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Mingxiang Cai,1,* Huizhen Peng,1,* Minyi Liu,1,* Maohua Huang,2,3 Wen Zheng,1 Guilan Zhang,1 Wenjia Lai,1 Chufang Liao,1 Lizhao Cai,1 Dongmei Zhang,2,3 Xiangning Liu1 1The First Affiliated Hospital of Jinan University, School of Stomatology, Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, 510630, People’s Republic of China; 2College of Pharmacy, Jinan University, Guangzhou, 510632, People’s Republic of China; 3Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, 510632, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangning Liu, The First Affiliated Hospital of Jinan University, School of Stomatology, Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, 510630, People’s Republic of China, Email liuxiangning@jnu.edu.cn Dongmei Zhang, College of Pharmacy, Jinan University, Guangzhou, 510632, People’s Republic of China, Email dmzhang701@jnu.edu.cnPurpose: Blood vessels distribute cells, oxygen, and nutrients throughout the body to support tissue growth and balance. Pericytes and endothelial cells form the inner wall of blood vessels, crucial for organ development and tissue homeostasis by producing paracrine signaling molecules. In the skeletal system, pericyte-derived vascular factors along with angiogenic factors released by bone cells regulate angiogenesis and bone formation. Although the involvement of angiogenic factors and skeletal blood vessels in bone homeostasis is relatively clear, the role of pericytes and the underlying mechanisms remain unknown. Here, our objective was to elucidate the significance of pericytes in regulating osteoclast differentiation.Methods: We used tissue staining to detect the coverage of pericytes and osteoclasts in femoral tissues of osteoporotic mice and mice of different ages, analyzing their correlation. We developed mice with conditionally deleted pericytes, observing changes in bone mass and osteoclast activity using micro-computer tomography and tissue staining to detect the regulatory effect of pericytes on osteoclasts. Pericytes-derived exosomes (PC-EVs) were collected and co-cultured with monocytes that induce osteoclast differentiation to detect the effect of the former on the exosomes. Finally, the specific mechanism of PC-EVs regulating osteoclast differentiation was verified using RNA sequencing and Western blotting.Results: Our study indicates a significant correlation between pericytes and age-related bone resorption. Conditional deletion of pericytes activated bone resorption and led to osteopenia in vivo. We discovered that PC-EVs inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which is mediated by tumor necrosis factor receptor-associated factor 3 (Traf3), negatively regulating osteoclast development and bone resorption. Silencing Traf3 in PC-EVs canceled their inhibitory effect on osteoclast differentiation.Conclusion: Our study provides a novel perspective into the regulatory role of pericytes on bone resorption and may provide potential strategies for developing novel anti-bone resorption therapies. Keywords: pericytes, exosomes, bone resorption, Traf3

Qi Yang,1– 4 Yalan Luo,1– 3 Peng Ge,1– 3 Bowen Lan,1– 3 Jin Liu,1– 3 Haiyun Wen,1– 3 Yinan Cao,1– 3 Zhenxuan Sun,1– 3 Guixin Zhang,1– 3 Huiming Yuan,5 Lihua Zhang,5 Hailong Chen1– 3 1Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Department of Traditional Chinese Medicine, the Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China; 5CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023, People’s Republic of ChinaCorrespondence: Hailong Chen, Email chenhailong@dmu.edu.cnBackground: Numerous preclinical investigations have exhibited the beneficial impact of emodin (EMO) on the management of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). However, the potential of EMO to mitigate organ damage through the modulation of exosome (Exo)-specific miRNA expression profiles remains unclear.Methods: The SAP rat model was established by retrograde injection of 5% sodium taurocholate into the pancreatic bile duct. Rats received intragastric administration of EMO at 2 h and 12 h post-modeling. Plasma and bronchoalveolar lavage fluid (BALF)-derived exosomes were isolated and purified from SAP rats treated with EMO. The therapeutic effects of these Exos in SAP rats were assessed using hematoxylin-eosin staining and measurement of inflammatory factor levels. MicroRNA (miRNA) sequencing was conducted on plasma and BALF-derived Exos, and rescue experiments were performed to investigate the function of NOVEL miR-29a-3p in the treatment of SAP using EMO.Results: EMO exhibits ameliorative effects on pancreatic and lung injury and inflammation in rats with SAP. Plasma/BALF-derived Exos from EMO-treated SAP rats also have therapeutic effects on SAP rats. The miRNA expression profile of plasma and BALF-derived Exos in SAP rats underwent significant changes upon exposure to EMO. In particular, 34 differentially expressed miRNAs (DEmiRNAs) were identified when comparing BALF-SAP+EMO-Exo and BALF-SAP-Exo. 39 DEmiRNAs were identified when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo. We found that SAP rats treated with Exos derived from BALF exhibited a more potent therapeutic response than those treated with Exos derived from plasma. EMO may rely on NOVEL-rno-miR-29a-3p expression to prevent pulmonary injury in SAP rats.Conclusion: The mechanism of action of EMO is observed to have a significant impact on the miRNA expression profile of Exos derived from plasma and BALF in SAP rats. NOVEL-rno-miR-29a-3p, which is specific to Exos, and is derived from BALF, may play a crucial role in the therapeutic efficacy of EMO. Plain Language Summary: Exosomes extracted from plasma/BALF of EMO-treated SAP rats show a substantial therapeutic impact on SAP-Associated ALI, with BALF-derived exosomes having a higher therapeutic effect than plasma-derived exosomes.EMO dramatically altered the miRNA expression patterns of plasma and BALF-derived exosomes in SAP rats.The lung protective effect of EMO in SAP rats is somewhat reliant on Novel-rno-miR-29a-3p expression.Keywords: severe acute pancreatitis, acute lung injury, emodin, exosome, microRNA

Daopeng Fan,1,* Shuqi Wang,1,* Ran Huang,1,* Xiaoning Liu,1 Hua He,1 Gaiping Zhang1– 3 1College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China; 2Longhu Laboratory, Zhengzhou, 450046, People’s Republic of China; 3School of Advanced Agriculture Sciences, Peking University, Beijing, 100871, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua He, College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China, Email hhe@henau.edu.cnBackground: Nanomedicine presents a promising alternative for cancer treatment owing to its outstanding features. However, the therapeutic outcome is still severely compromised by low tumor targeting, loading efficiency, and non-specific drug release.Methods: Light-assisted “nano-neutrophils (NMPC-NPs)”, featuring high drug loading, self-amplified tumor targeting, and light-triggered specific drug release, were developed. NMPC-NPs were composed of neutrophil membrane-camouflaged PLGA nanoparticles (NPs) loaded with a hypoxia-responsive, quinone-modified PTX dimeric prodrug (hQ-PTX2) and photosensitizer (Ce6).Results: hQ-PTX2 significantly enhanced the drug loading of NPs by preventing intermolecular π–π interactions, and neutrophil membrane coating imparted the biological characteristics of neutrophils to NMPC-NPs, thus improving the stability and inflammation-targeting ability of NMPC-NPs. Under light irradiation, extensive NMPC-NPs were recruited to tumor sites based on photodynamic therapy (PDT)-amplified intratumoral inflammatory signals for targeted drug delivery to inflammatory tumors. Besides, PDT could effectively eliminate tumor cells via reactive oxygen species (ROS) generation, while the PDT-aggravated hypoxic environment accelerated hQ-PTX2 degradation to realize the specific release of PTX, thus synergistically combining chemotherapy and PDT to suppress tumor growth and metastasis with minimal adverse effects.Conclusion: This nanoplatform provides a prospective and effective avenue toward enhanced tumor-targeted delivery and synergistic cancer therapy.Keywords: neutrophil, self-amplified tumor targeting, high drug loading, hypoxia-responsive, chemo-photodynamic therapy

Tao Wang,1,2,&ast; Qianwen Yang,3,&ast; Yan Gao,2 Rongping Zhang,2 Chaoxin Zhou,2 Weifang Kong,1 Guojin Zhang,1 Xinyue Chen,4 Hong Pu,1 Lan Shang1 1Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Radiology, The First People’s Hospital of Liangshan Yi Autonomous Prefecture, Xichang, Sichuan, People’s Republic of China; 3School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 4CT Collaboration, Siemens-Healthineers, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Pu; Lan Shang, Department of Radiology, The First Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, No. 32, West Section 2, 1st Ring Road, Chengdu, Sichuan Province, 60072, People’s Republic of China, Tel +86 13882267217, Fax +86 87294280, Email ph196797@163.com; shanglan8282@163.comPurpose: This study aimed to investigate clinical features and computed tomography (CT) manifestations of rifampicin primary drug-resistant pulmonary tuberculosis in Liangshan Yi Autonomous Prefecture.Patients and Methods: A total of 100 inpatients with confirmed primary rifampicin-resistant pulmonary tuberculosis were recruited from January 2020 to December 2022 at an infectious disease hospital located in the Liangshan Yi Autonomous Prefecture. Additionally, 100 inpatients with confirmed drug-susceptible pulmonary tuberculosis during the same period were matched to the rifampicin-resistant group based on gender, age, and ethnicity. The clinical characteristics of the two groups were recorded separately. Furthermore, the CT manifestations in these patients were independently analyzed by three radiologists.Results: The results showed that comorbid diabetes mellitus was more prevalent in the drug-resistant tuberculosis (DR-TB) group than in the drug-susceptible tuberculosis (DS-TB) group (9% vs 0%, p=0.0032). In terms of imaging presentation, DR-TB patients exhibited a higher frequency of calcifications (55% vs 35.00%, p=0.0068), greater median number of cavities (5 vs 2, p=0.0027), and larger maximum cavity diameter (52.08± 25.55 mm vs 42.72± 17.48 mm, p=0.0097). Additionally, bilateral involvement was more common in DR-TB patients at the site of the lesion (89% vs 76%, p=0.0246), with a higher prevalence in the right middle (82% vs 68%, p=0.0332), right lower (82% vs 68%, p=0.0332), left upper (91% vs 77%, p=0.0113), and left lower lobes (92% vs 66%, p< 0.0001). Conversely, the involvement of only one lobe was less frequent in patients with DR-TB than in those with DS-TB (4% vs 13%, p=0.0398), whereas the involvement of all five lobes was more common (68% vs 51%, p=0.0209).Conclusion: Patients with DR-TB exhibit a higher prevalence of severe imaging manifestations, highlighting the importance of CT in the early detection and diagnosis of DR-TB.Keywords: drug-resistant tuberculosis, drug-susceptible tuberculosis, tuberculosis, comorbid diabetes mellitus

Linxi Zeng,1 Sen Feng,1 Lulu Yao,1 Jiaqing Zhao,1 Guoqiang Zhang1,2 1Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, People’s Republic of China; 2Candidate Branch of National Clinical Research Center for Skin Diseases, Shijiazhuang, People’s Republic of ChinaCorrespondence: Guoqiang Zhang, The First Hospital of Hebei Medical University, 89 Donggang Road, Yuhua District, Shijiazhuang City, Hebei Province, People’s Republic of China, Email zlx090702@163.comAbstract: Herpes zoster is typically a blister rash involving a single skin group, caused by the reactivation of primary varicella zoster virus infection. Disseminated herpes zoster refers to the presence of more than 20 small blisters outside the primary or adjacent skin, which is rare and usually occurs in individuals with weakened immune function. This case described a patient diagnosed with disseminated herpes zoster, with a decrease in CD4 count (379 cells/mm3) and certain skin lesions. He was subsequently screened positive for HIV. Also, we summarized other studies on the CD4 value of HIV patients with herpes zoster. Overall, for herpes zoster patients with decreased CD4 levels and certain skin manifestations, such as diffuse, ulcerative, or pustular lesions, clinicians should be aware of HIV infection.Keywords: disseminated herpes zoster, CD4, HIV infection

Lietao Wang,1,&ast; Xin Fu,1,&ast; Min He,1,&ast; Lvyuan Shi,1 Dingyuan Wan,1 Yucong Wang,1 Qin Wu,1 Jing Yang,1 Bayuan Cai,2 Hongtao Xia,3 Hongxu Chen,4 Ge Zhang,5 Xianying Lei,6 Wei Zhang,7 Zhongxue Feng,7 Bo Wang,1 Zhongwei Zhang1 On behalf of Heat Stroke Research Group in Southwestern China1Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Critical Care Medicine, The People’s Hospital of Jiajiang, Leshan, People’s Republic of China; 3Department of Critical Care Medicine, Suining Central Hospital, Suining, People’s Republic of China; 4Department of Critical Care Medicine, The Hospital of Traditional Chinese Medicine of Leshan, Leshan, People’s Republic of China; 5Department of Critical Care Medicine, The First People’s Hospital of Longquanyi District, Chengdu, People’s Republic of China; 6Department of Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 7Department of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Wang; Zhongwei Zhang, Department of Critical Care Medicine, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, People’s Republic of China, Tel/Fax +86-28-85422739, Email wchicu@126.com; 716461751@qq.comObjective: The aim of this nationwide multicenter study was to ascertain the risk factors associated with in-hospital mortality in patients with heat stroke admitted to intensive care units (ICUs) and to develop a nomogram for prognostic prediction.Methods: A retrospective analysis was conducted on clinical data collected from ICU patients diagnosed with heat stroke across multiple centers nationwide. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors for in-hospital mortality. Based on the results of the multivariate analysis, a nomogram was constructed to estimate the individualized probability of mortality. Internal validation of the nomogram was performed, and its performance was assessed using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA).Results: A total of 292 ICU patients with heat stroke were included in this study. Three risk factors, namely Cr (creatinine), AST (aspartate aminotransferase), and SBP (systolic blood pressure), were found to be significantly associated with in-hospital mortality. These risk factors were incorporated into the nomogram, which exhibited good discriminative ability (area under the ROC curve of the training and validation cohorts were 0.763 and 0.739, respectively) and calibration. Internal validation and decision curve analysis confirmed the stability and reliability of the nomogram.Conclusion: This nationwide multicenter study identified key risk factors for in-hospital mortality in ICU patients with heat stroke. The developed nomogram provides an individualized prediction of mortality risk and can serve as a valuable tool for clinicians in the assessment and management of ICU patients with heat stroke.Keywords: heat stroke, intensive care unit, in-hospital mortality, risk factors, nomogram

