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Fangbing Tian,1 Nana Xie,1 Wenjin Sun,2 Wencong Zhang,1 Wenyuan Zhang,1 Jia Chen,1 Qiurong Ruan,3,* Jianxin Song1,* 1Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Infectious Diseases, Ezhou Central Hospital, Ezhou, People’s Republic of China; 3Institute of Pathology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianxin Song, Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email songsingsjx@sina.com Qiurong Ruan, Institute of Pathology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email ruanqiurong@sina.comPurpose: Hemophagocytic lymphohistiocytosis (HLH) is a critical syndrome with a high mortality rate. In clinical practice, some patients with fever of unknown origin (FUO) can develop HLH, further complicating the diagnosis and treatment. However, studies on HLH in adults with FUO are limited. This study aimed to investigate the clinical characteristics of adult patients with FUO to facilitate the early identification of those at high risk of developing HLH.Patients and Methods: We collected data from hospitalized patients with FUO between January 2014 and December 2020. Risk factors for HLH in adults with FUO were analyzed using univariate and multivariate analysis.Results: A total of 988 patients with FUO were included in the study. The incidence of HLH in adults with FUO was 6.4%, with hematological tumors being the primary cause. Multivariate analysis indicated that skin rash and elevated alanine aminotransferase, total bilirubin, triglycerides, lactate dehydrogenase, and ferritin levels were independent risk factors for HLH in adults with FUO.Conclusion: This study revealed the incidence rate, etiology distribution, and risk factors for HLH in adults with FUO. Comprehensive assessment of clinical and laboratory data at admission can assist in the early identification of FUO patients at risk for HLH.Keywords: Hemophagocytic lymphohistiocytosis, fever of unknown origin, etiology distribution, risk factors

Zhaolin Zhang,1,* Yongbin Wang,2,* Yifeng Zhou,1 Jiachao Pei,1 Guoan Zhao,1,3 Pingshuan Dong,4 Kan Yang,5 Hui Liu,6 Na Xie,7 Xuefang Li,3 Xiayan Zang,3 Fei Lin,1,3 Zhigang Chen1 1Department of Cardiology,The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, People’s Republic of China; 2Department of Epidemiology and Health Statistics, Xinxiang Medical University, Xinxiang, 453003, People’s Republic of China; 3Henan Engineering Technology Research Center of Environmental Meteorological Medicine, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, People’s Republic of China; 4Department of Cardiology,The First Affiliated Hospital of Henan University of Science and Technology, Luoyan, 471000, People’s Republic of China; 5Department of Cardiology,Nanyang Central Hospital, Nanyang, 473005, People’s Republic of China; 6Department of Cardiology,Anyang District Hospital, Anyang, 455000, People’s Republic of China; 7Department of Cardiology,The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fei Lin; Zhigang Chen, Department of Cardiology,The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui, Henan, People’s Republic of China, Tel +86 18567557937, Email 1fy2000129@xxmu.edu.cn; 1fy2015157@xxmu.edu.cnPurpose: The effect of the diurnal temperature range (DTR) on human health in diverse geographic areas and the potential confounding factors are not fully understood. Additionally, while a robust association has been reported between temperature and cardiomyopathy (CM), evidence of the impact of DTR is relatively limited. Here, we determined whether an association exists between DTR and CM hospitalisations in vulnerable populations.Methods: CM admission data (2016– 2021) were collected from seven tertiary hospitals in Henan.We used a GAM combined with a distributed lag non-linear model (DLNM) to investigate the delayed effects of DTR on daily hospitalisations for CM.Stratified analysis was performed in subgroups according to sex, age, and season. Attributable fractions (AF) and attributable numbers (AN) were employed to illustrate the disease burden and investigate the association between temperature and DTR.Results: Overall, 5,757 CM cases were identified. DTR and CM admissions exhibited a non-linear correlation. High DTR (P95: 15.5 °C) and low DTR (P05: 3 °C) increased CM admission risk, with low DTR having a stronger effect. Males and warm seasons were significantly more susceptible to DTR, and low DTR affected youth and adults more than older adults. AF and AN of low DTR on CM admissions were 51% and 2,936, respectively.Conclusion: Our results revealed a significant association between DTR and CM hospitalisations, providing valuable insights for the development targeted prevention and control measures.Keywords: cardiomyopathy, diurnal temperature range, distributed lag non-linear model, time-series

