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Fu-Xing-Zi Li,1 Feng Xu,1 Chang-Chun Li,1 Li-Min Lei,1 Su-Kang Shan,1 Ming-Hui Zheng,1 Xiao Lin,2 Bei Guo,1 Ke-Xin Tang,1 Jia-Yue Duan,1 Yun-Yun Wu,1 Ye-Chi Cao,1 Jun-Jie Liu,3 Ling-Qing Yuan1 1Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Department of Periodontal Division, Hunan Xiangya Stomatological Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaCorrespondence: Ling-Qing Yuan, Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email allenylq@csu.edu.cnPurpose: Anecdotal reports have praised the benefits of cold exposure, exemplified by activities like winter swimming and cold water immersion. Cold exposure has garnered acclaim for its potential to confer benefits and potentially alleviate diabetes. We posited that systemic cold temperature (CT, 4– 8°C) likely influences the organism’s blood components through ambient temperature, prompting our investigation into the effects of chronic cold exposure on type 2 diabetic (T2DM) mice and our initial exploration of how cold exposure mitigates the incidence of T2DM.Methods: The effects of CT (4– 8°C) or room temperature (RT, 22– 25°C) on T2DM mice were investigated. Mice blood and organ specimens were collected for fully automated biochemical testing, ELISA, HE staining, immunohistochemistry, and immunofluorescence. Glucose uptake was assessed using flow cytometry with 2-NBDG. Changes in potential signaling pathways such as protein kinase B (AKT), phosphorylated AKT (p-AKT), insulin receptor substrates 1 (IRS1), and phosphorylated IRS1 (p-IRS1) were evaluated by Western blot.Results: CT or CT mice plasma-derived extracellular vesicles (CT-EVs) remarkably reduced blood glucose levels and improved insulin sensitivity in T2DM mice. This treatment enhanced glucose metabolism, systemic insulin sensitivity, and insulin secretion function while promoting glycogen accumulation in the liver and muscle. Additionally, CT-EVs treatment protected against the streptozocin (STZ)-induced destruction of islets in T2DM mice by inhibiting β-cell apoptosis. CT-EVs also shielded islets from destruction and increased the expression of p-IRS1 and p-AKT in adipocytes and hepatocytes. In vitro experiments further confirmed its pro-insulin sensitivity effect.Conclusion: Our data indicate that cold exposure may have a potentially beneficial effect on the development of T2DM, mainly through the anti-diabetic effect of plasma-derived EVs released during cold stimulation. This phenomenon could significantly contribute to understanding the lower prevalence of diabetes in colder regions.Keywords: cold exposure, plasma-derived extracellular vesicles, type 2 diabetes, insulin sensitivity, β‑cell destruction

Yong-Yao Wu,1,&ast; Jun-Yuan Li,1,&ast; Qiao-Jing Xia,1 Yi-Yi Gao,1 Chao Zhang,1 Peng-Jie Xu,1 Jiang Liu,1 Hao-Jie Zhang,1 Ri-Zhen Yu2 1Department of Nephrology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang Province, 315099, People’s Republic of China; 2Urology & Nephrology Center, Department of Nephrology, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang Province, 310014, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao-Jie Zhang, Department of Nephrology, Ningbo Medical Center Lihuili Hospital, No. 1111 Jiangnan Road, Yinzhou District, Ningbo City, Zhejiang Province, 315099, People’s Republic of China, Email zhang_haojie843@outlook.com Ri-Zhen Yu, Urology & Nephrology Center, Department of Nephrology, Affiliated People’s Hospital, Hangzhou Medical College, No. 158 Shangtang Road, Gongshu District, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel +86 571-85893889, Fax +86 571-85131448, Email rizhen_3180yu83@126.comObjective: Sarcopenia is more common in maintenance hemodialysis (MHD) patients, and the aim of this study is to analyze the risk factors associated with sarcopenia in MHD patients, along with its correlation to emotional status and quality of life.Methods: This is a cross-sectional cohort study. A total of 111 MHD patients who were treated in the Department of Nephrology of our hospital were selected as the study subjects by convenience sampling. The quality of life and emotional status were evaluated by health survey scale (SF-36), self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Regression analysis was used to explore the influencing factors of sarcopenia. Correlation analysis was used to investigate the correlation between sarcopenia and quality of life and emotional status.Results: The prevalence of sarcopenia was 59.8%. The results showed that age, gender, body mass index (BMI), dialysis time, economic status, marital status and pre-dialysis creatinine were significant factors affecting the development of sarcopenia in hemodialysis patients (p< 0.05). The SF-36 total score was significantly lower in the sarcopenia group (72.05± 12.28 vs 78.03± 10.55) than in the non-sarcopenia group, but the anxiety scale score (52.97± 4.67 vs 36.2± 3.36) and depression scale score (57.67± 4.58 vs 38.71± 3.77) were significantly higher than those in the non-sarcopenia group (p< 0.001). Correlation analysis showed that sarcopenia was positively correlated with SAS and SDS scores and negatively correlated with SF-36 total score (p < 0.05).Conclusion: The risk of sarcopenia was higher among MHD patients who were older, male, single, with a longer MHD duration, lower economic status, lower BMI, comorbid diabetes and lower levels of creatinine.Keywords: maintenance hemodialysis, sarcopenia, quality of life, risk factors, cross-sectional studies

Nan Zhang,1,&ast; Gui-yuan Song,2,3,&ast; Yong-jian Hu,4 Xia Wang,4 Tian-zhu Chao,1 Yao-yao Wu,1 Ping Xu1 1School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, 277160, People’s Republic of China; 2School of Public Health, Weifang Medical University, Weifang, Shandong, 261000, People’s Republic of China; 3Radiology Laboratory, Central Laboratory, Rizhao People’s Hospital, Rizhao, Shandong, 276800, People’s Republic of China; 4Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Xu, Tel +86 19863349848, Email 13273730271@163.comBackground: Radiation-induced lung injury (RILI) is a critical factor that leads to pulmonary fibrosis and other diseases. LncRNAs and miRNAs contribute to normal tissue damage caused by ionizing radiation. Troxerutin offers protection against radiation; however, its underlying mechanism remains largely undetermined.Methods: We established a model of RILI in mice pretreated with troxerutin. The lung tissue was extracted for RNA sequencing, and an RNA library was constructed. Next, we estimated the target miRNAs of differentially expressed (DE) lncRNAs, and the target mRNAs of DE miRNAs. Then, functional annotations of these target mRNAs were performed using GO and KEGG.Results: Compared to the control group, 150 lncRNA, 43 miRNA, and 184 mRNA were significantly up-regulated, whereas, 189 lncRNA, 15 miRNA, and 146 mRNA were markedly down-regulated following troxerutin pretreatment. Our results revealed that the Wnt, cAMP, and tumor-related signaling pathways played an essential role in RILI prevention via troxerutin using lncRNA-miRNA-mRNA network.Conclusion: These evidences revealed that the abnormal regulation of RNA potentially leads to pulmonary fibrosis. Therefore, targeting lncRNA and miRNA, along with a closer examination of competitive endogenous RNA (ceRNA) networks are of great significance to the identification of troxerutin targets that can protect against RILI.Keywords: troxerutin, radiation-induced lung injury, ceRNA, lncRNA-miRNA-mRNA network, AKT, wnt signal pathway

Ya-Chun Chu,1,2,&ast; Hsu-Wei Fang,2,3,&ast; Yu-Yi Wu,1 Yu-Jun Tang,1 Erh-Hsuan Hsieh,1 YiZhou She,4 Che-Yi Chang,1 I-Chan Lin,5,6 Yin-Ju Chen,1,7– 9 Guei-Sheung Liu,1,10– 12 Ching-Li Tseng1,8,9,13 1Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 2Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei City, Taiwan; 3Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan; 4School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 5Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan; 6Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; 7Department of Radiation Oncology, Taipei Medical University Hospital, Taipei City, Taiwan; 8International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan; 9Center for Precision Medicine and Translational Cancer Research, Taipei Medical University Hospital, Taipei City, Taiwan; 10Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia; 11Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia; 12Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; 13Research Center of Biomedical Device, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Li Tseng, Tel +886 2 2736 1661 (ext. 5214), Email chingli@tmu.edu.twBackground: Corneal neovascularization (NV) is a process of abnormal vessel growth into the transparent cornea from the limbus and can disturb the light passing through the cornea, resulting in vision loss or even blindness. The use of nanomedicine as an effective therapeutic formulation in ophthalmology has led to higher drug bioavailability and a slow drug release rate. In this research, we designed and explored the feasibility of a new nanomedicine, gp91 ds-tat (gp91) peptide-encapsulated gelatin nanoparticles (GNP-gp91), for inhibiting corneal angiogenesis.Methods: GNP-gp91 were prepared by a two-step desolvation method. The characterization and cytocompatibility of GNP-gp91 were analyzed. The inhibition effect of GNP-gp91 on HUVEC cell migration and tube formation was observed by an inverted microscope. The drug retention test in mouse cornea was observed by in vivo imaging system, fluorescence microscope, and DAPI/TAMRA staining. Finally, the therapeutic efficacy and evaluation of neovascularization-related factors were conducted through the in vivo corneal NV mice model via topical delivery.Results: The prepared GNP-gp91 had a nano-scale diameter (550.6 nm) with positive charge (21.7 mV) slow-release behavior (25%, 240hr). In vitro test revealed that GNP-gp91 enhanced the inhibition of cell migration and tube formation capacity via higher internalization of HUVEC. Topical administration (eyedrops) of the GNP-gp91 significantly prolongs the retention time (46%, 20 min) in the mouse cornea. In chemically burned corneal neovascularization models, corneal vessel area with a significant reduction in GNP-gp91 group (7.89%) was revealed when compared with PBS (33.99%) and gp91 (19.67%) treated groups via every two days dosing. Moreover, GNP-gp91 significantly reduced the concentration of Nox2, VEGF and MMP9 in NV’s cornea.Conclusion: The nanomedicine, GNP-gp91, was successfully synthesized for ophthalmological application. These data suggest that GNP-gp91 contained eyedrops that not only have a longer retention time on the cornea but also can treat mice corneal NV effectively delivered in a low dosing frequency, GNP-gp91 eyedrops provides an alternative strategy for clinical ocular disease treatment in the culture.Graphical Abstract: Keywords: gp91 peptide, gelatin, nanoparticles, ocular retention, control release, corneal neovascularization, eye drops

