Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection
Xin Zou, Ke Chen, Jiawei Zou, Peiyi Han, Jie Hao, Zeguang Han
Front. Med.    2020, 14 (2): 185-192.   https://doi.org/10.1007/s11684-020-0754-0
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It has been known that, the novel coronavirus, 2019-nCoV, which is considered similar to SARS-CoV, invades human cells via the receptor angiotensin converting enzyme II (ACE2). Moreover, lung cells that have ACE2 expression may be the main target cells during 2019-nCoV infection. However, some patients also exhibit non-respiratory symptoms, such as kidney failure, implying that 2019-nCoV could also invade other organs. To construct a risk map of different human organs, we analyzed the single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems, including the respiratory, cardiovascular, digestive, and urinary systems. Through scRNA-seq data analyses, we identified the organs at risk, such as lung, heart, esophagus, kidney, bladder, and ileum, and located specific cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, ileum and esophagus epithelial cells, and bladder urothelial cells), which are vulnerable to 2019-nCoV infection. Based on the findings, we constructed a risk map indicating the vulnerability of different organs to 2019-nCoV infection. This study may provide potential clues for further investigation of the pathogenesis and route of 2019-nCoV infection.

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Coronavirus disease 2019 (COVID-19): a clinical update
Min Zhou, Xinxin Zhang, Jieming Qu
Front. Med.    2020, 14 (2): 126-135.   https://doi.org/10.1007/s11684-020-0767-8
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Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a significant threat to global health. It caused a total of 80 868 confirmed cases and 3101 deaths in Chinese mainland until March 8, 2020. This novel virus spread mainly through respiratory droplets and close contact. As disease progressed, a series of complications tend to develop, especially in critically ill patients. Pathological findings showed representative features of acute respiratory distress syndrome and involvement of multiple organs. Apart from supportive care, no specific treatment has been established for COVID-19. The efficacy of some promising antivirals, convalescent plasma transfusion, and tocilizumab needs to be investigated by ongoing clinical trials.

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Cited: Crossref(69) WebOfScience(51)
Back to the spring of 2020: facts and hope of COVID-19 outbreak
Guangbiao Zhou, Saijuan Chen, Zhu Chen
Front. Med.    2020, 14 (2): 113-116.   https://doi.org/10.1007/s11684-020-0758-9
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2019 novel coronavirus outbreak: a quiz or final exam?
Jiuyang Xu, Yijun Chen, Hao Chen, Bin Cao
Front. Med.    2020, 14 (2): 225-228.   https://doi.org/10.1007/s11684-020-0753-1
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The 2019 novel coronavirus (2019-nCoV) is an emerging pathogen and is threatening the global health. Strikingly, more than 28 000 cases and 550 deaths have been reported within two months from disease emergence. Armed with experience from previous epidemics in the last two decades, clinicians, scientists, officials, and citizens in China are all contributing to the prevention of further 2019-nCoV transmission. Efficient preliminary work has enabled us to understand the basic characteristics of 2019-nCoV, but there are still many unanswered questions. It is too early now to judge our performance in this outbreak. Continuous and strengthened efforts should be made not only during the epidemic, but also afterwards in order to prepare for any incoming challenges.

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Prevention and treatment of pancreatic fistula after pancreatic body and tail resection: current status and future directions
Li Jiang, Deng Ning, Xiao-ping Chen
Front. Med.    2020, 14 (3): 251-261.   https://doi.org/10.1007/s11684-019-0727-3
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Postoperative pancreatic fistula (POPF) is the most common and critical complication after pancreatic body and tail resection. How to effectively reduce the occurrence of pancreatic fistula and conduct timely treatment thereafter is an urgent clinical issue to be solved. Recent research standardized the definition of pancreatic fistula and stressed the correlation between POPF classification and patient prognosis. According to the literature, identification of the risk factors for pancreatic fistula contributed to lowering the rate of the complication. Appropriate management of the pancreatic stump and perioperative treatment are of great significance to reduce the rate of POPF in clinical practice. After the occurrence of POPF, the treatment of choice should be determined according to the classification of the pancreatic fistula. However, despite the progress and promising treatment approaches, POPF remains to be a clinical issue that warrants further studies in the future.

