Search

Fang Fang,1,* Yun Yan Chen,1,* Xin-Ming Zhang,2 Jin Tang,1 Yu-Hao Liu,1 Chen-Shuo Peng,1 Yu Sun1,3 1School of Pharmacy, Wannan Medical College, Wuhu, 241002, People’s Republic of China; 2School of Chemistry and Materials Science, Anhui Normal University, Wuhu, 241002, People’s Republic of China; 3Institute of Synthesis and Application of Medical Materials, Wannan Medical College, Wuhu, 241002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Sun, School of Pharmacy, Wannan Medical College, Wuhu, 241002, People’s Republic of China, Tel +86 553 3932026, Email whsunyu@163.comBackground: Epidermal growth factor receptor (EGFR) is a major target for the treatment of colorectal cancer. Thus, anti-EGFR antibody conjugated lipid-polymer hybrid nanoparticles can offer a potential means of enhancing the efficacy of chemotherapeutics in EGFR overexpressing cancers. In addition, the combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. Hence, it is highly desirable to develop a safe and effective delivery system for colorectal tumor therapy.Methods: In this study, EGFR-targeted and NIR-triggered lipid-polymer hybrid nanoparticles (abbreviated as Cet-Iri-NPs) were prepared with copolymer PPG-PEG, lipids DSPE-PEG-Mal and lecithin as carriers, CPT-11 as an anticancer chemotherapeutic agent, indocyanine green (ICG) as a photothermal agent, and cetuximab as a surface-targeting ligand.Results: In vitro analyses revealed that Cet-Iri-NPs were spherical with size of 99.88 nm, charge of 29.17 mV, drug entrapment efficiency of 51.72%, and antibody conjugation efficiency of 41.70%. Meanwhile, Cet-Iri-NPs exhibited a remarkable photothermal effect, and pH/NIR-triggered faster release of CPT-11 with near infrared (NIR) laser irradiation, which induced enhanced cytotoxicity against SW480 cells. Furthermore, the promoted tumor-growth suppression effect of Cet-Iri-NPs on SW480 tumor xenograft nude mice was achieved under NIR laser irradiation.Conclusion: These results indicate that the well-defined Cet-Iri-NPs are a promising platform for targeted colorectal cancer treatment with chemo-photothermal therapy. Keywords: Chemo-photothermal therapy, Targeted cancer therapy, Nanoparticles, Cetuximab, Indocyanine green

Jia-Wen Xie,1,2 Yin-Feng Guo,1,2 Ya-Wen Zheng,1,3 Mao Wang,1,2 Qiu-Yan Xu,1,2 Yu-Yan Chen,1,2 Li-Rong Lin1,2,4 1Center of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Institute of Infectious Disease, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 3Prenatal Diagnosis Center, Zhangzhou Municipal Hospital Affiliated to Fujian Medical University, Zhangzhou, People’s Republic of China; 4Department of Basic Medical Science, Xiamen Medical College, Xiamen, People’s Republic of ChinaCorrespondence: Yu-Yan Chen; Li-Rong Lin, Centre of Clinical Laboratory, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, 361004, People’s Republic of China, Tel +86-592-2993041, Fax +86-592-2993043, Email chenyuyan@xmu.edu.cn; linlirong@xmu.edu.cnPurpose: Accurate differentiation between early and late latent syphilis stages is pivotal for patient management and treatment strategies. Nontreponemal IgM antibodies have shown potential in discriminating latent syphilis staging by differentiating syphilis activity. This study aimed to develop a predictive nomogram model for latent syphilis staging based on nontreponemal IgM antibodies.Patients and Methods: We explored the correlation between nontreponemal IgM antibodies and latent syphilis staging and developed a nomogram model to predict latent syphilis staging based on 352 latent syphilis patients. Model performance was assessed using AUC, calibration curve, Hosmer–Lemeshow χ 2 statistics, C-index, Brier score, decision curve analysis, and clinical impact curve. Additionally, an external validation set was used to further assess the model’s stability.Results: Nontreponemal IgM antibodies correlated with latent syphilis staging. The constructed model demonstrated a strong discriminative capability with an AUC of 0.743. The calibration curve displayed a strong fit, key statistics including Hosmer–Lemeshow χ² at 2.440 (P=0.486), a C-index score of 0.743, and a Brier score of 0.054, all suggesting favorable model calibration performance. Decision curve analysis and clinical impact curve highlighted the model’s robust clinical applicability. The external validation set yielded an AUC of 0.776, Hosmer–Lemeshow χ² statistics of 2.440 (P=0.486), a C-index score of 0.767, and a Brier score of 0.054, further underscored the reliability of the model.Conclusion: The nontreponemal IgM antibody-based predicted model could equip clinicians with a valuable tool for the precise staging of latent syphilis and enhancing clinical decision-making.Keywords: syphilis, latent syphilis, latent syphilis staging, nontreponemal IgM antibody, predictive model

Chih-Yen Hsiao,1 Yi-Chien Lee,2,3 Douglas JH Shyu,4 Che-Ping Su,5 Man-Yi Lin,5 Nai-Yu Guo,6 Cheng-Lun Chiang,1 Yih-Yuan Chen5 1Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; 2Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan; 3School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Biological Science and Technology, National Pingtung University of Science and Technology, Neipu, Pingtung, Taiwan; 5Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan; 6Department of Respiratory Care, Chang-Gung University of Science and Technology, Chiayi, TaiwanCorrespondence: Yih-Yuan Chen, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan, Tel +886-5-271-7795, Email yychen@mail.ncyu.edu.twObjective: The most common extraintestinal pathogen and infection site is uropathogenic Escherichia coli (UPEC), which causes urinary tract infections (UTIs). UPEC is also a common pathogen in bloodstream infections; in severe cases, it can lead to death. Although host and bacterial virulence factors have been demonstrated to be associated with UTI pathogenesis, the role of the related contributing factors in UTI and urinary source bacteremia is not yet fully understood. This study aimed to compare and analyze the factors contributing to urinary bacteremia in patients with UTI.Methods: A total of 171 E. coli strains collected from patients with UTI and urinary source bacteremia at Chiayi Christian Hospital were used. Phylogenetic groups and virulence factors were determined using PCR. Drug resistance patterns were determined using the disk diffusion assay.Results: Previous studies have demonstrated that fimbriae and papGII may be associated with first-step infections and severe UTIs, respectively. As expected, highly virulent E. coli strains (belonging to the phylogenetic B2 and D groups) were dominant in the bacteremic UTI (90%) and UTI (86.27%) groups. However, our results showed that the UTI group had a significantly higher prevalence of sfa/focDE (belonging to the S and FIC fimbriae) than the bacteremic UTI group (29.4% vs 12.5%; p=0.008). In the bacteremic group, we found that sfa/focDE was only detected in highly virulent strains. The bacteremic UTI group had a significantly higher prevalence of papGII (belonging to P fimbriae) than the UTI group (55.8% vs 37.3%; p=0.026). In addition, the P fimbriae gene cluster, including papC, papEF, and papGII, was predominant in highly virulent strains. Notably, our results show that multidrug-resistant (MDR) strains were significantly less virulent than non MDR strains.Conclusion: Taken together, our results provide insights into the contributing factors in patients with UTI and urinary bacteremia.Keywords: Escherichia coli, urinary tract infection, urinary source bacteremia, virulence factors, multidrug resistance

