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Juan Li,1,* Ting Zhou,1,* Pei Wang,1,* Ruian Yin,1 Shengqi Zhang,1 Yile Cao,1 Lijuan Zong,1 Ming Xiao,2 Yongjie Zhang,3 Wentao Liu,4 Lingxiao Deng,5 Fei Huang,6 Jianfei Sun,7,* Hongxing Wang1,* 1Department of Rehabilitation Medicine, Zhongda Hospital Southeast University, Nanjing, 210024, People’s Republic of China; 2Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 3Department of Human Anatomy, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 4Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 5Department of Neurological Surgery, Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indianapolis, IN, 46202-2266, USA; 6Institute of Neurobiology, Binzhou Medical University, Yantai, 264003, People’s Republic of China; 7State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory of Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianfei Sun, State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory of Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of China, Email sunzaghi@seu.edu.cn Hongxing Wang, Department of Rehabilitation Medicine, Southeast University Zhongda Hospital, Nanjing, 210024, People’s Republic of China, Email 101012648@seu.edu.cnBackground: Gigantocellular reticular nucleus (GRNs) executes a vital role in locomotor recovery after spinal cord injury. However, due to its unique anatomical location deep within the brainstem, intervening in GRNs for spinal cord injury research is challenging. To address this problem, this study adopted an extracorporeal magnetic stimulation system to observe the effects of selective magnetic stimulation of GRNs with iron oxide nanoparticles combined treadmill training on locomotor recovery after spinal cord injury, and explored the possible mechanisms.Methods: Superparamagnetic iron oxide (SPIO) nanoparticles were stereotactically injected into bilateral GRNs of mice with moderate T10 spinal cord contusion. Eight-week selective magnetic stimulation produced by extracorporeal magnetic stimulation system (MSS) combined with treadmill training was adopted for the animals from one week after surgery. Locomotor function of mice was evaluated by the Basso Mouse Scale, Grid-walking test and Treadscan analysis. Brain MRI, anterograde virus tracer and immunofluorescence staining were applied to observe the tissue compatibility of SPIO in GRNs, trace GRNs’ projections and evaluate neurotransmitters’ expression in spinal cord respectively. Motor-evoked potentials and H reflex were collected for assessing the integrity of cortical spinal tract and the excitation of motor neurons in anterior horn.Results: (1) SPIO persisted in GRNs for a minimum of 24 weeks without inducing apoptosis of GRN cells, and degraded slowly over time. (2) MSS-enabled treadmill training dramatically improved locomotor performances of injured mice, and promoted cortico-reticulo-spinal circuit reorganization. (3) MSS-enabled treadmill training took superimposed roles through both activating GRNs to drive more projections of GRNs across lesion site and rebalancing neurotransmitters’ expression in anterior horn of lumbar spinal cord.Conclusion: These results indicate that selective MSS intervention of GRNs potentially serves as an innovative strategy to promote more spared fibers of GRNs across lesion site and rebalance neurotransmitters’ expression after spinal cord injury, paving the way for the structural remodeling of neural systems collaborating with exercise training, thus ultimately contributing to the reconstruction of cortico-reticulo-spinal circuit. Keywords: gigantocellular reticular nucleus, locomotion, magnetic stimulation, spinal cord injury, superparamagnetic iron oxide nanoparticles, treadmill training

Wenhao Zhang,1,2 Qingli Li,1,2,* Rutie Yin1,2,* 1Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rutie Yin, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email yrtt2013@163.com Qingli Li, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of China, Email liqingli73@163.comAbstract: WEE1 kinase is involved in the G2/M cell cycle checkpoint control and DNA damage repair. A functional G2/M checkpoint is crucial for DNA repair in cancer cells with p53 mutations since they lack a functional G1/S checkpoint. Targeted inhibition of WEE1 kinase may cause tumor cell apoptosis, primarily, in the p53-deficient tumor, via bypassing the G2/M checkpoint without properly repairing DNA damage, resulting in genome instability and chromosomal deletion. This review aims to provide a comprehensive overview of the biological role of WEE1 kinase and the potential of WEE1 inhibitor (WEE1i) for treating gynecological malignancies. We conducted a thorough literature search from 2001 to September 2023 in prominent databases such as PubMed, Scopus, and Cochrane, utilizing appropriate keywords of WEE1i and gynecologic oncology. WEE1i has been shown to inhibit tumor activity and enhance the sensitivity of chemotherapy or radiotherapy in preclinical models, particularly in p53-mutated gynecologic cancer models, although not exclusively. Recently, WEE1i alone or combined with genotoxic agents has confirmed its efficacy and safety in Phase I/II gynecological malignancies clinical trials. Furthermore, it has become increasingly clear that other inhibitors of DNA damage pathways show synthetic lethality with WEE1i, and WEE1 modulates therapeutic immune responses, providing a rationale for the combination of WEE1i and immune checkpoint blockade. In this review, we summarize the biological function of WEE1 kinase, development of WEE1i, and outline the preclinical and clinical data available on the investigation of WEE1i for treating gynecologic malignancies.Keywords: WEE1 inhibitor, cell cycle, gynecological malignancies, adavosertib, clinical trials

