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Xianling Feng,1,* Fucheng Tao,2,* Min Ren,3,* Mao Niu4 1School of Medical, Shenzhen University, Shenzhen, 518060, People’s Republic of China; 2Department of Stomatology, Shenzhen University General Hospital, Shenzhen, 518055, People’s Republic of China; 3Department of Stomatology, Rizhao Traditional Chinese Medicine Hospital, Rizhao, 276800, People’s Republic of China; 4School of Medical Technology and Nursing, Shenzhen Polytechnic University, Shenzhen, 518055, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mao Niu, School of Medical Technology and Nursing, Shenzhen Polytechnic University, 7098 Liuxian Avenue, Nanshan District, Shenzhen, 518055, People’s Republic of China, Tel +86 755 26011160, Fax +86 755 26018477, Email niu1037@szpu.edu.cnObject: The present study intended to evaluate the effect of simvastatin-loaded nanomicelles (SVNs) on promoting new bone formation and reducing alveolar ridge resorption at the tooth extraction sites at the early healing of the extraction sockets.Methods: SVNs were synthesized using a dialysis method. The rabbit tooth extraction model was established, SVNs and simvastatin (SV) were loaded on gelatin sponge and inserted into the extraction socket. CBCT scans were performed at 0, 2, and 4 weeks postoperatively to evaluate bone formation and alveolar ridge absorption in the extraction sockets. And all the animals were sacrificed and the mandibles were harvested. And HE staining and Masson staining were used for histological evaluation of the bone formation in the extraction sockets.Results: Radiographic evaluation showed that compared with the blank control group, at 2 and 4 weeks after extraction, SVNs increased the new bone density in the extraction sockets by 75.7% and 96.5%, and reduced the absorption rate of alveolar ridge length at the extraction sites by 60.8% and 49.1%, respectively. Histological evaluation showed that SVNs significantly improved the maturation of new bone tissue in the extraction sockets.Conclusion: SVNs can significantly accelerate healing and effectively reduce the absorption of alveolar ridge at the extraction sites in the early stage of tooth extraction socket healing.Keywords: alveolar ridge preservation, simvastatin-loaded nanomicelles, tooth extraction sites, bone formation

Kuocheng Yan,1,* Xiaohui Wang,2,* Yao Han,1,* Yuan Tian,1 Mengwei Niu,1 Xue Dong,1 Xiaowei Li,2 Hao Li,1 Yansong Sun1 1State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China; 2Department of Gastroenterology, the Sixth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, 100080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hao Li, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China, Email lihao88663239@126.com Xiaowei Li, Department of Gastroenterology, the Sixth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, 100080, People’s Republic of China, Email lixwei12@126.comBackground: Infection caused by Helicobacter pylori (H. pylori) affects approximately 50% of the global population. It is a major pathogenic factor for chronic gastritis and gastric cancer. Besides, the resistance to antibiotics such as clarithromycin could reduce the eradication rate. Currently, there is an urgent need for a swift, easy to perform, and highly sensitive detection method for H. pylori and clarithromycin resistance.Methods: We used FAM/Digoxin labeled primers to amplify specific H. pylori 23S rRNA fragments by Recombinase Aided Amplification (RAA), and resistance mutations were distinguished using CRISPR/Cas13a system combined with lateral flow strip. Twenty-eight saliva samples were analyzed using qPCR, gene sequencing and this method to evaluate the detection efficiency.Results: We developed a simultaneous detection method for H. pylori and clarithromycin resistance mutations named sensitive H. pylori easy-read dual detection (SHIELD). The results showed both A2142G and A2143G mutant DNAs causing clarithromycin resistance could be distinguished from the wild type with a concentration of 50 copies/μL, and no cross-reaction with other 5 common gastrointestinal bacteria was observed. For the detection of H. pylori in 28 saliva samples, the positive predictive value of this method was 100% (19/19) in comparison with qPCR. For detecting clarithromycin resistance, the positive predictive value of this method was 84.6% (11/13) compared with gene sequencing.Conclusion: SHIELD assay showed high sensitivity and specificity in detecting H. pylori and clarithromycin resistance mutations. It could be a potential measure in the rapid detection of H. pylori, large-scale screening and guiding clinical medication.Keywords: Helicobacter pylori, clarithromycin resistance mutation, recombinase aided amplification, CRISPR/Cas13a, nucleic acid detection

Wang L, Li D, Hao Y, et al. Int J Nanomedicine. 2017;12:3059-3075. The authors have advised Figures 9 and 11 on pages 3070 and 3071, respectively, are incorrect. The H&E staining image of tumor tissue in the PLGA/DTX@MnO2 group in Figure 9C and the X-ray CT images in Figure 11C were inadvertently misused during data acquisition. The correct Figure 9 is as follows. Figure 9 Inhibition of tumor growth in vivo by the drug delivery system.Abbreviations: H&E, hematoxylin and eosin; AuNR, gold nanorod; DTX, docetaxel; MnO2, manganese dioxide; PLGA, poly(lactic-co-glycolic acid); RF, radiofrequency.Notes: (A) Relative volumes of tumor-bearing mice; (B) body weight of the mice models (mean ± standard deviation; n=6); (C) H&E-stained tumor tissue sections: (a) control, (b) DTX, (c) PLGA/DTX@MnO2, (d) PLGA/DTX@MnO2 + RF, (e) PLGA/AuNR/DTX@MnO2, and (f) PLGA/AuNR/DTX@MnO2 + RF. The correct Figure 11 is as follows. Figure 11 Dual-mode imaging in vivo.Abbreviations: MR, magnetic resonance; CT, computed tomography.Notes: (A, B) T1-weighted MR images; (C) X-ray CT images: (a) control; (b) 4 h; (c) 8 h. The authors apologize for these errors and advise they do not affect the results and conclusions of the paper.

