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Kun Qin,1,2,* Ting Gong,3,* Shi-Fan Ruan,1,* Min Lin,1 Xinhong Su,1 Xiaoqing Lv,1 Bo Cheng,1,4 Chao Ji1,4 1Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, People’s Republic of China; 2Department of Dermatology, Jiangmen Central Hospital, Jiangmen, Guangdong, 529000, People’s Republic of China; 3Central Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, People’s Republic of China; 4Key Laboratory of Skin Cancer of Fujian Higher Education Institutions, The Fujian Medical University, Fuzhou, Fujian, 350000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao Ji; Bo Cheng, Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Taijiang District, Fuzhou, Fujian, 350000, People’s Republic of China, Tel +86 18651619908 ; Tel +86 13859024296, Email jichaofy@fjmu.edu.com; chengbo630415@126.comPurpose: Immune checkpoint inhibitors (ICIs) can cause life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Large-scale original research on ICI-induced SJS/TEN is limited. This study aimed to explore the unique clinical characteristics and potential pathophysiological mechanisms of SJS/TEN induced by ICIs.Methods: This cross-sectional study compared the clinical features of SJS/TEN induced by ICIs and non-ICIs, and reviewed the case characteristics of ICI-induced SJS/TEN. Clinical features were analyzed using independent t-tests, Mann–Whitney U-tests, and multivariable regression models.Results: This study enrolled 41 cases of ICI-induced SJS/TEN and 107 non-ICI-induced cases from January 22, 2015, to May 28, 2024. ICI-induced SJS/TEN patients exhibited a trend towards a longer latency period (β: 17, 95% CI: − 1.49 to 35.48), a smaller affected body surface area (BSA) (β: − 40.68, 95% CI: − 71.59 to − 9.77), and milder oral and ocular mucositis than non-ICI-induced cases. A literature review identified PD-1 inhibitors as the primary ICIs involved and systemic corticosteroids as the most frequent intervention. No statistically significant difference in mortality rate was observed between patients treated with systemic corticosteroids alone and those receiving combination therapies (P= 0.85). The mortality rate for ICI-induced SJS/TEN was 24.5%.Conclusion: This study offered the largest comparative analysis to date, highlighting the unique clinical features of ICI-induced SJS/TEN, including a smaller affected BSA, a prolonged latency period trend, and milder oral and ocular mucositis. We described the epidemiology, clinical presentation, and therapeutic strategies for ICI-induced SJS/TEN. These findings not only contribute to a deeper understanding of the complex immune-inflammatory pathways in severe immune-related cutaneous adverse events (ircAEs) but also may inform the development of more targeted and effective treatments.Keywords: comparative analysis, clinical characteristic, latency period, body surface area, treatment

Rui Gao,1,* Peihong Lin,1,* Wenjing Yang,1,* Zhengyu Fang,1 Chunxiao Gao,1 Bin Cheng,2 Jie Fang,3 Wenying Yu1 1School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zhejiang Pharmaceutical University, Ningbo, 315500, People’s Republic of China; 3Zhejiang Provincial Laboratory of Experimental Animal’s & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin Cheng; Wenying Yu, Email 44418972@qq.com; zjyuwenying@163.comBackground: Genistein (Gen), a natural polyphenolic compound, has emerged as a promising candidate for lung cancer treatment. However, the potential clinical application of Gen is limited due to its poor solubility, low bioavailability, and toxic side effects. To address these challenges, a biomimetic delivery platform with cell membranes derived from natural cells as carrier material was constructed. This innovative approach aims to facilitate targeted drug delivery and solve the problem of biocompatibility of synthetic materials.Methods: First, the liposomes (LPs) loaded with Gen (LPs@Gen) was prepared using the ethanol injection method. Subsequently, PLTM-LPs@Gen was obtained through co-extrusion after mixing platelet membrane (PLTM) and LPs@Gen. Additionally, the biological and physicochemical properties of PLTM-LPs@Gen were investigated. Finally, the targeting ability, therapeutic efficacy, and safety of PLTM-LPs@Gen for lung cancer were evaluated using both a cell model and a tumor-bearing nude mouse model.Results: The optimal preparation ratio for LPs@Gen was Gen: soybean lecithin: cholesterol: DSPE-PEG2000 (3:30:5:10, mass ratio), while the ideal fusion ratio of LPs@Gen and PLTM was 1:1. The particle size of PLTM-LPs@Gen was 108.33 ± 1.06 nm, and the encapsulation efficiency and drug loading were 94.29% and 3.09% respectively. Gen was released continuously and slowly from PLTM-LPs@Gen. Moreover, PLTM-LPs@Gen exhibited good stability within one week. The results of in vitro cellular uptake and in vivo distribution experiments indicated that the carrier material, PLTM-LPs, has the immune escape ability and tumor targeting ability. Consequently, it showed better therapeutic effects than free drugs and traditional LPs in vitro and in vivo tumor models. In addition, safety experiments demonstrated that PLTM-LPs@Gen possesses good biocompatibility.Conclusion: Biomimetic nanomedicine provides a new strategy for the precision treatment of lung cancer in clinical practice.Keywords: bionic technology, platelet membrane, genistein, liposomes, lung cancer, targeted therapy

Shi-Fan Ruan,1– 3,* Xinhong Su,1,2,* Zhixun Xiao,1,2,* Yihua Zhang,1,2,* Tingting Lin,1,2 Renwei Luo,1,2 Niu Xiang,1,2 Bo Cheng,1– 3 Ting Gong,4 Chao Ji1– 3 1Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, People’s Republic of China; 2Key Laboratory of Skin Cancer of Fujian Higher Education Institutions, Fuzhou, Fujian, 350000, People’s Republic of China; 3Fujian Provincial Clinical Research Center for Immune Skin Diseases, Fuzhou, Fujian, 350000, People’s Republic of China; 4Central Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ting Gong, Central Laboratory, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian, 350000, People’s Republic of China, Email gongtingfy@fjmu.edu.cn Chao Ji, Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, Fujian, 350000, People’s Republic of China, Email jichaofy@fjmu.edu.cnPurpose: Recent studies have shown that novel biologics may provide significant clinical benefits for patients with generalized pustular psoriasis (GPP). Ustekinumab and secukinumab have been approved in Japan for GPP treatment in adult patients. However, the differences in efficacy and safety of these two drugs in GPP are not known.Aim: Based on the genetic background, we aimed to compare the efficacy and safety of secukinumab and ustekinumab in patients with GPP.Methods: Patients with moderate to severe GPP who were treated with ustekinumab/secukinumab at our department from July 2019 to May 2022 were included in this study and followed up for 48 weeks. The difference in efficacy between ustekinumab and secukinumab was evaluated by assessing changes in body temperature, laboratory indices, recovery of skin lesions, and changes in quality of life. Additionally, we collected patients’ saliva for genotyping and explored the effect of CARD14 genetic mutations on clinical efficacy.Results: A total of 65 patients (32 adults and 33 children) with moderate to severe GPP were included in this study. 31 patients received ustekinumab therapy, and 34 patients were treated with secukinumab. Secukinumab demonstrated superiority to ustekinumab, as evidenced by a higher GPPASI 90 response at week 2. Additionally, the efficacy of ustekinumab and secukinumab was found to be independent of the presence of the CARD14 mutation.Conclusion: Secukinumab is superior to ustekinumab in rapidly clearing the skin and improving health-related quality of life. Moreover, the responses to ustekinumab/secukinumab in patients were not influenced by CARD14 gene mutations.Keywords: generalized pustular psoriasis, secukinumab, ustekinumab, clinical efficacy, safety, gene mutations

