization, macrophage recruitment, biocompatibility, biosafety and bone regenerative potential.Results: We found that GO/Cu-functionalized GelMA/β-TCP hydrogel scaffolds exhibited evidently promoted osteogenic activities, M2 type macrophage polarization, increased secretion of anti-inflammatory factors and excellent cytocompatibility, with favorable surface characteristics and sustainable release of Cu2+. Additionally, improved neovascularization, macrophage recruitment and tissue integration were found in mice implanted with the bioactive hydrogels. More importantly, the observations of microCT reconstruction and histological analysis in a calvarial bone defect model in rats treated with GO/Cu-incorporated hydrogel scaffolds demonstrated significantly increased bone morphometric values and newly formed bone tissues, indicating accelerated bone healing.Conclusion: Taken together, this BTE-based bone repair strategy provides a promising and feasible method for constructing multifunctional GO/Cu nanocomposite-incorporated biohybrid hydrogel scaffolds with facilitated osteogenesis, angiogenesis and immunoregulation in one system, with the optimization of material properties and biosafety, it thereby demonstrates great application potential for correcting craniofacial bone defects in future clinical scenarios. Keywords: nanomaterials, hybrid hydrogel, bone scaffolds, craniofacial bone defects, bone regeneration

Sifeng Shi, Weiran Shi, Bing Zhou, Shang Qiu Department of Orthopedic Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Sifeng Shi, Email shisifeng20071@163.com; Shang Qiu, Email shangqiu20132@163.comAbstract: Orthopedic infection is one of the most intractable orthopedic problems. Bacteria resistant to antibiotics also develop gradually. Chitosan is widely used in the Biomedical field because of its high biocompatibility, biodegradability, and antibacterial activity. Chitosan-based drug delivery systems are frequently utilized to produce controlled medication release. When combined with antibiotics, synergistic antibacterial effects can be achieved. Chitosan-based nanoparticles are one of the most widely used applications in drug delivery systems. The focus of this review is to provide information on new methods being developed for chitosan-based nanoparticles in the field of bone infection treatment, including chitosan nanoparticles for antibacterial purposes, Ch-loaded with antibiotics, Ch-loaded with metal, and used as immune adjuvants. It may Provide ideas for the fundamental research and the prospects of future clinical applications of orthopedic infections.Keywords: chitosan nanoparticles, orthopedic infection, chitosan-based nanoparticles, staphylococcus aureus

Jiayi Wang,1,&ast; Yuanyuan Wang,1,&ast; Bangguo Zhou,2 Lin Wang,3 Zhangqi Lai1 1The Third School of Clinical Medicine (School of Rehabilitation Medicine), Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Shanghai, People’s Republic of China; 3Key Laboratory of Exercise and Health Sciences (Shanghai University of Sport), Ministry of Education, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Wang, Key Laboratory of Exercise and Health Sciences (Shanghai University of Sport), Ministry of Education, Shanghai, People’s Republic of China, Email wanglin@sus.edu.cn Zhangqi Lai, The Third School of Clinical Medicine (School of Rehabilitation Medicine), Zhejiang Chinese Medical University, Binwen Road 548, Binjiang District, Hangzhou, People’s Republic of China, Email laizhangqi@126.comIntroduction: The risk of falls among the elderly significantly increases, which has become a serious public health concern. Falls can not only lead to serious complications such as fractures and brain injuries but also limit their mobility function, reducing quality of life. Foot intrinsic muscles (FIMs) are an essential part of foot core stability even overall postural stability. This study aimed to investigate the effects of aging on the function of FIMs and to explore the influence of FIMs on postural control in the elderly.Materials and Methods: 56 healthy old participants (60– 75 years) and 57 healthy young participants (18– 29 years) joined this study. An ergoFet dynamometer was used to determine foot muscle strength (Doming, T1, T23 and T2345), and ankle muscle strength (plantarflexion and dorsiflexion). The morphology of FIMs and extrinsic foot muscle was determined using a Doppler ultrasound system, whereas the postural stability was assessed through Limits of Stability test. Independent samples t-test was used to determine the differences in strength and morphological parameters and Spearman correlation analysis was used to determine whether an association existed between muscle strength and postural stability parameters in the elderly.Results: Compared with young adults, foot muscle strength and ankle muscle strength (Doming, T1, T23, T2345, dorsiflexion, and plantarflexion, all p < 0.05) and the morphology of foot muscles (all p < 0.05) were significantly reduced in the elderly. The strength of FIMs and the limit of stability (r = 0.302– 0.424, all p < 0.05) were significantly correlated in the elderly.Conclusion: Compared with young adults, the weakness of strength as well as the morphological decline of the intrinsic and extrinsic foot muscles were found in the elderly. In addition, a correlation was observed between FIM’s strength and postural stability in the elderly, suggesting their potential role in posture stability.Keywords: postural stability, aging, foot core system, fall, foot intrinsic muscle, FIMs

Jian Zhao,1 Surong Liang,2 Boyang Zhou,1 Min Li,3 Linfeng Li1 1Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Clinical Epidemiology and Evidence Based Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Linfeng Li, Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Beijing, 100050, People’s Republic of China, Tel +86-10-63139108, Email zoonli@sina.comObjective: To assess the correlations between Immunoglobulin E (IgE) levels, pruritus, and lesion severity in patients with eczema, atopic dermatitis, or urticaria.Methods: A retrospective study was conducted and data of 814 patients who visited the dermatology or allergy clinics of multiple hospitals, from December 2019 to December 2021, were collected. Patients were divided into children group (< 18 years, 325 cases), adult group (18– 60 years, 435 cases), and older population group (> 60 years, 54 cases) based on the age. Baseline information, pruritus severity, severity of skin lesions, total IgE level, and specific IgE level were recorded to analyze the complex relationship between them.Results: The prevalence of allergic conjunctivitis and allergic rhinitis in the children group was significantly higher than that in the adult and older population group (P < 0.01 or P < 0.05). The positive rate of specific IgE in children group was significantly higher than that in the adult and older population group (P < 0.01). The IgE levels in children with moderate pruritus were significantly lower than those of severe pruritus (63.39vs 114.42 IU/mL, P < 0.05). The IgE levels in children with mild and moderate skin lesions were significantly lower than those in children with severe skin lesions (58.95 vs 72.88 vs 169.15 IU/mL, P < 0.001 or P < 0.01, respectively).Conclusion: Relationships among age, severity of skin pruritus and lesions, and allergen-specific IgE response are complex and subtle, displaying dynamic patterns.Keywords: multi-center analysis, immunoglobulin E, pruritus severity, lesion severity

Jingchao Jia,1,2,&ast; Jing Yang,3,&ast; Leimin Qian,2 Biao Zhou,2 Xiaodong Tang,2 Shuanghai Liu,2 Li Wu,4 Jifeng Chen,5 Yuting Kuang1 1Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of General Surgery, Jiangyin Hospital Affiliated to Nantong University, Wuxi, People’s Republic of China; 3Jiangnan University Medical Center, Wuxi, People’s Republic of China; 4Department of Pharmaceutics, People’s Hospital of Shanggao, Yichun, People’s Republic of China; 5The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuting Kuang, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email yuting_kuang@163.com Jifeng Chen, The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, People’s Republic of China, Email chenjifeng-1987@163.comIntroduction: Spatiotemporally controlled release of siRNA for anti-tumor therapy poses significant challenges. Near-infrared (NIR) light, known for its exceptional tissue penetration and minimal tissue invasiveness, holds promise as a viable exogenous stimulus for inducing controlled siRNA release in vivo. However, the majority of light-responsive chemical bonds exhibit absorption wavelengths in the ultraviolet (UV) or short-wavelength visible light range.Methods: To achieve NIR-controlled siRNA release, the study synthesized a UV-sensitive triblock copolymer cRGD-poly(ethylene glycol)-b-poly(aspartic acid ester-5-(2’-(dimethylamino)ethoxy)-2-nitrobenzyl alcohol)-b-polyphenylalanine, abbreviated as cRGD-PEG-PAsp(EDONB)-PPHE. This copolymer is composed of a cRGD-capped PEG block (cRGD-PEG), a poly(aspartate) block modified with cationic moieties through UV-cleavable 2-nitrobenzyl ester bonds [PAsp(EDONB)], and a hydrophobic polyphenylalanine block (PPHE). The cationic amphiphilic polymer cRGD-PEG-PAsp(EDONB)-PPHE can assemble with hydrophobic upconversion nanoparticles (UCNPs) to form a cationic micelle designated as T-UCNP, which subsequently complexes with siRNA to create the final nanopolyplex T-si/UCNP. siRNA-PLK1 was employed to prepare T-PLK1/UCNP nanopolyplex for anti-tumor therapy.Results: T-PLK1/UCNP not only exhibited outstanding tumor cell targeting through cRGD modification but also achieved 980 nm NIR-controlled PLK1 gene silencing. This was achieved by utilizing the encapsulated UCNPs to convert NIR into UV light, facilitating the cleavage of 2-nitrobenzyl ester bonds. As a result, there was a significant suppression of tumor growth.Conclusion: The UCNPs-encapsulated nanopolyplex T-si/UCNP, capable of co-delivering siRNA and UCNPs, enables precise NIR-controlled release of siRNA at the tumor site for cancer RNAi therapy. This nanopolyplex can enhance the controllability and safety of RNAi therapy for tumors, and it also holds the potential to serve as a platform for achieving controlled release and activation of other drugs, such as mRNA and DNA.Keywords: NIR-controlled siRNA release, nanopolyplex, UCNPs, anti-tumor therapy

Jiongchao Guo,1,&ast; Yuan Zhou,1,&ast; Bingfeng Zhou2 1Department of Cardiology, the Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Cardiology, Hefei BOE Hospital, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bingfeng Zhou, Department of Cardiology, Hefei BOE Hospital, Hefei, Anhui, 230000, People’s Republic of China, Tel +8613956078803, Email xnkzbf@126.comBackground and Aims: Non-valvular atrial fibrillation (NVAF) patients face a 3– 5 times greater risk of acute ischemic stroke (AIS) compared to those without NVAF. This study aims to establish a novel clinical prediction model for AIS in elderly patients with NVAF by incorporating relevant biomarker indicators.Methods: A total of 301 individuals diagnosed with NVAF were selected for this investigation at the Third Affiliated Hospital of Anhui Medical University. Based on the presence of AIS, patients were categorized into two groups: the Stroke Cohort and the Non-Stroke Cohort. Predictor screening was performed using the least absolute shrinkage and selection operation (LASSO) regression algorithm. The binary logistic regression equation was applied to fit the model, followed by internal validation using the bootstrap resampling method (1000 times). Receiver operating characteristic (ROC) curve, calibration degree curve plots, and clinical decision curve analysis (DCA) were generated, respectively. Finally, a nomogram was constructed to present the prediction model.Results: The final results of this study revealed that neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW), lipoprotein(a) (Lp(a)), systolic pressure, history of stroke, hyperlipidemia were independent risk factors for AIS in elderly patients with NVAF (P< 0.05). And the high-density lipoprotein cholesterol (HDL-C) was an independent protective factor (P< 0.05). By incorporating these indicators, a nomogram prediction model for predicting AIS in elderly patients with NVAF was constructed. Comparative analysis between the nomogram predictive model and CHA2DS2-VASc score revealed that the AUC of the nomogram predictive model surpassed that of the CHA2DS2-VASc score (AUC: 0.881vs 0.850).Conclusion: NLR, RDW, Lp(a), SP, history of stroke, hyperlipidemia, and HDL-C emerge as independent prognostic factors for acute ischemic stroke in elderly patients with non-valvular atrial fibrillation. The predictive utility of the nomogram model may potentially surpass that of the CHA2DS2-VASc scoring system.Keywords: acute ischemic stroke, non-valvular atrial fibrillation, nomogram, clinical risk prediction model

