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 1
Midline2 is overexpressed in breast cancer, promotes cell proliferation and correlates with poor prognosis. The shown breast cancer sections are immunohistochemically stained to display Midline2 expression in tumors. (Courtesy of Dr. Mengfeng Li. See pages 41?51 by Lan Wang et al. for more information.
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REVIEW
Overview on acute-on-chronic liver failure
Jing Zhang,Shan Gao,Zhongping Duan,Ke-Qin Hu
Front. Med.. 2016, 10 (1): 1-17.  
https://doi.org/10.1007/s11684-016-0439-x

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Liver failure (LF) is defined as severe dysfunction in hepatic synthesis, detoxification, and metabolism induced by various etiologies. Clinical presentation of LF typically includes severe jaundice, coagulation disorder, hepatic encephalopathy, and ascites. LF can be classified into acute LF, acute-on-chronic LF (ACLF), and chronic LF. ACLF has been demonstrated as a distinct syndrome with unique clinical presentation and outcomes. The severity, curability, and reversibility of ACLF have attracted considerable attention. Remarkable developments in ACLF-related conception, diagnostic criteria, pathogenesis, and therapy have been achieved. However, this disease, especially its diagnostic criteria, remains controversial. In this paper, we systemically reviewed the current understanding of ACLF from its definition, etiology, pathophysiology, pathology, and clinical presentation to management by thoroughly comparing important findings between east and west countries, as well as those from other regions. We also discussed the controversies, challenges, and needs for future studies to promote the standardization and optimization of the diagnosis and treatment for ACLF.

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Therapeutic application of hydrogen sulfide donors: the potential and challenges
Dan Wu,Qingxun Hu,Yizhun Zhu
Front. Med.. 2016, 10 (1): 18-27.  
https://doi.org/10.1007/s11684-015-0427-6

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Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been considered a toxic gas and environment hazard. However, evidences show that H2S plays a great role in many physiological and pathological activities, and it exhibits different effects when applied at various doses. In this review, we summarize the chemistry and biomedical applications of H2S-releasing compounds, including inorganic salts, phosphorodithioate derivatives, derivatives of Allium sativum extracts, derivatives of thioaminoacids, and derivatives of anti-inflammatory drugs.

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Traditional Chinese medicine: potential approaches from modern dynamical complexity theories
Yan Ma,Kehua Zhou,Jing Fan,Shuchen Sun
Front. Med.. 2016, 10 (1): 28-32.  
https://doi.org/10.1007/s11684-016-0434-2

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Despite the widespread use of traditional Chinese medicine (TCM) in clinical settings, proving its effectiveness via scientific trials is still a challenge. TCM views the human body as a complex dynamical system, and focuses on the balance of the human body, both internally and with its external environment. Such fundamental concepts require investigations using system-level quantification approaches, which are beyond conventional reductionism. Only methods that quantify dynamical complexity can bring new insights into the evaluation of TCM. In a previous article, we briefly introduced the potential value of Multiscale Entropy (MSE) analysis in TCM. This article aims to explain the existing challenges in TCM quantification, to introduce the consistency of dynamical complexity theories and TCM theories, and to inspire future system-level research on health and disease.

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Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications
Aixiu Qiao,Feng Gu,Xiaojing Guo,Xinmin Zhang,Li Fu
Front. Med.. 2016, 10 (1): 33-40.  
https://doi.org/10.1007/s11684-016-0431-5

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Breast cancer is the most common malignant tumor in women, and the incidence of this disease has increased in recent years because of changes in diet, living environment, gestational age, and other unknown factors. Previous studies focused on cancer cells, but an increasing number of recent studies have analyzed the contribution of cancer microenvironment to the initiation and progression of breast cancer. Cancer-associated fibroblasts (CAFs), the most abundant cells in tumor stroma, secrete various active biomolecules, including extracellular matrix components, growth factors, cytokines, proteases, and hormones. CAFs not only facilitate the initiation, growth, angiogenesis, invasion, and metastasis of cancer but also serve as biomarkers in the clinical diagnosis, therapy, and prognosis of breast cancer. In this article, we reviewed the literature and summarized the research findings on CAFs in breast cancer.