Jialu Sun,1 Yijun Shi,1 Yaowei Ding,1 Siqi Wang,1 Lingye Qian,2 Xin Luan,1 Guoge Li,1 Yuxin Chen,1 Xiaotong Li,1 Hong Lv,1,3,4 Guanghui Zheng,1,3,4,&ast; Guojun Zhang1,3,4,&ast; 1Laboratory, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Laboratory, Beijing An Zhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 3NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanghui Zheng; Guojun Zhang, Beijing Tiantan Hospital, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 18600148997 ; +86 13811792425, Email zgh999@yeah.net; guojun.zhang@ccmu.edu.cnBackground: To investigate the factors associated with follow-up CSF cultures (FUCCs) in post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis and the effect of FUCCs on treatment management and patient outcomes.Methods: This single-centered retrospective cohort study enrolled post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis at a tertiary-care university hospital between 2012 and 2022. The risk factors for 28-day mortality were evaluated using multivariate Cox analysis. FUCC-related risk factors were also analyzed.Results: Among the 844 enrolled patients, 504 (59.7%) underwent FUCC, and FUCC was found to be associated with lower rates of both all-cause (hazard ratio (HR) 0.391; 95% confidence interval (CI), 0.235– 0.651; p< 0.001) and attributable mortality (HR 0.463; 95% CI, 0.239– 0.897; p=0.023) in Post-neurosurgical patients diagnosed with Gram-negative bacterial meningitis/encephalitis. Moreover, the results of the study underscored that patients with persistent gram-negative bacterial meningitis/encephalitis had a lower all-cause/attributable short-term survival rate according to 28-day mortality Kaplan–Meier analysis (P=0.001/0.006).Conclusion: Performing FUCC has been demonstrated to lower mortality rates in Post-neurosurgical patients suffering from Gram-negative bacterial meningitis/encephalitis. The higher mortality rate observed in patients with persistent gram-negative bacterial meningitis/encephalitis suggests that performing FUCC is a crucial component of proper patient care and management, and is therefore recommended for use by clinicians as a standard practice. This finding underscores the significance of consistent implementation of FUCC in the management and prognosis of patients with Post-neurosurgical infections.Keywords: gram-negative bacterial meningitis/encephalitis, follow-up cerebrospinal fluid cultures, all-cause 28-day mortality, persistent meningitis/encephalitis, risk factors

Xiangjun Chen,&ast; Wenting Li,&ast; Xueling Li, Keke Li, Guilong Zhang, Wei Hong School of Pharmacy, Shandong New Drug Loading & Release Technology and Preparation Engineering Laboratory, Binzhou Medical University, Yantai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Hong; Guilong Zhang, Tel/Fax +86-0535-6908191 ; Tel/Fax +86-0535- 6913719, Email hongwei_sy@bzmc.edu.cn; glzhang@bzmc.edu.cnIntroduction: As we enter the post-antibiotic era, the rise of antibiotic-resistant pathogenic bacteria is becoming a serious threat to public health. This problem is further complicated by antibiotic-resistant biofilms, for which current treatment options are limited.Methods: To tackle this challenge, we propose a novel approach that involves the use of photodynamic cationic pH-sensitive liposomes loaded with ultra-small copper oxide (Ce6@Lipo/UCONs) to effectively eliminate drug-resistant bacteria and eradicate biofilms while minimizing safety concerns and the risk of resistance development.Results: Our study demonstrates that Ce6@Lipo/UCONs have minimal toxicity to mammalian cells and can significantly enhance the association affinity with methicillin-resistant Staphylococcus aureus (MRSA) as confirmed by fluorescent microscope and flow cytometry, thereby greatly improving the bactericidal effect against planktonic MRSA. The cationic nature of Ce6@Lipo/UCONs also enables them to penetrate MRSA biofilms and respond to the acidic microenvironment within the biofilm, effectively releasing the loaded UCONs. Our results indicate that Ce6@Lipo/UCONs could effectively eliminate biofilms under light irradiation conditions, as evidenced by both biomass analysis and scanning electron microscopy observations. In addition, significant antibacterial effects and abscess healing were observed in MRSA-infected mice treated with Ce6@Lipo/UCONs upon light irradiation, while good biocompatibility was achieved in vivo.Conclusion: Taken together, our findings suggest that photodynamic cationic ultrasmall copper oxide nanoparticles-loaded liposomes are a highly promising nano platform for combating antibiotic-resistant microbial pathogens and biofilms. The effective biofilm penetration and synergistic effect between photodynamic inactivation and metal sterilization make them a valuable tool for overcoming the challenges posed by antibiotic resistance.Keywords: biofilm, antibiotic resistance, synergistic potential, photodynamic inactivation, metal sterilization

Jie Wu,1,2 Guangcun Zhang,3 Qiang Zhao,3 Lifeng Wang,3 Jiyong Yang,3 Junchang Cui1 1Department of Respiratory Diseases, The Eighth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; 2Medical School of Chinese People’s Liberation Army, Beijing, People’s Republic of China; 3Laboratory Medicine Department, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Junchang Cui, The Eighth Medical Center, Department of Respiratory Diseases, Chinese People’s Liberation Army General Hospital, No. 17 Heishanhu Road, Haidian District, Beijing, 100091, People’s Republic of China, Tel +86 010 6677 5010, Email guoguoyoumeng@163.comPurpose: To better guide clinical use, we determined the in vitro antimicrobial activity of the new drug eravacycline and other tetracycline derivatives against levofloxacin (LVFX)-non-susceptible and/or trimethoprim-sulfamethoxazole (TMP-SMZ)-resistant Stenotrophomonas maltophilia and evaluated their dosing regimens.Methods: Seventy-seven unique strains of S. maltophilia were isolated from sputa samples and airway aspirate samples that were either LVFX-non-susceptible and/or TMP-SMZ-resistant. Monte Carlo simulations were performed for different dosing regimens according to the population pharmacokinetic parameters of antibiotics in patients with respiratory tract infections at the minimum inhibitory concentration (MIC).Results: Eravacycline had excellent in vitro antibacterial activity against LVFX-non-susceptible and/or TMP-SMZ-resistant S. maltophilia. Monte Carlo simulations showed that for LVFX-non-susceptible strains, the cumulative fraction of response (CFR) of minocycline at the conventional recommended dose of 100 mg q12 h was 90.90%; for TMP-SMZ-resistant strains, the CFR of minocycline at a high dose of 200 mg q12 h was only 91.64%. For strains resistant to both LVFX and TMP-SMZ, the CFR of minocycline at a high dose of 200 mg q12 h was 89.81%. In contrast, the CFR of tigecycline was less than 40%, even at a dose of 100 mg q12 h.Conclusion: For pneumonia, minocycline is better for S. maltophilia that is non-susceptible to LVFX; for TMP-SMZ-resistant strains and strains that are not susceptible to either LVFX or TMP-SMZ, the efficiency of eravacycline requires further evaluation. Eravacycline may be a better choice for extremely resistant S. maltophilia strains that are non-susceptible to LVFX, TMP-SMZ, and minocycline.Keywords: eravacycline, tetracyclines, levofloxacin, trimethoprim, sulfamethoxazole drug combination, Stenotrophomonas maltophilia, Monte Carlo method

Tian Liu,1,&ast; Shangcong Han,2,&ast; Yu Yao,1 Guiming Zhang1 1Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guiming Zhang, Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, People’s Republic of China, Email zhangguiming9@126.comAbstract: In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.Keywords: monocarboxylate transporter, tumor, tumor microenvironment, function, regulation

Ding P, Jin Q, Chen X, et al. Int J Nanomedicine. 2019;14:7533-7548. At the author’s request, we, the Editor and Publisher of the journal International Journal of Nanomedicine have retracted the following article. During a recent review of the article, the authors identified an error in the use of the transmission electron microscopy (TEM) images for Figure 2A, which could potentially confuse readers. After discussing this issue with the editorial team and providing the original data, the authors agreed that the potential confusion could not be adequately addressed through simple correction. Although the results of TEM were independent of the in vivo and in vitro experiments and did not affect the effectiveness of the nanovaccines in the study, they could have compromised the accuracy and reliability of the findings. The authors apologize for the errors in the article and appreciate the readership’s understanding in this matter. However, the authors remain confident in the results and conclusions of this study and with the original material well preserved, hope to submit a revised version of the article for republication following reevaluation. The journal has acknowledged this. In the meantime, in the interest of upholding research integrity and ensuring the trustworthiness of the scientific record, the authors believe that it is necessary to retract the article. We, the Editor and Publisher, understand and agreed with this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Gang Qin,1 Bo Wang,2 Geng Zhang,2 Lili Wu,1 Peng Zhu,1 Qian Zhang2 1Department of Gastroenterology, Suining First People’s Hospital, Suining, People’s Republic of China; 2Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of ChinaCorrespondence: Qian Zhang, Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Email zhangqian105@swmu.edu.cnPurpose: To screen out potential prognostic biomarkers for HBV-related acute-on-chronic liver failure (HBV-ACLF).Patients and Methods: Peripheral blood samples of HBV-ACLF patients (n=56) and normal controls (n=15) from the Affiliated Hospital of Southwest Medical University from January 2021 to April 2022 were collected, 5 normal patients and 10 patients with ACLF were randomly selected for Data independent acquisition (DIA) mass spectrometry analysis, and the potential core proteins were screened out via bioinformatics. All samples were validated by Enzyme linked immunosorbent assays (ELISA) technology, and the survival curve was constructed based on the patient’s 90-day survival time.Results: A total of 247 differentially expressed proteins (DEPs) were screened, of which 148 were upregulated and 99 were down-regulated. The DEPs were mainly enriched in high-density lipoprotein particle remodeling, coagulation, and hemostasis and participated in signaling pathways such as cholesterol metabolism, coagulation cascades, and PPAR signaling pathway. Finally, bikunin was selected for further study and validated via the ELISA, compared with the normal group, bikunin was poorly expressed in the HBV-ACLF group, the difference was statistically significant (P < 0.0001), the area under the curve (AUC) for Receiver operating characteristic (ROC) analysis was 0.917. Furthermore, compared with the non-survival group, bikunin was highly expressed in the HBV-ACLF survival group, the difference was statistically significant (P=0.0015), and the survival curve showed a positive correlation with patient survival (P=0.0063).Conclusion: The level of plasma bikunin in HBV-ACLF is down-regulated, which is positively correlated with the survival of the patients with HBV-ACLF, and is expected to become a new prognostic biomarker.Keywords: HBV-ACLF, AMBP, bikunin, DIA

Lin Gao,1 Qindi Liu,2 Weiwei Zhang,1 Hong Sun,1 Zhiming Kuang,1 Guangping Zhang,1 Zhenfei Huang1 1Department of Intensive Care Unit, Ganzhou People’s Hospital, Ganzhou City, Jiangxi Province, 341000, People’s Republic of China; 2Department of Respiratory and Critical Medicine, Ganzhou Fifth People’s Hospital, Ganzhou City, Jiangxi Province, 341000, People’s Republic of ChinaCorrespondence: Zhenfei Huang, Department of Intensive Care Unit, Ganzhou People’s Hospital, No. 17, Hongqi Avenue, Zhanggong District, Ganzhou City, Jiangxi Province, 341000, People’s Republic of China, Email H13507977932@163.comIntroduction: Severe pneumonia progresses rapidly, so early assessment of the severity and prognosis is crucial for reducing mortality rates.Objective: We explore the role of serum microRNA-24 (miR-24) and microRNA-223 (miR-223) in the prognosis of severe pneumonia.Methods: There were a total of 96 patients with general pneumonia, 94 patients with severe pneumonia, and 93 healthy people, who were enrolled in this study. The levels of serum miR-24 and miR-223 were detected by real-time fluorescent quantitative PCR in all groups.Results: The serum miR-223 level in the severe group was higher than that in the common group and the control group, and the miR-24 level was lower than that in the common group and the control group (P< 0.05). The serum miR-223 levels and APACHEII scores in the death group were higher than those in the survival group on the first, third, and seventh day after admission, while the miR-24 levels were lower than those in the survival group (P< 0.05). The proportion of patients with mechanical ventilation in the death group was higher than that in the survival group (P< 0.05). The level of serum miR-24 was negatively correlated with APACHEII score and mechanical ventilation in patients who died of severe pneumonia (P< 0.05), and miR-223 was positively correlated with APACHEII score and mechanical ventilation (P< 0.05). The AUC predicted by serum miR-24, miR-223, and APACHEII scores alone and jointly were 0.867, 0.839, 0.791, and 0.952, respectively. MiR-24 and miR-223 are protective and independent risk factors for mortality in severe pneumonia patients, respectively (P< 0.05). MiR-24 was a protective factor affecting the death of patients with severe pneumonia, and miR-223 was an independent risk factor affecting the death of patients with severe pneumonia (P< 0.05).Conclusion: The combination of serum miR-24 and miR-223 levels on the first day after admission and APACHEII score can effectively predict prognosis.Keywords: severe pneumonia, micro RNA-24, micro RNA-223, prognosis

