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Behavioral methods for the functional assessment of hair cells in zebrafish
Qin Yang, Peng Sun, Shi Chen, Hongzhe Li, Fangyi Chen
Front. Med.    2017, 11 (2): 178-190.   https://doi.org/10.1007/s11684-017-0507-x
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Zebrafish is an emerging animal model for studies on auditory system. This model presents high comparability with humans, good accessibility to the hearing organ, and high throughput capacity. To better utilize this animal model, methodologies need to be used to quantify the hearing function of the zebrafish. Zebrafish displays a series of innate and robust behavior related to its auditory function. Here, we reviewed the advantage of using zebrafish in auditory research and then introduced three behavioral tests, as follows: the startle response, the vestibular-ocular reflex, and rheotaxis. These tests are discussed in terms of their physiological characteristics, up-to-date technical development, and apparatus description. Test limitation and areas to improve are also introduced. Finally, we revealed the feasibility of these applications in zebrafish behavioral assessment and their potential in the high-throughput screening on hearing-related genes and drugs.

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Cited: Crossref(3) WebOfScience(3)
Landscape of emerging and re-emerging infectious diseases in China: impact of ecology, climate, and behavior
Qiyong Liu, Wenbo Xu, Shan Lu, Jiafu Jiang, Jieping Zhou, Zhujun Shao, Xiaobo Liu, Lei Xu, Yanwen Xiong, Han Zheng, Sun Jin, Hai Jiang, Wuchun Cao, Jianguo Xu
Front. Med.    2018, 12 (1): 3-22.   https://doi.org/10.1007/s11684-017-0605-9
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For the past several decades, the infectious disease profile in China has been shifting with rapid developments in social and economic aspects, environment, quality of food, water, housing, and public health infrastructure. Notably, 5 notifiable infectious diseases have been almost eradicated, and the incidence of 18 additional notifiable infectious diseases has been significantly reduced. Unexpectedly, the incidence of over 10 notifiable infectious diseases, including HIV, brucellosis, syphilis, and dengue fever, has been increasing. Nevertheless, frequent infectious disease outbreaks/events have been reported almost every year, and imported infectious diseases have increased since 2015. New pathogens and over 100 new genotypes or serotypes of known pathogens have been identified. Some infectious diseases seem to be exacerbated by various factors, including rapid urbanization, large numbers of migrant workers, changes in climate, ecology, and policies, such as returning farmland to forests. This review summarizes the current experiences and lessons from China in managing emerging and re-emerging infectious diseases, especially the effects of ecology, climate, and behavior, which should have merits in helping other countries to control and prevent infectious diseases.

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Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors
Shuhang Wang,Yongping Song,Feifei Yan,Delong Liu
Front. Med.    2016, 10 (4): 383-388.   https://doi.org/10.1007/s11684-016-0488-1
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The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

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CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells
Yongping Zhang, Xingying Zhang, Chen Cheng, Wei Mu, Xiaojuan Liu, Na Li, Xiaofei Wei, Xiang Liu, Changqing Xia, Haoyi Wang
Front. Med.    2017, 11 (4): 554-562.   https://doi.org/10.1007/s11684-017-0543-6
Abstract   HTML   PDF (452KB)

T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of T cell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout T and CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.

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Epidemiology of fungal infections in China
Min Chen, Yuan Xu, Nan Hong, Yali Yang, Wenzhi Lei, Lin Du, Jingjun Zhao, Xia Lei, Lin Xiong, Langqi Cai, Hui Xu, Weihua Pan, Wanqing Liao
Front. Med.    2018, 12 (1): 58-75.   https://doi.org/10.1007/s11684-017-0601-0
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With the increasing number of immunocompromised hosts, the epidemiological characteristics of fungal infections have undergone enormous changes worldwide, including in China. In this paper, we reviewed the existing data on mycosis across China to summarize available epidemiological profiles. We found that the general incidence of superficial fungal infections in China has been stable, but the incidence of tinea capitis has decreased and the transmission route has changed. By contrast, the overall incidence of invasive fungal infections has continued to rise. The occurrence of candidemia caused by Candida species other than C. albicans and including some uncommon Candida species has increased recently in China. Infections caused by Aspergillus have also propagated in recent years, particularly with the emergence of azole-resistant Aspergillus fumigatus. An increasing trend of cryptococcosis has been noted in China, with Cryptococcus neoformans var. grubii ST 5 genotype isolates as the predominant pathogen. Retrospective studies have suggested that the epidemiological characteristics of Pneumocystis pneumonia in China may be similar to those in other developing countries. Endemic fungal infections, such as sporotrichosis in Northeastern China, must arouse research, diagnostic, and treatment vigilance. Currently, the epidemiological data on mycosis in China are variable and fragmentary. Thus, a nationwide epidemiological research on fungal infections in China is an important need for improving the country’s health.