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COVID-19 containment: China provides important lessons for global response
Shuxian Zhang, Zezhou Wang, Ruijie Chang, Huwen Wang, Chen Xu, Xiaoyue Yu, Lhakpa Tsamlag, Yinqiao Dong, Hui Wang, Yong Cai
Front. Med.    2020, 14 (2): 215-219.   https://doi.org/10.1007/s11684-020-0766-9
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The world must act fast to contain wider international spread of the epidemic of COVID-19 now. The unprecedented public health efforts in China have contained the spread of this new virus. Measures taken in China are currently proven to reduce human-to-human transmission successfully. We summarized the effective intervention and prevention measures in the fields of public health response, clinical management, and research development in China, which may provide vital lessons for the global response. It is really important to take collaborative actions now to save more lives from the pandemic of COVID-19.

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Combination of western medicine and Chinese traditional patent medicine in treating a family case of COVID-19
Li Ni, Ling Zhou, Min Zhou, Jianping Zhao, Dao Wen Wang
Front. Med.    2020, 14 (2): 210-214.   https://doi.org/10.1007/s11684-020-0757-x
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In December 2019, an outbreak of novel coronavirus (2019-nCoV) occurred in Wuhan, Hubei Province, China. By February 14, 2020, it has led to 66 492 confirmed patients in China and high mortality up to ~2.96% (1123/37 914) in Wuhan. Here we report the first family case of coronavirus disease 2019 (COVID-19) confirmed in Wuhan and treated using the combination of western medicine and Chinese traditional patent medicine Shuanghuanglian oral liquid (SHL). This report describes the identification, diagnosis, clinical course, and management of three cases from a family, suggests the expected therapeutic effects of SHL on COVID-19, and warrants further clinical trials.

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Tprn is essential for the integrity of stereociliary rootlet in cochlear hair cells in mice
Yuqin Men, Xiujuan Li, Hailong Tu, Aizhen Zhang, Xiaolong Fu, Zhishuo Wang, Yecheng Jin, Congzhe Hou, Tingting Zhang, Sen Zhang, Yichen Zhou, Boqin Li, Jianfeng Li, Xiaoyang Sun, Haibo Wang, Jiangang Gao
Front. Med.    2019, 13 (6): 690-704.   https://doi.org/10.1007/s11684-018-0638-8
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Tprn encodes the taperin protein, which is concentrated in the tapered region of hair cell stereocilia in the inner ear. In humans, TPRN mutations cause autosomal recessive nonsyndromic deafness (DFNB79) by an unknown mechanism. To determine the role of Tprn in hearing, we generated Tprn-null mice by clustered regularly interspaced short palindromic repeat/Cas9 genome-editing technology from a CBA/CaJ background. We observed significant hearing loss and progressive degeneration of stereocilia in the outer hair cells of Tprn-null mice starting from postnatal day 30. Transmission electron microscopy images of stereociliary bundles in the mutant mice showed some stereociliary rootlets with curved shafts. The central cores of the stereociliary rootlets possessed hollow structures with surrounding loose peripheral dense rings. Radixin, a protein expressed at stereocilia tapering, was abnormally dispersed along the stereocilia shafts in Tprn-null mice. The expression levels of radixin and β-actin significantly decreased. We propose that Tprn is critical to the retention of the integrity of the stereociliary rootlet. Loss of Tprn in Tprn-null mice caused the disruption of the stereociliary rootlet, which resulted in damage to stereociliary bundles and hearing impairments. The generated Tprn-null mice are ideal models of human hereditary deafness DFNB79.

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China’s local governments are combating COVID-19 with unprecedented responses ---- from a Wenzhou governance perspective
Fanghua Gong, Yong Xiong, Jian Xiao, Li Lin, Xiaodong Liu, Dezhong Wang, Xiaokun Li
Front. Med.    2020, 14 (2): 220-224.   https://doi.org/10.1007/s11684-020-0755-z
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The COVID-19 caused by a novel strain of coronavirus has been spreading rapidly since its occurrence in December 2019. It is highly communicable through human-to-human transmission. China has been making unprecedented efforts in treating the confirmed cases, identifying and isolating their close contacts and suspected cases to control the source of infection and cut the route of transmission. China’s devotion in handling this epidemic has effectively and efficiently curbed communication domestically and across the border. Representative measures adopted by Wenzhou, the worst hit city out of Hubei Province, are examined to elucidate those massive undertakings with the aim of enhancing international understanding and building global rapport in fighting this evolving epidemic situation.