Yao Wang,1,* Mingtang Zeng,1,* Tianfei Fan,1 Ming Jia,2 Ruxi Yin,1 Jia Xue,1 Longjun Xian,3 Ping Fan,1 Mei Zhan1 1Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Nanchong Institute for Food and Drug Control, Nanchong, People’s Republic of China; 3Department of Thoracic Surgery, Institute of Thoracic Oncology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Fan; Mei Zhan, Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email m13980602288@163.com; mandyzhanmei@163.comAbstract: Metal-organic frameworks (MOFs) are porous materials resulting from the coordination of metal clusters or ions with organic ligands, merging macromolecular and coordination chemistry features. Among these, zeolitic imidazolate framework-8 (ZIF-8) stands out as a widely utilized MOF known for its robust stability in aqueous environments owing to the robust interaction between its constituent zinc ions (Zn2+) and 2-methylimidazole (2-MIM). ZIF-8 readily decomposes under acidic conditions, serving as a promising candidate for pH-responsive drug delivery systems. Moreover, biomimetic materials typically possess good biocompatibility, reducing immune reactions. By mimicking natural structures or surface features within the body, they enhance the targeting of nanoparticles, prolong their circulation time, and increase their bioavailability in vivo. This review explores the latest advancements in biomimetic ZIF-8 nanoparticles for drug delivery, elucidating the primary obstacles and future prospects in utilizing ZIF-8 for drug delivery applications.Keywords: MOF, ZIF-8, cell membrane, biomimetic drug delivery

Feng Luo, Yingying Lu, Chen Chen, Dongdong Chang, Wei Jiang, Ronghua Yin Department of Oncology Zone II, Hai’an People’s Hospital, Haian, People’s Republic of ChinaCorrespondence: Ronghua Yin, Department of Oncology Zone II, Hai’an People’s Hospital, No. 17, Zhongba Middle Road, Haian, 226600, People’s Republic of China, Email 13606277858@163.comBackground: Esophageal cancer has a high incidence in China. Many patients also have a heavy psychological burden due to clinical features such as wasting and choking on food. This study analyzed the risk factors of negative emotions in esophageal cancer patients during the peri-radiotherapy period and its effects on malnutrition.Methods: We retrospectively analyzed 339 patients with esophageal cancer during the peri-radiotherapy who received treatment at our hospital from April 2017 to April 2020, and followed up for 3 years. t test and Chi-square test were used to analyze the relationship between patients’ negative emotions and clinical data. Binary logistics regression was performed to analyze the independent risk factors for the occurrence of negative mood and malnutrition in the patients. Kaplan-Meier survival curves were used to analyze survival rates.Results: Our results showed that 18.3% of patients undergoing radiotherapy for esophageal cancer had negative emotions, and 41.9% suffered from malnutrition. The results of the binary logistic regression analysis showed that monthly household income (OR = 0.470, P = 0.022), the TNM stage (OR = 2.030, P = 0.044), concomitant gastrointestinal symptoms (OR = 2.071, P = 0.024), sleep status (OR = 2.540, P = 0.003), swallowing disorders (OR = 1.919, P = 0.048), and post-radiotherapy complications were independent risk factors for the development of negative emotions in patients. Negative emotions (OR = 2.547, P = 0.038) were also a risk factor for malnutrition in patients with esophageal cancer.Conclusion: Many patients with esophageal cancer suffer from anxiety and depression in the peri-radiotherapy period, which might lead to complications such as malnutrition or aggravate and affect the prognosis of patients. Therefore, psychological care should be provided based on conventional care to effectively relieve their psychological pressure, and improve their prognosis and quality of life.Keywords: esophageal cancer, malnutrition, negative emotions, influencing factors

