Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2014, Volume 8 Issue 1
Immunohistochemistry of Twist in SCC specimens without lymph node metastasis. Cervical cancer tissue without lymph node metastasis shows lower Twist expression than those with metastasis. (Courtesy of Dr. Shixuan Wang. See Pages 106-112rong> By Tian Wang et al. for more information.)
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REVIEW
Hyperthermia on skin immune system and its application in the treatment of human papillomavirus-infected skin diseases
Xinghua Gao, Hongduo Chen
Front. Med.. 2014, 8 (1): 1-5.  
https://doi.org/10.1007/s11684-014-0309-3

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Hyperthermia is a condition characterized by increased body temperature as a consequence of failed thermoregulation. Hyperthermia occurs when a body produces or absorbs more heat than it dissipates. Hyperthermia also elicits various effects on the physiology of living cells. For instance, fever-range temperature (39β°C to 40β°C) can modulate the activities of immune cells, including antigen-presenting cells, T cells, and natural killer cells. Heat shock temperature (41β°C to 43β°C) can increase the immunogenicity of tumor cells. Cytotoxic temperature (>43β°C) can create an antigen source to induce an anti-tumor immune response. The immunomodulatory effect of hyperthermia has promoted an interest in hyperthermia-aided immunotherapy, particularly against tumors. Hyperthermia has also been used to treat deep fungal, bacterial, and viral skin infections. We conducted a series of open or controlled trials to treat skin human papillomavirus infection by inducing local hyperthermia. More than half of the patients were significantly cured compared with those in the control trial. A series of challenging clinical cases, such as large lesions in pregnant patients or patients with diabetes mellitus, were also successfully and safely managed using the proposed method. However, further studies should be conducted to clarify the underlying mechanisms and promote the clinical applications of hyperthermia.

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Talin and kindlin: the one-two punch in integrin activation
Feng Ye, Adam K. Snider, Mark H. Ginsberg
Front Med. 2014, 8 (1): 6-16.  
https://doi.org/10.1007/s11684-014-0317-3

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Proper cell-cell and cell-matrix contacts mediated by integrin adhesion receptors are important for development, immune response, hemostasis and wound healing. Integrins pass trans-membrane signals bidirectionally through their regulated affinities for extracellular ligands and intracellular signaling molecules. Such bidirectional signaling by integrins is enabled by the conformational changes that are often linked among extracellular, transmembrane and cytoplasmic domains. Here, we review how talin-integrin and kindlin-integrin interactions, in cooperation with talin-lipid and kindlin-lipid interactions, regulate integrin affinities and how the progress in these areas helps us understand integrin-related diseases.

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Vaccine therapies for chronic hepatitis B: can we go further?
Yumei Wen, Xuanyi Wang, Bin Wang, Zhenhong Yuan
Front Med. 2014, 8 (1): 17-23.  
https://doi.org/10.1007/s11684-014-0313-7

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Chronic hepatitis B is a major health burden worldwide. In addition to the recent progress in antiviral treatment, therapeutic vaccination is a promising new strategy for the control of chronic hepatitis B. On the basis of the major specific and non-specific immune dysregulations and defects in chronic hepatitis B patients, this paper presents the peptide and protein-based, DNA-based, cell-based, and antigen-antibody-based therapeutic vaccines, which have undergone clinical trials. The advantages, disadvantages, and future perspectives for these therapeutic vaccines are discussed.

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Osteopontin is a promoter for hepatocellular carcinoma metastasis: a summary of 10 years of studies
Lunxiu Qin
Front Med. 2014, 8 (1): 24-32.  
https://doi.org/10.1007/s11684-014-0312-8

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In this review, we summarize the novel findings from our series of studies on the leading metastasis-related gene, osteopontin (OPN). In our previous gene expression profiling study, OPN was identified as one of the leading genes associated with the metastasis of hepatocellular carcinoma (HCC). We focused on OPN to evaluate its prognostic values and important roles in HCC metastasis. A retrospective study of large cohorts of HCC patients demonstrated that plasma OPN level was one of the leading independent prognostic factors for HCC patients, even in the early stage of HCC, and could serve as a surrogate serologic biomarker for monitoring the treatment response and tumor recurrence after HCC resection. Using both in vitro and in vivo investigations, we found that OPN has an important role in metastasis and tumor growth of HCC and is an attractive potential therapeutic target for combating HCC metastasis. We also found that OPN+ HCC cells have much more amplifications at chromosomal regions, and promoter polymorphisms are important in the regulation of OPN expression and tumor growth and lung metastasis of HCC.

