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Bohai Du,1 Tianlan Li,1 Haoqi He,1 Xun Xu,2 Chunmei Zhang,1 Xianzhu Lu,1 Yuhan Wang,1 Jingyi Cao,1 Yinghan Lu,1 Yiwa Liu,1 Shanshan Hu,1 Juxiao Li,1 Li Li,1 Ming Shi1 1Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province, 523808, People’s Republic of China; 2Experimental Animal Center, Guangdong Medical University, Dongguan, Guangdong Province, 523808, People’s Republic of ChinaCorrespondence: Li Li; Ming Shi, School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province, 523808, People’s Republic of China, Tel +86-15889530426 ; +86-769-22896568, Email lily2017@gdmu.edu.cn; shiming@gdmu.edu.cnIntroduction: Studies have shown that microplastics (MPs) and nanoplastics (NPs) could accumulate in the human body and pose a potential threat to human health. The purpose of this study is to evaluate the biodistribution and toxicity of MPs/NPs with different particle sizes comprehensively and thoroughly.Methods: The purpose of this study was to investigate the biodistribution and in vivo toxicity of polystyrene (PS) MPs/NPs with different sizes (50 nm, 100 nm, and 500 nm). The BALB/c mice were given 100 μL of PS50, PS100 and PS500 at the dosage of 1 mg/kg BW or 10 mg/kg BW, respectively, by gavage once a day. After 28 consecutive days of treatment, the biodistribution of differently sized PS MPs/NPs was determined through cryosection fluorescence microscopy and fluorescent microplate reader analysis, and the subsequent effects of differently sized PS MPs/NPs on histopathology, hematology and blood biochemistry were also evaluated.Results: The results showed that the three different sizes of PS MPs/NPs were distributed in the organs of mice, mainly in the liver, spleen, and intestine. At the same time, the smaller the particle size, the more they accumulate in the body and more easily penetrate the tissue. During the whole observation period, no abnormal behavior and weight change were observed. The results of H&E staining showed that no severe histopathological abnormalities were observed in the main organs in the low-dose exposure group, while. Exposure of three sizes of PS MPs/NPs could cause some changes in hematological parameters or biochemical parameters related to heart, liver, and kidney function; meanwhile, there were size- and dose-dependencies.Conclusion: The biological distribution and toxicity of plastic particles in mice were more obvious with the decrease of particle size and the increase of concentration of plastic particles. Compared with MPs, NPs were easier to enter the tissues and produce changes in liver, kidney, and heart functions. Therefore, more attention should be paid to the toxicity of NPs.Keywords: microplastics, nanoplastics, polystyrene, size, biodistribution, nanotoxicology

Dawei Ren,1 Yan Zhang,1 Bo Du,1 Lina Wang,2 Meiheng Gong,1 Wei Zhu1 1Department of Otorhinolaryngology, the First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Pediatric Respiration, the First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Wei Zhu, Email zhuwei@jlu.edu.cnBackground: Electrical stimulation (ES) can effectively promote skin wound healing; however, single-electrode-based ES strategies are difficult to cover the entire wound area, and the effectiveness of ES is often limited by the inconsistent mechanical properties of the electrode and wound tissue. The above factors may lead to ES treatment is not ideal.Methods: A multifunctional conductive hydrogel dressing containing methacrylated gelatin (GelMA), Ti3C2 and collagen binding antimicrobial peptides (V-Os) was developed to improve wound management. Ti3C2 was selected as the electrode component due to its excellent electrical conductivity, the modified antimicrobial peptide V-Os could replace traditional antibiotics to suppress bacterial infections, and GelMA hydrogel was used due to its clinical applicability in wound healing.Results: The results showed that this new hydrogel dressing (GelMA@Ti3C2/V-Os) not only has excellent electrical conductivity and biocompatibility but also has a durable and efficient bactericidal effect. The modified antimicrobial peptides V-Os used were able to bind more closely to GelMA hydrogel to exert long-lasting antibacterial effects. The results of cell experiment showed that the GelMA@Ti3C2/V-Os hydrogel dressing could enhance the effect of current stimulation and significantly improve the migration, proliferation and tissue repair related genes expression of fibroblasts. In vitro experiments results showed that under ES, GelMA@Ti3C2/V-Os hydrogel dressing could promote re-epithelialization, enhance angiogenesis, mediate immune response and prevent wound infection.Conclusion: This multifunctional nanocomposite hydrogel could provide new strategies for promoting infectious wound healing. Keywords: MXene, GelMA, electrical stimulation, antimicrobial peptides, wound healing

