Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2018, Volume 12 Issue 3
A large amount of somatic genomic mutations have been reported in tumor samples of patients with lung squamous cell carcinoma. Here, Zhang, Qu, and Zhou et al. report that the counterpart normal lung tissues also harbor somatic genomic variations that are absent in tumor samples of patients or the human genome references. They call these v [Detail] ...
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REVIEW
Gut microbiota and its implications in small bowel transplantation
Chenyang Wang, Qiurong Li, Jieshou Li
Front. Med.. 2018, 12 (3): 239-248.  
https://doi.org/10.1007/s11684-018-0617-0

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The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBT and the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host–microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.

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NKT cells in liver diseases
Shasha Zhu, Huimin Zhang, Li Bai
Front. Med.. 2018, 12 (3): 249-261.  
https://doi.org/10.1007/s11684-018-0622-3

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Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CD1d-expressing cells or bystander cells.

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γδ T cells in liver diseases
Xuefu Wang, Zhigang Tian
Front. Med.. 2018, 12 (3): 262-268.  
https://doi.org/10.1007/s11684-017-0584-x

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γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

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Natural killer cells in liver diseases
Meijuan Zheng, Haoyu Sun, Zhigang Tian
Front. Med.. 2018, 12 (3): 269-279.  
https://doi.org/10.1007/s11684-018-0621-4

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The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct “killer” functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.

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RESEARCH ARTICLE
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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Sub-cytotoxic concentrations of ionic silver promote the proliferation of human keratinocytes by inducing the production of reactive oxygen species
Xiaodong Duan, Daizhi Peng, Yilan Zhang, Yalan Huang, Xiao Liu, Ruifu Li, Xin Zhou, Jing Liu
Front. Med.. 2018, 12 (3): 289-300.  
https://doi.org/10.1007/s11684-017-0550-7

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Silver-containing preparations are widely used in the management of skin wounds, but the effects of silver ions on skin wound healing remain poorly understood. This study investigated the effects of silver ions (Ag+) on the proliferation of human skin keratinocytes (HaCaT) and the production of intracellular reactive oxygen species (ROS). After treating HaCaT cells with Ag+ and/or the active oxygen scavenger N-acetyl cysteine (NAC), cell proliferation and intracellular ROS generation were assessed using CCK-8 reagent and DCFH-DA fluorescent probe, respectively. In addition, 5-bromo-2-deoxyUridine (BrdU) incorporation assays, cell cycle flow cytometry, and proliferating cell nuclear antigen (PCNA) immunocytochemistry were conducted to further evaluate the effects of sub-cytotoxic Ag+ concentrations on HaCaT cells. The proliferation of HaCaT cells was promoted in the presence of 106 and 105 mol/L Ag+ at 24, 48, and 72 h. Intracellular ROS generation also significantly increased for 5–60 min after exposure to Ag+. The number of BrdU-positive cells and the presence of PCNA in HaCaT cells increased 48 h after the addition of 106 and 105 mol/L Ag+, with 105 mol/L Ag+ markedly increasing the cell proliferation index. These effects of sub-cytotoxic Ag+ concentrations were repressed by 5 mmol/L NAC. Our results suggest that sub-cytotoxic Ag+ concentrations promote the proliferation of human keratinocytes and might be associated with a moderate increase in intracellular ROS levels. This study provides important experimental evidence for developing novel silver-based wound agents or dressings with few or no cytotoxicity.

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Prevention of laryngeal webs through endoscopic keel placement for bilateral vocal cord lesions
Jian Chen, Yilai Shu, Matthew R. Naunheim, Min Chen, Lei Cheng, Haitao Wu
Front. Med.. 2018, 12 (3): 301-306.  
https://doi.org/10.1007/s11684-017-0549-0

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Transoral microresection for treatment of vocal cord lesions involving the anterior commissure may result in anterior glottic webs. In this study, we retrospectively reviewed 54 patients who underwent microsurgery for bilateral lesions involving the anterior commissure and categorized them into two groups. The keel placement and control groups received endoscopic keel placement and mitomycin C, respectively. During the follow-up of at least 1 year, the laryngeal web formation rate significantly decreased in the keel placement group compared with that in the control group (18.6% versus 54.5%, P<0.05). Furthermore, the voice handicap index-10 scores for patients without web formation decreased in both the keel placement and control groups (P<0.0001 and P<0.001, respectively). A pseudomembrane covering the vocal cords was detected in 16.3% (7 of 43) cases after keel removal. A total of 100% (7 of 7) of these cases and 2.8% (1 of 36) of the other cases formed laryngeal webs (P<0.0001). Endoscopic keel placement could be an effective method for preventing anterior glottic webs after surgery for bilateral vocal cord diseases involving the anterior commissure. The pseudomembrane observed at the time of keel removal may imply a high risk of web formation.

