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Yaonan Hong,1,2,* Qi Liu,1,2,* Chuanao Xin,1,2,* Huijin Hu,1,2 Zhenchao Zhuang,1– 3 Hangping Ge,1,2,4 Yingying Shen,1,2,4 Yuechao Zhao,1,2,4 Yuhong Zhou,1,2,4 Baodong Ye,1,2,4 Dijiong Wu1,2,4,5 1Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China; 2The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China; 5Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dijiong Wu, Department of Hematology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Zhejiang, 310006, People’s Republic of China, Tel +86-571-86620325, Email wudijiong@zcmu.edu.cnBackground: Limited data were available to understand the significance of ferroptosis in leukemia prognosis, regardless of the genomic background.Methods: RNA-seq data from 151 AML patients were analyzed from The Cancer Genome Atlas (TCGA) database, along with 70 healthy samples from the Genotype-Tissue Expression (GTEx) database. Ferroptosis-related genes (FRGs) features were constructed by multivariate COX regression analysis and risk scores were calculated for each sample and a novel prediction model was identified. The validation was carried out using data from 35 AML patients and 13 healthy controls in our cohort. Drug sensitivity analysis was conducted on various chemotherapeutic drugs.Results: A signature of 10 FRGs was identified, as prognostic predictors for AML, and the risk scores were calculated to constructed the prognostic features of FRGs. Significantly lower overall survival was observed in the high-risk group. The predictive ability of these features for AML prognosis was confirmed using Cox regression analysis, ROC curves, and DCA. The prediction model performed well in our clinical practices, and had its potential superiority when comparing to classical NCCN risk stratification. Multiple chemotherapy drugs, including paclitaxel, dactinomycin, cisplatin, etc. had a lower IC50 in FRGs high-risk group than low-risk group.Conclusion: The AML prognosis model based on FRGs accurately predicts AML prognosis and drug sensitivity, and the drugs identified worthy further investigation.Keywords: ferroptosis, prediction model, TCGA, acute myeloid leukemia, drug sensitivity

Liyan Sun,1 Jinshuai Lan,1,2 Zhe Li,1,2 Ruifeng Zeng,1,2 Yi Shen,1 Tong Zhang,1,2 Yue Ding1– 3 1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3National Innovation Platform for Medical Industry-Education Integration, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Yue Ding; Tong Zhang, Email dingyue-2001@hotmail.com; zhangtongshutcm@hotmail.comAbstract: Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. This review introduced the expansive spectrum of BBR’s anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery. Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. Nano-delivery systems increase drug concentration at the tumor site by improving pharmacological activity and tissue distribution, enhancing drug bioavailability. Organic nanocarriers have advantages for berberine delivery including biocompatibility, encapsulation, and controlled release of the drug. While the advantages of inorganic nanocarriers for berberine delivery mainly lie in their efficient loading ability of the drug and their slow release ability of the drug. This review introduced the expansive spectrum of BBR’s anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery.Keywords: berberine, anti-cancer, nano drug delivery system, combination therapy

Jin-yu Shi,1,* Ting-ting Li,1,2,* Hui-ting Yang,1 Shi Zhang,2 Ran An,2 Liang Mao,2 Yang Li,2 Qian Li,2 Guang-yi Luan,2 Yan Shen,2 En-long Wang,2 Guang-hui Liu1,2 1First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guang-hui Liu, First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China; Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No. 33, Beiling Street, Huanggu District, Shenyang, Liaoning, 110032, People’s Republic of China, Email guanghui04-09@163.comObjective: This study aimed to investigate the features and underlying principles of acupuncture points used in the treatment of headaches associated with blood stasis syndrome.Methods: Literature on the treatment of blood stasis headache with acupuncture and moxibustion was searched across three Chinese databases and one English database from January 1st, 2000, to January 1st, 2024. Relevant data including titles, journals, authors, keywords, interventions, main acupoints, and outcomes were extracted for further analysis.Results: A total of 112 papers with 102 complete prescriptions were analyzed. Of the 77 acupoints examined, 72 were meridian points, and 5 were extraordinary points, used 699 times in total. The top ten acupoints by frequency were Fengchi (GB20), Taiyang (EX-HN5), Baihui (GV20), Hegu (LI4), Shuaigu (GB8), Taichong (LR3), Xuehai (SP10), Touwei (ST8), Geshu (BL17), and Waiguan (TE5). Yang meridian points were used more frequently than Yin meridian points (82.8% vs 17.2%), with the Gallbladder Meridian of Foot Shaoyang being the most common. Nearly half of the acupoints (49.9%) were on the head and neck, and 23.1% on the lower limbs. Specific acupoints accounted for 53.5% of the total frequency. Fengchi (GB20) and Taiyang (EX-HN5) showed the highest correlation. Association rule mining highlighted combinations like Fengchi (GB20) with Taiyang (EX-HN5) and Baihui (GV20). Cluster analysis yielded five clusters.Conclusion: The study provides insights into selecting effective acupoints and combinations for clinical acupuncture practice and experimental studies in treating blood stasis headaches. Acupoints like Fengchi (GB20), Taiyang (EX-HN5), and Baihui (GV20) may be effective for clinical treatment, but further studies are needed to validate their efficacy.Keywords: headache, blood stasis syndrome, acupuncture, treatment rule, data mining

Kunhui Sun,1,2,* Bing Wang,2,* Mengnan Li,2 Yanli Ge,1 Lijun An,2 Duanna Zeng,2 Yuhan Shen,1 Ping Wang,2 Meifang Li,2 Xuelei Hu,1 Xie-An Yu1,2 1Key Laboratory for Green Chemical Engineering Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, People’s Republic of China; 2NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanli Ge; Xie-An Yu, Email geyanli@wit.edu.cn; yuxieanalj@126.comBackground: How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors.Methods: Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile (ZnPc 1) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT).Results: It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer.Conclusion: Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy. Keywords: multimodality imaging guided synergistic cancer phototherapy, FL/PA/IR multimodal imaging, PDT/PTT dual synergistic therapy pathway, Zn phthalocyanine derivant

Mengjuan Sun,1,* Jun Wei,1,* Yanhui Su,1,* Yangjingwan He,1 Liang Ge,1 Yan Shen,1 Bohui Xu,2 Yanlong Bi,3 Chunli Zheng1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2School of Pharmacy, Nantong University, Nantong, People’s Republic of China; 3Pediatric Intensive Care Unit, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunli Zheng; Yanlong Bi, Email zhengchunli@cpu.edu.cn; pulong123@163.comPurpose: The purpose of this study is to address the high mortality and poor prognosis associated with Acute Respiratory Distress Syndrome (ARDS), conditions characterized by acute and progressive respiratory failure. The primary goal was to prolong drug circulation time, increase drug accumulation in the lungs, and minimize drug-related side effects.Methods: Simvastatin (SIM) was used as the model drug in this study. Employing a red blood cell surface-loaded nanoparticle drug delivery technique, pH-responsive cationic nanoparticles loaded with SIM were non-covalently adsorbed onto the surface of red blood cells (RBC), creating a novel drug delivery system (RBC@SIM-PEI-PPNPs).Results: The RBC@SIM-PEI-PPNPs delivery system effectively extended the drug’s circulation time, providing an extended therapeutic window. Additionally, this method substantially improved the targeted accumulation of SIM in lung tissues, thereby enhancing the drug’s efficacy in treating ARDS and impeding its progression to ARDS. Crucially, the system showed a reduced risk of adverse drug reactions.Conclusion: RBC@SIM-PEI-PPNPs demonstrates promise in ARDS and ARDS treatment. This innovative approach successfully overcomes the limitations associated with SIM’s poor solubility and low bioavailability, resulting in improved therapeutic outcomes and fewer drug-related side effects. This research holds significant clinical implications and highlights its potential for broader application in drug delivery and lung disease treatment.Keywords: acute lung injury, simvastatin, respiratory distress syndrome, pH response

Yan Ji,1 Haorong Li,1 Jiguo Li,2 Guangqiang Yang,1 Wenli Zhang,1 Yan Shen,1 Bohui Xu,3 Jianping Liu,1 Jingyuan Wen,4 Wenting Song1 1Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Nanjing Miaobang Meiye Enterprise Management Co, LTD, Nanjing, People’s Republic of China; 3School of Pharmacy, Nantong University, Nantong, 226001, People’s Republic of China; 4School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New ZealandCorrespondence: Wenting Song, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, People’s Republic of China, Email songwenting908@163.com Jingyuan Wen, School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New Zealand, Email j.wen@auckland.ac.nzPurpose: Acne vulgaris is a chronic inflammatory skin disorder centered on hair follicles, making hair follicle-targeted delivery of anti-acne drugs a promising option for acne treatment. However, current researches have only focused on the delivering to healthy hair follicles, which are intrinsically different from pathologically clogged hair follicles in acne vulgaris.Patients and Methods: Azelaic acid (AZA) micro/nanocrystals with different particle sizes were prepared by wet media milling or high-pressure homogenization. An experiment on AZA micro/nanocrystals delivering to healthy hair follicles was carried out, with and without the use of physical enhancement techniques. More importantly, it innovatively designed an experiment, which could reveal the ability of AZA micro/nanocrystals to penetrate the constructed clogged hair follicles. The anti-inflammatory and antibacterial effects of AZA micro/nanocrystals were evaluated in vitro using a RAW264.7 cell model stimulated by lipopolysaccharide and a Cutibacterium acnes model. Finally, both the anti-acne effects and skin safety of AZA micro/nanocrystals and commercial products were compared in vivo.Results: In comparison to commercial products, 200 nm and 500 nm AZA micro/nanocrystals exhibited an increased capacity to target hair follicles. In the combination group of AZA micro/nanocrystals and ultrasound, the ability to penetrate hair follicles was further remarkably enhanced (ER value up to 9.6). However, toward the clogged hair follicles, AZA micro/nanocrystals cannot easily penetrate into by themselves. Only with the help of 1% salicylic acid, AZA micro/nanocrystals had a great potential to penetrate clogged hair follicle. It was also shown that AZA micro/nanocrystals had anti-inflammatory and antibacterial effects by inhibiting pro-inflammatory factors and Cutibacterium acnes. Compared with commercial products, the combination of AZA micro/nanocrystals and ultrasound exhibited an obvious advantage in both skin safety and in vivo anti-acne therapeutic efficacy.Conclusion: Hair follicle-targeted delivery of AZA micro/nanocrystals provided a satisfactory alternative in promoting the treatment of acne vulgaris.Keywords: acne vulgaris, azelaic acid, hair follicle, micro/nanocrystals, targeted delivery

Sida Chen, Ling Wen, Jintao Ou, Yuting Lai, Yan Shen Department of Respiratory, Shenzhen Longgang Central Hospital, Shenzhen, Guangdong, 518000, People’s Republic of ChinaCorrespondence: Yan Shen, Shenzhen Longgang Central Hospital 6082 Longgang Boulevard (Longgang Section), Longgang District, Shenzhen, Guangdong, 518000, People’s Republic of China, Tel +86-0755-84806933-5901, Email shenyan5902@163.comBackground: Pulmonary infections are significant global health burdens, and conventional diagnostic methods (culture and polymerase chain reaction), are often limited by slow results and low sensitivity. Metagenomic next-generation sequencing (mNGS) offers a rapid, comprehensive alternative for identifying diverse pathogens, including rare and mixed infections. Thus, we assessed the diagnostic performance of mNGS in pulmonary infections, compared the findings with those of traditional pathogen detection methods, and explored its potential to enhance clinical diagnostics and patient care.Methods: We collected samples from 125 immunocompromised patients diagnosed with pulmonary infection at the Department of Respiratory Medicine of Shenzhen Longgang Central Hospital from March 2020 to July 2022. We compared the rate of pathogen positivity and pathogen distribution between conventional pathogen detection methods and mNGS using samples including sputum, blood, and bronchoalveolar lavage fluid.Results: Among the 125 cases of unexplained pulmonary infection, 82 (65.6%) and 40 (32.0%) tested positive for pathogens using mNGS and routine culture, respectively (P < 0.05). Both methods of pathogen detection were positive in 28 (22.4%) cases (complete match, 9; complete mismatch, 13; partial match, 6). However, 43.2% of cases only tested positive using mNGS, 9.4% only tested positive using routine tests, and 24.8% tested negative using both methods. A viral infection was present in 55.2% of cases. The detection rate of mycobacteria using mNGS (12.8%) was higher than that using conventional pathogen detection methods (5.6%).Conclusion: mNGS technology enhances pathogen detection in unexplained pulmonary infections, enabling targeted antimicrobial therapy and consequently helping to reduce broad-spectrum antibiotic use, aligning treatments more closely with the causative pathogens. Thus, mNGS offers significant clinical value by improving treatment efficacy and potentially reducing antibiotic resistance in pulmonary infection cases.Keywords: mNGS, Unexplained pulmonary infection, Pathogens, BALF