XiaoLang Miao,1 Yanxia Han,1 Zhenyun Wu,1 Xiaoliang Jin,1 Mei’e Niu,1 Qian Zhao,1 Xiangmin Lu2 1Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2School of Nursing, Soochow University, Suzhou, People’s Republic of ChinaCorrespondence: Mei’e Niu, Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, 899th, Pinghai Road, Suzhou, 215006, People’s Republic of China, Tel +86 13812671786, Email meniu_123@163.comPurpose: To translate a disease-specific anxiety questionnaire on chronic obstructive pulmonary disease (COPD) and test its reliability and validity in China.Patients and Methods: The German version of the revised COPD Anxiety Questionnaire (CAF-R) was initially validated using step-by-step translation, back-translation, and cross-cultural adaptation. The reliability and validity of the Chinese version of the CAF-R (CAF-R-CN) were tested among 448 patients with COPD (mean age =71.42± 9.33 years, 17.2% female) from four medical institutions in Suzhou, Jiangsu Province, using convenience sampling, from April 2022 to June 2023.Results: The CAF-R-CN included six dimensions with a total of 25 items. The item-level content validity index was 0.860– 1.000; the scale-level content validity index was 0.920. The structural validity χ2/df was 2.326, the root mean square error of approximation was 0.077, the comparative fit index was 0.924, and the Tucker–Lewis index was 0.912. The six-dimensional internal consistency index Cronbach’s α coefficient was 0.696– 0.910, and the test–retest reliability was 0.949. An optimal cut-off score of 50.5 was selected with a sensitivity of 0.786 and specificity of 0.870.Conclusion: The CAF-R-CN had satisfactory reliability and validity and can be used to identify and assess anxiety in COPD patients with a Chinese cultural background.Keywords: fear, scale, specificity, chronic respiratory disease, Chinese translation, assessment

Qingan Huang,1,* Yuan Li,2,3,* Mu Niu,2 Gaihe Chen4 1Department of General Ward, the Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 2Department of Cosmetic Dermatology, the Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 3Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Dermatology, the Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gaihe Chen, Department of Dermatology, the Fifth People’s Hospital of Hainan Province, No. 8 Longhua Road, Longhua District, Haikou, Hainan, 570100, People’s Republic of China, Email 279701157@qq.com Mu Niu, Department of Cosmetic Dermatology, the Fifth People’s Hospital of Hainan Province, No. 8 Longhua Road, Longhua District, Haikou, Hainan, 570100, People’s Republic of China, Email 382219948@qq.comAbstract: Superficial Acral fibroma (SAF), also known as osteofibroma, is a rare fibromatous tumor primarily involving superficial soft tissues. Clinically, SAF typically manifests as a slow-growing, solitary, well-defined nodule or mass. Although these lesions are generally asymptomatic, some cases may present with associated pain, often linked to a history of trauma. SAF lesions commonly exhibit hemispherical, polypoid, or warty growths, with occasional occurrences of ulceration and bleeding.The majority of SAFs express CD34 and CD99, but in the two cases we report, there was diffuse expression of CD34 and focal positive expression of CD68. CD68 positivity suggests a propensity for tumor cells to metastasize to secondary sites. Notably, previously reported cases of single SAF did not display positive CD68 expression, indicating a potential association with other aggressive tumors. However, the current clinical and pathological manifestations do not clarify the diagnosis of additional malignant tumors. Consequently, regular postoperative monitoring of the patient from the aforementioned two cases is essential to detect the presence of other malignant tumors. The significance of CD68-positive expression in this case lies in its potential association with such tumors.Keywords: superficial acral fibromyxoma, immunohistochemistry, CD34, CD68

Shicheng Jiao,1,* Mu Niu,2,* Jie Yang2 1Jiao Shicheng Medical Beauty Clinic, Haikou, Hainan, People’s Republic of China; 2Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Yang, Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, People’s Republic of China, Email 13337564169@163.comAbstract: A 53-year-old male presented to the clinic for “bilateral temporal dark yellow plaques with pruritus for 8 years.” The patient had bilateral temporal dark yellow plaques without obvious inducement 8 years ago and did not see doctors at that time. Five years ago, bilateral temporal skin lesions gradually increased and were accompanied by severe itching. On top of them, there were several blackheads and pimples with the size of needle tips up to the size of rice grains. After compression, lipid substances could be excreted and there was a clear odor. The patient sought medical attention at a local hospital, but the diagnosis and medication were unknown, and the symptoms did not improve. In the past month, due to the aggravation of skin lesions and itching that affected sleep, he visited the outpatient clinic of our hospital again. The patient was diagnosed with nodular elastoidosis with cysts and acne and was given 5% peroxybenzoyl gel and 0.1% tretinoin cream for topical use. After 2 weeks, the itching symptoms of the patient were significantly reduced.Keywords: nodular elastoidosis, cysts, acne

Zhen-Yun Wu,1,&ast; Xiang-Min Lu,2,&ast; Rui Liu,1,&ast; Yan-Xia Han,3 Hong-Ying Qian,1 Qian Zhao,1 Mei’e Niu3 1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2School of Nursing, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 3Department of Nursing, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mei’e Niu, Department of Nursing, the First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, Jiangsu, 215006, People’s Republic of China, Email meniu_123@163.com Qian Zhao, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, No. 188, Shizi Street, Suzhou, Jiangsu, 215006, People’s Republic of China, Email xujiali1983_01@163.comPurpose: This study was designed to investigate the differences in skeletal-muscle atrophy between patients with stable chronic obstructive pulmonary disease (COPD) and healthy controls; associated factors were also considered. The study comprised selected residents of communities near the First Affiliated Hospital of Soochow University in Suzhou City, East China.Patients and Methods: Included in this study were 123 COPD patients and 60 controls. All patients completed spirometry as well as examinations to determine their functional exercise capacity, body composition, and handgrip strength (HGS).Results: COPD patients had less fat-free mass (FFM), a lower FFM index (FFMI), and a lower 6-min walking distance (6MWD) compared with controls (P = 0.007, P = 0.020, and P < 0.001, respectively) (FFMI: 17.59 ± 1.83 vs 18.34 ± 1.64). The HGS of these patients was also lower compared with that of controls (32.88 ± 7.84 vs 35.48 ± 7.42), and HGS tended toward statistical significance (P = 0.064, respectively). In multivariate analysis, age (β = − 0.107, P < 0.001), gender (β = 0.212, P < 0.001), body mass index (BMI) (β = 0.462, P < 0.001), FEV1% (β = 0.108, P = 0.009), and calf circumference (CC) (β = 0.457, P < 0.001) were significantly associated with FFMI.Conclusion: Impaired skeletal muscle mass was more common in COPD patients than in controls. Multiple regression analysis showed that CC may be used to detect the degree of impairment, particularly by health-care providers working outside of the hospital.Keywords: airflow obstruction, calf circumference, chronic obstructive pulmonary disease, fat-free mass index, skeletal muscle atrophy, skeletal muscle mass

