Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Host protection against Omicron BA.2.2 sublineages by prior vaccination in spring 2022 COVID-19 outbreak in Shanghai
Ziyu Fu, Dongguo Liang, Wei Zhang, Dongling Shi, Yuhua Ma, Dong Wei, Junxiang Xi, Sizhe Yang, Xiaoguang Xu, Di Tian, Zhaoqing Zhu, Mingquan Guo, Lu Jiang, Shuting Yu, Shuai Wang, Fangyin Jiang, Yun Ling, Shengyue Wang, Saijuan Chen, Feng Liu, Yun Tan, Xiaohong Fan
Front. Med.    2023, 17 (3): 562-575.   https://doi.org/10.1007/s11684-022-0977-3
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The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic. Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022. Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020, BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood. In particular, severe/critical cases of COVID-19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment. Importantly, the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototype-inactivated vaccines, supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records. Furthermore, even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection, vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged ≥ 60 years old. Together, our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.

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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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Cited: Crossref(1449) WebOfScience(1468)
Primary assessment of the diversity of Omicron sublineages and the epidemiologic features of autumn/winter 2022 COVID-19 wave in Chinese mainland
Gang Lu, Yun Ling, Minghao Jiang, Yun Tan, Dong Wei, Lu Jiang, Shuting Yu, Fangying Jiang, Shuai Wang, Yao Dai, Jinzeng Wang, Geng Wu, Xinxin Zhang, Guoyu Meng, Shengyue Wang, Feng Liu, Xiaohong Fan, Saijuan Chen
Front. Med.    2023, 17 (4): 758-767.   https://doi.org/10.1007/s11684-022-0981-7
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With the recent ongoing autumn/winter 2022 COVID-19 wave and the adjustment of public health control measures, there have been widespread SARS-CoV-2 infections in Chinese mainland. Here we have analyzed 369 viral genomes from recently diagnosed COVID-19 patients in Shanghai, identifying a large number of sublineages of the SARS-CoV-2 Omicron family. Phylogenetic analysis, coupled with contact history tracing, revealed simultaneous community transmission of two Omicron sublineages dominating the infections in some areas of China (BA.5.2 mainly in Guangzhou and Shanghai, and BF.7 mainly in Beijing) and two highly infectious sublineages recently imported from abroad (XBB and BQ.1). Publicly available data from August 31 to November 29, 2022 indicated an overall severe/critical case rate of 0.035% nationwide, while analysis of 5706 symptomatic patients treated at the Shanghai Public Health Center between September 1 and December 26, 2022 showed that 20 cases (0.35%) without comorbidities progressed into severe/critical conditions and 153 cases (2.68%) with COVID-19-exacerbated comorbidities progressed into severe/critical conditions. These observations shall alert healthcare providers to place more resources for the treatment of severe/critical cases. Furthermore, mathematical modeling predicts this autumn/winter wave might pass through major cities in China by the end of the year, whereas some middle and western provinces and rural areas would be hit by the upcoming infection wave in mid-to-late January 2023, and the duration and magnitude of upcoming outbreak could be dramatically enhanced by the extensive travels during the Spring Festival (January 21, 2023). Altogether, these preliminary data highlight the needs to allocate resources to early diagnosis and effective treatment of severe cases and the protection of vulnerable population, especially in the rural areas, to ensure the country’s smooth exit from the ongoing pandemic and accelerate socio-economic recovery.

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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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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
Abstract   HTML   PDF (951KB)