Rong Yin, Shasha Xu, Jing Zhu, Haiou Zhu, Chao He Department of Hepatobiliary Center Ward II, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Rong Yin, Department of Hepatobiliary Center Ward II, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210029, People’s Republic of China, Email y13851709399@163.comBackground: Hilar cholangiocarcinoma (HCCA) is a common malignant tumor of the biliary system. Factors such as limited physical function, intractability, and high mortality caused by the tumor lead to negative emotions, such as anxiety and depression in patients. In this study, we investigated the risk factors for negative emotions in patients undergoing radical resection of HCCA during the perioperative period and its effect on prognosis to provide strategies for alleviating the negative emotional disorders of patients and improving prognosis.Methods: From September 2016 to August 2021, we retrospectively examined 205 patients with HCCA who underwent radical resection in our hospital. The incidence of negative emotions and the clinical parameters of patients were compared using Chi-square tests and t-tests. The independent risk factors for unfavorable feelings in patients during the perioperative period were determined using binary logistic regression. The key variables influencing the postoperative survival status of HCCA patients were identified using the log-rank univariate analysis and Cox proportional risk regression analysis.Results: The results of the binary logistic regression analysis showed that perioperative negative emotions were independently influenced by family monthly income (OR = 0.069), medical insurance (OR = 0.089), family care (OR = 0.013), sleep quality (OR = 0.071), TNF-α (OR = 5.851), and bile leakage (OR = 29.412) (P < 0.05). The age of the patient (OR = 2.003), preoperative CA19– 9 (OR = 2.038), lymph node metastases (OR = 2.327), and negative mood (OR = 3.054) were independent risk variables that affected the survival status of patients, as determined by the results of Cox regression analysis (P < 0.05).Conclusion: In this study, we found that anxiety and depression in patients undergoing radical operation of HCCA are related to family monthly income, medical insurance, sleep quality, family care, TNF-α, and bile leakage; also, negative emotions have adverse effects on prognosis.Keywords: hilar cholangiocarcinoma, radical resection, depression, anxiety, risk factors, prognosis

Ruoyun Yin,1 Yuan Yang,2 Yujiao Chang,3 Lei Tang,1 Qian Hu,1 Jian Yang,1 Chong Cheng,1 Lei Xiao,1 Fan Zhang1 1School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Cardiovascular Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Infection, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Fan Zhang, School of Public Health, Research Center for Medicine and Social Development, Chongqing Medical University, No. 61 Daxuecheng Middle Road, Shapingba District, Chongqing, 401331, People’s Republic of China, Email zhangfan@cqmu.edu.cnBackground: Drinking in summer vacation, as an important part of college students’ drinking behavior, has rarely been studied. At present, there is no research to explore the association between alcohol expectancy and college students’ drinking behavior during the summer vacation.Methods: A total of 487 college students were selected from three universities in Chongqing from July 30, 2017, to August 30, 2017, by cluster sampling. The electronic questionnaires were distributed to complete the anonymous survey related to drinking. The questionnaire on drinking mainly included baseline characteristics, influencing factors related to drinking, drinking behavior in the last year and summer vacation, and alcohol expectancy. Independent sample t-test and one-way ANOVA were used for multi-factor analysis. Multi-level logistic regression analysis and ordered logistic regression analysis were used for multivariate analysis.Results: The past drinking rate in the study group was 86.24%. In the past year, the drinking rate and binge drinking rate of college students were 63.24% and 23.20%. In summer drinking, these two indicators were 29.57% and 8.42%, respectively. About 92.50% of the moderate and heavy drinking groups among college students had drinking behavior during the summer vacation. The average negative expectancy among college students was 3.26 ± 0.87 while the average positive expectancy was 2.63 ± 0.66. In drinking last year, positive expectancy was a risk factor for occasional and light drinking compared with those of non-drinkers (P< 0.05). In summer vacation drinking, compared with those of non-drinkers, negative expectancy was a protective factor for occasional drinking (OR: 1.847, 95% CI: 1.293– 2.638), negative expectancy and positive expectancy were both influencing factors for light drinking (P< 0.05).Conclusion: The drinking rate in the study group was at a high level in the past. The association between alcohol expectancy and drinking behavior among college students would be different according to the period and amount of drinking.Keywords: drinking behavior, drinking pattern, alcohol expectancy, college students, summer vacation