Chen-Yu Chen,1,2 Ying-Hao Wang,1 Chie-Pein Chen,1 Fang-Ju Sun,3 Yi-Yung Chen,1 Yu-Jun Huang,1 Nan-Fu Chiu4,5 1Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, 10449, Taiwan; 2Department of Medicine, MacKay Medical College, New Taipei City, 252005, Taiwan; 3Department of Medical Research, MacKay Memorial Hospital, Taipei, 10449, Taiwan; 4Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, Taipei, 11677, Taiwan; 5Department of Life Science, National Taiwan Normal University, Taipei, 11677, TaiwanCorrespondence: Chen-Yu Chen, Department of Obstetrics and Gynecology, MacKay Memorial Hospital, No. 92, Section 2, Zhong-Shan North Road, Taipei, 10449, Taiwan, Tel +886-2-25433535, Fax +886-2-25433642, Email f122481@mmh.org.tw Nan-Fu Chiu, Laboratory of Nano-Photonics and Biosensors, Institute of Electro-Optical Engineering, National Taiwan Normal University, No. 88, Section 4, Ting-Chou Road, Taipei, 11677, Taiwan, Tel +886-2-77496722, Fax +886-2-86631954, Email nfchiu@ntnu.edu.twBackground: Preeclampsia, a major cause of adverse pregnancy outcomes, involves metalloproteinases pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 from placental trophoblasts. The graphene oxide (GO)-based surface plasmon resonance (SPR) biosensor has higher sensitivity, affinity, and selective ability than the traditional SPR biosensor. The aim of this study was to explore the feasibility of measuring first-trimester serum PAPP-A/PAPP-A2 ratio as a novel predictor of preeclampsia using the GO-SPR biosensor.Methods: This prospective case-control study of pregnant women was conducted at MacKay Memorial Hospital, Taipei, Taiwan between January 2018 and June 2020. The SPR angle shifts of first-trimester serum PAPP-A, PAPP-A2, and PAPP-A/PAPP-A2 ratio measured using the GO-SPR biosensor were compared between preeclampsia and control groups.Results: Serum samples from 185 pregnant women were collected, of whom 30 had preeclampsia (5 early-onset; 25 late-onset). The response time between the antibody-antigen association and dissociation only took about 200 seconds. The SPR angle shift of PAPP-A in the preeclampsia group was significantly smaller than that in the control group (median (interquartile range): 5.33 (4.55) versus 6.89 (4.10) millidegrees (mDeg), P = 0.008). Conversely, the SPR angle shift of PAPP-A2 in the preeclampsia group was significantly larger than that in the control group (5.70 (3.81) versus 3.63 (2.38) mDeg, P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict all preeclampsia of ≤ 0.76, with an area under the ROC curve (AUC) of 0.79 (95% CI 0.73– 0.85, P < 0.001). Sub-group analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict early-onset preeclampsia of ≤ 0.53 (AUC 0.99, 95% CI 0.96– 1.00, P < 0.001), and ≤ 0.73 to predict late-onset preeclampsia (AUC 0.75, 95% CI 0.68– 0.81, P < 0.001).Conclusion: Measuring first-trimester serum PAPP-A/PAPP-A2 ratio using the GO-SPR biosensor could be a valuable method for early prediction of preeclampsia. Keywords: graphene oxide, surface plasmon resonance, biosensor, preeclampsia, PAPP-A/PAPP-A2 ratio

Yun Zhang,1 Jie Wang,2 Yong-Mei Liu,2 Yin-Ying Chen,3 Xiao-Chen Yang,4 Lian Duan2 1Department of Immunology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 3Department of the Scientific Research Office, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 4Department of Cardiology & Health Care, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of ChinaCorrespondence: Jie WangDepartment of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of ChinaTel +86 010-88001148Email wangjiedoctor2015@163.comBackground and Purpose: Two Chinese herbal medicines Huang Qi (HQ, Astragalus mongholicus) and Dan Shen (DS, Salvia miltiorrhiza) are often combined to treat coronary heart disease (CHD). The purpose of this study was to identify the underlying synergistic effects and mechanisms of HQ and DS against CHD.Methods: The active components and targets of HQ and DS, CHD-related genes, and the biological progression were analysed by network pharmacology. The myocardial infarction (MI) rat model was established by ligating the left anterior descending coronary artery. Cardiac function was detected by ultrasonic electrocardiography. The MI size, fibrosis, cardiac hypertrophy, lipid metabolism, blood viscosity, and coagulation indexes were analysed by histological staining or chemical methods, respectively.Results: A total of 170 shared and specific seed genes of HQ and DS against CHD were identified. The shared and specific biological processes of HQ and DS against CHD were obtained. The LVEF and LVFS values significantly increased, the myocardium infarct size and fibrosis significantly decreased, the values of lipid metabolism indexes and blood viscosity indexes significantly reduced in the HQ + DS treatment group vs HQ or DS single treatment (P < 0.05); the LVEDd, LVEDs, and the CSA values significantly reduced in HQ single and HQ + DS treatment groups vs MI group (P < 0.05); the coagulation index (APTT, PT, TT, and FIB) values decreased significantly in the DS single and HQ + DS treatment groups vs MI group (P < 0.05).Conclusion: In MI rats, HQ and DS exhibited synergistic effects on improving cardiac function, reducing MI size, fibrosis, regulating hyperlipidaemia, and maintaining circulatory system homeostasis; HQ had the specific advantage of alleviating cardiac remodelling; DS had the specific advantage of regulating hypercoagulability. This study revealed that HQ and DS not only exerted synergistic effects but also exhibited complementary effects on CHD.Keywords: coronary heart disease, Astragalus mongholicus, Salvia miltiorrhiza, synergistic effects, network pharmacology, myocardial infarction