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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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CASE REPORT
Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism: a case report
Dong Wang, Min Tian, Guanglin Cui, Dao Wen Wang
Front. Med.. 2018, 12 (3): 319-323.  
https://doi.org/10.1007/s11684-017-0553-4

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Antithrombin and protein C are two crucial members in the anticoagulant system and play important roles in hemostasis. Mutations in SERPINC1 and PROC lead to deficiency or dysfunction of the two proteins, which could result in venous thromboembolism (VTE). Here, we report a Chinese 22-year-old young man who developed recurrent and serious VTE in cerebral veins, visceral veins, and deep veins of the lower extremity. Laboratory tests and direct sequencing of PROC and SERPINC1 were conducted for the patient and his family members. Coagulation tests revealed that the patient presented type I antithrombin deficiency combined with decreased protein C activity resulting from a small insertion mutation c.848_849insGATGT in SERPINC1 and a short deletion variant c.572_574delAGA in PROC. This combination of the two mutations was absent in 400 healthy subjects each from southern and northern China. Then, we summarized all the mutations of the SERPINC1 and PROC gene reported in the Chinese Han population. This study demonstrates that the combination of antithrombin deficiency and decreased protein C activity can result in severe VTE and that the coexistence of different genetic factors may increase the risk of VTE.

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A rare case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) translocation
Xiaofeng Shi, Rong Ba, Haiyan You, Qian Jiang, Jiansong Huang, Jianhua Mao, Lanxiu Han, Shuo Zhang, Qin Zhuang, Xianqiu Yu, Lixia Wang, Yun Wang, Dongya Li, Wei Zhu, Yong Zhang, Yan Zhu, Xiaodong Xi
Front. Med.. 2018, 12 (3): 324-329.  
https://doi.org/10.1007/s11684-017-0558-z

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Splenic lymphoma with villous lymphocytes (SLVL) or splenic marginal zone lymphoma with circulating villous lymphocytes is rare, and prolymphocytic transformation of SLVL is rarer. At present, only one case of SLVL with t(8;14)(q24;q32) translocation has been reported. In this study, we report a case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) chromosome translocation that we inclined to SLVL with a prolymphocytic transformation. A 73-year-old female showed marked hepatosplenomegaly and high lymphocytosis (lymphocytes>200×109/L). The abnormal lymphocytes had short coarse villi and round nuclei with prominent nucleoli. The immunophenotypes showed CD19+, CD20+, HLA-DR+, CD22+, CD5+, Kappa+, CD25dim, CD71dim, Lambda, CD7, CD10, CD23, CD34, CD33, CD13, CD14, CD117, CD64, CD103, and CD11c. The karyotype showed complex abnormality: 46XX,+3,−10, t(8;14)(q24;q32)[11]/46XX[9]. The cytoplasmic projection, immunological characteristics, and trisomy 3 chromosome abnormality supported the diagnosis of SLVL. However, the presence of prominent nucleoli and high lymphocytosis suggested prolymphocytic transformation, probably as a result of t(8,14) chromosome translocation. In this report, we described an unusual case of B-lymphoproliferative disorder with villous lymphocytes harboring t(8;14)(q24;q32) translocation, which could provide help in the diagnosis and differential diagnosis of B-lymphocytic proliferative diseases.

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Invasive mucinous adenocarcinoma with lepidic-predominant pattern coexisted with tuberculosis: a case report
Xinxin Xu, Yinshi Guo, Qiuying Li, Ling Yang, Jianqiang Kang
Front. Med.. 2018, 12 (3): 330-333.  
https://doi.org/10.1007/s11684-017-0545-4

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We observed a rare case of invasive mucinous adenocarcinoma (IMA) with a lepidic-predominant pattern accompanied by pulmonary tuberculosis. An 85-year-old man with repeated cough and sputum was admitted to Xinhua Hospital. T-SPOT test result was 212 pg/ml (reference value of negative is<14 pg/ml), Mycobacterium tuberculosis culture was positive, and tuberculin skin test (PPD) was negative (skin induration<5 mm). The patient was treated with several courses of antibiotics and anti-tuberculosis treatments. Repeated chest CT scans showed disease progression. Bronchoscopy yielded negative results. PET-CT scans showed negative results. A percutaneous lung biopsy revealed mucin-secreting cells lining the alveolar walls. IMA with a lepidic-predominant pattern was diagnosed after invasiveness was found after experimental treatments. Simultaneous occurrence of pulmonary tuberculosis and lung cancer are common; however, the present case of IMA having a lepidic-predominant pattern and coexisting with active tuberculosis has not been reported yet.