Lan Zhong,1,2 Rutie Yin,1,2 Liang Song1,2 1Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, 610041, People’s Republic of ChinaCorrespondence: Liang Song, Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, No. 20 The Third Section of South Renmin Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-19828966121, Email dr_songliang@163.comAbstract: PARP inhibitors (PARPi) are the maintenance therapy after first line platinum-based chemotherapy for patients with advanced epithelial ovarian cancer (EOC) with germline and pathogenic somatic BRCA1/2 mutations. However, as with chemotherapy, patients can develop resistance to PARPi. The selective pressure generated by heterogeneous somatic BRCA mutations may give rise to chemotherapy or PARPi resistant tumors. Here, we present the case of a patient harboring a pathogenic p.Glu143&ast; (c.427G>T) somatic BRCA1 mutation conferring resistance to olaparib following cytoreductive surgery and platinum-based chemotherapy. We ordered a plasma ctDNA analysis (tissue biopsy of recurrent lesions was contraindicated due to their anatomical location) to figure out the possible resistance mechanism. Analysis of ctDNA did not detect the pathogenic somatic BRCA1 p.Glu143&ast; (c.427G>T) mutation seen before. The tumor cells harboring the pathogenic BRCA1 mutation were probably eliminated by the platinum-based chemotherapy, leaving only those without BRCA mutations to proliferate.Keywords: PARPi resistance, BRCA1 mutation, ovarian carcinoma, circulating tumor DNA, sequencing

Zesong Hu, Jie Wang, Yangjing Xue, Qianqian Zhang, Qianqian Xu, Kangting Ji, Ripeng Yin Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Kangting Ji; Ripeng YinDepartment of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Xueyuanxi Road, No. 109, Wenzhou, 325000, Zhejiang, People’s Republic of China, Tel/Fax +86-577-88002216, Email jikt@wmu.edu.cn; 15948657@qq.comBackground: Neutrophils and albumin had been shown to be independent predictors of mortality from various diseases. Purpose of this study was to investigate the effect of neutrophil-to-albumin ratio (NPAR) as an independent predictor of mortality in heart failure (HF) patients.Methods: Data were extracted from Medical Information Mart for Intensive Care-III database. Primary outcome was 30-day mortality, secondary outcomes were in-hospital, 90-day, 365-day mortality, length of stay (LOS) in hospital. Cox proportional hazards regression model and receiver operating characteristic (ROC) curve analysis and Pearson correlation analysis were used.Results: The HR (95% CI) values of the mid-tertile and the upper tertile were 1.27 (1.01 to 1.59) and 2.29 (1.87 to 2.81) in 30-day mortality compared with the reference. The trend continued after adjusted for demographic and clinical variables. In the secondary outcomes were the same trends. The data of the Second Affiliated Hospital of Wenzhou Medical University showed the correlation coefficient between hospital LOS with NPAR.Conclusion: NPAR was an independent factor of mortality in HF patients, which was correlated with hospital LOS. Our results need to be verified by prospective studies.Keywords: neutrophils, albumin, neutrophil-to-albumin ratio, all-cause mortality, heart failure

Yingbei Weng, Ripeng Yin, Lala Qian, Zhi Chen, Jie Wang, Huaqiang Xiang, Yangjing Xue, Kangting Ji, Xueqiang Guan Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Kangting Ji; Xueqiang GuanDepartment of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Xueyuanxi Road, No. 109, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaEmail jikt@wzmc.edu.cn; wzsgxq@163.comObjective: The aims of this study were to investigate the relationship between low-density lipoprotein cholesterol (LDL-C) levels and all-cause mortality in coronary care unit (CCU) patients, adjusting for a wide range of potential confounding factors, to examine the potential of LDL-C in predicting the prognostic value of CCU patients.Methods: Clinical data were extracted from Medical Information Mart for Intensive Care-III database (MIMIC-III database version v.1.4). Baseline data were collected within 24 hours after the patient was first admitted to the hospital. The primary endpoint of our study is 30-day all-cause mortality. The secondary endpoints are 90-day and one-year all-cause mortality and infections. Cox proportional hazard regression and propensity score-matched (PSM) analysis were used to analyze the association between LDL-C levels and prognostic value of CCU patients.Results: We included a total of 1476 patients with an average age of 66.7 ± 14.1 years (66% male). For 30-day all-cause mortality, the hazard ratio (95% confidence interval) of high LDL-C level group (≥ 55 mg/dl) was 0.42 (0.29, 0.62), which was compared with low LDL-C level group (< 55 mg/dl) in unadjusted model. After adjusting for age, gender and race, the association still existed (P < 0.05), and the HR (95% CI) was 0.49 (0.33, 0.72). Further adjustment of possible covariates showed similar correlation (P < 0.05), and HR (95% CI) was 0.65 (0.43, 0.97). Similar correlations were observed for 90-day and one-year all-cause mortality. The relationship between all-cause mortality and LDL-C levels in CCU patients was further verified by propensity score-matched (PSM) analysis. In addition, the higher the LDL-C level, the lower the risk of infection, odds ratio (OR) values in the three models were less than 1 (P < 0.05).Conclusion: Our data suggest that high LDL-C level is associated with a reduced risk of 30-day, 90-day, and one-year mortality of patients in the CCU. And this result is still stable in the PSM model. The results need to be verified in prospective trials.Keywords: low-density lipoprotein cholesterol, coronary care unit, all-cause mortality, cardiovascular disease