Shiu-Ju Yang,1 Ting-Chun Wei,1 Chih-Hao Hsu,1 Sin-Ni Ho,1 Chi-Yun Lai,2 Shiu-Feng Huang,2,3 Yih-Yuan Chen,4 Shih-Jen Liu,1 Guann-Yi Yu,1 Horng-Yunn Dou1,5 1National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan; 2Pathology Core Laboratory, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan; 3National Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan; 4Department of Biochemical Science and Technology, National Chiayi University, Chia-Yi, 60070, Taiwan; 5Department of Biological Science & Technology, National Yang Ming Chiao Tung University, Hsinchu, TaiwanCorrespondence: Horng-Yunn DouNational Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County, 35053, TaiwanTel +886-37-206-166 ext 35529Fax +886-37-583-009Email hydou@nhri.edu.twBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus which caused a global respiratory disease pandemic beginning in December 2019. Understanding the pathogenesis of infection and the immune responses in a SARS-CoV-2-infected animal model is urgently needed for vaccine development.Methods: Syrian hamsters (Mesocricetus auratus) were intranasally inoculated with 105, 5× 105, and 106 TCID50 of SARS-CoV-2 per animal and studied for up to 14 days. Body weight, viral load and real-time PCR amplification of the SARS-CoV-2 N gene were measured. On days 3, 6 and 9, lung, blood, liver, pancreas, heart, kidney, and bone marrow were harvested and processed for pathology, viral load, and cytokine expression.Results: Body weight loss, increased viral load, immune cell infiltration, upregulated cytokine expression, viral RNA, SARS-CoV-2 nucleoprotein, and mucus were detected in the lungs, particularly on day 3 post-infection. Extremely high expression of the pro-inflammatory cytokines MIP-1 and RANTES was detected in lung tissue, as was high expression of IL-1β, IL-6, IL-12, and PD-L1. The glutamic oxalacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) ratio in blood was significantly increased at 6 days post-infection, and plasma amylase and lipase levels were also elevated in infected hamsters.Conclusion: Our results provide new information on immunological cytokines and biological parameters related to the pathogenesis and immune response profile in the Syrian hamster model of SARS-CoV-2 infection.Keywords: SARS-CoV-2, hamster, immune response, pathogenesis

Hao Lin,1 Wen-Hsin Chen,1 Chen-Hsuan Wu,1,2 Yu-Che Ou,3 Yu-Jen Chen,3 Ying-Yi Chen,1 Yu-Han Lin,4 Hung-Chun Fu1– 3 1Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Lin-Kou, Taiwan; 3Department of Obstetrics and Gynecology, Chia-Yi Chang Gung Memorial Hospital, Chia-Yi, Taiwan; 4Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan, TaiwanCorrespondence: Hung-Chun FuDepartment of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta Pei Road, Niao Sung District, Kaohsiung City, Taiwan, Republic of ChinaTel +886 7 731712Fax +886 7 7322915Email allen133@adm.cgmh.org.twAim: To investigate whether the time interval between primary debulking surgery (PDS) and initiating adjuvant chemotherapy affects survival in patients with epithelial ovarian cancer (EOC).Methods: We retrospectively reviewed FIGO stage IIB to IV EOC patients who received PDS followed by adjuvant chemotherapy in our hospital between January 2008 and December 2016. The optimal cut-off time interval to chemotherapy related to survival was determined using the Contal and O’Quigley method and Cox hazard models. Cox regression analysis was used to identify the independent effect of time interval on survival.Results: A total of 152 patients were identified and divided into three groups based on the time interval between PDS and initiating adjuvant chemotherapy: early (< 23 days), intermediate (23– 43 days) and late (> 43 days). The intermediate group had a significantly better median progression-free survival (PFS, 35.5 months) compared to the early (20 months) and late (22.6 months) groups. After adjustments for confounding factors, time interval was still an independent variable affecting PFS. The intermediate group was associated with a better PFS compared with the early and late groups (hazard ratio 0.27, 95% CI 0.10– 0.83, p=0.002). There was no statistical significance in overall survival (OS) in univariate or multivariate analysis, although there was a trend towards better OS in the intermediate group.Conclusion: Our results provide evidence that the time interval from PDS to chemotherapy influences PFS in patients with advanced EOC. The optimal time to initiate chemotherapy was between 23 and 43 days, within 3– 6 weeks post-operatively. Initiating chemotherapy early (< 23 days) did not appear to benefit PFS.Keywords: time interval, chemotherapy, ovarian cancer