Haopeng Wang,1,&ast; Hua Zhao,1,&ast; Zheng Chen,1,&ast; Xiaomin Cai,1 Xuhui Wang,1 Ping Zhou,1 Yinda Tang,1 Tingting Ying,1 Xin Zhang,1 Yiman Shen,1 Baimiao Wang,1 Wanchun Zhu,1 Jin Zhu,1 Xinjun Wang,2 Shiting Li1 1Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiting Li, Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China, Email lishiting@xinhuamed.com.cn Xinjun Wang, Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China, Email wangxj@zzu.edu.cnBackground: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism.Methods: CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments.Results: This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p.Conclusion: Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI. Keywords: hypoxic, BMSCs, exosomes, Schwann cells, facial nerve injury

Shanyu Liu,1,2,&ast; Xiaolin Hou,3,&ast; Min Shi,1 Yuling Shen,1,2 Zhaoying Li,1,2 Zhenzhu Hu,1,2 Dongdong Yang1 1Department of Neurology, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Department of Neurosurgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongdong Yang, Department of Neurology, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No. 39, Twelve Bridges Road, Chengdu, Sichuan Province, 610075, People’s Republic of China, Tel/Fax +86 028-87783481, Email dongdongyang2020@163.comPurpose: Previous studies have reported mixed results regarding the importance of cortical abnormalities in patients with migraines. However, cortical sulci, as a component of the cerebral cortex, have not been specifically investigated in migraine patients. Therefore, we aim to evaluate alterations in cortical sulcal morphology among patients with chronic migraine (CM), episodic migraine (EM), and healthy controls (HCs).Patients and Methods: In this cross-sectional study, structural magnetic resonance images were acquired from 35 patients with CM, 35 with EM, and 35 HCs. Cortical sulci were identified and reconstructed using the BrainVisa 5.0.4 software. We focused on regions involved in pain processing in which abnormal cortical structure were identified in previous neuroimaging studies. Morphometric analysis was performed to calculate sulcal parameters including mean depth, cortical thickness, and opening width. Partial correlation analyses of clinical characteristics and sulcal parameters were performed for CM, EM and the combined migraine (CM + EM) groups.Results: In comparison with HCs, both CM and EM groups showed increased opening width in bilateral insula. In comparison with HC and EM groups, CM patients showed increased cortical thickness in bilateral superior postcentral sulcus, bilateral median frontal sulcus and left superior parietal sulcus, as well as increased mean depth in the left anterior callosomarginal fissure and decreased mean depth in bilateral superior frontal sulcus and left median frontal sulcus. Migraine frequency and disease duration were both correlated with cortical thickness in bilateral superior postcentral sulcus.Conclusion: Abnormal sulcal morphometry primarily affected areas associated with pain processing in patients with migraine, with CM exhibiting more extensive abnormalities in areas related to sensory and affective processing. These changes may contribute to understanding the pathology of EM and CM.Keywords: sulcal morphometry, mean depth, cortical thickness, opening width, chronic migraine, episodic migraine

Changyou Luo,1,&ast; Ruiqing Zhang,2,&ast; Ji Liu,1,&ast; Xingyue He,1 Shengzhou Li,1 Chuanjiang Ran,1 Songbo Ma,3 Yan Shen1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 211100, People’s Republic of China; 2Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, 225300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Shen; Songbo Ma, Email shenyan@cpu.edu.cn; masongbo1978@163.comPurpose: Rapid detection and diagnosis of diseases facilitate timely and effective treatment of cardiovascular diseases (CVD). The establishment of a one-step rapid detection method provides a new method for the initial screening and disease risk assessment of patients with cardiovascular diseases in primary medical units.Methods: Hollow gold nanoparticles (HGNPs) were synthesized using a cobalt template method followed by use as signal amplification probes for ultra-sensitive quantitative detection of serum C-reactive protein (CRP). To induce the localized surface plasmon resonance (LSPR) and improve protein labeling efficiency, we developed a sensitive detection mode by coating polyvinylpyrrolidone (PVP-K30) on the HGNPs, resulting in a significant improvement in detection performance.Results: Compared to traditional colloidal GNP-based LFTA, PVP-coated HGNPs exhibit a lower visual detection limit of 1 ng/mL, which a 25-fold decrement compare to using GNPs as the antibody-labeled probe, and the detection limit could be reduced to 0.14 ng/mL under the quantitative instrument.Conclusion: The one-step method based on HGNP immunochromatographic strips modified with PVP established in this study can be used for the detection of CRP and hs-CRP in biological samples. The performance of the immunochromatographic technique designed in this study was evaluated from the perspective of synthetic markers, and the application conditions of this strip were screened, verifying its high specificity, indicating that it has high sensitivity and strong detection limit compared to colloidal gold. The sensitivity of the hollow gold immunochromatographic test strip in this article has been increased by about 25 times, providing a new method for rapid detection of CVD in clinical diagnosis.Keywords: C-reactive protein, lateral flow immunoassay, hollow gold nanoparticles, in vitro diagnostics, polyvinylpyrrolidone

Wei He,&ast; Quan Zhou,&ast; Jiaheng Lv,&ast; Yujie Shen, Hao Liu, Huilin Yang, Peng Yang, Tao Liu Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Yang; Tao Liu, Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 899 Pinhai Road, Suzhou, Jiangsu, 215006, People’s Republic of China, Tel +86-512-67781420, Fax +86-512-67781165, Email ypspine@163.com; liutao821108@163.comBackground: Few studies have focused on percutaneous kyphoplasty (PKP) in the treatment of thoracic osteoporotic vertebral compression fractures (OVCFs) with intervertebral cleft (IVC). Hence, the objective of this retrospective study was to compare the clinical and radiographic outcomes of PKP in elderly patients with thoracic OVCFs, with or without IVC.Methods: A total of 106 patients were enrolled in this study and divided into two groups: the IVC group and the NIVC group (without IVC). Radiographic measures included anterior vertebral height (AVH), thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Clinical function measures included Oswestry disability index (ODI) and visual analog scale (VAS) scores.Results: There were no significant differences in the preoperative basic data between the groups classified as IVC and NIVC. However, both groups showed significant improvements in AVH and TK throughout the follow-up periods compared to the preoperative measurements (P< 0.05). The recovery of AVH in the IVC group was found to be inferior to that in the NIVC group at 3 years after operation (P< 0.05). There were no significant differences in LL, PI, PT and SS in both groups compared with the preoperative results and no statistically significant differences between the two groups at the same follow-up time (P> 0.05). The VAS and ODI scores during all follow-up periods were significantly lower than those before operation (P< 0.05). At 3 years after operation, the VAS and ODI scores of the IVC group were higher than those of the NIVC group (P< 0.05).Conclusion: PKP is an adoptable measure to treat thoracic OVCFs with or without IVC. Our study revealed that the NIVC group was superior to the IVC group in terms of improved vertebral height and pain recovery at long-term follow-up (3 years).Keywords: percutaneous kyphoplasty, thoracic, osteoporotic vertebral compression fracture, intervertebral cleft, sagittal balance

Huangqi Duan,&ast; Yu Shen,&ast; Chen Wang, Weimin Xia, Shun Zhang, Shenggen Yu, Ding Xu, Qifeng Cao, Hailong Liu, Haibo Shen Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hailong Liu; Haibo Shen, Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email liuhailong@xinhuamed.com.cn; shenhaibo@xinhuamed.com.cnBackground: Cuproptosis-related gene and long non-coding RNA (lncRNA) modulation of cancer regulation is well-established. This investigation aimed to elucidate the prognostic implications of cuproptosis-associated lncRNAs in muscle-invasive bladder cancer (MIBC).Methods: Employing the Cancer Genome Atlas (TCGA) and IMvigor210 cohorts, bioinformatics and statistical analyses probed the prognostic relevance of cuproptosis-related lncRNAs.Results: Co-expression analysis revealed tight associations between lncRNA expression and cuproptosis-linked genes, with 13 cuproptosis-related lncRNAs found to correlate with MIBC prognosis. Lasso regression identified a six-lncRNA prognostic signature, enabling patient stratification into high- and low-risk categories. Tissue validation substantiated differential expression of FAM13A-AS1, GHRLOS, LINC00456, OPA1-AS1, RAP2C-AS1, and UBE2Q1-AS1 between MIBC tumor and normal tissues. Comparative analyses of tumor microenvironments and immune profiles between risk groups disclosed elevated immunosuppressive molecule expression, including programmed cell death-1 (PD-L1) and T-cell immunoglobulin-3 (TIM-3), in high-risk individuals.Conclusion: These findings suggest that cuproptosis-related lncRNAs may modulate the expression of immunosuppressive molecules, thereby influencing MIBC tumorigenesis and progression. Further exploration is warranted to unveil novel therapeutic targets for MIBC based on the expression patterns of cuproptosis-related lncRNAs and their impact on immune responses in the tumor microenvironment.Keywords: cuproptosis-related lncRNAs, immunosuppressive molecules, MIBC, prognostic, risk scores

Qing Zhang,1,&ast; Wenjun Hu,1,&ast; Mingxue Guo,1 Xinyu Zhang,1 Qin Zhang,1 Fengqi Peng,1 Liwen Yan,1 Zucheng Hu,1 Jakkree Tangthianchaichana,2 Yan Shen,3 Haiyan Hu,4 Shouying Du,1 Yang Lu1 1School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China; 2Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand; 3School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 4School of Pharmacy, Beijing Health Vocational College, Beijing, 101100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyan Hu, School of Pharmacy, Beijing Health Vocational College, Beijing, 101100, People’s Republic of China, Email yxyhhy@163.com Yang Lu, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email luyang@bucm.edu.cnIntroduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release.Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed.Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy.Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.Keywords: responsive drug delivery systems, peptide hydrogels, immunogenic cell death, PD-1/PD-L1 blockade

Xingyue He,1 Tianjiao Hao,1 Hongxu Geng,2 Shengzhou Li,1 Chuanjiang Ran,1 Meirong Huo,1 Yan Shen1 1State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 2School of Pharmacy, Yantai University, Yantai, 264005, People’s Republic of ChinaCorrespondence: Yan Shen; Meirong Huo, Email shenyan@cpu.edu.cn; meironghuo@cpu.edu.cnAbstract: Gold nanomaterials have become very attractive nanomaterials for biomedical research due to their unique physical and chemical properties, including size dependent optical, magnetic and catalytic properties, surface plasmon resonance (SPR), biological affinity and structural suitability. The performance of biosensing and biodiagnosis can be significantly improved in sensitivity, specificity, speed, contrast, resolution and so on by utilizing multiple optical properties of different gold nanostructures. Lateral flow immunochromatographic assay (LFIA) based on gold nanoparticles (GNPs) has the advantages of simple, fast operation, stable technology, and low cost, making it one of the most widely used in vitro diagnostics (IVDs). However, the traditional colloidal gold (CG)-based LFIA can only achieve qualitative or semi-quantitative detection, and its low detection sensitivity cannot meet the current detection needs. Due to the strong dependence of the optical properties of gold nanomaterials on their shape and surface properties, gold-based nanomaterial modification has brought new possibilities to the IVDs: people have attempted to change the morphology and size of gold nanomaterials themselves or hybrid with other elements for application in LFIA. In this paper, many well-designed plasmonic gold nanostructures for further improving the sensitivity and signal output stability of LFIA have been summarized. In addition, some opportunities and challenges that gold-based LFIA may encounter at present or in the future are also mentioned in this paper. In summary, this paper will demonstrate some feasible strategies for the manufacture of potential gold-based nanobiosensors of post of care testing (POCT) for faster detection and more accurate disease diagnosis.Keywords: gold nanomaterials, LFIA, sensitivity, POCT

