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1. Application of citric acid can enhance the accuracy for 13C-urea breath tests in the diagnosis of Helicobacter pylori infection in Chinese patients

Author

Gang Chen, Weiping Zhang, Qiaoling Wu, Qin Yu, Yongping Cai, Wenwu Luo, Jianming Xu, Lei Zhang, and Rutao Hong

Subjects
Medicine, Science
Abstract

Abstract Previous published data have confirmed that the addition of a citric acid meal improves the accuracy of the 13C-urea breath test (13C-UBT). However, some studies have suggested that a citric acid test meal may not be necessary. Thus, the aim of this study was to evaluate the combination of a 13C-UBT with a citric acid meal for the diagnosis of Helicobacter pylori (Hp) infection in a Chinese population, particularly for patients with results in the gray zone. In this paired self-controlled study, all subjects had previously undergone 13C-UBTs without citric acid meals and were randomly divided into two groups based on different doses of citric acid (a low-dose citric acid group and a high-dose citric acid group, comprising meals with 0.68 g and 3.84 g citric acid powder, respectively). Positive rapid urease test (CLO) test and histology results were considered the 'gold standard'. The mean delta over baseline (DOB) value, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were compared between the two groups, particularly for patients with results in the gray zone. In total, 285 patients were tested. Of these patients, 189 were included in the low-dose citric acid group, and 96 were included in the high-dose citric acid group. Among patients with a positive 13C-UBT result without citric acid [delta over baseline (DOB) value ≥ 4‰, n = 174] and a negative 13C-UBT result without citric acid (DOB value

Published
2024
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2. Cited2 inhibited hypoxia-induced proliferation and migration of PASMCs via the TGF-β1/Cited2/PPARγ pathway

Author

Hongjuan Wang, Lan Ma, and Qin Yu

Subjects
cited2, hypoxia-induced pulmonary hypertension, migration, proliferation, pulmonary artery smooth muscle cells, Medicine
Abstract

Objective(s): Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) contribute to hypoxia-induced pulmonary hypertension (HPH). The transcription factor Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (Cited2) has been implicated in the control of tumor cells and mesenchymal stem cell (MSC) and cardiomyocyte growth or migration. Whether Cited2 is involved in the proliferation and migration of PASMCs and the underlying mechanisms deserve to be explored. Materials and Methods: Cited2 expression was detected in rat PASMCs under hypoxia conditions and HPH rat models. The effect of Cited2 on the proliferation and migration of PASMC was detected by overexpression or knockdown of the Cited2 gene. After PAMSCs were treated with recombinant TGF-β1 and the lentivirus vector overexpressing Cited2, expression of peroxisome proliferator-activated receptor gamma (PPARγ) was examined by western blotting.Results: We revealed that hypoxia down-regulated the expression of Cited2 in PASMCs and rat pulmonary arteries. Cited2 overexpression inhibited the proliferation and migration of PASMCs under hypoxia, while Cited2 knockdown induced the proliferation and migration of PASMCs. Cited2 inhibits the negative regulation of the TGF-β1 pathway on PPARγ to inhibit the proliferation and migration of PASMCs.Conclusion: These findings suggest that increased Cited2 expression contributes to the inhibition of PASMCs proliferation and migration by regulating TGF-β1-mediated target gene expression in HPH and provides a new target for molecular therapy of HPH.

Published
2024
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3. Hepatitis E virus prevalence among blood donors in Wuhan urban agglomeration

Author

Qin YU, Tingting XU, Lijie ZHANG, and Lei ZHAO

Subjects
hepatitis e virus (hev), serological prevalence, blood donor, nucleic acid screening, Diseases of the blood and blood-forming organs, RC633-647.5, Medicine
Abstract

Objective To investigate the prevalence of Hepatitis E virus (HEV) among blood donors in Wuhan urban agglomeration, aimed at providing data support for the development of HEV screening strategies for blood donors. Methods A total of 3 329 blood samples were collected from four centralized testing areas (Ezhou, Tianmen, Xiantao and Qianjiang) and screened at Wuhan Blood Center from January to December 2021. Among them, 2 737 were eligible blood samples with normal ALT (ALT normal group) and 592 were with elevated ALT (ALT elevated group). Enzyme linked immunosorbent assay (ELISA) was used to detect anti-HEV IgG, anti-HEV IgM and HEV-Ag, and Real-time PCR was used to perform single HEV RNA detection on blood samples with elevated ALT and normal ALT anti-HEV IgM+ blood samples. A two-sided Pearson’s chi-squared test or Fisher's exact test was used to evaluate the differences in the positive rates of anti-HEV IgG and anti-HEV IgM in different regions and ALT groups. Results The overall positive rates of anti-HEV IgG, anti-HEV IgM, and HEV-Ag in 3 329 blood samples from four regions were 21.63%, 1.29%, and 0%, respectively. There was a significant difference in the positive rates of anti-HEV IgG among blood donors in different regions (P

Published
2024
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4. Overexpression of TPL2 may be a predictor of good prognosis in patients with breast invasive ductal carcinoma

Author

Qin Yu, Dan Wan, Rong Fu, Feng Li, and Yutao Zhang

Subjects
Medicine, Science
Abstract

Abstract The objective of this study was to investigate the clinical significance and roles of tumor progression locus 2 (TPL2) and peptidyl-prolyl cis–trans isomerase 1 (Pin1) in the occurrence and development of breast invasive ductal carcinoma (IDC). Immunohistochemistry was used to detect the expression of TPL2 and Pin1 in human breast tissues, which included normal breast tissues (Normal), tissues with fibrocystic changes (FCC), ductal carcinoma in situ (DCIS), and IDC. The roles of TPL2 and Pin1 in the occurrence and development of IDC, as well as the correlation between their expression levels and clinicopathological parameters, were analyzed. Compared with Normal and FCC groups, the overexpression of TPL2 and Pin1 was significantly increased in DCIS and IDC groups (DCIS vs Normal: P = 0.002/P

Published
2023
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5. Andrographolide alleviates paraquat-induced acute lung injury by activating the Nrf2/HO-1 pathway

Author

Degang Zhang, Fengqin Shen, Shiting Ma, Suting Nan, Yanhong Ma, Lili Ren, Hao Li, and Qin Yu

Subjects
acute lung injury, andrographolide, apoptosis, nrf2, oxidative stress, paraquat, Medicine
Abstract

Objective(s): Paraquat (PQ), a highly effective and rapidly non-selective herbicide, mainly targets the lungs and causes acute lung injury (ALI). So far, the scarcity of effective drug candidates against PQ-induced ALI remains a big challenge. Andrographolide (Andro), with its anti-inflammatory and antioxidant activities, has been demonstrated to alleviate ALI. Nevertheless, whether Andro could alleviate the PQ-mediated ALI remains unknown. Therefore, this study will explore the effects as well as the possible mechanism of Andro against ALI caused by PQ. Materials and Methods: C57BL/6J mice were injected with 20 mg/kg PQ intraperitoneally to establish an ALI model. PQ-treated MLE-12 cells were applied to a vitro model. Nuclear factor erythroid like-2 (Nrf2) was knocked out to explore the specific effects of the Nrf2/ Heme oxygenase-1 (OH-1) pathway in the protection of Andro against ALI caused by PQ.Results: Andro significantly reduced lung damage and the ratio of Wet/Dry (W/D) weight, decreased MDA, IL-6, IL-1β, and TNF-ɑ levels, reversed the decrease of CAT and SOD levels, and inhibited apoptosis caused by PQ. Andro obviously increased the ratio of Bcl-2/Bax while reducing caspase-3 and cleaved caspase-3 levels. Furthermore, Andro dramatically elevated the antioxidant proteins Nrf2, NQO-1, and HO-1 levels compared with the PQ group. This experiment demonstrated that Andro reduced ROS and inhibited apoptosis, induced by PQ in MLE-12 cells, by inducing Nrf2/HO-1 pathway activation.Conclusion: Andro effectively ameliorates oxidant stress and apoptosis in ALI caused by PQ, possibly through inducing Nrf2/HO-1 pathway activation.

Published
2023
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6. Identification of potential light deficiency response regulators in endangered species Magnolia sinostellata

Author

Danying Lu, Bin Xu, Qin Yu, Zhigao Liu, Mingjie Ren, Yaling Wang, Shouzhou Zhang, Chao Wu, and Yamei Shen

Subjects
Medicine, Science
Abstract

Abstract Magnolia sinostellata is one of the endangered species in China and largely suffers light deficiency stress in the understory of forest. However, the weak light response molecular mechanism remains unclear. More importantly, hub genes in the molecular network have not been pinpointed. To explore potential regulators in the mechanism, weighted gene co-expression network analysis (WGCNA) was performed to analysis the trancriptome data of M. sinostellata leaves subjected to weak light with different time points. Gene co-expression analysis illustrated that module 1, 2 and 3 were closely associated with light deficiency treatment, which. Gene ontology and KEGG analyses showed that genes in module 1 mainly participated in amino and nucleotide metabolism, module 2 mostly involved in carbon fixation and module 3 mostly regulated photosynthesis related pathways, among which 6, 7 and 8 hub genes were identified, respectively. Hub genes isoform_107196 in module 1 and isoform_55976 in module 2 were unique to M. sinostellata. This study found that light deficiency inhibited photosynthesis and stress tolerance, while improved carbon metabolism and flowering related pathways in M. sinostellata, which can impact its accumulation reserves of growth and reproduction in the next season. In addition, key shade response regulators identified in this study have laid a firm foundation for further investigation of shade response molecular mechanism and protection of other shade sensitive plants.

Published
2022
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7. Hepatitis E virus prevalence among blood donors in Wuhan

Author

Qin YU, Lei ZHAO, Tingting XU, Lijie ZHANG, and Qianhua WANG

Subjects
hev, prevalence, blood donor, Diseases of the blood and blood-forming organs, RC633-647.5, Medicine
Abstract

Objective To investigate the prevalence and risk factor of hepatitis E virus(HEV) infection among blood donors in Wuhan. Methods A total of 1 302 serum samples (including 1 076 with normal ALT and 226 with elevated ALT) from blood donors were randomly collected from January to December 2021 in Wuhan Blood Center. Anti-HEV IgG, IgM and HEV antigen (Ag) were examined by enzyme-linked immunosorbent assay (ELISA). The IgM or Ag positive and elevated ALT samples were subjected to real time-PCR to detect HEV RNA. Multivariable logistic regression modeling was used to examine the risk factors associated with HEV prevalence. Results Overall, the positive rates of anti-HEV IgG, IgM, and Ag were 16.44%, 1.0% and 0.08%, respectively. However, none of the serum samples were HEV RNA positive. The prevalence of anti-HEV IgG and anti-HEV IgM was similar in samples with increased ALT and normal ALT (IgG 13.72% vs 17.01%, P>0.05; IgM 1.33% vs 0.93%, P>0.05). Multivariate analysis revealed a strong statistical association between age and HEV IgG seroprevalence. The prevalence increased with increasing age, from 5.4% (18~25 years old) to 68.7%(the highest) in blood donors above 46 years (P

Published
2022
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8. Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort

Author

Rachel C. Newsome, Raad Z. Gharaibeh, Christine M. Pierce, Wildson Vieira da Silva, Shirlene Paul, Stephanie R. Hogue, Qin Yu, Scott Antonia, Jose R. Conejo-Garcia, Lary A. Robinson, and Christian Jobin

Subjects
Microbiome, Immunotherapy, Non-small cell lung cancer, Fecal microbiota transplant, Medicine, Genetics, QH426-470
Abstract

Abstract Background Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored. Methods RNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue. Results Responder patients have both a different microbial community structure than non-responders (P = 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the genera Ruminococcus, Akkermansia, and Faecalibacterium. Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI (P = 0.023, P = 0.019, P = 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the genera Bacteroides, Blautia, Akkermansia, and Faecalibacterium. Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the genera Colidextribacter, Frisingicoccus, Marvinbryantia, and Blautia which have not yet been reported. Conclusions The role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.

Published
2022
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9. Elevated expression of IGFL1 indicates unfavorable prognosis in lung adenocarcinoma through promotion of cell proliferation and inhibition of apoptosis

Author

Zhuo Wang, Xiaoqin Liang, Xiaojun Wang, and Qin Yu

Subjects
insulin growth factor-like family member 1, lung adenocarcinoma, biomarker, prognosis, proliferation, apoptosis., Medicine
Abstract

Non-small cell lung cancer (NSCLC) is one of the principal causes of death worldwide. The disease is often diagnosed late, at the stage of metastasis, which leads to a poor prognosis. With currently available treatment, most patients experience relapse and drug resistance. This study aimed to determine the potential role of insulin growth factor-like family member 1 (IGFL1) in lung adenocarcinoma (LUAD). We analyzed the expression of IGFL1 using TIMER, UALCAN, and GEPIA. The association of IGFL1 expression with symptoms and overall survival (OS) in LUAD patients was evaluated using a tissue microarray (TMA). Moreover, A549 and H1299 cells with selective IGFL1 knockdown were used to observe their proliferation and apoptosis in vitro. From the TIMER, UALCAN and GEPIA databases, we found that IGFL1 was upregulated in LUAD (p < 0.001). The level of promoter methylation in IGFL1 was significantly downregulated in LUAD and patient groups with different gender. Similar results were obtained in UALCAN. The semi-quantitative analysis revealed that IGFL1 expression is correlated with TNM stage (p < 0.001) and tumor size (p < 0.001) in TMA. High levels of IGFL1 expression were associated with poor OS (p < 0.05). Functional tests in A549 and H1299 cells showed that knocking down the expression of IGFL1 inhibited proliferation and enhanced apoptosis. Our study revealed the potential utility of IGFL1 as a predictive biomarker, which may play a biological role by regulating the proliferation and apoptosis of tumor cells.