Yang Zhao,1 Ruizhe Wang,2 Hebin Li,3 Chong Chen,4 Bowen Zhou,5 Xinying Weng,3 Yidi Hua,6 Yaqi Jia,7 Yajun Wu,8 Ying Li9 1Faculty of Law, Qingdao University, Qingdao, People’s Republic of China; 2HeXie Management Research Center, Xi’an Jiaotong-Liverpool University, Suzhou, People’s Republic of China; 3Department of Social and Behavioural Sciences, City University of Hong Kong, Hong Kong, People’s Republic of China; 4CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 5Department of Social Work, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 6School of Humanities and Social Science, The Hong Kong University of Science and Technology, Hong Kong, People’s Republic of China; 7Entrepreneurs College, Xi’an Jiaotong-Liverpool University, Suzhou, People’s Republic of China; 8Department of Applied Psychology, Guangdong University of Foreign Studies, Guangzhou, People’s Republic of China; 9School of Urban Governance and Public Affairs, Suzhou City University, Suzhou, People’s Republic of ChinaCorrespondence: Ying Li, Email yingli.szcityu@gmail.comIntroduction: This longitudinal study aims to investigate the relationship between fear of COVID-19, support-seeking behaviors, and perceived social support among Chinese college students during two distinct periods of the COVID-19 pandemic: the period of strict control (time 1) and the period following a relaxation of restrictions (time 2).Methods: A total of 408 Chinese college students participated in this study. Data collection included demographic information, measures of fear of COVID-19, support-seeking behaviors, and perceived social support.Results: Fear of COVID-19 at time 1 showed a significant positive association with fear of COVID-19 at time 2. The relationship between support-seeking behavior at time 1 and fear of COVID-19 at time 2 was significantly mediated through a chain mediation effect of support-seeking behavior at time 1 and perceived social support at time 2.Discussion: This study contributes to the growing body of evidence on the psychological impacts of the COVID-19 pandemic and underscores the significance of social support in mitigating fear of COVID-19. It calls for a re-evaluation of public health policies considering their potential psychological effects and introduces new opportunities for developing psychosocial interventions.Keywords: fear of COVID-19, social support, Chinese students, COVID-19 policy, longitudinal study

Yanjie Yang,1,2,&ast; Nan Du,1,2,&ast; Jingqin Ma,1,2,&ast; Zhijie Peng,1,2 Bo Zhou,1,2 Jiaze Yu,1,2 Xin Zhou,1,2 Wen Zhang,1,2 Zhiping Yan1,2 1Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Institute of Medical Imaging, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiping Yan; Wen Zhang, Email zhipingyan@fudan.edu.cn; zhang.wen2@zs-hospital.sh.cnObjective: This study aimed to assess the treatment response, survival outcomes, and safety of a novel transarterial chemoembolization (TACE) technique with a three-stage mixed chemoembolic regimen (M-TACE) in patients with large unresectable hepatocellular carcinoma (HCC) measuring more than 5 cm in maximum diameter.Methods: Between January 2017 and March 2023, a total of 82 patients were enrolled in this retrospective cohort study. Treatment response was assessed in the first month after M-TACE; progression-free survival and overall survival (OS) were evaluated. The prognostic factors associated with patient survival were statistically analyzed by the Cox regression model. Adverse events were recorded.Results: The maximum diameter of the tumors ranged from 5.3 cm to 20.0 cm (mean 10.71 cm). The objective response (OR) and disease control rates were 74.4 and 92.7%, respectively, at 1-month follow-up. The median survival time was 22 months (95% CI, 13.10– 30.90 months). The OS rates were 82.0% at six months, 62.5% at one year, and 43.0% at two years. Targeted therapy and/or immunotherapy (P=0.001) and tumor response at one month (P=0.020) were protective factors for OS. In terms of safety, no major complications occurred and the only observed decrease within the normal range occurred in albumin and platelet levels one month after the embolization procedure. This decrease in levels did not show a significant relationship with the OR rates.Conclusion: M-TACE demonstrated a promising objective tumor response, making it a viable and effective treatment option for patients with large unresectable HCC.Plain Language Summary: 1. A groundbreaking TACE therapy for large unresectable hepatocellular carcinoma demonstrates enhanced safety and efficacy compared to conventional TACE methods. 2. The M-TACE technique effectively minimizes the required lipiodol dosage for the treatment of large unresectable hepatocellular carcinoma, optimizing patient care and reducing potential complications. 3. The M-TACE technique employs a three-stage approach, strategically implementing segmental embolization based on the diameter of the vessels, thereby enhancing the precision and efficacy of the treatment.Keywords: hepatocellular carcinoma, transarterial chemoembolization, treatment response, prognosis, adverse events

Jiongchao Guo,1,2 Min Chen,3 Yu Hong,1,2 Yating Huang,1,4 Haiyan Zhang,2 Yuan Zhou,1,2 Bingfeng Zhou,1,5 Minmin Fu1 1Department of Cardiology, The Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, 230000, People’s Republic of China; 2Graduate School, Anhui Medical University, Hefei, Anhui, 230000, People’s Republic of China; 3Department of Cardiology, the Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230000, People’s Republic of China; 4Department of Endocrinology department, the Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, 230000, People’s Republic of China; 5Department of Cardiology, Hefei BOE Hospital, Hefei, Anhui, 230000, People’s Republic of ChinaCorrespondence: Minmin Fu, Department of Cardiology, the Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, 230000, People’s Republic of China, Email fuminmin@126.com Bingfeng Zhou, Department of Cardiology, The Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei BOE Hospital, Hefei, Anhui, 230000, People’s Republic of China, Email xnkzbf@126.comBackground: Neutrophil to high-density lipoprotein cholesterol ratio (NHR) has demonstrated predictive value for coronary artery disease (CAD). However, few research has been conducted on the predictive capacity of NHR for Major Adverse Cardiovascular Events (MACE) following Percutaneous Coronary Intervention (PCI) or the degree of coronary artery stenosis in hospitalized ST-segment elevation myocardial infarction (STEMI) patients.Methods: The study involved 486 patients diagnosed with STEMI between the years 2020 and 2023. Univariate and multivariate logistic regression analyses were conducted to evaluate the risk factors for MACE after PCI and severe coronary artery stenosis during hospitalization. Receiver operating characteristic (ROC) curves were generated to determine predictive power of NHR and MHR. Spearman correlation analysis was performed to assess the correlation between NHR, MHR and the Gensini score (GS).Results: Multivariate logistic regression analysis showed that the NHR and MHR were the independent risk factor for MACE during hospitalization in STEMI patients (MHR: the odds ratio (OR)=2.347, 95% confidence interval (CI)=1.082– 5.089, P=0.031) (NHR: OR=1.092, 95% CI=1.025– 1.165, P=0.004). In addition, NHR was also an independent risk factor for high GS (NHR: OR=1.103, 95% CI=1.047– 1.162, P< 0.001), and the MHR was not an independent risk factor. The ROC curve analysis was performed to evaluate the predictive ability of NHR and MHR for in-hospital MACE in STEMI patients after primary PCI. The area under the curve (AUC) for NHR was 0.681. The AUC for MHR was 0.672. Regarding the prediction of high GS, the AUC for NHR was 0.649. The AUC for MHR was 0.587. Spearman correlation analysis showed that NHR exhibited stronger correlation with GS, while MHR was lower (NHR: r=0.291, P< 0.001) (MHR: r=0.156, P< 0.001).Conclusion: These findings highlight the potential clinical utility of NHR as a predictive indicator in STEMI patients after PCI during hospitalization, both for MACE events and the degree of coronary artery stenosis.Keywords: neutrophil to high-density lipoprotein cholesterol ratio, monocyte to high-density lipoprotein cholesterol ratio, acute myocardial infarction, coronary artery disease, cardiovascular disease

Xinli Mu,1,&ast; Jianghong Liang,2,&ast; Linyan Qian,3 Bing Zhou,4 Xuehan Zou,5 Ying Fu,6 Yongze Zhu,2 Xi Li,2 Jiana Shi7 1Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 3Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 4Heart Center, Department of Cardiovascular Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 5Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 7Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xi Li, Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel/Fax +86-571-8589-3267, Email lixi_0611@163.com Jiana Shi, Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel +86-571-8589-3899, Email shijjnn@126.comAbstract: Infective endocarditis (IE) is a rare disease but with high associated mortality. Currently, the mainstays of diagnosis are still echocardiography and blood cultures. Here, we reported a case of infective endocarditis with negative blood cultures, and blood and aortic valve tissue metagenomic next-generation sequencing (mNGS) results suggested Bartonella henselae. In addition, we obtained the whole genomic sequence of B. henselae ZJBH strain. To our knowledge, this is the first report of B. henselae genomic analysis isolated from clinic in China. Furthermore, we described the whole genome sequencing (WGS) data incorporating all B. henselae from diverse sources worldwide and shed light on underlying risk of B. henselae transmitted between cats and humans.Keywords: infective endocarditis, Bartonella henselae, metagenomic next-generation sequencing

Xiaoxiao Xu, Bin Zhou, Jun Liu, Qianli Ma, Tengyu Zhang, Xiang Wu The First Hospital of Ningbo University, Ningbo, 315211, People’s Republic of ChinaCorrespondence: Xiang Wu, The First Hospital of Ningbo University, Ningbo, 315211, People’s Republic of China, Email fywuxiang2@nbu.edu.cnPurpose: Ru360, a selective inhibitor of mitochondrial calcium uptake, maintains mitochondrial calcium homeostasis. To evaluate whether mitochondrial calcium uniporter (MCU)-mediated mitochondrial function is associated with the pathological process of Postoperative cognitive dysfunction (POCD), elucidate its relationship with neuroinflammation, and observe whether the relevant pathological process can be improved with Ru360.Methods: Aged mice underwent experimental open abdominal surgery after anesthesia. Open field tests, Novel object recognition tests and Y Maze Tests were used to conduct behavioral experiments. The reactive oxygen species (ROS) content, the levels of inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), intra-mitochondrial calcium, mitochondrial membrane potential (MMP) and the activity of antioxidant superoxide dismutase (SOD) in the hippocampus of mice were detected using kits. The expression of proteins was detected using Western blot.Results: After treatment with Ru360, MCU-mediated mitochondrial dysfunction was inhibited, neuroinflammation was reduced, and the learning ability of the mice was improved after surgery.Conclusion: Our study demonstrated that mitochondrial function plays a crucial role in the pathology of POCD, and using Ru360 to improve mitochondrial function may be a new and necessary direction for the treatment of POCD.Keywords: postoperative cognitive dysfunction, mitochondria, Ru360, mitochondrial calcium uniporter, neuroinflammation

Zhi Qiang Luo,1,&ast; Biao Zhou,2,3,&ast; Hui Xiong1 1Department of Graduate School, Hunan University of Chinese Medicine, Changsha City, Hunan Province, People’s Republic of China; 2Department of Orthopedics, Xiangtan First People’s Hospital, Xiangtan City, Hunan Province, People’s Republic of China; 3Department of Orthopedics, Wangjing Hospital of Chinese Academy of Chinese Medical Science, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Xiong, Department of Graduate School, Hunan University of Chinese Medicine, Changsha City, Hunan Province, People’s Republic of China, Tel +86 13808456990, Email xh_hn@hnucm.edu.cn Biao Zhou, Department of Orthopedics, Xiangtan First People’s Hospital, Xiangtan City, Hunan, People’s Republic of China, Email ortho_zhou1986@163.comPurpose: Osteoarthritis (OA) is a common clinical disease characterized by the destruction of articular cartilage, subchondral ossification, cystic degeneration and osteophyte formation. Recently, more and more scholars draw attention to exosomes in the field of OA, and exciting breakthroughs have been achieved in recent years. However, bibliometric analysis of the literature in this research field is lacking. Considering its potential in treatment of OA, this article aimed to analyze the research status and identify future hotspots of exosomes in osteoarthritis in recent 10 years by bibliometrics tools.Methods: Relevant publications in this field from 2012 to 2022 was retrieved from the Web of Science core collection database (WOSSCC). And we used Vosviewers, CiteSpace, an online analysis platform and the R package “Bibliometrix” for bibliometric analysis.Results: A total of 484 publications (including 319 articles and 165 reviews) from 51 countries, 720 institutions, were included in this study. IRCCS Ist Ortoped Galeazzi, Shanghai Jiao Tong University, and Sun Yat-sen University are the leading research institutions in this field. International Journal of Molecular Sciences contributed the largest number of articles, and Osteoarthritis and Cartilage is the most co-cited journal. Of the 2664 scholars who participated in the study, Ragni E, De Girolamo L, Orfei CP, and Colombini A had the largest number of articles. Zhang, SP is the most co-cited author. “Mesenchymal stem cell”, “biomaterials”, “Inflammation” and “regenerative medicine” are the keywords in the research.Conclusion: This is the first bibliometric analysis of exosomes in osteoarthritis. We explored current research status in recent years and identified frontiers and hot spots in this research field. We highlight the significant roles of mesenchymal stem cell-derived exosomes (MSC-Exos) in the treatment of osteoarthritis, and identified exosomal biomaterials as frontier in this research domain, which can provide reference for the researchers who focus on this research field.Keywords: exosomes, osteoarthritis, bibliometric analysis, CiteSpace, VOSviewer, R package “bibliometrix&#x201D