Yu Mao,1 Yuan Xie,1 Jiani Tang,1 Yujing Shen,2 Yang Liu,1 Bing Sun1 1Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Department of Echocardiography, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Bing Sun, Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Putuo District, Shanghai, 200065, People’s Republic of China, Tel +86 21-66111048, Email woowoocncn@163.comPurpose: The purpose of this study was to assess the left ventricular function effects of permanent left bundle branch pacing (LBBP) versus traditional right ventricular pacing (RVP).Patients and Methods: Consecutive patients receiving pacemaker implantation were included and divided into left bundle branch block (LBBB) group and right ventricular pacing (RVP) group. Baseline characteristics were collected, and they received 1-year follow-up. Electrocardiogram (ECG) characteristics and pacing parameters were assessed before and after implantation. Cardiac function parameters such as left ventricular ejection fraction (LVEF) and tricuspid regurgitation (TR) were recorded and compared.Results: Of 78 patients included, 45 patients received LBBP (mean age, 72.7 ± 12.2 years; male, 55.6%) and 33 patients underwent RVP (mean age 72.9 ± 11.8 years; male, 63.6%). The pacing parameters were satisfactory during the implantation and remained stable during mid-term follow-up. During the follow-up period, LBBP patients had a greater decrease in LVEDD and LVESD. The TR in the LBBP group was significantly improved as compared to the RVP group (P=0.016).Conclusion: Permanent LBBP achieves favorable cardiac hemodynamic effects with good stability and safety. LBBP may reduce severe TR at 1-year follow-up, and LBBP may be an option for patients with severe TR.Keywords: left bundle branch pacing, electrical synchrony, mechanical synchrony, left ventricular function, tricuspid regurgitation

Yanping Li,1,&ast; Yu Shen,2,&ast; Qian Cao,3 Yingzhang Cheng,4 Lijun Xu,3 Zhenyu Tang3 1Department of Neuroelectrophysiology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 4Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenyu Tang, Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China, Email tangzyjr@163.comObjective: Unexplained dizziness remains a clinical challenge. Our previous studies have shown that unexplained dizziness may be related to patent foramen ovale (PFO). This study aims to explore whether the degree of shunt is correlated with the degree of unexplained dizziness and looking for the possible clinical intervention for patients with unexplained dizziness.Methods: This study was a large single-center, prospective, controlled study. From March 2019 to March 2022, patients with unexplained dizziness and explained dizziness and healthy controls were recruited. Contrast-enhanced transcranial Doppler sonography (c-TCD) was performed to detect the existence of right-to-left shunt (RLS) and shunt grading. The dizziness handicap inventory (DHI) was completed to evaluate the dizziness. Unexplained dizziness patients with large amount of PFO were volunteered to receive medication treatment and transcatheter PFO closure and followed up six months.Results: A total of 387 patients (132 unexplained, 123 explained and 132 controls) were enrolled. There was a statistical difference in the RLS grading with three groups (p < 0.001). The Spearman correlation coefficient of RLS grading and DHI scores in unexplained dizziness patients (r=0.122, p=0.163) and explained dizziness patients (r=0.067, p=0.460). In the unexplained group, there were 49 cases with massive grading RLS. Of which 25 patients received percutaneous PFO closure treatment and 24 cases received medication treatment. Followed up six months after treatment, the amount of DHI scores change in patients who received the percutaneous PFO closure was significantly higher than that in the medication treatment group (p < 0.001).Conclusion: RLS may play an important role in unexplained dizziness. For unexplained dizziness patients, PFO closure may contribute to better outcomes. In the future, large-scale randomized controlled studies are still needed.Keywords: unexplained dizziness, dizziness handicap inventory, DHI, patent foramen ovale, PFO, right to left shunt, RLS, contrast-enhanced transcranial Doppler sonography, c-TCD

Yuhao Zeng,1,&ast; Sha Zhu,1,&ast; Zilin Wang,1 Junru Chen,1 Jindong Dai,1 Zhenhua Liu,1 Guangxi Sun,1 Jiayu Liang,1 Xingming Zhang,1 Zhipeng Wang,1 Jinge Zhao,1 Yuchao Ni,1 Jiyu Yang,1 Minghao Wang,1 Qiang Wei,1 Xiang Li,1 Ni Chen,2 Zhiping Li,3 Xin Wang,3 Yali Shen,3 Jin Yao,4 Rui Huang,5 Jiyan Liu,6 Diming Cai,7 Hao Zeng,1 Pengfei Shen1 1Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 6Department of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 7Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengfei Shen; Hao Zeng, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Email cdhx510@163.com; kucaizeng@163.comPurpose: Multidisciplinary team (MDT) discussion is a widely used model to manage patients diagnosed with cancer. However, there has been no direct evidence to prove its effect on the prognosis of metastatic renal cell carcinoma (mRCC) patients, so this study explored the impact of MDT discussion on mRCC patient survival.Methods: The clinical data of 269 mRCC patients were retrospectively collected from 2012 to 2021. The cases were grouped into the MDT and non-MDT groups, then subgroup analysis was performed according to different histology types, as well as exploring the role of MDT in patients who have undergone multiple-line therapy. Overall survival (OS) and progression free survival (PFS) were set as the study endpoint.Results: Approximately half (48.0%, 129/269) of the patients were in the MDT group, with univariable survival analyses showing these patients had remarkably longer median OS (MDT group: 73.7 months; non-MDT group: 33.2 months, hazard ratio (HR): 0.423 (0.288, 0.622), p< 0.001) and longer median PFS (MDT group: 16.9 months, non-MDT group: 12.7 months, HR: 0.722 (0.542, 0.962), p=0.026). Furthermore, MDT management resulted in longer survival for both ccRCC and non-ccRCC subgroups. Patients in the MDT group were more likely to receive multi-line therapy (MDT group: 79/129, 61.2% vs non-MDT group: 56/140, 40.0%, p< 0.001), and within this patient group, MDT management still resulted in longer OS (MDT group: 94.0 months; non-MDT group: 43.5 months, p=0.009).Conclusion: MDT is associated with prolonged overall survival in mRCC independent of histology, ensuring that patients receive better management and precise treatment.Keywords: mRCC, MDT, overall survival, prognosis, ccRCC, non-ccRCC, multi-line treatment

Yifeng Shen,1,2 Qiaoyin Zhou,1,3 Xiaojie Sun,4 Shiliang Li,1,3,4 Weiguang Zhang5 1College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 2Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Key Laboratory of Orthopedics & Traumatology of Traditional Chinese Medicine and Rehabilitation (Fujian University of TCM), Ministry of Education, Fuzhou, People’s Republic of China; 4Department of Acupuncture and Moxibustion, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5Health Science Center, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Shiliang Li, Department of Acupuncture and Moxibustion, China-Japan Friendship Hospital, Beijing, People’s Republic of China, Email zrlishiliang1963@163.com Weiguang Zhang, Health Science Center, Peking University, Beijing, People’s Republic of China, Email zhangwg@bjmu.edu.cnBackground: De Quervain’s disease is a painful stenosing tenosynovitis of the first dorsal compartment of the hand affecting the tendons of the abductor pollicis longus and extensor pollicis brevis. This study aimed to evaluate the safety and efficacy of percutaneous first extensor compartment releases performed on embalmed cadaveric models by acupotomy operation with or without US guidance.Methods: Percutaneous release was performed with an acupotomy on 59 wrists of cadavers; 23 wrists were operated with US guidance, and 39 wrists were operated without US guidance. Each arm was dissected and assessed regarding the amount of release as well as the extent of neurovascular and tendon injury. Anatomical structures were also observed in this study.Results: Twenty cases (87%) were successfully released with ultrasound-assisted techniques, and 27 cases (75%) were successfully released with blind techniques. No neurovascular injury occurred in any arm, regardless of technique. No significant tendon injury was seen in any arm. Although minor surface scratches were visualized in 11 cases, they occurred in 3 cases (13.04%) with ultrasound assistance and in 8 cases (22.22%) with blind techniques. There was no statistically significant difference between the two groups in the measurement of the distance from the incision marks to the blood vessels and nerves. A fibrous septum and bony protrusions were found in the first dorsal compartment, which may be anatomical factors affecting the success of treatment.Conclusion: Both traditional and US-guided percutaneous release by acupotomy of the first extensor tendon compartment can be performed for all wrists. US-guided techniques can improve the success rate and reduce damage during acupotomy operations.Keywords: de Quervain’s disease, tendonitis, acupotomy, acupuncture, ultrasound guidance, anatomy

Rui Ni,1– 3 Lele Huang,3 Zhen Li,4 Wenli Zhang,4 Yajie Wang,4 Yan Shen,4 Jianxin Wang,1 Weigen Lu2 1School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2China State Institute of Pharmaceutical Industry, Shanghai, People’s Republic of China; 3National Advanced Medical Engineering Research Center, Shanghai, People’s Republic of China; 4Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of ChinaCorrespondence: Jianxin Wang, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China, Email jxwang@shmu.edu.cn Weigen Lu, China State Institute of Pharmaceutical Industry, Shanghai, 201203, People’s Republic of China, Email sipiluwg@163.comPurpose: To enhance tumor penetration by formulation design and tumor microenvironment (TME) modulation, herein a novel reactive oxygen species (ROS)-responsive size/shape transformable lipid-polymer hybrid nanoparticle (LPN) has been fabricated for the co-delivery of an anticancer and collagen-inhibition drug.Methods: A ROS-responsive poly(D, L-lactide)-thioketal-polyethylene glycol (PLA-TK-PEG) co-polymer was synthesized. LPNs were then fabricated by encapsulation of losartan (LST)-loaded micelles as the core to support paclitaxel (PTX)-loaded liposomes. The PEG content in the lipid shell of LPNs was then adjusted to obtain the size-/shape-transformable LPNs (M/LST-Lip/PTX-PEG5%). The ROS-responsiveness was observed in vitro by transmission electron microscopy and the tumor-penetration of the LPNs was evaluated in 3D tumor spheroids by confocal laser scanning microscopy. Tumor-targeting, tumor-penetrating, and antitumor efficacies of the NPs in 4T1 tumor-bearing mice were determined by in vivo imaging.Results: ROS-responsive micellar core degradation and the transformation of spherical LPNs (120nm) to smaller 40 mm discoid nanoparticles (NP) were observed. The transformable LPNs exhibited enhanced capacity of penetration in contrast to the un-transformable preparations in three-dimensional (3D) tumor spheroids. Furthermore, synergetic penetrating enhancement was achieved by LST-loaded transformable LPNs in 4T1 and fibroblast cell mixed 3D tumor spheroids. The improved tumor penetration of LST-loaded transformable LPNs was observed in vivo, which could be due to their collagen inhibiting and size/shape transformable effect. Due to their enhanced penetrability, LST and PTX-loaded transformable LPNs demonstrated significant in vivo antitumor efficacy in comparison to other preparations.Conclusion: The results confirmed the efficacy of M/LST-Lip/PTX-PEG5% in tumor targeting, collagen inhibition in TME, and enhanced tumor penetration. This novel drug delivery system can therefore play a substantial role in improving the therapeutic efficacy of antitumor drugs combined with TME-improving agents.Keywords: lipid-polymer hybrid nanoparticles, losartan, paclitaxel, ROS responsiveness, drug delivery, collagen inhibition, tumor penetration, combination therapy