Published
2022
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10. Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial

Author

Jun Liu, Dan-Dan Li, Wei Dong, Yu-Qi Liu, Yang Wu, Da-Xuan Tang, Fu-Chun Zhang, Meng Qiu, Qi Hua, Jing-Yu He, Jun Li, Bai Du, Ting-Hai Du, Lin-Lin Niu, Xue-Jun Jiang, Bo Cui, Jiang-Bin Chen, Yang-Gan Wang, Hai-Rong Wang, Qin Yu, Jing He, Yi-Lin Mao, Xiao-Fang Bin, Yue Deng, Yu-Dan Tian, Qing-Hua Han, Da-Jin Liu, Li-Qin Duan, Ming-Jun Zhao, Cui-Ying Zhang, Hai-Ying Dai, Ze-Hua Li, Ying Xiao, You-Zhi Hu, Xiao-Yu Huang, Kun Xing, Xin Jiang, Chao-Feng Liu, Jing An, Feng-Chun Li, Tao Tao, Jin-Fa Jiang, Ying Yang, Yao-Rong Dong, Lei Zhang, Guang Fu, Ying Li, Shu-Wei Huang, Li-Ping Dou, Lan-Jun Sun, Ying-Qiang Zhao, Jie Li, Yun Xia, Fan Liu, Wen-Jin He, Jian-Cong Tan, Yang Lin, Ya-Bin Zhou, Jian-Fei Yang, Guo-Qing Ma, Hui-Jun Chen, He-Ping Liu, Zong-Wu Liu, Jian-Xiong Liu, Xiao-Jia Luo, Xiao-Hong Bin, Ya-Nan Yu, Hai-Xia Dang, Bing Li, Fei Teng, Wang-Min Qiao, Xiao-Long Zhu, Bing-Wei Chen, Qi-Guang Chen, Chun-Ti Shen, Yong-Yan Wang, Yun-Dai Chen, and Zhong Wang

Subjects
Medicine, Biology (General), QH301-705.5
Abstract

Abstract It’s a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86–19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82–20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06–15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r 2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

Published
2021
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11. The effect of coronary slow flow on left atrial structure and function

Author

Zhiyuan Shui, Yunzhi Wang, Mingxue Sun, Yiqun Gao, Shunji Liang, Yiran Wang, Xiaomei Wang, Qin Yu, Shulong Zhang, and Li Liu

Subjects
Medicine, Science
Abstract

Abstract The coronary slow flow phenomenon (CSFP) is common in coronary angiography, however its impact on left atrial (LA) function is still controversial. This study aims to evaluate the LA structure and function of patients with CSFP using two-dimensional speckle tracking echocardiography (2D-STE). Consecutive patients scheduled for coronary angiography from January 2016 to September 2017 were enrolled in this study. Patients’ demographic data, clinical histories, laboratory and angiographic findings were collected and recorded. Diagnostic criteria for CSFP is based on Beltrame et al. proposed in 2012. Meanwhile 139 patients who have no significant stenosis (≤ 40%) and normal blood flow were selected as control. All patients received an echocardiographic examination 24 h before coronary angiography. LA structure and function were measured with echocardiography and 2D-STE. Our results showed that among the 1,954 patients who had received coronary angiography, 512 patients were included in the analysis after the exclusion criteria was implemented. Of those, 101 patients met the CSFP criteria (5.5%). CSFP is mainly seen in LAD (~ 70%). There was no statistical difference in baseline characteristics between the CSFP group and control group, except for a higher proportion of smokers in the CSFP group (P = 0.001). The percentage of monocytes is an independent risk factor for the occurrence of CSFP (P = 0.036) after binary logistic regression analysis. The LA global longitudinal strain (LA-GLS, represents reservoir functions) decreased and LA strain rate at late diastole (LA-SRa, represents booster function) increased in patients with CSFP compared to the control group (P

Published
2021
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13. A convolutional recurrent neural network with attention framework for speech separation in monaural recordings

Author

Chao Sun, Min Zhang, Ruijuan Wu, Junhong Lu, Guo Xian, Qin Yu, Xiaofeng Gong, and Ruisen Luo

Subjects
Medicine, Science
Abstract

Abstract Most speech separation studies in monaural channel use only a single type of network, and the separation effect is typically not satisfactory, posing difficulties for high quality speech separation. In this study, we propose a convolutional recurrent neural network with an attention (CRNN-A) framework for speech separation, fusing advantages of two networks together. The proposed separation framework uses a convolutional neural network (CNN) as the front-end of a recurrent neural network (RNN), alleviating the problem that a sole RNN cannot effectively learn the necessary features. This framework makes use of the translation invariance provided by CNN to extract information without modifying the original signals. Within the supplemented CNN, two different convolution kernels are designed to capture information in both the time and frequency domains of the input spectrogram. After concatenating the time-domain and the frequency-domain feature maps, the feature information of speech is exploited through consecutive convolutional layers. Finally, the feature map learned from the front-end CNN is combined with the original spectrogram and is sent to the back-end RNN. Further, the attention mechanism is further incorporated, focusing on the relationship among different feature maps. The effectiveness of the proposed method is evaluated on the standard dataset MIR-1K and the results prove that the proposed method outperforms the baseline RNN and other popular speech separation methods, in terms of GNSDR (gloabl normalised source-to-distortion ratio), GSIR (global source-to-interferences ratio), and GSAR (gloabl source-to-artifacts ratio). In summary, the proposed CRNN-A framework can effectively combine the advantages of CNN and RNN, and further optimise the separation performance via the attention mechanism. The proposed framework can shed a new light on speech separation, speech enhancement, and other related fields.

Published
2021
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14. Accessibility of Essential Medicines for Children in Sichuan Province of China: A Cross-Sectional Study

Author

Zhe Chen, Siyu Li, Imti Choonara, Linan Zeng, Zhi-jun Jia, Guo Cheng, Qin Yu, and Lingli Zhang

Subjects
children, medicine, accessibility, availability, price, affordability, Therapeutics. Pharmacology, RM1-950
Abstract

Background: Essential medicines for children are those medicines that satisfy the priority health care needs of children. Access to essential medicines for children is a big challenge, particularly in low- and middle-income countries. Our study aimed to assess the accessibility of essential medicines for children in public sector in Sichuan Province of China, based on availability, affordability, and price.Methods: We adopted the modified World Health Organization/Health Action International (WHO/HAI) standardization methodology to measure the availability, affordability, and prices of 30 essential medicines for children in 20 public hospitals in nine regions of the Sichuan Province, China. Availability was expressed as the percentage of public medicine outlets that stocked surveyed medicines on the day of data collection, and prices were expressed as median price ratio (MPR). Affordability was assessed as the number of Sichuan Province’s daily wages required for the lowest-paid government unskilled worker (11.03 USD per day) to purchase one standard treatment of an acute disease or treatment for chronic disease for a month.Results: The mean availability of originator brands (OBs) and lowest priced generics (LPGs) were 9.7 and 46.5% in public sector. MPRs of only 3 OBs could be calculated, ranging from 0.55 to 13.37. MPRs of 18 LPGs ranged from 0.07 to 25.05. Among them, 2 OBs and 11 LPGs were priced at more than 1.5 times their international reference prices (IRPs) in public sector, most of which were injections. Except for cefazolin injection and ceftriaxone injection, most LPGs were affordable for the treatment of childhood diseases in public sector, as they each cost one or less than the daily wage for the lowest-paid unskilled government worker.Conclusions: Although the availability of LPGs for children was higher than OBs in public sector, the availability of children’s essential medicines was low in surveyed public sector in Sichuan Province, which was similar to previous studies in other provinces of China. The price of most medicines surveyed was higher than their IRPs in surveyed public sector, especially for some injections. The affordability of most surveyed LPGs was reasonable in surveyed public sector, except for ceftriaxone injection and cefazolin injection.

Published
2022
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15. Anemia-Associated Platelets and Plasma Prothrombin Time Increase in Patients with Adenomyosis

Author

Qiao Lin, Tiantian Li, ShaoJie Ding, Qin Yu, and Xinmei Zhang

Subjects
adenomyosis, coagulation parameters, anemia, platelets, Medicine
Abstract

Patients with adenomyosis are hypercoagulable and often accompanied by anemia, but the specific changes in anemia-related coagulation parameters are still unclear. This study investigated the changes in and influencing factors of coagulation parameters related to anemia in patients with adenomyosis (AM). The coagulation parameters, including platelet count (PC), plasma prothrombin time (PT), activated partial prothrombin time (APTT), thrombin time (TT) and fibrinogen (FB), and hemoglobin (Hb), were measured in patients with adenomyosis (229 cases in AM group), uterine leiomyoma (265 cases in LM group), and undergoing tubal anastomosis (142 cases in the control group). The age of the control group was younger than that of the AM group and the LM group. Compared with the AM and LM groups, the uterus size of the control group was smaller; the AM group was larger than the LM group. The Hb concentration of the AM group was lower than that of the LM and control groups. Compared with the LM and control groups, PC increased and TT shortened in the AM group. APTT in the AM group was shorter than in the control group, and PT was longer than in the LM group. After adjustment using multiple logistic regression analysis, adenomyosis was correlated with Hb concentration (or = 0.971, 95% CI 0.954–0.988, p < 0.001), PC (or = 1.006, 95% CI 1.002–1.011, p = 0.004), PT (or = 3.878, 95% CI 2.347–6.409, p < 0.001), age (or = 1.062, 95% CI 1.013–1.114, p = 0.013), and uterine size (or = 1.103, 95% CI 1.011–1.203, p = 0.028). Correlation analysis showed that PC (r = −0.309) and PT (r = −0.252) were negatively correlated with anemia. The increase in Hb-related PC and PT in patients with adenomyosis indicates that the timely and early detection of coagulation parameters is needed for patients with severe anemia, older age, and larger uterine volume.

Published
2022
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16. Are medical record front page data suitable for risk adjustment in hospital performance measurement? Development and validation of a risk model of in-hospital mortality after acute myocardial infarction

Author

Chao Zhang, Lin Li, Yan Liu, Jun Wang, Xueke Bai, Qianying Wang, Jing Zhang, Zhong Li, Lili Sun, Yuzhen Zhang, Qian Wang, Lei Wu, Bo Yu, Hui Dai, Tianyu Liu, Guang Ma, Xiaoping Gao, Jie Wu, Shu Zhang, Junli Wang, Yan Han, Guiling Li, Yi Tian, Zheng Wan, Chuanyu Gao, Yin Zhou, Jian Liu, Xin Jin, Jian Guan, Yu Huang, Feng Sun, Ruijun Zhang, Wei Luo, Xuexin Li, Weiwei Zhou, Long Chen, Weimin Li, Qing Huang, Yong Yi, Bin Xu, Zhenqiu Lin, Chun Yuan, Ping Yang, Haifeng Wang, Zhiming Li, Kaihong Chen, Guangming Yang, Chun Wu, Liang Lu, Ge Zhang, Yong Gao, Hongyan Li, Xiaofei Li, Hua Lu, Yanlong Liu, Yuhong Liu, Ting Jiang, Yuhui Lin, Chaoqun Wu, Danwei Zhang, Tiannan Zhou, Guangda He, Shiping Weng, Shuying Xie, Lirong Wu, Jiulin Chen, Tianfa Li, Qin Yu, Shiguo Hao, Xuemei Wu, Yachen Zhang, Zhifeng Liu, Zhongxin Wang, Hao Jia, Bayin Bate, Badeng Qiqige, Xiang Jin, Fengqin Liu, Dayong Xu, Xuejin He, Shui Yang, Jiping Wang, Lihua Gu, Shijiao Chen, Yongchao Zhi, Shengcheng Zhou, Lingjiao Jin, Yong Leng, Liangchuan Zhang, Tianyun Deng, Yuanjin Wang, Wenhua Zhang, Xinmin Ma, Xuan Ge, Xiaoping Wu, Yanming He, Fanju Meng, Dexi Liao, Guangyong Liu, Wen Qin, Wen Long, Xiangwen Chen, Baohong Zhang, Yonghou Yin, Bin Tian, Chaoyong Wu, Baoqi Liu, Zhihui Zhao, Haiming Li, Yansong Guo, Xinjing Chen, Liquan Xiang, Lin Ning, Xiuqi Li, Xing’an Wu, Congjun Tan, Mingfang Feng, Meili Wang, Liangfa Wen, Xiang Fu, Qunxing Xie, Yanni Zhuang, Jiaqian Lu, Qiuling Hu, Chunhui Xiao, Xiaoli Hu, Yongshuan Wu, Qiuli Wang, Youlin Xu, Xuefei Yu, Jianhong Zhang, You Zhang, Wentang Niu, Xiaolei Ma, Xiaowen Pan, Lifu Miao, Yanping Yin, Zhiying Zhang, Shutang Feng, Aiping Wang, Jiangli Zhang, Feipeng Li, Lijun Yu, Xinxin Zhao, Yuansheng Shen, Lizhen He, Zhiyi Rong, Xueqiao Wang, Rongjun Wan, Jianglin Tang, Guanghan Wu, Xiaohe Wu, Sang Ge, Pian Pu, Pingcuo Duoji, Yuming Du, Jianping Shi, Peihua Zhao, Jingsheng Sun, Hongxiang Li, Wen Liang, Zhiwen Dong, Zhenhai Zhao, Yaofeng Yuan, Zhirong Li, Jinbo Gao, Qiu’e Guo, Ruiqing Zhao, Guangjun Song, Lize Wang, Haiyun Song, Jinwen He, Jinming He, Keyong Shang, Changjiang Liu, Kuituan Xi, Rihui Liu, Peng Guo, Chaoyang Guo, Xiangjun Liu, Rujun Zhao, Zeyong Yu, Wenzhou Li, Xudong Jing, Huanling Wang, Xiyuan Zhao, Meifa Wei, Shengde Chen, Yong Fang, Ying Liao, Suzhe Cheng, Yunke Zhou, Xiaoxia Niu, Huifang Cao, Zebin Feng, Feilong Duan, Haiming Yi, Yuanxun Xu, Anran Guo, Xianshun Zhou, Hongzhuan Cai, Peng Zheng, Gaofeng Guo, Minwu Bao, Shaoliang Chen, Haibo Jia, Hongjuan Peng, Duanping Dai, Shaoxiong Hong, Song Chen, Dongya Zhang, Yudong Li, Jianbu Gao, Shouzhong Yang, Junhu An, Chenyang Shen, Yunfeng Liu, Huan Qu, Saiyong Chen, Dehai Jiao, Manhong Wang, Qiu Wang, Yingliang Xue, Cheng Yuan, Jianqing Zhang, Chunmei Wei, Yanmei Shen, Hehua Zhang, Hongmei Pan, Xiaowen Ma, Yanli Liang, Tianbiao Wang, Daguo Zhao, Xiaoming Tu, Zhenyan Gao, Fangning Wang, Qiang Yang, Xiaoping Kang, Jianbin Fang, Dongmei Liu, Chengning Shen, Mengfei Li, Yingmin Guan, Wenfeng Wang, Ting Xiao, Fengyun Jiang, Kaiyou Wu, Songguo Wang, Xujie Fu, Lifang Gao, Kai Fu, Xiaojing Duan, Rui Xiao, Ruixia Wu, Hongtu Zhang, Yuerong Ma, Zhonghui Cao, Zhansheng Ba, Wanhai Fu, Jianjun Jiang, Yafei Mi, Shiyu Zheng, Yang Zhong, Fangjiang Li, Xiaoyuan Wang, Pingshuan Dong, Laijing Du, Zhaofa He, Meihua Jin, Zhuoyan Chen, Manli Cheng, Yuqiang Ji, Youhua Zhou, Jvyuan Li, Yizhi Pan, Tianxun Wang, Guiyu Huang, Jianjun Pan, Qingliang Cai, Yuanming Yi, Xuelian Deng, Wenhua Chen, RongCai; Bing Zhang, Yousheng Xu, Zhengqiu Wang, Jun Shu, Puxia Suo, Aimin Zhang, Yongfen Kang, Yuemin Sun, Bo Bian, Xuejun Hu, Dawa Ciren, Guojiong Jia, Jieli Pan, Guofu Li, Hongliang Zhang, Longliang Zhan, Junping Fang, Xinli Yu, Dacheng Wang, Dajun Liu, Xinhong Cao, Haisheng Zhu, Wanchuan Liu, Zhaohai Zhou, Wuwang Fang, Manxin Chen, Fuqin Han, Jianye Fu, Yunmei Wang, Binglu Liu, Yanliang Zhang, Xiupin Yuan, Qingfei Lin, Yuliang Zhu, Zhiqiang Cai, Xingping Li, Lirong Ao, Shubing Wu, Fusheng Zhao, Renfei Liu, Wenwei Ai, Jianbao Chang, Haijie Zhao, Qijun Ran, Xuan Ma, Shijun Jiang, Xiaochun Shu, Zhiru Peng, Jianbin Wang, Li Yang; Yu Shen, Xingcun Shang, Zhisong Liao, Meiying Cai, Lining You, Shuqin Li, Yingjia Li, Jianxun Yang, Song Ai, Jianfei Ma, Lailin Deng, Keyu Wang, Shitang Gao, Banghua He, Youyi Lu, Weirong Yang, Zhizhong Zhang, Xiaohong Chi, Ru Duan, and Guangli Wang

