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Dehua Liao,1 Jiwen Zhang,1,2 Ting Yan,1 Shanshan Chen,1 Wei Li,1 Dangang Shangguan,1,* Zhihua She3,* 1Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China; 2School of Pharmacy, University of South China, Hengyang, People’s Republic of China; 3Department of Medical Administration, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua She, Department of Medical Administration, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, People’s Republic of China, Email shegua@163.com Dangang Shangguan, Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China, Email shangguandangang@hnca.org.cnAbstract: As a novel third-generation ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown excellent systemic and intracranial activity in non-small cell lung cancer (NSCLC) patients who carry sensitizing ALK-activating mutations and progress on first- and second-generation TKIs. In comparison with other ALK-TKIs, lorlatinib has a unique safety profile for hyperlipidemia and central nervous system adverse events. Lorlatinib-induced adverse events are well tolerated, permanent discontinuations are rarely reported, and dose modifications and/or standard medical therapy are useful for the management of adverse events. Our present study reviews the safety profile of lorlatinib as well as the relevant management strategies. Our present study aims to provide a practical guide for the scientific management and application of lorlatinib.Keywords: ALK, lorlatinib, adverse event, NSCLC, therapy management

Jin Wang,1– 3,* Dongying Liao,1– 3,* Xuemin Zhang,1– 3 Changhong Miao,1– 3 Kuang Chen1– 3 1Department of Emergency, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People’s Republic of China; 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China; 3Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuang Chen, Department of Emergency, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, Tianjin, 300193, People’s Republic of China, Tel +86 18622150281, Email 18622150281@163.comAbstract: Breast cancer (BC) poses a severe threat to the health of women worldwide. Currently, different therapeutic regimens are used for BC according to the pathological classification of HER2-positive or HER2-negative. Clinical reports of HER2-low expression indicate that the condition is HER2-negative, which was ineligible for HER2-targeted therapy. In contrast to HER2-zero tumors, however, HER2-low BC is a heterogeneous disease with unique genetic characteristics, prognoses, and different therapeutic responses. Clinical efficacy has been demonstrated by numerous potent and innovative anti-HER2 medications, particularly antibody–drug conjugates (ADCs). Certain ADCs, including T-DXd, have demonstrated good efficacy in some trials either used alone or in conjunction with other medications. To enhance outcomes in individuals with HER2-low BC, immunotherapy and other treatments are frequently combined with HER2-targeted therapy. There are also alternative strategies that target both HER2 and HER3 or other antigenic sites. We hope more individuals with HER2-low BC will benefit from more precise treatment regimens in the future. This article provides a review of existing research and clinical trials.Keywords: HER2-low breast cancer, monoclonal antibodies, antibody–drug conjugates, trastuzumab deruxtecan, immunotherapy

Yongchao Yu,1– 3,* Jin Wang,1– 3,* Dongying Liao,1– 3 Dou Zhang,1– 3 Xiaojiang Li,1,2 Yingjie Jia,1,2 Fanming Kong1– 3 1Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China; 3Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fanming Kong, Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China, Tel +862227986525, Email kongfanming08@163.comAbstract: Although targeted drugs improved the therapeutic effect of HER2-positive breast cancer, the long-term prognosis was still poor. In this regard, the research and development of antibody-drug conjugates (ADCs) came into being and made a lot of progress. ADCs had the characteristics of both chemotherapeutic agents and targeted agents by combining chemotherapeutic agents and targeted agents through a linker. It not only had a strong anti-tumor effect on HER2-positive breast cancer, but also had certain anti-tumor effects on HER2-low and even HER2-negative patients. In addition, the clinical researches of ADCs combined with immune checkpoint inhibitors (ICIs) therapy had also made a great breakthrough. This review aimed to summarize the clinical progress of ADCs, in particular the two drugs approved by the US Food and Drug Administration (FDA) for HER2-positive metastatic breast cancer as well as to summarize the current status of ADCs in combination with ICIs.Keywords: breast cancer, HER2-positive, antibody-drug conjugates, immunotherapy, advances

Hai-Ying Chen,1,&ast; Ming-Chao Li,2,&ast; Dan Liao,1 Chi Li,1 Qiu-Ming Ji,1 Ping Guo,1 Zou Su,1 Yu-Hong Yang,1 Wen-Hao Xiao,1 Wen-Hui Zhai1 1Department of Psychiatry, Wuhan Wudong Hospital, Wuhan, People’s Republic of China; 2Department of Psychiatry, Wuhan Mental Health Center, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan Liao; Chi Li, Department of Psychiatry, Wuhan Wudong Hospital, No. 46 of Wudong Street, Qingshan District, Wuhan, 430084, People’s Republic of China, Tel +86 27 5052 8367, Fax +86 27 8643 8247, Email danliaodr@21cn.comObjective: Our study aimed to investigate the effects of computer-assisted cognitive remediation therapy (CCRT) on cognitive function, social function and quality of life in patients with vascular dementia (VD).Methods: Ninety-eight patients with VD were treated with CCRT in four 45-minute sessions per week over a course of 40 sessions to exercise four cognitive functions, including flexibility, working memory, plan execution and social cognition. The Mini-Mental State Examination (MMSE), Social Disability Screening Schedule (SDSS), Personal and Social Performance Scale (PSP), and Generic Quality of Life Inventory-74 (GQOL-74) were used to assess before and after treatment.Results: (1) The scores of orientation (5.60 ± 1.35), calculation (2.20 ± 0.79), verbal ability (7.10 ± 0.36), spatial ability (0.78 ± 0.42), immediate memory (2.42 ± 0.53), short-term memory (1.17 ± 0.78) and MMSE (23.36 ± 2.98) were all improved after treatment (P < 0.05) compared with those before treatment; (2) The scores of SDSS, PSP and Activities of Daily Living (ADL) after treatment were 8.23 ± 0.94, 81.36 ± 14.23, and 32.7 ± 12.1, and all of which improved (P < 0.05); (3) The scores of physical health were 68.24 ± 7.44, mental health were 69.75 ± 7.15, social function were 69.08 ± 7.43, material life were 37.46 ± 4.85 and the total score were 230.79 ± 9.56, all of which improved (P < 0.05).Conclusion: For patients with VD, CCRT can improve their cognitive function, social function, daily life ability and quality of life.Keywords: computer-assisted cognitive remediation, vascular dementia, cognitive function, social function, daily life ability