Mu Niu,1,&ast; Li-Jun Deng,2,&ast; Rui-Bin Wu,2 Zhen-Zhong Lu2 1Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Affiliated Dermatology Hospital of Hainan Medical University, Haikou, People’s Republic of China; 2Department of Dermatology, Wuzhong People’s Hospital, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui-Bin Wu; Zhen-Zhong Lu, Wuzhong People’s Hospital, Suzhou, People’s Republic of China, Email wrb1968@163.com; enigmaago@163.comAbstract: We present the first case of coma bullae observed in a 67-year-old woman due to pressure and ischemia associated with brachioradial artery. A skin biopsy taken from the ulcer border revealed extensive loss of the epidermis, fibrosis of dermis, mild infiltration by lymphocytes and neutrophils, and necrosis of the focal eccrine ducts. CT angiography of the right upper limb showed a high origin of the radial artery, meanwhile both high originating radial artery and the anastomoses were tortuous and were of relatively small caliber. The diagnosis of coma bullae was made. After tissue debridement, the skin lesions gradually recovered, leaving atrophic scars.Keywords: coma bullae, brachioradial artery

Jie Yang,&ast; Xiaohuan Hu,&ast; Mu Niu, Xiaole Zheng Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mu Niu; Xiaole Zheng, Department of Dermatology, The Fifth People’s Hospital of Hainan Province, No. 8 Longhua Road, Longhua District, Haikou City, Hainan Province, 570206, People’s Republic of China, Email 382219948@qq.com; 23124552@qq.comPurpose: We aimed to report a case of prurigo pigmentosa (PP) with blisters.Patients and Methods: A 21-year-old male patient presented to our hospital with erythema, papules, and blisters all over the front chest and back. Densely distributed round and oval edematous erythema was noted on the neck, front chest, and back of the patient. Histopathologic examination of the skin lesions (blisters) on the chest revealed epidermal cell hyperkeratosis. He was diagnosed with PP and was treated with oral minocycline.Results: After 1-week minocycline administration, the patient’s itching was relieved, and the blisters dried up. His skin lesions recurred following self-withdrawal from the medication; subsequently, the patient was administered oral minocycline treatment again. After 1-month continuous oral treatment, the drug was discontinued. No recurrence of symptoms was noted.Conclusion: Oral minocycline is effective for the treatment of PP.Keywords: prurigo pigmentosa, blister, minocycline, case report

Nan Tang,1,&ast; Qing-An Huang,2,&ast; Lan-Hua Cai,1 Dong-Mei Deng,3 Mu Niu4 1Departments of Traditional Chinese Medicine, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2Department of General Ward, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 3Health Management Center, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 4Department of Cosmetic Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mu Niu, Department of Cosmetic Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, People’s Republic of China, Email 382219948@qq.com Dong-Mei Deng, Health Management Center, The Fifth People’s Hospital of Hainan Province, Haikou, People’s Republic of China, Email m15289975100@163.comAbstract: We describe a 39-year-old woman with a 1-month-old linear erythema diagnosed with cutaneous larva migrans by reflectance confocal microscopy (RCM). This case reveals that the great significance of diagnosing and treating cutaneous larva migrans (CLM) by RCM and dermoscopy, which might provide novel insights into dermatological clinical practice.Keywords: reflectance confocal microscopy, cutaneous larva migrans, linear erythema

Yanxia Han,1,&ast; Zhenyun Wu,1,&ast; Qian Zhao,1 Bo Jiang,2 Xiaolang Miao,2 Xiangmin Lu,2 Hongying Qian,1 Meie Niu1 1Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2School of Nursing, Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meie Niu, Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, 188th, Shizi Street, Suzhou, 215006, People’s Republic of China, Tel +86 13812671786, Email meniu_123@163.comPurpose: Anthropometric indices are simple indicators of patient nutritional status. However, the association between these indices and skeletal-muscle atrophy in patients with stable chronic obstructive pulmonary disease (COPD) has not been fully investigated. In this study, we evaluated this association.Patients and Methods: We recruited 123 outpatients with stable COPD from a general hospital in China from 2020 to 2021. We recorded their demographic characteristics, including age, sex, course of illness, dyspnea score, body mass index (BMI), force expiratory volume in 1 second (FEV1), forced vital capacity (FVC), smoking status, and severity grading. In addition, patients’ anthropometric indices, including fat-free mass index (FFMI) and appendicular skeletal-muscle mass index (ASMI), were measured using a body composition analyzer, and measurements were taken of the triceps skinfold (TSF), midarm circumference (MAC), and calf circumference (CC). We drew and analyzed a receiver operating characteristic (ROC) curve to identify the best intercept point value for the assessment of skeletal-muscle atrophy.Results: The TSF, MAC, CC, FFMI, and ASMI of COPD patients were 1.08 ± 0.44 cm, 26.39 ± 2.92 cm, 34.5 ± 3.06 cm, 17.49 ± 1.86 kg/m2, and 8.17 ± 0.90 kg/m2, respectively. These anthropometric indices had a significant positive correlation with skeletal-muscle mass (correlation values, 0.481– 0.820). CC was strongly correlated with both FFMI and ASMI. The ROC curve showed an area-under-the-curve (AUC) value of 0.873– 0.959.Conclusion: Anthropometric indices were correlated with skeletal-muscle mass. CC showed the best diagnostic value in COPD patients, suggesting its effectiveness as a simple method for assessing skeletal-muscle atrophy and identifying patients with a noticeable reduction in muscle mass. Such patients require early, multidisciplinary intervention.Keywords: fat-free mass, skeletal-muscle mass, chronic obstructive pulmonary disease, anthropometric index, muscle atrophy

