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Qiang Shao,1,2,* Ying Zhang,2,* Zhiyuan Zhang,2 Wei Jiang,2 Yongcheng Yin,3 Yuepeng Fang,1 Ce Zhang,1 Qingfa Chen,2 Bin Ning1,2 1Cheeloo College of Medicine, Jinan Central Hospital, Shandong University, Jinan, People’s Republic of China; 2Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 3School of Clinical Medicine, Shandong Second Medical University, Weifang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin Ning; Qingfa Chen, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan, Shandong, 250013, People’s Republic of China, Tel +86-18866510349, Email bning@sdfmu.edu.cn; tsingfachan@163.comBackground: Post-spinal cord injury (SCI) inflammation correlates with neurologic recovery. Through sequencing, we explored the roles of a differentially expressed circRNA in mice after SCI, circGla, on inflammation and recovery of SCI.Methods: The T8–T10 SCI model was established in C57BL6 mice. HE staining and RT-qPCR verified circGla upregulation results after injury obtained through sequencing. RNase R digestion and primer amplification experiments confirmed the circular properties of circGla. Nucleus and cytoplasm isolation experiments and FISH confirmed circGla expression in the astrocyte cytoplasm. AAV was used to establish a circGla knockdown mouse model. Behavioral tests were conducted to assess the recovery of the neurological function. The key inflammatory molecules after SCI were evaluated through MRI, RT-qPCR, and ELISA. For in vitro experiments, circGla was upregulated or knocked down in mouse astrocytes to detect its effect. The binding between miR-488 and circGla was confirmed through RIP and the dual luciferase experiment. RT-qPCR and ELISA confirmed the content correlation of the two molecules and the in vitro inflammatory function of miR-488. The binding experiment in astrocytes confirmed the binding between miR-488 and MEKK1 mRNA. Western blotting of MAPK pathway-related proteins confirmed that MEKK1 is a downstream effector for circGla and miR-488 in astrocytes.Results: Following SCI, the circular RNA circGla levels increased and it existed in the astrocyte cytoplasm. circGla knockdown reduced inflammation and improved neurological recovery in vivo. The correlation between circGla and proinflammatory factors was confirmed in vitro. circGla bound to miR-488, and the high miR-488 level was associated with the low astrocyte inflammatory state. miR-488 bound to MEKK1 mRNA, and upregulation or knockdown of circGla or miR-488 affected MAPK pathway-related protein expression.Conclusion: Following SCI, downregulation of circGla expression in astrocytes can reduce inflammatory manifestations and stimulate long-term functional recovery in mice through miR-488 and MEKK1. Keywords: non-coding RNAs, inflammation, competing endogenous RNAs, traumatic spinal cord injury, secondary injury

Abstract Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery. We identify an oral commensal strain of Lactobacillus plantarum with an intrinsic cancer-binding mechanism and engineer the strain to enable the surface loading of anticancer prodrugs, with nasopharyngeal carcinoma (NPC) as a model cancer. The engineered commensals show specific binding to NPC via OppA-mediated recognition of surface heparan sulfate, and the loaded prodrugs are activated by tumor-associated biosignals to release SN-38, a chemotherapy compound, near NPC. In vitro experiments demonstrate that the prodrug-loaded microbes significantly increase the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered L. plantarum leads to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%.

Abstract Chemoselective modification of specific residues within a given protein poses a significant challenge, as the microenvironment of amino acid residues in proteins is variable. Developing a universal molecular platform with tunable chemical warheads can provide powerful tools for precisely labeling specific amino acids in proteins. Cysteine and lysine are hot targets for chemoselective modification, but current cysteine/lysine‐selective warheads face challenges due to cross‐reactivity and unstable reaction products. In this study, a versatile fluorescent platform is developed for highly selective modification of cysteine/lysine under biocompatible conditions. Chloro‐ or phenoxy‐substituted NBSe derivatives effectively labeled cysteine residues in the cellular proteome with high specificity. This finding also led to the development of phenoxy‐NBSe phototheragnostic for the diagnosis and activatable photodynamic therapy of GSH‐overexpressed cancer cells. Conversely, alkoxy‐NBSe derivatives are engineered to selectively react with lysine residues in the cellular environment, exhibiting excellent anti‐interfering ability against thiols. Leveraging a proximity‐driven approach, alkoxy‐NBSe probes are successfully designed to demonstrate their utility in bioimaging of lysine deacetylase activity. This study also achieves integrating a small photosensitizer into lysine residues of proteins in a regioselective manner, achieving photoablation of cancer cells activated by overexpressed proteins.