Xuan Wang,1,&ast; Dan Liao,2,&ast; Qiu-Ming Ji,2 Yu-Hong Yang,2 Ming-Chao Li,3 Xian-Yun Yi,2 Chi Li,2 Yu Chen,2 Hong-Bo Tao,2 Wen-Hui Zhai2 1Institute of Burns, Wuhan Third Hospital, Wuhan University, Wuhan, 430000, People’s Republic of China; 2Department of Psychiatry, Wuhan Wudong Hospital, Wuhan, 430084, People’s Republic of China; 3Department of Psychiatry, Affiliated Wuhan Mental Health Center, Tongji Medical College of Huazhong University Science & Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiu-Ming Ji; Yu-Hong Yang, Department of Psychiatry, Wuhan Wudong Hospital, No. 46 of Wudong Street, Qingshan District, Wuhan, 430084, People’s Republic of China, Tel +86 27 5052 8367, Fax +86 27 8643 8247, Email ji20210826@163.com; yinhua3355@163.comObjective: To examine the bactericidal effects of three different states of medical ozone (liquid, gas, and oil) against drug-resistant strains of common bacteria on burn wounds, which could as a clinical reference.Methods: Three multidrug-resistant strains of methicillin-resistant Staphylococcus aureus, pan-resistant Pseudomonas aeruginosa, and ESBLs Klebsiella pneumoniae were identified from burn wounds. The colonies of the three varieties of bacteria were each carried out using the pour plate method prior to the start of the experiment. Then, depending on the state of ozone, different treatment procedures are applied. Group of ozone gas: in a closed glass jar, the bacterial liquid was injected into a single layer of sterile gauze, and the ozone gas concentration was held at 50 g/mL. The bacterial liquid was diluted and combined directly with ozone water in the ozone water group. Ozone is a type of oil: after the emulsifier was added to the oil group. The gas, water, and oil groups were rapidly neutralized and counted again after 5, 10, and 30 minutes.Results: Ozone gas and oil groups totally eliminated multidrug resistant bacteria in the above study within 30 minutes. (2) At 5 and 10 minutes, the difference in bactericidal effect between ozone gas group and ozone water and oil group was statistically significant (P< 0.05), and there was no significant difference between ozone water and oil groups (P> 0.05); at the time of 30 minutes, the effects of bactericidal effect between ozone water group and ozone gas and oil had no significance (P> 0.05).Conclusion: Ozone has the ability to kill bacteria, depending on the treatment time, different ozone types should be chosen for sterilization and disinfection in clinical application.Keywords: ozone, burn, wound treatment, multidrug resistant bacteria

Yang Yang,1,2 Chiyi Wang,1,2 Jin Liu,1,2 Daqing Liao,2 Wensheng Zhang,1,2 Cheng Zhou2 1Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of ChinaCorrespondence: Cheng ZhouLaboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China, Tel +81-28-85164145, Fax +81-28-85164039, Email zhouc@163.com; Wensheng ZhangDepartment of Anaesthesiology and Laboratory of Anaesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China, Tel/Fax +81-28-85164144, Email zhang_ws@scu.edu.cnPurpose: Local anesthetics (LAs) are an important alternative for postoperative analgesia; however, the short duration of LAs limits their use. Thus, we previously developed LL-1, a mixture of QX-OH and levobupivacaine (LB) that produces regional anesthesia for more than 10 h in rats. The aim of this study is to investigate the long-acting mechanism of LL-1 in vivo and in vitro.Methods: Regional anesthetic effects and local toxicity of the LL-1, QX-OH and LB treatment groups were investigated in a sciatic nerve block rat model. Whole-cell patch-clamping recordings were used to measure the inhibition Nav currents (INa) in ND7/23 cells.Results: The onset of LL-1 (35mM QX-OH+10mM LB) and 10 mM LB was 10 min, which was much faster than 35 mM QX-OH (27 [18, 60] min, t[12] = − 4.535, p = 0.001). The duration of LL-1 (35mM QX-OH+10 mM LB) was significantly longer than 35 mM QX-OH or 10 mM LB alone (F[3, 35] = 191.336, p < 0.0001). No differences in local tissue toxicity were found between LL-1 and LB. In patch-clamping recordings, 5 mM QX-OH produced ∼ 20% inhibition of INa currents. LB at 40 μM inhibited INa by 65.51%± 3.63%, while QX-OH 2 mM+LB 40 μM inhibited INa by 77.37%± 3.36% (t[14] = 2.358, p = 0.025), and QX-OH 5 mM+LB 40 μM inhibited INa by 83.88%± 1.57% (t[13] = 4.191, p = 0.0003). Furthermore, INa inhibition by QX-OH+LB was more persistent than that of LB alone during washout.Conclusion: LL-1 can produce an additive and stable inhibition of Nagv currents, which can contribute to the long-lasting regional anesthetic action.Keywords: long-lasting local anesthetics, QX-OH, levobupivacaine, voltage-gated sodium channel, Nav