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The impact of hypoxia in hepatocellular carcinoma metastasis
Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Irene Oi-Lin Ng
Front Med. 2014, 8 (1): 33-41.  
https://doi.org/10.1007/s11684-013-0301-3

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Hypoxia is a common phenomenon in hepatocellular carcinoma (HCC). Hypoxia stabilizes transcription factor, hypoxia-inducible factor (HIF), to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondar y growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.

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Exome sequencing greatly expedites the progressive research of Mendelian diseases
Xuejun Zhang
Front Med. 2014, 8 (1): 42-57.  
https://doi.org/10.1007/s11684-014-0303-9

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The advent of whole-exome sequencing (WES) has facilitated the discovery of rare structure and functional genetic variants. Combining exome sequencing with linkage studies is one of the most efficient strategies in searching disease genes for Mendelian diseases. WES has achieved great success in the past three years for Mendelian disease genetics and has identified over 150 new Mendelian disease genes. We illustrate the workflow of exome capture and sequencing to highlight the advantages of WES. We also indicate the progress and limitations of WES that can potentially result in failure to identify disease-causing mutations in part of patients. With an affordable cost, WES is expected to become the most commonly used tool for Mendelian disease gene identification. The variants detected cumulatively from previous WES studies will be widely used in future clinical services.

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Sepsis biomarkers: an omics perspective
Xiao Liu, Hui Ren, Daizhi Peng
Front Med. 2014, 8 (1): 58-67.  
https://doi.org/10.1007/s11684-014-0318-2

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Sepsis is a common cause of death in hospitalized patients worldwide. The early detection of sepsis remains a great challenge for clinicians, and delayed diagnosis frequently undermines treatment efforts, thereby contributing to high mortality. Omics technologies allow high-throughput screening of sepsis biomarkers. This review describes currently available and novel sepsis biomarkers in the context of genomics, transcriptomics, proteomics, and metabolomics. The combination of these technologies can help refine the diagnosis of sepsis. This review paper serves as a reference for future studies that employ an integrated, multi-omics approach to disease identification.

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Genetic evidence in planar cell polarity signaling pathway in human neural tube defects
Chunquan Cai, Ouyan Shi
Front Med. 2014, 8 (1): 68-78.  
https://doi.org/10.1007/s11684-014-0308-4

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Neural tube defects (NTDs) are a group of birth anomalies having a profound physical, emotional, and financial effects on families and communities. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure and has been implicated in the pathogenesis of NTDs in animal models and human cohorts. This review summarizes the cumulative results of recent studies on PCP signaling pathway and human NTDs. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs.

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Regulation and function of histone acetyltransferase MOF
Yang Yang, Xiaofei Han, Jingyun Guan, Xiangzhi Li
Front Med. 2014, 8 (1): 79-83.  
https://doi.org/10.1007/s11684-014-0314-6

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The mammalian MOF (male absent on the first), a member of the MYST (MOZ, YBF2, SAS2, and Tip60) family of histone acetyltransferases (HATs), is the major enzyme that catalyzes the acetylation of histone H4 on lysine 16. Acetylation of K16 is a prevalent mark associated with chromatin decondensation. MOF has recently been shown to play an essential role in maintaining normal cell functions. In this study, we discuss the important roles of MOF in DNA damage repair, apoptosis, and tumorigenesis. We also analyze the role of MOF as a key regulator of the core transcriptional network of embryonic stem cells.