Dongmei Deng,1,&ast; Mu Niu,1,&ast; Jie Yang,1 Lijun Deng2 1Department of Cosmetic Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, People’s Republic of China; 2Department of Dermatovenereology, Wuzhong People’s Hospital, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Yang, Department of Cosmetic Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, People’s Republic of China, Email 13337564169@163.com Lijun Deng, Department of Dermatovenereology, Wuzhong People’s Hospital, Suzhou, 215128, People’s Republic of China, Email 474974283@qq.comAbstract: As scrotal simple lymphangioma is a rare benign proliferation of lymphatic vessels in the scrotum, a few reports were documented. A 68-year-old man gradually developed vesicles on the scrotum for ten years and easily ruptured due to friction. Physical examination showed diffuse millet-sized vesicles on the scrotum with milky white fluids and chyle-like exudates. Histopathological examination revealed proliferating and dilated lymphatic vessels with various sizes of lumens in the dermis. An immunohistochemical study showed positive staining for D2-40 and CD31. Therefore, the patient was diagnosed with scrotal lymphangioma and received carbon dioxide laser therapy. After the treatment, the vesicles markedly decreased, and no apparent exudates were observed. During one year of the follow-up, no relapse, scars, or other complications occurred.Keywords: lymphangioma, scrotum, carbon dioxide laser

Haiyang Meng,1 Lu Han,2 Mengxia Niu,3 Lu Xu,4 Min Xu,5 Qi An,1 Jingli Lu1 1Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Pharmacy, Zhengzhou Second People’s Hospital, Zhengzhou, People’s Republic of China; 3Department of Pharmacy, Zhengzhou Western Hospital of Traditional Chinese Medicine, Zhengzhou, People’s Republic of China; 4Department of Clinical Laboratory, Henan Children’s Hospital, Zhengzhou, People’s Republic of China; 5Department of Clinical Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Jingli Lu, Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China, Tel +86-371-66913047, Email lujingli123@163.comBackground: This study aimed to identify risk factors for mortality and outcomes in hematological malignancy (HM) patients with bloodstream infection (BSI) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP).Methods: A retrospective study was conducted at a tertiary teaching hospital in Henan Province, China, between January 2018 and December 2021. All BSIs caused by CRKP in hospitalized HM patients were identified. Data on patient demographics, disease, laboratory tests, treatment regimens, outcomes of infection, and the antimicrobial susceptibility of each isolate were collected from medical records.Results: A total of 129 patients with CRKP BSI were included in the study, and the 28-day mortality rate was 80.6% (104/129). In Cox analysis an absolute neutrophil count < 500 at discharge (hazard ratio [HR] 6.386, 95% confidence interval [CI] 3.074– 13.266, p < 0.001), intensive care unit admission (HR 1.834, 95% CI 1.065– 3.157, p = 0.029), and higher Pitt bacteremia score (HR 1.185, 95% CI 1.118– 1.255, p < 0.001) were independent risk factors associated with 28-day mortality. Survival curve analysis indicated that compared with ceftazidime-avibactam-based therapy, both polymyxin b (HR 8.175, 95% CI 1.099– 60.804, p = 0.040) and tigecycline (HR 14.527, 95% CI 2.000– 105.541, p =0.008) were associated with a higher risk of mortality.Conclusion: In HM patients CRKP BSI resulted in high mortality. Intensive care unit admission, higher Pitt bacteremia score, and absolute neutrophil count < 500 at discharge were independently associated with higher mortality. Early initiation of new agents such as ceftazidime-avibactam may improve outcomes.Keywords: bloodstream infection, carbapenem-resistant Klebsiella pneumonia, hematological malignancy, risk factor

Shuyi Li,1 Mengke Niu,2 Wenying Deng,1 Ning Li,1 Chen Wei,1 Chi Zhang,1 Suxia Luo1 1Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People’s Republic of China; 2Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People’s Republic of ChinaCorrespondence: Suxia LuoDepartment of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450008, Henan Province, People’s Republic of ChinaTel +86 371 65587805Email zlyyluosuxia0361@zzu.edu.cnBackground: Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare liver tumor, and there is no clear therapeutic recommendation for patients with advanced PHNEC. This study aims to compare the efficacy of platinum-based chemotherapy (etoposide combined with cisplatin/carboplatin, EP/EC) and transcatheter arterial chemoembolization (TACE) in patients with advanced PHNEC, and to evaluate the relevant prognostic factors.Patients and Methods: The clinical data of 41 patients with advanced PHNEC from June 2014 to October 2019 were retrospectively reviewed.Results: At a median follow-up time of 13.9 months, the median overall survival (OS) was 14.8 months in the EP/EC group and 12.2 months in the TACE group (P = 0.040). The median progression-free survival (PFS) was 4.4 months and 2.7 months in the EP/EC group and the TACE group, respectively (P = 0.005). No significant differences in the overall response rate and disease control rate were observed between the EP/EC group and the TACE group (26.1% vs 11.1%, P = 0.429; 73.9% vs 44.4%, P = 0.055, respectively). A univariate analysis indicated that the Eastern Cooperative Oncology Group performance status (ECOG PS), Ki-67, tumor number, and treatment options were prognostic factors for OS. A multivariate analysis further showed that ECOG PS (P < 0.001), Ki-67 (P = 0.003), and treatment options (P = 0.022) were independent prognostic factors for OS.Conclusion: Ki-67, ECOG PS, and treatment options were the independent prognostic factors for OS in patients with advanced PHNEC. EP/EC may be a better choice for patients with advanced PHNEC.Keywords: chemotherapy, transcatheter arterial chemoembolization, hepatic neuroendocrine carcinoma, prognosis