Shao C, Cheng C, Shao Q, Chen B. Int J Gen Med. 2021;14:3497–3509. We, the Editor and Publisher of the journal International Journal of General Medicine have retracted the published article. Following publication of the article, concerns were raised that the images used in Figure 3 were not taken from stomach adenocarcinoma (STAD) tissue or cancer cell lines as described. Specifically, The two immunohistochemical images of stomach adenocarcinoma (STAD) tissue for Figure 3A are not STAD tissues but are labelled as thyroid cancer tissues on the website (https://www.proteinatlas.org/ENSG00000182492-BGN/pathology/thyroid+cancer#img). The image used for Figure 3C does not show a cancer cell line, as stated in the figure legend, but an image from a normal human foreskin fibroblast cell line (BJ) as described on the website (https://www.proteinatlas.org/ENSG00000182492-BGN/subcellular#img). The corresponding author did not respond to our queries and was unable to provide a satisfactory explanation for how the images came to be incorrectly used or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Limin Tang,1 Min Sha,2 Ting Guo,2 Huimin Lu,2 Jingyu Qian,2 Qixiang Shao,1 Jun Ye2 1Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 2Department of Central Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, People’s Republic of ChinaCorrespondence: Jun Ye, Department of Central Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 399 Hailing Road, Taizhou, Jiangsu, 225300, People’s Republic of China, Tel +86-13625171902, Email m13625171902@163.comPurpose: The roles of T cell immunoreceptor with Ig and ITIM domains (TIGIT) in the diagnosis of primary breast cancer (PBC) are still unclear. This study was designed to investigate the expression of TIGIT in PBC patients, with an aim to analyze its diagnostic value in PBC.Patients and Methods: We first explore the expression of TIGIT in cancer patients based on TCGA database, and then we analyzed its correlation with clinicopathological features. Afterwards, we compared the protein and mRNA expressions of TIGIT in two BC cell lines (MCF-7 and MDA-MB-231) and normal breast epithelial cell line (MCF-10A). Subsequently, 56 PBC female patients admitted to the Taizhou People’s Hospital from October 2018 to June 2021 were included in this study. Flow cytometry was used to detect TIGIT level on peripheral blood CD3+ T cells of PBC patients and healthy controls. TIGIT expression in PBC tissues was detected by immunohistochemistry (IHC) and immunofluorescence staining.Results: TCGA database showed that compared with adjacent tissues, TIGIT was significantly upregulated in tumor tissues. High TIGIT expression was positively correlated with tumor stage and negatively correlated with recurrence free survival (RFS) and overall survival (OS). TIGIT level in BC cell lines, peripheral blood and tumor tissues of PBC patients was significantly higher than that of control (P < 0.05). TIGIT level was correlated with age (P < 0.05), rather than tumor size, pathological type, lymph node metastasis, ER, PR, HER-2, and P53. ROC curve showed that the optimal critical value of peripheral blood TIGIT for BC screening was 23.38%. Postoperative TIGIT level in peripheral blood was significantly decreased compared to the preoperative TIGIT level (P < 0.05).Conclusion: TIGIT was upregulated in PBC and was correlated with age. It may be a potential target for the diagnosis and immunotherapy of PBC.Keywords: TIGIT, primary breast cancer, immune checkpoint, tumor immunity, bioinformatics analysis