Yuan-yuan Wu,1 Wen-Hui Liao,1 Zong-ling Niu,1 Si-Han Zhou,1 Tian-Tian Wu,1 Zhe Li,2 Qi-Hua Zhao,1 Jing-Yuan Xu,2 Ming-jin Xie1 1School of Chemical Science and Technology, Yunnan University, Kunming, People’s Republic of China; 2Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Ming-jin Xie, Email mjxie@ynu.edu.cnBackground: Gallium (III) metal-organic complexes have been shown to have the ability to inhibit tumor growth, but the poor water solubility of many of the complexes precludes further application. The use of materials with high biocompatibility as drug delivery carriers for metal-organic complexes to enhance the bioavailability of the drug is a feasible approach.Methods: Here, we modified the ligands of gallium 8-hydroxyquinolinate complex with good clinical anticancer activity by replacing the 8-hydroxyquinoline ligands with 5-bromo-8-hydroxyquinoline (HBrQ), and the resulting Ga(III) + HBrQ complex had poor water solubility. Two biocompatible materials, bovine serum albumin (BSA) and graphene oxide (GO), were used to synthesize the corresponding Ga(III) + HBrQ complex nanoparticles (NPs) BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs in different ways to enhance the drug delivery of the metal complex.Results: Both of BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs can maintain stable existence in different solution states. In vitro cytotoxicity test showed that two nanomedicines had excellent anti-proliferation effect on HCT116 cells, which shown higher level of intracellular ROS and apoptosis ratio than that of cisplatin and oxaliplatin. In addition, the superior emissive properties of BSA/Ga/HBrQ NPs and GO/Ga/HBrQ NPs allow their use for in vivo imaging showing highly effective therapy in HCT116 tumor-bearing mouse models.Conclusion: The use of biocompatible materials for the preparation of NPs against poorly biocompatible metal-organic complexes to construct drug delivery systems is a promising strategy that can further improve drug delivery and therapeutic efficacy.Graphical Abstract: Keywords: gallium complex, nanomedicine, anticancer, colorectal cells, drug delivery, in vivo imaging

Yu-Yan Wu, Tian-Tian Shan, Xiang-Tao Pan Hematology Department, Taicang Hospital of Soochow University, Medical College of Soochow University, Taicang City, People’s Republic of ChinaCorrespondence: Xiang-Tao Pan, Hematology Department, Taicang hospital of Soochow University, Medical College of Soochow University, Taicang City, People’s Republic of China, Email panxiangtao@csco.ac.cnAbstract: This paper reports two cases of postpartum pulmonary embolism in Taicang First People’s Hospital affiliated to Soochow University. They share many similarities in age, fertilization way, birthing method, incidence of pulmonary embolism, treatment and prognosis. The main purpose is to inspire the current maternal PTE risk assessment, diagnosis and treatment, as well as to explore the existing limitations and problems.Keywords: postpartum pulmonary embolism, pulmonary embolism, in vitro fertilization, IVF, cesarean section, anticoagulation

Zhao-Yin Ma,1,&ast; Yong-Ya Wu,2,&ast; Hong-Yin-Long Cui,3 Guang-Yan Yao,3 Hong Bian3,4 1Department of Diagnostic, Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Emergency Critical Care Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 3Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 4Department of Neurology, Jinan Central Hospital, Shandong University, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Bian, Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China, Tel +86-15318816109, Fax +86-053188382085, Email jnbianh@163.comObjective: Type 2 diabetes mellitus (T2DM) and ischemic stroke, which are common diseases among older people, are closely related to cognitive impairment. This study aims to investigate the influencing factors of post-stroke cognitive impairment (PSCI) in patients with T2DM.Methods: We enrolled 161 patients with T2DM who experienced acute ischemic stroke and were hospitalized in the Department of Neurology, Jinan Central Hospital, Shandong, China. Cognitive function was evaluated with the Montreal Cognitive Assessment scale. According to the results, patients were divided into three groups—the cognitively normal group, mild cognitive impairment group, and severe cognitive impairment group. We analyzed general demographic data, laboratory information, imaging data, the results of neuropsychological evaluation, and clinical features as well as influencing factors of PSCI in these patients and established a prediction model.Results: The three groups of patients were significantly different in terms of age, education level, course of diabetes mellitus (DM), recurrent cerebral infarction (RCI), and other factors. RCI, course of DM, and glycated hemoglobin (HbA1c) were independent risk factors of PSCI in patients with T2DM, with odds ratio (95% confidence interval): 7.17 (2.09, 30.37), 5.39 (2.40, 14.59), and 3.89 (1.66, 10.04), respectively, whereas female, senior high school, serum albumin were protective factors: 0.28 (0.07, 0.95), 0.05 (0.01, 0.21), 0.20 (0.08, 0.42), respectively. Furthermore, we constructed a prediction model using sex, age, education level, RCI, DM course, HbA1c and serum albumin and obtained a receiver operating characteristic (ROC) curve. The area under the ROC curve is 0.966, suggesting the significant association of these influencing factors with PSCI in patients with T2DM.Conclusion: In this study, the occurrence of PSCI in patients with T2DM was related to RCI, course of DM, and HbA1c, among other factors. Attention to influencing factors is needed in these patients for early diagnosis and timely intervention of cognitive impairment.Keywords: blood glucose, cognitive impairment, ischemic stroke, risk factor

Chi-Fen Huang,1,2,&ast; Yu-Siou Lin,1 Yen-Nan Chiu,3 Susan Shur-Fen Gau,3 Vincent Chin-Hung Chen,4,5 Chiao-Fan Lin,5,6 Yi-Hsuan Hsieh,5,6 Wen-Sheng Liu,7– 11 Hsiang-Lin Chan,5,6,&ast; Yu-Yu Wu1 1Department of Psychiatry, YuNing Psychiatric Clinic, Taipei, Taiwan; 2Department of Psychiatry, Saint Paul’s Hospital, Taoyuan, Taiwan; 3Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; 4Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan; 5Department of Psychiatry, Chang Gung University, Taoyuan, Taiwan; 6Department of Child Psychiatry, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 7Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; 8College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan; 9Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; 10Division of Nephrology, Department of Medicine, Taipei City Hospital, Zhongxing Branch, Taipei, Taiwan; 11Department of Special Education, University of Taipei, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Yu-Yu Wu, Department of Psychiatry, YuNing Psychiatric Clinic, 3F., No. 6, Sec. 2, Fuxing S. Road, Taipei, 10664, Taiwan, Tel +886-2-27080706, Fax +886-2-27080987, Email ruthyuyuwu@gmail.comBackground: The Autism Diagnostic Interview-Revised (ADI-R) is an essential semi-structured diagnostic tool for autism spectrum disorder (ASD). This study aims to validate the Chinese version of the ADI-R in Taiwan.Methods: The Chinese version of the ADI-R was translated and back-translated by professional translators and was approved by the original authors. A group of child psychiatrists and psychologists corrected medical terminology for the final version. Then, a total of 74 participants with ASD (male, 59, 79.73%) and 33 control participants without ASD (male, 16, 48.48%) were recruited. All participants were between 3 years 4 months to 41 years old (mean: 14.63 ± 7.93 years). Exploratory factor analysis (EFA) was used to measure the factor structure.Results: Cronbach’s α showed good to excellent internal consistency (0.78– 0.98) over the three core symptom domains of the Chinese version of the ADI-R. Pearson’s correlation analysis revealed very high test–retest reliability (Pearson’s correlation coefficients ranging from 0.95 to 0.99). EFA supported three categories of factors. For correct diagnosis of ASD, the Chinese version of the ADI-R had high sensitivity (97.30%), specificity (100%), positive predictive value (PPV) (100%), and negative predictive value (NPV) (94.29%). All domains also showed excellent area under the curves (0.991– 1), sensitivity (94.59– 98.65%), specificity (96.97– 100%), Youden index (94.59– 98.65%), PPV (97.78– 100%), NPV (89.19– 100%), positive likelihood ratio (32.55– 33.00%) and negative likelihood ratio (0.00– 0.05) after statistical examination.Conclusion: The Chinese version of the ADI-R is a reliable and valid diagnostic tool for the diagnosis of ASD in Clinical settings in Taiwan.Keywords: ADI-R, autism spectrum disorders, Chinese version, reliability, validity