Mei Sun,* Yankai Wei,* Chengyuan Zhang, Hong Nian, Bei Du, Ruihua Wei Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruihua Wei, Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Nankai District, Tianjin, 300384, People’s Republic of China, Tel/Fax +86 86428862, Email rwei@tmu.edu.cnPurpose: Sjögren’s syndrome-related dry eye (SS-related dry eye) is an intractable autoimmune disease characterized by chronic inflammation of lacrimal glands (LGs), where epigenetic factors are proven to play a crucial role in the pathogenesis of this disease. However, the alteration of DNA methylation in LGs and its role in the pathogenesis of SS-related dry eye is still unknown. Here, we performed an integrated analysis of DNA methylation and RNA-Seq data in LGs to identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in the pathogenesis of SS-related dry eye.Methods: The DNA methylation and transcription profiles of LGs in NOD mice at different stages of SS-related dry eye (4-, 8-, 12- and 16 weeks old) were generated by reduced representation bisulfite sequencing (RRBS) and RNA-Seq. The differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were analyzed by MethylKit R package and edgeR. Correlation analysis between methylation level and mRNA expression was conducted with R software. The functional correlation of DMGs and DEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, LG tissues from another litter of NOD mice were collected for methylation-specific polymerase chain reaction (MSP) and quantitative real-time PCR (qRT-PCR) to validate the methylation and expression levels of key genes. CD4+ cell infiltration of LGs was detected by immunofluorescence staining.Results: Hypermethylation of LGs was identified in NOD mice with the progression of SS-related dry eye and the DMGs were mainly enriched in the GTPases activation and Ras signaling pathway. RNA-seq analysis revealed 1321, 2549, and 3712 DEGs in the 8-, 12- and 16-week-old NOD mice compared with 4-week-old normal control mice. For GO analysis, the DEGs were mainly enriched in T cell immune responses. Further, a total of 140 MeDEGs were obtained by integrated analysis of methylome and transcriptome, which were primarily enriched in T cell activation, proliferation and differentiation. Based on the main GO terms and KEGG pathways of MeDEGs, 8 genes were screened out. The expression levels of these key genes, especially Itgal, Vav1, Irf4 and Icosl, were verified to elevate after the onset of SS-related dry eye in NOD mice and positively correlated with the extent of inflammatory cell infiltration in LGs. Immunofluorescence assay revealed that CD4+ cell infiltration dramatically increased in LGs of SS-related dry eye mice compared with the control mice. And the expression levels of four genes showed significantly positive correlation with the extent of CD4+ cell infiltration in LGs. MSP showed the hypomethylation of the Irf 4 and Itgal promoters in NOD mice with SS-related dry eye compared to control group.Conclusion: Our study revealed the critical role of epigenetic regulation of T cell immunity-related genes in the progression of SS-related dry eye and reminded us that DNA methylation-regulated genes such as Itgal, Vav1, Irf4 and Icosl may be used as new targets for SS-related dry eye therapy.Keywords: Sjögren’s syndrome-related dry eye, lacrimal gland, DNA methylation, RNA-seq, T cell-mediated immune response