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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Lung function and air pollution exposure in adults with asthma in Beijing: a 2-year longitudinal panel study
Jun Wang, Wenshuai Xu, Xinlun Tian, Yanli Yang, Shao-Ting Wang, Kai-Feng Xu
Front. Med.    2022, 16 (4): 574-583.   https://doi.org/10.1007/s11684-021-0882-1
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The effect of air pollution on the lung function of adults with asthma remains unclear to date. This study followed 112 patients with asthma at 3-month intervals for 2 years. The pollutant exposure of the participants was estimated using the inverse distance weight method. The participants were divided into three groups according to their lung function level at every visit. A linear mixed-effect model was applied to predict the change in lung function with each unit change in pollution concentration. Exposure to carbon monoxide (CO) and particles less than 2.5 micrometers in diameter (PM2.5) was negatively associated with large airway function in participants. In the severe group, exposure to chronic sulfur dioxide (SO2) was negatively associated with post-bronchodilator forced expiratory flow at 50%, between 25% and 75% of vital capacity % predicted (change of 95% CI per unit: –0.34 (–0.55, –0.12), –0.24 (–0.44, –0.03), respectively). In the mild group, the effect of SO2 on the small airways was similar to that in the severe group, and it was negatively associated with large airway function. Exposure to CO and PM2.5 was negatively associated with the large airway function of adults with asthma. The negative effects of SO2 were more evident and widely observed in adults with severe and mild asthma than in adults with moderate asthma. Patients with asthma react differently to air pollutants as evidenced by their lung function levels.

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Deep learning in digital pathology image analysis: a survey
Shujian Deng, Xin Zhang, Wen Yan, Eric I-Chao Chang, Yubo Fan, Maode Lai, Yan Xu
Front. Med.    2020, 14 (4): 470-487.   https://doi.org/10.1007/s11684-020-0782-9
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deep learning (DL) has achieved state-of-the-art performance in many digital pathology analysis tasks. Traditional methods usually require hand-crafted domain-specific features, and DL methods can learn representations without manually designed features. In terms of feature extraction, DL approaches are less labor intensive compared with conventional machine learning methods. In this paper, we comprehensively summarize recent DL-based image analysis studies in histopathology, including different tasks (e.g., classification, semantic segmentation, detection, and instance segmentation) and various applications (e.g., stain normalization, cell/gland/region structure analysis). DL methods can provide consistent and accurate outcomes. DL is a promising tool to assist pathologists in clinical diagnosis.

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Applications of atomic force microscopy in immunology
Jiping Li, Yuying Liu, Yidong Yuan, Bo Huang
Front. Med.    2021, 15 (1): 43-52.   https://doi.org/10.1007/s11684-020-0769-6
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Cellular mechanics, a major regulating factor of cellular architecture and biological functions, responds to intrinsic stresses and extrinsic forces exerted by other cells and the extracellular matrix in the microenvironment. Cellular mechanics also acts as a fundamental mediator in complicated immune responses, such as cell migration, immune cell activation, and pathogen clearance. The principle of atomic force microscopy (AFM) and its three running modes are introduced for the mechanical characterization of living cells. The peak force tapping mode provides the most delicate and desirable virtues to collect high-resolution images of morphology and force curves. For a concrete description of AFM capabilities, three AFM applications are discussed. These applications include the dynamic progress of a neutrophil-extracellular-trap release by neutrophils, the immunological functions of macrophages, and the membrane pore formation mediated by perforin, streptolysin O, gasdermin D, or membrane attack complex.

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Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells
Guizhen Wang, Qun Zhao, Hui Zhang, Fan Liang, Chen Zhang, Jun Wang, Zhenyin Chen, Ran Wu, Hong Yu, Beibei Sun, Hua Guo, Ruie Feng, Kaifeng Xu, Guangbiao Zhou
Front. Med.    2021, 15 (2): 252-263.   https://doi.org/10.1007/s11684-021-0837-6
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An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%−18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.

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Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia
Sarah H. Alfaraj, Jaffar A. Al-Tawfiq, Talal A. Altuwaijri, Ziad A. Memish
Front. Med.    2019, 13 (1): 126-130.   https://doi.org/10.1007/s11684-017-0603-y
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Infection with Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 as an important respiratory disease with high fatality rates of 40%–60%. Despite the increased number of cases over subsequent years, the number of pediatric cases remained low. A review of studies conducted from June 2012 to April 19, 2016 reported 31 pediatric MERS-CoV cases. In this paper, we present the clinical and laboratory features of seven patients with pediatric MERS. Five patients had no underlying medical illnesses, and three patients were asymptomatic. Of the seven cases, four (57%) patients sought medical advice within 1–7 days from the onset of symptoms. The three other patients (43%) were asymptomatic and were in contact with patients with confirmed diagnosis of MERS-CoV. The most common presenting symptoms were fever (57%), cough (14%), shortness of breath (14%), vomiting (28%), and diarrhea (28%). Two (28.6%) patients had platelet counts of<150 × 109/L, and one patient had an underlying end-stage renal disease. The remaining patients presented with normal blood count, liver function, and urea and creatinine levels. The documented MERS-CoV Ct values were 32–38 for four of the seven cases. Two patients (28.6%) had abnormal chest radiographic findings of bilateral infiltration. One patient (14.3%) required ventilator support, and two patients (28.6%) required oxygen supplementation. All the seven patients were discharged without complications.