Yuan-Yuei Chen,1– 3 Tung-Wei Kao,3 Yi-Lin Chiu,4 Tao-Chun Peng,3 Hui-Fang Yang,3 Wei-Liang Chen3,4 1Department of Pathology, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China; 2Department of Pathology, Tri-Service General Hospital Songshan Branch, School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China; 3Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China; 4Department of Biochemistry, National Defense Medical Center, Taiwan, Republic of ChinaCorrespondence: Wei-Liang ChenDivision of Geriatric Medicine, Department of Family Medicine, Tri-Service General Hospital, National Defense Medical Center, Number 325, Section 2, Chang-Gong Road, Nei-Hu District, Taipei, 114, TaiwanTel +886-2-87923311 ext. 16567Fax +886-2-87927057Email weiliang0508@gmail.comBackground: Emerging studies have proposed that cytokines secreted following macrophage polarization may contribute to skeletal muscle aging. The current study primarily aimed to determine whether these cytokines have an impact on the progression of sarcopenia in an elderly population.Methods: In total, 120 elderly adults aged 65 years and older who underwent health examinations from 2015 to 2019 were included in this retrospective study. Sarcopenia was based on the criteria proposed by the European Working Group on Sarcopenia in Older People in 2019. Macrophages and cytokines datasets were obtained from Gene Expression Omnibus (GEO) database. Comprehensive assessments were performed for muscle strength, muscle mass, gait speed, tumor growth factor-β (TGF-β), and interleukin-12 (IL-12). Thereafter, the association between sarcopenia and cytokines was analyzed using regression models.Results: Low muscle strength and low-speed gait were negatively associated with IL-12 [β: − 8.96 (95% CI: − 14.12, − 3.79) and − 7.16 (95% CI: − 12.54, − 1.78), respectively]. Participants with more sarcopenia components and more severe sarcopenia had lower IL-12 (P for trend < 0.001). Conversely, more amount of sarcopenia components were associated with increased TGF-β (P for trend < 0.05). A definite diagnosis of sarcopenia was associated with decreased IL-12 and increased TGF-β with β of − 8.96 (95% CI: − 14.12, − 3.79) and 147.75 (95% CI: 36.27, 259.23). Furthermore, increased IL-12 levels were significantly associated with reduced occurrence of sarcopenia with and odd ratio (OR) of 0.36 (95% CI: 0.15– 0.834).Conclusion: Our findings on the relationship between cytokines and age-related muscle loss showed that IL-12 may be an early diagnosis indicator for sarcopenia in the elderly population.Keywords: gender, sarcopenia, IL-12, TGF-β, macrophage

Ling-Chun Lee,1,* Pi-Shan Hsu,2,3,* Kuen-Chang Hsieh,4– 6 Yu-Yawn Chen,7 Lee-Ping Chu,8 Hsueh-Kuan Lu,9 Yen-Chen Chiu,10 Lin Li,11 Chung-Liang Lai12,13 1Department of Physical Education, Chinese Culture University, Taipei, Taiwan; 2Department of Family Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 3Graduate Institute of Microbiology and Public Health, National Chung-Hsing University, Taichung, Taiwan; 4Fundamental Education Center, National Chin-Yi University of Technology, Taichung, Taiwan; 5Big Data Center, National Chung-Hsing University, Taichung, Taiwan; 6Office of Physical Education, Fu Jen Catholic University, New Taipei, Taiwan; 7Division of Food Nutrition, National Taitung Junior College, Taitung, Taiwan; 8Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan; 9General Education Center, National Taiwan University of Sport, Taichung, Taiwan; 10Department of Exercise Health Science, National Taiwan University of Sport, Taichung, Taiwan; 11Department of Physical Medicine and Rehabilitation, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 12Department of Physical Medicine and Rehabilitation, Puzi Hospital, Ministry of Health and Welfare, Chiayi, Taiwan; 13Department of Occupational Therapy, Asia University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Chung-Liang LaiDepartment of Physical Medicine and Rehabilitation, Puzi Hospital, Ministry of Health and Welfare, No. 42– 50, YungHo Vil., Puzi City, Chiayi County, 61347, TaiwanTel +886-5-379-0600Email laipeter57@yahoo.com.twPurpose: To investigate the potential of standing 8-electrode bioelectrical impedance analysis (BIA) for assessing visceral fat area (VFA) and body fat mass (BFM) in athletes.Materials and Methods: A total of 95 subjects (50 males and 45 females) were recruited. VFA and BFM measurements were obtained using three standing 8-electrode BIA devices, InBody230, InBody770, and IOI353. These acquired VFA and BFM were expressed as VFAIOI353, VFAInBody230, VFAInBody770 V, BFMIOI353, BFMInBody230, and BFMInBody770, respectively. As reference measurement, the VFA acquired from computer tomography (CT) was expressed as VFACT, and the BFM measured by dual-energy X-ray absorptiometry (DXA) was denoted as BFMDXA.Results: The coefficient of determination (r2) in regression analysis between the measurements by VFAIOI353, VFAInBody230, VFAInBody770 and VFACT were 0.425, 0.492, and 0.473, respectively. Also, the limits of agreement (LOA) obtained from Bland–Altman analysis were − 25.18 to 56.62, − 29.74 to 62.44, and − 32.96 to 71.93 cm2. For BFM, r2 in regression analysis between the measurements by BFMIOI353, BFMInBody230, BFMInBody770 and BMFDXA were 0.894, 0.950, and 0.955, respectively; LOA were − 7.21 to 5.75, − 4.70 to 4.05, and − 5.48 to 3.05 kg, respectively.Conclusion: The results showed when assessing BFM, these instruments delivered comparable measurements, and the degree of agreement ranged from excellent to moderate compared with the reference method. However, when assessing VFA, the agreements were weak. Therefore, the application of standing 8-electrode BIA devices for assessing athletes’ VFA still needs improvement.Keywords: bioelectrical impedance analysis, body fat mass, visceral fat area