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

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

Daliang Kong, Rui Gu, Chengtao Zhang, Ruofeng Yin Department of Orthopedics, China-Japan Union Hospital, Changchun, Jilin 130031, People’s Republic of ChinaCorrespondence: Ruofeng YinDepartment of Orthopedics, China-Japan Union Hospital, Changchun, Jilin 130031, People’s Republic of ChinaEmail yrf_wind@jlu.edu.cnBackground: Circular RNAs (circRNAs) play an important role in the progression of intervertebral disc (IVD) degeneration (IVDD). Using bioinformatics analysis, we have found that the expression of circRNA hsa_circ_0059955 was significantly downregulated in IVDD tissues. However, the relevant mechanism of hsa_circ_0059955 in the progression of IVDD remains unclear.Methods: CCK-8 and flow cytometry assays were used to evaluate cell proliferation and apoptosis. In addition, Western blot assay was used to detect the expressions of ITCH, p73, CDK2 in nucleus pulposus (NP) cells. Moreover, a puncture-induced IVDD rat model was established to explore the role of hsa_circ_0059955 in IVDD.Results: The level of hsa_circ_0059955 was significantly decreased in IVDD tissues from IVDD patients. Itchy E3 ubiquitin protein ligase (ITCH) is the host gene of hsa_circ_0059955, and downregulation of hsa_circ_0059955 significantly decreased the expression of ITCH in NP cells. In addition, downregulation of hsa_circ_0059955 markedly inhibited proliferation and induced apoptosis and cell cycle arrest in NP cells. Moreover, in vivo study illustrated that overexpression of hsa_circ_0059955 ameliorated IVDD in rats.Conclusion: Downregulation of hsa_circ_0059955 could induce apoptosis and cell cycle arrest in NP cells in vitro, while overexpression of hsa_circ_0059955 attenuated the IVDD in a puncture-induced rat model in vivo. Therefore, hsa_circ_0059955 might serve as a therapeutic target for the treatment of IVDD.Keywords: intervertebral disc degeneration, hsa_circ_0059955, Itchy E3 ubiquitin protein ligase, p73

Daina B Esposito,1 M Soledad Cepeda,2 Jennifer G Lyons,1 Ruihua Yin,1 Stephan Lanes1On behalf of The Members of the Opioid Post-Marketing Consortium Observational Studies Working Group1Department of Safety and Epidemiology, HealthCore, Inc, Wilmington, DE, USA; 2Department of Research and Development, Janssen, Titusville, NJ, USAObjectives: Doctor/pharmacy shopping, the practice of seeking prescriptions from multiple healthcare sources without their coordination, may be a measure of prescription medicine abuse. This cross-sectional study examined the relationship between a claims-based doctor/pharmacy shopping definition and medical record documented behaviors suggestive of misuse, diversion, abuse and/or addiction.Methods: Patients with ≥2 opioid dispensings starting in 2012 in a US administrative claims database were grouped into doctor/pharmacy shopping categories by number of providers and pharmacies used over 18 months: no shopping, minimal shopping, moderate shopping and severe shopping. Medical charts of opioid prescribers were reviewed to identify behaviors suggestive of misuse, diversion, abuse and/or addiction.Results: Among 581,940 opioid users, 78% were classified as no shopping, 11% minimal shopping, 8% moderate shopping and 3% severe shopping. Almost 40% of severe shopping patients had no medical record documented behaviors (positive predictive value: 24.3%). Compared with no shopping, the odds ratio [OR] of ≥3 behaviors was 1.70 (95% confidence interval [CI] 0.50–5.78) for minimal shopping, 1.81 (95% CI 0.54–6.03) for moderate shopping, and 8.93 (95% CI 3.12–25.54) for severe shopping.Conclusions: Claims-identified severe doctor/pharmacy shopping was strongly associated with behaviors suggestive of misuse, diversion, abuse and/or addiction, but the proportion of medical records documenting these was low.Keywords: opioid, doctor/pharmacy shopping, abuse, misuse, addiction