Min Lin,1,* Ting Gong,2,* Shifan Ruan,1,* Xiaoqing Lv,1 Rongying Chen,1 Xinhong Su,1 Bo Cheng,1 Chao Ji1 1Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, People’s Republic of China; 2Department of Central Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Cheng; Chao Ji, Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Taijiang District, Fuzhou, 350000, People’s Republic of China, Tel +86 13859024296 ; +86 18651619908, Email bochengg@163.com; jichaofy@fjmu.edu.cnObjective: Anticancer drugs have revolutionized tumor therapy, with cutaneous toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) being common immune-related adverse events. The debate over the efficacy of systemic corticosteroids in treating these conditions persists, while tumor necrosis factor (TNF)-alpha inhibitors show promise. This study aims to evaluate the effectiveness and safety of combination therapy involving the TNF-α inhibitor adalimumab for SJS/TEN induced by anticancer drugs.Methods: A literature review of SJS/TEN cases induced by anticancer drugs from 1992 to 2023 was conducted, alongside an analysis of patients admitted to the First Affiliated Hospital of Fujian Medical University during the same period. Clinical characteristics, skin healing time, mortality, and adverse events were evaluated in two treatment groups: SJS/TEN patients treated with targeted anticancer therapies and immunotherapies.Results: Among the 27 patients studied (18 with SJS or SJS-TEN overlapping and 9 with TEN), combination therapy with adalimumab significantly reduced mucocutaneous reepithelization time and healing duration compared to corticosteroid monotherapy. Patients receiving adalimumab combined with corticosteroids had lower actual mortality rates than those on corticosteroid monotherapy. The combination therapy also showed a trend towards reducing standardized mortality rates based on the Score of Toxic Epidermal Necrolysis (SCORTEN).Conclusion: The findings suggest that adalimumab in combination with corticosteroids provides significant clinical benefits and is safer than corticosteroids alone for treating SJS/TEN induced by targeted anticancer therapies and immunotherapies. This study contributes valuable insights into potential treatment strategies for severe cutaneous adverse reactions to anticancer drugs, highlighting the importance of exploring alternative therapies such as TNF-α inhibitors in managing these conditions effectively.Keywords: anti-TNF-α, adalimumab, treatment, Stevens-Johnson syndrome, toxic epidermal necrolysis

Shaoqi Zong,1,2,* Guokai Huang,1,3,* Bo Pan,1,* Shasha Zhao,4 Changquan Ling,1,3 Binbin Cheng1,3 1Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China; 2Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China; 3Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, People’s Republic of China; 4Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People’s Republic of China*These authors contributed equally to this workCorrespondence: Binbin Cheng, Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, 168 Changhai Road, Shanghai, 200043, People’s Republic of China, Email cbb8202@smmu.edu.cn Changquan Ling, Faculty of Traditional Chinese Medicine, Naval Medical University, 800 Xiangyin Road, Shanghai, 200043, People’s Republic of China, Email changquanling@smmu.edu.cnPurpose: Transcatheter arterial chemoembolization (TACE) is commonly used in the treatment of hepatocellular carcinoma (HCC). However, not all patients respond to this treatment. TACE typically leads to hypoxia in the tumor microenvironment. Therefore, we aimed to construct a prognostic model based on hypoxia-related differentially expressed microRNA (miRNAs) in hepatocellular carcinoma (HCC) and to investigate the potential target mRNAs for predicting TACE response.Methods: The hypoxia-related miRNAs (HRMs) were identified in liver cancer cells, then global test was performed to further select the miRNAs which were associated with recurrence and vascular invasion. A prognostic model was constructed based on multivariate Cox regression analysis; qRT-PCR analysis was used to validate the differentially expressed miRNAs in HCC cell lines under hypoxic condition. We further identified the putative target genes of the miRNAs and investigate the relationship between the target genes and TACE response, immune cells infiltration.Results: We established a HRMs prognostic model for HCC patients, containing two miRNAs (miR-638, miR-501-5p), the patients with high-HRMs score showed worse survival in discovery and validation cohort; qRT-PCR analysis confirmed that these two miRNAs are up-regulated in hepatoma cells under hypoxic condition. Furthermore, four putative target genes of these two miRNAs were identified (ADH1B, CTH, FTCD, RCL1), which were significantly associated with TACE response, immune score, immunosuppressive immune cells infiltration, PDCD1 and CTLA4.Conclusion: The HCC-HRMs signature may be utilized as a promising prognostic factor and may have implications for guiding TACE and immune therapy.Keywords: hypoxia, miRNA, signature, hepatocellular carcinoma, prognosis

