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
Abstract   HTML   PDF (1610KB)

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(716) WebOfScience(765)
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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Developing effective tumor vaccines: basis, challenges and perspectives
XU Qingwen, CHEN Weifeng
Front. Med.    2007, 1 (1): 11-19.   https://doi.org/10.1007/s11684-007-0003-9
Abstract   PDF (291KB)
A remarkable advance in tumor immunology during the last decade is the elucidation of the antigenic basis of tumor recognition and destruction. A variety of tumor antigens have been identified using several strategies including conventional experiments and newly developed bioinformatics. Among these antigens, cancer/testis antigen (CT antigen) is considered to be the most promising target for immunotherapy by vaccination. Successful immunotherapy of tumors requires understanding of the natural relationship between the immune system and tumor in the status of differentiation, invasion and maturation. Continued progress in development of effective cancer vaccines depends on the identification of appropriate target antigens, the establishment of optimal immunization strategies without harmful autoimmune responses and the ability of manipulating tumor microenvironment to circumvent immune suppression and to augment the anti-tumor immune response.
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Protective effect of tanshinone II A on signal transduction system protein kinase B in rats with myocardial hypertrophy
Enyuan TU MD, Yongjun PAN MM, Kang ZHENG MM, Zhaohua WANG MD, Qiansheng LIANG MD, Guangtian YANG MD,
Front. Med.    2009, 3 (4): 431-436.   https://doi.org/10.1007/s11684-009-0088-4
Abstract   PDF (144KB)
The effects of tanshinone II A on cell signal transduction system protein kinase B in rats with myocardial hypertrophy induced by the abdominal aorta partial coarctation were investigated. Rat models of myocardial hypertrophy were established by using abdominal aorta partial coarctation method. Forty-eight rats were randomly divided into sham group (S group), model group (M group), valsartan treatment group (X group), low-dose tanshinone treatment group (LD group), medium-dose tanshinone treatment group (MD group), and high-dose tanshinone treatment group (HD group) (n=8 in each group). Left ventricular mass index (LVMI), left ventricular posterior wall (LVPW), and septal thickness (IVS) were detected by high frequency ultrasonography. Myocardial fiber diameter (MFD) was examined by Hematoxylin-Eosin (HE) staining, and the contents of phosphorylated protein kinase B (p-Akt) and p-Gsk3&#946; in myocardium were assayed by Western blot. The results showed that compared with S group, the values of LVMI, LVPW, IVS and MFD were increased in other groups (P&lt;0.05), and the contents of p-Akt, and p-Gsk3&#946; were also increased in other groups. As compared with MD group, the values of LVMI, LVPW, IVS and MFD were decreased in all treatment groups (P&lt;0.05), and the contents of p-Akt, and p-Gsk3&#946; were also decreased in all treatment groups. However, there were no significant differences among LD, MD, and HD groups (P&gt;0.05), and there were no significant differences between X group and tanshinone treatment groups (P&gt;0.05). It was suggested that tanshinone II A could prevent myocardial hypertrophy by its action on the Akt signaling pathway.
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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
Abstract   PDF (295KB)
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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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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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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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
Abstract   HTML   PDF (299KB)

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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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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Inhibition of the nuclear export of p65 and IQCG in leukemogenesis by NUP98-IQCG
Mengmeng Pan,Qiyao Zhang,Ping Liu,Jinyan Huang,Yueying Wang,Saijuan Chen
Front. Med.    2016, 10 (4): 410-419.   https://doi.org/10.1007/s11684-016-0489-0
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NUP98 fuses with approximately 34 different partner genes via translocation in hematological malignancies. Transgenic or retrovirus-mediated bone marrow transplanted mouse models reveal the leukemogenesis of some NUP98-related fusion genes. We previously reported the fusion protein NUP98-IQ motif containing G (IQCG) in a myeloid/T lymphoid bi-phenoleukemia patient with t(3;11) and confirmed its leukemogenic ability. Herein, we demonstrated the association of NUP98-IQCG with CRM1, and found that NUP98-IQCG expression inhibits the CRM1-mediated nuclear export of p65 and enhances the transcriptional activity of nuclear factor-κB. Moreover, IQCG could be entrapped in the nucleus by NUP98-IQCG, and the fusion protein interacts with calmodulin via the IQ motif in a calcium-independent manner. Therefore, the inhibition of nuclear exports of p65 and IQCG might contribute to the leukemogenesis of NUP98-IQCG.