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Transforming bacterial disease surveillance and investigation using whole-genome sequence to probe the trace
Biao Kan, Haijian Zhou, Pengcheng Du, Wen Zhang, Xin Lu, Tian Qin, Jianguo Xu
Front. Med.    2018, 12 (1): 23-33.   https://doi.org/10.1007/s11684-017-0607-7
Abstract   HTML   PDF (348KB)

Two decades have passed since the first bacterial whole-genome sequencing, which provides new opportunity for microbial genome. Consequently, considerable genetic diversity encoded by bacterial genomes and among the strains in the same species has been revealed. In recent years, genome sequencing techniques and bioinformatics have developed rapidly, which has resulted in transformation and expedited the application of strategy and methodology for bacterial genome comparison used in dissection of infectious disease epidemics. Bacterial whole-genome sequencing and bioinformatic computing allow genotyping to satisfy the requirements of epidemiological study in disease control. In this review, we outline the significance and summarize the roles of bacterial genome sequencing in the context of bacterial disease control and prevention. We discuss the applications of bacterial genome sequencing in outbreak detection, source tracing, transmission mode discovery, and new epidemic clone identification. Wide applications of genome sequencing and data sharing in infectious disease surveillance networks will considerably promote outbreak detection and early warning to prevent the dissemination of bacterial diseases.

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The antibiotic resistome: gene flow in environments, animals and human beings
Yongfei Hu, George F. Gao, Baoli Zhu
Front. Med.    2017, 11 (2): 161-168.   https://doi.org/10.1007/s11684-017-0531-x
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The antibiotic resistance is natural in bacteria and predates the human use of antibiotics. Numerous antibiotic resistance genes (ARGs) have been discovered to confer resistance to a wide range of antibiotics. The ARGs in natural environments are highly integrated and tightly regulated in specific bacterial metabolic networks. However, the antibiotic selection pressure conferred by the use of antibiotics in both human medicine and agriculture practice leads to a significant increase of antibiotic resistance and a steady accumulation of ARGs in bacteria. In this review, we summarized, with an emphasis on an ecological point of view, the important research progress regarding the collective ARGs (antibiotic resistome) in bacterial communities of natural environments, human and animals, i.e., in the one health settings. We propose that the resistance gene flow in nature is “from the natural environments” and “to the natural environments”; human and animals, as intermediate recipients and disseminators, contribute greatly to such a resistance gene “circulation.”

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From SARS to MERS: evidence and speculation
Hainv Gao,Hangping Yao,Shigui Yang,Lanjuan Li
Front. Med.    2016, 10 (4): 377-382.   https://doi.org/10.1007/s11684-016-0466-7
Abstract   HTML   PDF (133KB)

The Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic pathogen. In 2012, the infectious outbreak caused by MERS-CoV in Saudi Arabia has spread to more than 1600 patients in 26 countries, resulting in over 600 deaths. Without a travel history, few clinical and radiological features can reliably differentiate MERS from SARS. But in real world, comparing with SARS, MERS presents more vaguely defined epidemiology, more severe symptoms, and higher case fatality rate. In this review, we summarize the recent findings in the field of MERS-CoV, especially its molecular virology, interspecies mechanisms, clinical features, antiviral therapies, and the further investigation into this disease. As a newly emerging virus, many questions are not fully answered, including the exact mode of transmission chain, geographical distribution, and animal origins. Furthermore, a new protocol needs to be launched to rapidly evaluate the effects of unproven antiviral drugs and vaccine to fasten the clinical application of new drugs.

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Molecular classification and precision therapy of cancer: immune checkpoint inhibitors
Yingyan Yu
Front. Med.    2018, 12 (2): 229-235.   https://doi.org/10.1007/s11684-017-0581-0
Abstract   HTML   PDF (155KB)

On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as “genetic interpreters” or “genetic translators” and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.