Ji C, Zhang Z, Chen L, et al. Drug Des Devel Ther. 2016;10:2491–2498. The Editor and Publisher of Drug Design, Development and Therapy are retracting the published article. Concerns were raised regarding the western blot analysis, and it was found that some western blot bands appeared to have been duplicated with those from Zhang Y, Chen C, Jiang Y, et al. PPARγ coactivator-1α (PGC-1α) protects neuroblastoma cells against amyloid-beta (Aβ) induced cell death and neuroinflammation via NF-κB pathway. BMC Neurosci. 2017;18:69. https://doi.org/10.1186/s12868-017-0387-7. Specifically, The western blot image for Figure 3B, A375, IRE1α, appears to have been duplicated with the image for Figure 4a, Nucleus, NF-κB p65 from Zhang et al (2017). The western blot image for Figure 3B, A375, p62, appears to have been duplicated with the image for Figure 4a, Cytoplasm, NF-κB p65 from Zhang et al (2017). The western blot image for Figure 3B, A375, β-actin, appears to have been duplicated with the image for Figure 4a, Cytoplasm, β-actin from Zhang et al (2017). The authors did not respond to our queries and did not provide any original data for their study. As the findings could not be adequately verified the Editor and Publisher made the decision to retract the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Yao Yao,&ast; Yumeng Jia,&ast; Yan Wen, Bolun Cheng, Shiqiang Cheng, Li Liu, Xuena Yang, Peilin Meng, Yujing Chen, Chun’e Li, Jingxi Zhang, Zhen Zhang, Chuyu Pan, Huijie Zhang, Cuiyan Wu, Xi Wang, Yujie Ning, Sen Wang, Feng Zhang Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng ZhangKey Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaEmail fzhxjtu@mail.xjtu.edu.cnPurpose: Most previous genetic studies of sleep behaviors were conducted individually, without comprehensive consideration of the complexity of various sleep behaviors. Our aim is to identify the genetic architecture and potential biomarker of the sleep health score, which more powerfully represents overall sleep traits.Patients and Methods: We conducted a genome-wide association study (GWAS) of sleep health score (overall assessment of sleep duration, snoring, insomnia, chronotype, and daytime dozing) using 336,463 participants from the UK Biobank. Proteome-wide association study (PWAS) and transcriptome-wide association study (TWAS) were then performed to identify candidate genes at the protein and mRNA level, respectively. We finally used linkage disequilibrium score regression (LDSC) to estimate the genetic correlations between sleep health score and other functionally relevance traits.Results: GWAS identified multiple variants near known candidate genes associated with sleep health score, such as MEIS1, FBXL13, MED20 and SMAD5. HDHD2 (PPWAS = 0.0146) and GFAP (PPWAS = 0.0236) were identified associated with sleep health score by PWAS. TWAS identified ORC4 (PTWAS = 0.0212) and ZNF732 (PTWAS = 0.0349) considering mRNA expression level. LDSC found significant genetic correlations of sleep health score with 3 sleep behaviors (including insomnia, snoring, dozing), 4 psychiatry disorders (major depressive disorder, attention deficit/hyperactivity disorder, schizophrenia, autism spectrum disorder), and 9 plasma protein (such as Stabilin-1, Stromelysin-2, Cytochrome c) (all LDSC PLDSC < 0.05).Conclusion: Our results advance the comprehensive understanding of the aetiology and genetic architecture of the sleep health score, refine the understanding of the relationship of sleep health score with other traits and diseases, and may serve as potential targets for future mechanistic studies of sleep phenotype.Keywords: sleep, sleep health score, genome-wide association study, genetics, complex-traits

Chen Chen,&ast; Yan-Mei Liu,&ast; Shu-Xia Xuan, Mei-Fang Zhou, Peng Zhou, Bin Cheng, Jin-Duan Lin, Wei-Guo Yin, Lin-Hai Li Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Guo Yin; Lin-Hai LiDepartment of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, 511518, People’s Republic of ChinaTel +86 763 311 3890Email wgy09dr_mn@163.com; lilinhai_abc@outlook.comObjective: To establish and verify the method for detecting the immune phenotype of peripheral blood T lymphocytes by cellular immune chip technology, analyze the immune status, and discuss its clinical diagnostic value of different populations in the Qingyuan area.Methods: First, a cellular immune chip was used to detect the number of T lymphocyte subsets CD3+, CD4+, CD8+, and CD4/CD8, followed by evaluating the accuracy and precision through a comparison with flow cytometry. After passing the performance verification, a large-scale detection was performed by a cellular immune chip in 8389 cases. Immunochip technology detects the expression of T lymphocyte subsets and analyzes the differences in cellular immune function among people with physical examination, inflammation, and cancer, as well as different cancer types and in genders.Results: The cell immunochip method and flow cytometry method have the same accuracy and precision in detecting specimens, and the former is fast and simple, and is suitable for clinical use; big data analysis is expected to establish a reference range for CD3+, CD4+, and CD8+ T cell counts in Qingyuan. There are statistical differences in CD3+, CD4+, CD8+ T cell counts in physical examination, inflammation and cancer populations; there are also certain differences in CD3+, CD4+, CD8+ T cell counts and CD4/CD8 ratios between different cancer types and different diseases.Conclusion: The method of cell immunochip technology to detect T lymphocyte subsets is simple and practical, with accurate results and rapid detection. It can be used for immune function monitoring and treatment prognosis evaluation of people with different diseases, and it is worthy of popularization and application in clinical practice.Keywords: T lymphocyte, physical examination, CD4/CD8, cellular immune chip

Xiaolin Wu,1,2 Yingjuan Liu,2 Lin Zhu,2 Yue Wang,2 Yuqian Ren,2 Baohe Cheng,3 Leiming Ren,4 Keli Ge,2 Hongyun Li1 1Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China; 2Institute of Integrative Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong, 266021, People’s Republic of China; 3Shandong Haoyun Guoji Stem Cells Hospital, Jinan, Shandong, 250001, People’s Republic of China; 4Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of ChinaCorrespondence: Hongyun LiDepartment of Neurology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao, Shandong, People’s Republic of ChinaEmail 18661808653@163.comKeli GeInstitute of Integrative Medicine, School of Basic Medicine, Qingdao University, No. 38, Dengzhou Road, Shibei District, Qingdao, Shandong, People’s Republic of ChinaEmail ntfadu@163.comIntroduction: Vascular dementia (VaD), one of the brain injuries, is difficult to be cured, so it is important to take active neuroprotective treatment after its occurrence. Many studies have shown that apoptosis serves an important role in VaD occurrence; therefore, inhibition of apoptosis may contribute to the recovery of neurological function after VaD occurrence. Cerebroprotein hydrolysate-I (CH-I), a neuropeptide preparation which consists of several amino acids and small molecular peptides as the main active constituent, is extracted using a method similar to cerebrolysin (CBL) which has neuroprotective and neurotrophic effects.Methods: In the present study, a VaD model which was constructed using bilateral common carotid artery occlusion (BCCAO) in Kunming mice was applied to examine the neuroprotective effects of CH-I.Results: The results show that CH-I treatment could attenuate the decrease of learning and memory ability, cell apoptosis in the hippocampal CA1 region and inhibit the activation of caspase-3 and caspase-9 in VaD mice. Furthermore, CH-I treatment could also upregulate Bcl-2 protein levels and activate PI3K and Akt.Discussion: We speculate that CH-I may induce a neuroprotective effect activating PI3K/Akt signaling pathway in VaD mice.Keywords: vascular dementia, cerebroprotein hydrolysate-I, apoptosis, PI3K/Akt