Shi-Tong Diao, Run Dong, Jin-Min Peng, Yan Chen, Shan Li, Shu-Hua He, Yi-Fan Wang, Bin Du, Li Weng On behalf of the China Critical Care Clinical Trials Group (CCCCTG)Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Li Weng, Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Shuai Fu Yuan, Beijing, 100730, People’s Republic of China, Email wengli@gmail.comBackground: Sepsis surveillance was important for resources allocation, prevention, and development of health policy.Objective: The aim of the study was to validate a modified International Classification of Diseases (ICD)-10 based algorithm for identifying hospitalized patients with sepsis.Methods: We retrospectively analyzed a prospective, single-center cohort of adult patients who were consecutively admitted to one medical ICU ward and ten non-ICU wards with suspected or confirmed infections during a 6-month period. A modified ICD-10 based algorithm was validated against a reference standard of Sequential Organ Failure Assessment (SOFA) score based on Sepsis-3. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and areas under the receiver operating characteristic curves (AUROCs) were calculated for modified ICD-10 criteria, eSOFA criteria, Martin’s criteria, and Angus’s criteria.Results: Of the 547 patients in the cohort, 332 (61%) patients met Sepsis-3 criteria and 274 (50%) met modified ICD-10 criteria. In the ICU setting, modified ICD-10 criteria had SE (84.47%), SP (88.57%), PPV (95.60), and NPV (65.96). In non-ICU settings, modified ICD-10 had SE (64.19%), SP (80.00%), PPV (80.33), and NPV (63.72). In the whole cohort, the AUROCs of modified ICD-10 criteria, eSOFA, Angus’s criteria, and Martin’s criteria were 0.76, 0.75, 0.62, and 0.62, respectively.Conclusion: This study demonstrated that modified ICD-10 criteria had higher validity compared with Angus’s criteria and Martin’s criteria. Validity of the modified ICD-10 criteria was similar to eSOFA criteria. Modified ICD-10 algorithm can be used to provide an accurate estimate of population-based sepsis burden of China.Keywords: sepsis, validation, International Classification of Diseases, administrative health data, identification

Hao Chen,1,2,&ast; Qing Ma,3,&ast; Bo Du,1 Yan Huang,1 Shi-Guang Zhu,1 Sheng-Li Li,4 De-Qin Geng,1 Xing-Shun Xu2,5,6 1Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of China; 3Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China; 4Department of Medical Records and Statistics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China; 5Institute of Neuroscience, Soochow University, Suzhou, 215000, People’s Republic of China; 6Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: De-Qin Geng, Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China, Tel +86 18052268197, Email gengdeqingdq@outlook.com Xing-Shun Xu, Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of China, Tel +86 13915411326, Email xuxingshunxxs@126.comObjective: The present study aims to analysis the mental health of high-risk health care workers (HHCWs) and low-risk HCWs (LHCWs) who were respectively exposed to COVID-19 wards and non-COVID-19 wards by following up on mental disorders in HCWs in China for 6 months.Methods: A multi-psychological assessment questionnaire was used to follow up on the psychological status of HCWs in the Affiliated Hospital of Xuzhou Medical University in Xuzhou City (a non-core epidemic area) at 6 months after the first evaluation conducted during the COVID-19 epidemic. Based on the risk of exposure to COVID-19 patients, the HCWs were divided into two groups: high-risk HCWs, who worked in COVID-19 wards, and low-risk HCWs, who worked in non-COVID-19 wards.Results: A total of 198 HCWs participated in the study, and 168 questionnaires were selected for evaluation. Among them, 93 (55.4%) were in the HHCW group and 75 (44.5%) were in the LHCW group. Significant differences were observed in salary, profession, and altruistic behavior between the two groups (P < 0.05). There were no significant differences in the anxiety, depression, insomnia, or posttraumatic stress disorder (PTSD) scores between the two groups. Logistic regression revealed that work stress was a major joint risk factor for mental disorders in HCWs. Among all the HCWs, a total of 58 voluntarily participated in psychotherapy; the analysis showed a significant decrease in anxiety, depression, PTSD, work stress, and work risk after attending psychotherapy. There were also significant differences in positive and negative coping styles before and after psychotherapy.Conclusion: In the present follow-up, work stress was the major contributing factor to mental disorders in HCWs. Psychotherapy is helpful in terms of stress management and should be provided to first-line COVID-19 HCWs.Keywords: COVID-19, anxiety, depression, posttraumatic stress disorder, insomnia, work stress