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Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies
Guangbiao Zhou, Saijuan Chen, Zhu Chen
Front. Med.    2020, 14 (2): 117-125.   https://doi.org/10.1007/s11684-020-0773-x
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Since the outbreak of the COVID-19 pandemic in early December 2019, 81 174 confirmed cases and 3242 deaths have been reported in China as of March 19, 2020. The Chinese people and government have contributed huge efforts to combat this disease, resulting in significant improvement of the situation, with 58 new cases (34 were imported cases) and 11 new deaths reported on March 19, 2020. However, as of March 19, 2020, the COVID-19 pandemic continues to develop in 167 countries/territories outside of China, and 128 665 confirmed cases and 5536 deaths have been reported, with 16 498 new cases and 817 new deaths occurring in last 24 hours. Therefore, the world should work together to fight against this pandemic. Here, we review the recent advances in COVID-19, including the insights in the virus, the responses of the host cells, the cytokine release syndrome, and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm. By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis, we believe that the community can efficiently develop effective vaccines and drugs, and the mankind will eventually win this battle against this pandemic.

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Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer
Yanfei Zhang, Xinchun Zhao, Yongchun Zhou, Min Wang, Guangbiao Zhou
Front. Med.    2020, 14 (3): 318-326.   https://doi.org/10.1007/s11684-019-0708-6
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In order to unveil ubiquitin pathway genes (UPGs) that are essential for non-small cell lung cancer (NSCLC) cell proliferation, we recently conducted a siRNA screening experiment to knockdown the expression of 696 UPGs found in the human genome in A549 and H1975 NSCLC cells. We found that silencing of one of the candidates, RFWD3 that encodes an E3 ubiquitin ligase essential for the repair of DNA interstrand cross-links in response to DNA damage, led to dramatic inhibition of NSCLC cell proliferation with significant Z-scores. Knockdown of RFWD3 suppressed colony forming activity of NSCLC cells. We further evaluated the significance of RFWD3 in NSCLCs and found that this gene was more elevated in tumor samples than in paired normal lung tissues and was inversely associated with the clinical outcome of patients with NSCLC. Moreover, RFWD3 expression was significantly higher in smokers than in non-smokers. These results show for the first time that RFWD3 is required for NSCLC cell proliferation and may have an important role in lung carcinogenesis.

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Protecting healthcare personnel from 2019-nCoV infection risks: lessons and suggestions
Zhiruo Zhang, Shelan Liu, Mi Xiang, Shijian Li, Dahai Zhao, Chaolin Huang, Saijuan Chen
Front. Med.    2020, 14 (2): 229-231.   https://doi.org/10.1007/s11684-020-0765-x
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The outbreak of a novel coronavirus disease (COVID-19, caused by the 2019-nCoV infection) in December 2019 is one of the most severe public health emergencies since the founding of People’s Republic of China in 1949. Healthcare personnel (HCP) nationwide are facing heavy workloads and high risk of infection, especially those who care for patients in Hubei Province. Sadly, as of February 20, 2020, over two thousand COVID-19 cases are confirmed among HCP from 476 hospitals nationwide, with nearly 90% of them from Hubei Province. Based on literature search and interviews with some HCP working at Wuhan, capital city of Hubei, we have summarized some of the effective measures taken to reduce infection among HCP, and also made suggestions for improving occupational safety during an infectious disease outbreak. The experience and lessons learned should be a valuable asset for international health community to contain the ongoing COVID-19 epidemic around the world.

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Cited: Crossref(21) WebOfScience(18)
Clinical characteristics of 19 neonates born to mothers with COVID-19
Wei Liu, Jing Wang, Wenbin Li, Zhaoxian Zhou, Siying Liu, Zhihui Rong
Front. Med.    2020, 14 (2): 193-198.   https://doi.org/10.1007/s11684-020-0772-y
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The aim of this study was to investigate the clinical characteristics of neonates born to SARS-CoV-2 infected mothers and increase the current knowledge on the perinatal consequences of COVID-19. Nineteen neonates were admitted to Tongji Hospital from January 31 to February 29, 2020. Their mothers were clinically diagnosed or laboratory-confirmed with COVID-19. We prospectively collected and analyzed data of mothers and infants. There are 19 neonates included in the research. Among them, 10 mothers were confirmed COVID-19 by positive SARS-CoV-2 RT-PCR in throat swab, and 9 mothers were clinically diagnosed with COVID-19. Delivery occurred in an isolation room and neonates were immediately separated from the mothers and isolated for at least 14 days. No fetal distress was found. Gestational age of the neonates was 38.6±1.5 weeks, and average birth weight was 3293±425 g. SARS-CoV-2 RT-PCR in throat swab, urine, and feces of all neonates were negative. SARS-CoV-2 RT-PCR in breast milk and amniotic fluid was negative too. None of the neonates developed clinical, radiologic, hematologic, or biochemical evidence of COVID-19. No vertical transmission of SARS-CoV-2 and no perinatal complications in the third trimester were found in our study. The delivery should occur in isolation and neonates should be separated from the infected mothers and care givers.

