Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2016, Volume 10 Issue 2
Immunohistochemistry of hFIX-expressing hepatocytes in hemophilia B mice that received 5×1011 vg of rscAAV8-LP1-FIX vector. (Courtesy of Dr. Jinzhong Chen. See pages 212-218 by Wei Lu et al. for more information.)
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REVIEW
Middle East respiratory syndrome coronavirus: current situation and travel-associated concerns
Jaffar A. Al-Tawfiq,Ali S. Omrani,Ziad A. Memish
Front. Med.. 2016, 10 (2): 111-119.  
https://doi.org/10.1007/s11684-016-0446-y

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The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 brought back memories of the occurrence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. More than 1500 MERS-CoV cases were recorded in 42 months with a case fatality rate (CFR) of 40%. Meanwhile, 8000 cases of SARS-CoV were confirmed in six months with a CFR of 10%. The clinical presentation of MERS-CoV ranges from mild and non-specific presentation to progressive and severe pneumonia. No predictive signs or symptoms exist to differentiate MERS-CoV from community-acquired pneumonia in hospitalized patients. An apparent heterogeneity was observed in transmission. Most MERS-CoV cases were secondary to large outbreaks in healthcare settings. These cases were secondary to community-acquired cases, which may also cause family outbreaks. Travel-associated MERS infection remains low. However, the virus exhibited a clear tendency to cause large outbreaks outside the Arabian Peninsula as exemplified by the outbreak in the Republic of Korea. In this review, we summarize the current knowledge about MERS-CoV and highlight travel-related issues.

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Middle East respiratory syndrome coronavirus: a comprehensive review
Mahmoud M. Shehata,Mokhtar R. Gomaa,Mohamed A. Ali,Ghazi Kayali
Front. Med.. 2016, 10 (2): 120-136.  
https://doi.org/10.1007/s11684-016-0430-6

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The Middle East respiratory syndrome coronavirus was first identified in 2012 and has since then remained uncontrolled. Cases have been mostly reported in the Middle East, however travel-associated cases and outbreaks have also occurred. Nosocomial and zoonotic transmission of the virus appear to be the most important routes. The infection is severe and highly fatal thus necessitating rapid and efficacious interventions. Here, we performed a comprehensive review of published literature and summarized the epidemiology of the virus. In addition, we summarized the virological aspects of the infection and reviewed the animal models used as well as vaccination and antiviral tested against it.

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Research progress in pathogenic genes of hereditary non-syndromic mid-frequency deafness
Wenjun Xia,Fei Liu,Duan Ma
Front. Med.. 2016, 10 (2): 137-142.  
https://doi.org/10.1007/s11684-016-0449-8

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Hearing impairment is considered as the most prevalent impairment worldwide. Almost 600 million people in the world suffer from mild or moderate hearing impairment, an estimated 10% of the human population. Genetic factors play an important role in the pathogenesis of this disorder. Hereditary hearing loss is divided into syndromic hearing loss (associated with other anomalies) and non-syndromic hearing loss (not associated with other anomalies). Approximately 80% of genetic deafness is non-syndromic. On the basis of the frequency of hearing loss, hereditary non-syndromic hearing loss can be divided into high-, mid-, low-, and total-frequency hearing loss. An audiometric finding of mid-frequency sensorineural hearing loss, or a “bowl-shaped” audiogram, is uncommon. Up to now, merely 7 loci have been linked to mid-frequency hearing loss. Only four genetic mid-frequency deafness genes, namely, DFNA10 (EYA4), DFNA8/12 (TECTA), DFNA13 (COL11A2), DFNA44 (CCDC50), have been reported to date. This review summarizes the research progress of the four genes to draw attention to mid-frequency deafness genes.

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Regeneration of hair cells in the mammalian vestibular system
Wenyan Li,Dan You,Yan Chen,Renjie Chai,Huawei Li
Front. Med.. 2016, 10 (2): 143-151.  
https://doi.org/10.1007/s11684-016-0451-1

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Hair cells regenerate throughout the lifetime of non-mammalian vertebrates, allowing these animals to recover from hearing and balance deficits. Such regeneration does not occur efficiently in humans and other mammals. Thus, balance deficits become permanent and is a common sensory disorder all over the world. Since Forge and Warchol discovered the limited spontaneous regeneration of vestibular hair cells after gentamicin-induced damage in mature mammals, significant efforts have been exerted to trace the origin of the limited vestibular regeneration in mammals after hair cell loss. Moreover, recently many strategies have been developed to promote the hair cell regeneration and subsequent functional recovery of the vestibular system, including manipulating the Wnt, Notch and Atoh1. This article provides an overview of the recent advances in hair cell regeneration in mammalian vestibular epithelia. Furthermore, this review highlights the current limitations of hair cell regeneration and provides the possible solutions to regenerate functional hair cells and to partially restore vestibular function.