Lin Li,1,2,* Yafei Cui,2,* Rulan Yin,3,* Shengnan Chen,2 Qian Zhao,2 Haoyang Chen,1 Biyu Shen1 1Department of Nursing, The Second Affiliated Hospital of Nantong University, Nantong,China; 2School of Nursing, Nantong University, Nantong, China; 3Department of Emergency ICU, The First Affiliated Hospital of Soochow University, Suzhou, China *Lin Li, Yafei Cui, Rulan Yin contributed equally to this work Objective: Disease activity of rheumatoid arthritis (RA) patients was often measured by the 28-joint count disease activity score (DAS-28), which consists of 28 swollen and tender joint counts, patient’s assessment of disease activity (visual analog scale [VAS]) and erythrocyte sedimentation rate. C-reactive protein was also used to measure disease activity in RA patients. The aim was to explore the impact of medication adherence on disease activity in patients with RA.Methods: A systematic search was performed in major electronic databases (PubMed, Web of Science, the Cochrane Library, CNKI, VIP and Wan fang) to identify studies reporting medication adherence and disease activity in RA patients. Results were expressed as mean difference (MD) and 95% CI.Results: A total of seven identified studies matched the inclusion criteria, reporting on a total of 1,963 adult RA patients in the analysis. The total score of DAS-28 was significantly lower in adherent patients than in nonadherent subjects (MD =-0.42, 95% CI [-0.80, -0.03], P=0.03). Similarly, a significant difference was observed between medication adherent and nonadherent groups in erythrocyte sedimentation rate (MD =-7.39, 95% CI [-11.69, -3.08], P

During the past decade, the technology to automate demand response (DR) in buildings and industrial facilities has advanced significantly. Automation allows rapid, repeatable, reliable operation. This study focuses on costs for DR automation in commercial buildings with some discussion on residential buildings and industrial facilities. DR automation technology relies on numerous components, including communication systems, hardware and software gateways, standards-based messaging protocols, controls and integration platforms, and measurement and telemetry systems. This paper discusses the impact factors that contribute to the costs of automated DR systems, with a focus on OpenADR 1.0 and 2.0 systems. In addition, this report compares cost data from several DR automation programs and pilot projects, evaluates trends in the cost per unit of DR and kilowatts (kW) available from automated systems, and applies a standard naming convention and classification or taxonomy for system elements. In summary, median costs for the 56 installed automated DR systems studied here are about $200/kW. The deviation around this median is large with costs in some cases being an order of magnitude greater or less than median. Costs to automate fast DR systems for ancillary services are not fully analyzed in this report because additional research is needed to determine the total such costs.