Jincheng Guan,1 Qiong Wang,1 Jiajia Hu,2 Yepeng Hu,1 Qiaoyu Lan,1 Guoqiang Xiao,1 Borong Zhou,2 Haitao Guan1 1Department of Neurology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Psychiatry, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Borong Zhou, Department of Psychiatry, the Third Affiliated Hospital of Guangzhou Medical University, No. 63, Duobao Road, Liwan District, Guangzhou, Guangdong, 510150, People’s Republic of China, Email zhoubr8@aliyun.com Haitao Guan, Department of Neurology, the Third Affiliated Hospital of Guangzhou Medical University, No. 63, Duobao Road, Liwan District, Guangzhou, Guangdong, 510150, People’s Republic of China, Email 1614794227@qq.comBackground and Purpose: Futile recanalization (FRC) is common among large artery occlusion (LAO) patients after endovascular therapy (EVT). We developed nomogram models to identify LAO patients at a high risk of FRC pre- and post-EVT to help neurologists select the optimal candidates for EVT.Methods: From April 2020 to July 2022, EVT and mTICI score ≥ 2b LAO patients were recruited. Nomogram models was developed by two-step approach for predicting the outcomes of LAO patients. First, the least absolute shrinkage and selection operator (LASSO) regression analysis was to optimize variable selection. Then, a multivariable analysis was to construct an estimation model with significant indicators from the LASSO. The accuracy of the model was verified using receiver operating characteristic (ROC), calibration curve, and decision curve analyses (DCA), along with validation cohort (VC).Results: Using LASSO, age, sex, hypertension history, baseline NIHSS, ASPECTS and baseline SBP upon admission were identified from the pre-EVT variables. Model 1 (pre-EVT) showed good predictive performance, with an area under the ROC curve (AUC) of 0.815 in the training cohort (TrC) and 0.904 in VC. Under the DCA, the generated nomogram was clinically applicable where risk cut-off was between 15%– 85% in the TrC and 5%– 100% in the VC. Moreover, age, ASPECTS upon admission, onset duration, puncture-to-recanalization (PTR) duration, and lymphocyte-to-monocyte ratio (LMR) were screened by LASSO. Model 2 (post-EVT) also demonstrated good predictive performance with AUCs of 0.888 and 0.814 for TrC and VC, respectively. Under the DCA, the generated nomogram was clinically applicable if the risk cut-off was between 13– 100% in the TrC and 22– 85% of VC.Conclusion: In this study, two nomogram models were generated that showed good discriminative performance, improved calibration, and clinical benefits. These nomograms can potentially accurately predict the risk of FRC in LAO patients pre- and post-EVT and help to select appropriate candidates for EVT.Keywords: acute ischemic stroke, AIS, futile recanalization, endovascular therapy, nomogram model, predictive model

Hongyu Meng,1,2,&ast; Ruixi Li,3,&ast; Yuankang Xie,1,&ast; Zhaohong Mo,2 Hang Zhai,2 Guangquan Zhang,3 Guohui Liang,4 Xianjie Shi,3 Boxuan Zhou1,2 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, People’s Republic of China; 2Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 4School of Clinical Medicine, Henan University, Kaifeng, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boxuan Zhou; Xianjie Shi, Email zhoubx3@mail2.sysu.edu.cn; shixianjie301@126.cmBackground: Circular RNAs (circRNAs) are becoming vital biomarkers and therapeutic targets for malignant tumors due to their high stability and specificity in tissues. However, biological functions of circRNAs in hepatocellular carcinoma (HCC) are still not well studied.Methods: Gene Expression Omnibus (GEO) database and qRT-PCR were used to evaluate expression of circROBO1 (hsa_circ_0066568) in HCC tissues and cell lines. CCK-8, colony formation, EdU staining, flow cytometry for cell cycle analysis, and xenograft model assays were performed to detect the circROBO1 function in vitro and in vivo. RNA pull-down, RNA immunoprecipitation (RIP), and Luciferase reporter assays were used to investigate the relationship among circROBO1, miR-130a-5p, and CCNT2. More importantly, we developed nanoparticles made from poly lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG) chains as the delivery system of si-circROBO1 and then applied them to HCC in vitro and in mice.Results: circROBO1 was obviously upregulated in HCC tissues and cell lines, and elevated circROBO1 was closely correlated with worse prognosis for HCC patients. Functionally, knocking down circROBO1 significantly suppressed HCC cells growth in vitro and in mice. Mechanistically, circROBO1 acted as a competing endogenous RNA to downregulate miR-130a-5p, leading to CCNT2 expression upregulation. Furthermore, miR-130a-5p mimic or CCNT2 knockdown reversed the role of circROBO1 overexpression on HCC cells, which demonstrated that circROBO1 promoted HCC development via miR-130a-5p/CCNT2 axis. In addition, we developed nanoparticles loaded with si-circROBO1, named as PLGA-PEG (si-circROBO1) NPs, which significantly prevented the proliferation of HCC cells, and did not exhibit apparent toxicity to major organs in vivo.Conclusion: Our findings firstly demonstrate that circROBO1 overexpression promotes HCC progression by regulating miR-130a-5p/CCNT2 axis, which may serve as an effective nanotherapeutic target for HCC treatment.Keywords: nanoparticles, hepatocellular carcinoma, circROBO1, cell proliferation, drug delivery

Aifan Li,1,&ast; Tianyi Han,2,&ast; Yongfang Li,1 Gaiqing Yang,3 Yuchao Zhang,4 Yanyang Huang,2 Baixue Zhou,2 Guoying Song,2 Ying He2 1Department of Neurology, The First People’s Hospital of Zhengzhou, Zhengzhou, 450000, People’s Republic of China; 2Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China; 3Department of Geriatric Medicine, the Center Hospital of Zhengzhou Affiliated Zhengzhou University, Zhengzhou, 450004, People’s Republic of China; 4Department of Genetics, First Affiliated Hospital of Xinxiang Medical College, Xinxiang, 453100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying He; Guoying Song, Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, People’s Republic of China, Tel +86-13938517041 ; +86-13633827880, Email heying39@163.com; songguoying226@zzu.edu.cnBackground and Purpose: Studies have shown that matrix metalloproteinase (MMP-2,3,9) plays an important role in the pathologic process of ischemic stroke (IS). The aim of this study was to investigate the relationship between C1306T, 1612– 5A/6A, C-1562T polymorphisms of MMP-2,3,9 genes and IS in Chinese Han population.Methods: The polymorphisms of MMP-2(C1306T), − 3(1612– 5A/6A), − 9(C-1562T) gene were detected by PCR-RFLP and SNaPshot sequencing. Then, stratified analysis was used to study the relationship between IS subtypes and MMP-2,3,9 polymorphisms.Results: For the MMP-2 gene C1306T polymorphism, TT genotype and T allele were significantly associated with a reduced risk of IS (P = 0.015, P = 0.003, respectively). T allele was significantly associated with a reduced risk of small artery occlusion (SAO) subtype compared with the control group (P = 0.012, OR = 0.550, 95% CI = 0.065– 1.291). For the MMP-3 gene-1612 (5A/6A) polymorphism, 5A/5A genotype was significantly increased in the IS group (P = 0.011, OR = 0.370, 95% CI = 0.168– 0.814), especially in the large-artery atherosclerosis (LAA) subtype (P = 0.001, OR = 2.345) as compared to the control group.Conclusion: Our study suggested that the T allele of MMP-2 may be a protective factor of IS, especially in SAO subtype, while the 5A/5A gene of MMP-3 may increase the risk of IS, especially in LAA subtype in Chinese Han population.Keywords: ischemic stroke, matrix metalloproteinase, polymorphism, association study

Avijit Sharma,1 Feng Dai,2 Lanya Tseng,1 Philip R Effraim,1 Bin Zhou,2 Robert B Schonberger,1 Jinlei Li1 1Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA; 2Yale Center for Analytical Sciences, Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USACorrespondence: Jinlei Li, Department of Anesthesiology, Yale University School of Medicine, 20 York Street, New Haven, CT, 06510, USA, Tel +1 917 601 6828, Fax +1 203 785 6664, Email jinlei.li@yale.eduPurpose: Glucocorticoids are commonly used as regional anesthesia adjuvants to improve blockade quality and duration. There are limited data in the literature regarding the potential systemic effects and safety of perineural glucocorticoids. This study examines the effects of perineural glucocorticoids on serum glucose, potassium, and white blood cell count (WBC) in the immediate postoperative period after primary total hip arthroplasty (THA).Patients and Methods: A retrospective cohort study was carried out at a tertiary academic medical center utilizing electronic health records of 210 patients who underwent THA, for which patients received either a periarticular local anesthetic injection alone (PAI, N=132) or additional peripheral nerve blocks (PNB, N=78) containing 10 mg dexamethasone and 80 mg methylprednisolone acetate (PAI+PNB). The primary outcome was change in serum glucose from a preoperative baseline on postoperative days (POD) 1, 2, and 3. Secondary outcomes included changes in WBC and serum potassium.Results: The change in serum glucose from baseline was found to be significantly higher in the PAI+PNB group compared to the PAI group on POD 1 (mean difference 19.87 mg/dL, 95% CI [12.42, 27.32]; P< 0.001) and POD 2 (mean difference 17.5 mg/dL, 95% CI [9.66, 25.44], P< 0.001). No significant difference was found on POD 3 (mean difference − 8.18 mg/dL, 95% CI [− 19.07, 2.70], P=0.14). Statistically significant but clinically insignificant differences were detected in serum potassium in the PAI+PNB group compared to the PAI group on POD1 (mean difference 0.16 mEq/L, 95% CI [0.02, 0.30], P=0.03) and WBC on POD 2 (mean difference 3.18 × 1000/mm3, 95% CI [2.14, 4.22], P< 0.001).Conclusion: Patients who underwent THA and received PAI+PNB with glucocorticoid adjuvants demonstrated higher elevations in serum glucose for the first two PODs compared to patients who received PAI alone. These differences resolved by a third POD and are likely to be of no clinical significance.Keywords: perineural glucocorticoid, perineural dexamethasone, perineural methylprednisolone acetate, total Hip arthroplasty, fascia plane block, serum glucose

Liu Tang,1 Jiefang Gao,2 Xiaolei Li,2 Xiaoqin Cao,3 Benhong Zhou1 1Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2School of Pharmaceutical Sciences, Wuhan University, Wuhan, People’s Republic of China; 3School of Medicine, Jianghan University, Wuhan, People’s Republic of ChinaCorrespondence: Liu Tang; Benhong Zhou, Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Email tangliu900402@whu.edu.cn; benhongzh@whu.edu.cnPurpose: To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation.Methods: TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB).Results: A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin.Conclusion: Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.Keywords: atopic dermatitis, luteolin, network pharmacology, target prediction, experimental validation

Peiyao Li1,2 &ast;, Jialin Qi3 &ast;, Baishun Zhou,1 Ting Ding,4 Juan Long,5 Heng Xiao1 1Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, China NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Department of Endocrinology, Yiyang Central Hospital, Yiyang, People’s Republic of China; 5Department of Dermatology, Hunan Children’s Hospital, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heng Xiao, Department of Pathology, School of Medicine, Hunan Normal University, 371 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel +86-731-88912501, Email emmaxiao1988@hotmail.comBackground: Hailey–Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD.Methods: In this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant.Results: Cycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn2+ solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi.Conclusion: These results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn2+ and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD.Keywords: ATPase secretory pathway Ca2+ transporting 1, Hailey–Hailey disease, pathogenesis, secretory pathway Ca2+/Mn2+-ATPase 1