Subjects
Medicine
Abstract

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

Published
2021
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17. Identification of colored wheat genotypes with suitable quality and yield traits in response to low nitrogen input.

Author

Xiaoli Fan, Zhibin Xu, Fang Wang, Bo Feng, Qiang Zhou, Jun Cao, Guangsi Ji, Qin Yu, Xiaofeng Liu, Simin Liao, and Tao Wang

Subjects
Medicine, Science
Abstract

Colored wheat is a valuable resource that is rich in anthocyanins and minerals and thus contributes additional nutritional value to a healthy human diet. However, the effects of nitrogen fertilization on anthocyanin content (AC) and the balance between quality and yield still merit discussion. In this study, blue, purple, and common-colored wheat genotypes were used to investigate three nutrient quality traits, seven processing quality traits, three yield traits and seven grain morphology traits at three nitrogen levels in two years to excavate their possible plasticity under low-nitrogen stress and the tradeoffs among these traits. The highest AC was found in the blue genotypes followed by the purple genotypes. Analysis of variance (ANOVA) showed that AC could be significantly increased by reducing N application, especially in the purple genotypes. Therefore, growing colored wheat with low nitrogen input could allow efficient harvesting of grain with higher AC. However, the other nutrient quality traits and most processing quality traits were observed to decrease under low-nitrogen (LN) stress. Additionally, a correlation analysis indicated that the nutrient quality traits had stable tradeoffs with thousand kernel weight at all N levels because of the significantly negative correlations among them. Therefore, the additive main effect and multiplicative interaction (AMMI) model was used to further identify the most suitable colored genotypes with the best yield potential and also nutrient quality relative characteristics under LN stress. The blue lines Lanmai2999 and purple varieties Zhongkezinuomai 168 were found to be specifically adapted to LN stress with the highest AC values and showed stable performance in the other nutrient quality- and yield-related features. To further investigate the possible mechanism of anthocyanin accumulation in response to reduced N application, the expression of four genes (TaCHS, TaFDR, TaCHI and TaANS) involved in the anthocyanin synthesis pathway was evaluated. All four genes were downregulated under high nitrogen fertilizer application, indicating that anthocyanin synthesis in colored wheat might be inhibited by nitrogen fertilizer. Therefore, this research provided information for optimizing nitrogen fertilizer management in producing colored wheat and also demonstrated that it is efficient and economical to plant colored wheat genotypes in nitrogen-poor areas for use in a healthy human diet, improving the benefits of wheat planting and facilitating nitrogen pollution control.

Published
2020
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18. 70274 TL1 team approach to investigating the adhesin gene fimH in adherent invasive E. coli induced inflammation and colorectal cancer development

Author

Rachel C Newsome, Qin Yu, Yoshitaka Murota, Derek Hood, Duy Nguyen, Ryan A Smolchek, Juan M Uruena, W Gregory Sawyer, and Christian Jobin

Subjects
Medicine
Abstract

ABSTRACT IMPACT: We are developing the 3D perfusion system for use with patient-derived bacteria to further characterize the mechanism behind bacterial-induced inflammation and cancer. OBJECTIVES/GOALS: We previously reported the adherent invasive E. coli NC101 promote colorectal cancer (CRC) in mice. FimH, a mannose-specific adhesin on type 1 fimbriae, is involved in bacterial surface adhesion. Herein, we investigated the role of FimH in E. coli NC101-induced adherence and carcinogenesis in a novel 3D perfusion culture imaging plate. METHODS/STUDY POPULATION: E. coli NC101 gene fimH was deleted byï ŲRed Recombinase System. Biofilm formation was assessed by crystal violet and congo red staining. 5 dpf (wild-type strain) zebrafish embryos were infected in 6x107 cfu/ml wild type (WT) or fimH-deleted (ï ,,fimH) E. coli NC101 for 24hr and gut dissected for bacterial culture. A 2D/3D infection culture system for IEC-6 and HT-29 cells was infected for 4 hr and imaged and then DNA damage examined by comet assay, cell cycle andÎ3H2AX accumulation. Germ-free (GF) Il10-/- (colitis) mice were orally gavaged with 108 cfu WT orï ,,fimH E. coli NC101 for 16 weeks. E. coli colonization were quantified by plate culture and qPCR. Lipocalin2 was quantified by ELISA. PCNA and β-catenin were evaluated by immunohistochemistry (IHC). RESULTS/ANTICIPATED RESULTS: Biofilm formation was reduced by more than 40% (p

Published
2021
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19. Comparison of multiple detection methods of antibody for the early diagnosis of pediatric mycoplasma pneumonia

Author

Yan Wu, Guikai Duan, Minggang Cheng, Weiqing Wu, Qin Yu, and Dapeng Yu

Subjects
Medicine
Abstract

Mycoplasma pneumoniae pneumonia (MPP) is a common disease in infants and young children. MPP can also be a potential cause of healthcare-associated pneumonia. However, it is challenging to make an accurate diagnosis in a timely fashion. Our goal is to determine the assay consistencies of acridinium ester chemiluminescence immunoassay (AECLIA) and gelatin particle agglutination (GPA) test for the detection of Mycoplasma pneumoniae (MP) antibody. In this study, a total of 1404 children with suspected MPP were enrolled. Among them, 130 were diagnosed as MPP positive by mycoplasma culture, and 186 were negative. MP antibodies were detected by AECLIA, enzyme-linked immunosorbent assay (ELISA) and GPA. Consistency rates, differences among assays, and diagnosis performance were compared for the three methods. The independent χ 2 test results of AECLIA and ELISA for the detection of MP-IgG and MP-IgM antibodies were χ 2 = 29.210, P

Published
2019
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20. Identification of four hub genes associated with adrenocortical carcinoma progression by WGCNA

Author

Wang-Xiao Xia, Qin Yu, Gong-Hua Li, Yao-Wen Liu, Fu-Hui Xiao, Li-Qin Yang, Zia Ur Rahman, Hao-Tian Wang, and Qing-Peng Kong

Subjects
ACC, WGCNA, Hub genes, Progression, Medicine, Biology (General), QH301-705.5
Abstract

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignant cancer in the adrenal cortex with poor prognosis. Though previous research has attempted to elucidate the progression of ACC, its molecular mechanism remains poorly understood. Methods Gene transcripts per million (TPM) data were downloaded from the UCSC Xena database, which included ACC (The Cancer Genome Atlas, n = 77) and normal samples (Genotype Tissue Expression, n = 128). We used weighted gene co-expression network analysis to identify gene connections. Overall survival (OS) was determined using the univariate Cox model. A protein–protein interaction (PPI) network was constructed by the search tool for the retrieval of interacting genes. Results To determine the critical genes involved in ACC progression, we obtained 2,953 significantly differentially expressed genes and nine modules. Among them, the blue module demonstrated significant correlation with the “Stage” of ACC. Enrichment analysis revealed that genes in the blue module were mainly enriched in cell division, cell cycle, and DNA replication. Combined with the PPI and co-expression networks, we identified four hub genes (i.e., TOP2A, TTK, CHEK1, and CENPA) that were highly expressed in ACC and negatively correlated with OS. Thus, these identified genes may play important roles in the progression of ACC and serve as potential biomarkers for future diagnosis.

Published
2019
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21. Uncovering critical properties of the human respiratory syncytial virus by combining in vitro assays and in silico analyses.

Author

Catherine A A Beauchemin, Young-In Kim, Qin Yu, Giuseppe Ciaramella, and John P DeVincenzo

Subjects
Medicine, Science
Abstract

Many aspects of the respiratory syncytial virus (RSV) are still poorly understood. Yet these knowledge gaps have had and could continue to have adverse, unintended consequences for the efficacy and safety of antivirals and vaccines developed against RSV. Mathematical modelling was used to test and evaluate hypotheses about the rate of loss of RSV infectivity and the mechanisms and kinetics of RSV infection spread in SIAT cells in vitro. While the rate of loss of RSV integrity, as measured via qRT-PCR, is well-described by an exponential decay, the latter mechanism failed to describe the rate at which RSV A Long loses infectivity over time in vitro based on the data presented herein. This is unusual given that other viruses (HIV, HCV, influenza) have been shown to lose their infectivity exponentially in vitro, and indeed an exponential rate of loss of infectivity is always assumed in mathematical modelling and experimental analyses. The infectivity profile of RSV in HEp-2 and SIAT cells remained consistent over the course of an RSV infection, over time and a large range of infectivity. However, SIAT cells were found to be ∼ 100× less sensitive to RSV infection than HEp-2 cells. In particular, we found that RSV spreads inefficiently in SIAT cells, in a manner we show is consistent with the establishment of infection resistance in uninfected cells. SIAT cells are a good in vitro model in which to study RSV in vivo dissemination, yielding similar infection timescales. However, the higher sensitivity of HEp-2 cells to RSV together with its RSV infectivity profile being similar to that of SIAT cells, makes HEp-2 cells more suitable for quantifying RSV infectivity over the course of in vitro RSV infections in SIAT cells. Our findings highlight the importance and urgency of resolving the mechanisms at play in the dissemination of RSV infections in vitro, and the processes by which this infectivity is lost.

Published
2019
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22. 4092 TL1 Team Approach to Investigating Host-Microbe Interactions in Cancer Using a 3D Perfusion Culture System

Author

Rachel Chantal Newsome, Derek L Hood, Qin Yu, W. Gregory Sawyer, and Christian Jobin

Subjects
Medicine
Abstract

OBJECTIVES/GOALS: We seek to develop a 3D perfusion culture imaging plate for human fecal bacteria co-culture with epithelial cells in a structure that mimics the gut epithelium. We will develop this system for use with patient fecal samples to characterize patient risk of developing cancer. METHODS/STUDY POPULATION: E. coli NC101, a strain that harbors the pks gene island, produces the genotoxin colibactin which causes DNA damage that can lead to colorectal cancer development. The genotoxic ability of this bacterium is dependent upon cell-to-cell contact. Here, we present 3D printed E. coli NC101 and intestinal epithelial cells (IEC-6) in a perfusion imaging plate, enabling visualization of the cytotoxic effects of the bacteria in real time using confocal microscopy, in combination with flow cytometry analysis for cell cycle arrest (a surrogate marker of DNA damage). RESULTS/ANTICIPATED RESULTS: 40,000 IEC-6 cells were 3D printed in a cylindrical layer in our triple well imaging plate. The cells were infected at an MOI of 100 for 18 hours and time lapse images of the infection were recorded by confocal microscopy. The cells were then harvested for analysis by flow cytometry for cell cycle arrest as a measure of DNA damage. Our images and flow cytometry data show that E. coli NC101 co-localizes with IEC-6 cells and causes cell cycle arrest in phase G2 (infected %G2 = 40.1), compared to uninfected cells (%G2 = 24.7, P = 0.034). Mutant strains lacking adhesion protein FimH or the ability to produce colibactin do not cause G2 cell cycle arrest (P = 0.844 and P = 0.644, respectively). DISCUSSION/SIGNIFICANCE OF IMPACT: We are able to recapitulate the DNA damage phenotype of E. coli NC101 in our 3D culture system. We show here that host-microbe interactions leading to cancer can be modeled in our 3D perfusion system, and we will next use patient fecal samples in our culture system.