Zhenfeng Huang,1,&ast; Shiyang Jin,1,&ast; Mengyao Zeng,2,&ast; Jing Shu,1 Yang Liu,1 Jinxing Zhang,1 Bingqi Xu,1 Ming Niu,1 Shanshan Sun,1 Abiyasi Nanding,3 Xiaobo Li,3 Ming Shan,4 Guoqiang Zhang4 1Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, People’s Republic of China; 2Department of Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 3Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, People’s Republic of China; 4 20th Floor Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Shan; Guoqiang Zhang Email shanming@ems.hrbmu.edu.cn; zhangguoqiang@hrbmu.edu.cnPurpose: To determine clinical predictors of recurrence and metastasis in patients with pathological complete response (pCR) after neoadjuvant chemotherapy (NCT).Methods: Patients treated with NCT who achieved pCR (n=285) were classified into three groups according to pre-NCT clinical stage (cStage): group I (IIa–IIb), group II (IIIa), and group III (IIIb–IIIc). Survival was analysed using the Kaplan–Meier method. The relationships between clinicopathological factors and recurrence were determined using Cox regression analysis.Results: The median follow-up was 31 months. The 3-year disease-free survival and overall survival rates in groups I, II, and III were 92.7%, 87.8%, and 66.7% (P < 0.01) and 98.6%, 98.3%, and 90.6% (P=0.370), respectively. Lymph node status and tumour size were independent risk factors for recurrence and metastasis after NCT. In the human epidermal growth factor receptor 2-positive subgroup, advanced cStage and lymph node metastasis were associated with recurrence (P < 0.01). In the hormone receptor-positive subgroup, disease-free survival rates differed for cStages I–II compared to cStage III (P=0.049) and clinical node status 0– 2 compared to clinical node status 3 (P=0.037).Conclusion: Pre-NCT cStage predicted the prognosis of pCR for different breast cancer subtypes. Patients with advanced cStage, lymph node metastasis, and large tumour sizes had a higher risk of recurrence or metastasis.Keywords: breast cancer, HER2, neoadjuvant chemotherapy, pathological complete response, prognosis

Jie Zhang,1,&ast; Jinghua Jiao,2,&ast; Meng Niu,3,&ast; Xiaotong Gao,4 Guisen Zhang,5 Honghua Yu,6,&ast; Xiaohong Yang,6 Lei Liu6,7 1Department of Ophthalmology, Weifang Eye Hospital, Weifang, 261041, People’s Republic of China; 2Department of Anesthesiology, Central Hospital, Shenyang Medical College, Shenyang, 110024, People’s Republic of China; 3Department of Radiology, First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 4Department of Endocrinology and Metabolism and the Institute of Endocrinology, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 5Department of Retina, Inner Mongolia Chaoju Eye Hospital, Hohhot, 010050, People’s Republic of China; 6Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences; School of Medicine, South China University of Technology, Guangzhou, 510120, People’s Republic of China; 7Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohong Yang; Lei Liu Email syyangxh@scut.edu.cn; liuleijiao@163.comAbstract: The complex drug delivery barrier in the eye reduces the bioavailability of many drugs, resulting in poor therapeutic effects. It is necessary to investigate new drugs through appropriate delivery routes and vehicles. Nanotechnology has utilized various nano-carriers to develop potential ocular drug delivery techniques that interact with the ocular mucosa, prolong the retention time of drugs in the eye, and increase permeability. Additionally, nano-carriers such as liposomes, nanoparticles, nano-suspensions, nano-micelles, and nano-emulsions have grown in popularity as an effective theranostic application to combat different microbial superbugs. In this review, we summarize the nano-carrier based drug delivery system developments over the last decade, particularly review the biology, methodology, approaches, and clinical applications of nano-carrier based drug delivery system in the field of ocular therapeutics. Furthermore, this review addresses upcoming challenges, and provides an outlook on potential future trends of nano-carrier-based drug delivery approaches in ophthalmology, and hopes to eventually provide successful applications for treating ocular diseases.Keywords: nano-carrier, nanomedicine, ocular disease, drug delivery system

Can Tu,1,2 Ming Niu,2 Ai-Wu Wei,3 Jin-Fa Tang,3 Le Zhang,2 Jing Jing,2 Xiao-He Xiao,2 Jia-Bo Wang2,4 1Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 3The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, People’s Republic of China; 4School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Jia-Bo WangSchool of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, People’s Republic of ChinaEmail pharm_sci@126.comXiao-He XiaoChina Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of ChinaEmail pharmacy302xxh@126.comBackground: Drug-induced liver injury is a common adverse effect in clinical practice, with severe cases resulting in liver failure and even death. Identification and prediction of individuals susceptible to idiosyncratic DILI continues to remain a challenge.Methods: In this study, we report that cytokines in human serum can be used to identify and predict individuals susceptible to Polygonum multiflorum-induced DILI (PM-DILI) in retrospective and prospective cohort studies.Findings: In the retrospective pilot study, we compared serum cytokine expression profiles of the PM-DILI group (n=10) and the PM-Tolerant group (n=12) and found 10 cytokines with significant differences. In the replication cohort study, differences in the 10 cytokines between PM-DILI (n =11) and PM-Tolerant (n=13) groups were verified. Among them, 6 cytokines showed no significant differences at two time points, including liver injury and recovery stage of PM-DILI, suggesting that these 6 cytokines have no correlation with PM-DILI, however, they may be related to susceptibility. Furthermore, all the retrospective cohorts were combined, and a PM-DILI susceptibility prediction model was built by screening the 6 cytokines. The combination of (TNF-α and CCL-2) or VEGF showed the highest sensitivity and specificity. Finally, the efficacy of the above 3 cytokine combination models in predicting PM-DILI-susceptible individuals was verified before PM exposure in another independent prospective cohort (n=24), with sensitivity and specificity of 66.7% and 83.3%, respectively.Conclusion: This proof-of-concept study demonstrates that the serum cytokine combination reflecting dysimmunity could be used as a new method to predict PM-DILI, thus providing a new perspective for improving the clinical management of IDILI.Keywords: drug-induced liver injury, Polygonum multiflorum, cytokine, prediction, susceptible individual