Tian-Yong Hu,1,* Hua Zhang,1,* Yan-Yan Chen,1 Wei-Hua Jiao,2 Jun-Ting Fan,3 Zhi-Qiang Liu,1 Hou-Wen Lin,2 Bao-Hui Cheng1 1Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, 518172, People’s Republic of China; 2Research Center for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People’s Republic of China; 3Department of Pharmaceutical Analysis, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hou-Wen LinShanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, People’s Republic of ChinaEmail franklin67@126.comBao-Hui ChengShenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, 3004, Longgang Avenue, Longgang District, Shenzhen, 518172, People’s Republic of ChinaEmail chengbaohui@sina.comBackground: Marine natural products harbor a variety of pharmacological activities, and the sea species have been becoming a main source of new drug candidate. In pursuit of safer and more effective anti-inflammation drug, the anti-inflammatory activities, anti-oxygenation effects and underlying molecular mechanisms of compound dysiarenone from Dysidea arenaria were investigated via LPS-induced RAW 264.7 cell model.Methods: Firstly, RAW 264.7 cells have been stimulated with LPS and treated with dysiarenone, and the cell viability of the LPS-treated RAW 264.7 cells was examined. One-step method, DCFH-DA fluorescence probe method was used to detect reactive oxygen species (ROS). The modulation of dysiarenone on anti-inflammation was detected by enzyme-linked immunosorbent assay by measuring the release of inflammatory cytokines (TNF-α and IL-6), and inflammatory mediators (LTB4). Further, the underlying anti-inflammatory mechanism of dysiarenone was explored by determining the expression of inducible 5-LOX, MAPKs, p-Akt, and p-NF-κB p65. Oxidative stress is tightly connected with inflammation, which was also evaluated through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (OH-1) signaling pathway.Results: Our study unraveled that dysiarenone between 2 and 8 μM reduces the inflammation responses via suppressing the production of inflammatory cytokines (TNF-α and IL-6) and inflammatory mediators (LTB4). Dysiarenone down-regulated the protein levels of inducible 5-LOX via the inhibition of phosphorylation of MAPKs (including p38, ERK), Akt and NF-κB p65. Additionally, dysiarenone decreases ROS accumulation by upregulating HO-1 expression via nuclear translocation of Nrf2.Conclusion: In conclusion, we demonstrated that dysiarenone possesses anti-inflammation and anti-oxidation activity via inhibiting 5-LOX/NF-κB/MAPK and Nrf2/HO-1 signaling pathway. Dysiarenone might be a promising lead compound for inflammatory diseases.Keywords: dysiarenone, Dysidea arenaria, Nrf2, HO-1, NF-κB

Yang Fu,1 Yuan Tang,2 Yue Zheng,1 Yue-Yun Chen,1 Ye Hong,1 Pei-Pei Wang,1 Qing Li,1 Ting Liu,1 Zhen-Yu Ding1 1Department of Biotherapy, Cancer Center, West China Hospital, West China Medical School, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, People’s Republic of China; 2Department of Pathology, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Zhen-Yu DingDepartment of Biotherapy, Cancer Center, West China Hospital, West China Medical School, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People’s Republic of ChinaTel +86 028 8542 2562Fax +86 028 8516 4059Email dingzhenyu@scu.edu.cnBackground: Epidermal growth factor receptor (EGFR) mutations are more frequently seen in miliary intrapulmonary metastases than EGFR wild-type non-small cell lung cancer (NSCLC). Also, small-scale retrospective studies showed that patients harboring EGFR mutation with miliary pulmonary metastases had a worse prognosis. This study aimed to explore the impact of imaging patterns on the outcomes of EGFR tyrosine kinase inhibitor (TKI) treatment.Methods: A cohort of treatment-naive NSCLC patients harboring EGFR mutation with intrapulmonary metastases who were prescribed with TKI were enrolled. The demographic feature, clinical outcome, and CT imaging of each patient were reviewed and analyzed.Results: A cohort of 174 patients were enrolled. Five intrapulmonary patterns of imaging were recognized: solid nodular, ground-glass nodular, miliary, multiple uniform nodular, and not otherwise specified. Among them, miliary and multiple uniform nodular patterns had similar poor prognosis, and, therefore, were combined as diffuse group. A worse PFS (9.0 mon, 95% CI: 8.0– 10.0 mon) was observed compared with the rest (non-diffuse group, 13.3 mon, 95% CI: 10.2– 16.4 mon, p< 0.001, HR=0.49). The objective response rates (ORR) between the two groups were 76.8% and 84.1%, respectively, with no significant difference (p = 0.474). The OS of the diffuse and the non-diffuse group were 25.6 mon (95% CI 21.9– 29.3 mon) and 35.0 mon (95% CI: 27.5– 42.5, p = 0.01, HR= 0.59). Organs like bone (p=0.167), liver (p=0.513), and adrenal gland (p=0.375) were involved in similar frequencies in both groups. However, brain (p=0.070) and leptomeningeal (p=0.078) metastases were less common in the non-diffuse group with marginally statistical significance. The 2 groups contained similar missense mutations, and gene amplification was more common in the non-diffuse group.Conclusion: Patients with diffuse intrapulmonary metastases had inferior outcomes after TKI treatment. More aggressive treatments might be warranted for these patients.Keywords: epidermal growth factor receptor, EGFR, tyrosine kinase inhibitor, TKI, CT imaging, outcome, genetic aberration

Lin-Wei Wang,* Li Li,* Hong-Yan Zhang, Yuan-Yuan Chen, Ya-Hua Zhong Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ya-Hua Zhong Email doctorzyh73@163.comPurpose: Radiotherapy is a powerful strategy to prevent chest wall recurrence (CWR) of postmastectomy breast cancer (BC). This retrospective study aims at analyzing patterns of CWR to explore the delineation of clinical target volume.Patients and Methods: Detailed clinicopathological information of postmastectomy BC patients with CWR was collected from our single cancer center based on clear criteria. To describe recurrent positions more accurately, the chest wall was divided into three layers: skin layer (skin and subcutaneous tissues), pectoralis layer (pectoralis major and minor), and rib layer (rib and intercostal muscle). The frequency distribution of recurrence location and its association with clinical pathological factors were analyzed.Results: A total of 121 postmastectomy BC with CWR were included in this study. The percentages of breast tumor located in the upper outer quadrant, upper inner quadrant, lower inner quadrant, lower outer quadrant, overlapping quadrant, and areola area were 31.0% (35/113), 26.5% (30/113), 12.4% (14/113), 5.3% (6/113), 21.1% (25/113), and 2.7% (3/113), respectively. HER2-positive BC (51/113, 45.1%) is the most common BC subtype. Analysis on the patterns of CWR showed that recurrences locating in the skin layer, pectoralis layer, rib layer, mixed layers, and incision periphery accounted for 58.6% (68/116), 9.5% (11/116), 1.7% (2/116), 30.2% (35/116), and 60.5% (46/76), respectively. Rates of recurrences located in the skin and/or pectoralis layers for all BC patients, patients with concomitant distance metastasis, and patients without concomitant distance metastasis were 82.8% (96/116), 85.9% (49/57), and 81.0% (47/58), respectively.Conclusion: For BC patients receiving mastectomy, skin, subcutaneous tissues, pectoralis, and area around incision have a high risk of recurrence, which should be paid more attention in chest wall radiotherapy.Keywords: breast cancer, radiotherapy, chest wall recurrence, clinical target volume