Yujie Wang,1 Tingting Deng,1 Xi Liu,2 Xueyang Fang,1 Yongpan Mo,3 Ni Xie,4 Guohui Nie,1 Bin Zhang,1 Xiaoqin Fan1,4 1Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Department of Otolaryngology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, 518035, People’s Republic of China; 2Department of Nephrology, Shenzhen Longgang Central Hospital, Shenzhen, 518116, People’s Republic of China; 3Department of Breast Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, 518035, People’s Republic of China; 4The Bio-Bank of Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, 518035, People’s Republic of ChinaCorrespondence: Bin Zhang; Xiaoqin Fan, Email binzhang@email.szu.edu.cn; fanxiaoqin83@163.comAbstract: The tumor microenvironment (TME) is a complex and dynamic entity, comprising stromal cells, immune cells, blood vessels and extracellular matrix, which is intimately associated with the occurrence and development of cancers, as well as their therapy. Utilizing the shared characteristics of tumors, such as an acidic environment, enzymes and hypoxia, researchers have developed a promising cancer therapy strategy known as responsive release of nano-loaded drugs, specifically targeted at tumor tissues or cells. In this comprehensive review, we provide an in-depth overview of the current fundamentals and state-of-the-art intelligent strategies of TME-responsive nanoplatforms, which include acidic pH, high GSH levels, high-level adenosine triphosphate, overexpressed enzymes, hypoxia and reductive environment. Additionally, we showcase the latest advancements in TME-responsive nanoparticles. In conclusion, we thoroughly examine the immediate challenges and prospects of TME-responsive nanopharmaceuticals, with the expectation that the progress of these targeted nanoformulations will enable the exploitation, overcoming or modulation of the TME, ultimately leading to significantly more effective cancer therapy. Keywords: tumor microenvironment, stimulus-responsive, drug delivery, cancer therapy, intelligent biomedicine

Lvwen Ning,1,2 Ni Xie1 1Biobank, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, People’s Republic of China; 2Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of ChinaCorrespondence: Ni Xie, Email xn100@szu.edu.cnBackground: The Sirtuin (SIRT) family consists of seven evolutionary conserved NAD-dependent deacetylases that play important roles in various cancers, including breast cancer (BC). SIRTs expression has been reported to have prognostic value in BC, but these studies used limited sample size and yielded inconsistent conclusions. This study evaluated the association of SIRT3 and other SIRT family members with survival and neoadjuvant chemotherapy outcomes.Methods: BC patients’ data was obtained from the TCGA-BRCA, METABRIC and GEO databases, comprising 4336 samples. SIRTs expression and overall survival (OS) were analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. SIRT3 expression levels were compared between pathologic complete response (pCR) and non-pCR groups after neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Protein-protein interaction networks were constructed using the STRING database. Gene set enrichment analysis (GSEA) was performed to explore potential functions of SIRT3.Results: Through systematic analysis of SIRTs expression and OS of BC using three independent cohorts: TCGA-BRCA, METABRIC and GSE16446, we found that high SIRT3 expression was significantly associated with worse OS in TNBC in the TCGA-BRCA cohort, which was validated in the METABRIC and GSE16446 cohorts. SIRT3 expression was correlated with BC subtypes and American Joint Committee on Cancer (AJCC) T stage, but not with age-at-diagnosis, race, or tumor stage. Moreover, TNBC patients with higher SIRT3 expression had lower pCR rates after neoadjuvant chemotherapy (p = 6.40e-03) and SIRT3 expression was significantly lower in the pCR group than in the non-pCR group in TNBC (p = 4.2e-03). GSEA indicated that SIRT3 was involved in drug-related pathways such as oxidative phosphorylation, metabolism of xenobiotics by cytochrome P450, and drug metabolism.Conclusion: Our study suggests that SIRT3 is a potential biomarker for both OS and neoadjuvant chemosensitivity in TNBC. It may also assist in selecting suitable candidates and treatment options for TNBC patients.Keywords: SIRT3, biomarker, breast cancer, neoadjuvant chemotherapy, prognosis