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Biological properties and clinical applications of berberine
Danyang Song, Jianyu Hao, Daiming Fan
Front. Med.    2020, 14 (5): 564-582.   https://doi.org/10.1007/s11684-019-0724-6
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Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, has a wide range of pharmacological properties. Berberine can be used to treat many diseases, such as cancer and digestive, metabolic, cardiovascular, and neurological diseases. Berberine has protective capacities in digestive diseases. It can inhibit toxins and bacteria, including Helicobacter pylori, protect the intestinal epithelial barrier from injury, and ameliorate liver injury. Berberine also inhibits the proliferation of various types of cancer cells and impedes invasion and metastasis. Recent evidence has confirmed that berberine improves the efficacy and safety of chemoradiotherapies. In addition, berberine regulates glycometabolism and lipid metabolism, improves energy expenditure, reduces body weight, and alleviates nonalcoholic fatty liver disease. Berberine also improves cardiovascular hemodynamics, suppresses ischemic arrhythmias, attenuates the development of atherosclerosis, and reduces hypertension. Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic. Furthermore, berberine exerts protective effects against other diseases. The mechanisms of its functions have been extensively explored, but much remains to be clarified. This article summarizes the main pharmacological actions of berberine and its mechanisms in cancer and digestive, metabolic, cardiovascular, and neurological diseases.

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Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2--) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials
Wenjie Zhu, Binghe Xu
Front. Med.    2021, 15 (2): 208-220.   https://doi.org/10.1007/s11684-020-0795-4
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New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR+/HER2-- advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR+/HER2-- ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR= 0.547, P<0.001), overall survival (pooled HR= 0.755, P<0.001), and tumor response rates (ORR, pooled OR= 1.478, P<0.001; CBR, pooled OR= 1.201, P<0.001) with manageable toxicities (pooled OR= 3.280, P<0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR= 0.686, P<0.001) yet pronounced toxicities (pooled OR=2.154, P<0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.

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Advances in tissue state recognition in spinal surgery: a review
Hao Qu, Yu Zhao
Front. Med.    2021, 15 (4): 575-584.   https://doi.org/10.1007/s11684-020-0816-3
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Spinal disease is an important cause of cervical discomfort, low back pain, radiating pain in the limbs, and neurogenic intermittent claudication, and its incidence is increasing annually. From the etiological viewpoint, these symptoms are directly caused by the compression of the spinal cord, nerve roots, and blood vessels and are most effectively treated with surgery. Spinal surgeries are primarily performed using two different techniques: spinal canal decompression and internal fixation. In the past, tactile sensation was the primary method used by surgeons to understand the state of the tissue within the operating area. However, this method has several disadvantages because of its subjectivity. Therefore, it has become the focus of spinal surgery research so as to strengthen the objectivity of tissue state recognition, improve the accuracy of safe area location, and avoid surgical injury to tissues. Aside from traditional imaging methods, surgical sensing techniques based on force, bioelectrical impedance, and other methods have been gradually developed and tested in the clinical setting. This article reviews the progress of different tissue state recognition methods in spinal surgery and summarizes their advantages and disadvantages.

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Application of artificial intelligence in surgery
Xiao-Yun Zhou, Yao Guo, Mali Shen, Guang-Zhong Yang
Front. Med.    2020, 14 (4): 417-430.   https://doi.org/10.1007/s11684-020-0770-0
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Artificial intelligence (AI) is gradually changing the practice of surgery with technological advancements in imaging, navigation, and robotic intervention. In this article, we review the recent successful and influential applications of AI in surgery from preoperative planning and intraoperative guidance to its integration into surgical robots. We conclude this review by summarizing the current state, emerging trends, and major challenges in the future development of AI in surgery.