Runze Li,1,2,&ast; Chuanxiao Wang,3,&ast; Quandong Bu,4 Wenshen Pu,5 Bin Zhou,4 Lin Che,4 Hui Zhang,4 Yan Xu,4 Hong Luan4 1Department of Medicine, Qingdao University, Qingdao, People’s Republic of China; 2Department of Endocrine, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Thoracic Surgery, Qingdao Municipal Hospital, Qingdao, People’s Republic of China; 4Department of Nephrology, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 5Department of Nephrology, Baoshan People’s Hospital, Baoshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Luan, Department of Nephrology, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, People’s Republic of China, Tel +86 18661803208, Fax +86 532-82911601, Email luanhong985@qdu.edu.cnPurpose: Madelung’s disease (MD) is a rare disease characterized by the deposition of unencapsulated fat masses on the face, neck, chest, back and other areas of patients. The aim of the study was to analyze the clinical characteristics, comorbidities and treatment of MD in Chinese populations.Patients and Methods: We retrospectively reviewed the medical records of 54 patients who were diagnosed with MD at the Affiliated Hospital of Qingdao University and Qingdao Municipal Hospital from January 2005 to February 2021 and collected the subjects’ demographic information, clinical indicators, location of fat deposits, treatment, complications and prognostic data.Results: Among 54 MD patients in the study, only 1 (1.85%) was female, and the subjects had an average age of 56.65 ± 7.93 years. More than 70% of patients had a history of long-term smoking or/and alcohol abuse. In our study, type I accounted for approximately 61.11% of cases according to Donhauser’s classification, and almost all patients had neck fat deposition. MD patients often have multiple comorbidities across several systems, such as the endocrine, digestive, circulatory, urinary, and neurological systems. Among these, endocrine system diseases were the most common comorbidities in our study, accounting for 81.48%. Notably, up to 20.37% of cases were complicated with cancer, especially digestive system tumors. More than 70% of the patients received surgical treatment, and nearly 40% experienced postoperative recurrence.Conclusion: Considering that MD patients often have comorbidities of multiple systems and that a small number of cases are even complicated by cancer, we recommend that clinicians comprehensively assess a patient’s condition and complications, advocate that patients quit consuming alcohol and smoking as soon as possible, establish healthy dietary and living habits, and formulate individualized and comprehensive diagnosis and treatment plans.Keywords: Madelung’s disease, multiple symmetric lipomatosis, Launois-Bensaude syndrome, benign symmetric lipomatosis, alcohol abuse

Rui Zhao,1 Jianbo Xue,1 Xueli Zhang,1 Maohuan Peng,1 Jing Li,1 Bing Zhou,1 Long Zhao,1 Thomas Penzel,2 Meir Kryger,3 Xiao Song Dong,1 Zhancheng Gao,1 Fang Han1 1Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Sleep Medicine Center, Charité-Universitätsmedizin, Berlin, Germany; 3Division of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USACorrespondence: Xiao Song Dong; Zhancheng Gao, Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, No. 11 Xizhimen Nandajie, Xicheng District, Beijing, 100044, People’s Republic of China, Email dongxiaosong@pkuph.edu.cn; zcgao@bjmu.edu.cnObjective: A novel ring-worn oximeter (Circul) uses reflective photoplethysmography and automated signal processing to calculate oxygen desaturations. We evaluated the ability of Circul to detect obstructive sleep apnea in Chinese adults.Methods: We recruited 207 Chinese Han subjects: 70% males, mean age 48.2± 14.7 years, mean BMI 27.6± 4.8 kg/m2 and mean AHI 28.6± 25.2 events/h. All participants underwent simultaneous polysomnography (PSG) and Circul testing in a sleep laboratory. Oxygen desaturation index (ODI), mean oxygen saturation (MSpO2), cumulative time at SpO2< 90% (CT90), cumulative percentage of sleep time spent with SpO2< 90% (CT90/TST) were derived and compared for the Circul and the PSG.Results: The ODI was 25.3± 24.5 events/h using PSG and 22.2± 24.5 events/h using Circul (P< 0.0001), with an intraclass correlation coefficient (ICC) of 0.884. CT90 and CT90/TST between the two methods were not different; the MSpO2 level calculated by PSG was slightly lower than Circul, 95.0% (93.0– 96.0%) vs 95.3% (93.9– 96.6%), P< 0.0001. Circul-ODI had a good correlation (r=0.91, p< 0.0001) and close agreement with PSG-AHI (Bland-Altman analysis: Mean Difference 6.4, 95% CI − 14.8 to 27.5 events/h). Using a threshold of AHI ≥ 5 events/h, the Circul had 87% sensitivity, 83% specificity, 5.09 positive likelihood ratio (LR+), 86% accuracy, and 0.929 area under the curve (AUC).Conclusion: Circul ring pulse oximetry can detect OSA with reasonable reliability. The Circul system is a reliable and comfortable choice for OSA assessment.Keywords: obstructive sleep apnea, reflective photoplethysmography, pulse oximetry, polysomnography

Nicole M Del Toro-Pagán,1,2 Feng Dai,3 Trevor Banack,4 Jill Berlin,4 Satya A Makadia,4 Lee E Rubin,5 Bin Zhou,3 Phu Huynh,6 Jinlei Li4 1Department of Pharmacy, Yale New Haven Health - Bridgeport Hospital, Bridgeport, CT, USA; 2Applied Precision Pharmacotherapy Institute, Tabula Rasa HealthCare, Moorestown, NJ, USA; 3Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA; 4Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA; 5Department of Orthopedics and Rehabilitation, Yale School of Medicine, New Haven, CT, USA; 6Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USACorrespondence: Jinlei Li, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, PO Box 208051, New Haven, CT, 06520-8051, USA, Tel + 1 475 434 4038, Email jinlei.li@yale.eduPurpose: Opioid consumption after total knee arthroplasty (TKA) remains a challenge with single injection nerve blocks even with common local anesthetic adjuvants dexamethasone (DEX). This study aimed to investigate the effects of adding methylprednisolone acetate (MPA) to adductor canal blocks (ACB) and interspace between the popliteal artery and capsule of the posterior knee (iPACK) blocks on postoperative opioid consumption.Methods: A retrospective analysis was conducted on 100 consecutive TKA patients equally assigned into two groups, with one group receiving DEX through ACB and iPACK block and the other group receiving DEX and methylprednisolone acetate (DEX/MPA) through the same nerve blocks. The primary outcome was cumulative opioid consumption (oral milligram morphine equivalent, OME) during hospitalization for up to three days. Secondary outcomes included daily opioid consumption, highest rest and active pain scores, prosthetic knee joint active range of motion (AROM), laboratory studies including fasting serum glucose (FSG) and white blood cell count (WBC) on each postoperative day (POD), and length of hospital stay.Results: Cumulative opioid consumption was significantly lower in the DEX/MPA group vs DEX group (median difference (95% CI) = − 45.3 (− 80.5 to − 10), P = 0.011). The highest rest and active pain scores were both significantly lower in the DEX/MPA group than in DEX group on POD 2 (least square mean difference (95% CI) = − 1.3 (− 2.3 to − 0.4), P = 0.005 and − 0.9 (− 1.8 to − 0.1), P = 0.031, respectively). Except on POD 1, FSG values were significantly lower in the DEX/MPA group (median difference (95% CI) = − 22.5 (− 36 to − 8.9), P = 0.001). AROM, WBC, and length of stay were comparable between both groups.Conclusion: Compared to perineural DEX alone, the addition of MPA further decreases postoperative opioid consumption without clinically significant changes on FSG and WBC.Level of Evidence: III.Keywords: perineural, arthroplasty, glucocorticoids, total knee arthroplasty, TKA, peripheral nerve block, PNB, methylprednisolone acetate

Xi Wang,1,2,* Chang Kong,1,3,* Pan Liu,1,2 Baofeng Zhou,1,2 Wujun Geng,1,2 Hongli Tang1,2 1Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Wenzhou Key Laboratory of Perioperative Medicine, Wenzhou, People’s Republic of China; 3Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongli Tang; Wujun Geng, Doctor’s Degree, Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang, 325000, People’s Republic of China, Tel +86 13587436057; +86 15325502139, Fax +86 0577-88069555, Email tanghongliok@126.com; gengwujun@126.comPurpose: Sepsis, which is deemed as a systemic inflammation reaction syndrome in the face of infectious stimuli, is the primary cause of death in ICUs. Sepsis-induced cardiomyopathy (SIC) may derive from systemic inflammation reaction and oxidative stress. Retinoic acid (RA) is recognized by its beneficial roles in terms of the immunoresponse to infections and antioxygen actions. However, the treatment efficacy and potential causal links of RA in SIC are still elusive.Methods: By virtue of the STITCH database, we identified the targets of RA. Differentially expressed genes in SIC were acquired from the GEO database. The PPI network of intersected targets was established. GO and KEGG pathway enrichment analysis was completed. Hub genes were analyzed by cytoHubba plug-in. In the process of experimental validation, a mouse sepsis model was established by lipopolysaccharide (LPS), and the treated mice were intraperitoneally injected with RA or Dexamethasone (DEX) 60 min prior to LPS injections. Survival conditions, cardiac functions and antioxidant levels of the mice were assessed. Cardiac inflammation and injury were detected by HE and TUNEL. The levels of key genes and signal pathway expression were analyzed by RT-PCR and Western blot.Results: PPARA, ITGAM, VCAM-1, IGF-1 and IL-6 were identified as key therapeutic targets of RA by network pharmacology. PI3K-Akt signaling pathway is the main regulatory pathway of RA. In vivo researches unraveled that RA can improve the survival rate and cardiac function of LPS-treated mice, inhibit inflammatory factors and myocardial injury, and regulate the expression of key therapeutic targets and key pathways, which is PI3K-Akt signaling pathway.Conclusion: Network pharmacological method offers a predicative strategy to explore the treatment efficacy and causal links of RA in endotoxemic myocarditis. Through experimental verification, we discover that RA can reduce lipopolysaccharide-induced cardiac dysfunction by regulating the PI3K-Akt signaling pathway and key genes.Keywords: retinoic acid, lipopolysaccharide, sepsis-induced cardiomyopathy, network pharmacology, inflammatory response

Yimin Cai,1,&ast; Zhoumin Shen,1,&ast; Bifang Zhou,2 Xiali Zheng,3 Yulian Li,2 Yuming Liu,3 Jiayu Yang,3 Nian Xie,4 Hongjiao Chen4 1Department of Nursing, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005, People’s Republic of China; 2Department of Interventional Vascular Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China; 3Department of Pediatrics, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China; 4Department of Nursing, Medical School, Medical College of Hunan Normal University, Changsha, Hunan, 410013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bifang Zhou, Department of Interventional Vascular Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), No. 61 of Jiefang West Road, Furong District, Changsha, 410005, People’s Republic of China, Tel +86-13755027990, Fax +86-0731-82278012, Email yul_2021@21cn.comObjective: To investigate the psychological status of women during their second pregnancy.Methods: A total of 162 women who were pregnant for the second time were selected as the research subjects. The general demographic data and pregnancy-related conditions of the subjects were investigated by a questionnaire developed for this study. The anxiety and depression of the subjects were evaluated with a self-rating anxiety scale (SAS) and a self-rating depression scale (SDS).Results: The subjects scored themselves on the SAS and on the SDS. There was a statistically significant difference when comparing the scores and total scores with the domestic norm. Statistical data analysis was conducted using SPSS 19.0 software. The results of a multi-factor logistics regression analysis showed that four factors, namely a low age, low education level, low monthly household income and foetal sex expectations, were the main influencing factors for the occurrence of anxiety among women during their second pregnancies (p < 0.05). Three factors, namely a low education level, low monthly household income and a poor relationship between the husband and wife, were the main influencing factors for the occurrence of depression among the subjects (p < 0.05).Conclusion: During their second pregnancies, women have different degrees of anxiety and depression. Measures should be taken to intervene and guide women who develop these adverse emotions.Keywords: second child, psychological condition, anxiety, depression, influencing factors