Jinghan Zhang,1 Fei Yan,2 Wei Zhang,1 Lei He,1 Yi Li,3 Shuai Zheng,1 Yuanyuan Wang,4 Tengfei Yu,1 Lijuan Du,1 Yuanyuan Shen,5 Wen He1 1Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Center for Cell and Gene Circuit Design, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China; 3Department of Radiology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 4Department of Ultrasound, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 5National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Bio Medical Engineering, Health Science Center, Shenzhen University, Shenzhen, People’s Republic of ChinaCorrespondence: Yuanyuan Shen; Wen He, Email shenyy@szu.edu.cn; hewen@bjtth.orgBackground: Focused ultrasound (FUS) combined with microbubbles (MBs) has emerged as a potential approach for opening the blood–brain barrier (BBB) for delivering drugs into the brain. However, MBs range in size of microns and thus can hardly extravasate into the brain parenchyma. Recently, growing attention has been paid to gas vesicles (GVs), which are genetically encoded gas-filled nanostructures with protein shells, due to their potential for extravascular targeting in ultrasound imaging and therapy. However, the use of GVs as agents for BBB opening has not yet been investigated.Methods: In this study, GVs were extracted and purified from Halobacterium NRC-1. Ultrasound imaging performance of GVs was assessed in vitro and in vivo. Then, FUS/GVs-mediated BBB opening for small molecular Evans blue or large molecular liposome delivery across the BBB was examined.Results: The results showed a good contrast performance of GVs for brain perfusion ultrasound imaging in vivo. At the acoustic negative pressure of 1.5 MPa, FUS/GVs opened the BBB safely, and effectively enhanced Evans blue and 200-nm liposome delivery into the brain parenchyma.Conclusion: Our study suggests that biosynthetic GVs hold great potential to serve as local BBB-opening agents in the development of new targeted drug delivery strategies for central nervous system disorders.Keywords: gas vesicles, blood–brain barrier, focused ultrasound, drug delivery, nanoparticles

Xin Zhang,1,&ast; Yang Zhang,2,&ast; Ning Wang,1 Yetong Shen,1 Qing Chen,2 Lu Han,1 Bo Hu1 1Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, 110122, People’s Republic of China; 2School of Pharmacy, Shenyang Medical College, Shenyang, 110034, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Hu, Email bhu@cmu.edu.cn; 86hubo86@163.comIntroduction: To present a safer tumor therapy based on bacteria and identify in detail how the activation and infection behavior of spores can be controlled remotely by near-infrared light (NIR-irradiation) based on nanoheaters’ modification.Methods: Spores bring a better tolerance to surface modification. Transitive gold-nanorods-allied-nanoclusters-modified spores (Spore@NRs/NCs) were constructed by covalent glutaraldehyde crosslink. The photothermal properties of nanoheaters before and after attachment to spores were studied by recording temperature–irradiation time curves. The controlled viability and infection behavior of Spore@NRs/NCs were investigated by NIR-irradiation.Results: In this work, a controllable sterilizing effect to activated vegetative bacteria was obtained obviously. When met with a suitable growth-environment, Spore@NRs/NCs could germinate, activate into vegetative bacteria and continue to reproduce. Without NIR-irradiation, nanoheaters could not affect the activity of both spores and vegetative bacterial cells. However, with NIR-irradiation after incubating in growth medium, nanoheaters on spores could control the spores’ germination and affect the growth curve as well as the viability of the vegetative bacterial cells. For Spore@NRs/NCs (Spore:NCs:NRs=1:1:4, 67.5 μg mL− 1), a ~98% killing rate of vegetative bacterial cells was obtained with NIR-irradiation (2.8 W cm− 2, 20 min) after 2 h-incubation. In addition, these nanoheaters modified on spores could be taken not only to the vegetative bacteria cells, but also to the first-generation bacteria cells with their excellent photothermal and bactericidal performance, as well as synergetic anticancer effect. NIR-irradiation after 2 h-incubation could also trigger Spore@NRs/NCs (1:1:4, 6 μL) to synergistically reduce the viability of HCT116 cells to 15.63± 2.90%.Conclusion: By using NIR-irradiation, the “transitive” nanoheaters can remotely control the activity of both bacteria (germinated from spore) and cancer cells. This discovery provides basis and a feasible plan for controllable safer treatment of bacteria therapy, especially anaerobes with spores in hypoxic areas of the malignant solid tumors.Graphical Abstract: Keywords: transitive nanoheaters, modified spores, NIR-remotely triggered, controlled sterilization, hyperthermia, adjustable activity behavior

Shengwei Meng,1,&ast; Derong Xu,1,&ast; Shuo Han,1 Guanghui Li,1 Yan Wang,1 Yanqing Shen,2 Kai Zhu,1 Antao Lin,1 Ruiting Wang,3 Xuexiao Ma,1 Chuanli Zhou1 1Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Operating Room, Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 3Medical Insurance Audit Department, Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chuanli Zhou; Xuexiao Ma, Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, Shandong, 266000, People’s Republic of China, Tel +8618661809796 ; +8618661807895, Email justin_5257@hotmail.com; maxuexiaospinal@163.comPurpose: To evaluate the outcomes, feasibility, and safety of endoscopic unilateral laminectomy, bilateral decompression and discectomy (Endo-ULBDD) for central lumbar spinal stenosis (CLSS) combined with disc herniation (DH).Methods: This study includes 39 patients diagnosed with CLSS combined with DH who met the inclusion criteria and underwent surgery for Endo-ULBDD from April 2020 to March 2021. The mean age of the patients, operation time, hospitalization time, time in bed, and complications were recorded. Patients were followed up for at least 12 months. Visual analog scale (VAS) scores for low-back and lower-limb pain and Oswestry Disability Index (ODI) scores were evaluated preoperatively, before discharge, and at 3, 6, and 12 months postoperatively. To evaluate clinical effectiveness 12 months postoperatively, the modified MacNab criteria were used.Results: The mean age of the patients was 59.9 years, the mean operation time was 82.1 minutes, the mean hospitalization time was 3.7 days, and the mean time in bed was 20.9 hours. The mean VAS scores of low-back and lower-limb pain improved from 5.9 and 7.2 to 2.0 and 1.6, respectively (P < 0.05). The ODI score improved from 56.0 to 16.7 (P < 0.05). The overall excellent-good rate of the modified MacNab criteria was 89.7%. Two kinds of complications occurred in 4 patients (10.3%), including 1 patient whose inferior articular process was excessively removed and 3 patients who suffered from postoperative dysesthesia. No other severe complications were noted.Conclusion: Endo-ULBDD is a safe, feasible, efficient, and minimally invasive approach to treating CLSS combined with DH.Keywords: endoscopic spinal surgery, laminectomy, discectomy, lumbar spinal stenosis, intervertebral disc displacement

Yu Shen,1 Yilei Zheng,1 Daojun Hong1,2 1Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Medical Genetics, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of ChinaCorrespondence: Daojun Hong, Department of Neurology, The First Affiliated Hospital of Nanchang University, 17# Yongwaizheng St, Nanchang, 330006, People’s Republic of China, Tel/Fax +86-791-8869-2511, Email hongdaojun@hotmail.comAbstract: Over the past decades, advances in genetic sequencing have opened a new world of discovery of causative genes associated with numerous pain-related syndromes. Familial episodic pain syndromes (FEPS) are one of the distinctive syndromes characterized by early-childhood onset of severe episodic pain mainly affecting the distal extremities and tend to attenuate or diminish with age. According to the phenotypic and genetic properties, FEPS at least includes four subtypes of FEPS1, FEPS2, FEPS3, and FEPS4, which are caused by mutations in the TRPA1, SCN10A, SCN11A, and SCN9A genes, respectively. Functional studies have revealed that all missense mutations in these genes are closely associated with the gain-of-function of cation channels. Because some FEPS patients may show a relative treatability and favorable prognosis, it is worth paying attention to the diagnosis and management of FEPS as early as possible. In this review, we state the common clinical manifestations, pathogenic mechanisms, and potential therapies of the disease, and provide preliminary opinions about future research for FEPS.Keywords: familial episodic pain syndromes, voltage-gated sodium channel, transient receptor potential A1, dorsal root ganglia, nociceptive pain

Mingqiang Gong,1,2,&ast; Yunxia Shen,2,&ast; Wenbin Liang,2 Zhen Zhang,3 Chunxue He,4 Mingwu Lou,2 ZiYu Xu2 1Department of Acupuncture and Moxibustion, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China; 2Department of Radiology, Longgang Central Hospital, Shenzhen, People’s Republic of China; 3Department of Radiology, The Third People’s Hospital of Longgang District, Shenzhen, People’s Republic of China; 4Department of Radiology, Shenzhen Clinical Medicine College, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingwu Lou; ZiYu Xu, Department of Radiology, Longgang Central Hospital, No. 6082, Longgang Avenue, Longgang District, Shenzhen, 518000, People’s Republic of China, Tel +86 13808854650 ; +86 13824321925, Email mingwulou@sina.com; xuziyu82@163.comPurpose: Methamphetamine use may cause severe neurotoxicity and cognitive impairment, leading to addiction, overdose, and high rates of relapse. However, few studies have systematically focused on functional impairments detected by neuroimaging in methamphetamine abstainers (MAs) during short-term abstinence. This study aimed to investigate effective connectivity, resting-state networks, and internetwork functional connectivity in MA brains to improve clinical treatment.Methods: Twenty MAs and 27 age- and education-matched healthy controls underwent resting-state functional magnetic resonance imaging. The amplitude of low-frequency fluctuations and Granger causality were analyzed to investigate disrupted brain regions and effective connectivity, respectively. Independent component analysis and functional network connectivity were used to identify resting-state networks and internetwork functional connectivity, respectively.Results: Compared with healthy controls, MAs demonstrated abnormal amplitudes of low-frequency fluctuations in the bilateral precuneus, left posterior cingulate cortex (PCC), left middle frontal gyrus (MFG), left superior parietal lobule, left supplementary motor area (SMA), and left inferior parietal lobule (IPL). Moreover, MAs showed decreased effective connectivity from the left PCC to the left precuneus, increased effective connectivity from the left precuneus to the left MFG and from the right precuneus to the left SMA, and altered functional connectivity within the default mode network (DMN), frontoparietal network, sensorimotor network, ventral attention network, cerebellar network, and visual network. Importantly, hyperconnectivity between the DMN and ventral attention network and hypoconnectivity between the DMN and cerebellar network as well as the DMN and frontoparietal network were demonstrated in MAs.Conclusion: Our study implies that in short-term methamphetamine abstinence, disruptions to the DMN and executive network may a play key role, providing new insights for early rehabilitation.Keywords: methamphetamine, abstinence, network, Granger causality analysis, independent component analysis

Huan Tang, Yizhuo Xie, Ming Zhu, Juan Jia, Rui Liu, Yujia Shen, Yucui Zheng, Xin Guo, Dongfanghui Miao, Jin Pei Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Jin Pei, Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, Changchun, 130021, People’s Republic of China, Tel +86 431 85619725, Email peijin@jlu.edu.cnPurpose: Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages.Methods: ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP.Results: Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC50 values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs.Conclusion: ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.Graphical Abstract: Keywords: ovarian cancer, combination therapy, drug delivery system, liposome, estrogen receptor