Yuqian Ren,1 Xiaoqing Ma,1 Tingting Wang,1 Baohe Cheng,2 Leiming Ren,3 Zehua Dong,4 Hongling Liu5 1Institute of Cerebrovascular Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 2Shandong Haoyun International Hospital of Stem Cells, Jinan, Shandong, 250001, People’s Republic of China; 3Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 4Department of Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 5Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaCorrespondence: Zehua Dong; Hongling Liu Tel +86-139 63958230; +86-18661808612Email gonewithwind18@163.com; lhl3798@126.comObjective: To investigate the neuroprotective effect and mechanism of cerebroprotein hydrolysate-I (CH-I) on cerebral ischemia/reperfusion injury in rats.Methods: A total of 100 adult healthy male SD rats were randomly divided into a sham group, model group, CH-I treated group, and cerebrolysin (CBL) positive group, consisting of 20 rats in each group. The middle cerebral artery occlusion/reperfusion (MCAO/R) model of rats was built by inserting a suture into the left external carotid artery (ECA) through the internal carotid artery (ICA). Treatment was performed by intraperitoneal injection of CH-I (20 mg/kg). The neurobehavioral function of rats was evaluated by modified neurological severity scores (mNSS). TTC staining was used to detect the cerebral infarction volume (CIV) of rats. The morphological and structural changes of nerve cells were observed by HE staining and the neuronal apoptosis was counted by TUNEL assay. Immunohistochemical (IHC) analysis was used to detect BDNF and pMEK1/2 expressions. The expressions of BDNF, pMEK1/2, pERK1/2, and pCREB were determined with Western blotting.Results: After treatment with CH-I, the mNSS and CIV of rats were improved (P< 0.05). And the CH-I can reduce the degeneration and apoptosis of nerve cells in rats (P< 0.01). Western blotting showed that the expressions of pMEK1/2, pERK1/2, and pCREB in rats were increased, while the expression of BDNF was decreased after modeling (P< 0.05). After treatment, the expressions of pMEK1/2, pERK1/2, and pCREB in the CH-I group were decreased (P< 0.05), while the expression of BDNF was significantly increased (P< 0.05) compared with the model group. IHC showed that the expression of BDNF and pMEK1/2 was consistent with Western blotting.Conclusion: It is suggested that the CH-I might play a neuroprotective role by inhibiting the expression of MEK-ERK-CREB and enhancing the expression of BDNF after cerebral ischemia/reperfusion injury, thus improving the neurobehavioral function of MCAO/R rats.Keywords: cerebroprotein hydrolysate-I, cerebral ischemia/reperfusion injury, apoptosis, MAPK/ERK1/2 signaling pathway, rats

Li-Ping Zhu,1,&ast; Wei-Lan Yin,2,&ast; Lei Peng,1,&ast; Xiao-Hong Zhou,3 Peng Zhou,1 Shu-Xia Xuan,1 Ying Luo,1 Chen Chen,1 Bin Cheng,1 Jin-Duan Lin,1 Yan-Mei Liu,1 Feng-Jun Tan,4 Wei-Guo Yin1,&ast; 1Department of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, 511518, Guangdong, People’s Republic of China; 2Department of Physiology & Institute of Neuroscience, University of South China, Hengyang, 421001, Hunan, People’s Republic of China; 3Kingmed Diagnostic Center for Clinical Laboratory, Guangzhou, 510330, Guangdong, People’s Republic of China; 4Department of Otorhinolaryngology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, 511518, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Guo YinDepartment of Molecular Diagnosis Center, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, No. B24, Xincheng Yinquan Road, Qingcheng District, Qingyuan, 511518, Guangdong, People’s Republic of ChinaTel +86 763 311 3890Email wgy09dr_mn@163.comObjective: This study explored the correlation between myocardial infarction (MI) and the Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene in the Qingyuan area.Methods: The Glu504Lys polymorphism of the ALDH2 gene was analyzed using the polymerase chain reaction and deoxyribonucleic acid microarray analysis for 468 patients diagnosed with MI for the first time and 132 healthy subjects.Results: There was a significant difference in the distribution of the ALDH2 genotype between the MI group and the control group (P = 0.0492), but there was no significant difference in allele frequency between the two groups (P = 0.1363). The clinical data showed that there were statistically significant differences (P < 0.05) in the two groups’ gender and age distributions, rates of diabetes and hypertension, levels of alcohol and tobacco use, serological levels of heart markers, blood lipids and glucose. The subgroup analysis of ALDH2 genotypes found that alcohol consumption, high levels of myoglobin, and low levels of high-density lipoprotein cholesterol were significantly associated with a higher incidence of MI (P < 0.05). After adjusting for gender, hypertension, diabetes, and other related influencing factors, logistic regression analysis showed that the ALDH2 genotype GA/AA was an independent risk factor for MI (P < 0.05, OR = 1.479, 95% CI = 1.003– 2.179).Conclusion: The presence of risk alleles with the genetic effect (ALDH2 genotype GA/AA) is an independent risk factor for MI.Keywords: myocardial infarction, aldehyde dehydrogenase 2, polymorphism

Xin-Li Xie,* Yan Liu,* Bing Cheng, Xiao-Guang Du, Qiao Ruan, Xing-Min Han Department of Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People’s Republic of China*These authors contributed equally to this work.Correspondence: Xing-Min HanDepartment of Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 Of Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, People’s Republic of ChinaTel +86 371 66915504Fax +86 371 66913059Email hanxingmin_cn@126.comObjective: The aim of the study was to explore the nature of a V-shaped sign in the backbone of the fifth lumbar vertebra revealed by whole-body bone scintigraphy (WBBS).Methods: A local single-photon emission computed tomography (SPECT) scan plus a computed tomography (CT) scan were performed on 41 patients in our department who had a V-shaped sign in the backbone of the fifth lumbar vertebra detected by WBBS. Image fusion was conducted to understand the manifestations of the changes in the V-shaped sign in the CT images in WBBS and to determine the nature of the lesion.Results: All 41 patients presented with degenerative changes observed in the bilateral posterior zygapophysial joint of the fifth lumbar vertebra in the CT imaging bone window, bone hyperplasia of the articular process, joint surface hardening, and a joint gap. The vacuum sign could also be seen in some of these patients.Conclusion: The typical V-shaped sign in the posterior zygapophysial joint of the fifth lumbar vertebra revealed by WBBS suggests degenerative changes in the zygapophysial joint of the fifth lumbar vertebra.Keywords: lumbar, zygapophysial joints, degeneration, bone radionuclide imaging, MDP, single-photon emission computed tomography (SPECT)-CT, diagnosis