Published
2020
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23. SDF-1α/CXCR4 Axis Mediates The Migration of Mesenchymal Stem Cells to The Hypoxic-Ischemic Brain Lesion in A Rat Model

Author

Qin Yu, Lizhen Liu, Jie Lin, Yan Wang, Xiaobo Xuan, Ying Guo, and Shaojun Hu

Subjects
Mesenchymal Stem Cells, Migration, SDF-1 α, CXCR 4, Medicine, Science
Abstract

Objective: Transplantation of mesenchymal stem cells (MSCs) can promote functional recovery of the brain after hypoxic-ischemic brain damage (HIBD). However, the mechanism regulating MSC migration to a hypoxic-ischemic lesion is poorly understood. Interaction between stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXC chemokine receptor 4 (CXCR4) is crucial for homing and migration of multiple stem cell types. In this study, we investigate the potential role of SDF-1α/CXCR4 axis in mediating MSC migration in an HIBD model. Materials and Methods: In this experimental study, we first established the animal model of HIBD using the neonatal rat. Bone marrow MSCs were cultured and labeled with 5-bromo-21-deoxyuridine (BrdU) after which 6×106 cells were intravenously injected into the rat. BrdU positive MSCs in the hippocampus were detected by immunohistochemical analyses. The expression of hypoxia-inducible factor-1α (HIF-1α) and SDF-1α in the hippocampus of hypoxic-ischemic rats was detected by Western blotting. To investigate the role of hypoxia and SDF-1α on migration of MSCs in vitro, MSCs isolated from normal rats were cultured in a hypoxic environment (PO2=1%). Migration of MSCs was detected by the transwell assay. The expression of CXCR4 was tested using Western blotting and flow cytometry. Results: BrdU-labeled MSCs were found in the rat brain, which suggested that transplanted MSCs migrated to the site of the hypoxic-ischemic brain tissue. HIF-1α and SDF- 1α significantly increased in the hippocampal formations of HIBD rats in a time-dependent manner. They peaked on day 7 and were stably expressed until day 21. Migration of MSCs in vitro was promoted by SDF-1α under hypoxia and inhibited by the CXCR4 inhibitor AMD3100. The expression of CXCR4 on MSCs was elevated by hypoxia stimulation as well as microdosage treatment of SDF-1α. Conclusion: This observation illustrates that SDF-1α/CXCR4 axis mediate the migration of MSCs to a hypoxic-ischemic brain lesion in a rat model.

Published
2015

24. Evaluation of BACTEC MGIT 960 system for testing susceptibility of Mycobacterium tuberculosis to first-line drugs in China.

Author

Ping Zhao, Fang Fang, Qin Yu, Jiao Guo, Jian-Hua Zhang, Jifu Qu, and Yingjie Liu

Subjects
Medicine, Science
Abstract

The purpose of this study was to evaluate the performance of the BACTEC MGIT 960 (M960) system compared with the proportion method (PM) on Löwenstein-Jensen (L-J) medium in a peripheral laboratory in China for the testing of Mycobacterium tuberculosis (MTB) susceptibility to streptomycin (SM), isoniazid (INH) rifampicin (RIF) and ethambutol (EMB) a combination known as SIRE.The susceptibility of 205 clinical isolates of MTB to SM, INH, RIF and EMB was performed with the M960 system. The drugs were tested at the following concentrations: 1.0 µg/ml for SM, 0.1 µg/ml for INH, 1.0 µg/ml for RIF, and 5.0 µg/ml for EMB. The results were compared with those obtained by the L-J PM. The L-J PM at an arbiter site was used to resolve any discordant results.The overall consistency was 96.6% and concordance values were 95.6% for SM, 97.6% for INH, 98.0% for RIF and 95.1% for EMB. The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the M960 system for PM (the standard method) was 95.6%, 97.3%, 96.2% and 96.9% respectively, and the sensitivity were 93.3% for SM, 96.9% for INH, 97.4% for RIF and 94.6% for EMB, the specificity were 96.9% for SM, 98.2% for INH, 98.4% for RIF and 95.5% for EMB, the PPV were 94.6% for SM, 97.9% for INH, 97.4% for RIF and 94.6% for EMB, the NPV were 96.2% for SM, 97.3% for INH, 98.4% for RIF and 95.5% for EMB. The turnaround time with the M960 system (median 8.0 days, ranged from 5 to 14 days) was significantly shorter than that with the PM (28 days or 42 days).There was a substantial degree of agreement between the two methods. The M960 system was a reliable and rapid method for SIRE susceptibility testing of tuberculosis in China.

Published
2014
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25. Genetic diversity of Mycobacterium tuberculosis isolates from Inner Mongolia, China.

Author

Qin Yu, Yunkai Su, Bing Lu, Yan Ma, Xiuqin Zhao, Xiaomin Yang, Haiyan Dong, Yao Liu, Lulu Lian, Li Wan, Yimou Wu, and Kanglin Wan

Subjects
Medicine, Science
Abstract

BACKGROUND: Tuberculosis (TB) is a serious public health problem in China, and within China, Inner Mongolia has a high prevalence area of TB. Though studies on the genetic diversity of Mycobacterium tuberculosis (MTB) have been reported in many provinces, there are no such studies to date in Inner Mongolia. In this study, we investigated the genetic diversity of MTB in Inner Mongolia. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed 372 clinical MTB isolates with 22-loci mycobacterial interspersed repetitive unit and variable-number tandem repeats (MIRU-VNTR), spoligotyping, large sequence polymorphism (LSP), and NTF region analysis to understand the TB genotypes prevalent in Inner Mongolia. We found that the Beijing family was the most prevalent genotype (85.48%, 318/372), and the "modern" sublineage accounted for 76.73% (244/318) of the isolates. Our data also showed that there was no statistically significant association between the two major nationalities and the Beijing genotype (χ(2) = 3.612, P = 0.057; P>0.05). CONCLUSION/SIGNIFICANCE: The Beijing genotype is the most prevalent family of M. tuberculosis in Inner Mongolia, and we do not find any correlation between the Beijing genotype and the major nationalities.

Published
2013
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26. TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression.

Author

Yixuan Gong, Evita Scott, Rong Lu, Yin Xu, William K Oh, and Qin Yu

Subjects
Medicine, Science
Abstract

Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase-1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1.

Published
2013
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27. Frequency of regulatory T-cells in the peripheral blood of patients with pulmonary tuberculosis from shanxi province, china.

Author

Hui Pang, Qin Yu, Buping Guo, Yi Jiang, Li Wan, Jun Li, Yanjun Wu, and Kanglin Wan

Subjects
Medicine, Science
Abstract

BACKGROUND: Tuberculosis (TB) is a disease caused by the chronic and continuous infection of the pathogen Mycobacterium tuberculosis (M. tuberculosis). M. tuberculosis is an intracellular bacterial pathogen and is eliminated mainly through CD4(+) effector Th cells. M. tuberculosis induces regulatory T lymphocytes (Tregs) that mediate immune suppression by cell-to-cell contact or by secreting cytokines such as transforming growth factor-β (TGF-β). To understand the role of regulatory T-cells in the pathogenesis of TB, we have measured the in vivo frequency of regulatory T-cells and associated in vivo cytokine production in pulmonary tuberculosis patients. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed blood samples from 3 different populations (Group 1: patients with active TB, Group 2: patients recovered from TB and Group 3: healthy controls). We measured natural regulatory T-cell expression in peripheral blood using flow cytometry, and levels of blood serum IFN-γ and TGF-β1 using ELISA. The in vivo function of inductive regulatory T cells was mainly indicated by the expression of IFN-γ, TGF-β1, etc. Frequencyof natural regulatory T cells and inductive regulatory T cells in the peripheral blood samples from Group 1 patients were all significantly higher (P

Published
2013
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28. Etiologic diagnosis of lower respiratory tract bacterial infections using sputum samples and quantitative loop-mediated isothermal amplification.

Author

Yu Kang, Rui Deng, Can Wang, Tao Deng, Peichao Peng, Xiaoxing Cheng, Guoqing Wang, Minping Qian, Huafang Gao, Bei Han, Yusheng Chen, Yinghui Hu, Rong Geng, Chengping Hu, Wei Zhang, Jingping Yang, Huanying Wan, Qin Yu, Liping Wei, Jiashu Li, Guizhen Tian, Qiuyue Wang, Ke Hu, Siqin Wang, Ruiqin Wang, Juan Du, Bei He, Jianjun Ma, Xiaoning Zhong, Lan Mu, Shaoxi Cai, Xiangdong Zhu, Wanli Xing, Jun Yu, Minghua Deng, and Zhancheng Gao

Subjects
Medicine, Science
Abstract

Etiologic diagnoses of lower respiratory tract infections (LRTI) have been relying primarily on bacterial cultures that often fail to return useful results in time. Although DNA-based assays are more sensitive than bacterial cultures in detecting pathogens, the molecular results are often inconsistent and challenged by doubts on false positives, such as those due to system- and environment-derived contaminations. Here we report a nationwide cohort study on 2986 suspected LRTI patients across P. R. China. We compared the performance of a DNA-based assay qLAMP (quantitative Loop-mediated isothermal AMPlification) with that of standard bacterial cultures in detecting a panel of eight common respiratory bacterial pathogens from sputum samples. Our qLAMP assay detects the panel of pathogens in 1047(69.28%) patients from 1533 qualified patients at the end. We found that the bacterial titer quantified based on qLAMP is a predictor of probability that the bacterium in the sample can be detected in culture assay. The relatedness of the two assays fits a logistic regression curve. We used a piecewise linear function to define breakpoints where latent pathogen abruptly change its competitive relationship with others in the panel. These breakpoints, where pathogens start to propagate abnormally, are used as cutoffs to eliminate the influence of contaminations from normal flora. With help of the cutoffs derived from statistical analysis, we are able to identify causative pathogens in 750 (48.92%) patients from qualified patients. In conclusion, qLAMP is a reliable method in quantifying bacterial titer. Despite the fact that there are always latent bacteria contaminated in sputum samples, we can identify causative pathogens based on cutoffs derived from statistical analysis of competitive relationship.ClinicalTrials.gov NCT00567827.

Published
2012
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29. Merlin is a negative regulator of human melanoma growth.

Author

Lucas B Murray, Ying-Ka Ingar Lau, and Qin Yu

Subjects
Medicine, Science
Abstract

Merlin is encoded by the neurofibromatosis type 2 (NF2) gene and is a member of the Band 4.1 protein family. This protein acts as a linker that connects cell surface proteins to the actin cytoskeleton. Defects caused by mutations of the NF2 gene give rise to NF2 disease, which is generally characterized by the formation of bilateral vestibular schwannomas and, to a lesser extent, meningiomas and ependymomas. In addition to these tumor types, NF2 is mutated and/or merlin expression is reduced or lost in numerous non-NF2 associated tumors, including melanoma. However, the role of merlin in human melanoma growth and the mechanism underlying its effect are currently unknown. In the present study, we show that merlin knockdown enhances melanoma cell proliferation, migration, and invasion in vitro and that decreased merlin expression promotes subcutaneous melanoma growth in immunocompromised mice. Concordantly, we find that increased expression of merlin in a metastatic melanoma cell line reduced their in vitro migration and proliferation, and diminished their ability to grow in an anchorage independent manner. Increased merlin expression also inhibits in vivo growth of these melanoma cells. Lastly, we demonstrate that higher merlin levels in human melanoma cells promote the H(2)O(2)-induced activation of MST1/2 Ser/Thr kinases, which are known tumor suppressors in the Hippo signaling pathway. Taken together, these results provide for the first time evidence that merlin negatively regulates human melanoma growth, and that loss of merlin, or impaired merlin function, results in an opposite effect. In addition, we show that increased merlin expression leads to enhanced activation of the MTS1/2 kinases, implying the potential roles of MST1/2 in mediating the anti-melanoma effects of merlin.

Published
2012
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30. Differential Survival Outcomes Between De Novo and Secondary Acute Promyelocytic Leukemia: An Updated Population-based study

Author

Yuan-Yuan Liu, Mengyu Jia, Yi Tao, Ya-Qin Yu, and Lu Gao

Subjects
Male, Acute promyelocytic leukemia, Cancer Research, medicine.medical_specialty, Prostate cancer, Breast cancer, Leukemia, Promyelocytic, Acute, immune system diseases, Internal medicine, medicine, Surveillance, Epidemiology, and End Results, Humans, neoplasms, Aged, Proportional hazards model, business.industry, Mortality rate, Hematology, Middle Aged, medicine.disease, Survival Analysis, Minimal residual disease, Treatment Outcome, Oncology, Marital status, business, SEER Program
Abstract

Background Whether the characteristics and outcome of secondary acute promyelocytic leukemia (s-APL) are similar to de no APL (dn-APL) remains unknown. Patients and Methods Using the SEER database, we identified 3877 patients with APL diagnosed from 2000 to 2014, including 465 s-APL and 3412 dn-APL. Results Compared with dn-APL, s-APL werecharacterized by older median age, and a higher early mortality rate. Multivariate Cox model showed s-APL, older age, earlier year of diagnosis, and male gender were independently associated with worse survival. Notably, s-APL had a significantly inferior survival regardless of gender, race, marital status, and year of diagnosis. However, the difference between the 2 cohorts was only evident in younger patients (≤ 65 years) but was lost in older patients (> 65 years). Additionally, the majority of index cancer type was breast and prostate in female and male s-APL, respectively. Latency Conclusions Inferior survival of s-APL points to the need for treatment improvement.