Yunfei Xia,1,* Rulan Yin,1,2,* Ting Fu,1,2 Lijuan Zhang,1,2 Qiuxiang Zhang,1,2 Genkai Guo,1 Liren Li,2 Zhifeng Gu11Department of Rheumatology, Affiliated Hospital of Nantong University, 2School of Nursing, Nantong University, Nantong, People’s Republic of China *These authors contributed equally to this work Objective: Nonadherence in rheumatoid arthritis (RA) patients using disease-modifying antirheumatic drugs (DMARDs) may lead to joint damage and function loss. The aim of this cross-sectional study was to explore Chinese RA patients’ adherence rates and investigate potential risk factors for nonadherence.Methods: A total of 122 RA patients were recruited from the Affiliated Hospital of Nantong University from January 2014 to April 2015. Patients were asked to complete a set of standardized self-report questionnaires (Compliance Questionnaire on Rheumatology, Health Assessment Questionnaire, Short Form-36 questionnaire, 28-joint Disease Activity Score, Hospital Anxiety and Depression Scale, and Visual Analog Scale). Independent samples t-tests, chi-square analyses, and logistic regression modeling were used to analyze these data.Results: Based on Compliance Questionnaire on Rheumatology, 38% of the patients adhered to DMARDs. Adherence was associated with education, income, depression, and the total number of DMARDs. Other demographic and clinical characteristics were not associated with adherence. Logistic regression models identified income, depression, and the total number of DMARDs as predictors of medication nonadherence.Conclusion: In this study, 62% of patients with RA were not adherent to their DMARD prescription. Education, income, depression, and the total number of DMARDs were associated with medication adherence, and income, depression, and the total number of DMARDs were independent predictors of medication adherence in patients with RA. These findings could help medical personnel develop helpful interventions to improve adherence in RA patients by paying more attention to the patients with these accompanying risk factors and, finally, improve RA patients’ quality of life.Keywords: rheumatoid arthritis, disease-modifying antirheumatic drugs, adherence

Qingli Li,1,2 Mark J Lambrechts,1 Qiuyang Zhang,1 Sen Liu,1 Dongxia Ge,1 Rutie Yin,2 Mingrong Xi,2 Zongbing You1 1Departments of Structural and Cellular Biology and Orthopaedic Surgery, Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane Center for Stem Cell Research and Regenerative Medicine, and Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA, USA; 2Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China Abstract: Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. Keywords: serine hydroxymethyltransferase, prostate cancer, apoptosis

During the past decade, the technology to automate demand response (DR) in buildings and industrial facilities has advanced significantly. Automation allows rapid, repeatable, reliable operation. This study focuses on costs for DR automation in commercial buildings with some discussion on residential buildings and industrial facilities. DR automation technology relies on numerous components, including communication systems, hardware and software gateways, standards-based messaging protocols, controls and integration platforms, and measurement and telemetry systems. This paper discusses the impact factors that contribute to the costs of automated DR systems, with a focus on OpenADR 1.0 and 2.0 systems. In addition, this report compares cost data from several DR automation programs and pilot projects, evaluates trends in the cost per unit of DR and kilowatts (kW) available from automated systems, and applies a standard naming convention and classification or taxonomy for system elements. In summary, median costs for the 56 installed automated DR systems studied here are about $200/kW. The deviation around this median is large with costs in some cases being an order of magnitude greater or less than median. Costs to automate fast DR systems for ancillary services are not fully analyzed in this report because additional research is needed to determine the total such costs.

Although the thermal mass of floors in buildings has been demonstrated to help shift cooling load, there is still a lack of information about how floor covering can influence the floor’s load shifting capability and buildings’ demand flexibility. To fill this gap, we estimated demand flexibility based on the daily peak cooling load reduction for different floor configurations and regions, using EnergyPlus simulations. As a demand response strategy, we used precooling and global temperature adjustment. The result demonstrated an adverse impact of floor covering on the building’s demand flexibility. Specifically, under the same demand response strategy, the daily peak cooling load reductions were up to 20–34% for a concrete floor whereas they were only 17–29% for a carpet-covered concrete floor. This is because floor covering hinders convective coupling between the concrete floor surface and the zone air and reduces radiative heat transfer between the concrete floor surface and the surrounding environment. In hot climates such as Phoenix, floor covering almost negated the concrete floor’s load shifting capability and yielded low demand flexibility as a wood floor, representing low thermal mass. Sensitivity analyses showed that floor covering’s effects can be more profound with a larger carpet-covered area, a greater temperature adjustment depth, or a higher radiant heat gain. With this effect ignored for a given building, its demand flexibility would be overestimated, which could prevent grid operators from obtaining sufficient demand flexibility to maintain a grid. Our findings also imply that for more efficient grid-interactive buildings, a traditional standard for floor design could be modified with increasing renewable penetration.