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Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma
Yue Wang, Jinxia Zhang, Yunfan Wang, Shufang Wang, Yu Zhang, Qi Miao, Fei Gao, Huiying He
Front. Med.    2019, 13 (6): 730-740.   https://doi.org/10.1007/s11684-019-0687-7
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GATA binding protein 3 (GATA3) and mismatch repair (MMR) deficiency contribute to the development of urothelial carcinoma. However, the combined expression of GATA3 and microsatellite instability (MSI) in upper tract urothelial carcinoma (UTUC) and its prognostic value have not been investigated. Here, we immunohistochemically stained GATA3 and MMR proteins in 108 UTUC samples. GATA3 was positive in 74 cases, and its expression was significantly lower than in adjacent benign urothelium (P<0.001). Loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters, such as advanced stage, lymphovascular invasion, neural invasion, lymph node metastasis, and extensive necrosis. Cancer-specific survival (CSS, P=0.028) and disease-free survival (DFS, P=0.024) were significantly shorter in patients with GATA3 negative tumors than in patients with GATA3 positive tumors. The absence of MMR proteins was observed in 8.3% of the cases, and focal staining was identified in 13.0%. When using “lax criteria” which resulted in counting cases as negative where MMR staining was in fact focally positive (<5%), we found that GATA3 was inversely associated with MSI (P=0.005). Moreover, GATA3/microsatellite stability (MS) tumors were correlated with advanced pT stage (P<0.001) and poor outcome (P=0.019 for CSS, P=0.016 for DFS) compared with GATA3+/MSI ones. The GATA3/MSI cases had unfavorable clinical outcomes compared with GATA3+/MSI cases (P=0.008 for CSS, P=0.023 for DFS). This finding raises a question as to whether GATA3 interacts with MSI through the TGF-β signaling pathway and regulates UTUC progression.

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Astragaloside IV suppresses post-ischemic natural killer cell infiltration and activation in the brain: involvement of histone deacetylase inhibition
Baokai Dou, Shichun Li, Luyao Wei, Lixin Wang, Shiguo Zhu, Zhengtao Wang, Zunji Ke, Kaixian Chen, Zhifei Wang
Front. Med.    2021, 15 (1): 79-90.   https://doi.org/10.1007/s11684-020-0783-8
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Natural killer (NK) cells, a type of cytotoxic lymphocytes, can infiltrate into ischemic brain and exacerbate neuronal cell death. Astragaloside IV (ASIV) is the major bioactive ingredient of Astragalus membranaceus, a Chinese herbal medicine, and possesses potent immunomodulatory and neuroprotective properties. This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells. ASIV reduced brain infarction and alleviated functional deficits in MCAO rats, and these beneficial effects persisted for at least 7 days. Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia, and this infiltration was suppressed by ASIV. Strikingly, ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia. ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2+ NK cell levels in the ischemic brain. Meanwhile, ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γ production. ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain, suggesting inhibition of histone deacetylase (HDAC). Simultaneously, ASIV prevented p65 nuclear translocation. The effects of ASIV on reducing CCL2 production, restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate, an HDAC inhibitor, in astrocytes subjected to oxygen-glucose deprivation. Our findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery, which together contribute to the beneficial effects of ASIV against brain ischemia. Furthermore, ASIV’s effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.