Ying Zhang,1,* Li-Rong Liang,2,* Shu Zhang,1 Yong Lu,1 Yang-Yu Chen,1 Huan-Zhong Shi,1 Ying-Xiang Lin1 1Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People’s Republic of China; 2Clinical Epidemiology and Tobacco Dependence Treatment Research Department, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huan-Zhong Shi; Ying-Xiang LinDepartment of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti Nanlu, Chaoyang District, Beijing 100020, People’s Republic of ChinaTel/ Fax +86 10 65935208Email shihuanzhong@sina.com; bjlin666@163.comPurpose: Peripheral blood eosinophilic counts are susceptible to many factors and have variability over time. There are limited studies on association of blood eosinophilia with long-term mortality of chronic obstructive pulmonary disease (COPD) patients and these results remain controversial. Our aims were to explore the association of blood eosinophilia at index hospitalization and stability of blood eosinophilia stability over 5 years with all-cause mortality of patients hospitalized for acute exacerbation of COPD (AECOPD).Patients and Methods: Eight hundred twenty-nine patients hospitalized for AECOPD between 2013 and 2014 were included in this study and grouped into two groups according to blood eosinophil with 150 cells/μL used as the cutoff value to form eosinophilic and non-eosinophilic groups. Two hundred forty-one COPD inpatients with at least three blood eosinophils measured from different hospitalizations were used for analysis of longitudinally eosinophilic stability and divided into three groups according to the same cutoff value: predominantly (PE), intermittently (IE) and rarely (RE) eosinophilic groups. Cox regression analysis was used to determine the association of blood eosinophilia and all-cause mortality.Results: In patients hospitalized for AECOPD, 261 (31.5%) at baseline and 41 (17%) based on at least three measurements of blood eosinophils had increased blood eosinophils. For all-cause mortality, eosinophilic COPD patients at index hospitalization had a lower all-cause mortality compared with non-eosinophilic COPD patients (hazard ratio 0.77, 95% confidence interval 0.6– 0.99, P=0.04). In patients readmitted for AECOPD by longitudinal eosinophil stability, with the RE group used as reference, the PE group was associated with a lower all-cause mortality of AECOPD patients (hazard ratio 0.43, 95% confidence interval 0.22– 0.85, P=0.016), compared to the IE group (hazard ratio 0.72, 95% confidence interval 0.47– 1.11, P=0.133).Conclusion: Patients with increased eosinophils (using eosinophil 150 cells/μL as a cutoff value), especially predominantly increased eosinophil levels based on multiple measurements, had a lower risk of all-cause mortality. Blood eosinophilia can be used as a biomarker in hospitalized COPD exacerbations for predicting the risk of all-cause mortality.Keywords: acute exacerbation, chronic obstructive pulmonary disease, blood eosinophilia, mortality

Lijun Xue,1,2 Yang Yizhi Chen,1 Zhiyun Yan,3 Wei Lu,1 Dong Wan,4 Huifeng Zhu11College of Pharmaceutical Sciences and Traditional Chinese Medicine, Southwest University, Chongqing 400715, People’s Republic of China; 2College of Pharmaceutical Engineering, Chongqing Chemical Industry Vocational College, Chongqing, 400020, People’s Republic of China; 3Wuhan Wusteel Good Life Service Co. LTD, Wuhan, 430000, People’s Republic of China; 4Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaAbstract: Staphylococcus aureus is an important and common Gram-positive bacteria which causes clinical infections and food-poisoning cases. Therapeutic schedules for treatment of S. aureus infections are facing a challenge because of the emergence of multidrug resistance strains. It is urgent to find new antiinfective drugs to control S. aureus infection. S. aureus strains are capable of producing the golden carotenoid pigment: staphyloxanthin, which acts as an important virulence factor and a potential target for antivirulence drug design. This review is aimed at presenting an updated overview of this golden carotenoid pigment of S. aureus from the biosynthesis of staphyloxanthin, its function, and the genes involved in pigment production to staphyloxanthin: a novel target for antivirulence therapy.Keywords: staphyloxanthin, target, antiinfective drug, antivirulence therapy

Wen-Chi Chou,1 Yen-Yang Chen,2 Chia-Yen Hung,1,3 Jen-Shi Chen,1 Chang-Hsien Lu,4 Pei-Hung Chang5 1Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 4Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan; 5Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan Background: Only 5-fluorouracil (5-FU), cisplatin, and gemcitabine have been reimbursed for metastatic pancreatic cancer (mPC) treatment in Taiwan since 2003. It is uncertain whether the reimbursement of S-1 in June 2014 might change the treatment pattern and improve the survival of mPC patients in Taiwan. Patients and methods: A total of 645 patients with newly diagnosed mPC who received palliative chemotherapy between 2010 and 2016 in Taiwan were analyzed retrospectively. Patients were stratified according to year at diagnosis of mPC for analysis of chemotherapeutic treatment pattern and survival. Results: Overall, the most common chemotherapeutic agents used for the treatment of mPC were gemcitabine (94.8%), followed by cisplatin (52.4%), S-1 (38.1%), and 5-FU (29.7%). The percentage of patients treated with S-1 between 2010 and 2016 increased from 2.6% to 74.0% (P

Ying-Yi Chen, Tsai-Wang Huang, Hung Chang, Shih-Chun LeeDivision of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Introduction: The rationale for oncologic surveillance following pulmonary lobectomy is to detect recurrent disease or a second primary lung cancer early enough so that an intervention can increase survival and/or improve quality of life. Therefore, we reviewed literature for international guidelines and reorganized these useful factors associated with non-small-cell lung cancer (NSCLC) recurrence as remedies in postoperative follow-up. Method: The population of interest for this review was patients who had been treated with complete resection for primary NSCLC and were in follow-up. Result: Guidelines on follow-up care for NSCLC vary internationally. Because of the production of progressive medical modalities, the current follow-up care should be corrected. Conclusion: The specific follow-up schedule for computed tomography imaging may be more or less frequent, depending upon risk factors for recurrence. Many different predictors of postoperative recurrence may help to optimize the patient selection for specified surveillance guidelines and personalized adjuvant therapies to prevent possibly occult micrometastases and to get a better outcome. Keywords: lung cancer, follow-up, surveillance, recurrence