Published
2022

31. Establishment of Assessment System for Medical Quality of General Practice in Chongqing General Hospitals

Author

QIN Yueqi, XIE Bo, ZHANG Yu, FENG Guibo, GONG Fang

Subjects
general hospital, general practice, medical quality evaluation, chongqing municipality, delphi technique, Medicine
Abstract

Background General practice (GP) plays a key role in carrying out the"Healthy China initiative", but the standardized medical quality evaluation involved remains incompletely established. The establishment of an appropriate quality evaluation indicator system for GP has to be settled urgently. Objective To evaluate the medical quality of GP in general hospitals of Chongqing, the medical quality evaluation indicator system for GP is established, and the indicator system would also provide reference for the construction of GP and the research work of Centers for General Medical Quality Control in Chongqing. Methods The evaluation indexes were formulated in February-April 2022 using the literature analysis method. Based on Delphi method, the indicator system was revised according to the correspondence consultation from 25 general practice experts of 20 general hospitals (including clinical residential training bases) in Chongqing. The final draft was combined with the suggestions of experts from the Center for Medical Quality Control of GP. Results Among the selected experts, men accounted for 64.0%, and 76.0% had middle or senior titles. Two rounds of experts' consultation responses were 21 and 20 copies respectively, and the experts' authoritative coefficient were 84.00% and 95.24%. Corresponding degree of authority above 0.85. After two rounds of experts' consultation and the suggestions of the quality control center, the medical quality evaluation indicator system of general practice for general hospital was finally established including 5 first-class indexes, 10 second-class indexes and 28 third-class indexes. Conclusion The evaluation indicator system based on Delphi method is of great significance for standardizing the quality of general practice service in general hospitals, promoting the construction of general practice service in Chongqing and strengthening the supervision of medical quality control center.

Published
2024
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32. Organisation of services and systems of care in paediatric spinal cord injury rehabilitation in seven countries: a survey with a descriptive cross-sectional design

Author

Tal Krasovsky, Mona Strøm, Vivien Jørgensen, Renat Sukhov, Katharina S. Sunnerhagen, Kerstin Wahman, Marika Augutis, Chen Yang, Kristine M. Vege, Kirsti Skavberg Roaldsen, Olga Zakharova, Qin Yu-Xi, Wiebke Höfers, Johan K. Stanghelle, Dafna Guttman, Per Ertzgaard, Liu Genlin, Susanne Sällström, Peter W New, Atheer Ghatasha, and Tamara Bushnik

Subjects
medicine.medical_specialty, Spinal cord injury rehabilitation, Rehabilitation, business.industry, Cross-sectional study, medicine.medical_treatment, Staffing, General Medicine, medicine.disease, Qualitative analysis, Neurology, Family medicine, Medicine, Neurology (clinical), Catchment area, business, Spinal cord injury, Paediatric population
Abstract

STUDY DESIGN International multicentre cross-sectional study. OBJECTIVES To describe the organisation and systems of paediatric spinal cord injury (SCI) rehabilitation services in seven countries and compare them with available recommendations and key features of paediatric SCI. SETTING Ten SCI rehabilitation units in seven countries admitting children and adolescents with SCI

Published
2021

33. MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA

Author

Qin Yu, Yorgo Modis, Alba Herrero del Valle, Rahul Singh, Yu, Qin [0000-0001-9265-632X], Herrero Del Valle, Alba [0000-0001-8153-6146], Singh, Rahul [0000-0001-8397-0202], Modis, Yorgo [0000-0002-6084-0429], Apollo - University of Cambridge Repository, and Herrero del Valle, Alba [0000-0001-8153-6146]

Subjects
Models, Molecular, 82/29, Interferon-Induced Helicase, IFIH1, Protein Conformation, ATPase, viruses, General Physics and Astronomy, medicine.disease_cause, 631/45/173, 631/45/535/1258/1259, Adenosine Triphosphate, 0302 clinical medicine, ATP hydrolysis, Interferon, Adenosine Triphosphatases, 0303 health sciences, Mutation, Multidisciplinary, biology, Chemistry, 631/45/500, article, food and beverages, MDA5, Chronic inflammation, 3. Good health, Cell biology, RNA silencing, Enzyme mechanisms, RNA, Viral, Protein Binding, medicine.drug, Science, Allosteric regulation, Mutation, Missense, General Biochemistry, Genetics and Molecular Biology, 96/95, 03 medical and health sciences, medicine, Humans, 82/83, RNA, Double-Stranded, 030304 developmental biology, Inflammation, 631/250/262/2106/2518, Cryoelectron Microscopy, 101/28, fungi, RNA, General Chemistry, Immunity, Innate, HEK293 Cells, 631/250/256/2515, RIG-I-like receptors, biology.protein, Nucleic Acid Conformation, 030217 neurology & neurosurgery
Abstract

Our innate immune responses to viral RNA are vital defenses. Long cytosolic double-stranded RNA (dsRNA) is recognized by MDA5. The ATPase activity of MDA5 contributes to its dsRNA binding selectivity. Mutations that reduce RNA selectivity can cause autoinflammatory disease. Here, we show how the disease-associated MDA5 variant M854K perturbs MDA5-dsRNA recognition. M854K MDA5 constitutively activates interferon signaling in the absence of exogenous RNA. M854K MDA5 lacks ATPase activity and binds more stably to synthetic Alu:Alu dsRNA. CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis show that the K854 sidechain forms polar bonds that constrain the conformation of MDA5 subdomains, disrupting key steps in the ATPase cycle- RNA footprint expansion and helical twist modulation. The M854K mutation inhibits ATP-dependent RNA proofreading via an allosteric mechanism, allowing MDA5 to form signaling complexes on endogenous RNAs. This work provides insights on how MDA5 recognizes dsRNA in health and disease., MDA5 is the primary immune sensor for SARS-CoV-2 and many other viruses. Mutations in MDA5 can cause disease. Here the authors employ CryoEM and biochemical methods to show how steric constraints cause MDA5 to misrecognize endogenous RNA as viral RNA.

Published
2021

34. Salidroside-pretreated mesenchymal stem cells contribute to neuroprotection in cerebral ischemic injury in vitro and in vivo

Author

Xiaohe Ma, Zhaoyun Wang, Liping Zhou, Lixia Jiang, Qin Yu, Panpan Yao, Guangxin Wen, Jintao Yang, and Binjie Zhou

Subjects
Male, Histology, Cell Survival, Physiology, Ischemia, Fluorescent Antibody Technique, Apoptosis, Pharmacology, Mesenchymal Stem Cell Transplantation, Neuroprotection, Brain Ischemia, chemistry.chemical_compound, Glucosides, Phenols, medicine, Animals, CA1 Region, Hippocampal, Cells, Cultured, Neuroinflammation, biology, business.industry, Salidroside, Mesenchymal stem cell, Disease Management, Mesenchymal Stem Cells, Cell Biology, General Medicine, medicine.disease, Immunohistochemistry, Rats, Transplantation, Disease Models, Animal, medicine.anatomical_structure, chemistry, biology.protein, NeuN, business, Biomarkers, Astrocyte
Abstract

Background: Mesenchymal stem cells (MSCs) are considered a promising tool for treating cerebral ischemic injury. However, their poor survival after transplantation limits their therapeutic effect and applications. Salidroside has been reported to exert potent cytoprotective and neuroprotective effects. This study aimed to investigate whether salidroside could improve MSC survival under hypoxic-ischemic conditions and, subsequently, alleviate cerebral ischemic injury in a rat model.Methods: MSCs were pretreated by salidroside under hypoxic-ischemic conditions. The cell proliferation, migratory capacity, and apoptosis were evaluated by means of Cell Counting Kit (CCK)-8, transwell assay, and flow cytometry. MSCs pretreated with salidroside were transplanted into the rats subsequent to middle cerebral artery occlusion. The grip strength, 2,3,5-triphenyltetrazolium chloride, and hematoxylin-eosin staining were used to analyze the therapeutic efficiency and pathological changes. The mature neuron marker NeuN and astrocyte marker GFAP in the focal area were detected by immunofluorescence.Results: These results indicated that salidroside promoted the proliferation, migration and reduced apoptosis of MSCs under hypoxic-ischemic conditions. In vivo experiments revealed that transplantation of salidroside-pretreated MSCs strengthened the therapeutic efficiency by enhancing neurogenesis and inhibiting neuroinflammation in the hippocampal CA1 area after ischemia.Conclusion: Our results suggest that pretreatment with salidroside could be an effective strategy to enhance the cell survival rate and the therapeutic effect of MSCs in treating cerebral ischemic injury.

Published
2021

35. MKRN1 Ubiquitylates p21 to Protect against Intermittent Hypoxia-Induced Myocardial Apoptosis

Author

Hui Yang, Yan Zhao, Xue Bai, Qin Yu, Jiayuan Pu, and Ying Jin

Subjects
rho GTP-Binding Proteins, Aging, Article Subject, Apoptosis, Nerve Tissue Proteins, Biochemistry, Rats, Sprague-Dawley, Mice, Downregulation and upregulation, Western blot, Ubiquitin, medicine, Animals, Humans, chemistry.chemical_classification, Reactive oxygen species, TUNEL assay, QH573-671, medicine.diagnostic_test, biology, Chemistry, Myocardium, Ubiquitination, Intermittent hypoxia, Cell Biology, General Medicine, Cell Hypoxia, Rats, Cell biology, Ribonucleoproteins, biology.protein, Immunohistochemistry, Cytology, Research Article
Abstract

Although chronic intermittent hypoxia- (IH-) induced myocardial apoptosis is an established pathophysiological process resulting in a poor prognosis for patients with obstructive sleep apnea syndrome, its underlying mechanism remains unclear. This study is aimed at exploring the role of makorin ring finger protein 1 (MKRN1) in IH-induced myocardial apoptosis and elucidating its molecular activity. First, the GSE2271 dataset was downloaded from the Gene Expression Omnibus database to identify the differentially expressed genes. Then, an SD rat model of IH, together with rat cardiomyocyte H9C2 and human cardiomyocyte AC16 IH models, was constructed. TUNEL, Western blot, and immunohistochemistry assays were used to detect cell apoptosis. Dihydroethidium staining was conducted to analyze the concentration of reactive oxygen species. In addition, RT-qPCR, Western blot, and immunohistochemistry were performed to measure the expression levels of MKRN1 and p21. The direct interaction between MKRN1 and p21 was determined using coimmunoprecipitation and ubiquitination analysis. MKRN1 expression was found to be downregulated in IH rat myocardial tissues as well as in H9C2 and AC16 cells. Upregulated expression of MKRN1 in H9C2 and AC16 cells alleviated the IH-induced reactive oxygen species production and cell apoptosis. Mechanistically, MKRN1 promoted p21 protein ubiquitination and the proteasome pathway degradation to negatively regulate p21 expression. Thus, MKRN1 regulates p21 ubiquitination to prevent IH-induced myocardial apoptosis.

Published
2021

36. Monitoring frequency of interferon gamma release assay for tuberculosis surveillance following infliximab therapy in patients with<scp>Crohn's</scp>disease

Author

Qin-Yu Yang, Lin Zhang, Cheng-Dang Wang, Yi-Juan Liu, and Xu Ye

Subjects
History of tuberculosis, medicine.medical_specialty, Crohn's disease, Tuberculosis, Latent tuberculosis, biology, Tuberculin Test, business.industry, Gastroenterology, Interferon gamma release assay, medicine.disease, biology.organism_classification, Inflammatory bowel disease, Infliximab, Mycobacterium tuberculosis, Interferon-gamma, Crohn Disease, Internal medicine, medicine, Humans, business, Retrospective Studies, medicine.drug
Abstract

OBJECTIVE To characterize the pattern of positive conversion of interferon gamma release assay (IGRA) in patients with Crohn's disease (CD) during infliximab therapy in China, which has a high burden of tuberculosis. METHODS Eligible patients with CD who received serial IGRA screening during infliximab therapy from January 2015 to March 2020 were retrospectively included. The positive conversion rate of IGRA and the risk of subsequent tuberculosis of the patients were analyzed. RESULTS A total of 128 patients with CD were included, and the median time from the initiation of IFX treatment to positive conversion or the last follow-up test of IGRA was 43.6 weeks. At baseline 3.9% of the patients were positive for IGRA and received prophylactic anti-tuberculosis treatment. In the other 123 patients with negative IGRA at baseline, 6.5% had IGRA positive conversion during infliximab treatment, and one (12.5%) who was exposed to Mycobacterium tuberculosis was diagnosed as having active tuberculosis. The conversion rate at 40 weeks, 2 years and 3 years after treatment were 10.0% (6/60), 2.2% (1/46) and 5.9% (1/17), respectively. Age, sex, history of smoking and alcohol consumption, disease severity (Crohn's disease activity index score) and immunosuppressive therapy were not significantly associated with latent tuberculosis test conversion. CONCLUSIONS Positive conversion of IGRA occurs early during treatment with infliximab for CD and the monitoring frequency of IGRA should be appropriately increased at the early stage of treatment. Physicians should pay attention to patient's history of tuberculosis exposure and carry out surveillance in a timely fashion.

Published
2021

37. A New Analytic Framework for Moderation Analysis — Moving Beyond Analytic Interactions

Author

Paul Crits-Christoph, Qin Yu, Xin Tu, and Wan Tang

Subjects
Variable (computer science), Computer science, Process (engineering), Theoretical definition, Econometrics, medicine, medicine.symptom, Moderation, Outcome (game theory), Article, Interpretation (model theory), Confusion
Abstract

Conceptually, a moderator is a variable that modifies the effect of a predictor on a response. Analytically, a common approach as used in most moderation analyses is to add analytic interactions involving the predictor and moderator in the form of cross-variable products and test the significance of such terms. The narrow scope of such a procedure is inconsistent with the broader conceptual definition of moderation, leading to confusion in interpretation of study findings. In this paper, we develop a new approach to the analytic procedure that is consistent with the concept of moderation. The proposed framework defines moderation as a process that modifies an existing relationship between the predictor and the outcome, rather than simply a test of a predictor by moderator interaction. The approach is illustrated with data from a real study.