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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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Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma
Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen
Front. Med.    2021, 15 (2): 275-291.   https://doi.org/10.1007/s11684-020-0779-4
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Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER=1.95, P=0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

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Linking key intervention timings to rapid declining effective reproduction number to quantify lessons against COVID-19
Zhihang Peng, Wenyu Song, Zhongxing Ding, Quanquan Guan, Xu Yang, Qiaoqiao Xu, Xu Wang, Yankai Xia
Front. Med.    2020, 14 (5): 623-629.   https://doi.org/10.1007/s11684-020-0788-3
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Coronavirus disease 2019 (COVID-19) is currently under a global pandemic trend. The efficiency of containment measures and epidemic tendency of typical countries should be assessed. In this study, the efficiency of prevention and control measures in China, Italy, Iran, South Korea, and Japan was assessed, and the COVID-19 epidemic tendency among these countries was compared. Results showed that the effective reproduction number(Re) in Wuhan, China increased almost exponentially, reaching a maximum of 3.98 before a lockdown and rapidly decreased to below 1 due to containment and mitigation strategies of the Chinese government. The Re in Italy declined at a slower pace than that in China after the implementation of prevention and control measures. The Re in Iran showed a certain decline after the establishment of a national epidemic control command, and an evident stationary phase occurred because the best window period for the prevention and control of the epidemic was missed. The epidemic in Japan and South Korea reoccurred several times with the Re fluctuating greatly. The epidemic has hardly rebounded in China due to the implementation of prevention and control strategies and the effective enforcement of policies. Other countries suffering from the epidemic could learn from the Chinese experience in containing COVID-19.

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Advances on immune-related adverse events associated with immune checkpoint inhibitors
Yong Fan, Yan Geng, Lin Shen, Zhuoli Zhang
Front. Med.    2021, 15 (1): 33-42.   https://doi.org/10.1007/s11684-019-0735-3
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Immunotherapy has recently led to a paradigm shift in cancer therapy, in which immune checkpoint inhibitors (ICIs) are the most successful agents approved for multiple advanced malignancies. However, given the nature of the non-specific activation of effector T cells, ICIs are remarkably associated with a substantial risk of immune-related adverse events (irAEs) in almost all organs or systems. Up to 90% of patients who received ICIs combination therapy experienced irAEs, of which majority were low-grade toxicity. Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs. In this review, the mechanisms of action of ICIs and how they may cause irAEs are described. Some unsolved challenges, however really engrossing issues, such as the association between irAEs and cancer treatment response, tumor response to irAEs therapy, and ICIs in challenging populations, are comprehensively summarized.

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Long non-coding RNA SAP30-2:1 is downregulated in congenital heart disease and regulates cell proliferation by targeting HAND2
Jing Ma, Shiyu Chen, Lili Hao, Wei Sheng, Weicheng Chen, Xiaojing Ma, Bowen Zhang, Duan Ma, Guoying Huang
Front. Med.    2021, 15 (1): 91-100.   https://doi.org/10.1007/s11684-020-0778-5
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Congenital heart disease (CHD) is the most common birth defect worldwide. Long non-coding RNAs (lncRNAs) have been implicated in many diseases. However, their involvement in CHD is not well understood. This study aimed to investigate the role of dysregulated lncRNAs in CHD. We used Gene Expression Omnibus data mining, bioinformatics analysis, and analysis of clinical tissue samples and observed that the novel lncRNA SAP30-2:1 with unknown function was significantly downregulated in damaged cardiac tissues from patients with CHD. Knockdown of lncRNA SAP30-2:1 inhibited the proliferation of human embryonic kidney and AC16 cells and decreased the expression of heart and neural crest derivatives expressed 2 (HAND2). Moreover, lncRNA SAP30-2:1 was associated with HAND2 by RNA immunoprecipitation. Overall, these results suggest that lncRNA SAP30-2:1 may be involved in heart development through affecting cell proliferation via targeting HAND2 and may thus represent a novel therapeutic target for CHD.