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Chemical transdifferentiation: closer to regenerative medicine
Aining Xu,Lin Cheng
Front. Med.. 2016, 10 (2): 152-165.  
https://doi.org/10.1007/s11684-016-0445-z

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Cell transdifferentiation, which directly switches one type of differentiated cells into another cell type, is more advantageous than cell reprogramming to generate pluripotent cells and differentiate them into functional cells. This process is crucial in regenerative medicine. However, the cell-converting strategies, which mainly depend on the virus-mediated expression of exogenous genes, have clinical safety concerns. Small molecules with compelling advantages are a potential alternative in manipulating cell fate conversion. In this review, we briefly retrospect the nature of cell transdifferentiation and summarize the current developments in the research of small molecules in promoting cell conversion. Particularly, we focus on the complete chemical compound-induced cell transdifferentiation, which is closer to the clinical translation in cell therapy. Despite these achievements, the mechanisms underpinning chemical transdifferentiation remain largely unknown. More importantly, identifying drugs that induce resident cell conversion in vivo to repair damaged tissue remains to be the end-goal in current regenerative medicine.

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Innovative development path of ethnomedicines: an overview of ethnomedicines in China
Zhaoyun Zhu,Ting Wang,Dehuan Fu,Yali Gui,Jingkun Wang,Tao Cui
Front. Med.. 2016, 10 (2): 166-177.  
https://doi.org/10.1007/s11684-016-0448-9

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In the long history of disease prevention and treatment, ancestral populations worldwide have gained knowledge and experiences in traditional medicines. For instance, ethnomedicines of Chinese ethnic minorities constitute an important part of traditional medicines. In our study, we firstly clarified the concept of ethnomedicines and the connotations of ethnopharmacology. The particularity of ethnomedicine research were then summed up, and the development profiles of the ethnomedicines of Chinese ethnic minorities were discussed by investigating the current status and existing problems. On this basis, we abstracted the innovative development path of ethnomedicines for the first time, which was found to follows:resource study → standardized development research → industrialization of the achievements and efforts for internationalization. We found that platform establishment and team training are keys to achieving innovative development. Hence, this study provided a basis for ethnomedicine development.

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RESEARCH ARTICLE
Bioinformatic exploration of MTA1-regulated gene networks in colon cancer
Chunxiao Li,Haijuan Wang,Feng Lin,Hui Li,Tao Wen,Haili Qian,Qimin Zhan
Front. Med.. 2016, 10 (2): 178-182.  
https://doi.org/10.1007/s11684-016-0442-2

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Metastasis-associated gene 1 (MTA1) controls a series of biological processes in tumor progression. Tumor progression is a complex process regulated by a gene network. The global cancer gene regulatory network must be analyzed to determine the position of MTA1 in the molecular network and its cooperative genes by further exploring the biological functions of this gene. We used TCGA data sets and GeneCards database to screen MTA1-related genes. GO and KEGG pathway analyses were conducted with DAVID and gene network analysis via STRING and Cytoscape. Results showed that in the development of colon cancer, MTA1 is linked to certain signal pathways, such as Wnt/Notch/nucleotide excision repair pathways. The findings also suggested that MTA1 demonstrates the closest relationship in a coregulation process with the key molecules AKT1, EP300, CREBBP, SMARCA4, RHOA, and CAD. These results lead MTA1 exploration to an in-depth investigation in different directions, such as Wnt, Notch, and DNA repair.

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Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis
Xinsen Xu,Yanyan Zhou,Runchen Miao,Wei Chen,Kai Qu,Qing Pang,Chang Liu
Front. Med.. 2016, 10 (2): 183-190.  
https://doi.org/10.1007/s11684-016-0440-4

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We performed weighted gene coexpression network analysis (WGCNA) to gain insights into the molecular aspects of hepatocellular carcinoma (HCC). Raw microarray datasets (including 488 samples) were downloaded from the Gene Expression Omnibus (GEO) website. Data were normalized using the RMA algorithm. We utilized the WGCNA to identify the coexpressed genes (modules) after non-specific filtering. Correlation and survival analyses were conducted using the modules, and gene ontology (GO) enrichment was applied to explore the possible mechanisms. Eight distinct modules were identified by the WGCNA. Pink and red modules were associated with liver function, whereas turquoise and black modules were inversely correlated with tumor staging. Poor outcomes were found in the low expression group in the turquoise module and in the high expression group in the red module. In addition, GO enrichment analysis suggested that inflammation, immune, virus-related, and interferon-mediated pathways were enriched in the turquoise module. Several potential biomarkers, such as cyclin-dependent kinase 1 (CDK1), topoisomerase 2α (TOP2A), and serpin peptidase inhibitor clade C (antithrombin) member 1 (SERPINC1), were also identified. In conclusion, gene signatures identified from the genome-based assays could contribute to HCC stratification. WGCNA was able to identify significant groups of genes associated with cancer prognosis.