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Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19
Lingling Tang, Yingan Jiang, Mengfei Zhu, Lijun Chen, Xiaoyang Zhou, Chenliang Zhou, Peng Ye, Xiaobei Chen, Baohong Wang, Zhenyu Xu, Qiang Zhang, Xiaowei Xu, Hainv Gao, Xiaojun Wu, Dong Li, Wanli Jiang, Jingjing Qu, Charlie Xiang, Lanjuan Li
Front. Med.    2020, 14 (5): 664-673.   https://doi.org/10.1007/s11684-020-0810-9
Abstract   HTML   PDF (301KB)

The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was identified in December 2019. The symptoms include fever, cough, dyspnea, early symptom of sputum, and acute respiratory distress syndrome (ARDS). Mesenchymal stem cell (MSC) therapy is the immediate treatment used for patients with severe cases of COVID-19. Herein, we describe two confirmed cases of COVID-19 in Wuhan to explore the role of MSC in the treatment of COVID-19. MSC transplantation increases the immune indicators (including CD4 and lymphocytes) and decreases the inflammation indicators (interleukin-6 and C-reactive protein). High-flow nasal cannula can be used as an initial support strategy for patients with ARDS. With MSC transplantation, the fraction of inspired O2 (FiO2) of the two patients gradually decreased while the oxygen saturation (SaO2) and partial pressure of oxygen (PO2) improved. Additionally, the patients’ chest computed tomography showed that bilateral lung exudate lesions were adsorbed after MSC infusion. Results indicated that MSC transplantation provides clinical data on the treatment of COVID-19 and may serve as an alternative method for treating COVID-19, particularly in patients with ARDS.

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Non-invasive continuous blood pressure monitoring: a review of current applications
Elena Chung, Guo Chen, Brenton Alexander, Maxime Cannesson
Front Med    2013, 7 (1): 91-101.   https://doi.org/10.1007/s11684-013-0239-5
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Blood pressure monitoring has come a long way from the initial observations made by Reverend Hales in the 18th century. There are none that deny the importance of monitoring perioperative blood pressure; however, the limited ability of the current prevalent technology (oscillometric blood pressure monitoring) to offer continuous blood pressure measurements leaves room for improvement. Invasive monitoring is able to detect beat-to-beat blood pressure measurement, but the risks inherent to the procedure make it unsuitable for routine use except when this risk is outweighed by the benefits. This review focuses on the discoveries which have led up to the current blood pressure monitoring technologies, and especially the creation of those offering non-invasive but continuous blood pressure monitoring capabilities, including their methods of measurement and limitations.

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Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection
Yun Tan, Feng Liu, Xiaoguang Xu, Yun Ling, Weijin Huang, Zhaoqin Zhu, Mingquan Guo, Yixiao Lin, Ziyu Fu, Dongguo Liang, Tengfei Zhang, Jian Fan, Miao Xu, Hongzhou Lu, Saijuan Chen
Front. Med.    2020, 14 (6): 746-751.   https://doi.org/10.1007/s11684-020-0822-5
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The ongoing pandemic of coronavirus disease 19 (COVID-19) is caused by a newly discovered β coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination. Here we examined, using ELISA, the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6–7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection. All samples were positive for IgGs against the S- and N-proteins of SARS-CoV-2. Notably, 14 samples available at 6–7 months post-infection all showed significant neutralizing activities in a pseudovirus assay, with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2. Furthermore, in 10 blood samples from cases at 6–7 months post-infection used for memory T-cell tests, we found that interferon γ-producing CD4+ and CD8+ cells were increased upon SARS-CoV-2 antigen stimulation. Together, these results indicate that durable anti-SARS-CoV-2 immunity is common in convalescent population, and vaccines developed from 614D variant may offer protection from the currently predominant 614D variant of SARS-CoV-2.