Ningning Zhang,1 Dan Tao,2 Haike Lei,3 Qing Shao,1 Yumin Liu,4 Hua Long,4 Xiaohua Zeng1 1Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 2Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 3Department of Appointment and Follow-up Center, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 4Department of Medical Record, Chongqing University Cancer Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Xiaohua Zeng, Department of Breast Cancer Center, Chongqing University Cancer Hospital, 181 Han Yu Road, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel/Fax +86-23-65310859, Email zxiaohuacqu@126.comPurpose: This study aimed to evaluate the influence of hepatitis B virus (HBV) infection status on the initial metastatic pattern and prognosis in metastatic breast cancer (MBC).Methods: MBC patients admitted to Chongqing University Cancer Hospital between January 2011 and December 2019 were enrolled. The association of HBV infection status with clinicopathological features was analyzed. The impact of HBV infection status on initial metastatic pattern and survival was evaluated.Results: A total of 1124 patients with MBC, including 310 with de novo (cohort A) and 814 with relapsed metastatic disease (cohort B), were eligible for this study. Seropositive HBsAg was identified in 28 (9.0%) and 68 (8.4%) patients in cohort A and B, respectively. The clinicopathological features are similar between HBsAg-positive and HBsAg-negative patients. There was no significant association of HBV infection status with the rate of metastasis at each site in de novo and relapsed MBC. HBsAg-positive patients tended to have longer metastasis-free survival (MFS) and/or overall survival (OS) time, but it was not the independent prognostic factor.Conclusion: In conclusion, HBV infection status does not influence the initial metastatic pattern and the prognosis of MBC patients.Keywords: hepatitis B virus, infection status, metastatic breast cancer, initial metastatic pattern, prognosis

A resurging interest in targeted covalent inhibitors (TCIs) focus on compounds capable of irreversibly reacting with nucleophilic amino acids in a druggable target. p97 is an emerging protein target for cancer therapy, viral infections and neurodegenerative diseases. Extensive efforts were devoted to the development of p97 inhibitors. The most promising inhibitor of p97 was in phase 1 clinical trials, but failed due to the off-target-induced toxicity, suggesting the selective inhibitors of p97 are highly needed. We report herein a new type of TCIs (i.e., FL-18) that showed proteome-wide selectivity towards p97. Equipped with a Michael acceptor and a basic imidazole, FL-18 showed potent inhibition towards U87MG tumor cells, and in proteome-wide profiling, selectively modified endogenous p97 as confirmed by in situ fluorescence scanning, label-free quantitative proteomics and functional validations. FL-18 selectively modified cysteine residues located within the D2 ATP site of p97. This covalent labeling of cysteine residue in p97 was verified by LC‒MS/MS-based site-mapping and site-directed mutagenesis. Further structure–activity relationship (SAR) studies with FL-18 analogs were established. Collectively, FL-18 is the first known small-molecule TCI capable of covalent engagement of p97 with proteome-wide selectivity, thus providing a promising scaffold for cancer therapy.

Xiaochen Yang,1,2 Yangjing Zhao,3 Qixiang Shao,3 Guoqin Jiang1 1Department of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu Province, People’s Republic of China; 2Department of Thyroid and Breast Surgery, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, 215300, Jiangsu Province, People’s Republic of China; 3Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu Province, People’s Republic of ChinaCorrespondence: Guoqin JiangDepartment of Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, People’s Republic of ChinaTel/Fax +86-512-67784797Email jiang_guoqin@suda.edu.cnQixiang ShaoJiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, People’s Republic of ChinaTel +86-511-80961661Fax +86-511-86102010Email shao_qx@ujs.edu.cnPurpose: Cytochrome b561 (CYB561) is a transmembrane protein and participates in ascorbate recycling and iron homeostasis. However, its role in breast cancer remains unclear.Patients and Methods: In this study, we explored the expression pattern and prognostic value of CYB561 in breast cancer through The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), PrognoScan and Kaplan–Meier Plotter and confirmed its mRNA expression in human breast cell lines. LinkedOmics, Metascape and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were applied to investigate the co-expression genes and construct microRNA (miRNA) networks associated with CYB561. The correlations between CYB561 and immune infiltration cells and genes were also illustrated.Results: The CYB561 expression was upregulated in breast cancer tissues and cell lines and significantly correlated with the clinical features of breast cancer patients. High CYB561 expression was associated with poor survival and was an independent risk factor for overall and disease-specific survival. Functional enrichment analysis showed that CYB561 and its co-expressed genes were mainly enriched in lipid biosynthetic process, Wnt signaling pathway, Hippo signaling pathway, etc. The miRNA network analysis suggested that hsa-miR-497 was negatively correlated with CYB561 expression and was predicted to direct target CYB561. CYB561 expression was positively correlated with infiltrating levels of CD4+ T cells, neutrophils and dendritic cells in breast cancer. Subsequent analysis found that B cells could predict the outcome of breast cancer. Also, CYB561 showed strong correlations with diverse immune marker sets in breast cancer.Conclusion: CYB561 may serve as a potential prognostic biomarker and target for breast cancer. Our findings laid foundation for future research on molecular mechanisms of CYB561 in breast cancer.Keywords: cytochrome b561, breast cancer, prognosis, biomarker, immune infiltrates