Published
2021

38. 4-Phenylbutyric acid improves free fatty acid-induced hepatic insulin resistance in vivo

Author

Evangelia Tsiani, Paresh Dandona, Allen Volchuk, Sandra Pereira, Wen Qin Yu, Jessy Moore, Adria Giacca, Yemisi Deborah Joseph, Filip Vlavcheski, Carolyn L. Cummins, Jia-Xu Li, and Husam Ghanim

Subjects
medicine.medical_specialty, FGF21, Endocrinology, Diabetes and Metabolism, Adipose tissue, liver, Diseases of the endocrine glands. Clinical endocrinology, Endocrinology, Insulin resistance, Downregulation and upregulation, Internal medicine, parasitic diseases, Internal Medicine, medicine, Protein kinase A, Protein kinase B, business.industry, Research, free fatty acids, RC648-665, medicine.disease, 4-phenylbutyric acid, Unfolded protein response, endoplasmic reticulum stress, Chemical chaperone, business
Abstract

Plasma free fatty acids (FFAs) are elevated in obesity and can induce insulin resistance via endoplasmic reticulum (ER) stress. However, it is unknown whether hepatic insulin resistance caused by the elevation of plasma FFAs is alleviated by chemical chaperones. Rats received one of the following i.v. treatments for 48 h: saline, intralipid plus heparin (IH), IH plus the chemical chaperone 4-phenylbutyric acid (PBA), or PBA alone and a hyperinsulinemic-euglycemic clamp was performed during the last 2 h. PBA co-infusion normalized IH-induced peripheral insulin resistance, similar to our previous findings with an antioxidant and an IκBα kinase β (IKKβ) inhibitor. Different from our previous results with the antioxidant and IKKβ inhibitor, PBA also improved IH-induced hepatic insulin resistance in parallel with activation of Akt. Unexpectedly, IH did not induce markers of ER stress in the liver, but PBA prevented IH-induced elevation of phosphorylated eukaryotic initiation factor-2α protein in adipose tissue. PBA tended to decrease circulating fetuin-A and significantly increased circulating fibroblast growth factor 21 (FGF21) without affecting markers of activation of hepatic protein kinase C-δ or p38 mitogen-activated protein kinase that we have previously involved in hepatic insulin resistance in this model. In conclusion: (i) PBA prevented hepatic insulin resistance caused by prolonged plasma FFA elevation without affecting hepatic ER stress markers; (ii) the PBA effect is likely due to increased FGF21 and/or decreased fetuin-A, which directly signal to upregulate Akt activation.

Published
2021

39. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author

Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C Quinn, Maria A Alfonso, Maria Antonieta Pereira Moraes, María Dolores Martínez-Ruíz, María Fernanda Canales, Maria Inês Caetano, Maria P Corral, Maria Pérez García, Maria Victoria Actis, Maria Aguirre, Maria Andreasson, Maria Aprile, Maria Colton, Maria Eugenia Martin, Maria Lasala, Maria Lorenzo, Maria Posada, Maria Shier, Maria Thottam, Mariana V Furtado, Mariana Yumi Okada, Marianna D A Dracoulakis, Marianne De Andrade, Mariano Rubio, Marie Essermark, Marielle Scherrer-Crosbie, Marija T Petrovic, Marija Zdravkovic, Marilyn Black, Marina Garcia, Mario J Garcia, Mariola Szulik, Marisa Orgera, Mark A de Belder, Mark Harbinson, Mark Hyun, Mark Peterson, Mark Xavier, Marlowe Mosley, Marta Capinha, Marta Marcinkiewicz-Siemion, Marta Swiderek, Martha Meyer, Martina Ceseri, Martina Tricoli, Marvin Kronenberg, Mary Williams, Mary Ann Champagne, Mary Colleen Rogge, Mary R Soltau, Mary Streif, Massimo Villella, Massoud Leesar, Matei Claudia, Mateusz Solecki, Matías Nicolás Mungo, Matthew Wall Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, 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Mokhtar, Noppon Taksaudom, Nor Asiah Basri, Nora Marchelletta, Norma Hogg, Nungshi Jungla, Nuno Ferreira, Oksana A Lubyanaya, Olga B Nikolaeva, Olga Cañavate, Olga Sobrino, Olga Walesiak, Olga Walter, Olga Zdończyk, Olivia J Lim, Olivia Anaya, Olivia Mancilla, Olivier Dubourg, Olugbenga Bello, Omar Almousalli, Omar Thompson, Oni Olurinde, Or Harel, Osama Raheem, Oscar Méndiz, Óscar Prada-Delgado, Oz Shapira, P Christian Schulze, Pachara Panpunuan, Pal Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, Raewyn Fisher, Rafael Beyar, Rafael Diaz, Rafael Selgas, Raffaele Bugiardini, Raffaele Fanelli, Raisa Kavalakkat, V S Rajalekshmi, Rajat S Barua, Rajeev Menon, Rajesh Gopalan Nair, Rajesh Francis, Rajiv Narang, Rakesh Yadav, Ralph Alan Huston, T Ramakrishnan, Ramesh de Silva, Rami El Mahmoud, Ramiro Carvalho, Ramon de Jesús-Pérez, Ramona Stevens, Ran Leng, Ranjan Kachru, Ranjit Kumar Nath, Raquel Sanchez, Raven R Dwyer, Raven Lee, Ray Wyman, Raymond C Wong, Raymond W Little, Raymundo Ocaranza Sanchez, Rebecca J Wimmer, Rebecca Bariciano, Rebecca Otis, Rebekah R Herrmann, Reem Yunis, Reinette Hampson, Renato Abdala Karam, Renee C Hessian, Renee Kaneshiro, Reshma Ravindran, Reto Andreas Gamma, Reyna Bhandari, Reza Arsanjani, Ricardo L Lopes, Ricardo Mendes Oliveira, Ricardo Costa, Richa Bhatt, Richard F Davies, Richard H J Trimlett, Richard Goldweit, Rik Hermanides, Rine Nakanishi, Rinu R Sidh, Risha Patel, Rita Coram, Rizwan A Siddiqui, Rob S Beanlands, Robert J Hamburger, Robert K Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M 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S.G., Ruzyllo W., Gosselin G., Maggioni A.P., White H.D., Bhargava B., Min J.K., John Mancini G.B., Berman D.S., Picard M.H., Kwong R.Y., Ali Z.A., Mark D.B., Spertus J.A., Krishnan M.N., Elghamaz A., Moorthy N., Hueb W.A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T.D., Szwed H., Doerr R., Keltai M., Selvanayagam J.B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N.O., Harrell F.E., Rockhold F.W., Broderick S., Bruce Ferguson T., Williams D.O., Harrington R.A., Stone G.W., Rosenberg Y, and ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, 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Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, 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Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud 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Maurovich-Horvat, Pallav Garg, Paloma Moraga, Pam Singh, Pamela Julian, Pamela Ouyang, Pamela Sigel, Pamela Woodard, Panpan Zhou, Paola Emanuela Poggio, Paola Smanio, Paolo Calabro, Paramjit Jeetley, Pascal Goube, Patricia K Nguyen, Patricia Alarie, Patricia Arakelian, Patricia Arsenault, Patricia Blaise, Patricia Brito, Patricia Cowper, Patricia Endsley, Patricia Mieses, Patrick B Alexander, Patrick Donnelly, Patrick Wilmot, Patrycja Lebioda, Paul C Gordon, Paul Der Mesropian, Paul Galiwango, Paul Hauptman, Paul Kennedy, Paula Beardsley, Paula García-González, Paulo Cury Rezende, Paulo Ricardo Caramori, Pavel S Kozlov, Pedro Canas Silva, Pedro Gabriel Melo Barros E Silva, Pedro Píccaro de Oliveira, Pedro Carvalho, Pedro Modas, Pedro Rio, Peeyush Jain, Peiyu He, Peter A McCullough, Peter H Stone, Peter M Pollak, Peter Douglass, Peter Henriksen, Peter OKane, Peter Ong, Philip Jones, Philip Rogal, Philippe Généreux, Philippe Menasche, Philippe Rheault, Phoebe Goold, Pierre Gervais, Pierre Michaud, Pilar Calvillo, Ping Chai, Piotr Jakubowski, Piotr Pruszczyk, Piotr Slomka, Piyamitr Sritara, Poay-Huan Loh, Poonam Sonawane, Pouneh Samadi, Pragnesh P Parikh, Prakash Deedwania, Pranav M Patel, Praneeth Polamuri, Pratiksha Sharma, Precilia Vasquez, Preeti Kamath, Prince Thomas, Priyadarshani Arambam, Puja K Mehta, Purvez Grant, Pushpa Naik, Qi Zhong, Qian Zhao, Qiang Zhou, Qianqian Yuan, Qin Yu, Qingxian Li, Qiulan Xie, Qiutang Zeng, R J Vindhya, R James Gerlach, Rachel King, Rada Vučić, Radmila Lyubarova, Radoslaw Pracon, Raewyn Fisher, Rafael Beyar, Rafael Diaz, Rafael Selgas, Raffaele Bugiardini, Raffaele Fanelli, Raisa Kavalakkat, V S Rajalekshmi, Rajat S Barua, Rajeev Menon, Rajesh Gopalan Nair, Rajesh Francis, Rajiv Narang, Rakesh Yadav, Ralph Alan Huston, T Ramakrishnan, Ramesh de Silva, Rami El Mahmoud, Ramiro Carvalho, Ramon de Jesús-Pérez, Ramona Stevens, Ran Leng, Ranjan Kachru, Ranjit Kumar Nath, Raquel Sanchez, Raven R Dwyer, Raven Lee, Ray Wyman, Raymond C Wong, Raymond W Little, Raymundo Ocaranza Sanchez, Rebecca J Wimmer, Rebecca Bariciano, Rebecca Otis, Rebekah R Herrmann, Reem Yunis, Reinette Hampson, Renato Abdala Karam, Renee C Hessian, Renee Kaneshiro, Reshma Ravindran, Reto Andreas Gamma, Reyna Bhandari, Reza Arsanjani, Ricardo L Lopes, Ricardo Mendes Oliveira, Ricardo Costa, Richa Bhatt, Richard F Davies, Richard H J Trimlett, Richard Goldweit, Rik Hermanides, Rine Nakanishi, Rinu R Sidh, Risha Patel, Rita Coram, Rizwan A Siddiqui, Rob S Beanlands, Robert J Hamburger, Robert K Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M Rivest, Sandra S Zier, Sandra Ahoud, Sandy Carr, Sanjay Ganapathi, Sanjay Shetty, Sanjeev Sharma, Santa Jimenez, Santhosh Satheesh, Santiago A Garcia, Sara Fernandez, Sara Karlsson, Sara Salkind, Sara Temiyasathit, Sarah Medina Rodriguez, Sarah Beaudry, Sarah Hadjih, Sarah Williams, Sarah Zahrani, Sarju Ralhan, Sasa Hinic, Sasko Kedev, Satinder Singh, Satoshi Yasuda, Satvic Cholenahally Manjunath, Sau Lee, Scott M Kaczkowski, Scott Kinlay, Sean W Hayes, Sebastian Sobczak, Senait Asier, Sergey A Sayganov, Seth I Sokol, Shaheen Pandie, Shaiful Azmi Yahaya, Shamir Mehta, Shao-Ping Nie, Sharad Chandra, Sharder Islam, Sharon Tai, Sheetal Rupesh Karwa, Sheri Ussery, Sheromani Bajaj, Sherron C Crook, Shigeyuki Nishimura, Shintaro Nakano, Shirin Heydari, Shiv Kumar Choudhary, Shivali Patel, Shobana Ganesan, Shruti Pandey, Shuyang Zhang, Shweta Hande, Siddharth Gadage, Sik-Yin V Tan, Silvia Zottis Poletti, Silvia Riera, Silvia Valbuena, Simon Walsh, Simona Maspoli, Simone Savaris, Si-Ting Feng, So Yang Cho, Solomon Yakubov, Songlin Zhu, Songtao Wang, Sonia Guerrero, Sonika Gupta, Sonja Salinger Martinovic, Sonya Brons, Sorin Brener, Sothinathan Gurunathan, Souheil Saba, Soundarya Nayak, Sowjanya Reddy, Srinivasa Potluri, Sriram Sudarshan, Srun Kuanprasert, Stacie Van Oosterhout, Stamatios Lerakis, Stanley E Cobos, Stefan C Bertog, Stefan M Simović, Stefan Weikl, Stefano Di Marco, Stefano Provasoli, Stephanie A Tirado, Stephanie C Boer, Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello Duarte, Tauqir Huk, Téodora Dutoiu, Terrance Chua, Terry Weyand, Thabitha Charles, Theodoros Kofidis, Theresa McCreary, Thierry Lefevre, Thippeekaa Arumairajah, Thitipong Tepsuwan, Thomas J Mulhearn, Thomas M Meyer, Thomas P Rocco, Thomas R Downes, Thomas Crain, Thomas Haldis, Thomas Mathew, Thomas Redick, Thounaojam Indira Devi, Thuraia Nageh, Tia Cauthren, Tiago Silva, Tiffany Little, Tijana Andric, Tina Harding, Titus Lau, Tiziana Formisano, Tiziano Moccetti, Tomasz Ciurus, Tomasz Mazurek, Tomasz Tarchalski, Toshiyuki Nagai, Tri Tran, Tricia Youn, Trish Tucker, Trudie Milner, Tuhina Bose, Tushar Kotecha, Udo Sechtem, Uma S Valeti, Umberto Cucchini, Umesh Badami, Upendra Kaul, V K Bahl, V S Narain, Valentina Casali, Valeria Godoy, Valerie Robesyn, Vamshi P Priya, Vandana Yadav, Vera McKinney, Veronica De Lenges, Veronica Tinnirello, Vicente Miro, Victor Navarro, Victoria Gumerova, Victoria Hernandez, Vidya Seeratan, Vijay Kumar, Vikentiy Y Kozulin, Viktoria Bulkley, Vilmar Veiga Jr, Vincent Setang, C P Vineeth, Virginai Pubull Nuñez, Virginia Fernández-Figares, Vitor Gomes, Viviana Gabriel, Viviane Dos Santos, Viviane Almeida, Vlad A Iliescu, Vladan Mudrenovic, Vladimir Dzavik, Vojislav L Giga, Walter Enrique Mogrovejo, Wan Xian Chan, Wanda C Marfori, Wanda Parker, Warangkana Mekara, Wassim Nona, Wayne Old, Wayne Pennachi, Weerachai Nawarawong, Wei Chen, Wei Su, Weibing Xing, Wei-Ren Lan, Wenda Crawford, Wendy L Stewart, Wendy Drewes, Wenhua Lin, William B Abernethy, William D Salerno, William F Fearon, William Vergoni, William Weintraub, Winnie C Sia, Wlodzimierz J Musial, Xacobe Flores-Ríos, Xavier Garcia-Moll Marimon, Xi Su, Xiang Ma, Xiangqiong Gu, Xiao Wang, Xiaomei Li, Xiaowei Yao, Xin Fu, Xin Su, Xin Zeng, Xinchun Yang, Xiuhong Li, Xuehua Fang, Xutong Wang, Yaming Geng, Yan Yan, Yanek Pépin-Dubois, Yanfu Wang, Yang Wang, Yanmeng Tian, Yaping Huang, Yechen Han, Yesenia Zambrano, Yi-Hsuan Yang, Ying Tung Sia, Yining Yang, Yitong Ma, Yolayfi Peralta, Yongjian Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits