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NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation inhibition
Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li
Front. Med.    2019, 13 (6): 646-657.   https://doi.org/10.1007/s11684-018-0643-y
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NES1 gene is thought to be a tumor-suppressor gene. Our previous study found that overexpression of NES1 gene in PC3 cell line could slow down the tumor proliferation rate, associated with a mild decrease in BCL-2 expression. The BCL-2 decrease could increase the sensitivity of radiotherapy to tumors. Thus, we supposed to have an “enhanced firepower” effect by combining overexpressed NES1 gene therapy and 131I radiation therapy uptake by overexpressed hNIS protein. We found a weak endogenous expression of hNIS protein in PC3 cells and demonstrated that the low expression of hNIS protein in PC3 cells might be the reason for the low iodine uptake. By overexpressing hNIS in PC3, the radioactive iodine uptake ability was significantly increased. Results of in vitro and in vivo tumor proliferation experiments and 18F-fluorothymidine (18F-FLT) micro-positron emission tomography/computed tomography (micro-PET/CT) imaging showed that the combined NES1 gene therapy and 131I radiation therapy mediated by overexpressed hNIS protein had the best tumor proliferative inhibition effect. Immunohistochemistry showed an obvious decrease of Ki-67 expression and the lowest BCL-2 expression. These data suggest that via inhibition of BCL-2 expression, overexpressed NES1 might enhance the effect of radiation therapy of 131I uptake in hNIS overexpressed PC3 cells.

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What will the future hold for artificial organs in the service of assisted reproduction: prospects and considerations
Mara Simopoulou, Konstantinos Sfakianoudis, Petroula Tsioulou, Anna Rapani, Polina Giannelou, Nikolaos Kiriakopoulos, Agni Pantou, Nikolaos Vlahos, George Anifandis, Stamatis Bolaris, Konstantinos Pantos, Michael Koutsilieris
Front. Med.    2019, 13 (6): 627-638.   https://doi.org/10.1007/s11684-019-0697-5
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Assisted reproduction provides a wide spectrum of treatments and strategies addressing infertility. However, distinct groups of infertile patients with unexplained infertility, congenital disorders, and other complex cases pose a challenge in in vitro fertilization (IVF) practices. This special cohort of patients is associated with futile attempts, IVF overuse, and dead ends in management. Cutting edge research on animal models introduced this concept, along with the development of artificial organs with the aim to mimic the respective physiological functions in reproduction. Extrapolation on clinical application leads to the future use of infertility management in humans. To date, the successful clinical application of artificial reproductive organs in humans is not feasible because further animal model studies are required prior to clinical trials. The application of these artificial organs could provide a solution to infertility cases with no other options. This manuscript presents an overview on the current status, future prospects, and considerations on the potential clinical application of artificial ovary, uterus, and gametes in humans. This paper presents how the IVF practice landscape may be shaped and challenged in the future, along with the subsequent concerns in assisted reproductive treatments.

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White blood cell count and the incidence of hyperuricemia: insights from a community-based study
Jian Liu, Pingyan Shen, Xiaobo Ma, Xialian Yu, Liyan Ni, Xu Hao, Weiming Wang, Nan Chen
Front. Med.    2019, 13 (6): 741-746.   https://doi.org/10.1007/s11684-017-0579-7
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Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). The relationship between HUA and white blood cell (WBC) count remains unknown. A sampling survey for CKD was conducted in Sanlin community in 2012 and 2014. CKD was defined as proteinuria in at least the microalbuminuric stage or an estimated GFR of 60 mL/(min·1.73 m2). HUA was defined as serum uric acid>420 µmol/L in men and>360 µmol/L in women. This study included 1024 participants. The prevalence of HUA was 17.77%. Patients with HUA were more likely to have higher levels of WBC count, which was positively associated with HUA prevalence. This association was also observed in participants without CKD, diabetes mellitus, hyperlipidemia, or obesity. Multivariate logistic regression analysis showed that WBC count was independently associated with the risk for HUA in male and female participants. Compared with participants without HUA, inflammatory factors such as high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin 6 increased in participants with HUA. Hence, WBC count is positively associated with HUA, and this association is independent of conventional risk factors for CKD.