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RESEARCH ARTICLE
Nicotine gum or patch treatment for smoking cessation and smoking reduction: a multi-centre study in Chinese physicians
Dan Xiao, Nanshan Zhong, Chunxue Bai, Qingyu Xiu, Canmao Xie, Dayi Hu, Yun Mao, Roland Perfekt, Elisabeth Kruse, Qing Li, John Jiangnan Liu, Chen Wang
Front Med. 2014, 8 (1): 84-90.  
https://doi.org/10.1007/s11684-014-0311-9

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In China, around 23% of physicians (41% male, 3% female) currently smoke. Pharmacotherapy for tobacco dependence is available, but is not widely used in China. The purpose of this study was to estimate the effectiveness and the safety on smoking cessation of nicotine gum and nicotine patch in Chinese healthcare professionals. Three hundred regular smokers motivated to quit were recruited from six hospitals in China. All subjects were accepted nicotine replacement therapy, and they could choose nicotine gum (2 mg or 4 mg, depending on baseline smoking level) or nicotine patch (15 mg/16 h) for 12 weeks, with a 12-week follow-up. Limited behavioural support was provided. At Week 24, the 2--24 weeks continuous abstinence rate (verified by expired carbon monoxide) was 17%, the point prevalence abstinence rate (no smoking since the previous visit) was 35%, and 38% of subjects had continuously reduced their daily cigarette consumption by at least 50% versus baseline. Compliance with treatment was good, particularly with patch. No serious adverse event was reported, and most adverse events were mild or moderate. The most common treatment-related adverse events were gastro-intestinal (both gum and patch) and local irritation symptoms. Nicotine patch and gum were well tolerated in Chinese smokers. Abstinence rates were comparable to those previously reported with nicotine replacement therapy, and many smokers who did not quit substantially reduced their cigarette consumption.

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Clinical outcomes and prognostic factors of patients with epithelial ovarian cancer subjected to first-line treatment: a retrospective study of 251 cases
Yunfeng Fu, Xinyu Wang, Zimin Pan, Xing Xie
Front Med. 2014, 8 (1): 91-95.  
https://doi.org/10.1007/s11684-014-0305-7

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A total of 251 patients with epithelial ovarian cancer (EOC) treated between 2002 and 2008 was retrospectively analyzed to investigate the long-term outcomes and prognostic factors of these patients, particularly those who underwent primary debulking surgery followed by platinum-based chemotherapy. Clinico-pathological parameters, including progression-free survival (PFS) and overall survival (OS), were also analyzed. The median follow-up period from the end of initial treatment to June 2010 was 58 months. The three-year PFS rate was 61.7% for International Federation of Gynecology and Obstetrics (FIGO) I–II, 19.9% for FIGO III–IV, and 33.9% for all stages. By comparison, the five-year PFS rate was 44.6% for FIGO I–II, 17.7% for FIGO III–IV, and 28.3% for all stages. The three-year OS rate was 67.9% for FIGO I–II, 41.7% for FIGO III–IV, and 50.2% for all stages. The five-year OS rate was 52.7% for FIGO I–II, 30.8% for FIGO III–IV, and 39.2% for all stages. Univariate analysis revealed that advanced FIGO stage, serum CA125, and suboptimal debulking were significant factors affecting PFS and OS. In multivariate analysis, PFS was significantly influenced by FIGO stage and suboptimal debulking. However, OS was significantly influenced by advanced FIGO stage only. Our study confirms the efficacy of surgery followed by platinum-based chemotherapy for EOC. FIGO stage is considered as one of the most reliable predictors of the prognosis of patients with EOC.

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Clinical significance of para-aortic lymph node dissection and prognosis in ovarian cancer
Xianxian Li, Hui Xing, Lin Li, Yanli Huang, Min Zhou, Qiong Liu, Xiaomin Qin, Min He
Front Med. 2014, 8 (1): 96-100.  
https://doi.org/10.1007/s11684-014-0316-4