Jialuo Han, Jianwei Guo, Xuexiao Ma, Guoqing Zhang, Shuo Han, Hao Zhang, Houchen Liu, Mingrui Chen, Yan Wang Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, Shandong, People’s Republic of ChinaCorrespondence: Yan Wang, Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong, 266000, People’s Republic of China, Tel +86 17853297089, Email sanwang1986@163.comPurpose: The objective of this study was to describe the Mazor Renaissance robotic system-assisted CBT (cortical bone trajectory) screw technique as a salvage strategy for failed lumbar spine surgery.Patients and Methods: Between January 2018 and June 2022, 7 patients underwent salvage surgery with the CBT screw fixation technique assisted by the Mazor Renaissance robot system in our institution. Intraoperative observations were recorded for blood loss, duration of operation, and fluoroscopy time. Complications related to CBT screws were also recorded. The accuracy of CBT screws was recorded in accordance with the modified Gertzbein-Robbins classification. The JOA (Japanese Orthopedic Association) score for low back pain was used to evaluate surgical outcomes.Results: A total of 26 CBT screws were placed in 7 patients, including 4 females and 3 males. Three patients underwent ASD (adjacent segment disease) and four patients underwent lumbar union failure with loose or compromised PSs (pedicle screws). The mean operation time was 129.29 ± 32.97 minutes, the mean blood loss was 180 ± 52.60 mL, and the mean intraoperative fluoroscopy time was 14.29 ± 3.15 s. All screws were clinically acceptable according to the Gertzbein-Robbins classification. There were no complications related to CBT screws in any of the cases. The JOA scores for low back pain of all patients were significantly improved at the final follow-up.Conclusion: The CBT screw fixation technique supplemented the traditional PS fixation technique, which can be performed as a salvage strategy for failed lumbar spine surgery and achieved good clinical results. The spinal robot was very helpful in evaluating pedicle size and determining CBT screw direction, especially in a previously instrumented lumbar pedicle.Keywords: CBT screw, robot-assisted, salvage strategy, ASD

Liping Shi,1,2 Xiaoqing Du,3 Jing Li,1,2 Guoqiang Zhang1,2 1Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Candidate Branch of National Clinical Research Center for Skin Diseases, Shijiazhuang, People’s Republic of China; 3Department of Dermatology, Bethune International Peace Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Guoqiang Zhang, The First Hospital of Hebei Medical University, 89 Donggang Road, Yuhua District, Shijiazhuang City, Hebei Province, People’s Republic of China, Tel +8618633888122, Email zlx090702@163.comObjective: This study aimed to identify hub genes and common pathways shared between psoriasis and cardiovascular disease (CVD) using bioinformatics analysis and predict the transcription factors (TFs) of hub genes.Methods: GSE133555 data from the Gene Expression Omnibus (GEO) database were used to identify differentially expressed genes (DEGs) between involved and uninvolved skin lesions in psoriasis, employing the limma package in R. Additionally, CVD-related genes were obtained from the GeneCards database. The intersection of DEGs and CVD-related genes yielded CVD-DEGs. Gene Ontology and signaling pathway analyses were performed using the clusterProfiler package in R. Hub genes were identified by intersecting six algorithms in the CytoHubba plugin of Cytoscape. To identify potential biomarkers, the GSE14905 dataset was subjected to receiver operating characteristic analysis, resulting in the identification of eight central hub genes. Finally, the NetworkAnalyst web tool was used to identify the TFs of the eight hub genes.Results: We identified 92 significant DEGs out of 1825 CVD-related genes in psoriasis obtained from the GSE13355 and GeneCard data. Functional enrichment analysis revealed the involvement of these genes in various signaling pathways, including the interleukin-17 signaling, tumor necrosis factor signaling, lipid and atherosclerosis, chemokine signaling, and cytokine signaling pathways in the immune system. The eight hub genes identified included interleukin-1 beta, C-X-C motif chemokine ligand 8, signal transducer and activator of transcription 3, C-C motif chemokine ligand 2, arginase 1, C-X-C motif chemokine receptor 4, cyclin D1, and matrix metallopeptidase 9, with forkhead box C1 also identified as an associated TF of these genes. These hub genes and TF may act as key regulators in the context of CVD.Conclusion: This study identified several hub genes and signaling pathways associated with both CVD and psoriasis. These findings lay the groundwork for potential therapeutic interventions for patients with psoriasis affected by CVD.Keywords: psoriasis, cardiovascular disease, signaling pathway, gene expression omnibus

Wan He,1,&ast; Changbu Wu,2,3,&ast; Guanping Chen,2– 4 Guili Zhang,2,3 Zihan Zhao,2,3 Shu’an Wen,2,3 Yuan Zhou,2,3 Xue Deng,2,3 Yu Feng,2,3 Lan-Lan Zhong,2,3 Guo-Bao Tian,2– 4 Min Dai1 1School of Laboratory Medicine, Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 2Department of Immunology and Microbiology, Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 3Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, People’s Republic of China; 4Department of Immunology, School of Medicine, Sun Yat-Sen University, Shenzhen, 518107, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Dai, School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan Province, People’s Republic of China, Tel +86 28-62739128, Email daimin1015@163.com Guo-Bao Tian, Department of Immunology and Microbiology, Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, People’s Republic of China, Tel/Fax +86 20 87335387, Email tiangb@mail.sysu.edu.cnBackground: The emergence and spread of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) is a potential epidemiological threat that needs to be monitored. However, the transmission and pathogenic characteristics of hv-CRKP in China remain unclear. We investigated the epidemiological characteristics of gut colonized hv-CRKP in a hospital in Guangdong Province, China.Methods: A total of 46 gut colonized hv-CRKP isolates were collected from Sun Yat-Sen Memorial Hospital (Guangzhou, China) from August 31st to December 31st, 2021. Minimum inhibitory concentrations (MICs) were obtained for 15 antibiotics for 46 hv-CRKP isolates. BALB/C mice infection model and mucoviscosity assay was used to evaluate the virulence of the isolates. The characteristics of genome, phylogenetic relationship and the structure of the plasmid of 46 gut colonized hv-CRKP isolates were compared with pathogenic isolates from GeneBank based on whole-genome data.Results: The hv-CRKP isolation rate of all gut colonized carbapenem-resistant Klebsiella pneumoniae was 17% (46/270), and the intestinal colonization rate of hv-CRKP was irrelevant to the sex, age, department of hospitalization, and history of antibiotic use of the host. The gut colonized hv-CRKP showed pandrug resistance and hypervirulence. The gut colonized hv-CRKP and pathogenic hv-CRKP prevalent in China were mainly ST11 hv-CRKP and had two major epidemic clades. The similarities in genomic characteristics between gut colonized hv-CRKP and pathogenic hv-CRKP were consistent. The gut colonized hv-CRKP carried an incomplete structure pK2044 virulence plasmid from hypervirulent K. pneumoniae NTUH-K2044 by analyzing the virulence plasmid structure.Conclusion: Our results suggest that the gut colonized ST11 hv-CRKP may serve as a reservoir for the clinical pathogenic ST11 HV-CRKP. It is necessary to further strengthen the monitoring of gut colonized hv-CRKP and research the potential mechanism of infection caused by gut colonized hv-CRKP.Keywords: K. pneumoniae, intestinal colonization, hypervirulent, genomic characterization, carbapenemase

Hang Qian,1 Xu Wang,1 Pengbo Wang,1 Guangyang Zhang,1 Jun Liu,1 Xiaoqian Dang,1 Jianbin Guo,2 Ruiyu Liu1 1Department of Orthopedics, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Orthopedics, Honghui Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Ruiyu Liu, Department of Orthopaedics, The Second Affiliated Hospital, Xi’an Jiaotong University, No. 157, Xiwu Road, Xi’an, Shaanxi, 710004, People’s Republic of China, Email liuryu@126.comObjective: Hip ankylosis is a prevalent condition in patients with Ankylosing spondylitis (AS) that can significantly impact their psychological well-being. This study aimed to investigate the impact of Total Hip Arthroplasty (THA) on anxiety and depression among AS patients.Methods: 62 AS patients undergoing primary THA were recruited and separated into two groups based on preoperative hip motion. The 40 patients with hip mobility of 0° were assigned to group A, and others were assigned to group NA. Self-rating Anxiety Scale (SAS), Self-rating Depression scale (SDS), Harris hip scores (HHS) and 36-Item Short Form Survey (SF-36) were obtained one week before and there, six and twelve months after THA.Results: The study found that AS patients in group A had significantly higher levels of anxiety and depression (SAS score = 75.05± 2.79, SDS index score = 0.74± 0.02) compared to group B (SAS score = 54.58± 3.35, SDS index score= 0.64± 0.03, P=0.01). However, both groups showed significant improvements in anxiety and depression scores from there to twelve months after THA (P< 0.001). Correlation analyses revealed that the improvement in group NA was associated with hip pain relief (p< 0.001), while the improvement in group A was related to joint function, disease duration, age at THA and spine imaging lesions (p< 0.001).Conclusion: Some degree of anxiety and depression was present in both groups of AS patients. Levels of depression and anxiety were higher in patients with combined hip ankylosis. And their improvement was associated with improved hip function and quality of life after THA. Hip pain relief played a significant role in patients without hip joint ankylosis. The impact of the degree of lesion on spinal imaging on psychological status needs to be considered in both groups.Keywords: ankylosing spondylitis, depression and anxiety, hip pain, hip joint range of motion, hip ankylosing

Guizhen Zhang,1,&ast; Xuejian Li,1,&ast; Chunyun Huang,1 Yuanyuan Jiang,1 Jian Su,1 Ying Hu2 1Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, People’s Republic of China; 2Faculty of Pharmacy, Guangxi University of Chinese Medicine, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Su, Guangxi Key Laboratory of Zhuang and Yao Ethnic Medicine, Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, 13 Wuhe Avenue, Nanning, Guangxi, 530200, People’s Republic of China, Tel +86-0771-3946492, Fax +86-0771-3946492, Email sujian5000@hotmail.com Ying Hu, Department of Pharmacology, Faculty of Pharmacy, Guangxi University of Chinese Medicine, 13 Wuhe Avenue, Nanning, Guangxi, 530200, People’s Republic of China, Tel +86-0771-3946492, Fax +86-0771-3946492, Email huying5000@hotmail.comPurpose: The aim of this study was to develop a liposome gel containing levo-tetrahydropalmatine (l-THP) and evaluate its transdermal properties.Methods: A L16 (43) orthogonal experiment was conducted to optimize the preparation of l-THP liposomes and assess their characterization and stability in a gel. The transdermal features were analyzed through in vivo and in vitro experiments on rats and Strat-M® membrane, respectively. The metabolism of l-THP in liver and skin S9 fractions was also studied.Results: The optimization of the orthogonal experiment revealed that the ideal mass ratio of phosphatidylcholine, cholesterol, and l-THP during preparation was 10:1:3. The resulting liposome exhibited a particle size of 68 nm, a PDI of 0.27, a drug loading of 4.33%, an encapsulation of 18.79%, and a zeta potential of − 41.27 mV. Both the l-THP and its liposome-gel formulation were found to be stable for a duration of 45 days at 4 °C and 30 °C. During the in vivo transdermal study, the maximum concentration (Cmax) of l-THP from the liposome gel was 0.16 μg/mL, and the time to reach this maximum concentration (tmax) was 1.2 hours. The relative bioavailability of l-THP in the liposome gel was 233.8% compared to the emulsion. The concentration of l-THP (prepared in PBS) decreased at a rate of 0.0067 μg/mL/min in the liver S9 fraction and 0.0027 μg/mL/min in the skin S9 fraction, however, this difference was not observed when l-THP was encapsulated in liposomes. l-THP passed through the Strat-M® membrane at a rate of 0.0032 mg/cm2/h and 0.002 mg/cm2/h for the emulsion and liposome gel, respectively.Conclusion: The optimal process for the preparation of l-THP liposomes was obtained. Compared to the emulsion, the liposomes provided greater bioavailability when used transdermally. The liposomes also provided greater stability for l-THP during storage.Graphical Abstract: Keywords: liposome, transdermal property, l-tetrahydropalmatine, S9 fraction, orthogonal experiment, stability