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Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer
Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu
Front. Med.    2020, 14 (1): 60-67.   https://doi.org/10.1007/s11684-019-0694-8
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Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

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Long-term effects of various types of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on changes in glomerular filtration rate in Korea
Seo Yeon Baik, Hyunah Kim, So Jung Yang, Tong Min Kim, Seung-Hwan Lee, Jae Hyoung Cho, Hyunyong Lee, Hyeon Woo Yim, Kun-Ho Yoon, Hun-Sung Kim
Front. Med.    2019, 13 (6): 713-722.   https://doi.org/10.1007/s11684-018-0661-9
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Few long-term follow-up studies have compared the changes in renal function according to the type of statin used in Korea. We compared the long-term effects of statin intensity and type on the changes in the glomerular filtration rate (GFR). We extracted data of patients who took statin for the first time. We analyzed whether or not different statins affect the changes in GFR at 3 months after baseline and 4 years after. We included 3678 patients and analyzed the changes in GFR. The GFR decreased by 3.2%±0.4% on average 4 years after the first statin prescription, indicating statistically significant deterioration (from 83.5±0.4 mL/min/1.73 m2 to 79.9±0.4 mL/min/1.73 m2, P<0.001). When comparing the GFR among different statins, significant differences were observed between atorvastatin and fluvastatin (−5.3%±0.7% vs. 1.2%±2.2%, P<0.05) and between atorvastatin and simvastatin (−5.3%±0.7% vs. −0.7%±0.8%, P<0.05). In pitavastatin (odds ratio [OR]=0.64, 95% confidence interval [CI]=0.46–0.87, P<0.005) and simvastatin (OR=0.69, 95% CI=0.53–0.91, P<0.008), the GFR rate that decreased by<60 mL/min/1.73 m2 was significantly lower than that of atorvastatin. Regarding long-term statin intake, GFR changed with the type of statin. This work is the first in Korea to compare each statin in terms of changes in the GFR after the statin prescription.

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Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome
Qiqi Zhao, Xin Gao, Guangli Yan, Aihua Zhang, Hui Sun, Ying Han, Wenxiu Li, Liang Liu, Xijun Wang
Front. Med.    2020, 14 (3): 335-356.   https://doi.org/10.1007/s11684-019-0705-9
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Sijunzi decoction (SJZD) is a Chinese classical formula to treat spleen qi deficiency syndrome (SQDS) and has been widely used for thousands of years. However, the quality control (QC) standards of SJZD are insufficient. Chinmedomics has been designed to discover and verify bioactive compounds of a variety of formula rapidly. In this study, we used Chinmedomics to evaluate the SJZD’s efficacy against SQDS to discover the potential quality-markers (q-markers) for QC. A total of 56 compounds in SJZD were characterized in vitro, and 23 compounds were discovered in vivo. A total of 58 biomarkers were related to SQDS, and SJZD can adjust a large proportion of marker metabolites to normal level and then regulate the metabolic profile to the health status. A total of 10 constituents were absorbed as effective ingredients that were associated with overall efficacy. We preliminarily determined malonyl-ginsenoside Rb2 and ginsenoside Ro as the q-markers of ginseng; dehydrotumulosic acid and dihydroxy lanostene-triene-21-acid as the q-markers of poria; glycyrrhizic acid, isoglabrolide, and glycyrrhetnic acid as the q-markers of licorice; and 2-atractylenolide as the q-marker of macrocephala. According to the discovery of the SJZD q-markers, we can establish the quality standard that is related to efficacy.

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Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit
Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li
Front. Med.    2020, 14 (1): 101-111.   https://doi.org/10.1007/s11684-019-0698-4
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Growing evidence suggests that somatic hypermutational status and programmed cell death-1 overexpression are potential predictive biomarkers indicating treatment benefits from immunotherapy using immune checkpoint inhibitors. However, biomarker-matched trials are still limited, and many of the genomic alterations remain difficult to target. To isolate the potential somatic hypermutational tumor from microsatellite instability low/microsatellite stability (MSI-L/MSS) cases, we employed two commercial kits to determine MSI and forensic short tandem repeat (STR) alternations in 250 gastrointestinal (GI) tumors. Three types of forensic STR alternations, namely, allelic loss, Aadd, and Anew, were identified. 62.4% (156/250) of the patients with GI exhibited STR alternation, including 100% (15/15) and 60% (141/235) of the microsatellite high instability and MSI-L/MSS cases, respectively. 30% (75/250) of the patients exhibited STR instability with more than 26.32% (26.32%–84.21%) STR alternation. The cutoff with 26.32% of the STR alternations covered all 15 MSI cases and suggested that it might be a potential threshold. Given the similar mechanism of the mutations of MSI and forensic STR, the widely used forensic identifier STR kit might provide potential usage for identifying hypermutational status in GI cancers.