Chunyan Shao,1– 5,&ast; Ziwei Yu,1– 5,&ast; Tongwang Luo,1– 5,&ast; Bin Zhou,1– 5 Quanjiang Song,1– 5 Zhuoyue Li,1– 5 Xiaoqiang Yu,1– 5 Sheng Jiang,1– 5 Yingshan Zhou,1– 5 Wanyu Dong,1– 5 Xingdong Zhou,1– 5 Xiaodu Wang,1– 5 Houhui Song1– 5 1Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Hangzhou, Zhejiang, 311300, People’s Republic of China; 2Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Hangzhou, Zhejiang, 311300, People’s Republic of China; 3Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, Hangzhou, Zhejiang, 311300, People’s Republic of China; 4China-Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang, 311300, People’s Republic of China; 5College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, 311300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Houhui Song; Xiaodu Wang, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, 311300, People’s Republic of China, Tel +86 15064890670 ; +86 18806537583, Email songhh@zafu.edu.cn; xdwang@zafu.edu.cnIntroduction: Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly prevalent and endemic swine pathogen that causes significant economic losses to the global swine industry. Selenium nanoparticles (SeNPs) have attracted increasing attention in the biomedical field, given their antiviral effects. This study aimed to investigate the inhibitory effect of chitosan-coated SeNPs (CS-SeNPs) on PRRSV replication.Methods: In this study, CS-SeNPs were synthesized by chemical reduction and characterized by assessing the morphology, size distribution, zeta potential, and element composition. Marc-145 cells were infected with r-PRRSV-EGFP (0.1 MOI) and inoculated with CS-SeNPs (10 μM). Subsequently, the concentrations of hydrogen peroxide (H2O2) and glutathione (GSH), and glutathione peroxidase (GSH-Px) activity were measured using specific commercial assay kits. ORF5 RNA expression, viral titer, and nucleocapsid (N) protein expression were assessed using qRT-PCR, TCID50, and Western blot. ROS generation, apoptosis rates, and JNK /caspase-3/PARP protein expression were evaluated using dihydroethidium staining, flow cytometry, and Western blot.Results: The results showed that CS-SeNPs treatment significantly suppressed oxidative stress induced by r-PRRSV-EGFP infection by increasing GSH-Px activity, promoting GSH production, and inhibiting H2O2 synthesis. CS-SeNPs treatment significantly inhibited ORF5 gene expression, viral titers, and N protein of r-PRRSV-EGFP at 24 and 48 hours post-infection (hpi) in Marc-145 cells. The increase in apoptosis rates induced by r-PRRSV-EGFP infection was significantly decreased by CS-SeNPs inoculation through inhibiting ROS generation, JNK phosphorylation levels, and cleavage of caspase-3 and PARP mainly at 48 hpi.Conclusion: These results demonstrated that CS-SeNPs suppress PRRSV-induced apoptosis in Marc-145 cells via the ROS/JNK signaling pathway, thereby inhibiting PRRSV replication, which suggested the potential antiviral activity of CS-SeNPs that deserves further investigation for clinical applications.Keywords: chitosan-coated selenium nanoparticles, PRRSV, apoptosis, ROS, JNK signaling pathways

Jian Wang,&ast; Hui Zhang,&ast; Peng Shao, Xu Zhang, Bin Zhou Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xu Zhang; Bin Zhou, Tel/Fax +86-25-83284735, Email zhanmusi1991@163.com; zbjszl@126.comPurpose: Pancreatic adenocarcinoma has a poor prognosis and chemotherapy has its limitation due to tumor heterogeneity. It is essential to find novel targets involving in tumorigenesis of pancreatic adenocarcinoma. Growing evidences indicated that pyroptosis is involved in tumorigenesis of many cancers, but the relationship between pyroptosis and pancreatic adenocarcinoma still remains to be elucidated. Our object is to explore whether pyroptosis-related different expression genes have association with survivals of pancreatic adenocarcinoma patients and the mechanism they may participate in. Besides, we also analyzed their effect on immune cell infiltration in tumor microenvironment.Patients and Methods: We used the bioinformatic analysis tool including GEPIA, cBioPortal, STRING, GeneMANIA, R software 4.03 and TIMER2.0 to investigate the different expression, prognostic value, protein-protein interaction, gene ontology, pathway and effect of immune cell infiltration of pyroptosis-related genes in PAAD.Results: Many pyroptosis-related genes express differently between pancreatic adenocarcinoma and normal tissues and they are associated with survival of PAAD. GABARAP and IL18 may play a key role in tumorigenesis of PAAD, for they are connected with overall survival, disease free survival and pathological stages at the same time. The function of pyroptosis-related genes includes cytokine production, endopeptidase activity, regulation of inflammation and inflammasome complex and pyroptosis-related genes have effect on immune cells infiltration in PAAD microenvironment.Conclusion: Lots of pyroptosis-related DEGs may get involved in pathogenesis of PAAD and their high expression have an effect on survival. GABARAP and IL18 could be valuable research targets of PAAD.Keywords: pyroptosis, pyroptosis-related gene, pancreatic adenocarcinoma, immune cell, microenvironment

Lei Zhu,1,&ast; Bin Zhou,1,&ast; Xi Zhu,1,&ast; Feng Cheng,1 Ying Pan,2 Yi Zhou,2 Yong Wu,1 Qingna Xu3 1Thyroid Surgery Department, The Fifth Hospital Affiliated to Wenzhou Medical University, Lishui Central Hospital, Lishui City, Zhejiang Province, People’s Republic of China; 2Breast Surgery Department, The Fifth Hospital Affiliated to Wenzhou Medical University, Lishui Central Hospital, Lishui City, Zhejiang Province, People’s Republic of China; 3Health Care Office, The Fifth Hospital Affiliated to Wenzhou Medical University, Lishui Central Hospital, Lishui City, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingna Xu, Health Care Office, The Fifth Hospital Affiliated to Wenzhou Medical University, Lishui Central Hospital, No. 289, Kuocang Road, Lishui City, Zhejiang Province, People’s Republic of China, Tel +86 13735910709, Email 1186896319@qq.comPurpose: This study aimed to investigate the effects of body mass index (BMI) on infertility in women of childbearing age.Patients and Methods: We performed a cross-sectional study using data from 3624 participants from the National Health and Nutrition Examination Survey (NHANES). We used BMI and fertility status in the survey as independent and dependent variables, respectively. We evaluated their relationship and used smoothed curve fitting and multivariate logistic regression analysis as well as a generalized additive model (GAM) to determine the effect of BMI.Results: Logistic regression model analysis linked BMI and infertility after adjusting for potential confounders OR 1.03, 95%Cl: 1.02– 1.05). There was a non-linear relationship between BMI and infertility, with each unit increase in BMI reducing the risk of infertility by 33% when BMI was < 19.5 kg/m2. In contrast, when BMI ≥ 19.5 kg/m2, each unit increase in BMI predicted a 3% increase in the risk of infertility.Conclusion: The relationship between infertility and BMI presented a U-shaped curve. Therefore, a BMI that lay at the extremes of the spectrum tended to predict infertility. We believe that this study will support the maintenance of suitable BMI levels in women preparing for pregnancy.Keywords: BMI, infertility, nonlinear, NHANES

Na Yu,1 Nan Gu,1 Yuxin Wang,1 Bin Zhou,2 Difei Lu,1 Jianping Li,3 Xiaowei Ma,1 Junqing Zhang,1 Xiaohui Guo1 1Department of Endocrinology, Peking University First Hospital, Beijing, 100034, People’s Republic of China; 2Department of Cardiology, Fuwai Hospital, National Centre for Cardiovascular Diseases, National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China; 3Department of Cardiology, Peking University First Hospital, Beijing, 100034, People’s Republic of ChinaCorrespondence: Xiaowei MaDepartment of Endocrinology, Peking University First Hospital, Beijing, People’s Republic of ChinaTel/Fax +86-010-83572574Email xiaowei.ma@pkufh.comPurpose: We aimed to examine the association between plasma trimethylamine N-oxide (TMAO), a gut microbial metabolite from dietary phosphatidylcholine, and coronary atherosclerotic burden in patients with type 2 diabetes (T2D).Methods: In total, 349 patients with T2D were studied, including 70 controls and 279 patients with coronary artery disease (CAD) by coronary angiography. Coronary atherosclerotic burden is quantified by the number of diseased coronary branches and SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score. Plasma TMAO levels were determined by UHPLC–MS/MS technique.Results: The TMAO concentration was significantly higher in the patients with triple vessel disease (TVD) (3.33 [IQR: 1.81– 6.65] μM) than those without TVD (2.62 [IQR: 1.50– 4.73] μM) (P = 0.015). A similar difference was found between patients with SYNTAX score > 22 (3.93 [IQR: 1.81– 6.82] μM) and those with SYNTAX score ≤ 22 (2.54 [IQR: 1.44– 4.54] μM) (P = 0.014). TMAO was not significantly correlated with the presence of CAD. Among patients with eGFR < 60 mL/min/1.73 m2, the highest tertile of TMAO was significantly associated with TVD (OR = 25.28, 95% CI [2.55– 250.33], P = 0.006) and SYNTAX score > 22 (OR = 7.23, 95% CI [1.51– 34.64], P = 0.013) independent of known risk factors of CAD, compared with lower TMAO tertiles.Conclusion: TMAO was not independently correlated with the presence of CAD and severity of coronary atherosclerosis in the included population. Nevertheless, the significant association between circulating TMAO and higher coronary atherosclerotic burden was observed in patients with eGFR of lower than 60 mL/min/1.73 m2.Keywords: trimethylamine N-oxide, coronary artery disease, SYNTAX score, type 2 diabetes

Xue Tian,1,&ast; Feiyue Yang,2,&ast; Fenghu Li,1 Li Ran,1 Jianying Chang,1 Jiehui Li,1 Wei Hong,3 Lang Shan,1 Yanjun Du,1 Lili Hu,1 Fan Mei,1 Mingyuan He,1 Yongxia Li,1 Heran Wang,1 Kai Zuo,1 Bo Zhou,4 Shuying Chen,1 Wanli Mao1 1Department of Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 2Department of Gynecologic Oncology, Guizhou Provincial People’s Hospital, Guiyang, 550004, People’s Republic of China; 3Department of Radiotherapy, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 4Surgical Department of Gynecological Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fenghu Li; Li Ran Email 769654418@qq.com; ranli171@hotmail.comPurpose: To examine the clinical significance of unoperated cervical cancer patients treated with different neoadjuvant chemotherapy (NACT) schemes followed by concurrent chemotherapy and radiotherapy (CCRT).Methods: This retrospective analysis included women with locally advanced cervical cancer treated with NACT-CCRT between September 2011 and September 2014. Neoadjuvant chemotherapy included paclitaxel plus cisplatin (TP group; 62 patients) or paclitaxel plus loplatin (TL group; 58 patients), which were administered three weekly, and cisplatin or loplatin, which were administered weekly for synchronous chemotherapy. External beam radiation therapy (50.4– 56.35 Gy/28 f, 180– 215 cGy/f, 5 f/w) was followed by intracavitary brachytherapy (5 Gy per fraction, mostly 5 fractions, Ir192 based).Results: One hundred twenty women were included in the analysis. The complete/partial response rate was 99.2% after treatment. The one-year, three-year, and five-year survival rates were 99.2%, 82.5%, and 70.8%, respectively. In the TP and TL groups, the three-year and five-year survival rates were 85.5% vs 77.6% and 75.8% vs 65.5%, respectively, with no significant difference. The 5-year overall survival (OS) rates between patients with stage IIB and stage IIIB disease were not significantly different (69.2% vs 64.7%). In the TP group, grade 3 or 4 digestive reactions were more frequent than those in the TL group. Leukopenia, neutropenia, and thrombocytopenia were more common in the TL group. No significant difference was found in anemia, radiation enteritis, radiation proctitis, or radiation cystitis between the groups.Conclusion: Lobaplatin may be used as an alternative drug for patients with severe digestive system reactions or contraindications to cisplatin, but hematological toxicity must be considered, particularly in dose-intensive schemes. Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy (NACT-CCRT) warrants further prospective study in cervical cancer patients with a wide range of tumor invasion (eg, mass size ≥ 5 cm or stage IIIB).Keywords: cervical cancer, neoadjuvant chemotherapy, survival benefit, side effects