Guiyun Zhang,1 Yufeng Lu,2 Bin Liu,3 Yanmei Wang,4 Wenyi Li,1 Yangchun Xu1 1Department of Dermatology, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China; 2Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130000, People’s Republic of China; 3Department of Breast Surgery, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China; 4Department of Clinical Nutrition, Jilin Province People’s Hospital, Changchun, 130021, People’s Republic of ChinaCorrespondence: Yangchun Xu, Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, People’s Republic of China, Tel +86-431-8113-6244, Email xuyc@jlu.edu.cnIntroduction: Bowen’s disease (BD) commonly occurs in sites of chronic sunlight exposure such as head, neck and extremities. It rarely distributes on the nipple and areola.Case Presentation: A 59-year-old female presented with crusted plaque on the right breast for over 1 month. Physical examination found an asymptomatic plaque (5 cm × 5 cm) with irregular shape on the right breast. Histopathological examination suggested irregularly acanthotic epidermis and atypical epidermal cells. Dermis showed inflammatory cell infiltration. Immunohistochemical staining showed negative staining for cytokeratin 7 and cytokeratin 20, and positive staining for Ki67 (60%). The mass was excised and no recurrence occurred in the follow-up. Additionally, we reviewed the literature about BD of the breast and summarized the clinical manifestations, histological features, and treatment options.Conclusion: We reported a rare BD case involving nipple and areola. Wide local excision and complete nipple excision are effective for patients with BD of the nipple and areola.Keywords: Bowen’s disease, breast, nipple, case report

Liping Shi,1,2 Jiaqing Zhao,1,2 Linxi Zeng,1,2 Lihong Wang,3 Guoqiang Zhang1,2 1Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Candidate Branch of National Clinical Research Center for Skin Diseases, Shijiazhuang, People’s Republic of China; 3Department of Dermatology, Luancheng People’s Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Guoqiang Zhang, The First Hospital of Hebei Medical University, 89 Donggang Road, Yuhua District, Shijiazhuang City, Hebei Province, People’s Republic of China, Tel +8618633888122, Email zlx090702@163.comAbstract: Dermatosis neglecta (DN) is a rare psychogenic dermatosis. To our knowledge, this is the first reported case of DN based on exanthematous drug eruption. We report a 68-year-old Chinese male patient who presented with thick, yellowish-brown crusting on his face and scalp and scaly skin for 6 days. Dermoscopy revealed diffusely distributed yellow-green serescrust-like plaques with different sizes and uneven thickness on a red background, and some demonstrated dot or globular hemorrhages. We considered DN and exanthematous drug eruptions based on the combination of the clinical medication and the history before the rash.Keywords: cutaneous dirt-adherent, malassezia infection, drug allergy, autoantibody

Gang Zhang,1 Xiaotong Wang,2 Mingyue Tong,1 Jian Chen,1 Qian Ji3 1Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230000, People’s Republic of China; 2Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 3Department of Emergency, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210003, People’s Republic of ChinaCorrespondence: Qian Ji, Department of Emergency, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210003, People’s Republic of China, Email jiqian19881212@126.comBackground: In the United States (U.S.) general population, the association between standardized serum 25-hydroxyvitamin D (25(OH)D) concentration and risk of low muscle mass (LMM) remains unclear. Our research aimed to determine whether or not there was a relationship between serum 25(OH)D concentration and risk of LMM.Methods: We analyzed the cross-sectional data of the US population that participated in the National Health and Nutrition Examination Survey between 2011 and 2014. The relationship between serum 25(OH)D concentration and LMM risk was evaluated using restricted cubic spline (RCS) with multivariate logistic regression model and subgroup analysis.Results: In all, we included 10,256 people in our analysis. The RCS plot demonstrated a U-shaped relationship between serum 25(OH)D concentration and risk of LMM (P for nonlinearity < 0.05). At a Vitamin D concentration of 38.5 nmol/L, LMM risk was at its lowest. Based on analyses stratified by age, sex, hypertension, and diabetes mellitus (DM), serum 25(OH)D concentration and risk of LMM were U-curve correlated for those age 40 or older, male, with hypertension, or without DM. However, LMM risk was positively related to serum 25(OH)D concentration in those younger than age 40 or in women.Conclusion: There is a U-shaped relationship between serum 25(OH)D concentration and the risk of LMM in the general U.S. population. Careful monitoring and appropriate Vitamin D supplementation might lessen the risk of LMM.Keywords: cross-sectional study, low muscle mass, serum 25-hydroxyvitamin D concentration, National Health and Nutrition Examination Survey, United States

Lulu Xv,&ast; Bin Wang,&ast; Qing Zhu, Guoqiang Zhang&ast; The First Hospital of Hebei Medical University, Shijiazhuang, China&ast;These authors contributed equally to this workCorrespondence: Guoqiang Zhang, No. 89, DongGang Road, Shijiazhuang, Hebei Province, People’s Republic of China, Tel +8618633888122, Email zlx090702@163.comAbstract: This is a 58-year-old woman who has had itching on her right back for 10 days; a month ago she developed blisters on her right back with no apparent cause and pain, and was diagnosed with “herpes zoster”. Erythema and blisters with itching reappeared 10 days ago on the right side of the back, where the original blisters had subsided. The histopathological manifestations of the lesions were: mild hyperkeratosis of the epidermis, pustules within the stratum corneum, irregular proliferation of the spinous layer, spongiosis, local destruction of the basal layer, infiltration of eosinophils, neutrophils, histiocytes and scattered plasma cells in the dermis and subcutis. According to the medical history, clinical manifestations and histopathology of the lesions, the diagnosis was Wolf’s isotopic response after herpes zoster.Keywords: Wolf’s isotopic response, herpes zoster, eosinophilic pustular folliculitis

Dongxue Wang,1,&ast; Zhe Xu,2,&ast; Linxi Zeng,1 Jinfang Zhang,1 Guoqiang Zhang1 1Department of Dermatology, The First Hospital of Hebei Medical University, Candidate Branch of National Clinical Research Center for Skin Diseases, Shijiazhuang, People’s Republic of China; 2Department of Dermatology, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqiang Zhang, Department of Dermatology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050031, People’s Republic of China, Tel +86 18633888122, Email zlx090702@163.comBackground: Herpes zoster is a disease caused by varicella-zoster virus infection, which is characterized by dense clusters of vesicles distributed along unilateral bands of nerves and accompanied by neuralgia. Although the disease is self-limited, some patients may develop neurological, ocular, skin, or visceral complications.Case Presentation: We report a 65-year-old Chinese man with ulceration secondary to cutaneous blister rupture on the left lumbar abdomen, who was diagnosed with herpes zoster and did not respond to conventional treatment. Dermatological examination showed diffuse dark erythema with clear boundaries on his left waist and abdomen. Deep ulcers of different sizes were densely distributed with steep edges and relatively dry base, while yellow secretions and black scabs could be seen. Fungal microscopy showed a few pseudohyphae and clusters of spores. Meanwhile, the fungal culture of the secretions showed Candida albicans growth. Skin biopsy of the affected skin from the ulcer of the left abdomen revealed epidermal absence and clusters of spores in the superficial dermis. PAS staining was positive. The patient was diagnosed with gangrenous herpes zoster complicated with Candida albicans infection. After antifungal treatment based on the results of drug sensitivity, the patient’s condition was improved.Conclusion: This case reveals the co-existence of herpes zoster and Candida albicans infection, expands our understanding of overlapping diseases, and provides value for clinical diagnosis and treatment.Keywords: gangrenous herpes zoster, skin wound, fungal infection, Candida albicans

Ran Huang,1,&ast; Daopeng Fan,1,&ast; Hanghang Cheng,1 Jian Huo,1 Shuqi Wang,1 Hua He,1 Gaiping Zhang1,2 1College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China; 2Longhu Laboratory, Zhengzhou, 450046, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua He, College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China, Email hehua1123@126.com Gaiping Zhang, College of Veterinary Medicine, International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou, 450046, People’s Republic of China, Email zhanggaip@126.comBackground: Advanced breast cancer is a highly metastatic tumor with high mortality. Simultaneous elimination of primary tumor and inhibition of neutrophil-circulation tumor cells (CTCs) cluster formation are urgent issues for cancer therapy. Unfortunately, the drug delivery efficiency to tumors and anti-metastasis efficacy of nanomedicine are far from satisfactory.Methods: To address these problems, we designed a multi-site attack, neutrophil membrane-camouflaged nanoplatform encapsulating hypoxia-responsive dimeric prodrug hQ-MMAE2 (hQNM-PLGA) for enhanced cancer and anti-metastasis therapy.Results: Encouraged by the natural tendency of neutrophils to inflammatory tumor sites, hQNM-PLGA nanoparticles (NPs) could target delivery of drug to tumor, and the acute hypoxic environment of advanced 4T1 breast tumor promoted hQ-MMAE2 degradation to release MMAE, thus eliminating the primary tumor cells to achieve remarkable anticancer efficacy. Alternatively, NM-PLGA NPs inherited the similar adhesion proteins of neutrophils so that NPs could compete with neutrophils to interrupt the formation of neutrophil-CTC clusters, leading to a reduction in extravasation of CTCs and inhibition of tumor metastasis. The in vivo results further revealed that hQNM-PLGA NPs possessed a perfect safety and ability to inhibit tumor growth and spontaneous lung metastasis.Conclusion: This study demonstrates the multi-site attack strategy provides a prospective avenue with the potential to improve anticancer and anti-metastasis therapeutic efficacy.Keywords: neutrophil membrane, high drug loading, hypoxia-responsive, CTC-neutrophil cluster, cancer and anti-metastasis therapy

Xiujuan Chang,1,&ast; Shumin Yu,2,&ast; Jianzhi Pang,1 Wei Zhang,1 Huifang Kong,1 Jiagan Huang,1 Guojie Zhang,1 Huixin Zhang,1 Yueyue Gu,1,3 Yan Chen,1 Bin Yang,1 Jingping Liu,4 Zhen Zeng1– 3 1Department of Liver Disease Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 2 302 Clinical Medical School Peking University, Beijing, 100039, People’s Republic of China; 3The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, Anhui Province, 230032, People’s Republic of China; 4Oncology Department, Electric Power Hospital of Beijing, Beijing, 100073, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen Zeng, Department of Liver Disease Medicine, The Fifth Medical Center of Chinese PLA General Hospital, No. 100 West 4th Ring Middle Road, Beijing, 100039, People’s Republic of China, Tel +86 15010540233, Email zengzhen1970@sina.comBackground: We explore the dose–efficacy relationship of lenvatinib plus anti-PD-1 in patients with unresectable hepatocellular carcinoma (u-HCC) infected with hepatitis B virus (HBV) in real-world practice. Furthermore, we identify the population sensitive to lenvatinib plus anti-PD-1 treatments.Methods: This retrospective study included 70 patients treated with lenvatinib plus at least 3 cycles of anti-PD-1 and 140 with lenvatinib alone. Stabilized inverse probability of treatment weighting (SIPTW) was used to balance clinical features between the two groups. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. Subpopulation treatment effect pattern plot (STEPP) estimated treatment-effect differences between the two groups.Results: The median age was 54 years, and 189 (90%) cases were male. A total of 180 (85%) patients were infected with HBV. A slowly increasing 12-month survival rate was with the cycles of anti-PD-1, and 5 cycles and more of anti-PD-1 appeared the most beneficial and stable survival rate. The lenvatinib plus at least 3 cycles anti-PD-1 group had better OS (21.4 vs 14 months, p = 0.041), PFS (8.0 vs 6.3 months, p = 0.015) than the lenvatinib alone group in unadjusted cohorts, and the SIPTW adjusted cohorts had confirmed it. For patients with portal vein trunk invasion (PVTI) or extrahepatic spread (EHS) combined with Child-Pugh class B (CPB), lenvatinib plus anti-PD-1 made the 12-month survival rate increase by 38%, while, in the other population, it did only 18%. The two groups had similar AEs (p ≥ 0.05).Conclusion: The lenvatinib combined with at least 3 cycles of anti-PD-1 was efficacy and safe for u-HCC patients infected with HBV. Especially, patients with PVTI or EHS combined with CPB may benefit most from the combination therapy.Graphical Abstract: Keywords: hepatocellular carcinoma, real-world study, anti-PD-1, lenvatinib