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Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum
Chunyu Li, Ming Niu, Zhaofang Bai, Congen Zhang, Yanling Zhao, Ruiyu Li, Can Tu, Huifang Li, Jing Jing, Yakun Meng, Zhijie Ma, Wuwen Feng, Jinfa Tang, Yun Zhu, Jinjie Li, Xiaoya Shang, Zhengsheng Zou, Xiaohe Xiao, Jiabo Wang
Front. Med.    2017, 11 (2): 253-265.   https://doi.org/10.1007/s11684-017-0508-9
Abstract   HTML   PDF (690KB)

The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent “knock-out” and “knock-in” strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

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iTRAQ-based quantitative proteomic analysis on differentially expressed proteins of rat mandibular condylar cartilage induced by reducing dietary loading
Liting Jiang,Yinyin Xie,Li Wei,Qi Zhou,Ning Li,Xinquan Jiang,Yiming Gao
Front. Med.    2017, 11 (1): 97-109.   https://doi.org/10.1007/s11684-016-0496-1
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As muscle activity during growth is considerably important for mandible quality and morphology, reducing dietary loading directly influences the development and metabolic activity of mandibular condylar cartilage (MCC). However, an overall investigation of changes in the protein composition of MCC has not been fully described in literature. To study the protein expression and putative signaling in vivo, we evaluated the structural changes of MCC and differentially expressed proteins induced by reducing functional loading in rat MCC at developmental stages. Isobaric tag for relative and absolute quantitation-based 2D nano-high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization time-of-flight/ time-of-flight (MALDI-TOF/TOF) technologies were used. Global protein profiling, KEGG and PANTHER pathways, and functional categories were analyzed. Consequently, histological and tartrate-resistant acid phosphatase staining indicated the altered histological structure of condylar cartilage and increased bone remodeling activity in hard-diet group. A total of 805 differentially expressed proteins were then identified. GO analysis revealed a significant number of proteins involved in the metabolic process, cellular process, biological regulation, localization, developmental process, and response to stimulus. KEGG pathway analysis also suggested that these proteins participated in various signaling pathways, including calcium signaling pathway, gap junction, ErbB signaling pathway, and mitogen-activated protein kinase signaling pathway. Collagen types I and II were further validated by immunohistochemical staining and Western blot analysis. Taken together, the present study provides an insight into the molecular mechanism of regulating condylar growth and remodeling induced by reducing dietary loading at the protein level.

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Genomic variations in the counterpart normal controls of lung squamous cell carcinomas
Dalin Zhang, Liwei Qu, Bo Zhou, Guizhen Wang, Guangbiao Zhou
Front. Med.    2018, 12 (3): 280-288.   https://doi.org/10.1007/s11684-017-0580-1
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Lung squamous cell carcinoma (LUSC) causes approximately 400 000 deaths each year worldwide. The occurrence of LUSC is attributed to exposure to cigarette smoke, which induces the development of numerous genomic abnormalities. However, few studies have investigated the genomic variations that occur only in normal tissues that have been similarly exposed to tobacco smoke as tumor tissues. In this study, we sequenced the whole genomes of three normal lung tissue samples and their paired adjacent squamous cell carcinomas. We then called genomic variations specific to the normal lung tissues through filtering the genomic sequence of the normal lung tissues against that of the paired tumors, the reference human genome, the dbSNP138 common germline variants, and the variations derived from sequencing artifacts. To expand these observations, the whole exome sequences of 478 counterpart normal controls (CNCs) and paired LUSCs of The Cancer Genome Atlas (TCGA) dataset were analyzed. Sixteen genomic variations were called in the three normal lung tissues. These variations were confirmed by Sanger capillary sequencing. A mean of 0.5661 exonic variations/Mb and 7.7887 altered genes per sample were identified in the CNC genome sequences of TCGA. In these CNCs, C:G→T:A transitions, which are the genomic signatures of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes. Twenty five genes in CNCs had a variation rate that exceeded 2%, including ARSD (18.62%), MUC4 (8.79%), and RBMX (7.11%). CNC variations in CTAGE5 and USP17L7 were associated with the poor prognosis of patients with LUSC. Our results uncovered previously unreported genomic variations in CNCs, rather than LUSCs, that may be involved in the development of LUSC.