Changming Shao,1,&ast; Chunfa Cheng,2,&ast; Qinshu Shao,3 Bing Chen1 1Department of Vascular Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, Zhejiang, People’s Republic of China; 2Department of Vascular Surgery, The First People’s Hospital of Yuhang District, Hangzhou, 311100, Zhejiang, People’s Republic of China; 3Department of General Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, 310009, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bing ChenDepartment of Vascular Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 1511 Jianghong Road, Binjiang District, Hangzhou, 310000, Zhejiang, People’s Republic of ChinaEmail 2114008@zju.edu.cnQinshu ShaoDepartment of General Surgery, Zhejiang Provincial People’s Hospital, 158 Shangtang Road, Xiacheng District, Hangzhou, 310009, Zhejiang, People’s Republic of ChinaEmail chmshao@126.comObjective: Previous studies have confirmed the biglycan (BGN) as a core gene in stomach adenocarcinoma (STAD). Present study aimed at conducting further investigations to reveal the potential function of BGN in STAD.Methods: The mRNA and protein expressions of BGN in STAD were firstly evaluated, followed by immune infiltration analyses. The influence of BGN expression on the overall survival of STAD patients was subsequently analyzed, and a restrict survival analysis was performed as well. The protein–protein interaction (PPI) network analysis on the co-expressed genes with BGN was finally adopted to obtain the most important module in the whole network, and significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway associated with hub genes within the main module was further predicted.Results: (1) We verified the mRNA high expression of BGN in STAD (all P< 0.05), and higher expression was observed in patients with stage 4 (P< 0.001) and grade 3 (P< 0.001). The BGN protein was mainly localized to the golgi apparatus, and protein expression displayed an individual difference. (2) Immune infiltration analysis showed the strongest correlation between BGN expression and abundance of natural killer cell (P< 0.001), Transforming Growth Factor beta 1 (TGFB1) (P< 0.001), TNF Receptor Superfamily Member 4 (TNFRSF4) (P< 0.001) and C-X-C Motif Chemokine Ligand 12 (CXCL12) (P< 0.001) in STAD. BGN expression was also correlated to immune subtypes (P=0.0347) and molecular subtypes (P=0.0263) in STAD. (3) High expression of BGN shortened the overall survival time of STAD patients (all P< 0.01). The influence of BGN expression on the prognosis was statistically affected by several clinical phenotypes and cohorts of patients. Cox regression showed that BGN can be considered as a prognostic predictor of STAD (P< 0.05). (4) Pathway analysis indicated that BGN possibly participated in ECM–receptor interaction, focal adhesion, human papillomavirus infection and PI3K-Akt signaling pathway (all P< 0.001).Conclusion: BGN was highly expressed in STAD, implying a poor prognosis of patients. Relevant signal pathways associated with BGN were distinguished as well. BGN could be used as a potential therapeutic biomarker for STAD.Keywords: biglycan, stomach adenocarcinoma, high expression, immune infiltration, prognosis