Shichao Wu,1– 4,* Di Liao,3– 5,* Xi Li,3– 5 Zeyu Liu,3– 5 Lin Zhang,3– 5 Fong Ming Mo,1,2,4 Shuo Hu,1,2,4 Jian Xia,3– 5 Xiangrui Yang1– 4 1Department of Nuclear Medicine (PET Center), Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 2Key Laboratory of Nanobiological Technology of National Health Commission, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 5Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan, 410008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangrui Yang; Jian Xia Email yangxr@csu.edu.cn; xjian1216@csu.edu.cnIntroduction: Although the preparation of lipid nanoparticles (LNPs) achieves great success, their retention of highly hydrophobic drugs is still problematic.Methods: Herein, we report a novel strategy for efficiently loading hydrophobic drugs to LNPs for stroke therapy. Oleoylethanolamide (OEA), an endogenous highly hydrophobic molecule with outstanding neuroprotective effect, was successfully loaded to OEA-SPC&DSPE-PEG lipid nanoparticles (OSDP LNPs) with a drug loading of 15.9 ± 1.2 wt%. Efficient retention in OSDP LNPs greatly improved the pharmaceutical property and enhanced the neuroprotective effect of OEA.Results: Through the data of positron emission tomography (PET) and TTC-stained brain slices, it could be clearly visualized that the acute ischemic brain tissues were preserved as penumbral tissues and bounced back with reperfusion. The in vivo experiments stated that OSDP LNPs could significantly improve the survival rate, the behavioral score, the cerebral infarct volume, the edema degree, the spatial learning and memory ability of the MCAO (middle cerebral artery occlusion) rats.Discussion: These results suggest that the OSDP LNPs have a great chance to develop hydrophobic OEA into a potential anti-stroke formulation.Keywords: stroke, oleoylethanolamide, OEA, lipid nanoparticles, neuroprotective, positron emission tomography, PET

Juan Jiang,1,2 Xia Wang,3 Jian He,3 Donglei Liao,3 Xiaolu Deng3 1Department of Respiratory Medicine (National Key Clinical Specialty), Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Hunan Provincial Clinical Research Center for Respiratory Diseases, Changsha, People’s Republic of China; 3Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Xiaolu DengDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaTel +86 13786113654Email dengxiaolu1019@163.comBackground: Pneumocystis jirovecii pneumonia (PCP) is a serious opportunistic infection in immunocompromised children. Real-time polymerase chain reaction (PCR) is widely used for the diagnosis of PCP due to its good accuracy. However, the diagnostic performance of multiplex real-time PCR on sputum in children with PCP has never been explored.Methods: Medical records of 63 consecutive pediatric patients were analyzed retrospectively, including 13 cases with PCP and 50 with non-PCP pneumonia. Pneumocystis jirovecii (P. jirovecii) and other co-pathogens detected by multiplex real-time PCR in sputum samples were summarized. Using clinical composite diagnosis as the reference standard, we further compared the diagnostic performance of multiplex real-time PCR to combined serological markers (1,3)-β-D-glucan plus lactate dehydrogenase. Additionally, modifications of antimicrobial treatment for pediatric PCP patients after the report of multiplex real-time PCR results were reviewed.Results: In children with PCP, nonproductive cough and shortness of breath were more common, lymphocyte count in peripheral blood was markedly lower, and serum levels of (1,3)-β-D-glucan and lactate dehydrogenase were much higher than non-PCP group. Multiplex real-time PCR reached a sensitivity of 100% in diagnosing PCP, which was better than serum (1,3)-β-D-glucan plus lactate dehydrogenase (76.9%). Its specificity (98.0%) significantly surpassed serum (1,3)-β-D-glucan plus lactate dehydrogenase (84.4%). Furthermore, multiplex real-time PCR showed a good performance in identifying co-pathogens in sputum of pediatric PCP patients. Cytomegalovirus, Epstein–Barr virus and Streptococcus pneumoniae were the most common co-pathogens in these patients. Initial antimicrobial treatment was modified in 76.9% of children with PCP after the report of PCR results.Conclusion: Multiplex real-time PCR on sputum is a diagnostic tool with good performance for the identification of P. jirovecii as well as co-pathogens in children with PCP. Sputum may be an alternative to bronchoalveolar lavage fluid for PCR assay in children when bronchoscopic examination is not feasible.Keywords: immunocompromised population, children, Pneumocystis jirovecii pneumonia, multiplex real-time polymerase chain reaction, sputum

Dongying Liao,1,2 Yongchao Yu,1,2 Qingyun Mei,1,2 Ziwei Wang,1,2 Xiaojiang Li,1,2 Yingjie Jia,1,2 Fanming Kong1,2 1Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Nankai District, Tianjin, 300193, People’s Republic of China; 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Nankai District, Tianjin, 300193, People’s Republic of ChinaCorrespondence: Fanming KongDepartment of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, Tianjin, 300193, People’s Republic of ChinaTel + 86 136 52123653Email kongfanming08@163.comAbstract: Malignant pleural mesothelioma (MPM) represents the uncommon cancer originating from pleural mesothelial cells, which is associated with dismal prognostic outcome. According to CheckMate-743 results, nivolumab plus ipilimumab has been approved to treat the unresectable MPM in treatment-naive patients as a first-line therapy by the FDA in October 2020. Immunotherapy is expected to be the best choice for MPM treatment. In the following article, the past treatment plan and the progress of immunotherapy for MPM will be reviewed.Keywords: malignant pleural mesothelioma, immunotherapy, progression, ipilimumab, nivolumab