Kuo-Shao Sun,1,2* Ming-Shian Lin,1,2* Yi-Jen Chen,1,2 Yih-Yuan Chen,3 Solomon Chih-Cheng Chen,4 Wei Chen1,5,6 1Division of Pulmonary and Critical Care Medicine, 2Department of Respiratory Care, Chang Gung University of Science and Technology, 3Department of Internal Medicine, 4Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 5College of Nursing, Dayeh University, Changhua, 6Department of Respiratory Therapy, China Medical University, Taichung, Taiwan, Republic of China *These authors contributed equally to this work Objective: Symptomatic peripheral arterial disease (PAD) is associated with impaired walking endurance in patients with chronic obstructive pulmonary disease (COPD). However, it is unknown whether asymptomatic PAD is associated with impaired walking endurance in patients with COPD. Methods: This prospective cross-sectional study enrolled 200 COPD patients (mean age: 70.9 years) who volunteered to perform ankle-brachial index (ABI) and 6-minute walk test (6MWT) consecutively. Demographic data, lung function, dyspnea scales, and cardiovascular risk factors were recorded. The ABI was used to detect PAD (ABI

Chun-Wei Lin,1,2 Yih-Yuan Chen,3 Yi-Jen Chen,1,4 Chi-Yen Liang,1 Ming-Shian Lin,1,4 Wei Chen1,5,6 1Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chia-Yim, 2Division of Chest, Division of Pulmonary Medicine, Kuang Tien General Hospital, Taichung, 3Department of Internal Medicine, Chia-Yi Christian Hospital, 4Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, 5College of Nursing, Dayeh University, 6Department of Respiratory Therapy, China Medical University, Taichung, Taiwan Background: Data regarding osteoporosis in COPD patients in Taiwan remain limited. The primary end point of this study was to evaluate the prevalence and risk factors of osteoporosis in COPD patients in Taiwan. The secondary end point was to examine the association between osteoporosis and health-related quality of life (HRQL) in COPD patients.Materials and methods: This prospective cross-sectional study enrolled 125 COPD patients (mean age 73.6 years, forced expiratory volume in 1 second [FEV1] 1.19±0.43 L) who had bone mineral-density measurements performed consecutively. Demographic data, lung function, and HRQL including modified Medical Research Council dyspnea scale, St George’s Respiratory Questionnaire, oxygen-cost diagram, Center for Epidemiologic Studies – depression scale, and COPD Assessment Test scores were recorded. Results: A total of 50 (40%) participants were diagnosed as having osteoporosis. In a multivariate logistic regression model including age, smoking amount (pack-year), body mass index (BMI), and FEV1, only BMI (odds ratio 0.824, 95% confidence interval 0.73–0.93; P=0.002) and FEV1 (odds ratio 0.360, 95% confidence interval 0.13–0.98; P=0.046) were negatively associated with an increased risk of osteoporosis in COPD patients. In addition, COPD patients with osteoporosis had significantly higher modified Medical Research Council dyspnea scale scores (1.7±0.8 vs 1.4±0.8, P=0.046), St George’s Respiratory Questionnaire scores (36.6 vs 28.0, P=0.01), and COPD Assessment Test scores (14.7±8 vs 11.5±7, P=0.019), and lower oxygen-cost diagram score (4.8±1.8 vs 5.4±1.6, P=0.045) than patients without osteoporosis. Conclusion: The prevalence of osteoporosis in COPD patients was high at a community hospital in Taiwan. BMI and FEV1 were the independent risk factors for osteoporosis in COPD. In addition, COPD patients with osteoporosis had worse HRQL than those without osteoporosis. Keywords: osteoporosis, chronic obstructive pulmonary disease, bone density

Char-Wen Chen,1,* Yih-Yuan Chen,2,* Chin-Li Lu,3 Solomon Chih-Cheng Chen,3 Yi-Jen Chen,1,4 Ming-Shian Lin,1,4 Wei Chen1,5,6 1Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi, 2Department of Internal Medicine, Chia-Yi Christian Hospital, Chiayi, 3Department of Medical Research, Ditmanson Medical Foundation, Chia-Yi Christian Hospital, Chiayi, 4Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus; Changhua, 5College of Nursing, Dayeh University, Changhua 6Department of Respiratory Therapy, China Medical University, Taichung, Taiwan *These authors contributed equally to this work Background: Acute respiratory failure (ARF) is a life-threatening event, which is frequently associated with the severe exacerbations of chronic obstructive pulmonary disease (COPD). Hypoalbuminemia is associated with increased mortality in patients with COPD. However, to date, little is known regarding whether or not hypoalbuminemia is a risk factor for developing ARF in COPD.Methods: We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. A total of 42,732 newly diagnosed COPD patients (age ≥40 years) from 1997 to 2011 were enrolled. Among them, 1,861 (4.36%) patients who had received albumin supplementation were defined as hypoalbuminemia, and 40,871 (95.6%) patients who had not received albumin supplementation were defined as no hypoalbuminemia.Results: Of 42,732 newly diagnosed COPD patients, 5,248 patients (12.3%) developed ARF during the 6 years follow-up period. Patients with hypoalbuminemia were older, predominantly male, had more comorbidities, and required more steroid treatment and blood transfusions than patients without hypoalbuminemia. In a multivariable Cox regression analysis model, being elderly was the strongest independent risk factor for ARF (adjusted hazard ratio [HR]: 4.63, P