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Association between telomere length and survival in cancer patients: a meta-analysis and review of literature
Xinsen Xu,Kai Qu,Qing Pang,Zhixin Wang,Yanyan Zhou,Chang Liu
Front. Med.. 2016, 10 (2): 191-203.  
https://doi.org/10.1007/s11684-016-0450-2

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The relationship between telomere length and cancer survival has been widely studied. To gain a deeper insight, we reviewed the published studies. A total of 29 studies evaluated telomere length in the peripheral blood; 22 studies evaluated telomere length in the tumor tissue. First, in the peripheral blood studies, for solid tumor patients with shortened telomere length, the combined hazard ratios (HRs) for mortality and tumor progression were 1.21 (95%CI, 1.10–1.32) and 1.71 (95%CI, 1.37–2.13), respectively. Meanwhile, in hematology malignancy, the combined HRs for mortality and tumor progression were 2.83 (95%CI, 2.14–3.74) and 2.65 (95%CI, 2.18–3.22), respectively. Second, in the studies that use tumor tissue, for patients with shortened telomeres, the combined HRs for mortality and tumor progression were 1.26 (95%CI, 0.95–1.66) and 1.65 (95%CI, 1.26–2.15), respectively. In the studies that calculate the telomere length ratios of tumor tissue to adjacent normal mucosa, for patients with lower telomere length ratios, the combined HRs were 0.66 (95%CI, 0.53–0.83) and 0.74 (95%CI, 0.41–1.32) for mortality and tumor progression, respectively. In conclusion, shortened telomere in peripheral blood and tumor tissue might indicate poor survival for cancer patients. However, by calculating the telomere length ratios of tumor tissue to adjacent normal mucosa, the lower ratio might indicate better survival.

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CD176 single-chain variable antibody fragment inhibits the adhesion of cancer cells to endothelial cells and hepatocytes
Jiangnan Liu,Bin Yi,Zhe Zhang,Yi Cao
Front. Med.. 2016, 10 (2): 204-211.  
https://doi.org/10.1007/s11684-016-0443-1

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CD176 (Thomsen-Friedenreich antigen) is a tumor-associated carbohydrate epitope (glycotope) functionally involved in blood spread and liver metastasis of cancer cells by mediating the adhesion of cancer cells to endothelial cells and hepatocytes, respectively. CD176 could be a promising target for antitumor immunotherapy. We applied B lymphocytes obtained from mice immunized with CD176 antigen and constructed a phage display library. A positive clone of CD176 single-chain variable antibody fragment (scFv) was successfully screened from this library. The CD176 scFv was expressed in Escherichia coli and purified. The purified scFv can bind to the natural CD176 expressed on the surface of cancer cells. Furthermore, the CD176 scFv inhibits the adhesion of CD176+ cancer cells to endothelial cells and hepatocytes. This CD176 scFv provides a basis for future development of recombinant CD176-specific antibodies that can be used in therapeutic application.

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Gene therapy for hemophilia B mice with scAAV8-LP1-hFIX
Wei Lu,Qingzhang Zhou,Hao Yang,Hao Wang,Yexing Gu,Qi Shen,Jinglun Xue,Xiaoyan Dong,Jinzhong Chen
Front. Med.. 2016, 10 (2): 212-218.  
https://doi.org/10.1007/s11684-016-0438-y

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Hemophilia B is a hemorrhagic disease caused by the deficiency of clotting factor IX (FIX). Gene therapy might be the ultimate strategy for the disease. However, two main problems that should be solved in gene therapy for hemophilia B are immunity and safety. Self-complementary adeno-associated virus serotype 8 (scAAV8), a non-human primate AAV featuring low immunogenicity and high transfection efficiency in liver cells, might be a potential vector for hemophilia B gene therapy. A strong liver-specific promoter-1 (LP1) was inserted and mutant human FIX Arg338Ala was introduced into plasmid scAAV8-LP1 to develop an optimized AAV8 vector that expresses human clotting factor FIX (hFIX). The efficiency of scAAV8-LP1-hFIX administered through normal systemic injection or hydrodynamic injection was compared. A high expression was achieved using hydrodynamic injection, and the peak hFIX expression levels in the 5×1011 and 1×1011 virus genome (vg) cohorts were 31.94% and 25.02% of normal level, respectively, at 60 days post-injection. From the perspective of long-term (200 days) expression, both injection methods presented promising results with the concentration value maintained above 4% of normal plasma. The results were further verified by enzyme-linked immunosorbent assay and activated partial thromboplastin time. Our study provides a potential gene therapy method for hemophilia B.