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Effects of different doses of cadmium on secondary metabolites and gene expression in Artemisia annua L.
Liangyun Zhou,Guang Yang,Haifeng Sun,Jinfu Tang,Jian Yang,Yizhan Wang,Thomas Avery Garran,Lanping Guo
Front. Med.    2017, 11 (1): 137-146.   https://doi.org/10.1007/s11684-016-0486-3
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This study aims to elucidate the underlying molecular mechanisms of artemisinin accumulation induced by cadmium (Cd). The effects of different Cd concentrations (0, 20, 60, and 120 μmol/L) on the biosynthesis of Artemisia annua L. were examined. Intermediate and end products were quantified by HPLC-ESI-MS/MS analysis. The expression of key biosynthesis enzymes was also determined by qRT-PCR. The results showed that the application of treatment with 60 and 120 μmol/L Cd for 3 days significantly improved the biosynthesis of artemisinic acid, arteannuin B, and artemisinin. The concentrations of artemisinic acid, arteannuin B, and artemisinin in the 120 μmol/L Cd-treated group were 2.26, 102.08, and 33.63 times higher than those in the control group, respectively. The concentrations of arteannuin B and artemisinin in 60 μmol/L Cd-treated leaves were 61.10 and 26.40 times higher than those in the control group, respectively. The relative expression levels of HMGR, FPS, ADS, CYP71AV1, DBR2, ALDH1, and DXR were up-regulated in the 120 μmol/L Cd-treated group because of increased contents of artemisinic metabolites after 3 days of treatment. Hence, appropriate doses of Cd can increase the concentrations of artemisinic metabolites at a certain time point by up-regulating the relative expression levels of key enzyme genes involved in artemisinin biosynthesis.

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Poor adherence to P2Y12 antagonists increased cardiovascular risks in Chinese PCI-treated patients
Yang Sun,Chenze Li,Lina Zhang,Dong Hu,Xudong Zhang,Ting Yu,Min Tao,Dao Wen Wang,Xiaoqing Shen
Front. Med.    2017, 11 (1): 53-61.   https://doi.org/10.1007/s11684-017-0502-2
Abstract   HTML   PDF (180KB)

Low adherence to secondary prevention medications (ATM) of patients after acute coronary syndrome (ACS) is associated with poor clinical outcomes. However, literature provides limited data on assessment of ATM and risks associated with poor in Chinese patients with ACS. In the current work, ATM was assessed in consecutively recruited patients with ACS in Tongji Hospital from November 5, 2013 to December 31, 2014. A total of 2126 patients were classified under low adherence (proportion of days covered (PDC)<50%) and high adherence (PDC>50%) groups based on their performance after discharge. All patients were followed up at the 1st, 6th, and 12th month of discharge while recording ATM and major adverse cardiac events (MACE). Bivariate logistic regression was used to identify the factors associated with ATM. Cox regression was used to analyze the association between ATM and MACE within one year after discharge. Results showed that coronary artery bypass grafting (CABG) alone had significantly lower proportion of high adherence to P2Y12 antagonists (83.0% vs. 90.7%, P<0.01) than patients treated with percutaneous coronary intervention (PCI) only. Moreover, in patients undergoing PCI, high adherence to P2Y12 antagonists decreased the risk of MACE (hazard ratio=0.172, 95% confidence interval: 0.039–0.763; P=0.021). In conclusion, PCI-treated patients are more prone to remaining adherent to medications than CABG-treated patients. High adherence to P2Y12 antagonists was associated with lower risk of MACE.

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Antimicrobial activity of topical agents against Propionibacterium acnes: an in vitro study of clinical isolates from a hospital in Shanghai, China
Ying Ma,Nanxue Zhang,Shi Wu,Haihui Huang,Yanpei Cao
Front. Med.    2016, 10 (4): 517-521.   https://doi.org/10.1007/s11684-016-0480-9
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This study aimed to compare the antimicrobial activities of topical agents against Propionibacterium acnes isolated from patients admitted to a hospital in Shanghai, China. The minimal inhibitory concentrations of the cultured P. acnes were determined in accordance with the Clinical and Laboratory Standards Institute. Susceptibilities to clindamycin and erythromycin were compared in terms of gender, age, disease duration, previous treatment, and disease severity. A total of 69 P. acnes strains were isolated from 98 patients (70.41%). The susceptibility to triple antibiotic ointment (neomycin/bacitracin/polymyxin B) and bacitracin was 100%. The susceptibility to fusidic acid was 92.7%. The resistance rates to neomycin sulfate, erythromycin, and clindamycin were 11.7%, 49.3%, and 33.4%, respectively. The high resistance rate to clindamycin and erythromycin was significantly affected by gender, previous treatment, and disease severity rather than by age and disease duration. Topical antibiotics should not be used separately for long-term therapy to avoid multiresistance. The use of topical antibiotics should be determined by clinicians on the basis of clinical conditions.