Yunfang Luo,1,* Fang Yu,1,* Xianjing Feng,1 Di Liao,1 Yuanlin Ying,1 Xi Li,1 Qin Huang,1 Zeyu Liu,1 Minping Wei,1 Tingting Zhao,1 Lin Zhang,1 Ruxin Tu,1 Jian Xia1– 3 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Clinical Research Center for Cerebrovascular Disease of Hunan Province, Central South University, Changsha, Hunan, People’s Republic of China; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian XiaDepartment of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaTel +86 731 84327216Fax +86 731 84327401. Email xjian1216@csu.edu.cnPurpose: Previous studies have shown a rising incidence of early-onset symptomatic intracranial atherosclerosis (sICAS), which has brought a severe economic burden to social development. This study aimed to evaluate the molecular biomarkers associated with early-onset sICAS and to seek possible intervention strategies for early prevention.Patients and Methods: We consecutively recruited patients with sICAS and divided them into two groups based on age: early-onset sICAS group as age ≤ 60 years old and late-onset sICAS group as age > 60 years old. We collected and compared the demographic data and laboratory results of each group. A bivariate logistic regression model was applied to evaluate the independent molecular biomarkers of early-onset sICAS.Results: A total of 1007 subjects with sICAS were enrolled in this study, comprising 519 patients in the early-onset sICAS group and 488 patients in the late-onset sICAS group. Bivariate logistic regression analysis demonstrated an increased level of white blood cell, platelet, albumin globulin ratio, free triiodothyronine, and a decreased level of total bile acid, urea nitrogen, high-density lipoprotein, homocysteine, and fibrinogen in the early-onset sICAS group when compared to the late-onset group.Conclusion: Our study showed the relevance between early sICAS and circulating levels of different molecular biomarkers. Detection of these related molecular biomarkers may provide a simple way for early sICAS preventions in the future.Keywords: ischemic stroke, symptomatic intracranial atherosclerosis, molecular biomarkers

In this study, a hypoplastic model is developed to describe the mechanical behaviors of cemented sand under both monotonic and cyclic loading conditions. A state variable is proposed to qualify the bonding strength, and it is incorporated into the model to reflect the influence of cementation on the strength, stiffness, and dilatancy of sand. To reflect the bonding degradation, this variable evolves during the shearing following a simple evolution rule and may vanish after large deformation. The critical void ratio and friction angle are related to the initial cemented content to consider the variation of the critical state induced by the cementation. The model is subsequently extended to account for cyclic loading by incorporating the intergranular strain, fabric change effect, and semifluidized state. The capability of the model is demonstrated by simulating the behavior of cemented sand under both monotonic and cyclic loading conditions. [ABSTRACT FROM AUTHOR]

Chunmei Geng,1 Yujin Guo,1 Changshui Wang,2 Changmeng Cui,3 Wenxiu Han,1 Dehua Liao,4 Pei Jiang1 1Department of Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining 272000, People’s Republic of China; 2Department of Clinical Translational Medicine, Jining Life Science Center, Jining 272000, People’s Republic of China; 3Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, People’s Republic of China; 4Department of Pharmacy, Hunan Cancer Hospital, Central South University, Changsha 410011, People’s Republic of ChinaCorrespondence: Pei JiangDepartment of Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining 272000, People’s Republic of ChinaTel/Fax +86 537 2106208Email jiangpeicsu@sina.comPurpose: Substantial evidence indicates that lipopolysaccharide (LPS) exposure can lead to systemic inflammatory response syndrome (SIRS) and multiple organ failure. Previous metabolomic studies have mainly focused on LPS-induced depression or hepatic and renal effects. However, no comprehensive metabolomics-based analysis of the serum, liver, kidney, hippocampus, and heart following exposure to LPS has been undertaken to date.Material and Methods: Male Sprague–Dawley rats were randomly allocated to a control and a LPS-treated group (n=8). LPS for 2 weeks (0.5 mg/kg every other day) was given via intraperitoneal injection. Gas chromatography–mass spectrometry (GC–MS) was used for metabolite determination, while multivariate statistical analysis was performed to identify differentially expressed metabolites between the two groups.Results: Our study revealed that 24, 13, 12, 7, and 12 metabolites were differentially expressed between the LPS treatment group and the control group in the serum, liver, kidney, hippocampus, and heart, respectively. We further identified that these metabolic changes were mainly involved with aminoacyl-tRNA biosynthesis; glutathione metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; arginine biosynthesis; bile acid biosynthesis; and glycerolipid metabolism.Conclusion: We have systematically elucidated the metabolic changes underlying LPS-induced SIRS, thereby providing insight into the mechanisms associated with these alterations.Keywords: systemic inflammatory response syndrome, metabolites, gas chromatography–mass spectrometry, multivariate statistical analysis