Bo Cheng,* Hongsheng Deng,* Yi Zhao,* Feng Zhu, Hengrui Liang, Caichen Li, Ran Zhong, Jianfu Li, Shan Xiong, Zhuxing Chen, Wenhua Liang, Jianxing He Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenhua Liang; Jianxing HeDepartment of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, 151, Yanjiang Road, Guangzhou, 510120, People’s Republic of ChinaTel +86-20-83337792Fax +86-20-83350363Email liangwh1987@163.com; drjianxing.he@gmail.comAbstract: There are increasing numbers of synchronous multiple primary lung cancer (SMPLC) patients in clinical practice, with most lesions presenting as ground-glass opacity (GGO). For SMPLC patients, surgical resection should be a prior option for all lesions suspected of being malignant, if medically and technically feasible. However, it is frequently a dilemma for the management of residual GGO lesions that were unresected simultaneously with the main tumor in SMPLC patients. We report a case of SMPLC, in which the patient underwent surgical resection of the major lesion with EGFR mutation and then received compelling EGFR-TKI treatment for one enlarging residual GGO lesion after 12 months since operation. Furthermore, a comprehensive literature review about the risk for the progress of GGOs unresected simultaneously with the main lesion and the management of these residual GGOs was also summarized. With the treatment of EGFR-TKI gefitinib for 3 months, the biggest residual GGO lesion (more than 10mm) achieved a complete response (CR), three lesions reduced in size, and the other three lesions remained stable in this case. Surgical resection for major lesion and EGFR-TKI treatment on unresected GGOs might bring favorable outcome for patients with EGFR-mutated multifocal lung cancer. This strategy is safe and effective, which could be a promising therapeutic approach for unresectable GGO lesions in EGFR-mutated SMPLC patients after primary surgery. Notably, folate receptor-positive circulating tumor cell (FR+-CTC) for therapeutic monitoring was more sensitive for GGO-featured lung adenocarcinoma than serum markers.Keywords: multiple primary lung cancer, ground-glass opacity, epidermal growth factor receptor-tyrosine kinases inhibitor, folate receptor-positive circulating tumor cell, literature review

Lei Guo,1,* Jingjing Lin,2,* Weiyang Ying,3 Chanfan Zheng,4 Linshuang Tao,2 Binyu Ying,1 Bihuan Cheng,1 Shengwei Jin,4 Beilei Hu2 1Department of Critical Care Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 3Department of Pain Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 4Clinical Research Unit, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Beilei HuDepartment of Neurology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaEmail hubeilei902@126.comShengwei JinDepartment of Anesthesia and Critical Care Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaEmail jinshengwei69@163.comObjective: The WHO has upgraded the status of coronavirus disease 2019 (COVID-19) from epidemic to global pandemic. The psychometric properties aspects of COVID-19 patients without comorbidities in the short term after discharge have not been reported. In this study, the Short Form 36 (SF-36) was used to evaluate the psychometric properties and to find relevant risk factors.Methods: The study was conducted in seven hospitals from January 2020 to April 2020. The SF-36 questionnaire was administered one month after discharge. Univariate analysis and multivariate regression model were used to analyze the risk factors of psychometric properties impairment.Results: In univariate analysis of independent risk factors, according to the comparison of whether the duration of positive nucleic acid was greater than 20 days, the positive nucleic acid duration was independently related to the decreased role-emotional value [100, IQR (66– 100) vs 100, IQR (0, 100); p = 0.0156]. In addition, multivariable linear regression model showed that male sex and positive nucleic acid duration were related to decreased role-emotional value (p = 0.03< 0.05; p = 0.01< 0.05, respectively). Mental health was associated with age (p= 0.0435). Subsequently, we divided into three subgroups: less than seven days, 7 to 14 days and more than 14 days according to the positive nucleic acid duration. The results revealed that there were significant differences in the vitality value and mental health value of patients aged 46 to 69 in the subgroup where the positive nucleic acid duration longer than 14 days (p= 0.0472; p= 0.0311< 0.05, respectively). Similarly, there are also significant differences in role-emotional value in different genders (p= 0.0316).Conclusion: The study described the psychometric properties of COVID-19 patients without comorbidities shortly after discharge. Risk factors for psychometric properties damage included age, male sex, and nucleic acid duration.Keywords: COVID-19, psychometric factor, SF-36

Hengrui Liang,1,* Caichen Li,1,* Yi Zhao,1,* Shen Zhao,2,* Jun Huang,1 Xiuyu Cai,2,3 Bo Cheng,1 Shan Xiong,1 Jianfu Li,1 Wei Wang,1 Changbin Zhu,4 Weiwei Li,5 Jianxing He,1 Wenhua Liang1 1Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, People’s Republic of China; 2Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 3Department of General Internal Medicine, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4BGI Genomics, BGI-Shenzhen, Shenzhen 518083, People’s Republic of China; 5BGI-Guangzhou Medical Laboratory, BGI-Shenzhen, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianxing He; Wenhua LiangDepartment of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, People’s Republic of ChinaTel +86-20-83337792Fax +86-20-83350363Email liangwh1987@163.comObjective: Differences in efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been observed between non-small cell lung cancer (NSCLC) patients with 19 exon deletion (19Del) and L858R mutation. We explored whether the total number or pattern of concomitant mutations of 19Del and L858R may explain their different sensitivities.Patients and Methods: This study contained the mutational profiles of EGFR-mutated NSCLC patients from two cohorts: Guangzhou (G1) and database (G2). Concomitant mutation status and EGFR-TKI response information were retrieved.Results: A total of 403 patients covered 283 genes in the G1 and 803 patients with a different gene set in the G2 were included. Similar prevalence of total concomitant mutation number was observed in both G1 ( 19Del 32.48% vs L858R 30.45%; P=0.68) and G2 ( 19Del 74.9% vs L858R 73.2%; P=0.65) cohorts. Only HGF/c-Met pathway same more related to L858R mutation. EGFR-TKI response information was recorded for 134 patients in the G2 cohort. 19Del showed a higher objective response (OR) rate compared with L858R, regardless of concomitant mutations. Compared to patients with OR, non-OR patients had more concomitant mutations, both in 19Del (53.8% vs 83.3%; P=0.021) and L858R (51.4% vs 77.8%; P=0.029). In particular, total concomitant mutations (OR=0.27; P=0.03), sensitive EGFR mutations (OR=2.21; P=0.04), and T790M (OR=0.244; P=0.02) significantly affected the TKI response.Conclusion: Concomitant mutations were widespread in 19Del and L858R and were associated with poorer OR to EGFR-TKIs. However, 19Del and L858R had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.Keywords: epidermal growth factor receptor mutation, 19Del, L858R, non-small cell lung cancer, concomitant mutation