Yi Zheng,1 Pan-Pan Ye,2 Yue Zhou,1 Su-Ying Wu,3 Xi-Ting Liu,1 Bin Du,1 Bo-Hao Tang,1 Min Kan,1 Ai-Qing Nie,1 Rui Yin,1 Meng Wang,1 Guo-Xiang Hao,1 Lin-Lin Song,2 Xin-Mei Yang,2 Xin Huang,2 Le-Qun Su,2 Wen-Qi Wang,2 John van den Anker,4– 6 Wei Zhao1,2 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China; 2Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, 250014, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA; 5Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA; 6Department of Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, SwitzerlandCorrespondence: Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of ChinaEmail zhao4wei2@hotmail.comPurpose: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis.Methods: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9– 42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2.Results: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age.Conclusion: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.Keywords: CYP3A activity, ontogeny, inflammation, pharmacokinetic, mice

Yue Zhou,1 Ai-Qing Nie,1 Shang Chen,2 Meng-Meng Wang,1 Rui Yin,1 Bo-Hao Tang,1 Yue-E Wu,1 Fan Yang,1 Bin Du,1 Hai-Yan Shi,3 Xin-Mei Yang,3 Guo-Xiang Hao,1 Xiu-Li Guo,4 Qiu-Ju Han,5 Yi Zheng,1,* Wei Zhao1,3,* 1Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Institute of Biochemical and Biotechnological Drug, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 5Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zheng; Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhengyi@sdu.edu.cn; zhao4wei2@hotmail.comPurpose: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL.Subjects and Methods: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).Results: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway.Conclusion: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments.Keywords: disease-induced pharmacokinetic change, renal transporters, inflammatory cytokines, clearance

Jingjun Li, Baoshun Du, Xiuqin Geng, Lin Zhou Department of Endocrinology, Xinxiang Central Hospital, Xinxiang, Henan Province, 453003, People’s Republic of ChinaCorrespondence: Jingjun LiDepartment of Endocrinology, Xinxiang Central Hospital, Xinxiang, Henan Province, 453000, People’s Republic of ChinaTel +86-0373-2048900Email wp9150@163.comAim: Long non-coding RNA (lncRNA) SNHG17 has been shown to participate in type 2 diabetes mellitus, while its role in gestational diabetes mellitus (GDM) is unknown.Methods: Quantitative real-time PCR (qRT-PCR) assays were conducted to compare the differential expression of SNHG17 among 60 GDM patients and 60 healthy pregnant female controls. In addition, peripheral blood samples from 240 pregnant females were collected to evaluate the predictive value of SNHG17 for GDM patients. All females were followed-up until delivery to record the occurrence of GDM and perinatal outcomes. GDM-free curves were plotted to compare the occurrence of GDM between high- and low- SNHG17 expression groups. The diagnostic value of plasma SNHG17 for GDM was analyzed by ROC curve analysis. Moreover, the cell counting kit (CCK-8) assay was performed to evaluate the impact of SNHG17 on cell viability of INS-1, and the level of insulin secretion was detected by enzyme linked immunosorbent assay (ELISA) after overexpression or knockdown of SNHG17.Results: SNHG17 was downregulated in GDM patients compared to normal pregnant females. Low plasma expression levels of SNHG17 were closely correlated with the high incidence rate of GDM (GDM-free curve). Remarkably, plasma expression levels of SNHG17 at 4 weeks before the diagnosis of GDM (diagnosed by standard method) can be used to distinguish (ROC curve) GDM patients (diagnosed during follow-up) from normal pregnant females (GDM was not diagnosed during follow-up).Conclusion: Plasma circulating SNHG17 is downregulated in GDM and has predictive values.Keywords: gestational diabetes mellitus, lncRNA SNHG17, prediction