Boran Cheng,1,* Zhaobo He,2,* Libo Zhao,2,* Yuan Fang,1 Yuanyuan Chen,1 Rongxiang He,2 Fangfang Chen,1 Haibin Song,1 Yuliang Deng,2 Xingzhong Zhao,2 Bin Xiong1 1Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan, Hubei, People’s Republic of China; 2Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Abstract: Circulating tumor cells (CTCs) in the blood which have detached from both the primary tumor and any metastases may be considered as a “liquid biopsy” and are expected to replace tumor biopsies in the monitoring of treatment response and determining patient prognosis. Here, we introduce a facile and efficient CTC detection material made of hydroxyapatite/chitosan (HA/CTS), which is beneficial because of its transparency and excellent biological compatibility. Atomic force microscopy images show that the roughness of the HA/CTS nanofilm (HA/CTSNF) substrates can be controlled by changing the HA:CTS ratio. Enhanced local topographic interactions between nano-components on cancer cell membranes, and the antibody coated nanostructured substrate lead to improved CTC capture and separation. This remarkable nanostructured substrate has the potential for CTC culture in situ and merits further analysis. CTCs captured from artificial blood samples were observed in culture on HA/CTSNF substrates over a period of 14 days by using conventional staining methods (hematoxylin eosin and Wright’s stain). We conclude that these substrates are multifunctional materials capable of isolating and culturing CTCs for subsequent studies. Keywords: cell capture, cell culture, nanofilms, hydroxyapatite/chitosan

© 2018. The American Astronomical Society. All rights reserved. The Kepler-9 system harbors three known transiting planets. The system holds significant interest for several reasons. First, the outer two planets exhibit a period ratio that is close to a 2:1 orbital commensurability, with attendant dynamical consequences. Second, both planets lie in the planetary mass "desert" that is generally associated with the rapid gas agglomeration phase of the core accretion process. Third, there exist attractive prospects for accurately measuring both the sky-projected stellar spin-orbit angles as well as the mutual orbital inclination between the planets in the system. Following the original Kepler detection announcement in 2010, the initially reported orbital ephemerides for Kepler-9 b and c have degraded significantly, due to the limited time base-line of observations on which the discovery of the system rested. Here, we report new ground-based photometric observations and extensive dynamical modeling of the system. These efforts allow us to photometrically recover the transit of Kepler-9 b and thereby greatly improve the predictions for upcoming transit mid-times. Accurate ephemerides of this system are important in order to confidently schedule follow-up observations of this system, for both in-transit Doppler measurements as well as for atmospheric transmission spectra taken during transit.

Background: T cells expressing chimeric antigen receptors (CARs) have shown exciting promise in cancer therapy, particularly in the treatment of B-cell malignancies. However, optimization of CAR-T cell production remains a trial-and-error exercise due to a lack of phenotypic benchmarks that are clearly predictive of anti-tumor functionality. A close examination of the dynamic changes experienced by CAR-T cells upon stimulation can improve understanding of CAR-T-cell biology and identify potential points for optimization in the production of highly functional T cells. Methods: Primary human T cells expressing a second-generation, anti-CD19 CAR were systematically examined for changes in phenotypic and functional responses to antigen exposure over time. Multi-color flow cytometry was performed to quantify dynamic changes in CAR-T cell viability, proliferation, as well as expression of various activation and exhaustion markers in response to varied antigen stimulation conditions. Results: Stimulated CAR-T cells consistently bifurcate into two distinct subpopulations, only one of which (CARhi/CD25+) exhibit anti-tumor functions. The use of central memory T cells as the starting population and the resilience-but not antigen density-of antigen-presenting cells used to expand CAR-T cells were identified as critical parameters that augment the production of functionally superior T cells. We further demonstrate that the CARhi/CD25+ subpopulation upregulates PD-1 but is resistant to PD-L1-induced dysfunction. Conclusions: CAR-T cells expanded ex vivo for adoptive T-cell therapy undergo dynamic phenotypic changes during the expansion process and result in two distinct populations with dramatically different functional capacities. Significant and sustained CD25 and CAR expression upregulation is predictive of robust anti-tumor functionality in antigen-stimulated T cells, despite their correlation with persistent PD-1 upregulation. The functionally superior subpopulation can be selectively augmented by careful calibration of antigen stimulation and the enrichment of central memory T-cell type.

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.

Cornelia de Lange Syndrome (CdLS) is a severe developmentaldisorder frequently associated with heterozygous loss-of-functionNIPBL mutations. NIPBL loads cohesin onto chromatin. Cohesinmediates sister chromatid cohesion important for mitosis, but isalso increasingly being recognized as a regulator of gene expression.In CdLS patient cells and animal models, the presence of multiplegene expression changes with little or no cohesion defect suggeststhat disruption of gene regulation underlies this disorder. However,the effect of NIP BL haploinsufficiency on cohesin binding, and howthis relates .to the clinical presentation of CdLS, has not been fullyinvestigated. We examined genome-wide cohesin binding and itsrelationship to gene expression using mouse embryonic fibroblasts(MEFs) from Nipbl +I- mice that recapitulate the CdLS phenotype.We found a global decrease in cohesin binding, includingthose at CTCF sites and repeat regions. Cohesin-bound genes areenriched for H3K4me3 at the promoters and are mostly downregulatedin Nipbl mutant MEFs with evidence for reduced promoter-enhancer interaction, suggesting that gene activation is theprimary co he sin function sensitive to Nip bl reduction. Over 50% ofgenes affected in mutant MEFs are cohesin target genes, includingthose involved in adipogenesis, indicating their direct contributionsto the Nipbl haploinsufficiency-induced CdLS phenotype.Interestingly, mutations in several cohesin subunit genes exhibitmild and somewhat distinct phenotypes compared to that of NIP BLhaploinsufficiency, raising the possibility that NIPBL may haveunique functions independent of cohesin. We will discuss ourrecent findings that su11port the notion that the cohesin-independentrole ofNIPBL also contributes to the CdLS pathogenesis. Thiswork was supported in part by NIH grants P01-HD052860 and R21HD062951.

© 2014 Zhao et al.Antibodies are ubiquitous and essential reagents for biomedical research. Uses of antibodies include quantifying proteins, identifying the temporal and spatial pattern of expression in cells and tissue, and determining how proteins functi

The compounds Ce3Sn, Ce3In and Ce3Al are characterized by a small energy scale that is reflected in the magnetic susceptibility and temperature dependent electrical resistance. We have investigated the effect of hydrostatic pressure on their electrical resistance and find a response that is typical of Kondo lattice behavior. In addition, both Ce3In and Ce3Al undergo a phase transition induced by pressure which, in the case of Ce3Al, is reminiscent of the γ-α transition in cerium. © 1987.