Ying Du,1,2 Shujun Wang,3 Jianfeng Luan,3 Meilin Zhang,1,2 Baoan Chen,1,2,&ast; Yanfei Shen2,&ast; 1Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, People’s Republic of China; 2School of Medicine, Southeast University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Blood Transfusion, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baoan Chen, Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China, Email cba8888@hotmail.com Yanfei Shen, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China, Email Yanfei.Shen@seu.edu.cnBackground: Glucose oxidase (GOx)-based starvation therapy is a new cancer treatment strategy. However, the characteristics such as limited curative effect and hypoxic tumor environment hinder its further application seriously.Methods: Herein, doxorubicin (DOX) loaded in hollow mesoporous copper sulfide (HMCuS) nanoparticles assembled with manganese dioxide (HMMD) as nanoshell was prepared. We developed a targeted enhanced cancer treatment method to camouflage HMMD by GOx-functionalized platelet (PLT) membranes (HMMD@PG).Results: GOx can be specially transported to the tumor site with PLT membrane for effective starvation treatment. Glucose and oxygen (O2) in the tumor were converted to H2O2 under the catalysis of GOx. HMMD can catalyze H2O2 to produce O2 and consume glutathione (GSH) in time, which regulates the tumor microenvironment (TME) and improves the adverse conditions of anti-tumor. In addition, DOX encapsulated in HMCuS-MnO2 release was accelerated from the nanoparticles after the “gatekeeper” MnO2 is consumed. The study of anti-tumor mechanism shows that the remarkable tumor suppressive ability of HMMD@PG comes from the three peaks synergy of starvation treatment, photothermal treatment (PTT), and chemotherapy. This nanoplatform disguised by PLT membrane has significant tumor inhibition ability, good biocompatibility and almost has no side effects in main organs.Conclusion: This work broadens the application mode of GOx and shows the new development of a multi-mode collaborative processing system of nanoplatforms based on cell membrane camouflage.Keywords: glucose oxidase, PLT membrane, nanoparticles, tumor microenvironment, tumor treatment

Yujuan Mao,1 Yumeng Chen,2 Chang Liu,2 Xingyue He,2 Yi Zheng,1 Xiaolan Chen,1 Ying Wang,1 Wei Chen,1 Yanling Wu,1 Yan Shen,2 Haifeng Yang,1 Songbo Ma3 1Jiangsu Animal Husbandry and Veterinary College, Taizhou, Jiangsu, 225300, People’s Republic of China; 2State Key Laboratory of Natural Medicines, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, Taizhou People’s Hospital, Taizhou, Jiangsu, 225300, People’s Republic of ChinaCorrespondence: Haifeng Yang, Email yhf8142@sina.com; Songbo Ma, Email masongbo1978@163.comIntroduction: Cefquinome sulfate (CS) is the first fourth-generation antibiotic for animals, which has a wide antibacterial spectrum, strong antibacterial activity and low drug resistance. However, it is accompanied by problems of poor therapeutic efficacy. In this context, the use of nanosuspensions have been found to be an attractive strategy. The main objective of this work is to develop a new oily nanosuspension to improve bioavailability and stability of CS formulations.Methods: After screening the formulations, cefquinome sulfate oily nanosuspension (CS-NSP) was prepared by mortar grinding, using propylene glycol dicaprolate/dicaprate (Labrafac™ PG) as oil medium and caprylocaproyl polyoxyl-8 glycerides (Labrasol®) as stabilizer. The properties of CS-NSP were investigated by testing its physicochemical characteristics, stability, in vitro release, hemolysis, and muscle irritation. The in vivo pharmacokinetics of CS-NSP was studied using rats.Results: Results show that CS-NSP presents suitable stability, physicochemical properties and safety. Moreover, a rapid release and high bioavailability of CS-NSP have also been verified in the study. Pharmacokinetic experiments in vivo showed that the bioavailability of CS-NSP was about 1.6 times that of commercial cefquinome sulfate injection (CS-INJ, Chuangdao®) (p< 0.01). These advantages of CS-NSP were carried out by small particle size and low viscosity, being associated with the use of Labrafac PG and stabilizer Labrasol.Conclusion: The results proved that the new preparation is safe and effective and is expected to become a promising veterinary nanodelivery system.Keywords: cefquinome sulfate, oily nanosuspension, Labrafac PG, labrasol, pharmacokinetics

Lei Dong,1,&ast; Nana Li,1,&ast; Xixi Wei,2 Yongling Wang,2 Liansheng Chang,3 Hongwei Wu,4 Liujiang Song,5 Kang Guo,6 Yuqiao Chang,1 Yaling Yin,2 Min Pan,7 Yuanyuan Shen,8 Feng Wang1 1Henan Key Laboratory of Medical Tissue Regeneration, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 3Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 4Department of Chemistry, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 5Department of Ophthalmology, Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA; 6Department of Oncology, The Third affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 7Department of Ultrasound, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518034, People’s Republic of China; 8National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Wang, Henan Key Laboratory of Medical Tissue Regeneration, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan, 453002, People’s Republic of China, Email wfeng100@126.com Min Pan, Department of Ultrasound, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, No. 6001 Beihuan Avenue, Shenzhen, 518034, People’s Republic of China, Email min.pan@siat.ac.cnBackground: The blood–brain barrier (BBB) inhibits the delivery of macromolecular chemotherapeutic drugs to brain tumors, leading to low utilization rates and toxic side effects to surrounding tissues and organs. Ultrasonic targeted microbubble destruction (UTMD) technology can open the BBB, leading to a new type of drug delivery system with particular utility in glioma.Purpose: We have developed a new type of drug-loaded microbubble complex based on poly(lactic-co-glycolic acid) (PLGA) that targets gambogic acid (GA) to the area of brain tumors through UTMD.Methods: GA/PLGA nanoparticles were prepared by the double emulsification method, and cationic microbubbles (CMBs) were prepared by a thin film hydration method. The GA/PLGA-CMB microbubble complex was assembled through electrostatic attractions and was characterized chemically. The anti-glioblastoma effect of GA/PLGA-CMB combined with focused ultrasound (FUS) was evaluated by biochemical and imaging assays in cultured cells and model mice.Results: GA/PLGA-CMB combined with FUS demonstrated a significant inhibitory effect on glioblastoma cell lines U87 and U251 as compared with controls (P< 0.05). Tumor access and imaging analyses demonstrated that administration of GA/PLGA-CMBs combined with FUS can open the BBB and target the treatment of glioblastoma in a mouse model, as compared with control groups (P< 0.05).Conclusion: The combination of PLGA-CMB with FUS provides an effective and biocompatible drug delivery system, and its application to the delivery of GA in a mouse glioblastoma model was successful.Keywords: microbubbles, cavitation effect, glioblastoma, focused ultrasound

Liwei Yao,1 Xudong Xu,2 Gang Chen,2 Yanqin Shen,2,* Weixian Jiang1,* 1Department of Nursing, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanqin Shen, Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, No. 208 East Huancheng Road, Hangzhou, Zhejiang, People’s Republic of China, Email yanqinshen@yeah.net Weixian Jiang, Department of Nursing, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, No. 208 East Huancheng Road, Hangzhou, Zhejiang, People’s Republic of China, Email jwxmed@163.comPurpose: To evaluate the diagnostic accuracy of the CapitalBio Mycobacterium real-time polymerase chain reaction assay (CapitalBio test) testing of core needle biopsy (CNB) specimens for tuberculous lymphadenitis (TBL) and to compare it with Xpert MTB/RIF.Methods: We retrospectively analyzed the medical data on patients with suspected peripheral TBL. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of the CapitalBio test, Xpert MTB/RIF, and parallel test (positive result for either of these two tests) were calculated to evaluate their diagnostic efficacy compared with the final clinical diagnosis.Results: The study included 114 patients. For diagnosing TBL using CNB samples, the sensitivity, specificity, PPV, NPV, and AUC were 65.0%, 100.0%, 100.0%, 28.6%, and 0.83, respectively, for the CapitalBio test; 72.0%, 100.0%, 100.0%, 33.3%, and 0.86, respectively, for Xpert MTB/RIF; and 82.0%, 100.0%, 100.0%, 43.8%, and 0.91, respectively, for the parallel test.Conclusion: The accuracy of the CapitalBio test and Xpert MTB/RIF for diagnosing TBL using CNB specimens was moderate, while the sensitivity and NPV of these two tests were relatively low. The diagnostic accuracy of the CapitalBio test was slightly lower than that of Xpert MTB/RIF, but the difference between the two was not statistically significant. Parallel test might improve the diagnostic accuracy but not substantially over a single test.Keywords: CapitalBio test, Xpert, tuberculous lymphadenitis, core needle biopsy, diagnostic accuracy

Qun Li,1 Yangli Jin,2 Zhisen Shen,1 Huigao Liu,3 Yi Shen,1 Zhenhua Wu1 1Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, People’s Republic of China; 2Department of Doppler Ultrasonic, Ningbo Yinzhou No.2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 3Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Zhenhai Longsai Hospital, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Zhenhua WuDepartment of Otorhinolaryngology Head and Neck Surgery, Ningbo Medical Center Lihuili Hospital, No. 57 Xingning Road, Yinzhou District, Ningbo, 315040, People’s Republic of ChinaTel +86-574-87018634Fax +86-574-87018634Email wuzhenhua1975@126.comBackground: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant cancers, and few studies have demonstrated the value of ferroptosis-related genes in prognosis.Methods: The original counts of RNA sequencing data and clinicopathological data were obtained from TCGA and GSE65858 datasets. Common ferroptosis-related genes related to prognosis were identified from the training set and were included in LASSO to determine the best prognosis. To evaluate the efficacy, time-dependent ROC and Kaplan–Meier (KM) survival analyses were applied. Moreover, univariate and multivariate Cox regression analyses were used to screen independent parameters of prognosis and build a nomogram. Eventually, possible biological pathways were proposed based on GSEA.Results: Among 242 ferroptosis-related genes, we identified that the FLT3, IL6, Keap1, NQO1, SOCS1 and TRIB3 genes were significantly connected with HNSCC patient prognosis as a six-gene signature. After, the patients were divided into high- and low-risk groups based on the six-gene signature. The KM survival curves demonstrated that the high-risk group had worse OS (p < 0.0001) and higher AUC values (0.654, 0.735, and 0.679 for 1-, 3-, and 5-year survival, respectively) for the prognostic signature of the six genes compared with other genes, which were also validated in the GSE65858 dataset. Moreover, GSEA suggested that the epithelial mesenchymal transition pathway was abundant and that the mesenchymal status in the high-risk group was substantially higher than that in the low-risk group. Finally, the immune microenvironment and differences in the content of immune cell types were demonstrated.Conclusion: We established a six-ferroptosis-related-gene model crossing clinical prognostic parameters that can predict HNSCC patient prognosis and provide a reliable prognostic evaluation tool to assist clinical treatment decisions.Keywords: head and neck squamous cell carcinoma, ferroptosis, prognosis, TCGA

Zixuan Ye,1,&ast; Lizhen Liang,1,&ast; Huazhen Lu,1 Yan Shen,2 Wenwu Zhou,3 Yanan Li1 1School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, People’s Republic of China; 2State Key Laboratory of Natural Medicines, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3National Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanan LiSchool of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, People’s Republic of ChinaTel +8615051850598Email liyanan@njnu.edu.cnWenwu ZhouNational Experimental Teaching Demonstration Center of Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of ChinaEmail dancingzww@163.comAbstract: Bacteria and their derivatives (membrane vesicles, MVs) exhibit great advantages for targeting hypoxic tumor cores, strong penetration ability and activating immune responses, holding great potential as auspicious candidates for therapeutic and drug-delivery applications. However, the safety issues and low therapeutic efficiency by single administration still need to be solved. To further optimize their performance and to utilize their natural abilities, scientists have strived to modify bacteria with new moieties on their surface while preserving their advantages. The aim of this review is to give a comprehensive overview of a non-genetic engineering modification strategy that can be used to optimize the bacteria with nanomaterials and the design strategy that can be used to optimize MVs for better targeted therapy. Here, the advantages and disadvantages of these processes and their applicability for the development of bacteria-related delivery system as antitumor therapeutic agents are discussed. The prospect and the challenges of the above targeted delivery system are also proposed.Keywords: bacteria, nanomaterial, targeted delivery, immune response, membrane vesicles