The charging load from Electric vehicles (EVs) is modeled as deferrable load, meaning that the power consumption can be shifted to different time windows to achieve various grid objectives. In local community scenarios, EVs are considered as controllable storage devices in a global optimization problem together with other microgrid components, such as the building load, renewable generations, and battery energy storage system, etc. Various objectives have been investigated before, such as following a given load profile, reducing load fluctuation and minimizing the total operational cost. However, the uncertainties inside the behaviors of individual drivers have tremendous impact on the cost effectiveness of microgrid operations, which have not been carefully studied. In this paper, we propose a predictive management strategy in a community microgrid, using datasets of system base load, solar generation and EV charging behaviors from real-world cases. Two stage operations are modeled for cost-effective EV management, i.e. wholesale market partition in the first stage and load profile following in the second stage. Predictive control strategies, including receding horizon control, are adapted to solve the energy allocation problem in a decentralized fashion. The experimental results indicate the proposed approach can considerably reduce the total energy cost and decrease the ramping index of total system load up to 56.3%.

Demand responsive industrial loads with high thermal inertia have potential to provide ancillary service for frequency regulation in the power market. To capture the benefit, this study proposes a new hierarchical framework to coordinate the demand responsive industrial loads with thermal power plants in an industrial park for secondary frequency control. In the proposed framework, demand responsive loads and generating resources are coordinated for optimal dispatch in two-time scales: (1) the regulation reserve of the industrial park is optimally scheduled in a day-ahead manner. The stochastic regulation signal is replaced by the specific extremely trajectories. Furthermore, the extremely trajectories are achieved by the day-ahead predicted regulation mileage. The resulting benefit is to transform the stochastic reserve scheduling problem into a deterministic optimization; (2) a model predictive control strategy is proposed to dispatch the industry park in real time with an objective to maximize the revenue. The proposed technology is tested using a real-world industrial electrolysis power system based upon Pennsylvania, Jersey, and Maryland (PJM) power market. Various scenarios are simulated to study the performance of the proposed approach to enable industry parks to provide ancillary service into the power market. The simulation results indicate that an industrial park with a capacity of 500 MW can provide up to 40 MW ancillary service for participation in the secondary frequency regulation. The proposed strategy is demonstrated to be capable of maintaining the economic and secure operation of the industrial park while satisfying performance requirements from the real world regulation market.

BackgroundPort-wine stain (PWS) is a vascular malformation characterized by progressive dilatation of postcapillary venules, but the molecular pathogenesis remains obscure.ObjectivesTo illustrate that PWS endothelial cells (ECs) present a unique molecular phenotype that leads to pathoanatomical PWS vasculatures.MethodsImmunohistochemistry and transmission electron microscopy were used to characterize the ultrastructure and molecular phenotypes of PWS blood vessels. Primary culture of human dermal microvascular endothelial cells and in vitro tube formation assay were used for confirmative functional studies.ResultsMultiple clinicopathological features of PWS blood vessels during the development and progression of the disease were shown. There were no normal arterioles and venules observed phenotypically and morphologically in PWS skin; arterioles and venules both showed differentiation impairments, resulting in a reduction of arteriole-like vasculatures and defects in capillary loop formation in PWS lesions. PWS ECs showed stemness properties with expression of endothelial progenitor cell markers CD133 and CD166 in non-nodular lesions. They also expressed dual venous/arterial identities, Eph receptor B1 (EphB1) and ephrin B2 (EfnB2). Co-expression of EphB1 and EfnB2 in normal human dermal microvascular ECs led to the formation of PWS-like vasculatures in vitro, for example larger-diameter and thick-walled capillaries.ConclusionsPWS ECs are differentiation-impaired, late-stage endothelial progenitor cells with a specific phenotype of CD133+ /CD166+ /EphB1+ /EfnB2+ , which form immature venule-like pathoanatomical vasculatures. The disruption of normal EC-EC interactions by coexistence of EphB1 and EfnB2 contributes to progressive dilatation of PWS vasculatures.

Cosimulation platforms are necessary to study the interactions of complex systems integrated in future smart grids. The Virtual Grid Integration Laboratory (VirGIL) is a modular cosimulation platform designed to study interactions between demand-response (DR) strategies, building comfort, communication networks, and power system operation. This paper presents the coupling of power systems, buildings, communications, and control under a master algorithm. There are two objectives: first, to use a modular architecture for VirGIL, based on the functional mockup interface (FMI), where several different modules can be added, exchanged, and tested; and second, to use a commercial power system simulation platform, familiar to power system operators, such as DIgSILENT PowerFactory. This will help reduce the barriers to the industry for adopting such platforms, investigate and subsequently deploy DR strategies in their daily operation. VirGIL further introduces the integration of the quantized state system (QSS) methods for simulation in this cosimulation platform. Results on how these systems interact using a real network and consumption data are also presented.