Jing Li,1,&ast; Haitao Chen,1,2,&ast; Jiaxuan Chen,1,&ast; Bin Zhou,1 Jinlin Hou,1 De-Ke Jiang1 1State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: De-Ke Jiang; Jinlin HouState Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of ChinaTel +86-20-62786533; +86-20-61641941Email dekejiang17@smu.edu.cn; jlhousmu@163.comPurpose: Granulysin (GNLY) is a cytotoxic granule that has been reported to have various antimicrobial activities. We evaluated the association between a missense variant in GNLY (rs11127) and treatment efficacy of pegylated interferon-alpha (PegIFNα) or nucleos(t)ide analogs (NUCs) in patients with chronic hepatitis B (CHB).Patients and Methods: We included a total of 1823 patients with hepatitis B e antigen (HBeAg)-positive CHB (954 patients treated with PegIFNα and 869 patients treated with NUCs) in four Phase IV multicenter randomized controlled trials. The association of the GNLY rs11127 genotype with the combined response (CR), defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA level < 2000 IU/mL was evaluated. A polygenic score (PGS) was constructed to evaluate the cumulative effect of multiple single-nucleotide polymorphisms (SNPs), including rs11127 and several other SNPs, STAT4 rs7574865, CFB rs12614, and CD55 rs28371597, which were reported to be associated with CR.Results: GNLY rs11127 was significantly associated with CR in patients treated with PegIFNα. The CR rate in patients with the rs11127 CC genotype was higher than that with the CT or TT genotype (40.98% vs 30.34% or 27.09%, P = 0.003). Furthermore, a PGS integrating GNLY rs11127 and three other SNPs was significantly associated with CR in PegIFNα-treated patients (P < 0.001). However, no significant correlation was found between GNLY rs11127 and CR in NUCs-treated patients.Conclusion: GNLY rs11127 is an independent biomarker for predicting the response to PegIFNα therapy in HBeAg-positive CHB patients. Furthermore, the PGS, including GNLY rs11127, provides new insights for individualized treatment in clinical practice.Keywords: GNLY, rs11127, chronic hepatitis B, PegIFNα treatment, polygenic score

Danyun Jia,1 Jinyu Zheng,2 Yiyang Zhou,2 Jinqiu Jia,3 Xiaoxiao Ye,4 Bingbing Zhou,4 Xingxing Chen,4 Yunchang Mo,1 Junlu Wang1 1Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 3Department of Pediatric, Taizhou Women and Children’s Hospital of Wenzhou Medical University, Taizhou, 317599, Zhejiang, People’s Republic of China; 4Department of Nursing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Yunchang Mo; Junlu Wang Email myc1104@163.com; wjlprof2020@163.comPurpose: To evaluate whether ferroptosis is involved in hyperoxic acute lung injury (HALI) and its mechanisms through the HALI model.Methods: HE staining was used to assess lung injury pathology after the establishment of neonatal rat HALI model. ELISA was used to detect ROS, GPX4, and GSH expression. Prussian blue staining and Western Blot were used to detect iron deposition and the expression of ferroptosis-related proteins, respectively.Results: The HALI group showed pathological changes with larger and fewer alveoli and thicker alveolar septa after HE staining. Prussian blue staining detected significant iron deposition in the lung tissue of the HALI group. GPX4, GSH, GSS, and SLC7A11 expressions were significantly decreased in the HALI group than in the normal control group. In contrast, ROS, TFRC, FHC, and FLC expressions showed opposite results (p< 0.05).Conclusion: Ferroptosis may be involved in the pathological process of hyperoxic lung injury in neonatal rats.Keywords: ferroptosis, hyperoxic lung injury, neonatal rats

Wanyong Huang,&ast; Bo Zhou,&ast; Yingwei Li,&ast; Yuansheng Shao, Bo Peng, Xianchun Jiang, Tao Xiang Department of Neurosurgery, People’s Hospital of Guanghan City, Guanghan City, Sichuan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wanyong HuangDepartment of Neurosurgery, People’s Hospital of Guanghan City, 75 Hankou Road, Luocheng Town, Guanghan City, Sichuan Province, People’s Republic of ChinaEmail huangwy459088699@163.comObjective: Decompressive craniectomy as a treatment is often used in the rescue treatment of critically ill patients in neurosurgery; however, there are many complications after this operation. Subdural effusion is a common complication after decompressive craniectomy. Once it occurs, it can cause further problems for the patient. Therefore, the purpose of this study was to explore the safety and effectiveness of pressure dressings for subdural effusion after decompressive craniectomy.Methods: Patients who underwent decompressive craniectomy in our hospital from January 2016 to January 2021 were included in this study, and all patients were followed up for 6 months or more. After the operation, the patients were divided into two groups according to whether they received a pressure dressing or a traditional dressing. Subdural effusion, cerebrospinal fluid leakage, hydrocephalus and other complications were compared between the two groups, and the differences in hospital duration, cost and prognosis between the two groups were analyzed.Results: A total of 123 patients were included in this study. Among them, 62 patients chose pressure dressings, and 61 patients chose traditional dressings. The incidence of subdural effusion in the pressure dressing group was significantly lower than that in the traditional dressing group (P< 0.05). There was no difference between the two groups in cerebrospinal fluid leakage and hydrocephalus (P > 0.05). In addition, the length of hospital stay and the total cost in the pressure dressing group were significantly lower (P< 0.05).Conclusion: Pressure dressing can effectively reduce the occurrence of subdural effusion after decompressive craniectomy, and it does not increase the occurrence of other cerebrospinal fluid-related complications.Keywords: decompressive craniectomy, complication, pressure dressing, subdural effusion

Haoming Mai,&ast; Haisheng Xie,&ast; Jia Hou,&ast; Haitao Chen, Bin Zhou, Jinlin Hou, Deke Jiang State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deke Jiang; Jinlin HouState Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel +86-20-62786533; +86-20-61641941Email dekejiang17@smu.edu.cn; jlhousmu@163.comPurpose: Activation of actin cytoskeleton remodeling is an important stage preceding cancer cell metastasis. Previous genome-wide association studies (GWAS) have identified multiple hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)-associated risk loci. However, limited sample size or strict significance threshold of GWAS may cause HBV-related HCC risk-associated genetic loci to be undetected. We aimed to investigate the performance of the SNP rs13025377 in PPP1CB in HCC.Patients and Methods: We performed a case–control study including 1161 cases and 1353 controls to evaluate associations between single nucleotide polymorphisms (SNPs) from 98 actin-cytoskeleton regulatory genes and risk of HBV-related HCC. The effects of SNPs on HBV-related HCC risk were assessed under logistic regression model and corrected by false discovery rate (FDR).Results: We found that rs13025377 in PPP1CB was significantly associated with HBV-related HCC risk [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.72∼ 0.91, P = 4.88× 10– 4]. The risk allele A of rs13025377 increased PPP1CB expression levels in normal liver tissue. SNP rs4665434 was tagged by rs13025377 (r2 = 0.9) and its protective allele disrupted CTCF and Cohesin motifs. According to public datasets, PPP1CB, CTCF and Cohesin expression levels are increased in tumor tissues. Kaplan–Meier plots demonstrated that higher PPP1CB expression was significantly associated with shorter overall survival (OS). Moreover, we observed strong correlation between CTCF, Cohesin, and PPP1CB in various liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that PPP1CB plays a role in HCC through actin-cytoskeleton regulation.Conclusion: Thus, these findings indicated that PPP1CB may be a key gene in actin-cytoskeleton regulation and rs13025377 contributes to the risk of HBV-related HCC by regulating PPP1CB expression.Keywords: genome-wide association studies, PPP1CB, CTCF, cohesin, SNP, HBV-related hepatocellular carcinoma

Haoming Mai,1,&ast; Jiaxuan Chen,1,&ast; Haitao Chen,1,2,&ast; Zhiwei Liu,3,&ast; Guanlin Huang,1 Jialin Wang,1 Qianyi Xiao,4 Weihua Ren,5 Bin Zhou,1 Jinlin Hou,1 Deke Jiang1 1State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China; 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; 4School of Public Health, Fudan University, Shanghai, 200032, People’s Republic of China; 5Central Laboratory, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan Province, 471009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deke Jiang; Jinlin HouState Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of ChinaTel +86-20-62786533; +86-20-61641941Email dekejiang17@smu.edu.cn; jlhousmu@163.comIntroduction: Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive.Methods: With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) < 0.20). A total of 14,930 variants within the MHC region were genotyped or imputed.Results: We identified two variants, rs114401688 (P = 1.05 × 10− 6, PFDR = 2.43 × 10− 3) and rs115126566 (P = 9.04 × 10− 5, PFDR = 1.77 × 10− 1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1&ast;04 and HLA-DRB1&ast;04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥ 50, P = 0.03).Discussion: Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.Keywords: fine mapping, susceptibility, MHC, hepatocellular carcinoma, HBV

Guohu Weng,1 Bo Zhou,2 Tao Liu,3 Zhengxin Huang,2 Shixiong Huang3 1Department of Encephalopathy, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, 570203, Hainan, People’s Republic of China; 2Department of Cardiology, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, 570203, Hainan, People’s Republic of China; 3Department of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, Hainan, People’s Republic of ChinaCorrespondence: Shixiong HuangDepartment of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou, 570311, Hainan, People’s Republic of ChinaTel/Fax +86-0898-68642129Email huangsx0813@163.comPurpose: Many researches have investigated the functions of tetramethylpyrazine (TMP) in Alzheimer’s disease (AD). This study aimed to discuss the underlying mechanism of TMP in AD mice.Methods: TMP (200 mg/kg) was administered to 6-month-old APP/PS1 transgenic mice, and behavioral changes and hippocampal nerve injury in AD mice were detected. Apoptosis and autophagy-related protein levels were detected. Changes in gene expression before and after TMP treatment were compared using transcriptome sequencing. The effects of Cullin 4B (CUL4B) overexpression and somatostatin receptor 4 (SSTR4) silencing on AD symptoms and SSTR4 ubiquitination in APP/PS1 mice were observed. SH-SY5Y and PC12 cells were treated with 25 μmol/L Aβ25– 35 and TMP to observe cell viability, apoptosis, and autophagy. Cell viability and apoptosis were measured again after treatment with proteasome inhibitor MG132 or lysosomal inhibitor 3-mA.Results: TMP treatment improved the behavioral cognition of APP/PS1 mice and improved the neuronal apoptosis and damage in brain tissue. CUL4B was significantly upregulated in APP/PS1 mouse brain tissue, and SSRT4 protein was downregulated, and the levels of CUL4B and SSRT4 were negatively correlated. TMP treatment downregulated CUL4B, inhibited SSRT4 ubiquitination and upregulated SSRT4 protein level in APP/PS1 mouse brain tissue, while CUL4B overexpression or SSRT4 silencing reversed the effect of TMP. TMP and MG132 improved the decreased activity, increased apoptosis and increased SSRT4 protein in SH-SY5Y and PC12 cells treated with Aβ25– 35, but not 3-mA. CUL4B overexpression promoted the ubiquitination of SSTR4 in cells, which partially reversed the effect of TMP.Conclusion: TMP could improve the cognitive ability of AD mice by inhibiting CUL4B expression and the ubiquitination degradation of SSTR, and alleviating neuronal apoptosis and injury. This study may offer a new therapeutic option for AD treatment.Keywords: Alzheimer disease, tetramethylpyrazine, somatostatin receptor 4, ubiquitination, Cullin 4B

Yanzhao Zhou,1,* Yi Yang,2,* Bingyan Zhou,3 Zhengzheng Wang,1 Ruili Zhu,1 Xun Chen,1 Jingzhong Ouyang,1 Qingjun Li,1 Jinxue Zhou1 1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450008, People’s Republic of China; 2Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 3School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinxue ZhouDepartment of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450008, People’s Republic of ChinaEmail zhoujx888@126.comAbstract: As an emerging minimally invasive treatment method, percutaneous ablation is more and more widely used in the treatment of liver tumors. It has been recommended by guidelines for diagnosis and treatment of hepatocellular carcinoma (HCC) as a curative treatment alongside surgical resection and liver transplantation. In recent years, with the continuous advancement and innovation of percutaneous ablation technologies, their clinical efficacy and safety have been significantly improved, which has led to the expanded application of percutaneous ablation in the treatment of HCC—more and more patients who were previously considered unsuitable for ablation therapies are now being treated with percutaneous ablation. Obviously, percutaneous ablation can reduce the risk of treatment changes from curative strategies to palliative strategies. Based on clinical practice experience, this review enumerates the advantages and disadvantages of different ablative modalities and summarizes the existing combinations of ablation techniques, thus will help clinicians choose the most appropriate ablative modality for each patient and will provide scientific guidance for improving prognosis and making evidence-based treatment decisions. In addition, we point out the challenges and future prospects of the ablation therapies, thereby providing direction for future research.Keywords: percutaneous ablation, hepatocellular carcinoma, assistive technology, image guidance