Fangqing Zhu,1 Sheng Li,2 Qiuping Gu,1 Ningsheng Xie,1 Yinxia Wu3 1Department of Gastroenterology, Ganzhou People’s Hospital, Ganzhou, Jiangxi, 341000, People’s Republic of China; 2Department of Gastroenterology, Yuebei People’s Hospital, Shantou University Medical College, Shaoguan, Guangdong, 512026, People’s Republic of China; 3Department of Rehabilitation, Ganzhou People’s Hospital, Ganzhou, Jiangxi, 341000, People’s Republic of ChinaCorrespondence: Fangqing Zhu; Yinxia Wu, Email wanliqingkong0707@163.com; xiaflora0608@163.comBackground: Pyroptosis is a form of proinfammatory gasdermin-mediated programmed cell death. Abnormal infammation in the intestine is a critical risk factor for Ulcerative colitis (UC). However, at present, it is not clear whether pyroptosis of colonic fibroblasts is involved in the pathogenesis and progression of UC.Methods: In this study, key genes associated with UC were identified by bioinformatics analysis. Datasets were downloaded from the Gene Expression Omnibus (GEO) database (GSE193677). The differentially expressed genes were analyzed, and the hub genes were screened by weighted gene co-expression network analysis (WGCNA) and differentially expressed genes. We also downloaded the dataset from GEO for single-cell RNA sequencing (GSE231993). The expression of key genes was verified by immunohistochemistry, immunofluorescence and Western blot, and the specific pathways of key genes inducing pyroptosis in cell lines were explored.Results: The results of bioinformatics analysis showed that the expression of APOL1 and CXCL1 in UC tissues was significantly higher than that in normal tissues. The results of single-cell analysis showed that the two genes were co-localized to fibroblasts. These results were consistent with the results of immunohistochemistry and immunofluorescence colocalization in human intestinal mucosa specimens. Furthermore, APOL1 overexpression induced NLRP3-caspase1-GSDMD-mediated pyroptosis of fibroblasts, which was confirmed by Western blot.Conclusion: APOL1 induces pyroptosis of fibroblasts mediated by NLRP3-Caspase1-GSDMD signaling pathway and promote the release of chemokines CXCL1. Fibroblasts may play a crucial role in the pathogenesis and progression of UC.Keywords: apolipoprotein L1, pyroptosis, fibroblasts, gasdermin-D, Ulcerative colitis