Jin-wen Huang, Qiu-yun Xu, Min Lin, Bo Cheng, Chao Ji Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, People’s Republic of ChinaCorrespondence: Chao Ji; Bo ChengDepartment of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, People’s Republic of ChinaEmail surpassing.ji@gmail.com; chengbo_fjmu1@163.comIntroduction: Skin, as the outermost organ, is exposed to a wide range of environmental risk factors including ultraviolet (UV) and all kinds of pollutants. Excessive UV exposure contributes to many disorders, such as photoaging, skin inflammation, and carcinogenesis.Methods: To determine the effects of bamboo extract (BEX) from our local plant, Acidosasa longiligula, on UV-irritated human skin, we conducted a variety of studies, including Western blot, apoptosis assays, reactive oxygen species (ROS) detection, and thioredoxin (TXN) and thioredoxin reductase (TXNRD) activity assays in primary skin keratinocytes.Results: We first determined that BEX protects human skin keratinocytes against UV radiation-induced apoptosis and ROS production. UV radiation can robustly impair TXN and TXNRD activity which can, in turn, be significantly rescued by BEX treatment. Moreover, BEX regulates TXN1 levels in primary skin keratinocytes and TXN1 is proved to be required for the protective function of BEX. Last, we found that the NF-κB/p65 pathway mediates the protective function of BEX against UV.Discussion: Collectively, our work delineates the beneficial role of BEX in UV-induced skin cell damage and provides a novel therapeutic reagent to prevent or alleviate the progress of photoaging and other UV-provoked skin diseases.Keywords: Acidosasa longiligula, bamboo extract, BEX, ultraviolet radiation, UV radiation, thioredoxin, TXN, NF-κB pathway

Most studies in the field of CHRNA5-A3 and CHRNB3-A6 have only focused on lung cancer risk; however, the associations with chronic obstructive pulmonary disease (COPD) risk and smoking cessation is less understood, particularly in the Chinese male population. In this study, samples from 823 male patients with COPD (non smokers: 416; still smoking: 407) and 435 smoking male healthy control subjects were performed with DNA extraction and single nucleotide polymorphism (SNP) genotyping. We studied three SNPS in two genes, namely rs667282 and rs3743073 in CHRNA5-A3 and rs4950 in CHRNB3-A6, and their distributions in the three groups are not statistically different (p >0.05). We grouped COPD patients according to whether they had successfully quit smoking, the CT genotype of rs667282 demonstrated association with an increased rate of successful smoking cessation compared with the TT genotype [adjusted odds ratio (OR) = 0.54, 95% confidence interval (95% CI) = 0.37-0.7, p 0.05). Our findings confirmed the hypothesis that CHRNA5-A3 and CHRNB3-A6 variation are not associated with the risk of COPD. We found CHRNA5-A3 and CHRNB3-A6 were significantly associated with successful smoking cessation in smoking COPD patients.

Yan Yu,1,* Niu Xiang,2,* Min Lin,2 Jin-Wen Huang,2 Jing Zhang,2 Bo Cheng,2 Chao Ji2 1Department of Dermatology, First Hospital of Jilin University, Changchun, Jilin 130021, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao JiDepartment of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, People’s Republic of ChinaEmail surpassing.ji@gmail.comBo ChengDepartment of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, People’s Republic of ChinaEmail chengbo_fjmu1@163.comBackground: Melanoma is known as the most aggressive and lethal type of cutaneous cancer due to its rapid development of drug resistance to chemotherapy drugs.Methods: In our study, we conducted a variety of studies, including quantitative PCR, Western blot, and autophagy and apoptosis assays to investigate the involvement of miR-26a and HMGB1 in modulation of dabrafenib sensitivity in human melanoma cell lines.Results: Our studies revealed that the expressions of miR-26a and HMGB1 were altered in two melanoma cell lines after dabrafenib treatment. Additionally, dabrafenib caused autophagy in melanoma and this autophagic process was regulated by miR-26a via modifying HMGB1 expression. Furthermore, silencing HMGB1-inhibited autophagy induced by dabrafenib in melanoma cells. Last, we verified that treatment with a miR-26a mimic and HMGB1 shRNA could increase the efficacy of dabrafenib in melanoma cells.Conclusion: Taken together, we showed that miR-26a is involved in the regulation of dabrafenib efficacy via a HMGB1-dependent autophagy pathway in melanoma cells. These results shed light on a novel treatment for conventional dabrafenib-based chemotherapy for melanoma.Keywords: melanoma, miR-26a, HMGB1, dabrafenib, autophagy, apoptosis

Zhipeng Xu1, Baoli Cheng1, Shuiqiao Fu2, Xu Liu3, Guohao Xie1, Zhongwang Li1, Yun Ji2, Qinghui Fu2, Zhinan Xu4, Xiangming Fang1 1Department of Anesthesiology and Intensive Care Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, People’s Republic of China; 2Department of Surgical Intensive Care Unit, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, People’s Republic of China; 3Department of Intensive Care Unit, The Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of China; 4Institute of Biological Engineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou City, Zhejiang Province, People’s Republic of ChinaCorrespondence: Xiangming FangDepartment of Anesthesiology and Intensive Care Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou City, Zhejiang Province 310003, People’s Republic of ChinaTel/Fax +86 5 718 820 8006Email xmfang@zju.edu.cnPurpose: Sepsis-associated coagulopathy (SAC) contributes to the development of multiple organ failure (MOF) and increasing mortality. The present study was conducted to investigate whether coagulative biomarkers on admission to the intensive care unit (ICU) can predict acute kidney injury (AKI) and mortality in patients with septic shock caused by intra-abdominal infection (IAI).Patients and methods: An observational retrospective study was conducted in the surgical ICU. We studied patients who met the criteria of septic shock (Sepsis-3) caused by IAI between January 1, 2013, and December 31, 2016. By adjusting for baseline characteristics, multivariate regression analyses were employed to identify independent risk factors for predicting AKI and mortality.Results: Of the 138 enrolled patients, 65 patients developed AKI. The patients who developed AKI exhibited a dramatically higher Sequential Organ Failure Assessment (SOFA) score (median, 12), Acute Physiology and Chronic Health Evaluation (APACHE) II score (median, 27.5) and mortality rate. In both models, we found that activated partial thromboplastin time (APTT) (odds ratio (OR)=1.074, 95% confidence interval (CI) 1.030–1.120, p=0.001), prothrombin time (PT) (OR=1.162, 95% CI 1.037–1.302, p=0.010) and D-dimer level (OR=1.098, 95% CI 1.002–1.202, p=0.045) on admission to the ICU were significant risk factors for AKI. Moreover, Cox regression analysis showed that prolonged APTT (OR=1.065, 95% CI 1.025–1.107, p=0.001) was independently associated with high mortality.Conclusion: In patients with septic shock caused by IAI, APTT, PT and D-dimer level on admission to the ICU were significantly associated with AKI. Furthermore, APTT was an independent predictor of 30-day mortality.Keywords: coagulopathy, biomarker, septic shock, acute kidney injury, intra-abdominal infection, mortality