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Talin and kindlin: the one-two punch in integrin activation
Feng Ye, Adam K. Snider, Mark H. Ginsberg
Front Med    2014, 8 (1): 6-16.   https://doi.org/10.1007/s11684-014-0317-3
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Proper cell-cell and cell-matrix contacts mediated by integrin adhesion receptors are important for development, immune response, hemostasis and wound healing. Integrins pass trans-membrane signals bidirectionally through their regulated affinities for extracellular ligands and intracellular signaling molecules. Such bidirectional signaling by integrins is enabled by the conformational changes that are often linked among extracellular, transmembrane and cytoplasmic domains. Here, we review how talin-integrin and kindlin-integrin interactions, in cooperation with talin-lipid and kindlin-lipid interactions, regulate integrin affinities and how the progress in these areas helps us understand integrin-related diseases.

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Insulin resistance and the metabolism of branched-chain amino acids
Jingyi Lu, Guoxiang Xie, Weiping Jia, Wei Jia
Front Med    2013, 7 (1): 53-59.   https://doi.org/10.1007/s11684-013-0255-5
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Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

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Progress on the research and development of human enterovirus 71 (EV71) vaccines
Zhenglun Liang, Qunying Mao, Fan Gao, Junzhi Wang
Front Med    2013, 7 (1): 111-121.   https://doi.org/10.1007/s11684-012-0237-z
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Enterovirus 71 (EV71) infections, which can cause severe complications, have become one of the serious public health issues in the Western Pacific region and China. To date, a number of pharmaceutical companies and institutes have initiated the research and development of EV71 vaccines as a countermeasure. As is the case with innovative vaccine development, there are several critical bottlenecks in EV71 vaccine development that must be overcome before the clinical trials, including the selection of vaccine strain, standardization of the procedure for quantifying neutralizing antibody (NTAb) and antigen, establishment and application of a reference standard and biological standards, development of animal models for the evaluation of protective efficacy, and identification of the target patient population. To tackle these technical obstacles, researchers in Mainland of China have conducted a series of studies concerning the screening of vaccine strains and the establishment of criteria, biological standards and detection methods, thereby advancing EV71 vaccine development. This review summarizes recent worldwide progress on the quality control and evaluation of EV71 vaccines.

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Prohibitin regulates mTOR pathway via interaction with FKBP8
Jiahui Zhang, Yanan Yin, Jiahui Wang, Jingjing Zhang, Hua Liu, Weiwei Feng, Wen Yang, Bruce Zetter, Yingjie Xu
Front. Med.    2021, 15 (3): 448-459.   https://doi.org/10.1007/s11684-020-0805-6
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The ability of tumor cells to sustain continuous proliferation is one of the major characteristics of cancer. The activation of oncogenes and the mutation or inactivation of tumor suppressor genes ensure the rapid proliferation of tumor cells. The PI3K--Akt--mTOR axis is one of the most frequently modified signaling pathways whose activation sustains cancer growth. Unsurprisingly, it is also one of the most commonly attempted targets for cancer therapy. FK506 binding protein 8 (FKBP8) is an intrinsic inhibitor of mTOR kinase that also exerts an anti-apoptotic function. We aimed to explain these contradictory aspects of FKBP8 in cancer by identifying a “switch” type regulator. We identified through immunoprecipitation--mass spectrometry-based proteomic analysis that the mitochondrial protein prohibitin 1 (PHB1) specifically interacts with FKBP8. Furthermore, the downregulation of PHB1 inhibited the proliferation of ovarian cancer cells and the mTOR signaling pathway, whereas the FKBP8 level in the mitochondria was substantially reduced. Moreover, concomitant with these changes, the interaction between FKBP8 and mTOR substantially increased in the absence of PHB1. Collectively, our finding highlights PHB1 as a potential regulator of FKBP8 because of its subcellular localization and mTOR regulating role.

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia
Bin Gu, Jianhong Chu, Depei Wu
Front. Med.    https://doi.org/10.1007/s11684-020-0763-z
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Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

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Traditional Chinese medicine for combating COVID-19
Kaixian Chen, Hongzhuan Chen
Front. Med.    2020, 14 (5): 529-532.   https://doi.org/10.1007/s11684-020-0802-9
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The “Traditional Chinese medicine regulating liver regeneration” treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data
Ling Dai, Xiang Gao, Zhihua Ye, Hanmin Li, Xin Yao, Dingbo Lu, Na Wu
Front. Med.    2021, 15 (3): 495-505.   https://doi.org/10.1007/s11684-020-0790-9
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On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of “traditional Chinese medicine (TCM) regulating liver regeneration.” A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of “TCM regulating liver regeneration” (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups (P<0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.