Yijia He,1 Sen Feng,1 Lulu Yao,1 Guoqiang Zhang1,2 1Department of Dermatology, the First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Candidate Branch of National Clinical Research Center for Skin Diseases, Shijiazhuang, People’s Republic of ChinaCorrespondence: Guoqiang Zhang, Department of Dermatology, the First Hospital of Hebei Medical University, No. 89, Donggang Road, Shijiazhuang, Hebei Province, People’s Republic of China, Email zlx090702@163.comAbstract: We report the case of a patient with Lymphocytic thrombophilic arteritis (LTA) with a history of 67 years. This is a relatively rare disease with no recognised guidelines for diagnosis and treatment. The long medical history from birth of this patient and the lack of positive progression may provide some new ideas for the treatment of this disease.Keywords: lymphocytic thrombophilic arteritis, macular lymphocytic arteritis, vasculitis, treatment, case report

Xiaona Lang,1 Jinlei Liu,2 Guangzhong Zhang,3 Xin Feng,1 Wenchao Dan3 1Pharmacy Department, Tianjin Hospital, Tianjin, People’s Republic of China; 2Cardiology Department, Guang ‘anmen Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing, People’s Republic of China; 3Dermatological Department, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Wenchao Dan, Dermatological Department, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China, Tel +86 13652001152, Email dan9521@foxmail.comBackground: In recent years, the emergence of new diseases and resistance to known diseases have led to increasing demand for new drugs. By means of bibliometric analysis, this paper studied the relevant articles on drug repositioning in recent years and analyzed the current research foci and trends.Methodology: The Web of Science database was searched to collect all relevant literature on drug repositioning from 2001 to 2022. These data were imported into CiteSpace and bibliometric online analysis platforms for bibliometric analysis. The processed data and visualized images predict the development trends in the research field.Results: The quality and quantity of articles published after 2011 have improved significantly, with 45 of them cited more than 100 times. Articles posted by journals from different countries have high citation values. Authors from other institutions have also collaborated to analyze drug rediscovery. Keywords found in the literature include molecular docking (N=223), virtual screening (N=170), drug discovery (N=126), machine learning (N=125), and drug-target interaction (N=68); these words represent the core content of drug repositioning.Conclusion: The key focus of drug research and development is related to the discovery of new indications for drugs. Researchers are starting to retarget drugs after analyzing online databases and clinical trials. More and more drugs are being targeted at other diseases to treat more patients, based on saving money and time. It is worth noting that researchers need more financial and technical support to complete drug development.Keywords: drug repositioning, drug discovery, bibliometric, citation analysis, trend analysis

Le Zhuang,1– 6,&ast; Jie Tian,1– 4,7,&ast; Binbin Lai,1– 4,7 Guohong Zhang,1– 4 Hang Li1– 4 1Department of Dermatology, Peking University First Hospital, Beijing, People’s Republic of China; 2National Clinical Research Center for Skin and Immune Diseases, Peking University First Hospital, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Peking University First Hospital, Beijing, People’s Republic of China; 4NMPA Key Laboratory for Quality Control and Evaluation of Cosmetics, Peking University First Hospital, Beijing, People’s Republic of China; 5Dermatology Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 6Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China; 7Institute of Medical Technology, Peking University Health Science Center, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hang Li, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of China, Tel +8613693058190, Fax +861083572350, Email drlihang@126.comBackground: Anti-programmed cell death ligand-1 (anti-PD-L1) immunotherapy is often used for advanced urothelial carcinoma and melanoma, including amelanotic melanoma, a relatively rare subtype with little to no pigment in the tumor cells. However, cellular heterogeneity of amelanotic melanoma during or after anti-PD-L1 immunotherapy treatments has not been described.Purpose: To investigate cellular heterogeneity in acral amelanotic melanoma after immunotherapy exposure.Methods: We evaluated subtle visual changes of the melanoma by dermoscopy and performed a pathological examination to analyze the heterogeneity of microscopic morphological and immunohistochemistry changes. The cellular transcriptional heterogeneity and corresponding biological function profiles of the melanoma were determined by single-cell RNA sequencing (scRNA-seq).Results: The dermoscopic examination revealed black globules and scar-like depigmentation areas against a homogeneous red background. Pigmented and amelanotic melanoma cells were observed microscopically. The pigmented cells were large and contained melanin granules expressing Melan-A and HMB45; the amelanotic cells were small and did not express HMB45. Ki-67 immunohistochemical staining revealed that the pigmented melanoma cells had a higher proliferative ability than the amelanotic cells. scRNA-seq identified three cell clusters: amelanotic cell cluster 1, amelanotic cell cluster 2, and pigmented cell cluster. Furthermore, a pseudo-time trajectory analysis showed that amelanotic cell cluster 2 originated from amelanotic cell cluster 1 and transformed into the pigmented melanoma cell cluster. The expression pattern of melanin synthesis-related and lysosome-endosome-related genes in different cell clusters supported the cell cluster transformation results. Also, upregulated expression of cell cycle genes indicated that the pigmented melanoma cells had a high proliferative ability.Conclusion: Coexisting amelanotic and pigmented melanoma cells indicated cellular heterogeneity in an acral amelanotic melanoma from a patient who underwent immunotherapy treatment. Additionally, the pigmented melanoma cells acquired a higher proliferative ability than the amelanotic melanoma cells.Keywords: amelanotic, acral melanoma, cellular heterogeneity, immunotherapy, drug resistance

Liping Shi,1,2 Linxi Zeng,1,2 Xin Huang,1,2 Bin Wang,1,2 Yuli Zhang,1,2 Guoqiang Zhang1,2 1Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Candidate Branch of National Clinical Research Center for Skin Diseases, Shijiazhuang, People’s Republic of ChinaCorrespondence: Guoqiang Zhang, Department of Dermatology, The First Hospital of Hebei Medical University, 89 Donggang Road, Yuhua District, Shijiazhuang, Hebei Province, People’s Republic of China, Tel +8618633888122, Email zlx090702@163.comAbstract: Acrodermatitis continua of Hallopeau (ACH) is a rare variant of pustular psoriasis that presents as a sterile pustular eruption of the periungual and subungual regions. It affects the skin and nail bed and can lead to distal phalangeal destruction as the disease progresses. ACH is an incurable disease that requires long-term maintenance therapy to prevent any complications. Because ACH is a variant of pustular psoriasis, it is commonly treated with anti-psoriatic therapies. Unfortunately, it is resistant to many available anti-psoriatic therapies, and there are no clinical guidelines for it; the treatment is therefore highly challenging. Current treatment strategies are mostly based on a few case reports and case series. In this study, we present a case of ACH in a 24-year-old man with a long history of severe skin lesions and overt onychodystrophy, successfully treated with Ustekinumab. In this patient, we observed rapid improvement in skin lesions and symptoms. Ustekinumab can considerably improve other symptoms besides plaque psoriasis. The treatment and excellent outcomes of Ustekinumab may provide clinical benefits to more patients and serve as a reference for other dermatologists.Keywords: pustular psoriasis, sterile pustules, anti-psoriatic therapies, biological agent

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

Junxiu Xu,1,&ast; Kai Zhang,2,&ast; Genhao Zhang3 1Department of Medical Laboratory, Zhengzhou University Fifth Affiliated Hospital, Zhengzhou, People’s Republic of China; 2Department of Medical Laboratory, Zhengzhou University Third Affiliated Hospital, Zhengzhou, People’s Republic of China; 3Department of Blood Transfusion, Zhengzhou University First Affiliated Hospital, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Genhao Zhang, Zhengzhou University First Affiliated Hospital, Jianshe Road 1&num;, Zhengzhou, 450052, People’s Republic of China, Email wangshuya617@bjmu.edu.cnBackground: Lysosomes play an important role in enhancing tumorigenesis and chemoresistance in hepatocellular carcinoma (HCC). Therefore, a detailed analysis of the role of lysosome-related genes could improve the poor prognosis of HCC patients.Methods: Lysosome-associated genes were downloaded from the GO and Genome Enrichment Analysis (GSEA) databases. After analyzing lysosome-associated differentially expressed genes (DEGs) between the TCGA and GTEx cohorts, we used univariate Cox regression, LASSO-Cox regression, stepwise Cox regression, and multivariate Cox regression analyses to build a predictive risk model. The ICGC cohort was used as a test cohort for the prognostic signature’s validation. It was also assessed how significantly the signature affected the tumor microenvironment (TME) and sensitivity to immune checkpoint inhibitors. To investigate the expression of this signature in clinical samples, qRT-PCR and immunohistochemistry (IHC) were carried out in 50 normal tissues and 59 HCC tissues.Results: A total of 894 lysosome-associated genes were obtained. After identifying 113 lysosome-associated DEGs, we constructed a five-gene prognostic signature (RRAGD, AP1M2, CRHBP, NCSTN, and SLCO4C1) that can be effectively applied to the prognostic classification of HCC patients in TCGA and ICGC cohorts. Additionally, we discovered that this signature can affect the proportion of macrophage infiltration in TME. We also evaluated several tumor-sensitive medicines that affect this signature. Finally, we discovered that HCC tissues had lower amounts of CRHBP compared to normal tissues by the qRT-PCR and IHC assay.Conclusion: We developed and validated a predictive signature of five lysosome-related genes for HCC patients and verified the downregulation of CRHBP expression in clinical samples, which may provide fresh perspectives for customized immunotherapy.Keywords: lysosome, signature, HCC, TME, prognosis

Zhang X, Lian T, Fan W, et al. Cancer Manag Res. 2020;12:9033–9043. We, the Editors and Publisher of Cancer Management and Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 2, 3, and 5 with images from other unrelated articles. Specifically, Images for Figure 2D have been duplicated with images for Figure 3D from Zhang RL, Aimudula A, Dai JH, Bao YX. RASA1 inhibits the progression of renal cell carcinoma by decreasing the expression of miR-223-3p and promoting the expression of FBXW7. Biosci Rep. 2020;40(7):BSR20194143. https://doi.org/10.1042/BSR20194143 and Figure 4D from Chen J, Li X, Yang L, Li M, Zhang Y, Zhang J. CircASH2L Promotes Ovarian Cancer Tumorigenesis, Angiogenesis, and Lymphangiogenesis by Regulating the miR-665/VEGFA Axis as a Competing Endogenous RNA. Front. Cell Dev. Biol. 2020;8:595585. doi: https://doi.org/10.3389/fcell.2020.595585. Images for Figure 3A have been duplicated with images for Figure 3A from Luo J, Jin Y, Li M, Dong L. Tumor suppressor miR‑613 induces cisplatin sensitivity in non‑small cell lung cancer cells by targeting GJA1. Molecular Medicine Reports. 2021;23:385. Images for Figure 3F have been duplicated with images for Figure 5C from Ruan L, Qian X. MiR-16-5p inhibits breast cancer by reducing AKT3 to restrain NF-κB pathway. Biosci Rep. 2019;39(8):BSR20191611. https://doi.org/10.1042/BSR20191611 (RETRACTED) and Figure 6F from Li Q, Wang W, Zhang M, Sun W, Shi W, Li F. Circular RNA circ-0016068 Promotes the Growth, Migration, and Invasion of Prostate Cancer Cells by Regulating the miR-330-3p/BMI-1 Axis as a Competing Endogenous RNA. Front. Cell Dev. Biol. 2020;8:827. doi: 10.3389/fcell.2020.00827. Images for Figure 5E have been duplicated with images for Figure 5G from Zhang RL, Aimudula A, Dai JH, Bao YX. RASA1 inhibits the progression of renal cell carcinoma by decreasing the expression of miR-223-3p and promoting the expression of FBXW7. Biosci Rep. 2020;40(7):BSR20194143. https://doi.org/10.1042/BSR20194143 and Figure 6I from Luo J, Jin Y, Li M, Dong L. Tumor suppressor miR‑613 induces cisplatin sensitivity in non‑small cell lung cancer cells by targeting GJA1. Molecular Medicine Reports. 2021;23:385. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Yuqin Li,1,2 Changlin Tian,1,2 Xiaofei Song,3 Mengying Du,4 Guoning Zhang,5 Hongtao Liu2 1Graduate School, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Otolaryngology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 4Performance Assessment Department, Quality Management Department, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 5Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Hongtao Liu, Email lhtyl16@126.comBackground: Cholestasis is challenging to treat due to lacked effective drugs. N-(3,4,5-trichlorophenyl)-2 (3-nitrobenzenesulfonamido) benzamide, abbreviated as IMB16-4, which may be effective for the treatment of cholestasis. However, its poor solubility and bioavailability seriously obstruct the research programs.Methods: A hot-melt extrusion (HME) preparation was first applied to increase the bioavailability of IMB16-4, the oral bioavailability, anti-cholestatic effect and vitro cytotoxicity of IMB16-4 and IMB16-4-HME were evaluated. Meanwhile, the molecular docking and qRT-PCR were used to validate the mechanism behind.Results: The oral bioavailability of IMB16-4-HME improved 65-fold compared with that of pure IMB16-4. Pharmacodynamics results demonstrated that IMB16-4-HME prominently decreased the serum levels of total bile acid (TBA) and alkaline phosphatase (ALP), but elevated the level of total bilirubin (TBIL) and direct bilirubin (DBIL). Histopathology revealed that IMB16-4-HME at lower dose exhibited stronger anti-cholestatic effect compared with pure IMB16-4. In addition, molecular docking demonstrated that IMB16-4 has great affinity with PPARα, and qRT-PCR results revealed that IMB16-4-HME significantly elevated the mRNA expression level of PPARα, but decreased the mRNA level of CYP7A1. Cytotoxicity assays demonstrated that the hepatotoxicity of IMB16-4-HME was absolutely attributed to IMB16-4, and the excipients of IMB16-4-HME may increase the drug load within HepG2 cells.Conclusion: The HME preparation significantly increased the oral bioavailability and anti-cholestatic effect of pure IMB16-4, but caused liver injury at high dose, which require a dose balance between the curative effect and safety in the future research.Keywords: IMB16-4, IMB17-15, peroxisome proliferator activated receptor α, cholestasis, molecular docking