Leyi Ma,1,&ast; Fan Wu,1,&ast; Qingqing Shao,1 Guang Chen,2 Lijun Xu,1 Fuer Lu1 1Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fuer Lu Email felu@tjh.tjmu.edu.cnBackground: Oxidative stress and inflammation play essential roles in the development and progression of diabetic nephropathy (DN). Baicalin (BAI), a natural flavonoid, has been showed to have a renoprotective effect in various renal diseases. However, its underlying mechanisms in DN remain unclear. In this study, we explored the potential effects and underlying mechanisms of BAI on DN using a spontaneous DN model.Methods: The protective effects of BAI on DN have been evaluated by detecting DN-related biochemical indicators, kidney histopathology and cell apoptosis. After that, we examined the level of renal oxidative stress and inflammation to explain BAI’s renoprotective effects. Then, Nrf2 pathway was tested to clarify its antioxidant activity, and kidney transcriptomics was conducted to elucidate its anti-inflammatory activity. Finally, Western blot was applied for final mechanism verification.Results: Our results found that BAI effectively ameliorated diabetic conditions, proteinuria, renal histopathological changes and cell apoptosis in DN. BAI significantly improved the kidney levels of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT), and reduced malondialdehyde (MDA) level. Meanwhile, the infiltration of inflammatory cells including T-lymphocytes, T-helper cells, neutrophils and macrophages, and the mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, MCP-1 and TNFα) were also obviously inhibited by BAI. Afterward, Western blot found that BAI significantly activated Nrf2 signaling and increased the expression of downstream antioxidant enzymes (HO-1, NQO-1). Kidney transcriptomics revealed that the inhibition of MAPK signaling pathway may contribute to BAI’s anti-inflammatory activity, which has also been verified in later experiment. BAI treatment did obviously inhibit the activation of canonical pro-inflammatory signaling pathway MAPK family, such as Erk1/2, JNK and P38.Conclusion: In summary, our data demonstrated that BAI can treat DN by alleviating oxidative stress and inflammation, and its underlying mechanisms were associated with the activation of Nrf2-mediated antioxidant signaling pathway and the inhibition of MAPK-mediated inflammatory signaling pathway.Keywords: baicalin, diabetic nephropathy, oxidative stress, inflammation, Nrf2, MAPK

Deqiang Luo,1,2 Fen Liu,1 Jianguo Zhang,1 Qiang Shao,1 Wenqiang Tao,1 Rui Xiao,1 Wei Dai,2 Chengzhi Ding,1 Kejian Qian1 1Department of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330000, People’s Republic of China; 2Department of Intensive Care Unit, The Fifth People’s Hospital of Shangrao City, Shangrao, 334000, People’s Republic of ChinaCorrespondence: Kejian QianDepartment of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Dong Lake District, Nanchang, Jiangxi Province, 330000, People’s Republic of ChinaEmail ndyfyicu@email.ncu.edu.cnPurpose: To explore the molecular mechanism and search for candidate lncRNA and mRNA associated with pyroptosis in the gene expression profile of LPS-induced acute lung injury (ALI).Methods: We investigated lncRNA and mRNA expression in lipopolysaccharide (LPS)-induced ALI at an early stage. RNA sequencing (RNA-Seq) was carried out to analyze lncRNA and mRNA expression profiles between the LPS-induced and control groups. We used bioinformatics analysis to predict target genes of early differential lncRNAs among obtained the differential mRNAs.Results: A total of 78 lncRNAs and 248 mRNAs were upregulated at 2 hours and downregulated at 9 hours, and 21 lncRNAs and 107 mRNAs were downregulated at 2 and upregulated at 9 hours in early ALI models. We predicted 7 cis-and trans-regulated target genes of the top 20 lncRNAs. Gene Ontology (GO) analysis indicated that the target genes for the screened lncRNAs were most enriched in three-terms: regulation of protein serine/threonine kinase activity, pertussis, and cellular response to LPS. Additionally, target genes of lncRNAs were the top three enriched in pertussis, osteoclast differentiation, and cAMP signaling pathways with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We also identified vital mRNAs and lncRNAs. Protein-protein interaction (PPI) network analysis suggested that Tnf, Jun, and Atf3 were the top three key genes. Hub lncRNA4344 (NONRATT004344.2) and cis-regulated target mRNA (NLRP3) were validated in vitro. Finally, luciferase assay results confirmed that lncRNA4344 sponged miR‐138-5p to promote pyroptosis in inflammatory responses to LPS‐induced acute lung injury by targeting NLRP3.Conclusion: Based on analysis of lncRNA and mRNA expression profiles by RNA-Seq and experimental verification, this study is the first to reveal that lncRNA4344 sponged miR‐138-5p to promote pyroptosis in inflammatory responses of LPS‐induced acute lung injury by targeting NLRP3. These newly identified lncRNA, miRNA, and mRNA might be novel potential targets for early treatment and prevention in early ALI.Keywords: acute lung injury, alveolar macrophage, ceRNA network long noncoding RNAs, pyroptosis, RNA sequencing