Yu-Yan Wu,&ast; Yong Tan,&ast; Min Yan, Zhen Cheng, Xiang-Tao Pan Department of Hematology, Taicang Hospital of Soochow University, Taicang, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang-Tao PanDepartment of Hematology, Taicang Hospital of Soochow University, No. 58. of South Changsheng Road, Taicang, Jiangsu, People’s Republic of ChinaTel +86 18915768003Email Panxt99xt@email.cnObjective: To investigate the characteristics of coagulation indicators, such as C-reactive protein (CRP), antithrombin (AT), and fibrinogen (FB) in patients with pulmonary thromboembolism (PTE) and their relationship with PTE.Methods: The clinical characteristics, CRP, AT, FB, plasma D-dimer (D-D) and platelet (PLT) counts, and blood coagulation indicators of 433 patients with PTE diagnosed by computed tomographic pulmonary angiography (CTPA) were comprehensively analyzed, and the relevant clinical significance was discussed.Results: The total incidence of PTE was 1.60% (433/270,983 cases), and the age group with the highest incidence was over 60 years old. D-D increased in 412 (95.2%) patients. PLT was normal in 331 (76.4%) cases, but decreased in 53 (12.3%) cases and increased in 49 (11.3%) cases. CRP increased in 76.0% (288/379 cases) and was normal in 24.0% (91/379 cases). AT decreased in 109 (25.2%) cases and FB increased in 102 (23.6%) cases. There were no significant changes in other coagulation indexes. CRP was positively correlated with PLT and FB (r = 0.1026, t = 2.0118, P < 0.05, and r = 0.5360, t = 12.2963, P < 0.01, respectively). CRP was negatively correlated with AT (r = – 0.2005, t = 4.0100, P < 0.01).Conclusion: The incidence of PTE was higher in hospitalized patients. Most patients with PTE have increased CRP and FB and decreased AT, and these levels may be related to the occurrence of PTE.Keywords: pulmonary thromboembolism, C-reactive protein, antithrombin, fibrinogen, D-dimer, platelets

Yu-Ying Wu,1,2 I-Fan Lin,1,3 Po-Yuan Chen,1,2 Cheng-Kai Lin,1,2 Cheng-Chun Wu,1 Cheng-Loong Liang,1,2 Yi-Che Lee,1,4 Chi-Wei Lin,1,5 Wei-Leng Chin,1,5 Hao Kuang Wang1,2,6 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 5Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, TaiwanCorrespondence: Hao Kuang WangDepartment of Neurosurgery, E-Da Hospital/ I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, TaiwanTel +866-975106080Email ed101393@gmail.comBackground: Osteoporotic fractures are a significant cause of morbidity and mortality affecting population worldwide. All guidelines recommended vertebral fracture assessment by dual-energy X-ray absorptiometry (DXA). This study aimed at evaluation of any associated benefits of screening with DXA in patients who had received vertebroplasty in Taiwan.Methods: Data were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. We retrospectively compared the data of patients, who were admitted for vertebroplasty, whether they received DXA screening or not. The outcomes of interest were recurrence of spinal fracture and mortality during a follow-up period of 10 years.Results: From this Taiwan national database, the screening rate of osteoporosis in patient who received vertebroplasty was 11.7%. The mean age in the non-DXA screened cohort (n=32,986) was 74.03± 12.21 years (71.98% female). In the DXA screened cohort (n=4361), the mean age was 76.43± 9.19 years (79.91% female). During the 10-year follow-up period, after matching, non-DXA patients had significantly higher mortality rates than their DXA counterparts, which were 42.37% and 37.73% (p-value < 0.0001), respectively. The re-fracture rates between non-DXA and DXA patients were not significantly different at 17.26% and 16.89% (p-value = 0.1766), respectively.Conclusion: The rate of DXA screening before patients receiving vertebroplasty was extremely low, at 11.7%. Our results showed that DXA screening before vertebroplasty in spinal fractures patients had lower mortality. From this national retrospective cohort study, routine screening of osteoporosis in spinal fracture patients can lead to reduction in mortality.Keywords: osteoporosis, vertebroplasty, DXA, mortality

Cheng-Kai Lin,1,2 Po-Yuan Chen,1,2 Yu-ying Wu,1,2 Cheng-Chun Wu,1 Han-Jung Chen,1,2 Cheng-Loong Liang,1,2 Yi-Che Lee,1,3 Chi-Wei Lin,1,4 Chao-Ming Hung,1,5,* Hao-Kuang Wang1,2,6,* 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 5Department of General Surgery, E-Da Cancer Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, Taiwan*These authors contributed equally to this workCorrespondence: Chao-Ming Hung; Hao-Kuang WangDepartment of Neurosurgery, E-Da Hospital/I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 82445, TaiwanTel +866-975106080Email ed100647@edah.org.tw; ed101393@gmail.comBackground: Statin treatment improves clinical outcomes in patients with ischemic strokes, although there is no evidence regarding the safety of statin therapy in patients with intracerebral hemorrhage (ICH). This study aimed at evaluating the effects of continuing statin treatment after ICH.Methods: Data were obtained from the National Health Insurance Research Database in Taiwan. We retrospectively compared the data of patients with and without statin exposure after ICH. The outcomes of interest were recurrence of hemorrhagic stroke and mortality during a follow-up period of 10 years.Results: During the 10-year follow-up period, the mortality rate was 32.73% in the statin group and 42.77% in the non-statin group. Statin therapy in patients with acute ICH with dyslipidemia can decrease mortality.Conclusion: Statin therapy reduced the risk of 10-year mortality in patients who experienced acute hemorrhagic stroke.Keywords: statin, hemorrhagic stroke, mortality

Yuan-Yuan Wu,* Shui-Feng Wang,* Pei-Wen Zhu, Qing Yuan, Wen-Qing Shi, Qi Lin, Biao Li, You-Lan Min, Qiong Zhou, Yi Shao Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiong Zhou; Yi ShaoDepartment of Ophthalmology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Donghu, Nanchang, Jiangxi 330006, People’s Republic of ChinaEmail 1357483244@qq.com; freebee99@163.comPurpose: The purpose was to investigate the differences in spontaneous functional connectivity (FC) of the primary visual cortex (V1) between patients with neovascular glaucoma (NVG) and healthy controls (HCs) using resting-state functional magnetic resonance imaging data.Methods: A total of 18 patients with NVG (nine males and nine females) and 18 HCs with similar age and sex background were enrolled in the study and inspected using resting-state functional magnetic resonance imaging. The differences in FC of the V1 between the two groups were compared using the independent samples t-test. We used the receiver operating characteristic (ROC) curve to compare the average FC values of NVG subjects with those of HCs.Results: FC in the left V1 and right fusiform gyrus, bilateral cuneus, and left precuneus was significantly decreased in the NVG group compared with that reported in the HC group. Meanwhile, patients with NVG presented increased FC between the right V1 and bilateral middle frontal gyrus. However, they also exhibited declining FC between the right V1 and left precuneus, and bilateral cuneus. The ROC curve analysis of each brain region indicated that the accuracy of the area under the ROC curves regarding NVG was excellent.Conclusion: NVG involves aberrant FC in the V1 in different brain areas, including the visual-related and cognitive-related regions. These findings may assist in unveiling the underlying neural mechanisms of impaired visual function in NVG.Keywords: neovascular glaucoma, functional connectivity, spontaneous brain activity, primary visual cortex