Jiejie Lu, Weiwei Wu, Ming Zhang, Ping Wang, Mu Niu, Xianxu Yang Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Branch of National Clinical Research Center for Skin and Immune Disease, Haikou, Hainan, People’s Republic of ChinaCorrespondence: Mu Niu; Xianxu YangDepartment of Dermatology, The Fifth People’s Hospital of Hainan Province, Branch of National Clinical Research Center for Skin and Immune Disease, No. 33, Southern Road of Longkun, Qiongshan District, Haikou, 570206, Hainan, People’s Republic of ChinaTel +86-18389485160; +86-13876300372Fax +86-898-66729550; +86-898-66729550Email 382219948@qq.com; 13876300372@139.comAbstract: Wells syndrome (WS), also known as eosinophilic cellulitis, is a rare inflammatory dermatosis of unknown etiology that typically presents with pruritic cellulitis-like plaques. The first line treatment options for WS are topical or systemic corticosteroids, however, the development of side effects of systemic corticosteroids usually led to a switch to the second line therapy. Here, we reported a rare case of facial Wells syndrome misdiagnosed with bacterial cellulitis. A 26-year-old female presented with a one-week history of erythematous, edematous and blushing plaques partially covered by bullae. A skin biopsy revealed diffuse infiltration of eosinophils in the entire dermis and “flame figures” compatible with WS. Initially, the patient was successfully treated with methylprednisolone. However, three month later, the disease relapsed. Because of weight gain and centripetal obesity, the patient refused to oral administration of methylprednisolone. Traditional Chinese Medicine tripterygium glycosides (TG) 60mg/day was prescribed and the lesions completely resolved after 4 weeks without any recurrence. Our case suggests that tripterygium glycosides may be a safe and effective treatment option for Wells syndrome.Keywords: Wells syndrome, tripterygium glycosides, facial cellulitis

Yaqin Wang,1,2,* Wenting Shang,2,* Meng Niu,1 Jie Tian,2,3 Ke Xu11Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Chinese Academy of Sciences Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China; 3Institute of Medical Interdisciplinary Innovation, Beihang University, Beijing, 100080, People’s Republic of China*These authors contributed equally to this workAbstract: Hypoxia is a hallmark of malignant tumors and often correlates with increasing tumor aggressiveness and poor treatment outcomes. Therefore, early diagnosis and effective killing of hypoxic tumor cells are crucial for successful tumor control. There has been a surge of interdisciplinary research aimed at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. These mainly include hypoxia-active nanoparticles, anti-hypoxia agents, and agents that target biomarkers of tumor hypoxia. Hypoxia-active nanoparticles have been intensively investigated and have demonstrated advanced effects on targeting tumor hypoxia. In this review, we present an overview of the reports published to date on hypoxia-activated prodrugs and their nanoparticle forms used in tumor-targeted therapy. Hypoxia-responsive nanoparticles are inactive during blood circulation and normal physiological conditions but are activated by hypoxia once they extravasate into the hypoxic tumor microenvironment. Their use can enhance the efficiency of tumor chemotherapy, radiotherapy, fluorescence and photoacoustic intensity, and other imaging and therapeutic strategies. By targeting the broad habitats of tumors, rather than tumor-specific receptors, this strategy has the potential to overcome the problem of tumor heterogeneity and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.Keywords: prodrug, tumor microenvironment, metal complex, bioreductive

Mao Niu,1,* Xianling Feng,2,* Lei Zhou3 1Department of Stomatology, School of Medical Technology and Nursing, Shenzhen Polytechnic, Shenzhen, 518055, China; 2Department of Pathology, School of Medical, Shenzhen University, Shenzhen, 518060, China; 3Center of Oral Implantology, Guangdong Provincial Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China *These authors contributed equally to this work and should be considered as co-first authors Objectives: The present study aimed to clarify the role of the ERK1/2 pathway in simvastatin (SV)-loaded nanomicelles (SVNs)- and SV-mediated promotion of cell osteogenic differentiation and explore the molecular mechanisms by which SVNs exhibited a greater efficacy in promoting osteogenic differentiation than SV.Materials and methods: SVNs were synthesized using a dialysis method. MG63 cells were treated with 2.5, 0.25, and 0.025 µmol/L of the drug. The optimal drug dosage was determined by examining the proliferative activity and ALP activity of the MG63 cells. Subsequently, Western blot analysis was performed to analyze the levels of the phosphorylated ERK1/2 proteins in each experimental group at various time points. Finally, the inhibitor PD98059 was used to effectively inhibit the ERK1/2 pathway. The resulting changes in the proliferative activity of MG63 cells and the osteogenesis-related markers were analyzed.Results: The SVNs synthesized in the present study had a mean diameter of 27 nm. The encapsulation and drug-loading efficiencies were 52.03% ± 4.05% and 9.42% ± 0.66%, respectively. SVNs and SV exhibited optimum osteogenesis-promoting effects when the drugs were administered at a concentration of 0.25 µmol/L. The drug-induced activation of the ERK1/2 pathway reached a peak at 15 minutes after administration and then declined rapidly. From 24 hours to 7 days, SVNs and SV exerted an inhibitory effect on the ERK1/2 pathway rather than an activating effect. Throughout the whole experimental process, the regulatory effect of SVNs on the ERK1/2 pathway was significantly greater than that of SV. Inhibition of the ERK1/2 pathway by PD98059 markedly reduced the proliferative activity of the cells in all experimental groups. In addition, the ALP activity and the expression levels of the osterix (OSX) and osteocalcin (OC) proteins were drastically increased.Conclusion: SVNs significantly increased the effect of SV-induced osteogenic differentiation by strongly inhibiting the ERK1/2 pathway.Keywords: simvastatin-loaded nanomicelles, ERK1/2 pathway, dental implant restoration, osteogenic effect