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Development of oncolytic virotherapy: from genetic modification to combination therapy
Qiaoshuai Lan, Shuai Xia, Qian Wang, Wei Xu, Haiyan Huang, Shibo Jiang, Lu Lu
Front. Med.    2020, 14 (2): 160-184.   https://doi.org/10.1007/s11684-020-0750-4
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Oncolytic virotherapy (OVT) is a novel form of immunotherapy using natural or genetically modified viruses to selectively replicate in and kill malignant cells. Many genetically modified oncolytic viruses (OVs) with enhanced tumor targeting, antitumor efficacy, and safety have been generated, and some of which have been assessed in clinical trials. Combining OVT with other immunotherapies can remarkably enhance the antitumor efficacy. In this work, we review the use of wild-type viruses in OVT and the strategies for OV genetic modification. We also review and discuss the combinations of OVT with other immunotherapies.

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Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia
Meng Lv, Xiaohui Zhang, Lanping Xu, Yu Wang, Chenhua Yan, Huan Chen, Yuhong Chen, Wei Han, Fengrong Wang, Jingzhi Wang, Kaiyan Liu, Xiaojun Huang, Xiaodong Mo
Front. Med.    2019, 13 (6): 667-679.   https://doi.org/10.1007/s11684-019-0702-z
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Chronic graft-versus-host disease (cGVHD) is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia (n=280). The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria. A total of 169 patients suffered from cGVHD. The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD (total, 66.0% vs. 53.7%, P=0.031; moderate to severe, 42.4% vs. 30.1%, P=0.036) than the patients who had 1 to 2 loci mismatched. The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD (49.2% vs. 32.9%, P=0.024) compared with the patients who had other donors. The patients who had grades III to IV acute GVHD (aGVHD) had higher 8-year incidence of cGVHD (total, 88.0% vs. 50.4%, P<0.001; moderate to severe, 68.0% vs. 27.0%, P<0.001) compared with the patients without aGVHD. In multivariate analysis, grades III to IV aGVHD was the only independent risk factor for cGVHD. Thus, further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

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New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions
Yuan Gao, Zhilei Wang, Jinfa Tang, Xiaoyi Liu, Wei Shi, Nan Qin, Xiaoyan Wang, Yu Pang, Ruisheng Li, Yaming Zhang, Jiabo Wang, Ming Niu, Zhaofang Bai, Xiaohe Xiao
Front. Med.    2020, 14 (1): 68-80.   https://doi.org/10.1007/s11684-019-0690-z
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Epimedii Folium (EF) combined with Psoraleae Fructus (PF) is a common modern preparation, but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years. Zhuangguguanjiewan pills (ZGW), which contain EF and PF, could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide (LPS) model. This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model. Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats; however, EF or PF alone could lead to liver injury in LPS-treated rats. Moreover, EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats. Furthermore, EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production, implying that IL-1β, which is processed and released by activating the NLRP3 inflammasome, is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity. Thus, EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome. In addition, the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model, suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways. Therefore, EF and PF combination indicates traditional Chinese medicine incompatibility, considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.

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Temporal echocardiography findings in patients with fulminant myocarditis: beyond ejection fraction decline
Houjuan Zuo, Rui Li, Fei Ma, Jiangang Jiang, Kun Miao, Haojie Li, Eike Nagel, Marijana Tadic, Hong Wang, Dao Wen Wang
Front. Med.    2020, 14 (3): 284-292.   https://doi.org/10.1007/s11684-019-0713-9
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The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients. In this study, changes in the left ventricular ejection fraction (LVEF) and global and layer-specific myocardial strains over time were monitored. We aimed to determine the echocardiographic patterns of FM and ascertain their significance in FM treatment. Twenty patients who were clinically diagnosed with FM and received mechanical life support were prospectively enrolled. Conventional echocardiographic measurements were obtained, and serial strain echocardiography was performed from admission to hospital discharge until LVEF recovery (>50%). Global/regional peak systolic longitudinal strains (GLS/RLS) and layer-specific longitudinal strains were quantified, and their changes with time were monitored in 14 FM patients. All patients had severely impaired cardiac function. Steep improvement in LVEF and GLS were observed within 6 days. Layer-specific strain analysis showed that reduction at admission or recovery at discharge in the endocardium and epicardium strains were equal. In conclusion, FM patients who received mechanical circulatory supports exhibited steep improvement in ventricular function within 6 days. The patchy and diffused distribution pattern of reduced RLS and equally and severely impaired strain in the endocardium and epicardium are valuable features in the diagnosis of FM.