Sophie Hsin-Yi Liang,1 Jen-Yu Chou,2 Yu-Yu Wu,3 Chin-Pang Lee,4 Brent Allan Kelsen,5 Yi-Chen Lee6 1Section of Department of Child and Adolescent Psychiatry, Department of Psychiatry, Chang Gung Memorial Hospital at Taoyuan and Chang Gung University College of Medicine, Taoyuan, Taiwan; 2Graduate Institute of Humanities in Medicine, Taipei Medical University, Taipei, Taiwan; 3Section of Department of Child and Adolescent Psychiatry, Department of Psychiatry, Chang-Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taiwan, YuNing Psychiatric Clinic, Taipei, Taiwan; 4Department of Psychiatry, Chang-Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan; 5Language Center, National Taipei University, New Taipei City, Taiwan, Department of Psychology, Auckland University of Technology, Auckland, New Zealand; 6Department of Psychiatry, Chang-Gung Memorial Hospital at Chiayi and Chang Gung University College of Medicine, Chiayi, TaiwanCorrespondence: Yi-Chen LeeSchool of Occupational Therapy, College of Medicine, National Taiwan University, Taipei, TaiwanEmail peggylee599@gmail.comBackground: The Devereux Early Childhood Assessment for Toddlers (DECA-T), which is one of the few standardized, norm-referenced behavioral rating scales related to young children’s mental health, resilience, and social-emotional development, was developed for toddlers aged between 18 and 36 months.Objective: The aim of this study was to test the clinimetric properties of the Chinese (Traditional) version of the DECA-T (C-DECA-T) using a classical test theory analysis and an item response theory analysis.Methods: Seventy-five community-based toddlers aged from 18 to 36 months and 50 clinic-based participants recruited in hospitals in northern Taiwan participated in this study. Social-emotional competence was assessed by the C-DECA-T and children’s behavior problems were rated via the Child Behavior Checklist 1.5 to 5 (CBCL/1.5–5). Homogeneity of the C-DECA-T was assessed by Mokken analysis; sensitivity and specificity were assessed via receiver operating characteristic curve.Results: The results showed the C-DECA-T demonstrated good test–retest reliability (r=0.8) and high internal consistency (Cronbach’s alpha = 0.94). Inter-rater reliability between father and mother was fair (ICC = 0.46). Convergent validity of the CBCL/1.5–5 total behavior problems (r=−0.26) demonstrated acceptable psychometric performance. The overall measure of the sampling adequacy of the C-DECA-T assessed by principal component analysis was 0.93. Mokken scale analysis showed the 36-items of the C- DECA-T formed a weak unidimensional scale (Hs=0.35), supporting its construct validity. The area under curve of the C-DECA-T in prediction of social-emotional disturbance was 0.70. The optimal cutoff of the Total Protective Factor score of the C-DECA-T was a T score of 40.1 (T40.1), with a sensitivity of 95% and a specificity of 68%. Item 2 (“show affection for a familiar adult”) and item 33 (“calm herself/himself”) provide a good amount of information for the assessment of social-emotional strength and needs of a toddler in clinical practice.Conclusion: The C-DECA-T showed good psychometric properties. Our findings of high internal consistency of the three subscales and total score of the C-DECA-T suggest symptom manifestation of social-emotional competence and needs in Taiwanese toddlers is not culturally different from American toddlers. The clinimetric properties of the C-DECA-T examined by a classical test theory analysis approach and an item response theory analysis approach suggest that the C-DECA-T is a reliable and valid instrument for measuring social-emotional strength and needs in the population in Taiwan.Keywords: Devereux Early Childhood Assessment for Toddlers, DECA-T, social-emotional competence, item response theory, Mokken scale analysis, principal component analysis

Yong-Yang Wu,1 Xin-Yu Liu,2 De-Xiang Zhuo,1 Huai-Bin Huang,1 Fa-Biao Zhang,1 Shang-Fan Liao1 1Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, China; 2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China Purpose: The aim of this study was to investigate whether the expression of the ligand-gated Ca2+ channel transient receptor potential vanilloid type-1 (TRPV1) in primary human renal cell carcinoma (RCC) is associated with clinicopathological features.Patients and methods: Fresh and frozen primary tumor and normal peritumoral kidney tissues from 127 patients diagnosed with RCC were analyzed for TRPV1 expression by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry.Results: Quantitative RT-PCR revealed that TRPV1 was decreased 3.20-fold in RCC tissue vs normal peritumoral kidney tissue (p=0.012). Significantly different TRPV1 mRNA expression was detected in RCC tissues of different Fuhrman grades and histopathological subtypes (F=4.282, p=0.015 and F=5.205, p=0.014, respectively). Decreased TRPV1 expression was correlated with RCC histopathological subtype (R=-0.554, p=0.003) and Fuhrman grade (R=−0.525, p=0.006). Western blot analysis of TRPV1 protein expression showed similar results. Immunohistochemical analysis showed strong expression of TRPV1 in kidney tubules but demonstrated weak or no immunostaining in RCC tissues.Conclusion: TRPV1 expression was decreased in RCC, which was significantly associated with tumor Fuhrman grades and histopathological subtypes. It seems to suggest that TRPV1 expression may be a valuable tool to predict the extent of RCC progression. Keywords: renal cell carcinoma, TRPV1, Fuhrman grade, histopathological subtype, prognostic factor

Yuanyuan Wu,1 Xinmiao Yao,2 Yongliang Jiang,1 Xiaofen He,1 Xiaomei Shao,1 Junying Du,1 Zui Shen,1 Qiaoying He,1 Jianqiao Fang1 1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China Abstract: Pain is considered a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component. The negative affective-motivational component of pain is different from the sensory component and amplifies the pain experience. Nowadays, a significant number of preclinical research groups have focused their attention on the affective symptoms of pain. In the present study, we investigated the pain aversion and anxiety-like behavior of the complete Freund’s adjuvant (CFA)-induced chronic pain model. CFA rats experienced spontaneous pain during pain-paired conditioning (pain aversion) and spontaneous pain produces an affective response (anxiety-like behavior). Moreover, pain aversion was gradually attenuated, while the anxiety-like behavior increased in 4 weeks. Therefore, although the negative effect (including pain aversion and anxiety) is always associated with hyperalgesia, the manifestations of negative effect may follow different time courses, which may influence the progress of primary disease. The findings illustrate that targeted therapy should focus on a specific aspect in different stages of pain. Our study emphasizes the necessity of using multiple tests to study pain comorbidities. Keywords: pain, pain aversion, pain affection, anxiety-like behavior, chronic inflammatory pain, rat

Yan Jiang,1,* Zhen-Lin Zhang,2,* Zhong-Lan Zhang,3 Han-Min Zhu,4 Yi-Yong Wu,5 Qun Cheng,4 Feng-Li Wu,5 Xiao-Ping Xing,1 Jian-Li Liu,3 Wei Yu,6 Xun-Wu Meng11Department of Endocrinology, Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 2Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 3Department of Gynecology and Obstetrics, General Hospital of the People's Liberation Army, Beijing, 4Department of Geriatrics, Shanghai Huadong Hospital, Shanghai, 5Department of Gynecology and Obstetrics, Beijing Hospital, Ministry of Public Health, Beijing, 6Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China*These authors contributed equally to this workObjective: To evaluate whether the efficacy and safety of menatetrenone for the treatment of osteoporosis is noninferior to alfacalcidol in Chinese postmenopausal women.Method: This multicenter, randomized, double-blinded, double-dummy, noninferiority, positive drug-controlled clinical trial was conducted in five Chinese sites. Eligible Chinese women with postmenopausal osteoporosis (N=236) were randomized to Group M or Group A and received menatetrenone 45 mg/day or alfacalcidol 0.5 µg/day, respectively, for 1 year. Additionally, all patients received calcium 500 mg/day. Posttreatment bone mineral density (BMD), new fracture onsets, and serum osteocalcin (OC) and undercarboxylated OC (ucOC) levels were compared with the baseline value in patients of both groups.Results: A total of 213 patients (90.3%) completed the study. After 1 year of treatment, BMD among patients in Group M significantly increased from baseline by 1.2% and 2.7% at the lumbar spine and trochanter, respectively (P0.05). In Group M, OC and ucOC decreased from baseline by 38.7% and 82.3%, respectively (P

The pretension of building membrane structures may relax over its service lifetime, which may cause engineering failure under external loads. Therefore, the pretension of building membrane structures should be monitored or estimated regularly to compare the actual pretension to its design pretension and then to adopt some strengthening measures to mitigate future problems. Based on the geometrically nonlinear vibration of a rectangular orthotropic membrane structure, a nondestructive detection method for monitoring its pretension is developed in this article. This method is achieved by impacting a low-velocity pellet onto the membrane surface to generate vibration and detecting its response amplitude. Then the detected amplitude is converted into a pretension estimate via a derived formula. In addition, experiments for three kinds of conventional membrane material (Heytex H5573, Xing Yi Da, and ZZF 3010) were carried out according to the theoretical idea. The experimental results proved this method is feasible and verified the theoretical derivation is reasonable.