Qin Huo, Lvwen Ning, Ni Xie Biobank, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University, Shenzhen, People’s Republic of ChinaCorrespondence: Ni Xie, Biobank, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University, No. 3002 Sungang West Road, Futian District, Shenzhen, 518035, People’s Republic of China, Tel +86 1 350 158 0802, Fax +86 7 558 300 3435, Email xn100@szu.edu.cnPurpose: Granzyme A (GZMA) is a potential prognostic target for various cancer types. However, its therapeutic significance in breast cancer with immune infiltration remains controversial. We analyzed GZMA expression and its prognostic value in breast cancer with immune cell infiltration.Patients and methods: Data was obtained from patients with breast cancer registered at The Cancer Genome Atlas. A correlation was performed between GZMA expression and patient’s clinicopathological features such as age, pathologic stage, metastasis stage, overall survival (OS), disease-specific survival (DSS), and progress free interval (PFI). Kaplan-Meier analyses and Cox proportional hazard regression model were used to examine the predictive significance of GZMA expression for breast cancer. The co-expression pattern of GZMA was assessed by the LinkedOmics web portal. The relationship between GZMA expression and immune cells was analyzed using the TIMER database. The correlation between GZMA and lymphocytes and immunomodulators was established with the TISIDB database.Results: There was a lower GZMA expression in breast cancer tissue than in normal tissue. Interestingly, GZMA expression was associated with age, pathologic stage, and the Tumour, Node, and Metastasis stage. Overexpression of GZMA was also associated with better OS, DSS, and PFI. Based on the Cox regression analysis, GZMA was identified as an independent favorable prognostic factor for breast cancer. Our findings demonstrated a strong association between GZMA and T-cell checkpoints (PD-1, PD-L1, and cytotoxic T lymphocyte-associated antigen (CTLA-4)) in breast cancer. Moreover, we evaluated the interactions between GZMA expression and markers of dendritic and CD8+ T cells using quantitative immunofluorescence. We discovered that increased infiltration of dendritic and CD8+ T cells was associated with GZMA expression in breast cancer.Conclusion: GZMA expression is associated with a favorable prognosis in breast cancer and is significantly correlated with immune cell infiltration. GZMA may be considered a promising therapeutic target for patients with breast cancer.Keywords: GZMA, expression, prognostic factor, immune infiltration, breast cancer

Yi-Zi Zheng,1,* Jia-Ying Li,2,3,* Lv-Wen Ning,3 Ni Xie3 1Department of Thyroid and Breast Surgery, Shenzhen Breast Tumor Research Center for Diagnosis and Treatment, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China; 2Hengyang Medical School, University of South China, Hengyang, Hunan, People’s Republic of China; 3Biobank, First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ni Xie, Biobank, First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen University, 3002 Sungang West Road, Shenzhen, 518035, Guangdong, People’s Republic of China, Tel +86-13501580802, Fax +86-0755-83003435, Email xn100@szu.edu.cnIntroduction: Tripartite motif-containing protein (TRIM) family members play crucial roles in carcinogenesis and chemotherapy resistance. In this study, we aimed to determine whether TRIM58 protein expression is related to patient responses to neoadjuvant therapy (NAT) and their survival outcome.Methods: Immunohistochemistry was performed on female breast cancer samples from biopsies before NAT in Shenzhen Second People’s Hospital. Univariate and multivariate logistic regression tests were used to analyze the association between TRIM58 protein expression and pathological complete response (pCR). The Cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) with a 95% confidence interval (95% CI). The Kaplan–Meier plotter database was used to analyze the prognostic value of TRIM58.Results: High TRIM58 expression was associated with small tumor size in all the patients (n = 58). Multivariate analysis suggested that low TRIM58 expression was an independent predictive factor for higher pCR (odds ratio = 0.06, 95% CI 0.005– 0.741, P = 0.028). The Kaplan–Meier Plotter dataset suggested that the TRIM58 high-expression group showed a worse 5-year overall survival than the low-expression group (HR = 1.34, 95% CI 1.07– 1.67, P = 0.01). Pathway analysis revealed the potential mechanisms of TRIM58 in chemoresistance.Discussion: Our study suggests that TRIM58 is a promising biomarker for both neoadjuvant chemosensitivity and long-term clinical outcomes in breast cancer. It may also help to identify candidate responders and determine treatment strategies.Keywords: chemosensitivity, pathological complete response, biomarker, patient stratification, predictive diagnostics

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

Jialang Zhuang,1,2,* Siqi Chen,1,3,* Ye Hu,1 Fan Yang,1 Qin Huo,1 Ni Xie1 1Biobank, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China; 2Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518035, People’s Republic of China; 3Graduate School of Guangzhou Medical University, Guangzhou, 510182, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ni Xie Email xn100@szu.edu.cnIntroduction: Metastatic breast cancer seriously harms women’s health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects.Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds.Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis.Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.Keywords: drug delivery, mesoporous silica nanoparticles, DNA aptamer, controlled release, metastatic breast cancer