Lei Wang,1–3 Dong Li,1,2 Yongwei Hao,1,2 Mengya Niu,1,2 Yujie Hu,1,2 Hongjuan Zhao,1,2 Junbiao Chang,2,3 Zhenzhong Zhang,1,2 Yun Zhang1,2 1School of Pharmaceutical Sciences, Zhengzhou University, 2Key Laboratory of Targeting Therapy and Diagnosis for Critical Disease, Henan Province, 3School of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, People’s Republic of China Abstract: Recently, photothermal therapy has become a promising strategy in tumor treatment. However, the therapeutic effect was seriously hampered by the low tissue penetration of laser. Therefore, in this study, radiofrequency (RF) with better tissue penetration was used for tumor hyperthermia. First, one type of gold nanorods (AuNRs) suitable for RF hyperthermia was selected. Then, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with AuNRs and docetaxel (DTX) (PLGA/AuNR/DTX) NPs were constructed. Finally, manganese dioxide (MnO2) ultrathin nanofilms were coated on the surfaces of PLGA/AuNR/DTX NPs by the reduction of KMnO4 to construct the PLGA/AuNR/DTX@MnO2 drug delivery system. This drug delivery system can not only be used for the combined therapy of chemotherapy and RF hyperthermia but can also produce Mn2+ to enable magnetic resonance imaging. Furthermore, the RF hyperthermia and the degradation of MnO2 can significantly promote the controlled drug release in a tumor region. The in vitro and in vivo results suggested that the PLGA/AuNR/DTX@MnO2 multifunctional drug delivery system is a promising nanoplatform for effective cancer theranostic applications. Keywords: poly(lactic-co-glycolic acid), gold nanorod, manganese dioxide, radiofrequency, hyperthermia, dual-mode imaging, controlled release

Shizhang Wei,1,2 Ming Niu,3 Jian Wang,2 Jiabo Wang,3 Haibin Su,4 Shengqiang Luo,5 Xiaomei Zhang,2,6 Yanlei Guo,6 Liping Liu,1 Fengqun Liu,1 Qingguo Zhao,1 Hongge Chen,1 Xiaohe Xiao,3 Pan Zhao,4,7 Yanling Zhao1,2 1Department of Pharmacy, 302 Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 2Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3China Military Institute of Chinese Medicine, 302 Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 4Liver Failure Therapy and Research Center, 302 Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 5Department of Integrative Medical Center, 302 Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 6Chong Qing Academy of Chinese Traditional Materia Medica, Key Laboratory of Chongqing TCM Resources, Chongqing, People’s Republic of China; 7Clinical Trial Center, 302 Hospital of People’s Liberation Army, Beijing, People’s Republic of China Ethnopharmacological relevance: San-Cao Granule (SCG) has been used in patients with liver fibrosis for many years and has shown good effect. However, its mechanism of therapeutic action is not clear because of its complex chemical system. The purpose of our study is to establish a comprehensive and systemic method that can predict the mechanism of action of SCG in antihepatic fibrosis.Materials and methods: In this study, a “compound–target–disease” network was constructed by combining the SCG-specific and liver fibrosis–specific target proteins with protein–protein interactions, and network pharmacology was used to screen out the underlying targets and mechanisms of SCG for treatment of liver fibrosis. Then, some key molecules of the enriched pathway were chosen to verify the effects of SCG on liver fibrosis induced by thioacetamide (TAA).Results: This systematic approach had successfully revealed that 16 targets related to 11 SCG compounds were closely associated with liver fibrosis therapy. The pathway-enrichment analysis of them showed that the TGF-β1/Smad signaling pathway is relatively important. Animal experiments also proved that SCG could significantly ameliorate liver fibrosis by inhibiting the TGF-β1/Smad pathway.Conclusion: SCG could alleviate liver fibrosis through the molecular mechanisms predicted by network pharmacology. Furthermore, network pharmacology could provide deep insight into the pharmacological mechanisms of Chinese herbal formulas. Keywords: San-Cao Granule, network pharmacology, liver fibrosis, TAA

Mengmeng Niu1, Yi Lu1, Lars Hovgaard2, Wei Wu11School of Pharmacy, Fudan University, Shanghai, People's Republic of China; 2Oral Formulation Development, Novo Nordisk A/S, Maalov, DenmarkBackground: Oral delivery of insulin is challenging and must overcome the barriers of gastric and enzymatic degradation as well as low permeation across the intestinal epithelium. The present study aimed to develop a liposomal delivery system containing glycocholate as an enzyme inhibitor and permeation enhancer for oral insulin delivery.Methods: Liposomes containing sodium glycocholate were prepared by a reversed-phase evaporation method followed by homogenization. The particle size and entrapment efficiency of recombinant human insulin (rhINS)-loaded sodium glycocholate liposomes can be easily adjusted by tuning the homogenization parameters, phospholipid:sodium glycocholate ratio, insulin:phospholipid ratio, water:ether volume ratio, interior water phase pH, and the hydration buffer pH.Results: The optimal formulation showed an insulin entrapment efficiency of 30% ± 2% and a particle size of 154 ± 18 nm. A conformational study by circular dichroism spectroscopy and a bioactivity study confirmed the preserved integrity of rhINS against preparative stress. Transmission electron micrographs revealed a nearly spherical and deformed structure with discernable lamella for sodium glycocholate liposomes. Sodium glycocholate liposomes showed better protection of insulin against enzymatic degradation by pepsin, trypsin, and a-chymotrypsin than liposomes containing the bile salt counterparts of sodium taurocholate and sodium deoxycholate.Conclusion: Sodium glycocholate liposomes showed promising in vitro characteristics and have the potential to be able to deliver insulin orally.Keywords: liposomes, glycocholate, insulin, enzymatic degradation, oral