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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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Recent advances in myeloid-derived suppressor cell biology
Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil, Homa Darmani, Ammar Daoud
Front. Med.    2021, 15 (2): 232-251.   https://doi.org/10.1007/s11684-020-0797-2
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In recent years, studying the role of myeloid-derived suppressor cells (MDSCs) in many pathological inflammatory conditions has become a very active research area. Although the role of MDSCs in cancer is relatively well established, their role in non-cancerous pathological conditions remains in its infancy resulting in much confusion. Our objectives in this review are to address some recent advances in MDSC research in order to minimize such confusion and to provide an insight into their function in the context of other diseases. The following topics will be specifically focused upon: (1) definition and characterization of MDSCs; (2) whether all MDSC populations consist of immature cells; (3) technical issues in MDSC isolation, estimation and characterization; (4) the origin of MDSCs and their anatomical distribution in health and disease; (5) mediators of MDSC expansion and accumulation; (6) factors that determine the expansion of one MDSC population over the other; (7) the Yin and Yang roles of MDSCs. Moreover, the functions of MDSCs will be addressed throughout the text.

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Proteins moonlighting in tumor metabolism and epigenetics
Lei Lv, Qunying Lei
Front. Med.    2021, 15 (3): 383-403.   https://doi.org/10.1007/s11684-020-0818-1
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Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signalmoonlighting proteinmetabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

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Clinical manifestations and pathogen characteristics in children admitted for suspected COVID-19
Xiaofang Cai, Hanlan Jiang, Simin Zhang, Shengying Xia, Wenhui Du, Yaoling Ma, Tao Yu, Wenbin Li
Front. Med.    2020, 14 (6): 776-785.   https://doi.org/10.1007/s11684-020-0820-7
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Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread around the world. However, approaches to distinguish COVID-19 from pneumonia caused by other pathogens have not yet been reported. We retrospectively analyzed the clinical data of 97 children with probable COVID-19. A total of 13 (13.4%) patients were confirmed positive for SARS-CoV-2 infection by nucleic acid RT-PCR testing, and 41 (42.3%) patients were found to be infected with other pathogens. Notably, no pathogen was detected in 43 (44.3%) patients. Among all patients, 25 (25.8%) had familial cluster exposure history, and 52 (53.6%) had one or more coexisting conditions. Fifteen (15.5%) patients were admitted or transferred to the PICU. In the 11 confirmed COVID-19 cases, 5 (45.5%) and 7 (63.6%) were positive for IgM and IgG against SARS-CoV-2, respectively. In 22 patients with suspected COVID-19, 1 (4.5%) was positive for IgG but negative for IgM. The most frequently detected pathogen was Mycoplasma pneumonia (29, 29.9%). One patient with confirmed COVID-19 died. Our results strongly indicated that the detection of asymptomatic COVID-19 or coexisting conditions must be strengthened in pediatric patients. These cases may be difficult to diagnose as COVID-19 unless etiologic analysis is conducted. A serologic test can be a useful adjunctive diagnostic tool in cases where SARS-CoV-2 infection is highly suspected but the nucleic acid test is negative.

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Zooming in and out of ferroptosis in human disease
Xue Wang, Ye Zhou, Junxia Min, Fudi Wang
Front. Med.    2023, 17 (2): 173-206.   https://doi.org/10.1007/s11684-023-0992-z
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Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?
Shi-Yong Sun
Front. Med.    2021, 15 (2): 221-231.   https://doi.org/10.1007/s11684-020-0812-7
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The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