Yuxin Sun,&ast; Yizhuo Xie,&ast; Huan Tang, Zhihui Ren, Xue Luan, Yan Zhang, Ming Zhu, Zhe Lv, Han Bao, Yan Li, Rui Liu, Yujia Shen, Yucui Zheng, Jin Pei Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, ChangChun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin PeiSchool of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, ChangChun, 130021, Jilin Province, People’s Republic of ChinaTel +86 431 85619725Email peijin@jlu.edu.cnBackground: Chemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin.Methods: Four kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice.Results: The ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin.Conclusion: In this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic.Keywords: estrogen receptors, chemotherapy, long-acting liposomes, targeted drug delivery, pharmacokinetics, antitumor activity

Kai Fang,&ast; Yiding Shen,&ast; Kendrick Hii Ru Yie, Zixin Zhou, Lei Cai, Shuyi Wu, Abdullrahman M Al-Bishari, Mohammed A Al-Baadani, Xinkun Shen, Pingping Ma, Jinsong Liu School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinkun Shen; Pingping MaSchool and Hospital of Stomatology, Wenzhou Medical University, 268#Xueyuan West Road, Lucheng District, Wenzhou City, 325000, People’s Republic of ChinaTel +86-577-88066010; +86-577-88066085Email 20111902015@cqu.edu.cn; ppma2012@sina.comBackground: Sandblasted/acid-etched titanium (SLA-Ti) implants are widely used for dental implant restoration in edentulous patients. However, the poor osteoinductivity and the large amount of Ti particles/ions released due to friction or corrosion will affect its long-term success rate.Purpose: Various zirconium hydrogen phosphate (ZrP) coatings were prepared on SLA-Ti surface to enhance its friction/corrosion resistance and osteoinduction.Methods: The mixture of ZrCl4 and H3PO4 was first coated on SLA-Ti and then calcined at 450°C for 5 min to form ZrP coatings. In addition to a series of physiochemical characterization such as morphology, roughness, wettability, and chemical composition, their capability of anti-friction and anti-corrosion were further evaluated by friction-wear test and by potential scanning. The viability and osteogenic differentiation of MC3T3-E1 cells on different substrates were investigated via MTT, mineralization and PCR assays.Results: The characterization results showed that there were no significant changes in the morphology, roughness and wettability of ZrP-modified samples (SLA-ZrP0.5 and SLA-ZrP0.7) compared with SLA group. The results of electrochemical corrosion displayed that both SLA-ZrP0.5 and SLA-ZrP0.7 (especially the latter) had better corrosion resistance than SLA in normal saline and serum-containing medium. SLA-ZrP0.7 also exhibited the best friction resistance and great potential to enhance the spreading, proliferation and osteogenic differentiation of MC3T3-E1 cells.Conclusion: We determined that SLA-ZrP0.7 had excellent comprehensive properties including anti-corrosion, anti-friction and osteoinduction, which made it have a promising clinical application in dental implant restoration.Keywords: titanium, zirconium hydrogen phosphate, anti-corrosion, anti-friction, osteoinduction

Yejing Shen,1,2 Xiaowen Xu,2 Siming Meng,2 Meng Qin,2 Hailing Li,2 Dejie Chu,1 Cuixia Zheng2 1Department of Respiratory Medicine, Shanghai Eighth People’s Hospital, Shanghai, 200235, People’s Republic of China; 2Department of Respiratory Medicine, Yangpu Hospital Affiliated to Tongji University, Shanghai, 200090, People’s Republic of ChinaCorrespondence: Dejie ChuDepartment of Respiratory Medicine, Shanghai Eighth People’s Hospital, 8 Caobao Road, Shanghai, 200235, People’s Republic of ChinaEmail chudejie@yandex.comCuixia ZhengDepartment of Respiratory Medicine, Yangpu Hospital Affiliated to Tongji University, 450 Tengyue Road, Shanghai, 200090, People’s Republic of ChinaEmail zhengcuixiash@163.comObjective: To assess the impact of blood glucose levels on the prognosis of patients with community-acquired pneumonia (CAP) who were elderly or middle-aged.Methods: From January 1, 2018, to December 31, 2020, patients with CAP (≥ 45 years) were retrospectively enrolled in this observational study. They were stratified by age (45– 64 or ≥ 65 years) and blood glucose level (≥ 11.1 or < 11.1 mmol/l). The effect of admission blood glucose on 28-day mortality was assessed with the Cox proportional hazards model, adjusted for demographic factors and comorbidity.Results: Among 1656 patients with CAP, increased blood glucose (HR=2.08, 95% CI: 1.38– 3.49; P< 0.01) and advanced age (HR=2.76, 95% CI: 1.65– 3.77; P< 0.01) were significantly associated with a higher risk of 28-day mortality, after controlling for potential confounding factors. The strength of the association of blood glucose level with 28-day mortality decreased with age (P=0.01 for the interaction) as the adjusted HRs for death were 4.48 (95% CI: 1.40– 13.65; P< 0.01) for middle-age patients 45– 64 years and 1.52 (95% CI: 1.09– 2.17; P=0.05) for elderly patients ≥ 65 years.Conclusion: The association of blood glucose level upon admission for CAP with all-cause mortality was stronger at younger ages.Keywords: age, community-acquired pneumonia, hyperglycemia, mortality, prognosis

Wenli Zhang,1,&ast; Enshi Hu,1,&ast; Yajie Wang,1,&ast; Si Miao,1 Yanyan Liu,1 Yumin Hu III,1 Ji Liu,1 Bohui Xu,2 Daquan Chen,3 Yan Shen1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 2School of Pharmacy, Nantong University, Nantong, 226001, People’s Republic of China; 3School of Pharmacy, Yantai University, State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, 264005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Shen; Daquan Chen Tel +86-25-83271305; +86-535-6706021Email shenyan@cpu.edu.cn; cdq1981@126.comAbstract: At present, some bacteria have developed significant resistance to almost all available antibiotics. One of the reasons that cannot be ignored is long-term exposure of bacteria to the sub-minimum inhibitory concentration (MIC) of antibiotics. Therefore, it is necessary to develop a targeted antibiotic delivery system to improve drug delivery behavior, in order to delay the generation of bacterial drug resistance. In recent years, with the continuous development of nanotechnology, various types of nanocarriers that respond to the infection microenvironment, targeting specific bacterial targets, and targeting infected cells, and so on, are gradually being used in the delivery of antibacterial agents to increase the concentration of drugs at the site of infection and reduce the side effects of drugs in normal tissues. Here, this article describes in detail the latest research progress on nanocarriers for antimicrobial, and commonly used targeted antimicrobial strategies. The advantages of the combination of nanotechnology and targeting strategies in combating bacterial infections are highlighted in this review, and the upcoming opportunities and remaining challenges in this field are rationally prospected.Keywords: nanocarriers, antimicrobial, drug delivery, targeting strategies

Qunxiang Qiu,1,&ast; Ping Zhang,2,&ast; Nan Zhang,1 Yan Shen,1 Shifeng Lou,1 Jianchuan Deng1 1Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 2Hematology Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianchuan DengDepartment of Hematology, The Second Affiliated Hospital, Chongqing Medical University, 76 Linjiang Road, Chongqing, 400010, People’s Republic of ChinaEmail dengjccq@hospital.cqmu.edu.cnPurpose: Acute myeloid leukaemia (AML) is a common haematological disease in adults. The overall survival (OS) remains unsatisfactory. It is critical to identify potential prognostic biomarkers and develop a nomogram that predicts overall survival in patients with AML.Patients and Methods: We used gene expression dataset and clinical data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to identify differential expression analysis, survival analysis, and prognostic value of IGHD gene family (IGHDs) in AML patients. A risk score model was built through Lasso analysis and multivariate Cox regression. We also developed a nomogram and evaluated its accuracy with Harrell’s Harmony Index (C-index) and calibration curve. Last, the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database was used for external validation.Results: IGHD1-20 mRNA expression level was an independent prognostic factor for patients with AML by multivariate analysis. After Lasso analysis and multivariate Cox regression, we constructed a 3-gene model (IGHD1-1, IGHD1-20, IGHD3-16) associated with OS in AML. Risk score and age were validated as independent risk factors for prognosis and were used to build a nomogram. The C index and calibration curve results show that its ability to predict 1-year, 3-year and 5-year overall survival is accurate.Conclusion: The mRNA level of IGHDs was increased in AML patients. IGHD1-20 was an independent risk factor for OS in AML patients. The IGHDs risk model (IGHD1-1, IGHD1-20, IGHD3-16) relates to the OS of AML patients. The nomogram, including risk score and age, can conveniently and effectively predict the overall survival rate of patients.Keywords: acute myeloid leukaemia, IGHD gene family, IGHD1-20, prognosis

Lu Tang,1,2,&ast; Yijun Mei,1,2,&ast; Yan Shen,1,2,&ast; Shun He,1,2 Qiaqia Xiao,1,2 Yue Yin,1,2 Yonggang Xu,3 Jie Shao,3 Wei Wang,1,2 Zihao Cai3 1State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 2NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 3Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei WangState Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of ChinaTel +86-25-83271102Email wangcpu209@cpu.edu.cnZihao CaiDepartment of General Surgery, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of ChinaTel +86-21-66895079Email davidcai1@163.comAbstract: Advanced research has revealed the crucial role of tumor microenvironment (TME) in tumorigenesis. TME consists of a complicated network with a variety of cell types including endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs) as well as the extracellular matrix (ECM). The TME-constituting cells interact with the cancerous cells through plenty of signaling mechanisms and pathways in a dynamical way, participating in tumor initiation, progression, metastasis, and response to therapies. Hence, TME is becoming an attractive therapeutic target in cancer treatment, exhibiting potential research interest and clinical benefits. Presently, the novel nanotechnology applied in TME regulation has made huge progress. The nanoparticles (NPs) can be designed as demand to precisely target TME components and to inhibit tumor progression through TME modulation. Moreover, nanotechnology-mediated drug delivery possesses many advantages including prolonged circulation time, enhanced bioavailability and decreased toxicity over traditional therapeutic modality. In this review, update information on TME remodeling through NPs-based targeted drug delivery strategies for anticancer therapy is summarized.Keywords: tumor microenvironment, nanotherapeutics, cancer treatment, targeted delivery, regulation strategy

Zixuan Ye,1,* Yue Zhang,1,* Yuanfen Liu,2,* Yanyan Liu,1 Jiasheng Tu,1 Yan Shen1 1Department of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Jiangsu Health Vocational College, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Shen; Jiasheng TuDepartment of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, People’s Republic of ChinaTel +86 25 83271305Email shenyan@cpu.edu.cn; jiashengtu@aliyun.comBackground: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab–valine–citrulline (vc)–doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells.Methods: Maleimidocaproyl–valine–citrulline–p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody–drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs.Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR–overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPsConclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.Keywords: bovine serum albumin, antibody–drug conjugate, cetuximab, doxorubicin, colonic carcinoma, epidermal growth factor receptor

Chen Ling,1 Xiaobo Wang,1 Yan Shen2 1School of Pharmacy, China Pharmaceutical University, Nanjing 211100, People’s Republic of China; 2Department of Pharmaceutics, China Pharmaceutical University, Nanjing 211100, People’s Republic of ChinaCorrespondence: Yan Shen Tel +86 (025) 83271305Email shenyan@cpu.edu.cnAbstract: Nanotechnology has prompted the development of hollow inorganic nanomedicine. These medicines are now widely investigated as photothermal-based therapies for various diseases due to their high loading capacity, tuneable wavelength, relatively small size and low density. We begin this review with a brief introduction, followed by a summary of the development of imaging-guided photothermal therapy (PTT) for cancer treatment during the last three years (from 2017 to 2020). We then introduce the antibacterial effects of these medicines on some bacterial infections, in which the pathogenic bacteria can be killed by mild photothermal effects, ions and antibiotic release. Other diseases can also be treated using hollow inorganic photothermal agents. Specifically, we discuss the use of PTT for treating Alzheimer’s disease, obesity and endometriosis. Finally, we share our perspectives on the current challenges and future prospects of using hollow inorganic materials in clinical PTT for various diseases.Keywords: hollow inorganic nanomedicine, photothermal therapy, diseases