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RESEARCH ARTICLE
Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer cell proliferation in vitro and in vivo
Lan Wang,Jueheng Wu,Jie Yuan,Xun Zhu,Hongmei Wu,Mengfeng Li
Front. Med.. 2016, 10 (1): 41-51.  
https://doi.org/10.1007/s11684-016-0429-z

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Midline2 (MID2) is an ubiquitin-conjugating E2 enzyme linked to tumor progression and a novel interacting partner of breast cancer 1, early-onset (BRCA1). However, the role of MID2 in breast cancer remains unknown. This study investigated the expression, prognostic value, and role of MID2 in breast cancer. The expression of MID2 mRNA and protein was significantly upregulated in breast cancer tissue and established cell lines compared with that in normal breast epithelial cells and paired adjacent non-tumor tissue (P<0.001). Immunohistochemical analysis demonstrated that MID2 was overexpressed in 272 of 284 (95.8%) paraffin-embedded, archived breast cancer tissue. Moreover, MID2 expression increased with advanced clinical stage (P<0.001). High MID2 expression was significantly associated with advanced clinical stages and T, N, and M staging (all P<0.05). Univariate and multivariate analyses indicated that high MID2 expression was an independent prognostic factor for poor overall survival in the entire cohort (93.73 vs. 172.1 months; P<0.001, log-rank test) and in subgroups with stages Tis+ I+ II and III+ IV. Furthermore, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide colony formation, and anchorage-independent growth ability assays were conducted. Results showed that siRNA silencing of MID2 expression significantly reduced MCF-7 and MDA-MB-231 cell proliferation in vitro and blocked the growth of MDA-MB-231 cell xenograft tumors in vivo (P<0.05). This study indicated that MID2 may be a novel prognostic marker and interventional target in breast cancer.

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Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma
Zhi Xu,Chunxiang Cao,Haiyan Xia,Shujing Shi,Lingzhi Hong,Xiaowei Wei,Dongying Gu,Jianmin Bian,Zijun Liu,Wenbin Huang,Yixin Zhang,Song He,Nikki Pui-Yue Lee,Jinfei Chen
Front. Med.. 2016, 10 (1): 52-60.  
https://doi.org/10.1007/s11684-016-0433-3

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Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P= 0.044). Kaplan-Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCC-specific overall survival (HR, 2.799; 95% CI, 1.346–5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.

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Comprehensive profiling of EBV gene expression in nasopharyngeal carcinoma through paired-end transcriptome sequencing
Lijuan Hu,Zhirui Lin,Yanheng Wu,Juqin Dong,Bo Zhao,Yanbing Cheng,Peiyu Huang,Lihua Xu,Tianliang Xia,Dan Xiong,Hongbo Wang,Manzhi Li,Ling Guo,Elliott Kieff,Yixin Zeng,Qian Zhong,Musheng Zeng
Front. Med.. 2016, 10 (1): 61-75.  
https://doi.org/10.1007/s11684-016-0436-0

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The latent expression pattern of Epstein-Barr Virus (EBV) genes in nasopharyngeal carcinoma (NPC) has been extensively investigated, and the expression of several lytic genes in NPC has been reported. However, comprehensive information through EBV transcriptome analysis in NPC is limited. We performed paired-end RNA-seq to systematically and comprehensively characterize the expression of EBV genes in NPC tissue and C666-1 NPC cell line, which consistently carries EBV. In addition to the transcripts restricted to type II latency infection, the type III latency EBNA3s genes and a substantial number of lytic genes, such as BZLF1, BRLF1, and BMRF1, were detected through RNA-seq and were further verified in C666-1 cells and NPC tissue through real-time PCR. We also performed clustering analysis to classify NPC patient groups in terms of EBV gene expression, which presented two subtypes of NPC samples. Results revealed interesting patterns of EBV gene expression in NPC patients. This clustering was correlated with many signaling pathways, such as those related to heterotrimeric G-protein signaling, inflammation mediated by chemokine and cytokine signaling, ribosomes, protein metabolism, influenza infection, and ECM-receptor interaction. Our combined findings suggested that the expression of EBV genes in NPC is restricted not only to type II latency genes but also to type III latency and lytic genes. This study provided further insights into the potential role of EBV in the development of NPC.