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Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection
Weibao Song, Hongjuan Zhang, Yu Zhang, Rui Li, Yanxing Han, Yuan Lin, Jiandong Jiang
Front. Med.    2021, 15 (3): 404-415.   https://doi.org/10.1007/s11684-021-0834-9
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Zika virus (ZIKV) is an emerging pathogen associated with neurological complications, such as Guillain–Barré syndrome in adults and microcephaly in fetuses and newborns. This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination. However, the development of antivirals against ZIKV is lagging. Although various strategies have been used to study anti-ZIKV agents, approved drugs or vaccines for the treatment (or prevention) of ZIKV infections are currently unavailable. Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections. The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical, safe, and efficacious approach to address ZIKV infections. This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs. Their characteristics, targets, and potential use in anti-ZIKV therapy are presented. This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.

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Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia
Jianfeng Li, Yuting Dai, Liang Wu, Ming Zhang, Wen Ouyang, Jinyan Huang, Saijuan Chen
Front. Med.    2021, 15 (3): 347-371.   https://doi.org/10.1007/s11684-020-0821-6
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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as DUX4 rearrangements, MEF2D rearrangements, ZNF384/ZNF362 rearrangements, NUTM1 rearrangements, BCL2/MYC and/or BCL6 rearrangements, ETV6-RUNX1-like gene expression, PAX5alt (diverse PAX5 alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic PAX5 alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

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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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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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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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Association of novel mutations and heplotypes in the preS region of hepatitis B virus with hepatocellular carcinoma
Jia-Xin XIE, Jian-Hua YIN, Qi ZHANG, Rui PU, Wen-Ying LU, Hong-Wei ZHANG, Guang-Wen CAO, Jun ZHAO, Hong-Yang WANG,
Front. Med.    2010, 4 (4): 419-429.   https://doi.org/10.1007/s11684-010-0160-0
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The association of viral mutations and haplotypic carriages with mutations in the preS region of hepatitis B virus (HBV) genotypes B and C with hepatocellular carcinoma (HCC) is of great significance for the prediction of this malignancy, but it remains obscure. We analyzed the preS sequences of HBV genotypes B and C from 1172 HBV-infected subjects including 231 patients with HCC. As compared with the HBV-infected subjects without HCC, C2875T, G2946C, A3054C, C3060A, T3066C, C3116T, A3120C, G3191A, A1C, C7A, C10A, A31C, C76T, G105C, and G147C in both genotypes were significantly associated with increased risks of HCC. C2875A, G2950A, G2951A, A3054T, C3060T, T3066A, T3069G, A3120T, and G3191C were significantly associated with increased risks of HCC in genotype C, whereas these mutations were inversely associated with HCC in genotype B. Multivariate regression analyses showed that C76A/T was a novel factor independently associated with an increased risk of HCC, as compared with those without HCC. The frequencies of haplotypes 2964A-3116T-preS2 start codon wild-type-7C, 2964C-3116T-7A-76C, and 2964A-3116T-7C-76A/T were significantly higher in the patients with HCC (P&lt;0.001), whereas a haplotypic carriage with a single mutation and another three wild-types were inversely associated with HCC. Conclusively, the association of HBV mutations in the preS region with HCC depends on HBV genotype and haplotypic carriage with two or more mutations that are each associated with an increased risk of HCC independently.
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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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Progress in systemic therapy for triple-negative breast cancer
Hongnan Mo, Binghe Xu
Front. Med.    2021, 15 (1): 1-10.   https://doi.org/10.1007/s11684-020-0741-5
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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.

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