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miRNAs in non-alcoholic fatty liver disease
Zhen He,Cheng Hu,Weiping Jia
Front. Med.    2016, 10 (4): 389-396.   https://doi.org/10.1007/s11684-016-0468-5
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Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver cirrhosis and hepatocellular carcinoma and is a considerable threat to public health. miRNAs are important post-transcriptional regulators of gene expression, and the dysregulation of miRNAs is involved in various biological processes in the liver, including lipid homeostasis, inflammation, apoptosis, and cell proliferation. Recently, a number of studies have described the association between miRNAs and NAFLD progression and have shown that circulating miRNAs reflect histological changes in the liver. Therefore, circulating miRNAs have potential use for the evaluation of NAFLD severity. In this review, we discuss the involvement of miRNAs in NAFLD pathogenesis and the key role of miRNAs in the screening, diagnosis, and staging of NAFLD.

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Neuroprotective effects of Ginkgo biloba extract and Ginkgolide B against oxygen–glucose deprivation/reoxygenation and glucose injury in a new in vitro multicellular network model
Xiaohan Yang, Tiezheng Zheng, Hao Hong, Nan Cai, Xiaofeng Zhou, Changkai Sun, Liying Wu, Shuhong Liu, Yongqi Zhao, Lingling Zhu, Ming Fan, Xuezhong Zhou, Fengxie Jin
Front. Med.    2018, 12 (3): 307-318.   https://doi.org/10.1007/s11684-017-0547-2
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Acute ischemic stroke (AIS), as the third leading cause of death worldwide, is characterized by its high incidence, mortality rate, high incurred disability rate, and frequent reoccurrence. The neuroprotective effects of Ginkgo biloba extract (GBE) against several cerebral diseases have been reported in previous studies, but the underlying mechanisms of action are still unclear. Using a novel in vitro rat cortical capillary endothelial cell-astrocyte-neuron network model, we investigated the neuroprotective effects of GBE and one of its important constituents, Ginkgolide B (GB), against oxygen–glucose deprivation/reoxygenation and glucose (OGD/R) injury. In this model, rat cortical capillary endothelial cells, astrocytes, and neurons were cocultured so that they could be synchronously observed in the same system. Pretreatment with GBE or GB increased the neuron cell viability, ameliorated cell injury, and inhibited the cell apoptotic rate through Bax and Bcl-2 expression regulation after OGD/R injury. Furthermore, GBE or GB pretreatment enhanced the transendothelial electrical resistance of capillary endothelial monolayers, reduced the endothelial permeability coefficients for sodium fluorescein (Na-F), and increased the expression levels of tight junction proteins, namely, ZO-1 and occludin, in endothelial cells. Results demonstrated the preventive effects of GBE on neuronal cell death and enhancement of the function of brain capillary endothelial monolayers after OGD/R injury in vitro; thus, GBE could be used as an effective neuroprotective agent for AIS/reperfusion, with GB as one of its significant constituents.

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Diagnosis and management of acquired thrombotic thrombocytopenic purpura in southeast China: a single center experience of 60 cases
Xinping Zhou,Xingnong Ye,Yanling Ren,Chen Mei,Liya Ma,Jiansong Huang,Weilai Xu,Juying Wei,Li Ye,Wenyuan Mai,Wenbin Qian,Haitao Meng,Jie Jin,Hongyan Tong
Front. Med.    2016, 10 (4): 430-436.   https://doi.org/10.1007/s11684-016-0492-5
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Acquired thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy. This study aimed to provide a profile of the diagnosis and management of patients with acquired TTP collected in 10 years in a single center in southeast China. A total of 60 patients diagnosed with acute acquired TTP from March 2005 to August 2015 were enrolled. Among the 60 patients, 52 patients presented with their first episodes, and eight patients had two or more episodes. The median age at presentation was 49 (range, 17 to 78) years with a female predominance (male:female ratio, 1:1.60). ADAMTS 13 activity were analyzed in 43 patients, among whom 33 (76.7%) patients had a baseline level of<5%. Mortality was 30%. Plasma exchange (PEX) was performed in 62 of 69 (89.9%) episodes. Corticosteroids were administered in 54 of 69 (78.3%) episodes. Other immunosuppressants (e.g., vincristine, cyclosporine, and cyclosporin) were used in 7 of 69 (10.1%) episodes. Rituximab was documented in 4 patients with refractory/relapsed TTP for 5 episodes, showing encouraging results. In conclusion, the diagnosis of TTP depended on a comprehensive analysis of clinical data. Plasma ADAMTS13 activity assay helped confirm a diagnosis. PEX was the mainstay of the therapy, and rituximab can be used in relapsed/refractory disease.