Na Xie,1 Lifang Jiang,1 Mingtao Chen,1 Guijun Zhang,1 Yanyan Liu,2 Jiabin Li,2 Xiaohui Huang1 1Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Xiaohui HuangDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province, 230032, People’s Republic of ChinaTel +86 138 5518 3138Email math2088@163.comJiabin LiDepartment of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Jixi Road, 218#, Hefei, Anhui Province, 230032, People’s Republic of ChinaFax +86 551 62922713Email lijiabin@ahmu.edu.cnObjective: The purpose of this study is to assess the in vitro/vivo activities of linezolid plus fosfomycin against Staphylococcus aureus (S. aureus) isolates with varying susceptibility to the study drugs.Methods: The increasing concentration stepwise method was used to induce S. aureus resistant strains. The in vitro antibacterial activity of linezolid combined with fosfomycin against S. aureus in vitro was studied by time-kill curve and PAE. The transmission electron microscopy (TEM) was employed to observe the cell morphology of bacteria treated with drug, and the changes of cell wall thickness were recorded. The Galleria mellonella infection model was established to demonstrate the in vivo efficacy of linezolid and fosfomycin against S. aureus with varying susceptibility.Results: The antibiotic combination showed excellent synergistic or additive effects on the original and the linezolid-resistant strain, but showed indifferent effect for fosfomycin-resistant strain. TEM images showed that fosfomycin alone and in combined could reduce the cell wall thickness of the strains resistant to linezolid and cell lysis, while linezolid increases the cell wall thickness of the strains resistant to fosfomycin. In the Galleria mellonella infection model, the survival rate of the antibiotic combined was improved compared with that of the single drug. There was a good correlation between in vivo efficacy and in vitro susceptibility.Conclusion: The type of interaction expressed in the test combination was highly dependent on fosfomycin resistance.Keywords: linezolid, fosfomycin, interaction, resistant, Staphylococcus aureus, Galleria mellonella

Chuanhao Jiang,1,2,* Ning Xie,3,* Taoli Sun,4 Wanjun Ma,2 Bikui Zhang,2 Wenqun Li2 1Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, People’s Republic of China; 3Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, People’s Republic of China; 4Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha, Hunan 410219, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenqun Li Email liwq1204@csu.edu.cnBackground: Xanthohumol (Xn) is the most abundant prenylated flavonoid in Hops (Humulus lupulus L.), and exhibits a range of pharmacological activities. This study aimed to investigate the effect of Xn on TGF-β 1-induced cardiac fibroblasts activation and elucidate the underlying mechanism.Materials and Methods: The cellTiter 96® AQueous one solution cell proliferation assay kit was adopted to determine the cell viability of cardiac fibroblasts, and the proliferation was detected through 5-ethynyl-2ʹ-deoxyuridine (EdU) incorporation assay. The α-SMA protein expression was measured by using immunofluorescence and Western blotting. Western blotting was conducted to test the protein expressions of collagen I and III, PTEN, p-Akt, Akt, p-mTOR, mTOR, p-Smad3, Smad3 and GAPDH. The mRNA levels of α-SMA, collagen I and III were determined by quantitative real-time polymerase chain reaction (PCR).Results: Xn inhibited the TGF-β 1-induced proliferation, differentiation and collagen overproduction of cardiac fibroblasts. TGF-β 1 induced the down-regulated PTEN expression, Akt and mTOR phosphorylation. These effects of TGF-β 1 were suppressed by Xn, while blocking of PTEN reduced Xn-mediated inhibitory effect on cardiac fibroblasts activation induced by TGF-β 1.Conclusion: Xn inhibits TGF-β 1-induced cardiac fibroblasts activation via mediating PTEN/Akt/mTOR signaling pathway.Keywords: xanthohumol; Xn, cardiac fibrosis, cardiac fibroblasts, TGF-β 1, PTEN/AKT/mTOR pathway