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Lymph node metastasis has an important effect on prognosis of patients with ovarian cancer. Moreover, the impact of para-aortic lymph node (PAN) removal on patient prognosis is still unclear. In this study, 80 patients were divided into groups A and B. Group A consisted of 30 patients who underwent PAN+ pelvic lymph node (PLN) dissection, whereas group B consisted of 50 patients who only underwent PLN dissection. Analysis of the correlation between PAN clearance and prognosis in epithelial ovarian cancer was conducted. Nineteen cases of lymph node metastasis were found in group A, among whom seven cases were positive for PAN, three cases for PLN, and nine cases for both PAN and PLN. In group B, 13 cases were positive for lymph node metastasis. Our study suggested that the metastatic rate of lymph node is 40.0%. Lymph node metastasis was significantly correlated with FIGO stage, tumor differentiation, and histological type both in groups A and B (P<0.05). In groups A and B, the three-year survival rates were 77.9% and 69.0%, and the five-year survival rates were 46.7% and 39.2%, respectively. However, the difference was not statistically significant (P>0.05). The three-year survival rates of PLN metastasis in groups A and B were 68.5% and 41.4%, and the five-year survival rates were 49.7% and 26.4%, respectively. Furthermore, PLN-positive patients who cleared PAN had significantly higher survival rate (P=0.044). In group A, the three-year survival rates of positive and negative lymph nodes were 43.5% and 72.7%, and the five-year survival rates were 27.2% and 58.5%, respectively. The difference was statistically significant (P=0.048). Cox model analysis of single factor suggested that lymph node status affected the survival rate (P<0.01), which was the death risk factor. Consequently, in ovarian carcinoma cytoreductive surgery, resection of the para-aortic lymph node, which has an important function in clinical treatment and prognosis of patients with ovarian cancer, is necessary.

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Methodologies for the establishment of an orthotopic transplantation model of ovarian cancer in mice
Cunjian Yi, Lei Zhang, Fayun Zhang, Li Li, Shengrong Ling, Xiaowen Wang, Xiangqiong Liu, Wei Liang
Front Med. 2014, 8 (1): 101-105.  
https://doi.org/10.1007/s11684-014-0315-5

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This study used different methods to establish an animal model of orthotopic transplantation for ovarian cancer to provide an accurate simulation of the mechanism by which tumor occurs and develops in the human body. We implanted 4T1 breast cancer cells stably-transfected with luciferase into BALB/c mice by using three types of orthotopic transplantation methodologies: (1) cultured cells were directly injected into the mouse ovary; (2) cell suspension was initially implanted under the skin of the mouse neck; after tumor mass formed, the tumor was removed and ground into cell suspension, which was then injected into the mouse ovary; and (3) a subcutaneous tumor mass was first generated, removed, and cut into small pieces, which were directly implanted into the mouse ovary. After these models were established, in vivo luminescence imaging was performed. Results and data were compared among groups. Orthotopic transplantation model established with subcutaneous tumor piece implantation showed a better simulation of tumor development and invasion in mice. This model also displayed negligible response to artificial factors. This study successfully established an orthotopic transplantation model of ovarian cancer with high rates of tumor formation and metastasis by using subcutaneous tumor pieces. This study also provided a methodological basis for future establishment of an animal model of ovarian cancer in humans.

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Correlation of Twist upregulation and senescence bypass during the progression and metastasis of cervical cancer
Tian Wang, Yan Li, Abidan Tuerhanjiang, Wenwen Wang, Zhangying Wu, Ming Yuan, Shixuan Wang
Front Med. 2014, 8 (1): 106-112.  
https://doi.org/10.1007/s11684-014-0307-5

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Cervical carcinoma is associated with high propensity for local invasion and lymph node metastasis. However, the molecular alterations that drive progression and metastasis of cervical cancer remain unclear. Cellular senescence has been proposed as the mechanism that protects an organism against cancer progression and metastasis. In addition, Twist, a basic helix-loop-helix transcription factor, has been suggested as an oncogene because it is overexpressed in many types of human cancer. This gene also exhibits a positive function in regulating invasion and metastasis. In this study, Twist was strongly and positively expressed in normal tissue, squamous cell carcinoma (SCC) IA--IIA, and SCC IIB--IIIB (4.3%, 44%, and 88.9%, respectively). The strong positive expressions of the senescence marker CBX3 were 39.1%, 32%, and 15.6%, respectively. The strong positive expressions of Twist in the SCC groups with or without lymph node metastasis were 80.8% and 50%. For CBX3, such expressions were 7.7% and 29.5%, respectively. Results also showed that the expression of Twist was inversely correlated with that of CBX3. Moreover, the knockdown of Twist with target siRNA in SiHa triggered the induction of the chromatin marker of the cellular senescence CBX3 and senescence-associated β-galactosidase activity. Our results suggested that the expression of Twist increased during the progression and metastasis of cervical cancer. Furthermore, Twist-induced senescence bypass is important in this process.