As a powerful tool to advance drug discovery, molecular imaging may provide new insights into the process of drug effect and therapy at cellular and molecular levels. When compared with other detection methods, fluorescence-based strategies are highly attractive and can be used to illuminate pathways of drugs’ transport, with multi-color capacity, high specificity and good sensitivity. The conjugates of fluorescent molecules and therapeutic agents create exciting avenues for real-time monitoring of drug delivery and distribution, both in vitro and in vivo. In this short review, we discuss recent developments of small molecule-based fluorophore-drug conjugates, including non-cleavable and cleavable ones, that are capable of visualizing drug delivery.

Xuanxuan Jing,1,* Chen Li,1,2,* Jintang Sun,1 Jin Peng,3 Yu Dou,4 Xiaofei Xu,3 Chao Ma,1 Zhaogang Dong,5 Yanguo Liu,6 Hui Zhang,3 Qianqian Shao,1 Hui Zhang,7 Lijie Wang,3 Yun Zhang,1 Xun Qu1 1Institute of Basic Medical Sciences, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic China; 2Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People’s Republic of China; 3Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China; 4Department of Stomatology and Institute of Stomatology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic China; 5Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic China; 6Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China; 7Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xun Qu; Lijie Wang Email quxun@sdu.edu.cn; wangljie@hotmail.comPurpose: The aim of this study was to find the most useful marker of endometriosis-related infertility and evaluate predictive and diagnostic values of systemic inflammatory response markers (preoperative white blood–cell subtypes, neutrophil:lymphocyte ratio [NLR], platelet:lymphocyte ratio [PLR], and monocyte:lymphocyte ratio [MLR]) and CA125 levels in endometriosis patients.Methods: This study comprised 662 women who had undergone laparoscopic surgery and been pathologically confirmed as having endometriosis and 83 patients pathologically confirmed with benign ovarian tumors. Related inflammatory factors in endometriosis complicated by infertility were analyzed via logistic regression analysis. Diagnostic values of the inflammatory response markers were obtained by receiver operating–characteristic analysis.Results: We firstly identified that lower NLR level was an independent risk factor of infertility. Serum lymphocytes were significantly higher in endometriosis patients, while serum CA125, NLR, MLR, and PLR were elevated. For differentiating endometriosis from other benign ovarian tumors, the combination of NLR and CA125 achieved greater sensitivity than CA125 alone. In addition, both CA125 and NLR were positively correlated with stage, oviduct adhesion, and diameter of ovarian ectopic cysts.Conclusion: NLR may be used as a simple and easily obtained predictive marker for endometriosis with infertility. Moreover, NLR can be a neoadjuvant biomarker for serum CA125 to diagnose endometriosis.Keywords: endometriosis, endometrioma, uterine leiomyoma, infertility, NLR, PLR, CA125

Fang Wang,1,2 Jia-Bin Lu,3 Xiao-Yan Wu,2 Yan-Fen Feng,1,3 Qiong Shao,2 Xin An,4 Hai-Yun Wang1,21State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 2Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 3Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China; 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of ChinaBackground: Large-cell lung carcinomas (LCLCs) were reclassified by the World Health Organization 2015 criteria. and remain fairly unknown at the molecular level and targeted-therapeutic options.Methods: Data of 184 lung cancer patients were retrieved from clinical records, of which 54 were found to be pathologically diagnosed as LCLC. The genetic alterations EGFR/KRAS/BRAF mutations, MET copy number, and exon 14 mutation, ALK and ROS1 rearrangements, and PDL1 expression were investigated using clinical technologies. The relationship between clinicopathologic and genetic features was analyzed, and the Kaplan–Meier method with log-rank test was used for analyzing patient survival.Results: Major events, including EGFR, KRAS, and BRAF mutations and MET copy-number gain, were found in 5.6%, 16.7%, 1.9%, and 18.5% in LCLC, respectively. No ALK or ROS1 translocation was detected. PDL1 expression in tumor cells and in tumor-infiltrating lymphocytes was observed in 24 (44.4%) and 16 (29.6%) patients. Kaplan–Meier analysis showed that patients with a KRAS mutation had ower 5-year overall survival than those with wild-type KRAS (25.4% vs 47.8%, P=0.028) and that patients with negative PDL1 stained in tumor cells but positive for tumor-infiltrating lymphocytes had significantly favorable overall survival compared to those with solitary and positive PDL1 stained in tumor cells (62.5% vs 20.6%, P=0.044).Conclusion: KRAS mutations and PDL1 expression can predict patient survival and be potential target options in LCLC.Keywords: large-cell lung cancer, driver mutations, PD-L1, KRAS