Janne Fassov,1 Donghua Liao,2 Christina Brock,3 Lilli Lundby,4 Søren Laurberg,4 Klaus Krogh1 1Department Of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; 2GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital and Clinical Institute, Faculty of Health Sciences Aalborg University, Aalborg, Denmark; 4Department of Surgery, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Janne FassovDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, DenmarkTel +45 26756602Email janfas@rm.dkPurpose: Irritable bowel syndrome is a common gastrointestinal disorder with a global prevalence of approximately 11%. Onset or worsening of symptoms following digestion is one of the characteristics of the condition. The present study aimed at evaluating the postprandial sensory and motor response before and after treatment with sacral nerve modulation.Patients and Methods: Twenty-one irritable bowel syndrome patients, 12 diarrhea-predominant and 9 mixed, were eligible for a 6-week sacral nerve modulation test period. Patients were investigated with multimodal impedance planimetry including a standardized meal at baseline and at the end of 2 weeks of suprasensory stimulation embedded in the 6-week sacral nerve modulation period.Results: There was no statistical significant difference in the sensory response to heat or cold before and after sacral nerve modulation, p> 0.05. At baseline, wall tension increased after the meal (mean 124.79 [range 82.5 to 237.3] mmHg.mm before the meal, mean 207.76 [range, 143.5 to 429] mmHg.mm after the meal), p=0.048 indicating a postprandial response. During sacral nerve modulation, the postprandial increase in wall tension did not reach statistical significance (mean 86.79 [range 28.8 to 204.5] mmHg.mm before the meal, mean 159.71 [range 71.3 to 270.8] mmHg.mm after the meal), p=0.277. However, there was no statistically significant difference between the postprandial wall tension at baseline and during sacral nerve modulation, p=0.489. Likewise, we found no difference between pressure or stretch ratio at baseline and during sacral nerve modulation, p> 0.05.Conclusion: Sacral nerve modulation does not exert its positive treatments effects in diarrhea-predominant and mixed irritable bowel syndrome through a modulation of the postprandial response.Keywords: sacral nerve stimulation, sacral nerve modulation, postprandial response, gastrocolic response, irritable bowel syndrome

Dehua Liao,1,2,* Yun Chen,1,* Yujin Guo,3 Changshui Wang,4 Ni Liu,1 Qian Gong,1 Yingzhou Fu,1 Yilan Fu,1 Lizhi Cao,1 Dunwu Yao,1 Pei Jiang3 1Department of Pharmacy, Hunan Cancer Hospital, Changsha, Hunan 410013, People’s Republic of China; 2Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Institute of Clinical Pharmacy & Pharmacology, Jining First People’s Hospital, Jining, Shandong 272000, People’s Republic of China; 4Department of Clinical Translational Medicine, Jining Life Science Center, Jining, Shandong 272000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pei Jiang Tel/ Fax + 86 537 2106208Email jiangpeicsu@sina.comIntroduction: Depression is one of the most common neuropsychiatric illnesses which leads to a huge social and economic burden on modern society. So, it is necessary to develop an effective and safe pharmacological intervention for depression. Accumulating evidence has shown that adenosine monophosphate-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway plays a pivotal role in the development of depression. Our present study aimed to investigate the antidepressant effect and possible mechanisms of salvianolic acid B (SalB) in a chronic mild stress (CMS)-induced depression model in rats.Materials and Methods: The rats were randomly divided into three groups: control group with no stressor, CMS group and CMS+SalB (30 mg/kg/d) group. After administration for 28 consecutive days, the behavior tests were performed. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis.Results: It was observed that the administration of SalB for 28 consecutive days successfully corrected the depressive-like behaviors in CMS-treated rats. SalB could effectively reduce the gene expression of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α), as well as nuclear factor-kappa B (NF-κB) p65 protein. In addition, inhibitor of NF-κB (IκB) protein expression was significantly increased after the administration of SalB. Moreover, SalB could effectively decrease protein expression of oxidative stress markers such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) and increase the activity of catalase (CAT). SalB treatment also reversed CMS-induced inhibition of Nrf2 signaling pathway, along with increasing the mRNA expression of NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1). Regarding the endoplasmic reticulum (ER) stress markers, the protein expressions of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 kD (GRP78) were also significantly reduced after SalB administration. Furthermore, the supplementation of SalB could effectively activate the AMPK/SIRT1 signaling pathway, which indicated significant increase in pAMPK/AMPK ratio and SIRT1 protein expression.Conclusion: Our study demonstrated that SalB relieved CMS-induced depressive-like state through the mitigation of inflammatory status, oxidative stress, and the activation of AMPK/SIRT1 signaling pathway.Keywords: SalB, depression, CMS, AMPK/SIRT1

Duwu Liao,1,* Guang Yang,2,* Yuan Yang,3,* Xueyong Tang,4,* Haixia Huang,5 Jichun Shao,1 Qi Pan4 1Department of Urology Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, People’s Republic of China; 2Department of Urology Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 5Department of Critical Care Medicine, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jichun ShaoDepartment of Urology Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation, 416 Hospital, 4# Second Ring Road, North Fourth Section, Chengdu, Sichuan 610057, People’s Republic of ChinaEmail shaoji93@163.comQi PanDepartment of Dermatology, Chongqing Traditional Chinese Medicine Hospital, 40# Daomenkou, Yuzhong District, Chongqing 400011, People’s Republic of ChinaEmail qi_pan@vip.sina.comPurpose: Prostate cancer (PCa) is a widespread urinary neoplasm and one of the most prevalent and second most frequent malignancies diagnosed in males worldwide. This study aimed to identify a candidate marker and explore its molecular mechanism in PCa.Methods: Gene expression datasets, GSE55945 (n=21) and GSE46602 (n=50), were downloaded from the Gene Expression Omnibus database. Bioinformatic approaches were applied to identify potential markers. Effects of the candidate marker on proliferation, migration, invasion, and ferroptosis (ferrous iron and malondialdehyde (MDA)) in PCa cells and its mechanism were assessed after performing cell transfection.Results: A total of 1435 common differentially expressed genes were identified in GSE55945 and GSE46602. Five key gene modules were listed based on a protein–protein interaction network, containing five hub genes. Pannexin 2 (PANX2), a candidate marker was identified, and findings revealed substantial upregulation of its expression levels in PCa cell lines. Blocking expression of PANX2 resulted in suppression of proliferation, migration, and invasion in PCa cells, while increasing ferrous iron and MDA levels. However, these effects were rescued by Nrf2 activator, oltipraz. The Nrf2 signaling pathway was consequently applied to determine underlying mechanism of PANX2 in PCa cells. We established that silencing PANX2 remarkably reduced protein expression levels in members of Nrf2 signaling pathway (Nrf2, HO-1, and FTH1).Conclusion: Our study demonstrated that PANX2 is implicated in the pathogenesis of PCa, which regulates malignant phenotypes and ferroptosis through Nrf2 signaling pathway, and maybe a potential therapeutic target for PCa.Keywords: prostate cancer, ferroptosis, PANX2 and Nrf2 signaling pathways