Chao Hou, Yanli Dong, Bo Du Department of Stomatology, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277100, People’s Republic of ChinaCorrespondence: Bo DuDepartment of Stomatology, Zaozhuang Municipal Hospital, 41 Zhonglongtou Road, Zaozhuang, Shandong 277100, People’s Republic of ChinaEmail dubo_zzmunicipal@163.comPurpose: Long intergenic non-protein-coding RNA 00466 (LINC00466) promotes lung adenocarcinoma progression. Nonetheless, the expression and precise roles of LINC00466 in tongue squamous cell carcinoma (TSCC) remains uncertain and warrant further investigation. Hence, the present study aimed to examine the LINC00466 effects on the aggressive TSCC cell characteristics and to elucidate the potential underlying mechanisms.Methods: First, LINC00466 expression in TSCC was determined by reverse transcription-quantitative PCR. Subsequently, cell proliferation, apoptosis, migration, and invasion in vitro, as well as tumor growth in vivo were assessed to examine the LINC00466 effects on TSCC cells.Results: LINC00466 was upregulated in TSCC. This upregulation was notably associated with shorter overall TSCC patient survival. In vitro experiments indicated that LINC00466 depletion suppressed TSCC cell proliferation, migration and invasion, and promoted apoptosis. An in vivo experiment revealed that LINC00466 downregulation attenuated TSCC tumor growth in vivo. Mechanistic analysis revealed that LINC00466 functions as a microRNA-493 (miR-493) molecular sponge, a miRNA that targets high-mobility group AT-hook 2 (HMGA2) mRNA. LINC00466 upregulated HMGA2 in TSCC cells, and this phenomenon was regulated by the miR-493 sponge. Rescue experiments revealed a decrease in the miR-493/HMGA2 axis output, partially reversing the effects of LINC00466 downregulation on aggressive TSCC cell behavior.Conclusion: These findings demonstrate that LINC00466 promotes TSCC cell oncogenicity in vitro and in vivo by upregulating the miR-493/HMGA2 axis output. These results may provide a new perspective and new insight into the molecular mechanisms of TSCC.Keywords: long intergenic non-protein-coding RNA 00466, tongue squamous cell carcinoma pathogenesis, targeted therapy

Weizhen Liu,1,* Bing Du,2,* Siyi Tan,3 Qin Wang,4 Yi Li,1 Lei Zhou5 1Department of Periodontics, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Center of Stomatology, The Second People’s Hospital of Foshan, Foshan, Guangdong, People’s Republic of China; 3Center of Stomatology, Panyu Central Hospital, Guangzhou, Guangdong, People’s Republic of China; 4Department of Oral Maxillofacial Surgery, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 5Center of Oral Implantology, School of Stomatology, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei ZhouCenter of Oral Implantology, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, People’s Republic of ChinaTel +86 20 8423 3801Fax +86 20 8443 3177Email zho668@263.netIntroduction: Vertical bone augmentation without osseous walls to support the stability of clots and bone grafts remains a challenge in dental implantology. The objectives of this study were to confirm that cortical perforation of the recipient bed is necessary and to evaluate whether nanohydroxyapatite (nHA) block grafts coated with recombinant human vascular endothelial growth factor165 (rhVEGF165) and cortical perforation can improve vertical bone regeneration.Materials and Methods: We prepared nHA blocks coated with or without rhVEGF165 on the rabbit calvarium through cortical perforation, and designated the animals as the nonperforated group (N-nHA), rhVEGF165 group (NV-nHA), perforated group (P-nHA) and rhVEGF165 on perforated group (PV-nHA). Micro-computed tomography (micro-CT) and fluorescence microscopy were selected to evaluate parameters of vertical bone regeneration at 4 and 6 weeks.Results: The ratio of the newly formed bone volume to the titanium dome volume (BV/TV) and the bone mineral density (BMD) were significantly higher in the PV-nHA group than in the N-nHA group at 4 and 6 weeks, as determined using micro-CT. The fluorescence analysis showed slightly greater increases in new bone regeneration (NB%) and vertical height (VH%) gains in the P-nHA group than in the N-nHA group. Greater increases in NB% and VH% were observed in groups treated with rhVEGF165 and perforation than in the blank groups, with significant differences detected at 4 and 6 weeks (N-nHA compared with PV-nHA, p< 0.05). A greater VH% that was observed at the midline of the block in the PV-nHA group than in the other three groups at both time points (0.75± 0.53% at 4 weeks and 0.83± 0.42% at 6 weeks).Conclusion: According to the present study, cortical perforation is necessary and nHA blocks coated with rhVEGF165 and decoration could work synergistically to improve vertical bone regeneration by directly affecting primary osteoblasts and promoting angiogenesis and osteoinduction.Keywords: cortical perforation, vertical bone regeneration, hydroxyapatite blocks, fluorescence, angiogenesis