© 2015 Springer Science+Business Media New York Solid-state processes of bonding 1 mm copper (Cu) wires on Cu substrates and silicon (Si) chips, respectively, were developed. To overcome Cu oxidation issue, the bonding surface on the wire was plated a silver (Ag) layer. An annealing step followed to make the Ag layer much easier to deform and conform to the Cu or Si bonding surfaces. The bonding process was performed at 300 °C with 6.89 MPa. Wire-bond cross sections were studied using optical and electron microscopy, respectively. The images obtained exhibit nearly perfect Ag–Cu bonding interface. For wire-bonds made on Cu substrate, in-plane (shear) pull test measured a breaking of force 20.7–23.7 kg, comparable to the 22.5 kg breaking force of the Cu wire itself. Breaking forces on vertical (peel) pull test are about one-half of in-plane pull test results. For wire-bonds made on Si chip, breaking forces are about 80 % of those made on Cu substrate. Fracture modes were evaluated in details. 90 % of the wire-bonds broke with three modes mixed together: near Cu–Ag plating interface, inside Ag layer, and Ag–Cu bonding interface. Thus, the bonding interface is as strong as other regions of the wire-bond. This solid-state wire bonding process is expected to have valuable applications in high power and high temperature devices and modules where the wire-bonds have to stand alone without protection due to lack of high temperature molding compound and reinforcing materials.

Two copper (Cu) substrates were bonded using silver (Ag) and indium (In) and annealed at 200-250 °C to convert the joints into the solid solution (Ag) for enhanced strength and ductility. Cu-Cu pair was chosen so that the samples break in the joint during shear test. The upper Cu was electroplated with 15 μm Ag. The lower Cu was plated with 15 μm Ag, followed by In and 0.1 μm Ag to inhibit indium oxidation. Two designs were implemented, using 8 μm and 5 μm In, respectively. The Cu substrates were bonded at 180 °C in 100 mTorr vacuum without flux. Afterwards, samples were annealed at 200 °C for 1000 h (first design) and at 250 °C for 350 h (second design), respectively. Scanning electron microscope with energy dispersive X-ray analysis (SEM and EDX) results indicate that the joint of the first design is an alloy of mostly (Ag) with micron-size Ag2In and (ζ) regions, and that of second design has converted to a single (Ag) phase. Shear test results show that the samples are very strong. The breaking forces far exceed requirements in MILSTD- 883H standards. Fracture incurs inside the joint and is a mix of brittle and ductile modes or only ductile mode. The joint solidus temperatures are 600 °C and 900 °C for the first and second designs, respectively. Copyright © 2014 by ASME.

Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, causes increased levels of tyrosine phosphorylation and blocks, at noncytotoxic concentrations, the differentiative response of rat pheochromocytoma (PC12) cells to beta-nerve growth factor (beta NGF) and basic fibroblast growth factor (bFGF) in a reversible manner. It also prevents growth factor-induced neurite proliferation in primed cells and causes the retraction of previously formed neurites, even in the presence of beta NGF or bFGF. It is equally effective in blocking neurite proliferation by 8-Br-cAMP. Zinc chloride and ammonium molybdate, two other inhibitors of tyrosine phosphatases, also cause parallel decreases in neurite proliferation. Orthovanadate generally reduces the transcription of immediate early response genes (TIS 8 and c-fos) and secondary response genes (ornithine decarboxylase (ODC), acetyl-cholinesterase (AChE) and SCG 10) induced by beta NGF, bFGF, EGF, and PMA, albeit in a variable fashion. There was no observed effect on the kinetics of expression as judged by TIS 8 induction by beta NGF and protein kinase C (PKC) downregulation did not change the levels of inhibition by orthovanadate seen in control cells. Orthovanadate does not affect the production of diacylglycerol induced by beta NGF or bFGF. These observations are consistent with the view that growth factor stimulation of differentiation in PC12 cells involves at least one other PKC independent pathway, and that cAMP and PMA (and their active analogs) activate tyrosine kinases (albeit probably secondarily), which are at least partially responsible for their actions. Although the exact site(s) of action of orthovanadate that lead to the inhibition of growth factor-induced neurite proliferation are unknown, the results presented suggest that it prolongs tyrosine phosphorylations by nonreceptor tyrosine kinases that act downstream from the receptor kinases.

[beta],[beta]-Dimethylacrylshikonin is one of the most abundant naphthoquinones in the root extracts of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), which have been reported to have antitumor effects. This study evaluated the antiproliferative activity of [beta],[beta]-dimethylacrylshikonin on human hepatocellular carcinoma (HCC) cells both in vitro and in vivo. In vitro, the MTT assay showed that [beta],[beta]-dimethylacrylshikonin inhibited the proliferation of SMMC-7721 cells in both dose- and time-dependent manners with its 50% inhibitory concentration (IC(50) ) at 48 h being 15.01 ± 0.76 ug/mL. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) and Hoechst staining detected the characteristics of cell apoptosis in [beta],[beta]-dimethylacrylshikonin-treated cells and the apoptotic rates of treated groups were increased in a dose-dependent manner. Flow cytometric analysis revealed that [beta],[beta]-dimethylacrylshikonin could block the cell cycle arrest at G2 phase. Furthermore, [beta],[beta]-dimethylacrylshikonin down-regulated the mRNA and protein expression of Bcl-2 but up-regulated that of Bax. The cleaved caspase-3 protein was also detected in treated cells. The experiment in vivo showed that [beta],[beta]-dimethylacrylshikonin significantly suppressed the growth of H(22) transplantable hepatoma, and induced the activation of caspase-3 determined by immunohistochemistry. The results indicate that [beta],[beta]-dimethylacrylshikonin has significant antitumor effects on hepatocellular carcinoma both in vitro and in vivo. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background/purpose: The activating JAK2 mutation with a G-C to T-A transversion at codon 617 (JAK2(V617F)) is associated with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis. Here, we report a technical advance in the diagnosis of JAK2(V617F) in MPNs by melting curve analysis (MCA).Methods: From January through December 2006, we prospectively enrolled 78 patients with PV (n = 21), ET (n = 32), myelofibrosis (n = 5), secondary erythrocytosis (n = 4), secondary thrombocytosis (n = 2), acute myelocytic leukemia (n = 4), chronic myelocytic leukemia (n = 8), and myelodysplastic syndrome (n = 2). Mutation analysis for JAK2(V617F) was performed on either bone marrow or peripheral blood cells using allele-specific polymerase chain reaction (AS-PCR) or sequencing and fluorescence resonance energy transfer (FRET) probes with MCA.Results: For the initial 30 samples, the detection rate of JAK2(V617F) using MCA was comparable to the gold standard of the PCR sequencing methods. However, the turnaround times for MCA and PCR were 2 hours and 2 days, respectively. The detection rate of JAK2(V617F) was 76.2% for PV (homozygous in 14.3%), 46.9% for ET, 80% for myelofibrosis (homozygous in 20%), and 0% for the other conditions. In PV, patients with homozygous JAK2(V617F) presented with significantly longer disease durations than heterozygous patients. In ET, there were no differences in the clinical parameters of patients harboring JAK2(V617F) compared with those with wild-type JAK2.Conclusion: Heterozygous and homozygous JAK2(V617F) mutations can be identified using the rapid and reliable assay based on FRET probes and MCA. Detection of JAK2(V617F) can be used to assist in the diagnosis of BCR/ABL-negative MPNs. [ABSTRACT FROM AUTHOR]

Purpose: Prophylactic lamivudine to prevent chemotherapy-induced hepatitis B virus (HBV) reactivation has been widely adopted in hematological cancer patients. We examined the deferred preemptive strategy, upon rising viremia, in breast cancer (BC) patients based on sensitive serum HBV DNA level monitoring in a non-randomized controlled study.Patients and Methods: Baseline virological profiles before cytotoxic chemotherapy were retrospectively analyzed in historical BC and non-BC patients. A prospective cohort study, including 22 early BC patients (Group I) who were hepatitis B surface antigen (HBsAg)± and required adjuvant chemotherapy, were enrolled and had deferred preemptive use of lamivudine upon viremic surge. During the study period, another 23 BC patients, who did not participate in the above-mentioned study, received prophylactic use of lamivudine as routine practice (Group 2). Chemotherapy-induced hepatitis events and the lamivudine treatment course were compared.Results: There was no significant difference in the incidence of hepatitis during chemotherapy between these two groups. Patients in Group I had statistically significant shorter duration of lamivudine use during chemotherapy. However, once lamivudine had been initiated, the treatment course is not significantly shorter than those patients given prophylactically.Conclusions: Deferred preemptive strategy is feasible to control HBV replication and prevent its reactivation in BC patients undergoing chemotherapy. However, it may not be superior to prophylactic strategy and clinically practical. [ABSTRACT FROM AUTHOR]