Wei Wang,1 Yingjie Zhang,1 Min Xu,1 Qian Shao,1 Tao Sun,2 Ting Yu,1,3 Xijun Liu,1 Jianbin Li1 1Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Jinan, Shandong 250117, China; 2Department of Medical Physics, Shandong Cancer Hospital affiliated with Shandong University, Jinan, Shandong 250117, China; 3School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China Objective: To evaluate the incidental coverage dose to the internal mammary nodes (IMN) in patients treated with postmastectomy radiotherapy (PMRT) and its relationship with the treatment plan.Patients and methods: We retrospectively analyzed 138 patients undergoing PMRT and divided them into three groups: three-dimensional conformal radiotherapy (3D-CRT), field-in-field forward intensity-modulated radiotherapy (F-IMRT), and inverse intensity-modulated radiotherapy (I-IMRT). The IMN were contoured according to the Radiation Therapy Oncology Group consensus and not included in the planning target volume. We analyzed incidental IMN dose coverage and its relationship with the lung and heart.Results: The mean dose (Dmean) to the IMN was 32.85 Gy for all patients, and the dose delivered to the IMN showed no differences in 3D-CRT, F-IMRT, and I-IMRT (33.80, 29.65, and 32.95 Gy, respectively). In addition, 10.42%, 2.04%, and 9.76% of patients achieved ≥45 Gy with 3D-CRT, F-IMRT, and I-IMRT, respectively. No differences were evident among the three treatment plans regarding IMN dose in the first three intercostal spaces (ICS1–3). The Dmean, V20, V30, V40, and V50 of ICS2 and ICS3 were superior to those of ICS1 for all three plans. For 3D-CRT, a moderate positive correlation was evident between the Dmean to the IMN and the Dmean to the heart. For F-IMRT and I-IMRT, positive correlations were evident between the Dmean of the IMN and the Dmean and V20 of the lung.Conclusion: The mean incidental dose to the IMN for IMRT (F-IMRT and I-IMRT) and 3D-CRT after modified radical mastectomy was insufficient to treat subclinical disease. A substantial dose was delivered to the IMN in some patients. Higher incidental doses to the IMN were associated with a higher heart mean dose for 3D-CRT and a higher dose to the lung for IMRT. Future prospective studies should further explore subgroups that do not require IMN irradiation. Keywords: postmastectomy radiotherapy, internal mammary chain incidental irradiation dose, three-dimensional conformal radiotherapy, field-in-field forward intensity-modulated radiotherapy, inverse IMRT

Jing Li,1,* Tao Zhang,2,* Qingmiao Shao3 1Department of Transplantation, The First Central Hospital of Tianjin, 2Department of Nephrology, The First Affiliated Hospital of Tianjin Chinese Medical University, 3Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China *These authors contributed equally to this work Background: Previous studies have revealed that restless legs syndrome (RLS) not only is frequently prevalent in dialysis patients but also increases the risk of death in dialysis patients, especially in hemodialysis (HD) patients. However, inconsistent results also still exist, having attracted confusion and discussion. Owing to mixed and inconclusive results, we conducted to perform the comprehensive meta-analysis to evaluate the potential prognostic value of RLS in HD patients. Materials and methods: We conducted a systematic literature search using electronic databases (PubMed, Ovid, Embase and Web of Science) to identify relevant studies reporting on all-cause mortality and cardiovascular (CV) events in HD patients suffering from RLS. We searched the literature published up to December 5, 2016, or earlier. We used both fixed- and random-effects models to calculate the overall effect estimate. An I2>50% indicates at least moderate statistical heterogeneity. A sensitivity analysis and subgroup analysis were performed to find the origin of heterogeneity. Results: A total of four studies including 1,839 patients found that there was no significant association between RLS and all-cause mortality (hazard ratio [HR]: 1.649; 95% confidence interval [CI]: 0.778–3.496) and CV events (HR: 0.863; 95% CI: 0.600–1.127) in HD patients. Heterogeneity among the studies was observed for all-cause mortality (I2=80.7%, P=0.001). Conclusion: Our meta-analysis suggests that there was no significant effect of RLS on all-cause mortality and CV events in HD patients. Therefore, large-scale and well-designed studies are needed to validate the association between RLS and the risk of death in HD patients. Keywords: restless legs syndrome, hemodialysis, cardiovascular events, mortality, meta-analysis