Gaozan Zhang,1 Fenfen Yan,1 Fei He,1 Dingxi Liu,2 Libo Wang1 1Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, 130031, People’s Republic of China; 2Department of Clinical Medicine, Zunyi Medical University, Zhuhai, 519041, People’s Republic of ChinaCorrespondence: Dingxi Liu; Libo Wang, Email 3274415580@qq.com; wang_libo@jlu.edu.cnAbstract: Multiple micro-organisms associated with Neuralgic Amyotrophy (NA) have been reported and Brucella species should be an important and overlooked infectious cause or trigger.We report a rare case of neuralgic amyotrophy associated with Brucella infection and is believed to be the first such case report in China. A 42-year-old male with brucellosis was confirmed serologically, who presented recurrent fever and fatigue and suddenly developed severe pain in the right shoulder within one week, followed by the inability to lift and abduct the proximal end of the right upper limb. Based on typical clinical manifestions, MRI neuroimaging of the brachial plexus and neuro-electrophysiological studies to confirm a diagnosis of NA and presented spontaneous recovery during this period, immunomodulatory treatment with corticosteroid or intravenous immunoglobulin had not been attempted, leaving a serious movement disorder in the right upper limb. Even rare, NA and other neurobrucellosis forms should be considered as complications of Brucella infection.Keywords: Brucella infection, neuralgic amyotrophy, immune-mediated nature, diagnosis and treatment

Cheng Ma,1– 4,&ast; Yin Cao,1,&ast; Guang Zhang,1– 3,&ast; Jiannan Qiu,2 Yan Zhou,1 Peng Wang,2 Shuo Wang,2 Dongliang Yan,1 Ding Ma,2 Chunping Jiang,1– 3 Zhongxia Wang1– 3 1Department of Hepatobiliary Surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 3Department of Tissue Engineering, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People’s Republic of China; 4Department of Gastrointestinal Surgery, Xuzhou Central Hospital, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhongxia Wang; Chunping Jiang, Email freud_t@126.com; chunpingjiang@163.comBackground: The prediction of prognosis of hepatocellular carcinoma (HCC) is of great significance in improving disease outcome and optimizing clinical management, while reliable prognostic indicators are lacking. This study was conducted to develop readily-to-use nomograms for prognosis prediction of HCC after hepatectomy.Materials and Methods: Data of eligible patients were collected and analyzed retrospectively. Independent prognostic factors were identified by Cox regression, and nomograms for the prediction of disease-free survival (DFS) and overall survival (OS) were developed. The performance of the nomograms was evaluated by receiver operating characteristics (ROC) curves, C-indexes and calibration curves and was verified by the validation cohort. The predictive value of the nomograms was also compared with the 8th edition of American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) and the Barcelona Clinic Liver Cancer (BCLC) staging systems.Results: In total, 599 patients were enrolled in the analysis: 420 in the training cohort and 179 in the validation cohort. The optimal cut-off value of Gamma-Glutamyl Transpeptidase-to-Lymphocyte Ratio (GLR) was 19.5. GLR contributed significantly to the nomograms with good predictive power. In ROC analyses, the areas under curve (AUCs) of the nomograms for 1-, 3- and 5-year DFS and OS prediction were 0.758, 0.756, 0.734 and 0.810, 0.799, 0.758, respectively. The C-indexes of the DFS nomogram were 0.697 (95% CI 0.665– 0.729) in the training cohort and 0.710 (95% CI 0.664– 0.756) in the validation cohort. For OS prediction, the C-indexes were 0.741 (95% CI 0.704– 0.778) and 0.758 (95% CI 0.705– 0.811) in the training and validation cohorts, respectively. The calibration curves demonstrated satisfactory agreement between nomogram predictions and actual observations. The nomograms demonstrated superior predictive performance to the TNM and the BCLC staging systems.Conclusion: Our novel nomograms showed adequate performance in the prediction of HCC prognosis after hepatectomy, which may facilitate the risk stratification and individualized management of HCC patients.Keywords: hepatocellular carcinoma, nomogram, gamma-glutamyl transferase, lymphocyte, hepatectomy

Gongxing Chen,1,2 Guiyuan Zhang,2 Yingsi Yang,3,4 Jiamiao Zhang,2,5 Yingying Hu2 1College of Education for the Future, Beijing Normal University at Zhuhai, Zhuhai, People’s Republic of China; 2Center for Mental Health, Guangxi Vocational College of Water Resources and Electric Power, Nanning, People’s Republic of China; 3School of Economics and Management, Beijing University of Posts and Telecommunications, Beijing, People’s Republic of China; 4School of Management, Guilin University of Aerospace Technology, Guilin, People’s Republic of China; 5School of Psychology, Central China Normal University, Wuhan, People’s Republic of ChinaCorrespondence: Yingsi Yang, Beijing University of Posts and Telecommunications, Xitucheng Road 10, Haidian District, Beijing, 100876, People’s Republic of China, Email yangyingsi@bupt.edu.cnObjective: External events affect individuals through their cognitive process, a model on how and when negative life events are associated with depressive symptoms was tested by considering individuals’ internal and external factors based on the conservation of resource theory (COR).Methods: We conducted a survey to test our hypotheses. Participants were college students who were selected with the cluster sampling method and were asked to complete the scales measuring negative life events, perceived social support, psychological capital (PsyCap), rumination, and depressive symptoms in the classroom with a unit of class. A total of 764 questionnaires were distributed and returned, and 703 valid data were obtained finally.Results: The present study found that (1) the relationship between negative life events and depressive symptoms was moderated by perceived social support negatively, such that the relationship was stronger with low perceived social support; (2) the relationship between negative life events and depressive symptoms was mediated by rumination; (3) the relationship between rumination and depressive symptoms was moderated by PsyCap negatively, such that the relationship was stronger with low PsyCap; (4) the indirect relationship between negative life events and depressive symptoms through rumination was moderated by PsyCap negatively, such that the indirect relationship got stronger with low PsyCap.Conclusion: Rumination is an essential process for negative life events to affect depressive symptoms, PsyCap and perceived social support help alleviate the detrimental effect of negative life events from internal and external perspectives, respectively. Our research conclusion has a theoretical and practical implementation for reducing depressive symptoms in college students.Keywords: depressive symptoms, perceived social support, rumination, psychological capital, negative life events

Peng Li,1 Xiaonan Su,2 Xiaotong Zhang,3 Lijiang Sun,1 Guiming Zhang1 1Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 2Department of Urology, Zoucheng People’s Hospital, Jining, 273500, People’s Republic of China; 3Department of Vascular Surgery, Qingdao Eighth People’s Hospital, Qingdao, 266100, People’s Republic of ChinaCorrespondence: Guiming Zhang, Email zhangguiming9@126.comObjective: This study aimed to summarize and analyze the clinical and pathological features and prognostic risk factors of adrenocortical carcinoma (ACC).Methods: We retrospectively analyzed clinical and pathological data and the prognoses of 39 adult ACC patients confirmed by pathologic diagnosis at the Affiliated Hospital of Qingdao University between August 2009 and October 2021. Kaplan–Meier curves and univariate and multivariate Cox regression models were used to analyze correlations between clinical and pathological parameters and prognosis. A nomogram prediction model was constructed for overall survival (OS) based on the independent prognostic factors and externally validated it with The Cancer Genome Atlas (TCGA) dataset.Results: The mean age of the patient cohort was 53.87 ± 11.1 years (range: 29– 80 years), which included 17 men and 22 women. The 1-, 2-, and 5-year OS rates were 83.7%, 64.4%, and 59.8%, respectively; the recurrence-free survival (RFS) rates at the same time points were 76.1%, 45.8%, and 23.5%, respectively. Kaplan–Meier curves showed that patients with poor OS were associated with M1 stage (P = 0.008), late ENSAT stage (P = 0.017), presence of venous tumor thrombus (P = 0.015), Ki67 > 20% (P = 0.006), R1/R2 status (P = 0.018), and poorly differentiated tumors (P = 0.047). Patients with late ENSAT stage (P = 0.017), combined with venous tumor thrombus (P = 0.008), Ki67 > 20% (P = 0.022) were more likely to have tumor recurrence. However, age, gender, BMI, tumor diameter, clinical symptoms and postoperative treatment were not correlated with OS or RFS (P > 0.05). Univariate and multivariate COX analyses showed that Ki67 > 20% (P = 0.013) and R1/2 status (P = 0.040) were independent risk factors for OS, while only Ki67 > 20% (P = 0.032) was an independent risk factor for RFS. A nomogram for predicting OS was constructed based on the above factors, and the area under the receiver characteristic curve (ROC)-1, 3, and 5-year survival were 0.8, 0.825 and 0.902, respectively. The C-index of the predicted nomogram was 0.813 and a high C-index value of 0.846 could still be achieved in the external validation of TCGA.Conclusion: ACC is a rare and deadly endocrine malignancy with a high rate of recurrence. High Ki67 index (> 20%) and R1/R2 resection status were independent risk factors for poor prognosis in ACC patients. A novel nomogram with a relatively good accuracy was established to assist clinicians in assessing the risk of OS in patients with ACC.Keywords: adrenocortical carcinoma, clinical diagnosis, survival, recurrence, risk factors, prognosis, nomogram

Mudan He,1,&ast; Guoqing Zhang,2,&ast; Fang Shen,1 Xingjing Li1 1Department of Respiratory, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, People’s Republic of China; 2Department of Respiratory, Jiading Branch of Shanghai General Hospital, Shanghai Jiao tong University School of Medicine, Shanghai, 200803, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingjing Li, Department of Respiratory, Zhongshan Hospital Wusong Branch, Fudan University, No. 101 of North Tongtai Road, Baoshan District, Shanghai, 201900, People’s Republic of China, Tel +86 13816446543, Email lixingjinglxj9a@126.comBackground and Objectives: Smoking can lead to airway inflammation and mucus secretion through the nucleotide-binding domain-like receptor protein 3/caspase-1 pathway. In this study, z-VaD-Ala-Asp-fluoromethyl ketone(Z-VAD), a pan-caspase inhibitor, and acetyl-Asp-Glu-Val-Asp-aldehyde(Ac-DEVD), a caspase-3 inhibitor, were used to investigate the effect of caspase inhibitors on the expression of interleukin(IL)-1β and IL-8, airway inflammation, and mucus secretion in mice exposed to cigarette smoke(CS).Methods: Thirty-two C57BL/6J male mice were divided into a control group, Smoke group, Z-VAD group, and Ac-DEVD group. Except for the control group, the animals were all exposed to CS for three months. After the experiment, lung function was measured and hematoxylin and eosin staining and periodic acid–Schiff staining were performed. The levels of IL-1β, IL-8, and mucin 5ac(Muc5ac) in serum and bronchoalveolar lavage fluid(BALF) were determined by enzyme-linked immunosorbent assay.Results: Compared with the control group, the lung function of mice exposed to smoke was poorer, with a large number of inflammatory cells infiltrating around the airway, collapse of alveoli, expansion and fusion of distal alveoli, and formation of emphysema. The Z-VAD group was relieved compared with the smoke group. Airway inflammation was also reduced in the Ac-DEVD group compared with the Smoke group, but the degree of emphysema was not significantly improved. Although Z-VAD relieved airway inflammation and emphysema, Ac-DEVD only relieved inflammation. Z-VAD and Ac-DEVD decreased serum IL-1β and IL-8 levels. In BALF, IL-1β was decreased in Z-VAD group and IL-8 was highest in Smoke +Ac-DEVD group compared with control group and Ac-DEVD group. There was no significant difference in the expression of Muc5ac in serum. However, in BALF, levels of Muc5ac were higher in the smoking group and the lowest in the Ac-DEVD group.Conclusion: Mice exposed to smoke had decreased lung function and significant cilia lodging, epithelial cell shedding, and inflammatory cell infiltration, with significant emphysema formation. The pan-caspase inhibitor, Z-VAD, improved airway inflammation and emphysema lesions in the mice exposed to smoke and reduced IL-1β and IL-8 levels in serum. The caspase-3 inhibitor, Ac-DEVD, reduced airway inflammation, serum IL-1β and IL-8 levels, and Muc5ac levels in BALF, but it did not improve emphysema.Keywords: cigarette smoke, Z-VAD-FMK, Ac-DEVD-CHO, inflammation, mucin 5ac

(Mo,W)Si2 composite powders with the grain size of about 1 μm were synthesized at 1150℃ for 2 h. The high purity molybdenum concentrate (with the main component of MoS2), W and Si powders were utilized as raw materials and lime as desulfurizer. The graphite felt was laid between the compact (made of MoS2, W and Si) and the lime to facilitate the separation of the produced composite powders from desulfurization product. The phase composition, microstructure evolution, and residual sulfur content during the silicothermic reduction reaction were evaluated. The experimental results showed that the reaction could be completed after a reaction time of 1150℃ for 2 h, and the residual sulfur content of the product was 0.087 wt.%. It was concluded that the interactions between Si and the intermediate products of SiS and SiS2 are crucial for the preparationof (Mo,W)Si2 composite powders at low temperatures. The preparation process could be divided into three stages: solid state reactions between MoS2, W and Si to produce MoSi2, WSi2 and gaseous SiS; gas-solid reaction between MoS2, W and gaseous SiS to generate MoSi2, WSi2 and gaseous SiS2; and gas-solid reaction between gaseous SiS2 and Si to form SiS gas. With this short flow process, fine-grained (Mo,W)Si2 composite powders can be produced at low cost at low temperature, which has great application potential.