RATIONALE: Claudin (CLDN)-1, a key component of tight junction complexes, was down-regulated in human lung adenocarcinomas. OBJECTIVES: To investigate the clinical significance of CLDN1 expression in patients with lung adenocarcinoma and its role in cancer invasion and metastasis. METHODS: We examined the CLDN1 mRNA expression in tumor specimens from 64 patients with lung adenocarcinoma and protein expression by immunohistochemistry in an independent cohort of 67 patients with lung adenocarcinoma. CLDN1 functions in cancer cell migration, invasion, and metastatic colonization were studied by overexpression and knockdown of CLDN1. Affymetrix microarrays were performed to identify gene expression changes associated with CLDN1 overexpression. MEASUREMENTS AND MAIN RESULTS: We found that low-CLDN1 mRNA expression had shorter overall survival (P = 0.027, log-rank test) in 64 patients with lung adenocarcinoma, and we confirmed by immunohistochemistry that low CLDN1 expression had shorter overall survival (P = 0.024, log-rank test) in an independent cohort of 67 patients with lung adenocarcinoma. Overexpression of CLDN1 inhibited cancer cell dissociation in time-lapse imaging of wound healing, and suppressed cancer cell migration, invasion, and metastasis. Knockdown CLDN1 expression increased cancer cell invasive and metastatic abilities. Affymetrix microarrays identified a panel of genes altered by CLDN1 overexpression. CLDN1 increased expressions of cancer invasion/metastasis suppressors (e.g., connective tissue growth factor [CTGF], thrombospondin 1 [THBS1], deleted in liver cancer 1 [DLC1], occludin [OCLN], zona occludens 1 [ZO-1]) and suppressed expressions of invasion/metastasis enhancers (e.g., secreted phosphoprotein 1 [SPP1], cut-like homeobox 1 [CUTL1], transforming growth factor alpha [TGF-alpha], solute carrier family 2 [faciliated glucose transporter] member 3 [SLC2A3], placental growth factor [PGF]), supporting a role for CLDN1 as an invasion and metastasis suppressor. CONCLUSIONS: CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for patients with lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Few studies have specifically investigated the cognitive correlates of employment for persons with mental retardation. To evaluate the relationship of cognitive and adaptive functioning to work status, 56 competitively employed and 55 unemployed individuals with mental retardation underwent a comprehensive neuropsychological and adaptive behavioral evaluation. Results of multivariate analysis of covariance (MANCOVA) revealed significant group differences in cognitive and adaptive behavioral domains controlling for gender and severity of mental retardation. Follow-up ANCOVAs showed that the employed group performed significantly better than the unemployed group on measures of attention, memory, verbal comprehension, visual perception, and adaptive behavior. Using discriminant function analysis, 73.2 percent of the employed and 76.4 percent of the unemployed people were predicted correctly. These results suggest that adaptive behavior and specific aspects of cognitive functioning are significant predictors of successful employment for persons with mental retardation. [Copyright &y& Elsevier]

Cold temperatures have been shown to slow skin wound healing. However, the specific mechanisms underlying cold-induced impairment of wound healing remain unclear. Here, we demonstrate that small extracellular vesicles derived from cold-exposed mouse plasma (CT-sEVs) decelerate re-epithelialization, increase scar width, and weaken angiogenesis. CT-sEVs are enriched with miRNAs involved in the regulation of wound healing-related biological processes. Functional assays revealed that miR-423-3p, enriched in CT-sEVs, acts as a critical mediator in cold-induced impairment of angiogenic responses and poor wound healing by inhibiting phosphatase and poly(A) binding protein cytoplasmic 1 (PABPC1). These findings indicate that cold delays wound healing via miR-423-3p in plasma-derived sEVs through the inhibition of the ERK or AKT phosphorylation pathways. Our results enhance understanding of the molecular mechanisms by which cold exposure delays soft tissue wound healing., Competing Interests: Declarations. Consent for publication: All authors agree for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objectives: NOTCH3 pathologic variants cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which presents with stroke and dementia and is characterized by white matter hyperintensities (WMHs) on brain MRI. The R544C variant is a common pathologic variant in Taiwan, but not all carriers exhibit significant symptoms. We investigated whether WMHs occur before clinical symptoms in carriers with pathogenic variants, examined factors associated with WMHs, and explored their relationship with cognitive functions., Methods: We enrolled 63 R544C carriers without overt clinical disease (WOCD) and 37 age-matched and sex-matched noncarriers as controls from the Taiwan Precision Medicine Initiative data set. All participants underwent clinical interviews, comprehensive neuropsychological assessments, and brain MRI. We calculated total and regional WMH volumes, determined the age at which WMHs began increasing in carriers, and examined the relationship between WMHs and neuropsychological performance. Factors associated with WMH volumes were analyzed using multivariable linear regression models., Results: Compared with controls, R544C carriers WOCD had increased WMH volume, except in the occipital and midbrain areas, and showed a rapid increase in WMHs starting at age 48. They scored lower on the Mini-Mental State Examination (median = 28.4 vs 29.0, p = 0.048), Montreal Cognitive Assessment (MoCA) (median = 28.3 vs 29.0, p = 0.013), and memory and executive function tests than controls. After adjusting for age, sex, and education, MoCA scores were associated with whole-brain (r = -0.387, p adj = 0.008) and regional WMHs (all p adj < 0.05) except in the midbrain area. Age (β = 0.034, 95% CI 0.021-0.046, p < 0.001), hypercholesterolemia (β = 0.375, 95% CI 0.097-0.653, p = 0.009), and the vascular risk factor (VRF) index (β = 0.132, 95% CI 0.032-0.242, p = 0.019) were associated with the WMH severity in carriers., Discussion: Our study revealed that WMHs are extensively distributed in R544C carriers WOCD. They exhibited a rapid increase in WMHs beginning at age 48, approximately 7 years earlier than the reported age at symptomatic onset. Age was the strongest predictive factor of WMHs, and VRF, particularly hypercholesterolemia, might be modifying factors of WMHs.

Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated Proteins (CRISPR/Cas) system can accurately identify and cleave target DNA sequences, while the effective combination of DNA nanomatrix and entropy-driven self-assembled enzymes can significantly enhance the sensitivity, stability, and diversified functionality of sensors through highly ordered molecular arrangement and spontaneous efficient assembly processes. Herein, a carbon-encapsulated MoS 2 hollow nanorod (C-MoS 2 ) with excellent conductivity and multiple active sites is used to construct bioanode of biofuel cell by integrating it with an entropy-driven self-assembled enzyme-DNA nanomatrix cascade DNAzyme-CRISPR/Cas system. When thrombin binds aptamer, it exposes the trigger strand on the anode, initiating chain displacement. This activates DNAzyme, triggering a cascade reaction that cleaves and releases the probe strand. The probe then binds CrRNA, forming a multimeric complex with Cas protein.When non-specific cleavage of the single strand occurs, it leads to the release of glucose oxidase (GOD) from the DNA matrix and causes a significant decrease in the value of the system's open-circuit voltage (E OCV ). The E OCV values show a good negative correlation with the concentration of thrombin (TB) in the range of 0.00001-100 nM, achieving a limit of detection of 3.55 fM (S/N = 3)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Miller fisher syndrome (MFS) is a variant of Guillain-Barré syndrome, an acute immune-mediated peripheral neuropathy that is often secondary to viral infections. Anti-ganglioside antibodies play crucial roles in the development of MFS. The positive rate of ganglioside antibodies is exceptionally high in MFS patients, particularly for anti-GQ1b antibodies. However, the presence of other ganglioside antibodies does not exclude MFS., Case Summary: We present a 56-year-old female patient who suddenly developed right blepharoptosis and progressively worsening vision in both eyes. There were flu symptoms prior to onset, and a coronavirus disease 2019 test was positive. On physical examination, the patient exhibited bilateral extraocular muscle paralysis, weakened reflexes in both limbs, and impaired coordination. The cerebrospinal fluid examination results showed no obvious abnormalities. Bilateral peroneal nerve F-waves were not extracted. Serum anti-GD1b IgG and anti-GT1a IgG antibodies were positive. The patient received intravenous methylprednisolone (1000 mg/day), with the dosage gradually decreased. Additionally, intravenous high-dose immunoglobulin treatment was administered for 5 days (0.4 g/kg/day) from day 2 to day 6 of hospitalization. The patient's symptoms improved after treatment with immunoglobulins and hormones., Conclusion: Positive ganglioside antibodies may be used as supporting evidence for the diagnosis; however, the diagnosis of MFS is more reliant on clinical symptoms., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