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Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern China?
Lizhe Ai, Yaqin Yu, Xiaoli Liu, Chong Wang, Jieping Shi, Hui Sun, Qiong Yu
Front Med. 2014, 8 (1): 113-117.  
https://doi.org/10.1007/s11684-014-0310-x

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Papillary thyroid carcinoma (PTC) is one of the most common tumors of the thyroid gland. The common risk factors of PTC include ionizing radiation, positive family history, and thyroid nodular disease. PTC was identified in Europeans by conducting a genome-wide association study, and a strong association signal with PTC was observed in rs944289 and NKX2-1 (located at the 14q13.3 locus), which was probably the genetic risk factor of PTC. This study aimed to examine the association of this gene with PTC in Chinese. A total of 354 patients with PTC and 360 healthy control subjects from the Han population of Northern China were recruited in the study. These individuals were genotyped to determine rs12589672, rs12894724, rs2076751, and rs944289. The association of rs944289 with PTC was obtained (C vs. T, P=0.027, OR=1.264, 95% CI=1.026-1.557; and C/C-C/T vs. T/T, P=0.034, OR=1.474, 95% CI=1.028-2.112). Conducting a subgroup analysis, we found a marginal difference in the allele frequency distribution of rs944289 (adjusted P=0.062) between the patients with PTC and multi-nodular goiter and the control subjects. We also observed an interaction (P=0.029; OR=2.578, 95% CI=1.104-6.023) between rs944289 and diabetes in patients with PTC. In conclusion, rs944289 was associated with an increased risk of PTC in the Han population of Northern China, but no clear association was observed in either of the tag single nucleotide polymorphisms of NKX2-1.

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Sclerosing cholangitis in critically ill patients: an important and easily ignored problem based on a German experience
Ting Lin, Kai Qu, Xinsen Xu, Min Tian, Jie Gao, Chun Zhang, Ying Di, Yuelang Zhang, Chang Liu
Front Med. 2014, 8 (1): 118-126.  
https://doi.org/10.1007/s11684-014-0306-6

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Intensive care unit (ICU) is important in the rehabilitation of critically ill patients. In the past decades, many patients who received aggressive treatment in ICU developed sclerosing cholangitis in multiple centers. Sclerosing cholangitis in critically ill patients (SC-CIP) is a relatively new issue. To investigate the causes, clinical manifestation, treatment, and prognosis of SC-CIP, we searched for published cases in the databases of PubMed, Highwire, and Elsevier from 2001 to 2012. Data were extracted using a standard form and retrospectively analyzed. Twelve eligible studies covering 88 patients, with 64 men and 24 women, were enrolled in this analysis. The mean age was 49.8 years. All of the patients recovered from critical illnesses, such as trauma, infection, burn, and major surgeries. High pressure positive end-expiratory pressure (PEEP, peak level at 12.8 cm H2O) was utilized for all patients, with the average duration of 36.3 d. In addition, vasopressor agents were administered in approximately 60% of SC-CIP. A rapid increase in cholestasis and irregular strictures in the intrahepatic bile ducts was observed in the following months. With an average follow-up period of 17.9 months, poor outcomes were observed in 54 patients, including 34 deaths. In conclusion, ischemic injury of the biliary tree, which may be affected by PEEP and/or vasopressor administration, affects cholangiopathic procedure. As a newly discovered type of secondary sclerosing cholangitis, SC-CIP is a severe progressive complication of patients in ICU and should be carefully monitored by clinicians.

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16 articles