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Effects of vitrification and cryostorage duration on single-cell RNA-Seq profiling of vitrified-thawed human metaphase II oocytes
Ying Huo, Peng Yuan, Qingyuan Qin, Zhiqiang Yan, Liying Yan, Ping Liu, Rong Li, Jie Yan, Jie Qiao
Front. Med.    2021, 15 (1): 144-154.   https://doi.org/10.1007/s11684-020-0792-7
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Oocyte cryopreservation is widely used for clinical and social reasons. Previous studies have demonstrated that conventional slow-freezing cryopreservation procedures, but not storage time, can alter the gene expression profiles of frozen oocytes. Whether vitrification procedures and the related frozen storage durations have any effects on the transcriptomes of human metaphase II oocytes remain unknown. Four women (30–32 years old) who had undergone IVF treatment were recruited for this study. RNA-Seq profiles of 3 fresh oocytes and 13 surviving vitrified-thawed oocytes (3, 3, 4, and 3 oocytes were cryostored for 1, 2, 3, and 12 months) were analyzed at a single-cell resolution. A total of 1987 genes were differentially expressed in the 13 vitrified-thawed oocytes. However, no differentially expressed genes were found between any two groups among the 1-, 2-, 3-, and 12-month storage groups. Further analysis revealed that the aberrant genes in the vitrified oocytes were closely related to oogenesis and development. Our findings indicated that the effects of vitrification on the transcriptomes of mature human oocytes are induced by the procedure itself, suggesting that long-term cryostorage of human oocytes is safe.

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Oxidative stress and diabetes: antioxidative strategies
Pengju Zhang, Tao Li, Xingyun Wu, Edouard C. Nice, Canhua Huang, Yuanyuan Zhang
Front. Med.    2020, 14 (5): 583-600.   https://doi.org/10.1007/s11684-019-0729-1
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Diabetes mellitus is one of the major public health problems worldwide. Considerable recent evidence suggests that the cellular reduction–oxidation (redox) imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in β-cell dysfunction and insulin resistance. Reactive oxide species (ROS) can also directly oxidize certain proteins (defined as redox modification) involved in the diabetes process. There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility, storage instability and non-selectivity of antioxidants. Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS. We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus. Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.

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Relationship of adrenomedullin expression and microvessel density and prognosis in smooth muscle tumor of uterus
JIANG Yuan, TIAN Xuehong, YUAN Jie, JIN Yuemei, TAN Yusong
Front. Med.    2007, 1 (4): 398-400.   https://doi.org/10.1007/s11684-007-0077-4
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The aim of this paper was to investigate the relationship between the expression of adrenomedullin (ADM) and microvessel density (MVD) and prognosis in smooth muscle tumor of uterus. The expression of ADM was detected using immunohistochemical staining in specimens from 15 normal controls, 28 cases of uterine leiomyoma (LE) and 19 cases of uterine leiomyosarcoma (LES). The MVD was assayed by immunostainting with CD34. There was a positive correlation between the ADM expression and MVD in LE and LES respectively (rs = 0.823, P<0.01; rs = 0.793, P<0.01). The expression of ADM in LE was statistically lower than that in LES (P<0.05). There was a positive correlation between the ADM expression and mitotic figures in LES (P<0.05): the more mitotic figures, the higher levels of the ADM expression and poor prognosis. The ADM is an important angiogenic factor in smooth muscle tumor of uterus. The ADM can be used as an accessory marker in estimating the malignant potency of LE and judging the pro gnosis of LES, and as a novel molecular target of anti-angiogenic and anticarcinogenic strategies.
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Four-protein model for predicting prognostic risk of lung cancer
Xiang Wang, Minghui Wang, Lin Feng, Jie Song, Xin Dong, Ting Xiao, Shujun Cheng
Front. Med.    2022, 16 (4): 618-626.   https://doi.org/10.1007/s11684-021-0867-0
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Patients with lung cancer at the same stage may have markedly different overall outcome and a lack of specific biomarker to predict lung cancer outcome. Heat-shock protein 90 β (HSP90β) is overexpressed in various tumor cells. In this study, the ELISA results of HSP90β combined with CEA, CA125, and CYFRA21-1 were used to construct a recursive partitioning decision tree model to establish a four-protein diagnostic model and predict the survival of patients with lung cancer. Survival analysis showed that the recursive partitioning decision tree could distinguish the prognosis between high- and low-risk groups. Results suggested that the joint detection of HSP90β, CEA, CA125, and CYFRA21-1 in the peripheral blood of patients with lung cancer is plausible for early diagnosis and prognosis prediction of lung cancer.

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