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Innovative development path of ethnomedicines: the interpretation of the path
Zhaoyun Zhu,Dehuan Fu,Yali Gui,Tao Cui,Jingkun Wang,Ting Wang,Zhizhong Yang,Yanfei Niu,Zhennan She,Li Wang
Front. Med.    2017, 11 (1): 32-47.   https://doi.org/10.1007/s11684-016-0495-2
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One of the primary purposes of the innovative development of ethnomedicines is to use their excellent safety and significant efficacy to serve a broader population. To achieve this purpose, modern scientific and technological means should be referenced, and relevant national laws and regulations as well as technical guides should be strictly followed to develop standards and to perform systemic research in producing ethnomedicines. Finally, ethnomedicines, which are applied to a limited extent in ethnic areas, can be transformed into safe, effective, and quality-controllable medical products to relieve the pain of more patients. The innovative development path of ethnomedicines includes the following three primary stages: resource study, standardized development research, and industrialization of the achievements and efforts for internationalization. The implementation of this path is always guaranteed by the research and development platform and the talent team. This article is based on the accumulation of long-term practice and is combined with the relevant disciplines, laws and regulations, and technical guidance from the research and development of ethnomedicines. The intention is to perform an in-depth analysis and explanation of the major research thinking, methods, contents, and technical paths involved in all stages of the innovative development path of ethnomedicines to provide useful references for the development of proper ethnomedicine use.

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Gut microbial balance and liver transplantation: alteration, management, and prediction
Xinyao Tian, Zhe Yang, Fangzhou Luo, Shusen Zheng
Front. Med.    2018, 12 (2): 123-129.   https://doi.org/10.1007/s11684-017-0563-2
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Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia–reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

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Detection of digestive malignancies and post-gastrectomy complications via gastrointestinal fluid examination
Lei Huang,Aman Xu
Front. Med.    2017, 11 (1): 20-31.   https://doi.org/10.1007/s11684-016-0493-4
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To date, gastric carcinoma (GC) is one of the common and fatal digestive malignancies worldwide. The prognosis of GC is not always satisfactory because of late diagnosis. Scholars are keen on discovering novel accurate and economical biomarkers in body liquids for GC screening to detect and evaluate the lesion before the results of imaging techniques are obtained. While traditional serum assays have limited sensitivity and specificity, gastrointestinal juice may provide relevant specific biomarkers because of its close contact with the tumor. Herein, the current progress in the relationship between gastrointestinal fluid analyses and GC is systematically and comprehensively reviewed. The detection of gastric juice pH, fluorescence spectrum, cytology, Helicobacter pylori-associated markers, nitrosamines, conventional tumor markers, amino acids, proteomics, microRNAs, long noncoding RNAs, protein-coding genes, vitamin C, etc., and combination tests of different category markers could provide important diagnostic and prognostic clues for gastrointestinal diseases. Particularly, early GC may be efficiently screened using gastric juice. Gastrointestinal fluid examination could also predict the adverse effects of postgastrectomy, such as pancreatic leakage, fistula, and abscess. Gastric fluid markers should be further studied to reveal the early predicators of malignancy and complications. The methods for obtaining the samples of gastrointestinal juice with minimum incision should also be comprehensively investigated.

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Incremental value of contrast echocardiography in the diagnosis of left ventricular noncompaction
Xiaoxiao Zhang,Li Yuan,Linli Qiu,Yali Yang,Qing Lv,Lin Li,Jing Wang,Lin He,Li Zhang,Xinfang Wang,Mingxing Xie,Xu Yu Jin
Front. Med.    2016, 10 (4): 499-506.   https://doi.org/10.1007/s11684-016-0473-8
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Contrast echocardiography with left ventricular opacification (LVO) improves the definition of endocardium in two-dimensional echocardiography (2DE). This study was aimed to determine whether LVO offered added diagnostic value in noncompaction of left ventricular myocardium (NCVM). A total of 85 patients (40±20 years, 54 males) with suspected NCVM were subjected to transthoracic 2DE and LVO, and 40 healthy volunteers were examined with 2DE and assigned as control subjects. The location of NCVM, the thickness ratio of noncompacted to compacted myocardium (NCR), and the cavity size and ejection fraction of LV were quantified. Results revealed that NCVM was mainly located in the LV medium (53.2%), apical (46.2%) segments, and lateral wall (39.8%). The NCR obtained through LVO was greater than that detected through 2DE (4.2±1.3 vs. 3.3±1.2, P<0.001), and higher inter-correlations and less intra- and inter-observer variabilities were determined in the former than in the latter. The NCVM detection rates were also increased from 63.5% via 2DE to 83.5% via LVO and 89.4% via 2DE combined with LVO (2DE+ LVO) (P = 0.0004). The LV cavity size was greater and the LV ejection fraction (LVEF) was lower in the NCVM patients than in the control group (P<0.01). In the NCVM group, the LV cavity size was higher and the LVEF was lower in LVO than in 2DE (P<0.01). In conclusion, contrast echocardiography contributes significant sensitivity and reproducibility to routine transthoracic echocardiography in NCVM diagnosis. Therefore, this technique should be clinically performed to diagnose suspected NCVM.