Ning Xie,1,* Tao Qin,1,* Wei Ren,1 Herui Yao,1,2 Yunfang Yu,1 Huangming Hong1 1Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People’s Republic of China; 2Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunfang Yu; Huangming Hong Tel +86-20-34071337Fax +86-20-81332833Email yunfangyu@foxmail.com; honghm3@mail.sysu.edu.cnPurpose: To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib).Materials and Methods: This study based on randomized Phase 2 or 3 trials of CDKi plus ET compared with placebo plus ET for women with HR+/HER2−ABC and identify relevant randomized clinical trials (RCTs) published prior to February 2020. The primary endpoint was progression-free survival (PFS), the secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit response (CBR) and safety. The PROSPERO registry number is 42018081105.Results: The results from eight trials including 4580 participants were pooled. Evidence indicated that the PFS of CDKi group was significantly prolonged (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50– 0.60, P < 0.01) compared with placebo group. The ORR and CBR were better (risk ratio [RR] 1.47, 95% CI 1.30– 1.67, P < 0.01; 1.24, 95% CI 1.15– 1.35, P < 0.01) in the CDKi group. The OS of CDKi group (HR 0.75, 95% CI 0.67– 0.85, P < 0.01) was significantly longer than ET alone. Subgroup analyses confirmed that the benefit was consistent across most subgroups. Subgroup analyses showed no statistically significant difference of PFS among three CDKi: palbociclib vs ribociclib (HR 0.55, 95% CI 0.49– 0.60, P = 0.34), palbociclib vs abemaciclib (HR 0.53, 95% CI, 0.47– 0.59, P = 0.61), and ribociclib vs abemaciclib (HR 0.56, 95% CI, 0.51– 0.62, P = 0.72). Treatment-related grade 3 or 4 hematologic adverse events (AEs) were more frequently in CDKi group.Conclusion: CDKi combined with ET can significantly prolong PFS and improve the ORR, CBR and OS in patients with HR+/HER2− ABC. However, the advantage of different CDKi has not been established.Keywords: CDK4/6 inhibitor, HR-positive, HER2-negative, advanced breast cancer