Jeremy WD McGowan,1 Qingmei Shao,1 Parminder JS Vig,1,2 Gene L Bidwell III1,2 1Department of Neurology, 2Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA Abstract: Bypassing the blood–brain barrier is one of the primary considerations when designing compounds intended to function in the central nervous system (CNS). Intranasal (IN) administration of otherwise blood–brain barrier impermeable molecules can result in high CNS concentrations and low systemic accumulation, indicating that IN administration may be a useful method of delivering therapeutics to the CNS. Elastin-like polypeptide (ELP) is a large, non-immunogenic, highly manipulable biopolymer with extensive evidence supporting its use as a carrier with the ability to improve drug pharmacokinetics and drug targeting. The ability of ELP to reach the CNS via IN administration has been shown previously. Previous studies have also identified the ability of cell penetrating peptides (CPPs) to increase the uptake of molecules in some instances, including via the IN route. Here, we compared and contrasted the biodistribution of ELPs with or without addition of the CPPs Tat or SynB1 via both the IN and intravenous routes. Administration of ELP via the IN route led to significant accumulation in the brain, especially in the olfactory bulbs. When injected intravenously,

Qing Shao,1,2,* Wei Quan,1,2,* Xiaoni Jia,1 Jianbo Chen,1 Shanbo Ma,3 Xiaohong Zhang11Xi’an Mental Health Center, Institute of Mental Health, Xi’an Medical University, Xi’an, Shaanxi, People’s Republic of China; 2Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workAbstract: Psychotropic medications have been known to cause cardiac conduction disturbances. Not much is known about the cardiovascular side effects of newer atypical antipsychotics such as aripiprazole. A case of a 13-year-old girl with schizophrenia is presented. An analysis of the presented patient’s clinical history indicates the need for a detailed analysis of the severe arrhythmia induced by aripiprazole. This presented case report contains valuable guidelines that can be of assistance in the treatment of patients with aripiprazole.Keywords: schizophrenia, aripiprazole, arrhythmia, antipsychotics

We use temperature-dependent Hall measurements to identify contributions of spin Hall, magnetic proximity, and sublattice effects to the anomalous Hall signal in heavy metal/ferrimagnetic insulator heterostructures with perpendicular magnetic anisotropy. This approach enables detection of both the magnetic proximity effect onset temperature and the magnetization compensation temperature and provides essential information regarding the interfacial exchange coupling. Onset of a magnetic proximity effect yields a local extremum in the temperature-dependent anomalous Hall signal, which occurs at higher temperature as magnetic insulator thickness increases. This magnetic proximity effect onset occurs at much higher temperature in Pt than W. The magnetization compensation point is identified by a sharp anomalous Hall sign change and divergent coercive field. We directly probe the magnetic proximity effect using x-ray magnetic circular dichroism and polarized neutron reflectometry, which reveal an antiferromagnetic coupling between W and the magnetic insulator. Finally, we summarize the exchange-coupling configurations and the anomalous Hall-effect sign of the magnetized heavy metal in various heavy metal/magnetic insulator heterostructures.

Remarkable progress has been made in the development of cysteine‐targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K–E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D‐targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide‐based small‐molecule inhibitors capable of inducing intramolecular cross‐linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide‐facilitated, ligand‐induced mechanism leading to intramolecular kinase cross‐linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative. [ABSTRACT FROM AUTHOR]