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Histone variants: critical determinants in tumour heterogeneity
Tao Wang, Florent Chuffart, Ekaterina Bourova-Flin, Jin Wang, Jianqing Mi, Sophie Rousseaux, Saadi Khochbin
Front. Med.    2019, 13 (3): 289-297.   https://doi.org/10.1007/s11684-018-0667-3
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Malignant cell transformation could be considered as a series of cell reprogramming events driven by oncogenic transcription factors and upstream signalling pathways. Chromatin plasticity and dynamics are critical determinants in the control of cell reprograming. An increase in chromatin dynamics could therefore constitute an essential step in driving oncogenesis and in generating tumour cell heterogeneity, which is indispensable for the selection of aggressive properties, including the ability of cells to disseminate and acquire resistance to treatments. Histone supply and dosage, as well as histone variants, are the best-known regulators of chromatin dynamics. By facilitating cell reprogramming, histone under-dosage and histone variants should also be crucial in cell transformation and tumour metastasis. Here we summarize and discuss our knowledge of the role of histone supply and histone variants in chromatin dynamics and their ability to enhance oncogenic cell reprogramming and tumour heterogeneity.

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Yellow fever and Hajj: with all eyes on Zika, a familiar flavivirus remains a threat
Qanta A. Ahmed,Ziad A. Memish
Front. Med.    2016, 10 (4): 527-530.   https://doi.org/10.1007/s11684-016-0487-2
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Hajj is among the world’s largest mass gatherings, drawing between 2 and 3.5 million Muslims from 183 nations annually to perform pilgrimage in Mecca, Saudi Arabia. Infectious disease outbreaks can be imported both into the Hajj population and exported internationally by returning pilgrims. The domestic Saudi population can also be at risk of outbreaks traveling amid this mass migration. With yellow fever reported for the first time in China following the infection of expatriate Chinese workers in Angola and a full blown outbreak underway in wider West Africa, the prospect of yellow fever outbreaks in Asia threatens to impact Saudi Arabia, both during and beyond the Hajj season. With global focus trained on Zika, the rising threat of yellow fever cannot be overlooked. Strategies to mitigate risk to Saudi Arabia and the global population are thereby suggested.

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New medical risks affecting obstetrics after implementation of the two-child policy in China
Qiang Li, Dongrui Deng
Front. Med.    2017, 11 (4): 570-575.   https://doi.org/10.1007/s11684-017-0552-5
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China recently instituted a two-child policy in response to its aging population, declining workforce and demographic dividend, and the need to develop asocial economy. Additionally, women generally delay having a second child because of the overwhelming pressure in their lives. With the improvements in assisted fertility technologies in recent years, the number of elderly women attempting to bear children has increased. The quality of woman’s eggs and a man’s sperm declined dramatically with increasing age, leading to an increased risk of pregnancy-related complications among older women. Therefore, the types of fertility problems experienced by elderly females must be provided with considerable attention by obstetricians. This commentary article focuses on the medical problems faced by older second-child pregnant women. This work discusses their increased rates of infertility, spontaneous abortion, fetal malformation, gestational diabetes, cesarean section, placenta previa, postpartum hemorrhage, postpartum depression, and hypertensive disorders, which complicate pregnancy.