Zhenxiong Zhao, Shuya Bai, Ronghua Wang, Si Xiong, Yawen Li, Xiju Wang, Wei Chen, Bin ChengDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of ChinaPurpose: Both cancer-associated fibroblasts (CAFs) and liver cancer stem cells (LCSCs) play an important part in the tumorigenesis, development and metastasis of hepatocellular carcinoma (HCC). Moreover, the stem-like properties in HCC cells could be promoted by CAFs. However, the mechanism remains largely unknown. Patients and methods: We used conditioned medium (CM) of CAFs to culture Huh7 cells. Stemness of the cells was then examined mainly by sphere formation assay while stemness-associated genes including Nanog, Sox2 and Oct4 were measured by Western blotting. Immunofluorescence staining, Transmission Electron Microscope as well as Western blotting were performed to detect the level of autophagy in Huh7 cells. Results: Increased level of stemness and autophagy was observed in HCC cells cultured in CAFs-CM compared to the control group. Activation of CAFs-induced autophagic flux could be inhibited by Chloroquine (CQ), which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Treatment of HCC cells with CQ effectively reversed the CAF-induced stemness, invasion, and metastasis ability in these cells. In vivo, Huh7 cells inoculated together with CAFs developed significantly larger tumors than Huh7 cells injected alone. Moreover, blockage of autophagy in Huh7 cells by CQ greatly reduced the growth of xenografted tumors of Huh7 cells combined with CAFs. Conclusion: These results reveal that CAFs are capable of promoting stemness and metastasis of HCC cells and blocking autophagy could markedly attenuate the stemness enhanced by CAFs, suggesting that targeting autophagy in HCC could be an effective strategy in HCC treatment.Keywords: cancer-associated fibroblasts, stemness, liver cancer, autophagy

Zhenxiong Zhao, Si Xiong, Ronghua Wang, Yawen Li, Xiju Wang, Yun Wang, Shuya Bai, Wei Chen, Yuchong Zhao, Bin ChengDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of ChinaPurpose: Because many hepatocellular carcinoma (HCC) cases develop from fibrotic or cirrhotic livers, fibroblasts are abundant in the microenvironment of HCC. Although the contribution of cancer-associated fibroblasts (CAFs) to the progression of HCC is well established, the role of fibroblasts has not been comprehensively revealed.Patients and methods: The RayBio Human Cytokine Antibody Array was used to elucidate the role of peri-tumor fibroblasts (PTFs) in promoting malignant properties of HCC. IL-6 and STAT3 signaling were inhibited in both HCC cell lines and non-tumor L-02 liver cells to further determine its role in the progression of HCC. Moreover, the expression of IL-6 and pTyr705 STAT3 was detected in HCC samples and peri-tumor liver tissues by immunohistochemical staining.Results: PTFs not only promoted the proliferation, invasion, and metastasis of liver cancer cells, but also stimulated the permanent malignant transformation of human non-tumor L-02 liver cells, resulting in hepatocarcinogenesis in vivo. The RayBio Human Cytokine Antibody Array indicated that PTFs secreted a higher level of soluble IL-6 than CAFs. IL-6 derived from PTFs greatly activated STAT3 Tyr705 phosphorylation in both non-tumor L-02 cells and HCC cells. IL-6-neutralizing antibody and STAT3 Tyr705 phosphorylation inhibitor, cryptotanshinone, largely abolished the positive effects of PTFs on HCC carcinogenesis and progression. Moreover, high expression of pTyr705 STAT3 in peri-tumor tissues was significantly correlated with tumor recurrence rate after three years in a postsurgical follow-up with patients with HCC.Conclusion: These results indicated that PTFs induce carcinogenesis and development of HCC via IL-6 and STAT3 signaling.Keywords: PTFs, HCC, carcinogenesis, metastasis, STAT3 signaling

Bo Cheng,1 Aimei Rong,2 Quanbo Zhou,3 Wenlu Li4 1Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; 2Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450000, China; 3Department of Anus and Intestine Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; 4Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China Background: Claudin 8 (CLDN8), an integral membrane protein that constitutes tight junctions in cell membranes, was recently implicated in tumor progression. However, its roles in colorectal cancer (CRC) progression and metastasis remain unknown. Methods: In this study, we examined the effect of CLDN8 on the progression of CRC, including cell proliferation, migration, and invasion, and determines its underlying molecular mechanism using in vitro CRC cell lines and in vivo mouse xenograft models. Results: We found that CLDN8 expression in human CRC tissues was significantly higher than that in adjacent normal tissues. The knockdown of CLDN8 markedly suppressed the proliferation, migration, and invasion of SW480 and HT-29 CRC cells, whereas the overexpression of CLDN8 notably promoted tumor progression in SW480 and HT-29 CRC cells. Mechanistic studies revealed that CLDN8 upregulated p-ERK (p-PKB/AKT) and MMP9 in CRC cells. Notably, the MAPK/ERK inhibitor PD98095 dramatically attenuated the effects of CLDN8 on p-ERK and MMP9. Moreover, PD98095 remarkably blocked the tumor-promoting activity of CLDN8. The knockdown of CLDN8 also inhibited the in vivo tumor growth in a nude mouse xenograft model. Collectively, CLDN8 promoted CRC cell proliferation, migration, and invasion, at least in part, by activating the MAPK/ERK signaling pathway. Conclusion: These findings suggest that CLDN8 exhibits an oncogenic effect in human CRC progression. Keywords: CLDN8, colorectal cancer, MAPK/ERK signaling

Bo Cheng,1,2 Xiaofu Qiu,1 Huanhui Li,1 Guosheng Yang1 1Department of Urology, Southern Medical University affiliated Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China Purpose: Laser therapy provides an alternative option for treating non-muscle-invasive bladder cancer (NMIBC). However, the clinical evidence for potassium-titanyl-phosphate (KTP) laser en bloc resection is still limited. Here, we investigated the efficacy and safety of the 120-W front-firing KTP laser for the treatment of NMIBC.Methods: A total of 64 patients with NMIBC treated with either a 120-W front-firing KTP-photoselective vapo-enucleation of the bladder tumor (PVEBT, n=34) or transurethral resection of the bladder tumor (TURBT, n=30) were included. En bloc resection was applied to the patients in PVEBT group.Results: There was no significant difference in rinsing time (P=0.292), indwelling catheter (P=0.080), pathologic type, and T stage (P=0.870) between the two groups. Compared with the TURBT group, patients treated with PVEBT had a shorter hospitalization stay (P=0.044), a shorter operation time (P=0.008), and a lower muscle miss rate (P=0.044). PVEBT is superior to TURBT in terms of the rate of 1-year recurrence (P=0.015) and tumor grade progression rate (P=0.019).Conclusion: The 120-W front-firing KTP laser en bloc enucleation technique is a safe and feasible procedure for treating patients with NMIBC. Further external validation in larger cohorts with a long follow-up period is warranted. Keywords: bladder cancer, transurethral resection, en bloc, laser surgery, recurrence