The use of mathematical equations to analyse population dynamics measurements is being increasingly applied to elucidate complex dynamic processes in biological systems, including cancer. Purely 'empirical' equations may provide sufficient accuracy to supp

Failure to understand evolutionary dynamics has been hypothesized as limiting our ability to control biological systems. An increasing awareness of similarities between macroscopic ecosystems and cellular tissues has inspired optimism that game theory will

Haohai Huang,1 Dan Liao,2 Yong Dong,3 Rong Pu41Department of Clinical Pharmacy, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, People’s Republic of China; 2Department of Gynaecology, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, People’s Republic of China; 3Department of Cancer Center, Dongguan Third People‘s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, People’s Republic of China; 4Department of Clinical Laboratory, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People‘s Hospital of Southern Medical University, Dongguan, Guangdong, People’s Republic of ChinaPurpose: The previous investigations which considered the possible effect of the quercetin supplementation for overweight and obesity have led to inconsistent results. Here, we aimed to evaluate the effects of quercetin on weight loss using a meta-analysis of randomized controlled clinical trials (RCTs).Methods: Relevant studies were systematically searched from the MEDLINE, EMBASE, Google Scholar, and Scopus databases. RCTs that investigated the effects of quercetin on weight loss in humans were included for quality assessment, meta-analyses, sensitivity analysis, subgroup analyses, and publication bias assessment. Effect size was expressed as weighted mean difference (WMD) and 95% CI by using a random-effects model. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to rate the level of evidence.Results: Nine RCTs (11 treatment arms) with 525 participants were finally included for data pooling. Our meta-analysis revealed that daily quercetin supplementation did not significantly affect the body weight (WMD: −0.35 kg, 95% CI: −2.03, 1.33; P=0.68), body mass index (WMD: −0.04 kg/m2 95% CI: −0.54, 0.45; P=0.87), waist circumference (WMD: −0.37 cm, 95% CI: −1.81, 1.06; P=0.61), and waist to hip ratio (WMD: −0.01, 95% CI: −0.03, 0.01; P=0.48). Subgroup analysis could not identify factors significantly influencing these parameters. These results were robust in sensitivity analysis, and no significant publication bias was found.Conclusion: The current evidence suggests that quercetin intake did not show a notably favorable effect on weight loss. Future well-designed and long-term clinical trials are required to confirm these results.Keywords: quercetin, body weight, obesity, overweight, meta-analysis

Zhilin Wu,1 Chen Chen,1 Bo Zhang,2 Liang Tang,2 Wei Shi,2 Danying Liao,2 Gaohong Di,1 Jacques RJ Davis,1 Hui Wang1 1Anesthesiology Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China; 2Haematology Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China Background: EGFP-EGF1-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticle (ENP) has a specific affinity to tissue factor (TF). The aim of this study was to investigate the target delivery of ENP to plaques and its uptake in a mouse model of atherosclerosis in vivo and in vitro. Materials and methods: Coumarin-6- and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-loaded ENPs were synthesized using a double-emulsion method. Mouse vascular smooth muscle cells (VSMCs) were induced with MCP-1 to obtain an increased TF expression. Fluorescence microscopy and flow cytometry assay were performed to examine the uptake of coumarin-6-loaded ENPs in cellular models. An animal model of atherosclerosis was established with an ApoE (-/-) mouse fed with continuous high-fat diets for 14 weeks. DiR-loaded ENPs (DiR-ENPs) were injected via the caudal vein. The distribution of DiR-ENPs was examined through organ imaging and confocal laser scanning microscopy. Results: Results indicated TFs were highly expressed in the cellular model. The uptake of coumarin-6-loaded ENPs was significantly higher than that of common PLGA nanoparticles. Thickening of intima and lipid deposition in the aorta could be observed in atherosclerosis mouse models. Confocal laser scanning microscopy organ imaging showed ENPs accumulated in vessels with atherosclerotic plaques, which coincided with high expressions of TF. Conclusion: This study showed that EGFP-EGF1-conjugated PLGA nanoparticles could be effectively delivered to atherosclerotic plaques in vivo and taken up by VSMCs with high TF expressions in vitro. Thus, it could be a promising carrier for targeted therapy of atherosclerosis. Keywords: tissue factor, atherosclerosis, nanoparticle, target delivery, EGFP-EGF1