High-altitude electromagnetic pulse (HEMP) has attracted considerable attention for its influence on electrical equipment. HEMP is divided into three parts: early time HEMP (E1), intermediate-time HEMP (E2), and late-time HEMP (E3). Most studies focused on E1 alone, while few investigated others. However, the electrical equipment may be disturbed by more than one part since these three parts co-exist in a HEMP environment. The pulse current injection (PCI) test is an effective immunity test method for evaluating the sensitivity and susceptibility of electrical equipment. To investigate the responses of electrical equipment excited by the consecutive E1 and E2 and compare with those under the individual E1 or E2, this paper builds a PCI platform that can carry out PCI tests with the consecutive E1 and E2 conducted current. To output the E1 current and the E2 current consecutively, which exhibit significant differences in the rise time (20 ns and 1.5 μs), peak current (2500 and 250 A), and full width at half maximum (FWHM, 500-550 ns and 3-5 ms), an E1&E2 coupler with a fast-closing high-current trigger switch is designed in this paper. Finally, some 10-kV epoxy insulators are tested in the developed platform, which shows the capacity of the proposed platform to test the immunity of electrical equipment with the consecutive E1 and E2 conducted current., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Aim: To investigate parenting and mother-child interactions in unaffected siblings of autistic children., Method: This cross-sectional study enrolled 274 probands with a DSM-5 diagnosis of autism spectrum disorder (ASD) (87.4% male; mean [SD] age = 11 years 4 months [3 years 2 months]), their unaffected siblings (n = 274, 46.72% male; mean [SD] age = 11 years 3 months [3 years 4 months]), and 296 age-balanced and sex-balanced typically developing children (82.77% male; mean [SD] age = 11 years 3 months [2 years 8 months]). Maternal parenting styles and mother-child interactions were assessed using maternal reporting., Results: Regardless of the child's age, maternal educational level, or presence of attention-deficit/hyperactivity disorder, autistic children received more overprotective and controlling parental behaviour than unaffected children. Correlates for parenting, mother-child interactions, and behavioural problems in the home setting in children with ASD and typically developing children were autistic traits, maternal anxiety and depressive symptoms, and maternal autistic characteristics; those in unaffected siblings were age, autistic traits, maternal educational level, and maternal autistic characteristics., Interpretation: The diagnosis of ASD in a child can significantly influence maternal parenting behaviours, mother-child interactions, and the child's behavioural problems in the home setting. Furthermore, maternal anxiety or depressive symptoms, along with autistic characteristics in both mother and child, might shape parenting practices and exacerbate behavioural difficulties in autistic children., What This Paper Adds: Autistic children received more overprotective and controlling parenting. In children with autism spectrum disorder and typically developing children, autistic traits, maternal anxiety and depression, and maternal autistic characteristics were correlated. In unaffected siblings, age, autistic traits, maternal education, and maternal autistic characteristics were correlated., (© 2024 Mac Keith Press.)

Owing to their high sensitivity across a wide stress range, mechanical reliability, and rapid response time, flexible polymer foam piezoresistive sensors have been extensively used in various fields. The reliable application of these sensors under harsh environments, however, is severely limited by structural devastation and poor interfacial bonding between polymers and conductive nanoparticles. To address the above issues, robust MXene/CNT nanocoatings on the foam surface, where the chemical assembly of MXene nanosheets and the physical anchoring of CNTs lead to strong interfacial bonding, are designed and described, which endows foams with structural reliability and unexpected multi-functionalities without compromising their instinct properties. The optimized foam nanocomposites thus maintain outstanding wide-temperature flexibility (-60-210 °C) and elasticity (≈3% residual strain after 1000 cycles). Moreover, the nanocomposites display good sensitivity at a relatively wide stress range of 0-70% and remarkable stability under acidic and alkaline settings. Furthermore, the foams with exceptional fire resistance (UL-94 V-0 rating) can provide stable sensing behavior (over 300 cycles) even after being exposed to flames for 5 s, making them one of the most reliable sensing materials so far. Clearly, this work widens applications of flexible piezoresistive sensors based on silicone foam nanocomposites for various harsh environments., (© 2024 Wiley‐VCH GmbH.)

Fluorosilicone rubber is essential for sealing in extreme temperatures and non-polar environments due to its exceptional adaptability. However, achieving a high yield of fluorosilicone polymers with medium and high fluorine content remains a challenge. Herein, a facile gradient strategy is developed that involves modifying the method of cyclic monomer addition based on the rate of ring-opening polymerization (ROP), to improve yield and adjust fluorine content precisely. The polymerization process is designed and tailored based on the reaction rates of anionic ring-opening polymerization (AROP) and cationic ring-opening polymerization (CROP) via an efficient gradient strategy. The effects of the polymerization process on the viscosity and yield of vinyl fluorosilicone polymers and hydrofluorosilicone polymers are investigated and optimized. Notably, the as-prepared vinyl-terminated fluoromethylsilane with 60% fluorine content (FMS-Vi-60F) has a high yield (86.6%) and high viscosity (150 000 mPa·s) in a short reaction time, which is superior to previous methods. Clearly, the gradient ring-opening method developed in this work provides a facile and efficient synthesis for fabricating fluorosilicone polymers with a high yield and tunable fluorine content., (© 2024 Wiley‐VCH GmbH.)

Objective: This study aimed to share preliminary experiences of single-incision plus two ports laparoscopic proximal gastrectomy with right-sided overlap and single-flap valvuloplasty (ROSF). Methods: Following the 6th edition of the Japanese Gastric Cancer Treatment Guidelines, proximal gastrectomy with lymphadenectomy was performed. Using a single-port approach, the esophagus was transected at least 2 cm above the tumor's upper margin with linear staplers. The stomach was then extracted through a periumbilical incision, and the proximal stomach was subsequently transected extracorporeally, while ensuring appropriate resection margins on both the greater and lesser curvatures. A single flap was created before returning the remnant stomach to the abdominal cavity and re-establishing pneumoperitoneum. The No.2 clip was used to grasp and elevate the esophageal stump. An incision was made at the right lower edge of the esophageal stump to guarantee that the esophageal lumen was open. The linear stapler was then inserted into the openings of the stomach and esophagus to perform a side overlap anastomosis with a length of 3 cm. Another barbed suture was used to close the common opening of the esophagus and the stomach, and the same barbed suture were used to suture the gastric wall to the lower edge of the muscle flap. The first barbed suture was then used to sequentially suture the proximal brim of the flap to the esophagus and the right brim of the flap to the right brim of the mucosal window. After completion of anastomosis, a drainage tube was inserted through the right upper port. This procedure was employed from November 2023 to March 2024 on five patients diagnosed with adenocarcinoma of the esophagogastric junction and upper stomach. The cohort consisted of three males and two females, with an age range of 62 to 75 years and a body mass index (BMI) of 13.7 to 24.2 kg/m². All cases were preoperatively staged as T1-2N0M0, confirmed by endoscopic biopsy and enhanced CT scans of the chest, abdomen, and pelvis. Results: All five patients successfully underwent the surgery. The median surgery time was 180-325 minutes, with the intraoperative blood loss of 30-50 ml. The number of lymph nodes harvested ranged from 18 to 27. The time to first flatus, and restore liquid diet and was 2.0-5.0 and 1.0-3.0 days, respectively. The postoperative length of stay was 9.0-11.0 days. The pain scores on the Numeric Rating Scale (NRS). On the first day, the pain scores were 3.0 in two cases, 2.0 in two cases, and 1.0 in one case. On the second day, the pain scores were 2.0 in two cases and 1.0 in three cases. On the third day, the pain scores were 1.0 in four cases and 2.0 in one case. No short-term postoperative complications were observed, and there were no perioperative deaths. Conclusion: Single-incision plus two ports laparoscopic proximal gastrectomy with ROSF is safe and feasible.

Background: Gastric cancer (GC) is a leading malignant disease in numerous countries, including Taiwan with limited therapeutic options. Animal viruses including oncolytic avian reovirus (ARV) have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. Here, we provide a novel insight into oncolytic ARV and UV-ARV-sensitized patient's peripheral blood mononuclear cells (P-PBMCs) and tumor infiltrating lymphocytes (TILs) killing primary GC (PGC) cells through the surface TLR3 and TRAIL/DR4/DR5 immunogenic apoptosis pathway., Methods: We conducted a comprehensive study to reveal whether ARV- or UV-inactivated ARV (UV-ARV)-modulated P-PBMCs or TILs killing ARV- and UV-ARV-sensitized AGS cells and PGC cells derived from clinical patients and to investigate the regulation of surface TLR3 receptor and upstream signaling pathways. Apoptosis analysis by flow cytometry and Western blot, suppression of signal pathway by specific inhibitors, in situ proximity ligation assay (PLA), time-resolved flurometry and lactate dehydrogenase (LDH) cytotoxicity assays, and an in vitro co-culture model were established to study the interplay between ARV- and UV-ARV-sensitized P-PBMCs and TILs to kill PGC cells and their upstream pathways., Results: Our results reveal that increased levels of DR4 and DR5 were observed in ARV and UV-ARV sensitized PGC cells through the TLR3/p38/p53 signaling pathway. Importantly, we found that the σC protein of ARV or UV-ARV interacted with surface TLR3 of CD8 + TILs, thereby triggering the TLR3/NF-κB/IFN-γ/TRAIL signaling pathway which induces immunogenic apoptosis of PGC cells. This study sheds further light on the molecular basis behind ARV oncolysis and facilitates the ARV or UV-ARV as a cancer therapeutic., Conclusions: The study provides novel insights into ARV- or UV-ARV-sensitized P-PBMCs and CD8 + TILs to kill PGC cells through the immunogenic apoptosis pathway. We conclude that P-PBMCs can easily be obtained from GC patients and provide a rich source as TILs to kill PGC cells., (© 2024. The Author(s).)