Huijie Dong,1,* Yingying Shen,1,2,* Yiping Shen,1,2 Dijiong Wu1,2 1First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 2Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dijiong WuDepartment of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, Zhejiang 310006, People’s Republic of ChinaEmail wudijiong@zcmu.edu.cnAbstract: A 49-year-old male patient who had been diagnosed with variable hairy cell leukemia (HCL-V) was treated with interferon for half a year but exert no obvious effect. After two courses of chemotherapy with cladribine, he achieved remission, and splenomegaly significantly improved (the length in craniocaudal dimension decreased from 15.8cm to 11.8cm). Four years later, the patient got disease relapse and was recommended for another cycle of cladribine (6mg for 7 days). On the last day of cladribine, the patient developed fever with needle-like red rashes on the face, limbs, and trunk. At the very beginning, the rash was lighter in color, sparsely distributed, and without obvious itching. Three days later, the rash gradually darkened, expanded and merged, with itching. With the application of high dose gamma globulin and corticosteroids (prednisolone combined with dexamethasone), the rash finally faded, and the patient was discharged. Rash caused by cladribine is not uncommon, such serious and widespread drug-induced rash is rare, and there are few reports. This article reviewed relevant studies and treatments.Keywords: hairy cell leukemia, cladribine, system rash, side effect

Buyankhishig Dorjsuren,1,* Birendra Chaurasiya,2,* Zixuan Ye,1 Yanyan Liu,1 Wei Li,3 Chaoyang Wang,1 Di Shi,4 Colin E Evans,2 Thomas J Webster,4 Yan Shen1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China; 2Department of Pediatrics, Critical Care Division, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou 225002, People’s Republic of China; 4Department of Chemical Engineering, Northeastern University, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Yan Shen; Thomas J Webster Tel +86 (025) 83271305; Tel +86 (025) 83271305; Email shenyan@cpu.edu.cn; th.webster@northeastern.eduBackground: One major limitation of cancer chemotherapy is a failure to specifically target a tumor, potentially leading to side effects such as systemic cytotoxicity. In this case, we have generated a cancer cell-targeting nanoparticle-liposome drug delivery system that can be activated by near-infrared laser light to enable local photo-thermal therapy and the release of chemotherapeutic agents, which could achieve combined therapeutic efficiency.Methods: To exploit the magnetic potential of iron oxide, we prepared and characterized citric acid-coated iron oxide magnetic nanoparticles (CMNPs) and encapsulated them into thermo-sensitive liposomes (TSLs). The chemotherapeutic drug, doxorubicin (DOX), was then loaded into the CMNP-TSLs, which were coated with an antibody against the epidermal growth factor receptor (EGFR), cetuximab (CET), to target EGFR-expressing breast cancer cells in vitro and in vivo studies in mouse model.Results: The resulting CET-DOX-CMNP–TSLs were stable with an average diameter of approximately 120 nm. First, the uptake of TSLs into breast cancer cells increased by the addition of the CET coating. Next, the viability of breast cancer cells treated with CET-CMNP-TSLs and CET-DOX-CMNP-TSLs was reduced by the addition of photo-thermal therapy using near-infrared (NIR) laser irradiation. What is more, the viability of breast cancer cells treated with CMNP-TSLs plus NIR was reduced by the addition of DOX to the CMNP-TSLs. Finally, photo-thermal therapy studies on tumor-bearing mice subjected to NIR laser irradiation showed that treatment with CMNP-TSLs or CET-CMNP-TSLs led to an increase in tumor surface temperature to 44.7°C and 48.7°C, respectively, compared with saline-treated mice body temperature ie, 35.2°C. Further, the hemolysis study shows that these nanocarriers are safe for systemic delivery.Conclusion: Our studies revealed that a combined therapy of photo-thermal therapy and targeted chemotherapy in thermo-sensitive nano-carriers represents a promising therapeutic strategy against breast cancer.Keywords: breast cancer, cetuximab, doxorubicin, iron oxide magnetic nanoparticles, epidermal growth factor receptors, combined therapy

Yanan Li,1 Pengcheng Xu,1 Dongsheng He,1 Bohui Xu,2 Jiasheng Tu,1 Yan Shen1 1China Pharmaceutical University, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Nanjing 210009, People’s Republic of China; 2School of Pharmacy, Nantong University, Nantong 226001, People’s Republic of ChinaCorrespondence: Yan Shen Tel/Fax +86-25-83271305Email shenyan@cpu.edu.cnIntroduction: Oxaliplatin (L-OHP) is a well-known third-generation platinum anticancer drug with severe systemic- and neuro-toxicity. The main objective of the current research was to develop a targeted long-circulating thermosensitive smart-release liposome (LCTL) system for better therapeutic efficacy and less toxicity.Methods: The reverse-phase evaporation method (REV) was used to prepare L-OHP loaded LCTL (L-OHP/LCTL). The physical characteristics were evaluated including encapsulation efficiency (EE), size, zeta potential and stability. The release behavior, cytotoxicity and in vivo evaluation were also carried out.Results: EE of LCTL was around 25% with a uniform size distribution, and LCTL achieved almost complete release at 42°C while it was only 10% at 37°C. Moreover, the LCTL showed significantly higher cytotoxicity at 42°C than that at 37°C. The in vivo results indicated LCTL could target tumors and enhance retention for more than 24 h, thereby enhancing anti-tumor efficacy on 4T1-bearing mice.Discussion: These results indicated that LCTL not only possessed a prolonged circulation time but it also enhanced accumulation and achieved selective release at the tumor sites. Conclusively, LCTL could serve as a promising carrier for oxaliplatin delivery to treat solid tumors.Keywords: delivery, oxaliplatin, thermosensitive, pharmacokinetic properties, tumor targeting

Xinyue Zhu,1,2 Zuyun Qiu,1,3 Zixiang Liu,1 Yifeng Shen,4 Qiaoyin Zhou,5 Yan Jia,1,3 Xiaojie Sun,1,3 Shiliang Li1 1Department of Acupuncture and Moxibustion, China–Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Rehabilitation Medicine, Beijing First Hospital of Integrated Chinese and Western Medicine, Beijing, People’s Republic of China; 3Graduate School, Beijing University of Traditional Chinese Medicine, Beijing, People’s Republic of China; 4Department of Traditional Chinese Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 5Chinese Medicine College, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaCorrespondence: Shiliang Li Department of Acupuncture and Moxibustion, China–Japan Friendship Hospital, 4 Sakura Garden Road, Beijing 100029, People’s Republic of ChinaTel +86-135-8177-6268Email zrlishiliang@163.comCase: The patient was a 62-year-old woman presenting with low-back pain of 3 years’ duration and numbness in the right leg.Diagnosis: She was diagnosed with lumbar spinal stenosis based on combined magnetic resonance imaging, physical examination, and symptoms.Interventions: Treatment with computed tomography–guided percutaneous release of the ligamentum flavum was delivered.Outcomes: Relief of symptoms immediately after treatment and complete resolution of symptoms after 1 month were achieved. At follow-up, there was no recurrence of symptoms after 2, 4, 6, and 12 months.Conclusion: Lumbar ligamentum flavum hypertrophy is an important cause of degenerative lumbar spinal stenosis. The hypertrophic ligamentum flavum can directly compress the spinal canal, squeeze the cauda equina, and simultaneously lead to a reduction in the anteroposterior diameter of the intervertebral foramen, which compresses the nerve roots and causes numbness and other symptoms of lower extremities. In clinical practice, doctors should combine imaging findings with patient symptoms for diagnosis and an individualized treatment plan for each patient with lumbar spinal stenosis, and conduct gradual stepwise treatment using conservative minimally invasive surgery to prevent excessive surgery.Keywords: CT guidance, ligamentum flavum, lumbar spinal stenosis, minimally invasive surgery, needle knife

Ji Wang,1,* Xia Wu,2,* Peng Shen,3 Jun Wang,4 Yidan Shen,1 Yan Shen,5 Thomas J Webster,6 Junjie Deng3 1Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Clinical Pharmacology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 3Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, People’s Republic of China; 4Department of General Surgery, The Fifth People’s Hospital of Wujiang, Suzhou, People’s Republic of China; 5Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 6Department of Chemical Engineering, Northeastern University, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Junjie DengWenzhou Institute, University of Chinese Academy of Sciences, No. 16 Xinsan Road, Hi-Tech Industry Park, Wenzhou, Zhejiang, People’s Republic of ChinaTel +86 577 88017548Fax +86 577 88017554Email j.deng@wibe.ac.cnThomas J WebsterDepartment of Chemical Engineering, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USATel +1 617 373 6585Email th.webster@neu.eduBackground: Cancer is one of the major causes of death and is difficult to cure using existing clinical therapies. Clinical cancer treatments [such as surgery, chemotherapy (CHT), radiotherapy (RT) and immunotherapy (IT)] are widely used but they have limited therapeutic effects and unavoidable side effects. Recently, the development of novel nanomaterials offers a platform for combinational therapy (meaning a combination of two or more therapeutic agents) which is a promising approach for cancer therapy. Recent studies have demonstrated several types of nanomaterials suitable for photothermal therapy (PTT) based on a near-infrared (NIR) light-responsive system. PTT possesses favorable properties such as being low in cost, and having high temporospatial control with minimal invasiveness. However, short NIR light penetration depth limits its functions.Methods: In this review, due to their promise, we focus on inorganic nanomaterials [such as hollow mesoporous silica nanoparticles (HMSNs), tungsten sulfide quantum dots (WS2QDs), and gold nanorods (AuNRs)] combining PTT with CHT, RT or IT in one treatment, aiming to provide a comprehensive understanding of PTT-based combinational cancer therapy.Results: This review found much evidence for the use of inorganic nanoparticles for PTT-based combinational cancer therapy.Conclusion: Under synergistic effects, inorganic nanomaterial-based combinational treatments exhibit enhanced therapeutic effects compared to PTT, CHT, RT, IT or PDT alone and should be further investigated in the cancer field.Keywords: photothermal agents, hyperthermia, chemotherapy, radiotherapy, immunotherapy, photodynamic therapy