Zhuang J, Chen S, Hu Y, Yang F, Huo Q, Xie N. Int J Nanomedicine. 2021;16:1691—1976. At the authors request, The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised following the authors request to remove images of lung metastatic nodules from Figure 7C. It was found images in Figure 7D appeared to have been duplicated with those from a similar article from the first author, Jialang Zhuang et al. Utilizing a high-throughput microdevice to study breast tumor cells clustering and metastasis, Analytica Chimica Acta 1151, 2021 (https://doi.org/10.1016/j.aca.2021.338222). Specifically, Figure 7D Saline, appears to have been duplicated with the same image in Figure 3F MDA-MB-231 Control, from Jialang Zhuang et al, 2021. Figure 7D MSN@Dox+siTIE2, appears to have been duplicated with the same image in Figure 3F MDA-MB-231 SB273005, from Jialang Zhuang et al, 2021. Figure 7D MSN-siTIE2/Apt@Dox, appears to have been duplicated with the same image in Figure 3F MCF-7, from Jialang Zhuang et al, 2021. The authors responded to our queries and explained the images were mistakenly duplicated during figure preparation by the first author, who accepts responsibility for this error. The authors provided data for the study, but it was not satisfactory. Both the Editor and authors agreed to retract the article and the authors wish to apologize for this error. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Ping Li,1–3,* Jian Wang,4,* Desheng Wu,3 Xiaohu Ren,3 Wen Wu,2,3 Ran Zuo,2 Qingbo Zeng,3 Bingyu Wang,2 Xi He,1 Jianhui Yuan,2,5 Ni Xie1,21Biobank, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, People’s Republic of China; 2Department of Medicine, University of South China, Hengyang 421001, People’s Republic of China; 3Department of Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen 518035, People’s Republic of China; 4Department of Thoracic Surgery, The Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China; 5Department of Occupational Health, Shenzhen Nanshan District Center for Disease Control and Prevention, Shenzhen 518054, People’s Republic of ChinaCorrespondence: Ni XieBiobank Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, No. 3002 Sungang West Road, Futian District, Shenzhen 518035, People’s Republic of ChinaTel +86 1 350 158 0802Fax +86 7 558 300 3435Email xn100@szu.edu.cnJianhui YuanDepartment of Occupational Health, Shenzhen Nanshan District Center for Disease Control and Prevention, No. 95 Nanshang Road, Nanshan District, Shenzhen 518054, People’s Republic of ChinaTel +86 1 350 158 0509Fax +86 7 558 300 3435Email jianhui_yuan@126.com*These authors contributed equally to this workPurpose: Lung cancer is one of the most life-threatening cancer worldwide with poor prognosis attributed to the lack of early diagnosis and proper therapy. The estrogen-related receptor alpha (ERRα) is a multifunctional protein not limited to bind ligands and has been reported to be associated with numerous cancers. This study aimed to investigate the potential role of ERRα in lung cancer and to provide a novel perspective for lung cancer early diagnosis, targeted therapy, and prognosis assessment.Methods: The correlation between ERRα mRNA expression and survival time of the online clinical data about lung cancer was analyzed by using Kaplan–Meier (KM) plotter. A mouse model of lung adenocarcinoma (LUAD) was constructed to detect the expression level of ERRα in tumor tissues. ERRα-knockdown LUAD cells were generated and the impacts of ERRα on cell proliferation, invasion, and metastasis were further analyzed. Cancerous and paracancerous tissues were collected to semi-quantitative the levels of ERRα in LUAD clinical samples (n=88), combined with clinical information for prognostic analysis.Results: The KM plotter analysis suggested that ERRα is correlated with poor prognosis in LUAD (n=720) rather than in lung squamous cell carcinoma (LSCC) (n=524). ERRα is also upregulated in tumor tissues obtained from LUAD model mice. Quantitative analysis suggested an abnormal elevation of ERRα in LUAD cells rather than in LSCC cells. The results demonstrated that downregulation of ERRα impairs proliferation, invasion and migration abilities (P

Yongsheng Su,1 Jian Hu,1 Zhibin Huang,1 Yubin Huang,1 Bingsheng Peng,1 Ni Xie,2 Hui Liu1 1Department of Burn and Plastic Surgery, The People’s Hospital of Baoan Shenzhen Affiliated to Southern Medical University, 2Core Laboratory, Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, People’s Republic of China Abstract: Malignant melanoma (MM) is the most dangerous type of skin cancer with annually increasing incidence and death rates. However, chemotherapy for MM is restricted by low topical drug concentration and multidrug resistance. In order to surmount the limitation and to enhance the therapeutic effect on MM, a new nanoformulation of paclitaxel (PTX)-loaded cholic acid (CA)-functionalized star-shaped poly(lactide-co-glycolide) (PLGA)-d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (NPs) (shortly PTX-loaded CA-PLGA-TPGS NPs) was fabricated by a modified method of nanoprecipitation. The particle size, zeta potential, morphology, drug release profile, drug encapsulation efficiency, and loading content of PTX-loaded NPs were detected. As shown by confocal laser scanning, NPs loaded with coumarin-6 were internalized by human melanoma cell line A875. The cellular uptake efficiency of CA-PLGA-TPGS NPs was higher than those of PLGA NPs and PLGA-TPGS NPs. The antitumor effects of PTX-loaded NPs were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that star-shaped PTX-loaded CA-PLGA-TPGS NPs were significantly superior to commercial PTX formulation Taxol®. Such drug delivery nanocarriers are potentially applicable to the improvement of clinical MM therapy. Keywords: malignant melanoma, paclitaxel, nanoparticles, enhanced therapeutic effects, drug delivery