The invasive fall armyworm (FAW), Spodoptera frugiperda, is a polyphagous pest that significantly threatens crops worldwide. FAW may undergo adaptation, enhancing its ability to infect specific plant hosts. However, there is limited knowledge on this topic. After 8 generations of constant rearing on peanut leaves, the performance and enzyme activities of FAW were investigated in this study. Compared to FAW fed on the peanut cultivars 'Fuhua 8' and 'Quanhonghua 1' for 2 generations, those grown on leaves for 5 to 8 generations had significantly shorter pre-adult development times and total preoviposition periods. Fecundity also increased significantly, resulting in an overall improvement in population fitness as measured by demographic parameters. However, the F2 generation of FAW fed on corn leaves outperformed the F8 generation of FAW fed on peanut leaves. In the F2 generation, the FAW peanut population exhibited 30-55% supernumerary larval molts, which decreased substantially in the F5 and F8 generations. Notably, supernumerary larval molts displayed pupation and emergence rates comparable to normal larvae, regardless of the peanut cultivar or rearing generation. The activities of lipase and acetylcholinesterase increased significantly from the F2 to F8 generations, showing substantial negative and positive correlations with larval development time and fecundity, respectively. In conclusion, FAW demonstrated inferior performance on peanut leaves compared to corn leaves, despite its performance was significantly improved after 5 to 8 generations of acclimation. These results suggest that corn will continue to be the primary target crop for FAW in China., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Arterial calcification, an independent predictor of cardiovascular events, increases morbidity and mortality in patients with diabetes mellitus (DM), but its mechanisms remain unclear. Extracellular vesicles (EVs) play an important role in intercellular communication. The study investigates the role and potential mechanisms of EVs derived from endothelial cells (ECs) in regulating vascular smooth muscle cell (VSMC) calcification under high glucose (HG) condition, with a goal of developing effective prevention and treatment strategies for diabetic arterial calcification., Results: The results showed that EVs derived from HG induced ECs (EC HG -EVs) exhibited a bilayer structure morphology with a mean diameter of 74.08 ± 31.78 nm, expressing EVs markers including CD9, CD63 and TSG101, but not express calnexin. EC HG -EVs was internalized by VSMCs and induced VSMC calcification by increasing Runx2 expression and mineralized nodule formation. The circ&#95;0008362 was enriched in EC HG -EVs, and it can be transmitted to VSMCs to promote VSMC calcification both in vitro and in vivo. Mechanistically, miR-1251-5p might be one of the targets of circ&#95;0008362 and they were co-localization in the cytoplasm of VSMCs. Runx2 was identified as the downstream target of miR-1251-5p, and circ&#95;0008362 acted as a sponge, enhancing Runx2 expression and then promoted VSMC calcification. Besides, circ&#95;0008362 could directly interact with Runx2 to aggravate VSMC calcification. Notably, DiR-labelled EC HG -EVs was detected in the vessels of mice. Meanwhile, the level of circ&#95;0008362 and Runx2 were increased significantly, while the expression of miR-1251-5p was decreased significantly in calcified artery tissues of mice. However, inhibiting the release of EVs by GW4869 attenuated arterial calcification in diabetic mice. Finally, the level of circulation of plasma EVs circ&#95;0008362 was significantly higher in patients with DM compared with normal controls. Elevated levels of plasma EVs circ&#95;0008362 were associated with more severe coronary and aorta artery calcification in patients with DM., Conclusions: Our findings suggested that circ&#95;0008362 was enriched in EVs derived from ECs and promoted VSMC calcification under HG conditions, both by sponging miR-1251-5p to upregulate Runx2 expression and through direct interaction with Runx2. Furthermore, elevated levels of plasma EVs circ&#95;0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. These results may serve as a potential prevention and therapeutic target for diabetic arterial calcification., (© 2024. The Author(s).)

Lung adenocarcinoma (LUAD) carries a poor prognosis at advanced stages underscoring the need to elucidate the underlying molecular mechanisms driving its pathogenesis. This study aimed to investigate the roles of eukaryotic translation initiation factor 3 subunit M ( EIF3M ) and its associated effector, serum amyloid A-like 1 ( SAAL1 ), in LUAD development and progression. Bioinformatic analyses such as TNMplot, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other public databases were used to evaluate EIF3M and SAAL1 expression levels, methylation status, clinical associations, and potential transcriptional regulators across LUAD datasets. Patient samples were analyzed for EIF3M / SAAL1 expression by qRT-PCR, immunohistochemistry, and ELISA. EIF3M and SAAL1 were overexpressed in LUAD tumor tissues compared with normal lung tissues, correlated with advanced stage, nodal metastasis, and poor survival outcomes. High EIF3M / SAAL1 levels associated with increased cell proliferation, epithelial-mesenchymal transition, metastasis, and regulatory T cell dysfunction based on gene set enrichment analysis (GSEA). Mechanistically, EIF3M / SAAL1 upregulation was linked to promoter hypomethylation, and transcriptionally regulated by JMJD1C, via hTFtarget prediction. The EIF3M / SAAL1 promote oncogenic cellular programs and immunosuppressive microenvironments that conferred unfavorable prognosis. These findings nominate EIF3M/SAAL1 as potential therapeutic targets and biomarkers in LUAD., Competing Interests: None., (AJCR Copyright © 2024.)

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc., Competing Interests: Competing interests statement:The authors declare no competing interest.

The global prevalence of type 2 diabetes mellitus (T2DM) continues to rise. Therefore, it has become a major concern health issue worldwide. T2DM leads to various complications, including metabolic-associated fatty liver disease (MAFLD). However, comprehensive studies on MAFLD as a diabetic complication at different stages are still lacking. Using advanced single-cell RNA-seq technology, we explored changes of livers in two T2DM murine models. Our findings revealed that increase activation of hepatic stellate cells (HSCs) exacerbated the development of MAFLD to steatohepatitis by upregulating transforming growth factor β1 induced transcript 1 ( Tgfb1i1 ). Upregulated thioredoxin-interacting protein ( Txnip ) contributed to hepatocyte damage by impairing reactive oxygen species clearance. Additionally, the capillarization of liver sinusoidal endothelial cells correlated with Fabp4 overexpression in endothelial cells. A novel subset of Kupffer cells (KCs) that expressed Cd36 exhibited an activated phenotype, potentially participating in inflammation in the liver of diabetic mice. Furthermore, ligand-receptor pair analysis indicated that activated HSCs interacted with hepatocytes or KCs through Thbs2 and Lamb2 in late-stage diseases. The reduction in cell-cell interactions within hepatocytes in diabetic mice, reflects that the mechanisms regulating liver homeostasis is disrupted. This research underscores the importance of dynamics in diabetic MAFLD, and provides new insights for targeted therapies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer., Methods: Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice., Results: HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice., Conclusions: These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody., (© 2024. Springer Nature Switzerland AG.)

M2-like macrophages exhibit immunosuppressive activity and promote pancreatic cancer progression. Reactive oxygen species (ROS) affect macrophage polarization; however, the mechanism remains unclear. This study aimed to elucidate the underlying molecular basis and design a gene therapy to inhibit M2-like polarization. Microarray analysis and immunofluorescence staining were performed in M1-like and M2-like macrophages to ascertain the expression of CYBB, a major intracellular ROS source. Coculture assay and syngeneic orthotopic pancreatic cancer mice models were used to study the mechanism of M2-like skewing. Decoy oligodeoxynucleotides (ODNs) were designed to manipulate CYBB transcription to inhibit M2-like polarization and control tumor growth. Lipopolysaccharide treatment polarized U937 cells to M1-like macrophages in which CYBB expression was increased. In contrast, coculture with PANC-1 cells induced M2-like polarization in U937 cells with CYBB downregulation. High CD204 M2-like expression in combination with low CYBB expression was associated with the worst prognosis in patients with pancreatic cancer. STAT6 and HDAC2 in U937 cells were activated by cancer cell-derived IL4 after coculture and then bound to the CYBB promoter to repress CYBB expression, resulting in M2-like polarization. Diphenyleneiodonium, 8λ³-iodatricyclo[7.4.0.02,⁷]trideca-1(13),2,4,6,9,11-hexaen-8-ylium chloride that inhibits ROS production could block this action. Knockdown of STAT6 and HDAC2 also inhibited M2-like polarization and maintained the M1-like phenotype of U937 cells after coculture. Decoy ODNs interrupting the binding of STAT6 to the CYBB promoter counteracted M2-like polarization and tumor growth and triggered antitumor immunity in vivo. Gene therapy using STAT6-CYBB decoy ODNs can inhibit M2-like polarization, representing a potential therapeutic tool for pancreatic cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)