Yan Cui, Xuena Li, Bulin Du, Yao Diao, Yaming Li Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaCorrespondence: Yaming LiDepartment of Nuclear Medicine, The First Hospital of China Medical University, North Nanjing Street 155, Shenyang, Liaoning 110001, People’s Republic of ChinaTel +86-24-83282142Fax +86-24-83282671Email ymli2001@163.comPurpose: This study aimed to evaluate the role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in expression of tumor programmed death ligand-1 (PD-L1) expression and prognostic significance of 18F-FDG PET/CT at different PD-L1 status in patients with lung adenocarcinoma.Patients and Methods: Seventy-three patients with primary lung adenocarcinoma who received 18F-FDG PET/CT before treatment were retrospectively included in this study. Expression of tumor PD-L1, programmed death-1 (PD-1) and glucose metabolic parameters were evaluated.Results: Tumor PD-L1 expression was positively correlated with maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), hexokinase II (HK-II) and glucose transporter 1 (GLUT-1) (P< 0.0001 for all). SUVmax was a unique independent predictor of tumor PD-L1 expression, with an optimal cut-off value of 9.5. For all the patients, tumor stage (P< 0.001) and SUVmax (P=0.009) were independent prognostic indicators of disease-free survival (DFS)/progression-free survival (PFS) while carcino-embryonic antigen (CEA) (P=0.003), Ki67 (P=0.042), PD-L1 (P=0.048) and TLG (P=0.004) were independent prognostic indicators of overall survival (OS). Tumor stage (P=0.004) and SUVmax (P=0.022) were independent prognostic indicators of DFS/PFS while TLG (P=0.012) and CEA (P=0.045) were independent prognostic indicators of OS in the PD-L1-positive group. In the PD-L1-negative group, tumor stage (P=0.002) and CEA (P=0.006) were unique independent prognostic indicators of DFS/PFS and OS, respectively.Conclusion: 18F-FDG PET/CT may potentially predict tumor PD-L1 expression and play a role in predicting prognosis of PD-L1/PD-1 immunotherapy in lung adenocarcinoma.Keywords: 18F-fluorodeoxyglucose, positron emission tomography, programmed death ligand-1, lung adenocarcinoma, prognosis

Wenli Mao,1,* Heng Yin,2,* Wenya Chen,1,* Tingxiu Zhao,1 Shaofeng Wu,3 He Jin,1 Biaoyan Du,1 Yuhui Tan,2 Ren Zhang,2,3 Yanli He1,3 1Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 2Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 3Research Center for Integrative Medicine of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanli He; Ren Zhang Tel +86 20-39358015; +86 20-39358007 Fax +86 20-39358020Email blhhh@gzucm.edu.cn; zren@gzucm.edu.cnPurpose: Dioscin, a natural glycoside derived from many plants, has been proved to exert anti-cancer activity. Several studies have found that it reverses TGF-β 1-induced epithelial–mesenchymal transition (EMT). Whether dioscin can reverse EMT by pathways other than TGF-β is still unknown.Methods: We used network-based pharmacological methods to systematically explore the potential mechanisms by which dioscin acts on lung cancer. Cell Counting Kit-8 assay, scratch healing, Transwell assay, Matrigel invasion assay, immunofluorescence assay, and Western blotting were employed to confirm the prediction of key targets and the effects of dioscin on EMT.Results: Here, using network-based pharmacological methods, we found 42 possible lung cancer-related targets of dioscin, which were assigned to 98 KEGG pathways. Among the 20 with the lowest p-values, the PI3K-AKT signaling pathway is involved and significantly related to EMT. AKT1 and mTOR, with high degrees (reflecting higher connectivity) in the compound-target analysis, participate in the PI3K-AKT signaling pathway. Molecular docking indicated the occurrence of dioscin-AKT1 and dioscin-mTOR binding. Functional experiments demonstrated that dioscin suppressed the proliferation, migration, invasion, and EMT of human lung adenocarcinoma cells in a dose-dependent manner, without TGF-β stimulation. Furthermore, we determined that dioscin downregulated p-AKT, p-mTOR and p-GSK3β in human lung adenocarcinoma cells without affecting their total protein levels. The PI3K inhibitor LY294002 augmented these changes.Conclusion: Dioscin suppressed proliferation, invasion and EMT of lung adenocarcinoma cells via the inactivation of AKT/mTOR/GSK3β signaling, probably by binding to AKT and mTOR, and inhibiting their phosphorylation.Keywords: dioscin, lung adenocarcinoma, epithelial–mesenchymal transition, network-based pharmacology