Guojun Zhang,1 Chuan Yang,2 Caixia Zhao,1 Feng Xian,3 Dong Qing,1 Qiyu Guo,1 Junmei Song,1 Xilin Liu,1 Jun Bie1 1Department of Oncology, Nanchong Central Hospital and The Second Clinical Medical College of North Sichuan Medical College, Nanchong, People’s Republic of China; 2Department of Oncology, Guangyuan Central Hospital, Guangyuan, People’s Republic of China; 3School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of ChinaCorrespondence: Jun Bie, Department of Oncology, Nanchong Central Hospital and The Second Clinical Medical College of North Sichuan Medical College, Hongguang Road, Shunqing District, Nanchong, People’s Republic of China, Email 78593860@qq.comBackground: The neutrophil-to-lymphocyte ratio (NLR) has been shown to have prognostic value in several common cancers. This study aimed to investigate the prognostic value of NLR in patients with advanced oesophageal squamous cell carcinoma (ESCC) after definitive chemoradiotherapy (dCRT).Methods: A retrospective analysis was performed on 158 patients with advanced ESCC who received dCRT from January 2012 to December 2018. The NLR for different treatment stages was calculated based on laboratory test results. The Kaplan–Meier (KM) method and Cox proportional regression model were used to analyse the relationship between NLR and overall survival (OS).Results: The mean NLR of 158 patients with ESCC was 3.403 ± 2.479. The pre-treatment NLR cut-off was 4.839, and patients were divided into the low NLR group (NLR < 4.839) and the high NLR group (NLR ≥ 4.839). NLR in patients with ESCC was related to N stage (P < 0.05). The KM analysis showed that the median OS of all enrolled patients was 29.3 months, the median OS periods of patients in the high and low NLR groups were 15.6 and 35.8 months, respectively, and the OS of the low NLR group was better than that of the high NLR group (P < 0.001). In the multivariate analysis, NLR was an independent prognostic factor that affects the prognosis of patients with ESCC receiving dCRT. Furthermore, patients who maintained a high NLR before and after treatment showed worse clinical outcomes than the other groups.Conclusion: Our findings suggest that NLR can effectively assess the prognosis of patients with advanced ESCC undergoing dCRT.Graphical Abstract: Keywords: oesophageal squamous cell carcinoma, radiochemotherapy, neutrophil-to-lymphocyte ratio

Weiping Li, Yanqing Liu, Xiaoling Xu, Qi Zhang, Xiao Zhang, Jie Zhang, Xiaochen Niu, Shiyao Yang, Xiaobo Zhang, Wenzhen Shi, Gejuan Zhang, Mingze Chang, Ye Tian Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, School of Life Sciences and Medicine, Northwest University, Xi’an, Shaanxi Province, People’s Republic of ChinaCorrespondence: Ye Tian; Wenzhen Shi, Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, No. 10, East Section of Fengcheng Third Road, Weiyang District, Xi’an, Shaanxi Province, People’s Republic of China, Tel +86 29-61816515, Email chhty@sina.com; shiwenzhen736@163.comBackground: Ischemic stroke (IS) was a multifactorial disease, which was the main cause of death and adult disability. Genetic factors cannot be ignored.Objective: The present study discussed the relationship between MMP17 variants and the susceptibility of IS.Methods: Based on the Agena MassARRAY platform, we genotyped single nucleotide polymorphisms (SNPs) on the MMP17 gene in 1345 participants (670 controls and 675 cases). We used logistic regression analysis to analyze the association of MMP17 SNPs with the risk of IS in the Chinese population, with odds ratio (OR) and 95% confidence intervals (CIs). False-positive report probability (FPRP) detected false positives on the significant results. Besides, we detected the SNP–SNP interaction to predict IS risk by multi-factor dimensionality reduction (MDR) analysis.Results: In the total analysis, MMP17 rs7975920 conferred an increased susceptibility to IS. After a stratified analysis by age and gender, the significant association between rs7975920 and IS risk was displayed in the subjects aged > 55 years old and females. After stratified analysis by smoking and drinking, MMP17 rs6598163 was related to the risk of IS in smokers and rs7975920 was associated with the risk of IS in smokers and was in correlation with IS risk in drinkers.Conclusion: In short, we first observed that MMP17 rs7975920 and rs6598163 were related to the risk of IS. The above results provided a theoretical basis for the elaboration of the role of MMP17 in IS in the Chinese population.Keywords: ischemic stroke, MMP17, single nucleotide polymorphisms, population

Jianyi Li,1,&ast; Keke Li,2,&ast; Yukun Du,1,&ast; Xiaojie Tang,3,&ast; Chenjing Liu,1 Shannan Cao,3 Baomeng Zhao,2 Hai Huang,3 Hongri Zhao,3 Weiqing Kong,1 Tongshuai Xu,3 Cheng Shao,1 Jiale Shao,1 Guodong Zhang,4 Hongbo Lan,5 Yongming Xi1 1Department of Orthopaedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Yantai Campus of Binzhou Medical University, Yantai, People’s Republic of China; 3Yantai Affiliated Hospital of Binzhou Medical University, Yantai, People’s Republic of China; 4Tengzhou Central People’s Hospital, Tengzhou, People’s Republic of China; 5Shandong Engineering Research Center for Additive Manufacturing Qingdao University of Technology, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongming Xi, Department of Orthopaedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China, Email xym700118@163.com Hongbo Lan, Shandong Engineering Research Center for Additive Manufacturing Qingdao University of Technology, Qingdao, 266520, People’s Republic of China, Email hblan99@126.comBackground: Successful treatment of infectious bone defect remains a major challenge in the orthopaedic field. At present, the conventional treatment for infectious bone defects is surgical debridement and long-term systemic antibiotic use. It is necessary to develop a new strategy to achieve effective bone regeneration and local anti-infection for infectious bone defects.Methods: Firstly, vancomycin / poly (lactic acid-glycolic acid) sustained release microspheres (VAN/PLGA-MS) were prepared. Then, through the dual-nozzle 3D printing technology, VAN/PLGA-MS was uniformly loaded into the pores of nano-hydroxyapatite (n-HA) and polylactic acid (PLA) scaffolds printed in a certain proportion, and a composite scaffold (VAN/MS-PLA/n-HA) was designed, which can not only promote bone repair but also resist local infection. Finally, the performance of the composite scaffold was evaluated by in vivo and in vitro biological evaluation.Results: The in vitro release test of microspheres showed that the release of VAN/PLGA-MS was relatively stable from the second day, and the average daily release concentration was about 15.75 μg/mL, which was higher than the minimum concentration specified in the guidelines. The bacteriostatic test in vitro showed that VAN/PLGA-MS had obvious inhibitory effect on Staphylococcus aureus ATCC-29213. Biological evaluation of VAN/MS-PLA/n-HA scaffolds in vitro showed that it can promote the proliferation of adipose stem cells. In vivo biological evaluation showed that VAN/MS-PLA/n-HA scaffold could significantly promote bone regeneration.Conclusion: Our research shows that VAN/MS-PLA/n-HA scaffolds have satisfying biomechanical properties, effectively inhibit the growth of Staphylococcus aureus, with good biocompatibility, and effectiveness on repairing bone defects. The VAN/MS-PLA/n-HA scaffold provide the clinic with an application prospect in bone tissue engineering.Graphical Abstract: Keywords: osteogenesis, dual-nozzle 3D printing technology, drug-loaded microspheres, vancomycin, nano-hydroxyapatite

Hao Tian,1,&ast; Tingting Zhao,1,&ast; Yanling Li,1,&ast; Na Sun,1 Dandan Ma,1 Qiyun Shi,1 Guozhi Zhang,1 Qingqiu Chen,1 Kongyong Zhang,1 Ceshi Chen,2,&ast; Yi Zhang,1 Xiaowei Qi1 1Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaowei Qi; Yi Zhang, Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Gaotanyan Street 29, Chongqing, 400038, People’s Republic of China, Tel/Fax +86-23-68754160, Email qxw9908@foxmail.com; zhangyi1489@sina.comBackground: Epigenetic modification of chromatin is an important step in the regulation of gene expression. The chromobox family proteins (CBXs), as epigenetic modifier, may play a vital role in tumorigenesis and cancer progression. Herein we explored the correlation between CBXs and breast cancer (BC) via the bioinformatics approach and qRT-PCR validation.Methods: Several databases, including GEPIA, TCGA, GEO, K-M plotter, STRING, DAVID, cBioPortal, CIBERSORT, and HPA were employed to analyze the expression levels of CBXs and the correlations between CBXs and prognosis (overall and recurrence-free survival) in BC. We analyzed molecular functions, genetic variations, transcription factors of CBXs, and immune cell infiltration status. ROC curve analysis was performed to determine the predictive value of CBXs. RNA extracted from 11 human BC and paired adjacent normal tissues were subjected to qRT-PCR.Results: The mRNA expression level of CBX1– 5 was significantly upregulated, while that of CBX7 was significantly downregulated in BC; no expression disparities were observed in CBX6/8 expression. Further, high mRNA expression of CBX1/2/3/4/8 correlated with advanced BC, whereas high mRNA expression of CBX6/7 correlated with early BC. High mRNA expressions of CBX1/2/3/5 predict poor OS and RFS, while higher mRNA expressions of CBX6/7 predict better OS and RFS in patients with BC. ROC curve analysis revealed that CBX3 showed excellent discriminatory ability. Gene ontology enrichment analysis showed that CBXs primarily participated in SUMOylation and post-/transcriptional regulation. Moreover, they presented varying degrees of amplification in BC tissues and were related to the infiltration of various immune cells.Conclusion: CBXs can serve as putative biomarkers for BC. Further studies are warranted to determine the exact molecular mechanisms underlying the action of CBXs in BC, particularly CBX1/2/3/5/7.Keywords: chromobox family proteins, breast cancer, prognosis, bioinformatics, qRT-PCR

Xiaodong Feng,1,&ast; Guiliang Zhang,1,&ast; Shiyang Zhang,2 Dihong Chen,3 Mengxue Zhou,1 Lihua Zeng,1 Tianmin Yang1 1Department of Critical Care Medicine, Mianzhu People’s Hospital, Mianzhu, 618200, People’s Republic of China; 2Department of Gastroenterology, Mianzhu People’s Hospital, Mianzhu, 618200, People’s Republic of China; 3Mianzhu People’s Hospital, Mianzhu, 618200, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong Feng, Department of Critical Care Medicine, Mianzhu People’s Hospital, No. 268, Section 1, Nanjing Avenue, Mianzhu, Sichuan Province, 618200, People’s Republic of China, Tel +8613518265506, Email fxd_3dek1@163.comPurpose: To explore an effective model to promote the homogeneous development of intensive care units (ICUs) in grassroot, impoverished and remote areas.Methods: A three-level remote alliance model (in-place and online assistance) was adopted to guide the cross-talk of ICUs between counties and cities. The observed indicators included the mortality of ICU patients and those with APACHE II scores ≥ 15 points, deep vein thrombosis, ventilator-associated pneumonia, the completion rate of septic shock goals in 3-hour and 6-hour bundles, and the rates of patient transfers.Results: After the implementation of the remote alliance, there was significant reduction in the mortality of ICU patients in the county and city-level tertiary hospitals (7.6% vs 4.5%, P = 0.004; OR = 1.734, 95% CI 1.189– 2.532) and the mortality rates of patients with APACHE II scores ≥ 15 points (11.9% vs 7.1%, P = 0.004; OR = 1.763, 95% CI 1.189– 2.614). There was a significant reduction in the incidence of ventilator-associated pneumonia (0.9% vs 5.0%, P < 0.001) and deep vein thrombosis (52.4% vs 13.6%, P < 0.001). The completion rate of 3-hour bundle therapies for septic shock was significantly improved (95.7% vs 68.4%, P < 0.001), as well as 6-hour bundle therapies for septic shock (97.9% vs 81.6%, P < 0.001). The hospital transfer rate decreased significantly in the grassroots and impoverished areas (2.6% vs 4.7%, P < 0.001).Conclusion: A three-level remote alliance might be helpful in improving the quality of critical care in remote areas and promoting the homogeneous development of disciplines.Keywords: medical quality, remote alliance, in-place and online, critical care medicine, mortality rate