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Xingnao Kaiqiao acupuncture combined with Angong Niuhuang Wan for a patient under persistent vegetative state: a case report
Hujie Song, Xiao Chen, Yalan Yu, Ling Zhang
Front. Med.. 2018, 12 (3): 334-339.  
https://doi.org/10.1007/s11684-017-0539-2

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Persistent vegetative state (PVS) is a clinical condition wherein the cerebral cortex loses its function although brain stem function remains relatively intact. It has high mortality and disability rates. Although treatment for PVS is extensively studied in developed countries, little breakthrough has been made. In China, many PVS patients who were treated with traditional Chinese medicine (TCM) and acupuncture therapy were reported to have regained consciousness. In our department, we have been investigating TCM diagnosis and treatment methods for PVS for many years and have summarized a set of curative programs. Our patient is a male and 5 years and 3 months of age. He had traumatic brain injury and had been unconscious for three months on admission. Considering his condition, we adopted Xingnao Kaiqiao acupuncture, oral Angong Niuhuang Wan, and Xingnaojing intravenous drip. After the 50-day treatment, his health significantly improved and is nearly similar to that of a healthy child, indicating that the treatment is effective for PVS. Therefore, we decided to report the case and treatment methods.

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LETTER TO FRONTIERS OF MEDICINE
Efficacy and safety of benralizumab in patients with eosinophilic asthma: a meta-analysis of randomized placebo-controlled trials
Ting Liu, Faping Wang, Geng Wang, Hui Mao
Front. Med.. 2018, 12 (3): 340-349.  
https://doi.org/10.1007/s11684-017-0565-0

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Benralizumab is a monoclonal antibody that targets interleukin-5 receptor α to deplete blood eosinophils and improve the clinical outcomes of allergic asthma. We conducted a meta-analysis to evaluate the safety and efficacy of different doses of benralizumab in patients with eosinophilic asthma. All randomized controlled trials involving benralizumab treatment for patients with eosinophilic asthma, which were searched in PubMed, Embase, and the Cochrane Library published until January 2017, as well as the rate of asthmatic exacerbation, pulmonary functionality, asthma control, quality of life scores, and adverse events were included. Randomized-effect models were used in the meta-analysis to calculate the pooled mean difference, relative risks, and 95% confidence intervals. Five studies involving 1951 patients were identified. Compared with the placebo, benralizumab treatment demonstrated significant improvements in the forced expiratory volume in 1?s (FEV1), Asthma Quality of Life Questionnaire scores, decreased asthmatic exacerbation and Asthma Control Questionnaire-6 (ACQ-6) scores. Benralizumab treatment was also not associated with increased adverse events. These findings indicated that benralizumab can be safely used to improve FEV1, enhance patient symptom control and quality of life, and reduce the risk of exacerbations and ACQ-6 scores in patients with eosinophilic asthma. Furthermore, our meta-analysis showed that benralizumab with 30 mg (every eight weeks) dosage can improve the health-related quality of life and appear to be more effective than 30 mg (every four weeks) dosage. Overall, data indicated that the optimal dosing regimen for benralizumab was possibly 30 mg (every eight weeks).

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Radical versus conservative surgical treatment of liver hydatid cysts: a meta-analysis
Qing Pang, Hao Jin, Zhongran Man, Yong Wang, Song Yang, Zongkuang Li, Yimin Lu, Huichun Liu, Lei Zhou
Front. Med.. 2018, 12 (3): 350-359.  
https://doi.org/10.1007/s11684-017-0559-y

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To date, the efficacy of radical surgery (RS) versus conservative surgery (CS) for liver hydatid cysts (LHC) remains controversial. This meta-analysis was conducted to compare the two interventions. PubMed, Embase, and Web of Science were searched from their inceptions until June 2016. Meta-analysis was performed using STATA 12.0 software. We identified 19 eligible studies from 10 countries by retrieval. In total, 1853 LHC patients who received RS were compared with 2274 patients treated by CS. The risk of postoperative overall complication, biliary fistula, and recurrence was significantly lower, and operation time was significantly longer in the RS group. However, no statistically significant differences were found in terms of mortality risk and the duration of hospital stay between RS and CS. No significant publication biases were observed in all the above analyses. In conclusion, RS reduces the rates of postoperative complications and recurrence, whereas no trend toward such a reduction in mortality was observed in LHC patients.

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14 articles