Baoying Du,1 Hongfeng Liao,2 Sheng Zhang3 1Department of Hepatopancreatobiliary Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pathology, Zhongshan Hospital of Xiamen University, Xiamen, People’s Republic of China; 3Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Sheng ZhangDepartment of Pathology, Hubei Cancer Hospital, No. 116, Zhuodaoquan South Road, Wuhan, Hubei Province, People’s Republic of ChinaTel/Fax +86-27-87670411Email zhangshengcmu@163.comPurpose: Hepatocellular carcinoma (HCC) remains one of the most common malignancies. While there is lack of markers capable of predicting which patients are at risk of aggressive course of the disease. Although a few protein phosphatase methyl-esterase-1 (PME-1) tumor-promoting mechanisms have been reported, the role of PME-1 in cancer including HCC occurrence and progression remains to be elucidated. The aim of this study was to explore the expression pattern and relationship between PME-1 with the pathological parameters in patients with HCC.Methods: PME-1 expression was assessed from HCC tissue chips via immunohistochemistry. Chi-square test was used to identify the association between PME-1 staining and clinicopathological variables of HCC patients. Kaplan–Meier analysis and Cox regression analysis were performed to draw survival curves and verify the independent prognostic factors of HCC patients, respectively.Results: We found that PME-1 expression was significantly higher in HCC tumor tissues compared with non-tumor tissues (P < 0.001). Furthermore, high expression level of PME-1 was significantly associated with differentiation (P = 0.047), tumor number (P = 0.001), intrahepatic or extrahepatic metastasis (P = 0.018), and recurrence (P = 0.001). Kaplan–Meier analysis revealed that high expression level of PME-1 was associated with shorter survival (P < 0.001). Univariate analysis with Log-rank test revealed that PME-1 expression status was significantly correlated with overall survival (P < 0.001). Furthermore, multivariate models with Cox proportional hazards analysis showed that high expression of PME-1 was a statistically independent predictive factor of poor prognosis in HCC patients (hazard ratio, 3.429; 95% confidence interval, 1.369– 8.589; P = 0.009).Conclusion: In conclusion, these findings indicated that PME-1 expression was associated with aggressive pathological features and worse oncological outcomes, suggesting its potential therapeutic value for patients with HCC.Keywords: hepatocellular carcinoma, PME-1, survival, immunohistochemistry

Peidi Yin,1 Huifeng Li,1 Chao Ke,2 Guangxu Cao,1 Xiaoqian Xin,3 Junjiao Hu,4 Xiangran Cai,4 Lingfeng Li,1 Xiaowen Liu,3 Bin Du1 1Department of Pathology, School of Medicine, Jinan University, Guangzhou 510632, People’s Republic of China; 2Department of Neurosurgery/Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China; 3Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, People’s Republic of China; 4Medical Imaging Center, The First Affiliated Hospital, Jinan University, Guangzhou 510630, People’s Republic of ChinaCorrespondence: Xiaowen Liu; Bin Du Email xwliu231@jnu.edu.cn; tdubin@jnu.edu.cnPurpose: Some chemotherapeutics have been shown to induce both the release of damage-associated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood–brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain.Methods: A new oligonucleotide nanoformulation (Au@PP)/poly(I:C)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(I:C)). Intracranial GL261 tumor-bearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(I:C) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses.Results: Au@PP/poly(I:C) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(I:C) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(I:C) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(I:C) plus TMZ group.Conclusion: This study demonstrates that intranasal administration of Au@PP/poly(I:C) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.Keywords: AuNPs, poly(I:C), intranasal administration, immunogenic cell death, in situ immune response activation