Subjects
Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Published
2020

40. Anti-inflammatory effects of paeoniflorin caused by regulation of the hif1a/miR-210/caspase1/GSDMD signaling pathway in astrocytes: a novel strategy for hypoxia-induced brain injury in rats

Author

Jun Chen, Jiqiang Wu, Xue Bai, Jiangjun Chen, Hailin Chen, Pingping Wanyan, Qin Yu, Zhenxiu Jiang, and Zelin Lei

Subjects
Male, 0301 basic medicine, Immunology, Context (language use), Inflammation, Pharmacology, Toxicology, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Glucosides, Downregulation and upregulation, Animals, Immunology and Allergy, Medicine, Hypoxia, Cells, Cultured, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Caspase 1, Intracellular Signaling Peptides and Proteins, Pyroptosis, General Medicine, Phosphate-Binding Proteins, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, Paeoniflorin, Rats, MicroRNAs, 030104 developmental biology, HIF1A, chemistry, Astrocytes, Brain Injuries, 030220 oncology & carcinogenesis, Monoterpenes, medicine.symptom, Signal transduction, business, Signal Transduction
Abstract

Context: Hypoxia-induced injury is a classic symptom of obstructive sleep apnea hypopnea syndrome (OSAHS), which is a risk factor of various diseases, such as hypertension, heart failure and stroke. However, there is no effective therapy for hypoxia-induced injury or OSAHS due to the elusive mechanism involved. Objective: This study aimed to assess the effects of paeoniflorin on hypoxia-induced injury and explore the underlying mechanism. Materials and methods: Hypoxic models of SD rats and CTX-TNA2 cells were used to assess the effect of paeoniflorin, and the expressions of hif1a, miR-210, caspase1 and GSDMD were detected using western blots and RT-PCR. Plasmid transfection was performed to explore the role of miR-210 in the effect of paeoniflorin. Results: Firstly, we confirmed that hypoxia induced severe neuronal injury and an enhancement of inflammation in the rat brain, with elevated expression of caspase1, IL1b and IL18. In addition, the results showed an activation of astrocytes and an increased level of pyroptosis under hypoxic conditions, which suggested a critical role of pyroptosis in hypoxiainduced injury of the brain. Furthermore, we found that compared with the controls, paeoniflorin treatment improved hypoxia-induced pyroptosis in astrocytes. Moreover, we detected the activation of hif1a/miR-210 signaling in the effects of paeoniflorin on astrocytes. As expected, the expression of hif1a and miR-210 was significantly upregulated in astrocytes when exposed to hypoxia, while paeoniflorin treatment reversed these enhancements. After transfection of miR-210 mimics, the attenuation of pyroptosis induced by paeoniflorin was suppressed, which was accompanied by an increase of ROS levels, as well as LDH release, indicating a critical role of miR-210 in pyroptosis in astrocytes. Conclusions: Our findings demonstrated that paeoniflorin improved hypoxia-induced pyroptosis in astrocytes via depressing hif1a/miR-210/caspase1/GSDMD signaling, providing robust evidence for the treatment of hypoxic injury and OSAHS.HighlightsHypoxia induces severe injury and inflammatory response in the rat brain;Hypoxia enhanced pyroptotic level and led to an activation of astrocytes.;Paeoniflorin alleviates hypoxia-induced pyroptosis in astrocytes;Transfection of miR-210 mimics suppressed the effects of paeoniflorin on hypoxia-induced pyroptosis in astrocytes. Hypoxia induces severe injury and inflammatory response in the rat brain; Hypoxia enhanced pyroptotic level and led to an activation of astrocytes.; Paeoniflorin alleviates hypoxia-induced pyroptosis in astrocytes; Transfection of miR-210 mimics suppressed the effects of paeoniflorin on hypoxia-induced pyroptosis in astrocytes.

Published
2021

41. Bioequivalence of 2 Aripiprazole Orally Disintegrating Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions

Author

Jin Xiang, Mao-Zhi Liang, Xueyan Wang, Linchuan Liao, Yuqi Zhu, Shiqing Shu, Songfan Li, Qin Yu, Nan Xu, Rui Yan, and Feng Nan

Subjects
Male, China, Drug Compounding, Aripiprazole, Cmax, Administration, Oral, Pharmaceutical Science, Bioequivalence, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Animal science, Pharmacokinetics, medicine, Humans, Pharmacology (medical), Cross-Over Studies, business.industry, Fasting, Middle Aged, Crossover study, Healthy Volunteers, Confidence interval, Therapeutic Equivalency, Tolerability, Area Under Curve, 030220 oncology & carcinogenesis, Female, Geometric mean, business, Tablets, medicine.drug
Abstract

To assess the bioequivalence of 2 formulations of aripiprazole orally disintegrating tablets and to monitor their safety and tolerability in Chinese subjects, a single-site, open-label, randomized, 2-preparation, single-dose, 2-period crossover design was conducted. All 60 subjects were randomly divided into the fasting group and the fed group. Blood samples were collected at scheduled times after a single oral dose of orodispersible tablets containing 10 mg of aripiprazole. In the fasting state, the geometric mean ratios (90% confidence intervals [CIs]) of the test/reference formulation were 92.22%-100.20% for the area under the concentration-time curve (AUC) from time zero to the last measured concentration (AUC0-t ), 91.73%-100.14% for the AUC from administration to infinite time (AUC0-∞ ), and 98.52%-112.52% for the maximum plasma concentration (Cmax ). In the fed state, AUC0-t , AUC0-∞ , and Cmax were 92.23%-100.20%, 91.73%-100.14%, and 95.91%-105.13%, respectively. The 90%CIs of the test/reference AUC ratio and Cmax ratio were within the acceptance range of 80.00%-125.00% for bioequivalence. Neither the maximum peak plasma concentration (tmax ) nor the terminal elimination half-life (t1/2 ) showed any significant difference. No serious adverse events) were encountered during the study. The test and reference formulations were bioequivalent under both fasting and fed conditions and were found to be safe and tolerated.

Published
2021

42. Effect of LHX2 gene methylation level and its function on radiotherapy of cervical cancer

Author

Hao Yang, Qin Yu, Lihe Zhang, Rong Yu, Yadi Wang, and Haiping Zhao

Subjects
Cervical cancer, Cancer Research, business.industry, medicine.medical_treatment, LHX2, medicine.disease, radiation therapy, Radiation therapy, methylation level, Oncology, embryonic structures, DNA methylation, Cancer research, Medicine, Original Article, Radiology, Nuclear Medicine and imaging, business, function analysis, Function (biology)
Abstract

Background Cervical cancer is the most common malignancy of the female reproductive system, for which radiotherapy is one of the main treatments. Gene methylation in cells is an important factor in tumorigenesis, and radiotherapy can change DNA methylation in cells. At the same time, combined with the clinical effect of radiotherapy, key genes of LIM homeobox 2 (LHX2) significantly related to cervical cancer. The LHX2 are LIM-homeobox genes that play important roles in signal transduction, cell differentiation, tissue-specific differentiation, and body formation. Methods In this study, bisulfite genomic sequencing (BSP-Seq) technology was used to analyze the methylation level of LHX2 in patients with cervical cancer before and after radiotherapy. In addition, combined with the clinical effect of radiotherapy, the function of LHX2 in siHA and C33A cells were analyzed with the help of overexpression, small interfering RNA (siRNA), cell invasion, and migration ability. The expression level of the migration- and apoptosis-related genes which were affected by LHX2 were tested with quantitative real time polymerase chain reaction (qRT-PCR). Results Combined with clinical treatment, methylation level difference, and correlation enrichment analysis, it was found that LHX2 genes were closely related to the occurrence and development of cervical cancer. After 5-aza-2’-deoxycytidine (5-Aza-dC) and radiotherapy, the methylation of LHX2 genes in siHA and C33A squamous cell carcinoma cells was decreased, and the messenger RNA (mRNA) and protein expression levels were relatively increased; meanwhile, the LHX2 could accelerate the ability for cell invasion and migration and inhibited the apoptosis of the cell after treatment with radiotherapy. Conclusions The methylation and expression levels of LHX2 genes are closely related to cervical cancer. The methylation level of LHX2 was reduced after radiation therapy. The LHX2 gene has a positive effect on cervical cancer through acceleration of the cell invasion and migration ability and inhibition of cell apoptosis after radiotherapy treatment.

Published
2021

43. Measuring the global, regional, and national burden of multiple myeloma from 1990 to 2019

Author

Qin Yu, Guoqing Wei, Kejia Hu, Yongxian Hu, He Huang, Linghui Zhou, Linqin Wang, and Yue Huang

Subjects
Burden of disease, Male, Cancer Research, Population ageing, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Age Distribution, Risk Factors, Multiple myeloma, Disability adjusted life-years, Genetics, medicine, Humans, 030212 general & internal medicine, Mortality, Sex Distribution, RC254-282, Aged, Aged, 80 and over, business.industry, Incidence (epidemiology), Mortality rate, Research, Incidence, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, medicine.disease, Global burden of disease, Death, Oncology, 030220 oncology & carcinogenesis, Western europe, Female, Quality-Adjusted Life Years, business, Demography
Abstract

Background Multiple myeloma (MM) is a major health concern. Understanding the different burden and tendency of MM in different regions is crucial for formulating specific local strategies. Therefore, we evaluated the epidemiologic patterns and explored the risk factors for MM death. Methods Data on MM were collected from the 2019 Global Burden of Disease study. We used incidence, mortality, and disability adjusted life-years to estimate the global, regional, and national burden of MM. Results In 2019, there were 155,688 (95% UI, 136,585 – 172,577) MM cases worldwide, of which 84,516 (54.3%, 70,924 – 94,910) were of men. The age-standardized incidence rate (ASIR) was 1.72/100,000 persons (95% UI, 1.59–1.93) in 1990 and 1.92/100,000 persons (95% UI, 1.68–2.12) in 2019. The number of MM deaths increased 1.19-fold from 51,862 (95% UI, 47,710–58,979) in 1990 to 113,474 (95% UI, 99,527 – 121,735) in 2019; the age-standardized death rate (ASDR) was 1.42/100,000 persons (95% UI, 1.24–1.52) in 2019. In recent 15 years, ASDR showed a steady tendency for men, and a downward tendency for women. Countries with high social-demographic indexes exhibited a higher ASIR and ASDR. Australasia, North America, and Western Europe had the highest ASIR and ASDR, with 46.3% incident cases and 41.8% death cases. Monaco had the highest ASIR and ASDR, which was almost half as high as the second highest country Barbados. In addition, United Arab Emirates and Qatar had the largest growth multiple in ASIR and ASDR, which was twice the third country Djibouti. Conclusions Globally, incident and death MM cases have more than doubled over the past 30 years. The increasing global burden may continue with population aging, whereas mortality may continue to decrease with the progression of medical technology. The global burden pattern of MM was diverse, therefore specific local strategies based on different burden patterns for MM are necessary.

Published
2021

44. Viologen-Based Cationic Metal–Organic Framework for Efficient Cr2O72– Adsorption and Dye Separation

Author

Xiaoman Yang, Qin Yu, Chaoyue Yan, Tingting Sang, Xin Li, Qingfu Zhang, Li Zhiyuan, Kecai Xiong, and Yanli Gai

Subjects
Ion exchange, 010405 organic chemistry, Cationic polymerization, Viologen, 010402 general chemistry, 01 natural sciences, 0104 chemical sciences, Congo red, Inorganic Chemistry, chemistry.chemical_compound, Adsorption, chemistry, Polymer chemistry, medicine, Methyl orange, Metal-organic framework, Physical and Theoretical Chemistry, Derivative (chemistry), medicine.drug
Abstract

A novel cationic metal-organic framework composed of {Cu2(COO)4} paddle-wheel units and a tetracarboxylic viologen derivative, namely, {[Cu2(bdcbp)(H2O)2]·2NO3·2H2O}n (Cu-CMOF, H4bdcbpCl2 = 1,1'-bis(3,5-dicarboxyphenyl)-4,4'-bipyridinium dichloride), has been successfully synthesized and structurally characterized. In Cu-CMOF, the {Cu2(COO)4} unit and viologen derivative both act as four-connected nodes forming an ssb-type cationic network with 42.84 topology, in which the positive charges are distributed on the organic viologen moieties. Deeper insight of the structure indicates that the 3D architecture of Cu-CMOF can be seen as packing of a 26-faceted polyhedral cage and two cuboid cages. Notably, Cu-CMOF displays a highly efficient anion exchange ability for capture and removal of anionic pollutants. UV-vis absorption spectra and digital images demonstrate that Cu-CMOF is capable of adsorbing the dichromate anion and anionic dyes effectively, such as methyl orange (MO-), Congo red (CR2-), and New Coccine (NC3-). Meaningfully, anionic dyes (MO-, CR2-, and NC3-) can be efficiently and selectively removed by Cu-CMOF in the presence of cationic dye methylene blue (MLB+). Such behaviors of anionic pollutant adsorption and dye separation are mainly caused by an ion-exchange process facilitated by the large cavity and decentralized distribution of positive charge in Cu-CMOF.