Jens Sundbøll,1 Sandra Kruchov Thygesen,1 Katalin Veres,1 Donghua Liao,2 Jingbo Zhao,2 Hans Gregersen,3 Henrik Toft Sørensen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3GIOME, Department of Surgery, Chinese University of Hong Kong, Shatin, Hong KongBackground: It remains unclear whether constipation is associated with cancer. We evaluated the risk of malignancies in patients with constipation requiring hospitalization.Methods: Using Danish medical registries, we calculated cumulative incidences and standardized incidence ratios (SIRs) for cancer. SIRs were computed as the observed number of gastrointestinal (GI) cancers and selected non-GI cancers in patients with constipation compared with the expected number based on national incidence rates by sex, age, and calendar year (1978–2013).Results: We identified 1,75,901 patients with constipation (59% females, median age 54 years). The cumulative incidences of GI cancers and non-GI cancers after 15 years of follow-up were 2.5% and 2.6%, respectively. During the first year of follow-up, the SIR for any GI cancer was 5.0 (95% confidence interval (CI): 4.8–5.3), driven by colon and pancreas cancers and higher for younger age groups. Beyond 1 year of follow-up, the risk declined to near unity for colorectal cancer. The risk of other GI cancers (including cancers of the esophagus, stomach, small intestine, liver, and pancreas) remained moderately increased (overall SIR =1.3, 95% CI: 1.2–1.4). Except for ovarian cancer (SIR =7.3, 95% CI: 6.3–8.4), the risk of non-GI cancers was only slightly increased during the first year of follow-up and declined to unity thereafter.Conclusions: Patients with constipation had increased short-term risk of a diagnosis of GI cancer. Beyond 1 year of follow-up, a moderately elevated risk persisted only for GI cancers other than colorectal cancer. The risk of non-GI cancers was elevated only during the first year of follow-up, particularly for ovarian cancer.Keywords: constipation, cancer, cohort study

Haohai Huang,1 Dan Liao,2 Rong Pu,3 Yejia Cui3 1Department of Clinical Pharmacy, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China; 2Department of Gynaecology, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China; 3Department of Clinical Laboratory, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China Purpose: Spirulina is generally used as a nutraceutical food supplement due to its nutrient profile, lack of toxicity, and therapeutic effects. Clinical trials have investigated the influence of spirulina on metabolic-related risk factors but have yielded conflicting results in humans. Here, we summarize the evidence of the effects of spirulina on serum lipid profile, glucose management, BP, and body weight by conducting a meta-analysis.Materials and methods: Relevant studies were retrieved by systematic search of MEDLINE, EMBASE, Scopus databases, and reference lists of relevant original studies from inception to July 2018. Data were extracted following a standardized protocol. Two investigators independently extracted study characteristics, outcomes measures, and appraised methodological quality. Effect sizes were performed using a random-effects model, with weighted mean differences (WMDs) and 95% CIs between the means for the spirulina intervention and control arms. Subgroup analyses were conducted to explore the possible influences of study characteristics. Publication bias and sensitivity analysis were also performed.Results: A total of 1,868 records were identified of which 12 trials with 14 arms were eligible. The amount of spirulina ranged from 1 to 19 g/d, and intervention durations ranged from 2 to 48 weeks. Overall, data synthesis showed that spirulina supplements significantly lowered total cholesterol (WMD = –36.60 mg/dL; 95% CI: −51.87 to –21.33; P=0.0001), low-density lipoprotein cholesterol (WMD = –33.16 mg/dL; 95% CI: −50.52 to –15.75; P=0.0002), triglycerides (WMD = –39.20 mg/dL; 95% CI: −52.71 to –25.69; P=0.0001), very-low-density lipoprotein cholesterol (WMD = –8.02 mg/dL; 95% CI: −8.77 to –7.26; P=0.0001), fasting blood glucose (WMD = –5.01 mg/dL; 95% CI: −9.78 to –0.24; P=0.04), and DBP (WMD = –7.17 mmHg; 95% CI: −8.57 to –5.78; P=0.001). These findings remained stable in the sensitivity analysis, and no obvious publication bias was detected.Conclusion: Our findings provide substantial evidence that spirulina supplementation has favorable effect on select cardiovascular and metabolic biomarkers in humans, including lipid, glucose, and DBP management. Keywords: blood pressure, body weight, blood glucose, CVD, lipid, spirulina

Haohai Huang,1 Honggang Chi,2 Dan Liao,3 Ying Zou2,4 1Department of Clinical Pharmacy, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China; 2Department of Traditional Chinese Medicine, Scientific Research Platform, The Second Clinical Medical College, Guangdong Medical University, Dongguan, China; 3Department of Gynaecology & Obstetrics, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China; 4Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong, China Background: The potential effects of coenzyme Q10 (CoQ10) supplementation in overweight/obese patients with type 2 diabetes mellitus are not fully established. In this article, we aimed to perform a pooled analysis to investigate the effects of CoQ10 intervention on cardiovascular disease (CVD) risk factors in overweight/obese patients with type 2 diabetes mellitus (T2DM). Methods: MEDLINE, Embase, and Cochrane databases were searched for randomized controlled trials that evaluated the changes in CVD risk factors among overweight and obese patients with T2DM following CoQ10 supplementation. Two investigators independently assessed articles for inclusion, extracted data, and assessed risk of bias. Major endpoints were synthesized as weighted mean differences (WMDs) with 95% CIs. Subgroup analyses were performed to check the consistency of effect sizes across groups. Publication bias and sensitivity analysis were also performed. Results: Fourteen eligible trials with 693 overweight/obese diabetic subjects were included for pooling. CoQ10 interventions significantly reduced fasting blood glucose (FBG; –0.59 mmol/L; 95% CI, −1.05 to –0.12; P=0.01), hemoglobin A1c (HbA1c; –0.28%; 95% CI−0.53 to –0.03; P=0.03), and triglyceride (TG) levels (0.17 mmol/L; 95% CI, −0.32 to –0.03; P=0.02). Subgroup analysis also showed that low-dose consumption of CoQ10 (