Yingzi Fan,1,2,* Tingting Bai,2,* Yaomei Tian,1 Bailing Zhou,1 Yuanda Wang,1 Li Yang1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, People’s Republic of China; 2Department of Laboratory Medicine, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li YangState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, People’s South Road, Chengdu 610041, People’s Republic of ChinaTel +86 18628182400Email yl.tracy73@gmail.comPurpose: This study aimed to describe a novel cancer vaccine developed using H2O2-inactivated Salmonella typhimurium RE88 [with deletions of AroA (the first enzyme in the aromatic amino acid biosynthesis pathway) and DNA adenine methylase] as the carrier.Methods: The pVLT33 plasmid was used to engineer an RE88 strain induced to express ovalbumin (OVA) by isopropylthiogalactoside (RE88-pVLT33-OVA). The immune responses and anticancer effects of H2O2-inactivated RE88-pVLT33-OVA were compared with those of non-inactivated RE88-pVLT33-OVA and OVA (positive control) in mice carrying OVA-expressing tumors (EG7-OVA) cells.Results: Anti-ovalbumin IgG (immunoglobulin G) titer following vaccination with H2O2-inactivated RE88-pVLT33-OVA was higher for subcutaneous than for intragastric vaccination. When subcutaneous administration was used, H2O2-inactivated RE88-pVLT33-OVA (2 × 109 CFU (colony forming units)/mouse) achieved an anti-ovalbumin IgG titer higher than that for the same dose of RE88-pVLT33-OVA and comparable to that for 10 μg ovalbumin (positive control). The binding of mouse serum antibodies to EG7-OVA cells was stronger for H2O2-inactivated RE88-pVLT33-OVA (2 × 109 CFU/mouse) than for 10 μg ovalbumin. Furthermore, subcutaneous vaccination with H2O2-inactivated RE88-pVLT33-OVA (2 × 109 CFU/mouse) induced greater activation of splenic T cells and more extensive tumor infiltration with CD4+/CD8+ T cells compared with 10 μg ovalbumin (positive control). The mice vaccinated subcutaneously with H2O2-inactivated RE88-pVLT33-OVA at a dose of 2 × 108 or 6 × 108 CFU/mouse had smaller tumors compared with mice in the negative control groups. Tumor weight in mice vaccinated with H2O2-inactivated RE88-pVLT33-OVA at a dose of 2 × 109 CFU/mouse was significantly lower than that in both negative control groups (P < 0.05) and decreased with the increasing dose of H2O2-inactivated RE88-pVLT33-OVA. H2O2-inactivated RE88-pVLT33-OVA was potentially safer than the non-inactivated strain, could carry exogenous antigens, and had specific epitopes that could be exploited as natural adjuvants to facilitate the induction of cellular and humoral immune responses.Conclusion: It was anticipated that H2O2-inactivated RE88-pVLT33-OVA could be used as a novel delivery system for new cancer vaccines.Keywords: cancer vaccine, H2O2 inactivation, RE88-pVLT33-OVA, whole-cell bacterial vaccine

Yi Zhang,1– 3 Bo Zhou,1,2,4 Min Wen,1 Mi Hu,1 Jin-Gang Peng,1– 3 Ying Wang,3 Lin-Lin Fan,1– 3 Lei Tang1– 3 1College of Basic Medical Sciences, Guizhou Medical University, Guizhou, 550004, People’s Republic of China; 2Engineering Technology Research Center for Chemical Drug R&D, Guizhou 550004, People’s Republic of China; 3College of Pharmacy, Guizhou Medical University, Guizhou 550004, People’s Republic of China; 4State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guizhou 550004, People’s Republic of ChinaCorrespondence: Lei Tang Tel +86 13308500332Email tlei1974@gmc.edu.cnPurpose: The aim of the present study was to investigate the hypoglycemic activity and potential mechanism of tetrahydrocarbazole derivatives ZG02 in high-fat diet/streptozotocin-induced type 2 diabetes model.Methods: C57BL/6 mice (n=30) were randomly assigned to three groups: control group (n=10) was fed with normal diet, the diabetes group (n=10) was fed with high-fat diet for eight weeks followed by intraperitoneal injection of streptozotocin (25 mg/kg) and the ZG02 group (n=10) injected intraperitoneally with ZG02 (30 mg/kg/day) for two weeks after successful modeling. The changes of weight, fasting blood glucose, oral glucose tolerance and fasting blood insulin levels in each group were evaluated. In addition, we also assessed the expression level of total AMPK, phosphorylation AMPK, SIRT1, PGC-1 and the activity of G6PC in liver.Results: The results demonstrated that ZG02 could significantly antagonize the high-fat diet/streptozotocin-induced fasting hyperglycemia, restore fasting blood insulin levels and also improve activity of G6PC in liver. The results from Western blot indicated that ZG02 significantly restored the expression level of phosphorylation AMPK, Sirt1 and PGC-1.Conclusion: ZG02 improve hepatic glucose metabolism and insulin sensitivity via activation AMPK/Sirt1 signaling pathways in type 2 diabetes mice model.Keywords: type 2 diabetes, glucose metabolism, ZG02, AMPK, high fat

Hanxi Yu,1,* Weichen Zhang,2,* Peilin Han,1 Beng Yang,2 Xiaode Feng,2 Ping Zhou,1 Xiaoxu Zhu,1 Bingqian Zhou,3 Wei Chen,4 Jianhua Qian,1 Jun Yu2 1Department of Gynecology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310006, People’s Republic of China; 2Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310006, People’s Republic of China; 3Department of Gynecology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Pujiang 322200, People’s Republic of China; 4Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou 310012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianhua Qian; Jun Yu Tel +86-0571-87236114Email qianjianhua@zju.edu.cn; dryujun@zju.edu.cnBackground: Mammalian Ste20-like kinase 4 (MST4), also known as serine/threonine kinase 26 (STK26), promotes development of several cancers and is found to be highly expressed in the placenta. However, in choriocarcinoma that originated from the placenta, the expression of MST4 was undetermined and its mechanism was unknown. In this study, the expression of MST4 in choriocarcinoma as well as the underlying mechanism was explored.Purpose: To detect the expression of MST4 in patient samples and mechanism of mediating EMT by MST4 in choriocarcinoma.Patients and Methods: The metastatic lesions of choriocarcinoma (n=17) and volunteer villus (n=17) were collected to determine MST4 expression using immunohistochemistry and H&E staining. We use siRNA and lentiviral vector to knockdown MST4 and use plasmid to overexpress MST4 in choriocarcinoma. Then, we apply real-time polymerase chain reaction (RT-PCR), Western blot assay and immunofluorescence assay to detect target protein expressions. Cell invasion and migration and cell proliferation were detected by transwell assay and wound healing assay and CCK-8 and cell colony formation.Results: MST4 is lowly expressed in the metastatic lesions of choriocarcinoma patients when compared with normal villus. Knockdown of MST4 activated epithelial–mesenchymal transition (EMT) process, significantly increasing the ability of invasion and migration in choriocarcinoma cell lines (JAR and JEG-3). In contrast, the EMT process was restrained in choriocarcinoma cell lines with overexpressed MST4. Meanwhile, genome-wide gene expression array, Western blot and ELISA revealed that tumor growth factor-beta 1 (TGF-β 1) has significantly increased. The EMT process and metastatic prompting biofunction were reversed after using TGF-β 1 inhibitor (LY364947) in the choriocarcinoma cell lines with MST4 knockdown.Conclusion: Our studies demonstrated that MST4 was lowly expressed in patient samples. Additionally, JAR and JEG-3 increase cell invasion and migration ability while there is no influence on cell proliferation with MST4 knockdown. Conversely, the metastatic ability of JAR and JEG-3 was decreased with overexpressed MST4. Moreover, TGF-β 1 was a key factor after MST4 knockdown. In conclusion, MST4 affects choriocarcinoma EMT by mediating TGF-β 1 expression.Keywords: choriocarcinoma, TGF-β 1, EMT, MST4

Hongfei Tong,1,* Zhen Huang,2,* Hui Chen,1 Bin Zhou,1 Yi Liao,1 Zhaohong Wang1 1Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325027, People’s Republic of China; 2Department of Pediatric Hematology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325027, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaohong Wang Department of Hepatobiliary SurgeryThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan West Road, Lucheng District, Wenzhou City, Zhejiang Province 325027, People’s Republic of ChinaTel +86-577-88002710Email wangzhaohong55@163.comBackground: Pancreatic cancer is one of the most malignant tumors, and gemcitabine has been considered as the standard treatment and been widely utilized as a first-line drug for advanced pancreatic cancer, but gemcitabine-resistance always occurs after a short period of treatment.Methods: Two pancreatic cancer cell lines Panc-1 and MIA-PaCa-2 were used as the study subject and their gemcitabine-resistant cells were established. Both drug-resistant cells were divided into four groups: blank, emodin, gemcitabine, and emodin+gemcitabine. Cell viability was detected by MTT assay. Flow cytometry was performed to detect cell apoptosis rate and P-gp function. Quantitative real-time polymerase chain reaction and Western blotting were used to detect Survivin, XIAP, Caspase-9/3, NF-κB p65, IKKβ and IκB-α mRNA/protein expressions, respectively. Electrophoretic mobility shift assay (EMSA) was performed to detect NF-κB binding activity. Rhodamine 123 efflux assay was used to detect P-gp function.Results: Emodin could inhibit cell activity in all cell lines. Both emodin and gemcitabine can significantly increase the apoptosis rate, and the combination of the two drugs can further significantly increase the apoptosis rate in normal pancreatic cancer cell lines. In both drug-resistant pancreatic cancer cell lines, it can be observed that although gemcitabine can increase the apoptosis rate, the effect of promoting apoptosis is significantly lower than that of emodin; the drug combination can still significantly increase the apoptosis rate on the basis of emodin alone. Emodin can significantly reduce the mRNA and protein expression levels of Survivin, XIAP, NF-κB, and IKKβ, and significantly increase the mRNA and protein expression levels of Caspase-3/9 and IκB-α. Emodin significantly reduced NF-κB activity and emodin significantly promoted P-gp fluorescence intensity from Rhodamine 123 efflux assay.Conclusion: Emodin inhibits the expression of IKKβ, thereby inhibiting the expression and activity of downstream NF-κB, and inhibits P-gp function at the same time, ultimately achieving the purpose of reversing the drug-resistance of pancreatic cancer cell lines.Keywords: emodin, pancreatic cancer, gemcitabine, NF-κB, IκB-α

Peng Chen,1,* Fuchao Chen,2,* Jiexin Lei,3 Benhong Zhou1 1Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of China; 2Department of Pharmacy, Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, People’s Republic of China; 3Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Benhong ZhouDepartment of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of ChinaTel +86 15335898431Email benhongzh@whu.edu.cnBackground and Objective: The combination of naloxone hydrochloride (NH) and fentanyl citrate (FC) in patient-controlled analgesia (PCA) is examined to reduce the risk of opioid-induced nausea and vomiting. However, there are no such commercially available drug mixtures, and there is also no published evidence on the compatibility and stability of NH and FC. Thus, the primary purpose of the current research is to investigate the physical compatibility and chemical stability of NH when mixed with FC over a 72-h period in a 0.9% sodium chloride injection solution for PCA administration under storage at 4°C and 25°C.Methods: Test solutions of 20 μg/mL FC and 4 μg/mL NH were prepared and stored in polyvinyl chloride (PVC) bags or glass bottles with a 0.9% sodium chloride injection solution as the diluent. During the 72-h storage period at 4°C or 25°C without light protection, the concentrations of the test drugs were assayed via high-performance liquid chromatography (HPLC), and the physical compatibility was determined with the naked eye. Furthermore, pH measurement of each sample was also performed with a pH meter.Results: The percentages of the initial concentrations of FC and NH in the various solutions were maintained at a minimum of 98% over the 72-h study period. All of the mixtures remained clear and colourless throughout the observation period, and no precipitation or turbidity was observed in any of the batches.Conclusion: The 20 μg/mL FC test solution was physically compatible and chemically stable with the 4 μg/mL NH test solution when stored at 4°C or 25°C in PVC bags or glass bottles containing the 0.9% sodium chloride injection solution.Keywords: fentanyl, naloxone, patient-controlled analgesia, 0.9% sodium chloride, drug stability