Fang Huang,1,* Jinjin Zhao,1,* Yiting Wei,1 Zhifa Wen,1 Yue Zhang,1 Xuru Wang,1 Yanfei Shen,2 Li-xin Wang,1 Ning Pan1 1Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People’s Republic of China; 2Department of Bioengineering, Medical School of Southeast University, Nanjing, Jiangsu Province 210009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-xin Wang; Ning PanDepartment of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu Province 210009, People’s Republic of ChinaEmail lxwang@seu.edu.cn; panningmicro@aliyun.comBackground and Aim: We have previously identified ubiquitinated proteins (UPs) from tumor cell lysates as a promising vaccine for cancer immunotherapy in different mouse tumor models. In this study, we aimed at developing a highly efficient therapeutic adjuvant built-in nanovaccine (α-Al2O3-UPs) by a simple method, in which UPs from tumor cells could be efficiently and conveniently enriched by α-Al2O3 nanoparticles covalently coupled with Vx3 proteins (α-Al2O3-CONH-Vx3).Methods: The α-Al2O3 nanoparticles were modified with 4-hydroxybenzoic acid followed by coupling with ubiquitin-binding protein Vx3. It was then used to enrich UPs from 4T1 cell lysate. The stability and the efficiency for the UPs enrichment of α-Al2O3-CONH-Vx3 were examined. The ability of α-Al2O3-UPs to activate DCs was examined in vitro subsequently. The splenocytes from the vaccinated mice were re-stimulated with inactivated tumor cells, and the IFN-γ secretion was detected by ELISA and flow cytometry. Moreover, the therapeutic efficacy of α-Al2O3-UPs, alone and in combination with chemotherapy, was examined in 4T1 tumor-bearing mice.Results: Our results showed that α-Al2O3-UPs were successfully synthesized and abundant UPs from tumor cell lysate were enriched by the new method. In vitro study showed that compared to the physical mixture of α-Al2O3 nanoparticles and UPs (α-Al2O3+UPs), α-Al2O3-UPs stimulation resulted in higher upregulations of CD80, CD86, MHC class I, and MHC class II on DCs, indicating the higher ability of DC activation. Moreover, α-Al2O3-UPs elicited a more effective immune response in mice, demonstrated by higher IFN-γ secretion than α-Al2O3+UPs. Furthermore, α-Al2O3-UPs also exhibited a more potent effect on tumor growth inhibition and survival prolongation in 4T1 tumor-bearing mice. Notably, when in combination with low dose chemotherapy, the anti-tumor effect was further enhanced, rather than using α-Al2O3-UPs alone.Conclusion: This study presents an adjuvant built-in nanovaccine generated by a new simple method that can be potentially applied to cancer immunotherapy and lays the experimental foundation for future clinical application.Keywords: ubiquitinated proteins, alumina nanoparticles, cancer vaccine, combination therapy

Hao Ren, Ying Shen,* Fang Luo* Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Luo; Ying ShenDepartment of Pain Management, Beijing Tiantan Hospital, Capital Medical University, No. 119 West Road, South 4th Ring Road, Fengtai District, Beijing 100050, People’s Republic of ChinaTel +86 13611326978; +86 18610791617Email luofangwt@yahoo.com; shenying1937@hotmail.comPurpose: There is no standard clinical treatment protocol for supraorbital neuralgia patients who respond poorly to conservative treatment. Radiofrequency thermocoagulation, a neurologically damaging procedure, is a treatment for supraorbital neuralgia. However, assessments of its long-term efficacy are lacking. Thus, this study aimed to evaluate the long-term efficacy and safety of ultrasound-guided radiofrequency thermocoagulation for treating supraorbital neuralgia.Patients and Methods: We retrospectively reviewed our clinical database for supraorbital neuralgia patients who underwent an ultrasound-guided radiofrequency thermocoagulation procedure. Demographic data and baseline characteristics, time of onset, postoperative pain intensity, time of recurrence, subsequent treatment, complications and side effects were collected and analysed. The Kaplan-Meier estimator was used to determine recurrence-free survival.Results: A total of 53 supraorbital neuralgia patients were included in this study. All patients experienced complete pain relief within one month. The median follow-up time of the 53 patients was 36.0 months (IQR, 12.0– 72.0 months). A total of 13 patients experienced pain recurrence, with a median recurrence-free time of 97 months according to the Kaplan-Meier estimator. The cumulative proportion of recurrence-free survival was 96.2% at 12 months, 88.4% at 24 months, 82.7% at 36 months, 70.0% at 48 months, 66.3% at 60 months, and 49.7% at 97 months. All but one patient with recurrent pain underwent a second or third radiofrequency thermocoagulation procedure and achieved complete pain relief. Numbness of supraorbital nerve innervation occurred in all patients. However, the numbness scores gradually decreased over time.Conclusion: Ultrasound-guided radiofrequency thermocoagulation is a safe, effective treatment for supraorbital neuralgia patients who respond poorly to conservative treatments. These patients attained excellent long-term pain relief with a gradual reduction in numbness.Keywords: supraorbital neuralgia, radiofrequency thermocoagulation, long-term efficacy, survival analysis

Yuzhu Ma,1,* Daolu Yuwen,2,* Jingwei Chen,1 Bingfeng Zheng,1 Jian Gao,1 Minmin Fan,1 Wenwen Xue,1 Yixuan Wang,1 Wuhao Li,1 Yongqian Shu,3 Qiang Xu,1 Yan Shen1 1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, People’s Republic of China; 2Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China; 3Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiang Xu; Yan ShenState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing 210093, People’s Republic of ChinaTel/Fax +86 25 8968 7620Email molpharm@163.com; shenyan@nju.edu.cnIntroduction: Exosomes are important mediators of intercellular communication. Previously, we characterized circulating exosomal miR-425-3p as a non-invasive prognostic marker for predicting clinical response to platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC).Methods: Circulating exosomal miR-425-3p was validated by qRT-PCR in paired serum samples from NSCLC patients during the course of platinum-based chemotherapy. Cell coculture was performed to examine the effects of exosomal miR-425-3p on the sensitivity of recipient A549 cells to cisplatin. Using bioinformatics, ChIP and luciferase reporter assays, the transcription factor essential for miR-425-3p expression was identified. Autophagic activity in the recipient cells was determined by Western blot and fluorescence microscopy.Results: Higher levels of exosomal miR-425-3p were found in serum samples from the patients in tolerance versus those at baseline. An upward trend in the expression of circulating exosomal miR-425-3p was revealed during chemotherapy. Furthermore, the expression of exosomal miR-425-3p could be induced by cisplatin in NSCLC cells. Exosomes isolated from either cisplatin-treated or cisplatin-resistant NSCLC cells conferred chemoresistance to sensitive A549 cells in a miR-425-3p-dependent manner. Cisplatin-induced c-Myc was found to directly bind the miR-425-3p promoter and transactivated its expression. Exosomal miR-425-3p facilitated autophagic activation in the recipient cells by targeting AKT1, eventually leading to chemoresistance.Discussion: Our results suggest that apart from a prognostic marker of treatment response, exosomal miR-425-3p might be a potential dynamic biomarker to tailor cisplatin resistance in NSCLC patients during the treatment and represent a promising therapeutic target for therapy-resistant NSCLC.Keywords: exosomes, miR-425-3p, NSCLC, chemoresistance, platinum-based chemotherapy, autophagy

Yanhai Xi,1,* Tingwang Jiang,2,* Birendra Chaurasiya,3 Yanyan Zhou,1 Jiangmin Yu,1 Jiankun Wen,1 Yan Shen,3 Xiaojian Ye,1 Thomas J Webster4 1Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 2Department of Immunology and Microbiology, Institution of Laboratory Medicine of Changshu, Changshu, Jiangsu 215500, People’s Republic of China; 3Department of Pharmaceutics, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, China Pharmaceutical University, Nanjing, People’s Republic of China; 4Department of Chemical Engineering, Northeastern University, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Xiaojian YeDepartment of Spine Surgery, Changzheng Hospital, Second Military Medical University, 360 Huntington Avenue, Shanghai, MA 200003, People’s Republic of ChinaTel +86 1 381 734 6934Email xjyespine@smmu.edu.cnThomas J WebsterDepartment of Chemical Engineering, Northeastern University, Boston, MA 02115, USATel +1 617 373 6585Email th.webster@neu.eduAbstract: Ankylosing spondylitis (AS) is a complex disease characterized by inflammation and ankylosis primarily at the cartilage–bone interface. The disease is more common in young males and risk factors include both genetic and environmental. While the pathogenesis of AS is not completely understood, it is thought to be an immune-mediated disease involving inflammatory cellular infiltrates, and human leukocyte antigen-B27. Currently, there is no specific diagnostic technique available for this disease; therefore conventional diagnostic approaches such as clinical symptoms, laboratory tests and imaging techniques are used. There are various review papers that have been published on conventional treatment approaches, and in this review work, we focus on the more promising nanomedicine-based treatment modalities to move this field forward.Keywords: ankylosing spondylitis, pathogenesis, genetic factors, environmental factors, treatment approaches

Hengli Yang,1,2,* Wenbin Cai,3,* Wei Lv,2 Ping Zhao,2 Yamei Shen,4 Longfang Zhang,1 Bin Ma,1 Lijun Yuan,2 Yunyou Duan,2 Kechun Yao11Department of Ultrasound Diagnosis, Air Force General Hospital, Beijing, People’s Republic of China; 2Department of Ultrasound Diagnosis, Tang Du Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China; 3Special Diagnosis Department, General Hospital of Tibet Military Command, Lhasa, People’s Republic of China; 4Department of Ultrasound Diagnosis, Shaanxi Provincial People’s Hospital, Xi’an, People’s Republic of China *These authors contributed equally to this workCorrespondence: Yunyou DuanDepartment of Ultrasound Diagnosis, Tang Du Hospital, Fourth Military Medical University, Xi’an 710038, People’s Republic of ChinaEmail duanyy@fmmu.edu.cnKechun YaoDepartment of Ultrasound Diagnosis, Air Force General Hospital, Beijing 100036, People’s Republic of ChinaEmail yaokc1959@hotmail.comBackground: Currently, effective detection and treatment of cutaneous malignant melanoma (CMM) still face severe challenges. Ultrasound molecular imaging as a noninvasive and easy-to-operate method is expected to bring improvements for tumor detection.Purpose: The aim of this research is to prepare novel phase-change ultrasound contrast agents, Nds-IR780, which can perform not only dual-mode molecule-targeted imaging but also targeted photothermal therapy for CMM.Methods: A double emulsion process was used to prepare the Nds-IR780. Then, the entrapment rate and drug loading of IR-780 iodide in Nds-IR780 were detected by high-performance liquid chromatography. The biocompatibility of Nds-IR780 was evaluated by a CCK-8 assay and the characteristics and stability of that were verified through the particle size analyzer, laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM). The abilities of dual-mode molecule-targeted imaging and targeted photothermal therapy for Nds-IR780 were confirmed via the in vitro and in vivo experiments.Results: Nds-IR780 had good size distribution, polydispersity index, stability and biosafety. The in vitro and in vivo experiments confirmed that Nds-IR780 were capable of targeting CMM cells with high affinity (22.4±3.2%) and facilitating dual-mode imaging to detect the primary lesion and sentinel lymph nodes (SLNs) of CMM. Furthermore, the photothermal ablation of CMM mediated by Nds-IR780 was very effective in vivo.Conclusion: The newly prepared Nds-IR780 were observed to be effective targeted theranostic probe for the precise detection and targeted treatment of CMM.Keywords: CMM, dual-mode phase-change nanodroplets, targeted accurate diagnosis and treatment

Yunli Shen,1,* Shiyu Gong,1,* Jiming Li,1,* Yunkai Wang,1 Xumin Zhang,1 Hao Zheng,1 Qi Zhang,1 Jieyun You,1 Zheyong Huang,2 Yihan Chen11Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, People’s Republic of China; 2Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workPurpose: Myocardial delivery of magnetic iron oxide nanoparticles (MNPs) might produce iron overload-induced myocardial injury, and the oxidative stress was regarded as the main mechanism. Therefore, we speculated antioxidant modification might be a reasonable strategy to mitigate the toxicity of MNPs.Methods and results: Antioxidant N-acetylcysteine (NAC) was loaded into magnetic mesoporous silica coated Fe3O4 nanoparticles. Neonatal rat hypoxia/reoxygenation (H/R) cardiomyocytes were incubated with nanoparticles for 24 hrs. NAC can effectively mitigate iron-induced oxidative injury of cardiomyocytes, evidenced by reduced production of MDA, 8-iso-PGF2α, and 8-OHDG and maintained concentrations of SOD, CAT, GSH-Px, and GSH in ELISA and biochemical tests; downregulated expression of CHOP, GRP78, p62, and LC3-II proteins in Western Blot, and less cardiomyocytes apoptosis in flow cytometric analysis.Conclusions: NAC modifying could suppress the toxic effects of Fe3O4 nanoparticles in H/R cardiomyocytes model in vitro, indicating a promising strategy to improve the safety of iron oxide nanoparticles.Keywords: N-acetylcysteine (NAC), iron oxide nanoparticles, oxidative stress, cardiomyocytes, hypoxia-reoxygenation