Qingjuan Zuo,1,2 Guorui Zhang,1,3 Lili He,2 Sai Ma,4 Huijuan Ma,5 Jianlong Zhai,6 Zhongli Wang,7 Tingting Zhang,2 Yan Wang,2 Yifang Guo1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Cardiology, the Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, People’s Republic of China; 4Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 5Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 6Department of Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 7Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Yifang Guo, Department of Geriatric Cardiology, Hebei General Hospital, No. 348, Heping West Road, Xinhua District, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-15100189182, Email guoyifang@hotmail.comPurpose: To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism.Methods: Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR.Results: Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1β, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPβ were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS.Conclusion: Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.Keywords: canagliflozin, hepatic steatosis, atherosclerosis, RNA-seq, dyslipidemia, inflammatory response, autophagy

Guanghui Zheng,1– 3 Siqi Wang,4 Hong Lv,1– 3 Guojun Zhang1– 3 1Laboratory of Beijing Tiantan Hospital, Capital Medical University, Beijing, 100076, People’s Republic of China; 2NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing, 100076, People’s Republic of China; 3Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing, 100076, People’s Republic of China; 4School of clinical laboratory diagnostics, Capital Medical University, Beijing, 100076, People’s Republic of ChinaCorrespondence: Guojun Zhang, Laboratory of Beijing Tiantan Hospital, Capital Medical University, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 15811219411, Email zgjlunwen@163.comObjective: To explore the clinical characteristics of post-neurosurgical meningitis (PNM) patients infected with nonfermenting Gram-negative bacilli (NFGNB) and to evaluate the related mortality risk factors.Methods: A cohort analysis of PNM patients infected with NFGNB in Beijing Tiantan Hospital and Capital Medical University from 2012.1 to 2020.12. The microbial distribution, antimicrobial sensitivity and genotypes were tested, and potential mortality risk factors were evaluated using Mann–Whitney U or chi-squared tests. Independent risk factors for mortality were established by constructing a logistic model.Results: A total of 2940 PNM patients were enrolled in this study, of whom 207 (17.1%) were infected with NFGNB. Among these patients, 29 died of NFGNB meningitis, with an overall mortality rate of 14.0%. The top three NFGNBs were Acinetobacter baumannii (105 cases, 50.7%), Pseudomonas aeruginosa (29 cases, 14.0%) and Acinetobacter lwoffii (20 cases, 9.7%). Nomogram analysis revealed that hypertension (OR 4.551, 95% CI: 1.464– 14.154, P = 0.009), external ventricular drainage (EVD) (OR 3.944, 95% CI: 1.286– 12.095, P = 0.016), and assisted mechanical ventilator (AMV) (OR 6.192, 95% CI: 1.737– 22.081, P = 0.005) were independent risk factors for mortality. In addition, antibiotic prophylaxis was shown to play a vital role in NFGNB-induced PNM therapy.Conclusion: PNM patients infected with NFGNB have a high mortality rate. Hypertension, EVD and AMV were independent mortality risk factors, and clinical attention should be paid to their prevention and treatment.Keywords: clinical characteristics, nomogram analysis, meningitis, mortality, nonfermenting Gram-negative bacilli

Min Tan,1,2 Mei Li,1,2 Hui’e Li,1,2 Jin Li,1,2 You Chang,1,2 Guanfei Zhang,1,2 Yiping Zhong1,2 1Department of Psychology, Hunan Normal University, Changsha, People’s Republic of China; 2Cognition and Human Behavior Key Laboratory of Hunan Province, Changsha, People’s Republic of ChinaCorrespondence: Yiping Zhong, Department of Psychology, School of Education Science, Hunan Normal University, No. 36 Lushan Road, Changsha, Hunan, People’s Republic of China, Tel/Fax +86 731-88872112, Email ypzhong@hunnu.edu.cnBackground: Previous studies have examined the negative effects of materialism, which refers to the importance of possessing material wealth and image, on the pro-environmental behavior. Recently, a study found that highly materialistic individuals showed more pro-environmental behaviors involving self-benefit (vs other-benefit) appeals. However, previous studies ignored the role of public accountability.Purpose: This study aimed to explore the relationship between advertising appeals and the pro-environmental behavior of materialistic individuals in public (vs private) situations.Methods: This study used the material values scale to measure the materialistic extent and employed different advertising pictures. Meanwhile, Study 1(N=593) used the public cue, and Study 2 (N=622) used the eye cue to manipulate public accountability. Environmental donation was an indicator of the pro-environmental behavior.Results: Studies 1 and 2 found that the pro-environmental behavior of participants low in materialism was significantly higher than that of participants high in materialism involving other-benefit appeals, while this difference was not significant for pro-environmental behavior involving self-benefit appeals in the private situation. Participants with low and high materialism were not significantly different in the pro-environmental behavior involving self-benefit and other-benefit appeals in the public situation.Conclusion: The relationship between materialism and pro-environmental behavior involving self-benefit and other-benefit appeals can be moderated by the public accountability. In the private context, self-benefit appeals led materialistic people to engage in more pro-environmental behavior, while in the public context, the effectiveness of self-benefit and other-benefit appeals on the pro-environmental behavior of materialistic individuals was similar.Keywords: materialism, pro-environmental behavior, advertising appeals, public situation, private situation, social exchange theory

Wai Yin Li,1 Cheuk Yan Lee,1 Kwan Ming Lee,2 Ge Zhang,1,3 Aiping Lyu,1,3 Kevin Kin Man Yue1 1School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 2Department of Biology, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 3Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong, People’s Republic of ChinaCorrespondence: Kevin Kin Man Yue, 4/F, Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, Tel +852 3411 2468, Email kkmyue@hkbu.edu.hkIntroduction: Diabetes mellitus (DM) is characterized by chronic hyperglycemia and diabetic complications. Exacerbated cortical neuronal degeneration was observed in Alzheimer’s disease (AD) patients with DM. In fact, DM is now considered a risk factor of AD, as DM-induced activation of stress responses in the central nervous system (CNS) such as oxidative stress and neuroinflammation may lead to various neurodegenerative disorders. Methylglyoxal (MG) is one of the most reactive advanced glycation end-product (AGE) precursors. Abnormal accumulation of MG is observed in the serum of diabetic patients. As MG is reported to promote brain cells impairment in the CNS, and it is found that AGEs are abnormally increased in the brains of AD patients. Therefore, the effect of MG causing subsequent symptoms of AD was investigated.Methods: 5-week-old C57BL/6 mice were intraperitoneally injected with MG solution for 11 weeks. The Morris water maze (MWM) was used to examine the spatial learning ability and cognition of mice. After MG treatment, MTT assay, real-time PCR analyses, and Western blot were performed to assess the harvested astrocytes and hippocampi.Results: Significantly longer escape latency and reduced percentage time spent in the target quadrant were observed in the 9-week-MG-treated mice. We have found in both in vitro and in vivo models that MG induced astrogliosis, pro-inflammatory cytokines, AD-related markers, and ERK activation. Further, trend of normalization of the tested markers mRNA expressions were observed after ERK inhibition.Conclusion: Our in vivo results suggested that MG could induce AD symptoms and in vitro results implied that ERK may regulate the promotion of inflammation and Aβ formation in MG-induced reactive astrocytes. Taken together, MG may participate in the dysfunction of brain cells resulting in possible diabetes-related neurodegeneration by promoting astrogliosis, Aβ production, and neuroinflammation through the ERK pathway. Our findings provide insight of targeting ERK as a therapeutic application for diabetes-induced AD.Keywords: diabetes, hyperglycemia, complications, advanced glycation end products, astrocytes, pathways

Junpu Zha,1,2 Guolei Zhang,1,2 Xiaoqing Wang,1 Jie Li,3 Jun Di,1,2 Junfei Guo1,2 1Department of Orthopaedics Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Orthopaedic Institute of Hebei Province, Shijiazhuang, People’s Republic of China; 3Department of Obstetrics and Gynecology, Hebei General Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Junfei Guo; Jun Di, Department of Orthopaedics Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, People’s Republic of China, Email drjfguo@163.com; dj6998@126.comBackground: Closed reduction and intramedullary nail fixation of tibial fractures may not utilize a fracture table or reduction aids like a femoral distractor, and only manual traction will help aid the reduction process. This study aimed to describe and further investigate the effectiveness of an originally designed minimally invasive traction repositor (MITR) for the treatment of tibial fractures.Methods: From January 2018 to April 2021, a total of 119 eligible patients with tibial shaft fractures were included and retrospectively assigned to two groups according to different reduction methods: MITR group vs conventional manual traction (CMT) group. The baseline characteristics between the two groups were comparable, including age, gender, BMI, residence, smoking history, drinking history, injury mechanism, fracture type, ASA, method of anesthesia, and surgical delay (all P > 0.05). The operation time, fracture reduction duration, intraoperative blood loss, fluoroscopy time, number of intraoperative fluoroscopies, VAS, HSS, fracture healing time, and complications were compared.Results: All patients completed the follow-ups with an average of 18.5 months (range 12– 42 months). The operation time, fracture reduction duration, intraoperative blood loss, fluoroscopy time, and number of fluoroscopies were significantly decreased in the MITR group (all P < 0.05). At one month postoperatively, the VAS score was statistically lower in the MITR group (1.8± 0.8) than in the CMT group (2.6± 1.5). At 6 months postoperatively, the HHS score was statistically higher in the MITR group (90.8± 2.3) than in the CMT group (86.4± 3.8). We observed no statistical difference in the mean fracture healing time, bone nonunion, implant failure, and infection between the two groups (all P > 0.05).Conclusion: Compared with CMT, MITR facilitates the minimally invasive treatment of tibial fractures and has the advantages of operation time, fracture reduction duration, intraoperative blood loss, fluoroscopy time, number of fluoroscopies, and satisfactory VAS and HSS scores.Keywords: comparative, intramedullary nail, minimally invasive, tibial fractures, traction repositor

Yalan Luo,1– 3,&ast; Peng Ge,1– 3,&ast; Haiyun Wen,1– 3,&ast; Yibo Zhang,1– 3 Jin Liu,1,3 Xuanchi Dong,1,3 Bowen Lan,1,3 Guixin Zhang,1– 3 Qi Yang,4 Hailong Chen1– 3 1Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, People’s Republic of China; 3Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 4Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qi Yang; Hailong Chen, Email dyeyyq1016@163.com; chenhailong@dmu.edu.cnObjective: C/EBPβ, a crucial transcription factor, regulates innate immunity and inflammatory responses. However, the role played by C/EBPβ in alveolar macrophage (AM) inflammatory responses remains unknown. This study aimed to investigate the role and mechanism of C/EBPβ in alveolar macrophages (AMs) from the transcriptional level and to search for natural compounds targeting C/EBPβ.Methods: Rat AMs were infected with Lv-sh-C/EBPβ and treated with LPS, and the expression levels of iNOS, TNF-α, IL-6, and IL-1β were measured by RT-qPCR, Western blotting, and ELISA. Mechanistically, transcriptome sequencing (RNA-seq) revealed changes in gene expression patterns in AMs after LPS stimulation and C/EBPβ knockdown. Functional enrichment analyses and rescue experiments identified and validated inflammation-associated cell signaling pathways regulated by C/EBPβ. Furthermore, virtual screening was used to search for natural compounds that inhibit C/EBPβ with the structure of helenalin as a reference.Results: Following stimulation with LPS, AMs exhibited an increased expression of C/EBPβ. C/EBPβ knockdown significantly decreased the expression levels of inflammatory mediators. A total of 374 differentially expressed genes (DEGs) were identified between LPS-stimulated C/EBPβ knockdown and negative control cells. The NOD-like receptor signaling may be a key target for C/EBPβ, according to functional enrichment analyses of the DEGs. Further experiments showed that the muramyl dipeptide (MDP, NOD2 agonist) reversed the downregulation of inflammatory mediators and the NF-κB pathway caused by the C/EBPβ knockdown. The virtual screening revealed that N-caffeoyltryptophan, orilotimod, and petasiphenone have comparable pharmacological properties to helenalin (a known C/EBPβ inhibitor) and demonstrate a great binding capacity to C/EBPβ.Conclusion: Ablation of C/EBPβ may attenuate LPS-induced inflammatory damage in AMs by inhibiting the NOD2 receptor signaling pathway. Three natural compounds, N-caffeoyltryptophan, orilotimod, and petasiphenone, may be potential C/EBPβ inhibitors.Graphical Abstract: Keywords: C/EBPβ, alveolar macrophage, RNA-seq, NOD-like receptor signaling pathway, IL-1β, virtual screening