Haohai Huang,1 Tao Li,2 Dan Liao,3,4 Zhu Zhu,4 Yong Dong5 1Department of Science and Education, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China; 2Department of Medical Oncology, People’s Hospital of Gaozhou, Gaozhou, Guangdong, China; 3Department of Gynaecology & Obstetrics, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China; 4China-American Cancer Research Institute, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, Guangdong, China; 5Department of Cancer Center, Dongguan Third People’s Hospital, Affiliated Dongguan Shilong People’s Hospital of Southern Medical University, Dongguan, Guangdong, China Background: Accumulating evidence has suggested a relationship between calcium-sensing receptor (CASR) polymorphisms and cancer risk in different types of cancer; however, the findings from epidemiologic studies have been conflicting. The purpose of this meta-analysis was to assess the clinical susceptibility of CASR polymorphisms in cancer patients. Materials and methods: This study systematically searched MEDLINE and EMBASE databases for eligible articles through March 2017. The strength of association was expressed as odds ratio and 95% CI. Publication bias, heterogeneity, sensitivity analysis, and subgroup analyses were also examined. Results: Fourteen related case–control studies were finally identified to be included in the present analysis. The pooled result showed that no significant associations were found among CASR rs1801725, rs1042636, rs12485716, rs4678174, rs1801726, rs17251221, rs10934578, and rs2270916 polymorphisms and cancer risk under all genetic models (P>0.05). The relationship between CASR rs1801725 polymorphism and risk of cancer was consistent in the subgroup analyses, and robust in sensitivity analysis. No publication bias was presented in our pooled-analysis. Conclusion: The current evidence for our pooled analysis suggests that the CASR polymorphisms are not associated with an increased risk of cancer. Further larger studies are still necessary to warrant and validate the findings in the current meta-analysis. Keywords: calcium-sensing receptor, polymorphism, cancer, susceptibility, meta-analysis

Dehua Liao,1,2 Yujin Guo,3 Daxiong Xiang,2 Ruili Dang,3 Pengfei Xu,3 Hualin Cai,2 Lizhi Cao,1 Pei Jiang3 1Department of Pharmacy, Hunan Cancer Hospital, 2Department of Pharmacy, Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, 3Department of Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining, People’s Republic of China Objective: Long-term use of doxorubicin (Dox) can cause neurobiological side effects associated with depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural function, much is still unknown concerning the biological link between the NRG1/ErbB pathway and the Dox-induced neurotoxicity. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the hippocampus of rats following Dox treatment.Materials and methods: The drug was administered every 2 days at a dose of 2.5 mg/kg, and the animals in different groups were treated with intraperitoneal injection for three or seven times, respectively.Results: Our data showed that the rats treated with Dox for seven times (DoxL group) exhibited depression-like behaviors, whereas the short-term treatment (DoxS group) had no effect on the behavioral changes. Dox treatment also induced the neural apoptosis with more severe neurotoxicity. Intriguingly, the expression of NRG1 and the ratio of pErbB4/ErbB4 and pErbB2/ErbB2 were significantly decreased in the DoxL group, but enhanced activation of ErbB receptors was observed in the DoxS group. In parallel, administration of Dox for seven times suppressed the downstream Akt and ERK phosphorylation, while the Akt phosphorylation was enhanced with the administration of Dox for three times.Conclusion: Our data first showed the Dox-induced alterations of the NRG1/ErbB system in the hippocampus, indicating the potential involvement of the NRG1/ErbB pathway in the Dox-induced nervous system dysfunction. Keywords: chemotherapy, neurotoxicity, depression, NRG1/ErbB system, Akt, ERK

Jingbo Zhao,1 Jian Yang,1 Donghua Liao,1 Hans Gregersen2 1Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2Giome Center, Department of Surgery, Chinese University of Hong Kong and Prince of Wales Hospital, Shatin, Hong Kong Background: Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective: We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design: Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results: Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P

Dosing of tumour necrosis factor-α inhibitors (TNFis) is not personalized causing interindividual variation in serum drug levels; however, dose optimization is not widely implemented. We hypothesized that some patients are overdosed; thus, drug prescription could be reduced by therapeutic drug monitoring (TDM). Independent of disease activity, 239 adults treated for rheumatoid arthritis (n = 99), psoriatic arthritis 15 (n = 48), or spondyloarthritis (n = 92) were recruited for a 48-week prospective, randomized open-label trial. Standard care alone or plus TDM was applied in chronic arthritis patients treated with infliximab (IFX), (n = 81), etanercept (ETN) (n = 79), or adalimumab (ADA) (n = 79). Serum TNFi trough levels assessed at inclusion and every 4 months determined patients within/outside predefined therapeutic intervals, supporting change in prescription or drug switch. The primary endpoint was reduced drug prescription. Compared to standard care, TDM reduced prescribed IFX [−12% (95% confidence interval −20, −3); p = 0.001] and ETN (−15% (−29, 1); p = 0.01], and prolonged the interdosing intervals of ETN [+235% (38, 432); p = 0.02] and ADA [+28% (6, 51); p = 0.04]. Time to drug switch was accelerated (χ2 = 6.03, p = 0.01). No group differences in adverse events, disease activity, or self-reported outcomes were shown, indicating equally sustained remission. TDM reduced prescription of IFX, ETN, and ADA and identified patients benefiting from accelerated drug switch, thereby minimizing treatment failure, risk of toxicity, and unnecessary adverse events. [ABSTRACT FROM AUTHOR]