Jianfei Liang,1,* Shanshan Xu,1,* Mingming Shen,2,* Bingkun Cheng,3 Yongfeng Li,4 Xiangwei Liu,1 Dongze Qin,1 Anuj Bellare,5 Liang Kong1 1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Disease & Shaanxi Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi’an, 2Department of Stomatology, Xinhua Hospital of Beijing, Beijing, 3Department of Oral and Maxillofacial Surgery, School of Stomatology, The Second Hospital of Hebei Medical University, Shijiazhuang, 4Department of Stomatology, Chinese PLA 532 Hospital, Huangshan, People’s Republic of China; 5Department of Orthopedic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA *These authors contributed equally to this work Abstract: An easier method for constructing the hierarchical micro-/nano-structures on the surface of dental implants in the clinic is needed. In this study, three different titanium surfaces with microscale grooves (width 0.5–1, 1–1.5, and 1.5–2 µm) and nanoscale nanoparticles (diameter 20–30, 30–50, and 50–100 nm, respectively) were obtained by treatment with different concentrations of hydrofluoric acid (HF) and at different etching times (1%, 3 min; 0.5%, 12 min; and 1.5%, 12 min, respectively; denoted as groups HF1, HF2, and HF3). The biological response to the three different titanium surfaces was evaluated by in vitro human bone marrow-derived mesenchymal stem cell (hBMMSC) experiments and in vivo animal experiments. The results showed that cell adhesion, proliferation, alkaline phosphatase activity, and mineralization of hBMMSCs were increased in the HF3 group. After the different surface implants were inserted into the distal femurs of 40 rats, the bone–implant contact in groups HF1, HF2, and HF3 was 33.17%±2.2%, 33.82%±3.42%, and 41.04%±3.08%, respectively. Moreover, the maximal pullout force in groups HF1, HF2, and HF3 was 57.92±2.88, 57.83±4.09, and 67.44±6.14 N, respectively. The results showed that group HF3 with large micron grooves (1.5–2.0 µm) and large nanoparticles (50–100 nm) showed the best bio-functionality for the hBMMSC response and osseointegration in animal experiments compared with other groups. Keywords: hydrofluoric acid etching, surface modification, micro-/nano-structures, osteogenic activity, titanium implant

Chao Ji,1,2 Ziping Zhang,1,2 Lihong Chen,1,2 Kunli Zhou,1,2 Dongjun Li,1,2 Ping Wang,1,2 Shuying Huang,1,2 Ting Gong,2 Bo Cheng1,2 1Department of Dermatology, the 1st Affiliated Hospital of Fujian Medical University, 2Fujian Institute of Dermatology and Venereology, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China Abstract: Melanoma is one of the deadliest skin cancers and accounts for most skin-related deaths due to strong resistance to chemotherapy drugs. In the present study, we investigated the mechanisms of dabrafenib-induced drug resistance in human melanoma cell lines A375 and MEL624. Our studies support that both endoplasmic reticulum (ER) stress and autophagy were induced in the melanoma cells after the treatment with dabrafenib. In addition, ER stress-induced autophagy protects melanoma cells from the toxicity of dabrafenib. Moreover, inhibition of both ER stress and autophagy promote the sensitivity of melanoma cells to dabrafenib. Taken together, the data suggest that ER stress-induced autophagy determines the sensitivity of melanoma cells to dabrafenib. These results provide us with promising evidence that the inhibition of autophagy and ER stress could serve a therapeutic effect for the conventional dabrafenib chemotherapy. Keywords: melanoma, dabrafenib, ER stress, autophagy, apoptosis

BACKGROUND: Glucocorticoids (GCs) are generally envisioned as immunosuppressive, but in conditions such as rosacea and perioral dermatitis they can lead to increased skin inflammation. In lung epithelia, GCs promote expression of the proinflammatory cytokine CCL20, which contributes to steroid-resistant asthma. In the skin, CCL20 stimulates inflammation by recruiting T helper 17 T lymphocytes and dendritic cells, and is elevated in papulopustular rosacea. OBJECTIVES: To understand if, and how, GCs affect CCL20 expression in human keratinocytes. CCL20 expression was assessed by quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. METHODS: Selective inhibition of candidate genes and signalling pathways was performed using RNA interference and chemical inhibitors. The binding of activated GC receptor to genomic DNA was determined by chromatin immunoprecipitation, and enhancer activity of genomic sequences was measured with a reporter assay. RESULTS: We found that GC treatment increased CCL20 expression in human keratinocytes and murine skin, both in the undisturbed state and with tumour necrosis factor-α stimulation. GC repressed proinflammatory signalling pathways, including nuclear factor kappa B and p38/mitogen-activated protein kinase, but these inhibitory effects were opposed by the direct binding of activated GC receptor to the CCL20 enhancer, promoting CCL20 expression. CONCLUSIONS: Viewed together, these findings demonstrate a mechanism by which GCs induce expression of CCL20 in keratinocytes, which may contribute to the inflammation seen in steroid-exacerbated skin conditions.

The recently discovered pressure-induced polymorphic transitions (PIPT) in high-entropy alloys (HEAs) have opened an avenue towards understanding the phase stability and achieving atomic structural tuning of HEAs. So far, whether there is any PIPT in the body-centered cubic (bcc) HEAs remains unclear. Here, we studied an ordered bcc-structured (B2 phase) AlCoCrFeNi HEA using in situ synchrotron radiation X-ray diffraction (XRD) up to 42 GPa and ex situ transmission electron microscopy, a PIPT to a likely-distorted phase was observed. These results highlight the effect of the lattice distortion on the stability of HEAs and extend the polymorphism into ordered bcc-structured HEAs.

Two dimensional inorganic–organic hybrid perovskites (2D perovskites) suffer from not only quantum confinement, but also dielectric confinement, hindering their application perspective in devices involving the conversion of an optical input into current. In this report, we theoretically predict that an extremely low exciton binding energy can be achieved in 2D perovskites by using high dielectric-constant organic components. We demonstrate that in (HOCH2CH2NH3)2PbI4, whose organic material has a high dielectric constant of 37, the dielectric confinement is largely reduced, and the exciton binding energy is 20-times smaller than that in conventional 2D perovskites. As a result, the photo-induced excitons can be thermally dissociated efficiently at room temperature, as clearly indicated from femtosecond transient absorption measurements. In addition, the mobility is largely improved due to the strong screening effect on charge impurities. Such low dielectric-confined 2D perovskites show excellent carrier extraction efficiency, and outstanding humidity resistance compared to conventional 2D perovskites.