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The epidemiology of norovirus gastroenteritis in China: disease burden and distribution of genotypes
Honglu Zhou, Songmei Wang, Lorenz von Seidlein, Xuanyi Wang
Front. Med.    2020, 14 (1): 1-7.   https://doi.org/10.1007/s11684-019-0733-5
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With the improvements of sanitation and nationwide safe water supply the occurrence of bacterial diarrhea declined remarkably, while viruses became the leading causes of acute gastroenteritis (AGE). Of these viruses, noroviruses (NoVs) are responsible for a considerable burden of gastroenteritis, especially in children<2 years and elderly≥65 years. NoVs circulating in the Chinese population are antigenically highly diverse with the genotype GII.4 being the dominant strain followed by GII.3. Given the widespread contamination in environmental sources, and highly infectious nature of NoVs, vaccination would be the desirable strategy for the control of NoV infections. However, a better understanding of acquired immunity after infection, and a reliable immunological surrogate marker are urgently needed, since two vaccine candidates based on virus-like particles (VLPs) are currently moving into clinical evaluations in China.

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New spinal robotic technologies
Bowen Jiang, Tej D. Azad, Ethan Cottrill, Corinna C. Zygourakis, Alex M. Zhu, Neil Crawford, Nicholas Theodore
Front. Med.    2019, 13 (6): 723-729.   https://doi.org/10.1007/s11684-019-0716-6
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Robotic systems in surgery have developed rapidly. Installations of the da Vinci Surgical System® (Intuitive Surgical, Sunnyvale, CA,, USA), widely used in urological and gynecological procedures, have nearly doubled in the United States from 2010 to 2017. Robotics systems in spine surgery have been adopted more slowly; however, users are enthusiastic about their applications in this subspecialty. Spinal surgery often requires fine manipulation of vital structures that must be accessed via limited surgical corridors and can require repetitive tasks over lengthy periods of time — issues for which robotic assistance is well-positioned to complement human ability. To date, the United States Food and Drug Administration (FDA) has approved 7 robotic systems across 4 companies for use in spinal surgery. The available clinical data evaluating their efficacy have generally demonstrated these systems to be accurate and safe. A critical next step in the broader adoption of surgical robotics in spine surgery is the design and implementation of rigorous comparative studies to interrogate the utility of robotic assistance. Here we discuss current applications of robotics in spine surgery, review robotic systems FDA-approved for use in spine surgery, summarize randomized controlled trials involving robotics in spine surgery, and comment on prospects of robotic-assisted spine surgery.

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Plasma soluble C-type lectin-like receptor-2 is associated with the risk of coronary artery disease
Min Fei, Li Xiang, Xichen Chai, Jingchun Jin, Tao You, Yiming Zhao, Changgeng Ruan, Yiwen Hao, Li Zhu
Front. Med.    2020, 14 (1): 81-90.   https://doi.org/10.1007/s11684-019-0692-x
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Accumulating evidence suggests that C-type lectin-like receptor-2 (CLEC-2) plays an important role in atherothrombosis. In this case-control study, we investigated the association between CLEC-2 and incidence of coronary artery disease (CAD). A total of 216 patients, including 14 cases of stable angina pectoris (SAP, non-ACS) and 202 cases of acute coronary syndrome (ACS), and 89 non-CAD control subjects were enrolled. Plasma levels of soluble CLEC-2 (sCLEC-2) were measured using the enzyme-linked immunosorbent assay (ELISA). Compared with the control group (65.69 (55.36–143.22) pg/mL), the plasma levels of sCLEC-2 were significantly increased in patients with CAD (133.67 (88.76–220.09) pg/mL) and ACS (134.16 (88.88–225.81) pg/mL). The multivariate adjusted odds ratios (95% confidence interval) of CAD reached 2.01 (1.52–2.66) (Ptrend<0.001) for each 1-quartile increase in sCLEC-2. Restricted cubic splines showed a positive dose-response association between sCLEC2 and CAD incidence (Plinearity<0.001). The addition of sCLEC-2 to conventional risk factors improved the C statistic (0.821 vs. 0.761, P = 0.004) and reclassification ability (net reclassification improvement: 57.45%, P<0.001; integrated discrimination improvement: 8.27%, P<0.001) for CAD. In conclusion, high plasma sCLEC-2 is independently associated with CAD risk, and the prognostic value of sCLEC-2 may be evaluated in future prospective studies.