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Anti-β2 glycoprotein I antibodies in complex with β2 glycoprotein I induce platelet activation via two receptors: apolipoprotein E receptor 2' and glycoprotein I bα
Wenjing Zhang,Fei Gao,Donghe Lu,Na Sun,Xiaoxue Yin,Meili Jin,Yanhong Liu
Front. Med.. 2016, 10 (1): 76-84.  
https://doi.org/10.1007/s11684-015-0426-7

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Anti-β2 glycoprotein I (anti-β2GP I ) antibodies are important contributors to thrombosis, especially in patients with antiphospholipid syndrome (APS). However, the mechanism by which anti-β2GP I antibodies are involved in the pathogenesis of thrombosis is not fully understood. In this report, we investigated the role of anti-β2GP I antibodies in complexes with β2GP I as mediators of platelet activation, which can serve as a potential source contributing to thrombosis. We examined the involvement of the apolipoprotein E receptor 2' (apoER2') and glycoprotein I ba (GP I bα) in platelet activation induced by the anti-β2GP I /β2GP I complex. The interaction between the anti-β2GP I /β2GP I complex and platelets was examined using in vitro methods, in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by measuring GP II b/ III a activation and P-selectin expression and thromboxane B2 production as well as p38 mitogen-activated protein kinase phosphorylation. Our results revealed that the anti-β2GP I /β2GP I complex was able to activate platelets, and this activation was inhibited by either the anti-GP I bα antibody or the apoER2' inhibitor. Results showed that the anti-β2GP I /β2GP I complex induced platelet activation via GP I bα and apoER2', which may then contribute to the prothrombotic tendency in APS patients.

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Coronary leukocyte activation in relation to progression of coronary artery disease
Marijke A. de Vries,Arash Alipour,Erwin Birnie,Andrew Westzaan,Selvetta van Santen,Ellen van der Zwan,Anho H. Liem,Noëlle van der Meulen,Manuel Castro Cabezas
Front. Med.. 2016, 10 (1): 85-90.  
https://doi.org/10.1007/s11684-016-0435-1

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Leukocyte activation has been linked to atherogenesis, but there is little in vivo evidence for its role in the progression of atherosclerosis. We evaluated the predictive value for progression of coronary artery disease (CAD) of leukocyte activation markers in the coronary circulation. Monocyte and neutrophil CD11b, neutrophil CD66b expression and intracellular neutrophil myeloperoxidase (MPO) in the coronary arteries were determined by flow cytometry in patients undergoing coronary angiography. The primary outcome included fatal and nonfatal myocardial infarction or arterial vascular intervention due to unstable angina pectoris. In total 99 subjects who were included, 70 had CAD at inclusion (26 patients had single-vessel disease, 18 patients had two-vessel disease and 26 patients had three-vessel disease). The median follow-up duration was 2242 days (interquartile range: 2142–2358). During follow-up, 13 patients (13%) developed progression of CAD. Monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO measured in blood obtained from the coronary arteries were not associated with the progression of CAD. These data indicate that coronary monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO do not predict the risk of progression of CAD.