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Perceived resource support for chronic illnesses among diabetics in north-western China
Huiqin Zhong,Ya Shao,Ling Fan,Tangshen Zhong,Lu Ren,Yan Wang
Front. Med.. 2016, 10 (2): 219-227.  
https://doi.org/10.1007/s11684-016-0441-3

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A high level of social support can improve long-term diabetes self-management. Support from a single source has been evaluated. This study aims to analyze support from multiple and multilevel sources for diabetic patients by using the Chronic Illness Resources Survey (CIRS). Factors influencing the utilization of the CIRS were also evaluated. A total of 297 patients with diabetes were investigated using the CIRS and Perceived Diabetes Self-management Scale in Shihezi City, China. Descriptive statistics were used to explain demographic variables and scores of the scales. Factors affecting the utilization of chronic illness resources were determined through univariate analysis and then examined by multivariate logistic regression analysis. Of the 297 diabetic patients surveyed, 67% failed to reach the standard (more than 3 points) of utilizing chronic illness resources. Moreover, utilization of chronic illness resources was positively moderately correlated with self-management of diabetes (r = 0.75, P <0.05). According to the multivariate logistic regression analysis, age (OR, 3.42; 95%CI, 1.19–9.84) and monthly income (OR, 5.27; 95%CI, 1.86–14.90) were significantly positively associated with the CIRS score. Individuals with high school (OR, 2.61; 95%CI, 1.13–6.05) and college (OR, 3.02; 95%CI, 1.13–8.04) degrees obtained higher scores in the survey than those with elementary school education. Results indicated that utilization of resources and support for chronic illness self-management, particularly personal adjustment and organization, were not ideal among diabetics in the communities of north-western China. Improved utilization of chronic illness resources was conducive for proper diabetes self-management. Furthermore, the level of utilization of chronic illness resources increased with age, literacy level, and monthly income.

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COMMENTARY
Curbing the burden of lung cancer
Alexandra Urman,H. Dean Hosgood
Front. Med.. 2016, 10 (2): 228-232.  
https://doi.org/10.1007/s11684-016-0447-x

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Lung cancer contributes substantially to the global burden of disease and healthcare costs. New screening modalities using low-dose computerized tomography are promising tools for early detection leading to curative surgery. However, the screening and follow-up diagnostic procedures of these techniques may be costly. Focusing on prevention is an important factor to reduce the burden of screening, treatment, and lung cancer deaths. The International Agency for Research on Cancer has identified several lung carcinogens, which we believe can be considered actionable when developing prevention strategies. To curb the societal burden of lung cancer, healthcare resources need to be focused on early detection and screening and on mitigating exposure(s) of a person to known lung carcinogens, such as active tobacco smoking, household air pollution (HAP), and outdoor air pollution. Evidence has also suggested that these known lung carcinogens may be associated with genetic predispositions, supporting the hypothesis that lung cancers attributed to differing exposures may have developed from unique underlying genetic mechanisms attributed to the exposure of interest. For instance, smoking-attributed lung cancer involves novel genetic markers of risk compared with HAP-attributed lung cancer. Therefore, genetic risk markers may be used in risk stratification to identify subpopulations that are at a higher risk for developing lung cancer attributed to a given exposure. Such targeted prevention strategies suggest that precision prevention strategies may be possible in the future; however, much work is needed to determine whether these strategies will be viable.

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LETTER TO FRONTIERS OF MEDICINE
Health: a dream from reality to the future
Chunsong Hu,Qinghua Wu
Front. Med.. 2016, 10 (2): 233-235.  
https://doi.org/10.1007/s11684-016-0444-0

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This paper argues that health is a realistic productive force that may enhance the index of happiness. As the basis of all developments and the source of a person’s and his/her family’s happiness, health requires not only primary and secondary prevention, but also policy prevention, that is to say, grade-zero prevention. Therefore, people should pay more attention to Health in All Policies. As a new preventive strategy, the policy prevention will help improve people’s health significantly and promote the concepts of “Healthy China” and “the Chinese Dream” or “the World Dream” to realize a dream from reality to the future.

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14 articles