Peipei Guan1, Yi Lu1, Jianping Qi1, Mengmeng Niu1, Ruyue Lian1, Fuqiang Hu2, Wei Wu11School of Pharmacy, Fudan University, Shanghai, People's Republic of China; 2School of Pharmacy, Zhejiang University, Hangzhou, People's Republic of ChinaAbstract: The main purpose of this study was to evaluate liposomes containing a bile salt, sodium deoxycholate (SDC), as oral drug delivery systems to enhance the oral bioavailability of the poorly water-soluble and poorly permeable drug, cyclosporine A (CyA). Liposomes composed of soybean phosphatidylcholine (SPC) and SDC were prepared by a thin-film dispersion method followed by homogenization. Several properties of the liposomes including particle size, polydispersity index, and entrapment efficiency were characterized. The in vitro release of CyA from these liposomes was less than 5% at 12 hours as measured by a dynamic dialysis method. The pharmacokinetic results in rats showed improved absorption of CyA in SPC/SDC liposomes, compared with CyA-loaded conventional SPC/cholesterol (Chol) liposomes and microemulsion-based Sandimmune Neoral®. The relative oral bioavailability of CyA-loaded SPC/SDC and SPC/Chol liposomes was 120.3% and 98.6%, respectively, with Sandimmun Neoral as the reference. The enhanced bioavailability of CyA was probably due to facilitated absorption by the liposomes containing SDC rather than improved release rate.Keywords: liposomes, bile salt, sodium deoxycholate, cyclosporine A, oral bioavailability

Yashi Ruan,1,&ast; Lixia Guan,2,&ast; Yuting Wang,2 Yifei Geng,2 Xiaoran Wang,2 Miao-Miao Niu,2 Li Yang,1 Cen Xu,1 Zhen Xu1 1Department of Urology, Reproductive Medicine and Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, People’s Republic of China; 2Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Yang; Cen Xu, Department of Urology, Reproductive Medicine and Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, People’s Republic of China, Email proyangli@163.com; cenxu263128@163.comPurpose: Dual inhibition of ataxia telangiectasia mutated (ATM) and histone deacetylase 2 (HDAC2) may be a potential strategy to improve antitumor efficacy in testicular cancer.Methods: A combined virtual screening protocol including pharmacophore modeling and molecular docking was used for screening potent dual-target ATM/HDAC2 inhibitors. In order to obtain the optimal lead compound, the dual ATM/HDAC2 inhibitory activity of the screened compounds was further evaluated using enzyme inhibition methods. The binding stability of the optimal compound to the dual targets was verified by molecular dynamics (MD) simulation. MTT assay and in vivo antitumor experiment were performed to validate antitumor efficacy of the optimal compound in testicular cancer.Results: Here, we successfully discovered six potent dual-target ATM/HDAC2 inhibitors (AMHs 1– 6), which exhibited good inhibitory activity against both ATM and HDAC2. Among them, AMH-4 showed strong inhibitory activity against both ATM (IC50 = 1.12 ± 0.03 nM) and HDAC2 (IC50 = 3.04 ± 0.08 nM). MD simulation indicated that AMH-4 binds to ATM and HDAC2 with satisfactory stability. Importantly, AMH-4 had significant antiproliferative activity on human testicular tumor cells, especially NTERA-2 cL.D1 cells, and no inhibitory effect on normal human testicular cells. In vivo experiments exhibited that AMH-4 was more effective than lartesertib and vorinostat in inhibiting the growth of NTERA-2 cL.D1 xenograft tumors with low toxicity.Conclusion: Overall, these results suggest that AMH-4 is an effective and low toxicity candidate for the treatment of testicular germ cell tumors.Keywords: ataxia telangiectasia mutated, histone deacetylase 2, dual-targeting inhibitors, testicular germ cell tumors, structure-based virtual screening

Ying Liu,1,* Man He,1,* Mengmeng Niu,1 Yiqing Zhao,1 Yuanzhang Zhu,1 Zhenhua Li,2 Nianping Feng1 1Department of Pharmaceutical Sciences, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Cedars-Sinai Medical Center, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Rapid drug release at the specific site of action is still a challenge for antitumor therapy. Development of stimuli-responsive hybrid nanocarriers provides a promising strategy to enhance therapeutic effects by combining the unique features of each component. The present study explored the use of drug–gold nanoparticle conjugates incorporated into liposomes to enhance antitumor efficiency. A model drug, vincristine sulfate, was physically conjugated with gold nanoparticles and verified by UV-visible and fourier transform infrared spectroscopy, and differential scanning calorimetry. The conjugates were incorporated into liposomes by film dispersion to yield nanoparticles (113.4 nm) with light-responsive release properties, as shown by in vitro release studies. Intracellular uptake and distribution was studied in HeLa cells using transmission electron microscopy and confocal laser scanning microscopy. This demonstrated liposome internalization and localization in endosomal–lysosomal vesicles. Fluorescence intensity increased in cells exposed to UV light, indicating that this stimulated intracellular drug release; this finding was confirmed by quantitative analyses using flow cytometry. Antitumor efficacy was evaluated in HeLa cells, both in culture and in implants in vivo in nude mice. HeLa cell viability assays showed that light exposure enhanced liposome cytotoxicity and induction of apoptosis. Furthermore, treatment with the prepared liposomes coupled with UV light exposure produced greater antitumor effects in nude mice and reduced side effects, as compared with free vincristine sulfate. Keywords: vincristine sulfate, vincristine sulfate–gold nanoparticle conjugates, liposomes, antitumor efficiency, light triggered drug release