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Effectiveness of preventive medicine education and its determinants among medical students in Malaysia
Shirin Anil,Mohamed Shukry Zawahir,Redhwan Ahmed Al-Naggar
Front. Med.. 2016, 10 (1): 91-100.  
https://doi.org/10.1007/s11684-016-0428-0

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Preventive medicine has been incorporated in the medical school curriculum, but its effectiveness and the factors that affect it are yet to be widely looked into in the context of Malaysia. We aimed to measure the familiarity with, perception about the importance to learn, and the ability to practice preventive medicine as well as its determinants among the medical students in Malaysia. Thus, a cross sectional study was conducted through an anonymous online survey among 387 randomly selected final year medical students of four large public medical schools in Malaysia from March to September 2014. Of the total sample, only 340 (response rate 87.8%) gave a written informed consent and took part in the survey. The familiarity of the sample with preventive medicine was measured in 19 preventive medicine areas, and their perception about the importance of preventive medicine and their ability to practice it were gauged on a Likert scale (low score indicates disagreement and high indicates agreement). Descriptive statistical analysis was performed, followed by logistic regression. The mean age of the respondents was 23.7 (SD 0.77) years, and 61.2% (n = 208) of them were females. Results showed that 22.9% of the sample (n = 78) had a low familiarity with preventive medicine, whereas 76.8% (n = 261) had a high familiarity. The study sample specified that among all the preventive medicine subjects, screening and control as well as smoking cessation and immunization are “extremely important to learn.” In univariable analysis, being a female, medical school, family size, and perception about the importance to learn preventive medicine were associated with the ability to practice it. In multivariable analysis, the perception towards the importance to learn preventive medicine was the only significant determinant: aOR (adjusted odds ratio) for those who “agreed” 17.28 (95% CI aOR 4.44 – 67.26, P<0.001) and for “strongly agreed” 35.87 (95% CI aOR 8.04 – 159.87, P<0.001). Considering these findings, the familiarity of medical students with preventive medicine should be increased. The perception about the importance to learn preventive medicine is a strong determinant for the ability to practice it.

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CASE REPORT
Ecthyma gangrenosum of the scrotum: a case report
Wei Phin Tan,Benjamin A. Sherer,Jerome Hoeksema
Front. Med.. 2016, 10 (1): 101-103.  
https://doi.org/10.1007/s11684-016-0437-z

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A 43-year-old man with pancytopenia from chemotherapy for acute myeloid leukemia developed left scrotal pain, fever, and rigors. Physical exam revealed an ulcerating lesion with central necrosis and eschar surrounded by a halo of erythema on the inferior aspect of the left scrotum. The condition indicated an early necrotizing soft tissue infection. The patient was started on broad-spectrum antibiotics and taken to the operating room for a wound debridement. Blood and tissue cultures grew Pseudomonas aeruginosa, which confirmed the diagnosis of ecthyma gangrenosum of the scrotum. The fever resolved, and the wound healed without further progression after wet to dry dressing changes.

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COMMENTARY
Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization
Shuyang Sun,Zhiyuan Zhang
Front. Med.. 2016, 10 (1): 104-110.  
https://doi.org/10.1007/s11684-016-0432-4

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Advances in next-generation sequencing and bioinformatics have begun to reveal the complex genetic landscape in human cancer genomes, including oral squamous cell carcinoma (OSCC). Sophisticated preclinical models that fully represent intra- and inter-tumoral heterogeneity are required to understand the molecular diversity of cancer and achieve the goal of personalized therapies. Patient-derived xenograft (PDX) models generated from human tumor samples that can retain the histological and genetic features of their donor tumors have been shown to be the preferred preclinical tool in translational cancer research compared with other conventional preclinical models. Specifically, genetically well-defined PDX models can be applied to accelerate targeted antitumor drug development and biomarker discovery. Recently, we have successfully established and characterized an OSCC PDX panel as part of our tumor bio-bank for translational cancer research. In this paper, we discuss the establishment, characterization, and preclinical applications of the PDX models. In particular, we focus on the classification and applications of the PDX models based on validated annotations, including clinicopathological features, genomic profiles, and pharmacological testing information. We also explore the translational value of this well-annotated PDX panel in the development of co-clinical trials for patient stratification and treatment optimization in the near future. Although various limitations still exist, this preclinical approach should be further tested and improved.

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12 articles