Published
2021

45. CRS-related coagulopathy in BCMA targeted CAR-T therapy: a retrospective analysis in a phase I/II clinical trial

Author

He Huang, Qin Yu, Huijun Xu, Guoqing Wei, Mi Shao, Xinyi Teng, Xin Guo, Alex Hongsheng Chang, Yongxian Hu, and Jiazhen Cui

Subjects
medicine.medical_specialty, medicine.medical_treatment, Immunotherapy, Adoptive, Gastroenterology, 03 medical and health sciences, Tissue factor, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Coagulopathy, Humans, B-Cell Maturation Antigen, Multiple myeloma, Coagulation Disorder, Retrospective Studies, Transplantation, Chemotherapy, Factor XII, Receptors, Chimeric Antigen, business.industry, Factor X, Hematology, Blood Coagulation Disorders, medicine.disease, Cytokine release syndrome, chemistry, 030220 oncology & carcinogenesis, Cytokine Release Syndrome, Multiple Myeloma, business, 030215 immunology
Abstract

Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) has shown promising effects in the treatment of patients with refractory/relapsed multiple myeloma (R/R MM) patients. In this retrospective analysis of phase I/II clinical trial (ChiCTR1800017404), 37 patients with R/R MM received their first BCMA-targeted CAR T-cells following lymphodepletion chemotherapy. The response rate was high (97%), while accompanied by a high incidence of adverse events including coagulation dysfunction. Of 37 patients, all (100%) had cytokine release syndrome (CRS) and 34 (91%) developed at least one abnormal coagulation parameter. The values of coagulation parameters were positively correlated with the severity of CRS as well as with the levels of some cytokines, such as interleukin (IL)-6, IL-10, and interferon (IFN)-γ, etc. Furthermore, levels of the plasma tissue factor (TF), Factor X (FX), Factor XII (FXII), and P-selectin also showed a positive correlation with severity of CRS as well as some specific cytokines, which indicates that these factors are likely to play important roles in CRS-related coagulopathy. Our study suggests that there exists relationship in some extent between coagulation disorder and CRS. Moreover, coagulation dysfunction can be managed with daily monitoring and early intervention despite high incidence.

Published
2021

46. Implications of the microbiome in the development and treatment of pancreatic cancer: Thinking outside of the box by looking inside the gut

Author

Qin Yu, Ryan M. Thomas, and Christian Jobin

Subjects
0301 basic medicine, Cancer Research, Pancreatic ductal adenocarcinoma, Carcinogenesis, GF, germ free, Review Article, medicine.disease_cause, Bioinformatics, lcsh:RC254-282, SPF, specific pathogen free, 03 medical and health sciences, 0302 clinical medicine, Immune system, Pancreatic cancer, medicine, Humans, Microbiome, Pancreas, Carcinogen, business.industry, Microbiota, Disease Management, Cancer, POPF, postoperative pancreatic fistula, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, medicine.disease, Combined Modality Therapy, PDAC, Pancreatic ductal adenocarcinoma, WT, wild-type, Gastrointestinal Microbiome, Pancreatic Neoplasms, Oncobiome, Natural history, Cell Transformation, Neoplastic, Treatment Outcome, 030104 developmental biology, Bacterial Translocation, 030220 oncology & carcinogenesis, qPCR, quantitative polymerase chain reaction, Disease Susceptibility, business, Biomarkers, Carcinoma, Pancreatic Ductal
Abstract

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. As one of the most lethal cancer types, the prognosis for patients diagnosed with pancreatic cancer remains dismal and novel investigations are urgently needed. Evidence for an association of microbes with pancreatic cancer risk, development, treatment response, and post-treatment survivorship is rapidly developing. Herein, we provide an overview on the role of the microbiome as it relates to the natural history of pancreatic cancer, including host immune interactions, alterations in metabolism, direct carcinogenic effect, and its role in treatment response.

Published
2021

47. Preparation and swelling behavior of end-linked hydrogels prepared from linear poly(ethylene glycol) and dendrimer-star polymers

Author

Jun Wang, Qin Yu, Xiangbin Liu, Guangna Qu, and Na Zhang

Subjects
Poly ethylene glycol, Materials science, Polymers and Plastics, General Chemical Engineering, technology, industry, and agriculture, 02 engineering and technology, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, 0104 chemical sciences, Chemical engineering, Star polymer, Dendrimer, Self-healing hydrogels, Materials Chemistry, medicine, Temperature sensitive, Swelling, medicine.symptom, 0210 nano-technology
Abstract

Linear diepoxide-terminated poly(ethylene glycol) (PEG) of molar mass 600, 1000 and 2000 g mol−1 was end-linked with dendrimer-star polymer (PAMAM) of generations 1.0 in water to prepare architecturally well-defined copolymer hydrogels. The structures and properties of the products were characterized using infrared, 1H NMR, DSC measurements, scanning electron microscopy (SEM) and swelling behavior tests. The swelling behavior of these hydrogels was tested in distilled water at constant temperature and the equilibrium swelling ratio (ESR) was determined for structurally different hydrogels and various environmental conditions, which showed that ESR was influenced by the molecular weight of PEG, the molar ratio of H amine groups/epoxy groups, temperature and pH. Higher ESR was obtained for either longer-chain PEG, non-stoichiometric H amine/epoxy groups ratio, acidic pH or lower temperatures. When the hydrogel was switched from 10 °C to 65 °C and pH 3.5 to 11.5, the swelling behavior of the hydrogels showed good reversibility for swelling–deswelling. When the molecular weight of PEG was changed in the range of 600–2000, the lower critical solution temperature (LCST) of hydrogel increased from 30 to 40 °C. When the molar ratio of H amine/epoxy groups was changed, the LCST was not significantly changed.

Published
2021

48. How Well Have Projected Lung Cancer Rates Predicted the Actual Observed Rates?

Author

Xue Qin Yu, Dianne L. O'Connell, Karen Canfell, Julia Steinberg, Qingwei Luo, and Michael Caruana

Subjects
Adult, Male, 0301 basic medicine, Lung Neoplasms, Population, Global Health, World health, 03 medical and health sciences, Age Distribution, age-period, 0302 clinical medicine, Predictive Value of Tests, Humans, Medicine, Registries, Sex Distribution, Lung cancer, education, Aged, cohort model, Statistical projections, education.field_of_study, Models, Statistical, business.industry, Incidence, Mortality rate, Incidence (epidemiology), Cancer, General Medicine, Middle Aged, medicine.disease, Survival Rate, 030104 developmental biology, mortality rates, generalized linear model, 030220 oncology & carcinogenesis, Percentage difference, Female, incidence rates, business, Research Article, Demography
Abstract

Background While many past studies have constructed projections of future lung cancer rates, little is known about their consistency with the corresponding observed data for the time period covered by the projections. The aim of this study was to assess the agreement between previously published lung cancer incidence and/or mortality rate projections and observed rates. Methods Published studies were included in the current study if they projected future lung cancer rates for at least 10 years beyond the period for which rates were used to obtain the projections, and if more recent observed rates for comparison covered a minimum of 10 years from the beginning of the projection period. Projected lung cancer incidence and/or mortality rates from these included studies were extracted from the publications. Observed rates were obtained from cancer registries or the World Health Organization's Mortality Database. Agreement between projected and observed rates was assessed and the relative difference (RD) for each projected rate was calculated as the percentage difference between the projected and observed rates. Results A total of 59 projections reported in 14 studies were included. Nine studies provided projections for 20 years or more. RDs were higher for those projections in which the lung cancer rates peaked during the projection period, and RDs increased substantially with the length of the projection period. When lung cancer rates peaked during the projection period, methods incorporating smoking data were generally more successful at predicting the trend reversal than those which did not incorporate smoking data. Mean RDs for 15-year projections comparing methods with or without smoking data were 12.7% versus 48.0% for males and 8.2% versus 42.3% for females. Conclusions The agreement between projected and observed lung cancer rates is dependent on the trends in the observed rates and characteristics of the population, particularly trends in smoking.

Published
2021

49. Recepteur d'origine nantais contributes to the development of endometriosis via promoting epithelial‐mesenchymal transition of a endometrial epithelial cells

Author

Gen Zou, Qin Yu, Xinmei Zhang, Xinxin Xu, Libo Zhu, Jianzhang Wang, Xuan Che, Tiantian Li, Xinyue Guo, Shaojie Ding, and Yangying Peng

Subjects
endometriosis, 0301 basic medicine, MAPK/ERK pathway, Epithelial-Mesenchymal Transition, Endometriosis, recepteur d'origine nantais, migration, Receptor tyrosine kinase, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Humans, Medicine, Epithelial–mesenchymal transition, Protein kinase A, Protein kinase B, Gene knockdown, epithelial‐mesenchymal transition, biology, Transition (genetics), business.industry, Receptor Protein-Tyrosine Kinases, Epithelial Cells, Original Articles, Cell Biology, invasion, medicine.disease, Immunohistochemistry, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Molecular Medicine, Female, Original Article, Disease Susceptibility, Mitogen-Activated Protein Kinases, business, Proto-Oncogene Proteins c-akt, Biomarkers, Signal Transduction
Abstract

Endometriosis is a benign, chronic inflammatory disease that commonly occurs in reproductive‐aged women. Epithelial‐mesenchymal transition (EMT) of endometrial epithelial cells plays an important role in the development of endometriosis. Recepteur d'origine nantais (RON), a receptor tyrosine kinase, has been reported to promote EMT and progression in tumours. However, whether and how RON mediates the EMT and endometriosis development is not known. Here, we found that RON activation could improve the migratory and invasive capabilities, change cellular morphologies, and decrease expression of E‐cadherin and increase expression of N‐cadherin in endometrial epithelial cells. Inhibition or knockdown of RON expression suppressed the migration and invasion of endometrial epithelial cells. Our studies also indicated that RON played its part in endometrial epithelial cells through protein kinase B (Akt) and mitogen‐activated protein kinase (MAPK) pathways. Treatment with a RON inhibitor could decrease the number of ectopic lesions in a mouse model of endometriosis and mediate expression of EMT markers in endometriotic lesions. These data suggest that RON contributed to endometriosis development by promoting EMT of endometrial epithelial cells. Therefore, RON may be a new therapeutic target for endometriosis.

Published
2021

50. Free CA125 promotes ovarian cancer cell migration and tumor metastasis by binding Mesothelin to reduce DKK1 expression and activate the SGK3/FOXO3 pathway

Author

Chen Xu, Qin Yu, Qianyu Huo, Lunhui Huang, Huijing Bao, Yanhong Shao, and Yunde Liu

Subjects
endocrine system diseases, MSLN, Protein Serine-Threonine Kinases, Applied Microbiology and Biotechnology, Metastasis, CA125, 03 medical and health sciences, Ovarian tumor, Cell Movement, Cell Line, Tumor, medicine, Humans, Mesothelin, Neoplasm Metastasis, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Ovarian Neoplasms, therapy, 0303 health sciences, biology, DKK1, business.industry, Carcinoma, Forkhead Box Protein O3, Membrane Proteins, Cell migration, Cell Biology, medicine.disease, female genital diseases and pregnancy complications, ovarian cancer, Apoptosis, CA-125 Antigen, biology.protein, Cancer research, Intercellular Signaling Peptides and Proteins, Female, Signal transduction, Ovarian cancer, business, Research Paper, Developmental Biology
Abstract

Objective: CA125/MUC16 is an O-glycosylated protein that is expressed on the surfaces of ovarian epithelial cells. This molecule is a widely used tumor-associated marker for diagnosis of ovarian cancer. Recently, CA125 was shown to be involved in ovarian cancer metastasis. The purpose of this study was to investigate the mechanism of CA125 during ovarian cancer metastasis. Methods: We analyzed the Oncomine and CSIOVDB databases to determine the expression levels of DKK1 in ovarian cancer. DKK1 expression levels were upregulated or downregulated and applied with CA125 to Transwell and Western blot assays to ascertain the underlying mechanism by which CA125 stimulates cell migration via the SGK3/FOXO3 pathway. Anti-mesothelin antibodies (anti-MSLN) were used to block CA125 stimulation. Then the expression levels of DKK1were tested by enzyme-linked immunosorbent assay (ELISA) to eliminate the blocking effect of anti-MSLN to CA125 stimulation. Xenograft mouse models were used to detect the effects of CA125 and anti-MSLN on ovarian cancer metastasis in vivo. Results: DKK1 levels were downregulated in ovarian tumor tissues according to the analyses of two databases and significantly correlated with FIGO stage, grade and disease-free survival in ovarian cancer patients. DKK1 levels were downregulated by CA125 stimulation in vitro. Overexpression of DKK1 reversed the ability of exogenous CA125 to mediate cell migration by activating the SGK3/FOXO3 signaling pathway. Anti-MSLN abrogated the DKK1 reduction and increased the apoptosis of ovarian cancer cells. The use of anti-MSLN in xenograft mouse models significantly reduced tumor growth and metastasis accelerated by CA125. Conclusions: These experiments revealed that the SGK3/FOXO3 pathway was activated, wherein decreased expression of DKK1 was caused by CA125, which fuels ovarian cancer cell migration. Mesothelin is a potential therapeutic target for the treatment of ovarian cancer metastasis.

Published
2021

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