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Phase- and epidemic region-adjusted estimation of the number of coronavirus disease 2019 cases in China
Ruijie Chang, Huwen Wang, Shuxian Zhang, Zezhou Wang, Yinqiao Dong, Lhakpa Tsamlag, Xiaoyue Yu, Chen Xu, Yuelin Yu, Rusi Long, Ning-Ning Liu, Qiao Chu, Ying Wang, Gang Xu, Tian Shen, Suping Wang, Xiaobei Deng, Jinyan Huang, Xinxin Zhang, Hui Wang, Yong Cai
Front. Med.    2020, 14 (2): 199-209.   https://doi.org/10.1007/s11684-020-0768-7
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The outbreak of the coronavirus disease 2019 in China was first reported in Wuhan in December 2019 and gradually spread to other areas in China. After implementation of prevention and control measures, the estimation of the epidemic trend is needed. A phase- and region-adjusted SEIR model was applied for modeling and predicting the number of cases in Wuhan, Hubei Province and regions outside Hubei Province in China. The estimated number of infections could reach its peak in late February 2020 in Wuhan and Hubei Province, which is 55 303–84 520 and 83 944–129 312, respectively, while the epidemic peaks in regions outside Hubei Province in China could appear on February 13, 2020 with the estimated 13 035–19 108 cases. According to the estimation, the outbreak would abate in March and April all over China. Current estimation provided evidence for planned work resumption under stringent prevention and control in China to further support the fight against the epidemic. Nevertheless, there is still possibility of the second outbreak brought by the work resumption and population migration, especially from Hubei Province and high intensity cities outside Hubei Province. Strict prevention and control measures still need to be considered in the regions with high intensity of epidemic and densely-populated cities.

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Acetylated HOXB9 at lysine 27 is of differential diagnostic value in patients with pancreatic ductal adenocarcinoma
Xiaoran Sun, Jiagui Song, Jing Zhang, Jun Zhan, Weigang Fang, Hongquan Zhang
Front. Med.    2020, 14 (1): 91-100.   https://doi.org/10.1007/s11684-019-0696-6
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Pancreatic ductal adenocarcinoma (PDAC) is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China. AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification that can predict the outcome in lung adenocarcinoma and colon cancer well. However, the role of AcK27-HOXB9 in PDAC is unclear. The present study aims to investigate the differential diagnostic role of patients with AcK27-HOXB9 PDAC. Tissue microarrays consisting of 162 pancreatic tumor tissue samples from patients with PDAC and paired normal subjects were used to examine HOXB9 and AcK27-HOXB9 levels and localizations by immunohistochemical analysis and Western blot assay, respectively. HOXB9 was upregulated (P<0.0001), and AcK27-HOXB9 (P=0.0023) was downregulated in patients with PDAC. HOXB9 promoted (P=0.0115), while AcK27-HOXB9 (P=0.0279) inhibited PDAC progression. AcK27-HOXB9 predicted favorable outcome in patients with PDAC (P=0.0412). AcK27-HOXB9 also suppressed PDAC cell migration in a cell migration assay. The results of this study showed that HOXB9 promoted and AcK27-HOXB9 suppressed PDAC progression. The determination of ratio between HOXB9 and AcK27-HOXB9 exhibited potential diagnostic value in patients with PDAC.

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Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development
Hui Jiang, Shan Zeng, Wenli Ni, Yan Chen, Wenyan Li
Front. Med.    2019, 13 (6): 705-712.   https://doi.org/10.1007/s11684-019-0703-y
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Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells (HCs) and supporting cells during mouse inner ear development; however, the relationship between the two signaling pathways in the mouse cochlea remains largely unknown. Here, we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+ progenitors during different cochlear development stages. We found that the downregulation of Notch1 in Lgr5+ cells from embryonic day (E) 14.5 to E18.5 can drive the quiescent Lgr5+ cells to re-enter the cell cycle and differentiate into extra HCs, whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells. No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+ cells from E10.5 to E14.5. We concluded that the roles of Notch1 in Wnt-responsive Lgr5+ cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+ progenitor activation during cochlear differentiation. Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.

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