Tu H, Wei G, Cai Q, et al. Onco Targets Ther. 2015;8:2227–2235. At the authors request, The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding similarities between the nontumor (NT) plot shown in Figure 1A with that from the nontumor plot of Figure 1A from Sun et al (2015) (https://doi.org/10.1016/j.fob.2015.11.001). These similarities were not expected to have occurred by chance. In addition, concerns were also raised regarding the alleged duplication of western blot bands in Figure 5 with those in Figure 4 from Kan et al (2015) (https://doi.org/10.1016/j.febslet.2014.11.031). Specifically, Figure 5A, GAPDH bands, appear to have been duplicated with similar bands in Figure 4B, GAPDH bands, from Kan et al (2015). The authors were unable to explain how these similarities occurred and were unable to retrieve the original data from their study. They requested to retract the article and the Editor agreed with this decision. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Bei Zhou, Cuiping Li, Yun Yang, Zhuo Wang Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, People’s Republic of ChinaCorrespondence: Bei Zhou Email zhoubeiwork@163.comBackground: The development and metastasis of cancer cells are regulated by tumor-associated macrophages (TAMs) present in the surrounding tumor microenvironment. RIG-I is a key pathogen recognition receptor against RNA viruses that regulates innate immunity in cancer progression. Till now, the mechanism of RIG-I regulation of the polarization of TAMs in the progression of hepatocellular carcinoma (HCC) has not been understood.Materials and Methods: Levels of RIG-I and the key proteins in the NF-κB pathway in HCC and paired paracancerous tissues were detected by Western blotting. The transfection efficiency of RIG-I was observed by fluorescence microscopy. The M1 and M2 markers were detected by real-time polymerase chain reaction and FACS assays. Apoptosis of RIG-I lentivirus-infected HCC cells was detected by flow cytometry assay. Death of Hepa1-6 and H22 cells was analyzed by lactate dehydrogenase releasing assay.Results: The level of RIG-I was decreased in HCC tissues as compared to that in the paired paracancerous tissues. Overexpression of RIG-I in mouse peritoneal macrophages increased the expression of the biomarkers CD16/32 and CD11c associated with M1 macrophages. The relative levels of IL-1β, TNF-α, IL-6, and iNOS were significantly increased in RIG-I lentivirus-infected macrophages, whereas the levels of Arg-1 and IL-10 were not significantly different in RIG-I-overexpressed peritoneal macrophages. Moreover, overexpression of RIG-I in peritoneal macrophages promoted apoptosis of Hepa1-6 and H22 cells. Furthermore, overexpression of RIG-I increased the levels of phosphorylated p65 and p-IκB and decreased the level of IκB in peritoneal macrophages. Importantly, the expression of MAVS and TRAF2 was significantly increased in RIG-I lentivirus-infected macrophages.Conclusion: Our results demonstrate that overexpression of RIG-I promoted apoptosis and death of HCC cells. Moreover, RIG-I promoted the polarization of M1 through the RIG-I/MAVS/TRAF2/NF-κB pathway in mice peritoneal macrophages, suggesting that RIG-I may be a novel target in the immunotherapy of HCC.Keywords: RIG-I, M1 macrophages, hepatocellular carcinoma, cell apoptosis, NF-κB pathway

Yuedi Ding ,1 Jun Fan ,1 Lili Deng ,1 Ying Peng ,1 Bin Zhou ,1 Biao Huang 1 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People’s Republic of ChinaCorrespondence: Biao Huang; Yuedi DingNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine,Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, People’s Republic of ChinaEmail huangbiao@jsinm.org; dingyuedi@jsinm.orgPurpose: Oncolytic viruses are emerging as promising options for clinical cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Aside from tumor lysis, oncolytic viruses can induce host immune responses against tumor cells and may thus be viewed as a form of immunotherapy.Methods: The attenuated vaccinia VG9-Luc, which originated from Chinese vaccinia Tian Tan strain, was constructed to express firefly luciferase for bioluminescence imaging and to disrupt the thymidine kinase gene for promoting tumor specificity. An in vivo bioluminescence imaging was performed to observe the virus distribution in live mice. The titers of neutralizing antiviral and antitumor antibodies in plasma were determined by time-resolved fluoroimmunoassay.Results: Except BALB/c mice treated with intravenous virus injection, all immunocompromised and immunocompetent mice showed obvious tumor targeting ability of vaccinia VG9-Luc. Besides, host immune response activated by vaccinia VG9-Luc showed the production of antiviral and antitumor antibodies, the process of which was similar between intravenous and intratumoral viral delivery systems. The results indicated that virus infection promoted tumor-specific immunity by increasing the production of antitumor antibodies. Moreover, virus reinjection was performed and a more rapid viral clearance was observed in immunocompetent mice compared with first virus infection.Conclusion: The thymidine kinase-deleted vaccinia Guang9 strain, which has the properties of tumor specificity and antitumor immunity, is a promising candidate vector for cancer therapy.Keywords: oncolytic virotherapy, vaccinia virus, tumor specificity, bioluminescence imaging, antitumor immunity

Wen Tian,1,2 Xianglin Yang,1,2 He Yang,1,2 Baosen Zhou1,2 1Department of Clinical Epidemiology, First Affiliated Hospital, China Medical University, Shenyang, People’s Republic of China; 2Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, People’s Republic of ChinaCorrespondence: Baosen Zhou Puhe Road, Shenyang, Liaoning 110012, People’s Republic of ChinaEmail bszhou@cmu.edu.cnBackground: Lung adenocarcinoma is one of the malignant tumors in the world. This study aimed to explore the biological mechanism of GINS2 in lung adenocarcinoma.Materials and Methods: Raw data were downloaded from GEO. WGCNA co-expression network and PPI network were established to identify the hub gene. The expression profile and clinical features of GINS2 were collected from TCGA-LUAD cohort. Survival analysis in TCGA-LUAD cohort was plotted by R package. GSEA was analyzed via GSEA software. MTS, Transwell and apoptosis assays were used to detect the proliferation, migration and apoptotic abilities of lung adenocarcinoma cells.Results: GINS2 was identified as the hub gene via WGCNA co-expression network and PPI network. Higher GINS2 expressions were observed in TCGA-LUAD cohort, GSE32863 and clinical samples dataset. Overexpression of GINS2 had a significantly negative connection with poor survival outcome. GSEA results revealed that GINS2 could be enriched in “HALLMARK_G2M_CHECKPOINT”, “HALLMARK_E2F_TARGETS”, “HALLMARK_DNA_REPAIR” and “HALLMARK_MYC_TARGETS_V2”. Overexpression of GINS2 promoted tumor cell proliferation and migration and suppressed cell apoptosis.Conclusion: Our results explored that GINS2 functioned as an oncogene in lung adenocarcinoma, and suggested that GINS2 could act as a promising prognosis biomarker for lung adenocarcinoma.Keywords: GINS2, lung adenocarcinoma, WGCNA, biological function

Xin Ji,* Muye Xia,* Bin Zhou, Shi Liu, GuiChan Liao, Shaohang Cai, Xiaoyong Zhang, Jie Peng State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie PengDepartment of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, Guangzhou 510515, People’s Republic of ChinaTel +86 20 6278 7428Fax +86 20 8771 9653Email pjie138@163.comBackground and Aim: Hepatitis B virus (HBV) RNA has attracted increasing attention as a novel serum marker for intrahepatic HBV replication. However, the predictive value of the serum level of HBV RNA for hepatitis B e-antigen (HBeAg) seroconversion and viral response among patients with a high viral load (HVL) is unclear. We evaluated the role of the serum level of HBV RNA as a predictor of treatment response in chronic HBV (CHB) patients with an HVL.Patients and Methods: The study cohort was 66 HBeAg-positive CHB patients with an HVL (serum HBV DNA > 1.9× 106 IU/mL) at baseline from our previous prospective cohort study treated with lamivudine (LAM) and adefovir dipivoxil(ADV) (N=31) or entecavir alone (N=35) for ≤ 96 weeks. The serum HBV RNA level was quantified by TaqMan® probe-based reverse transcription real-time quantitative polymerase chain reaction at four time points.Results: The baseline serum HBV RNA level (in log10 copies/mL) in patients treated with LAM+ADV and ETV monotherapy was 8.97± 1.22 and 9.15± 0.92, respectively. After nucleos(t)ide analog (NA) therapy, the serum HBV RNA level decreased steadily in all patients (week 0 vs week 12, p< 0.001; week 12 vs week 24, p=0.010; week 24 vs week 48, p< 0.001). Fifty-three (80.3%) patients achieved a virologic response (VR), and 12 (18.2%) achieved HBeAg seroconversion after 96 weeks. Multivariate analyses revealed that the serum HBV RNA level at week 12 could predict HBeAg seroconversion (OR 3.560, 95% CI: 1.39– 9.110, p=0.008) and VR (1.908, 1.115– 3.265, 0.018) at 96 weeks. Analyses of receiver operating characteristic curves indicated that the serum HBV RNA level 12 weeks after NA treatment had predictive value for HBeAg seroconversion (AUC=0.847, p< 0.001) and VR (AUC=0.736, p=0.011).Conclusion: The serum level of HBV RNA at 12 weeks could predict HBeAg seroconversion and a VR during NA treatment in CHB patients with an HVL.Keywords: HBV RNA, HBeAg seroconversion, virological response, high viral load, nucleos(t)ide analogs

Keda Zhang,1,2,* Li Yu,3,* Fu-Rong Li,4,* Xue Li,5 Zhefeng Wang,6 Xiaoting Zou,1,2 Chi Zhang,7 Kongpeng Lv,2 Boping Zhou,1 Samir Mitragotri,8 Ming Chen7 1Central Laboratory of Longhua Branch, Second Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, Shenzhen 518109, People’s Republic of China; 2Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, People’s Republic of China; 3Department of Plastic and Aesthetic Surgery, Second Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, Shenzhen 518020, People’s Republic of China; 4Translational Medicine Collaborative Innovation Center, Second Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, Shenzhen, 518020, People’s Republic of China; 5Institute of Mass Spectrometry and Atmospheric Environment, Jinan University, Guangzhou 510632, People’s Republic of China; 6Department of Cardiology, Second Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, Shenzhen 518020, People’s Republic of China; 7State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, College of Ocean and Earth Sciences, Xiamen University, Xiamen 361102, People’s Republic of China; 8School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA*These authors contributed equally to this workCorrespondence: Ming Chen; Boping Zhou Email ming.chen@xmu.edu.cn; bopingzhou@163.comPurpose: The topical application of exosomes secreted by mesenchymal stem cells (MSC-Exos) on the skin is a very new and interesting topic in the medical field. In this study, we aimed to investigate whether marine sponge Haliclona sp. spicules (SHSs) could effectively enhance the skin delivery of human umbilical cord-derived MSC-Exos (hucMSC-Exos), and further evaluate the topical application of hucMSC-Exos combined with SHSs in rejuvenating photoaged mouse skin.Materials and Methods: SHSs were isolated from the explants of sponge Haliclona sp. with our proprietary method, and hucMSC-Exos were prepared from the conditioned medium of hucMSCs using ultracentrifugation. The effects of SHSs on the skin penetration of fluorescently labeled hucMSC-Exos were determined using confocal microscopy in vitro (porcine skin) and in vivo (mouse skin). The therapeutic effects of hucMSC-Exos coupled with SHSs against UV-induced photoaging in mice were assessed by using microwrinkles analysis, pathohistological examination and real-time RT-PCR. We also tested the skin irritation caused by the combination of hucMSC-Exos and SHSs in guinea pigs.Results: In vitro results showed that hucMSC-Exos could not readily penetrate through porcine skin by themselves. However, SHSs increased the skin absorption of exosomes by a factor of 5.87 through creating microchannels. Similar penetration enhancement of hucMSC-Exos was observed after SHSs treatment in mice. The combined use of hucMSC-Exos and SHSs showed significant anti-photoaging effects in mice, including reducing microwrinkles, alleviating histopathological changes, and promoting the expression of extracellular matrix constituents, whereas hucMSC-Exos alone produced considerably weaker effects. Skin irritation test showed that the combination of hucMSC-Exos and SHSs caused slight irritation, and the skin recovered shortly.Conclusion: SHSs provide a safe and effective way to enhance the skin delivery of MSC-Exos. Moreover, the combination of MSC-Exos and SHSs may be of much use in the treatment of photoaging.Keywords: exosomes, mesenchymal stem cell, skin delivery, marine sponge spicules, photoaging