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Application of liquid biopsy in precision medicine: opportunities and challenges
Junyun Wang, Shuang Chang, Guochao Li, Yingli Sun
Front. Med.    2017, 11 (4): 522-527.   https://doi.org/10.1007/s11684-017-0526-7
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Precision medicine for cancer patients aims to adopt the most suitable treatment options during diagnosis and treatment of individuals. Detecting circulating tumor cell (CTC) or circulating tumor DNA (ctDNA) in plasma or serum could serve as liquid biopsy, which would be useful for numerous diagnostic applications. Liquid biopsies can help clinicians screen and detect cancer early, stratify patients to the most suitable treatment and real-time monitoring of treatment response and resistance mechanisms in the tumor, evaluate the risk for metastatic relapse, and estimate prognosis. We summarized the advantages and disadvantages of tissue and liquid biopsies. We also further compared and analyzed the advantages and limitations of detecting CTCs, ctDNAs, and exosomes. Furthermore, we reviewed the literature related with the application of serum or plasma CTCs, ctDNAs, and exosomes for diagnosis and prognosis of cancer. We also analyzed their opportunities and challenges as future biomarkers. In the future, liquid biopsies could be used to guide cancer treatment. They could also provide the ideal scheme to personalize treatment in precision medicine.

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Holistic integrative medicine: toward a new era of medical advancement
Daiming Fan
Front. Med.    2017, 11 (1): 152-159.   https://doi.org/10.1007/s11684-017-0499-6
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Medicine has encountered unprecedented problems associated with changes in nature, society, and environment, as well as with new human quests for survival, longevity, and health. In the meantime, the development of medicine is facing challenges that resulted from the over-division and specialization of disciplines and the fragmentation of medical knowledge. To construct a new medical system that is more suitable for human health and disease treatment, holistic integrative medicine (HIM), which regards the human body as a holistic entity, organically integrates the most advanced knowledge and theories in each medical field and the most effective practices in various clinical specialties to revise and adjust on the basis of social, environmental, and psychological conditions. HIM is the inevitable and necessary direction for the future development of medicine. In this article, we illustrated the connotation of HIM, the differences between HIM and other medical conceptions, and the practice of HIM in recent years.

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Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs
Fengmin Lu, Jie Wang, Xiangmei Chen, Dongping Xu, Ningshao Xia
Front. Med.    2017, 11 (4): 502-508.   https://doi.org/10.1007/s11684-017-0590-z
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Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen (HBsAg) that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a “para-functional cure,” a status nearly close to the functional cure of chronic hepatitis B, to distinguish the “functional cure” characterized as serum HBsAg loss with or without anti-HBs seroconversion.

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Efficacy and safety of JAK inhibitor INC424 in patients with primary and post-polycythemia vera or post-essential thrombocythemia myelofibrosis in the Chinese population
Xin Du,Daobin Zhou
Front. Med.    2016, 10 (4): 437-443.   https://doi.org/10.1007/s11684-016-0472-9
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A phase II study (A2202) was performed to evaluate the efficacy and safety of JAK inhibitor ruxolitinib in 63 Chinese MF patients. Ruxolitinib was given twice a day (bid) at a starting dose of 15 mg (n=25) or 20 mg (n=38) based on a baseline platelet count. About 94.7% of the patients achieved a reduction in spleen size, 27.0% of which exhibited significant reduction (≥35%) at week 24. Significant improvement in debilitating constitutional symptoms, as assessed by MFSAF v2.0, was observed in patients treated with ruxolitinib. Ruxolitinib treatment was generally well tolerated by Chinese patients. Although the treatment was associated with an increase in certain adverse events (AEs) that were established as identified risks (anemia and thrombocytopenia), these AEs were considered manageable in this clinical setting. Ruxolitinib provided substantial reductions in splenomegaly and improvements in symptoms, and was well-tolerated by Chinese patients with MF.

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Machine perfusion versus cold storage of livers: a meta-analysis
Sushun Liu,Qing Pang,Jingyao Zhang,Mimi Zhai,Sinan Liu,Chang Liu
Front. Med.    2016, 10 (4): 451-464.   https://doi.org/10.1007/s11684-016-0474-7
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Different organ preservation methods are key factors influencing the results of liver transplantation. In this study, the outcomes of experimental models receiving donation after cardiac death (DCD) livers preserved through machine perfusion (MP) or static cold storage (CS) were compared by conducting a meta-analysis. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to compare pooled data from two animal species. Twenty-four studies involving MP preservation were included in the meta-analysis. Compared with CS preservation, MP can reduce the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and hyaluronic acid (HA) and the changes in liver weight. By contrast, MP can enhance bile production and portal vein flow (PVF). Alkaline phosphatase (ALP) levels and histological changes significantly differed between the two preservation methods. In conclusion, MP of DCD livers is superior to CS in experimental animals.

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