Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2015, Volume 9 Issue 3
Disabled homolog 2 (DAB2) is an oncoprotein up-regulated along with prostate cancer progression and is required for migration and invasion of prostate cancer cells.(Courtesy of Dr. Qiuhua Huang. See pages 312-321 by Yinyin Xie et al. for more information.)
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REVIEW
Environmental pollution and DNA methylation: carcinogenesis, clinical significance, and practical applications
Yi Cao
Front. Med.. 2015, 9 (3): 261-274.  
https://doi.org/10.1007/s11684-015-0406-y

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Environmental pollution is one of the main causes of human cancer. Exposures to environmental carcinogens result in genetic and epigenetic alterations which induce cell transformation. Epigenetic changes caused by environmental pollution play important roles in the development and progression of environmental pollution-related cancers. Studies on DNA methylation are among the earliest and most conducted epigenetic research linked to cancer. In this review, the roles of DNA methylation in carcinogenesis and their significance in clinical medicine were summarized, and the effects of environmental pollutants, particularly air pollutants, on DNA methylation were introduced. Furthermore, prospective applications of DNA methylation to environmental pollution detection and cancer prevention were discussed.

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Molecular mechanisms of fatty liver in obesity
Lixia Gan,Wei Xiang,Bin Xie,Liqing Yu
Front. Med.. 2015, 9 (3): 275-287.  
https://doi.org/10.1007/s11684-015-0410-2

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Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

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Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases
Joseph Cannova,Peter Breslin S.J.,Jiwang Zhang
Front. Med.. 2015, 9 (3): 288-303.  
https://doi.org/10.1007/s11684-015-0412-0

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Toll-like receptors (TLRs), which are found in innate immune cells, are essential mediators of rapid inflammatory responses and appropriate T-cell activation in response to infection and tissue damage. Accumulating evidence suggests that TLR signaling is involved in normal hematopoiesis and specific hematologic pathologies. Particular TLRs and their downstream signaling mediators are expressed not only in terminally differentiated innate immune cells but also in early hematopoietic progenitors. Sterile activation of TLR signaling is required to generate early embryonic hematopoietic progenitor cells. In adult animals, TLR signaling directly or indirectly promotes differentiation of myeloid cells at the expense of that of lymphoid cells and the self-renewal of hematopoietic stem cells during infection and tissue damage. Activating mutations of the MyD88 gene, which codes for a key adaptor involved in TLR signaling, are commonly detected in B-cell lymphomas and other B-cell hematopathologies. Dysregulated TLR signaling contributes to the pathogenesis of many hematopoietic disorders, including bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia. Complete elucidation of the molecular mechanisms by which TLR signaling mediates the regulation of both normal and pathogenic hematopoiesis will prove valuable to the development of targeted therapies and strategies for improved treatment of hematopoietic disorders.

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RESEARCH ARTICLE
Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase
Lanping Xu,Huanling Zhu,Jianda Hu,Depei Wu,Hao Jiang,Qian Jiang,Xiaojun Huang
Front. Med.. 2015, 9 (3): 304-311.  
https://doi.org/10.1007/s11684-015-0400-4

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In the tyrosine kinase inhibitor (TKI) era, imatinib is the first-line therapy for patients with chronic myeloid leukemia (CML) in chronic or accelerated phase. Although second-generation TKIs (TKI2), including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 (n?=?33) and allo-HSCT (n?=?60) groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 (36.7%), 35 (58.3%), and 3 (10%) patients underwent allo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients (100%) achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate (42.9% vs. 86.4%, P = 0.002), 5-year event-free survival rate (14.3% vs. 76.1%, P<0.001), and 5-year progression-free survival (28.6% vs. 78.1%, P<0.001) than those in the allo-HSCT group. Multivariate analysis showed that male sex and TKI2 therapy were predictors of poor overall survival, whereas hemoglobin<100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase.

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Disabled homolog 2 is required for migration and invasion of prostate cancer cells
Yinyin Xie,Yuanliang Zhang,Lu Jiang,Mengmeng Zhang,Zhiwei Chen,Dan Liu,Qiuhua Huang
Front. Med.. 2015, 9 (3): 312-321.  
https://doi.org/10.1007/s11684-015-0401-3

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Disabled homolog 2 (DAB2) is frequently deleted or epigenetically silenced in many human cancer cells. Therefore, DAB2 has always been regarded as a tumor suppressor gene. However, the role of DAB2 in tumor progression and metastasis remains unclear. In this study, DAB2 expression was upregulated along with human prostate cancer (PCa) progression. DAB2 overexpression or knockdown effects in LNCaP and PC3 cell lines were verified to address the biological functions of DAB2 in PCa progression and metastasis. LNCaP and PC3 cell lines were generated from human PCa cells with low and high metastatic potentials, respectively. The results showed that DAB2 shRNA knockdown can inhibit the migratory and invasive abilities of PC3 cells, as well as the tumorigenicity, whereas DAB2 overexpression enhanced LNCaP cell migration and invasion. Further investigation showed that DAB2 regulated the cell migration associated genes in PC3 cells, and the differential DAB2 expression between LNCaP and PC3 cells was partly regulated by histone 4 acetylation. Therefore, DAB2 may play an important role in PCa progression and metastasis.

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TCGA whole-transcriptome sequencing data reveals significantly dysregulated genes and signaling pathways in hepatocellular carcinoma
Daniel Wai-Hung Ho,Alan Ka-Lun Kai,Irene Oi-Lin Ng
Front. Med.. 2015, 9 (3): 322-330.  
https://doi.org/10.1007/s11684-015-0408-9

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This study systematically evaluates the TCGA whole-transcriptome sequencing data of hepatocellular carcinoma (HCC) by comparing the global gene expression profiles between tumors and their corresponding non-tumorous liver tissue. Based on the differential gene expression analysis, we identified a number of novel dysregulated genes, in addition to those previously reported. Top-listing upregulated (CENPF and FOXM1) and downregulated (CLEC4G, CRHBP, and CLEC1B) genes were successfully validated using qPCR on our cohort of 65 pairs of human HCCs. Further examination for the mechanistic overview by subjecting significantly upregulated and downregulated genes to gene set enrichment analysis showed that different cellular pathways were involved. This study provides useful information on the transcriptomic landscape and molecular mechanism of hepatocarcinogenesis for development of new biomarkers and further in-depth characterization.

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MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility
Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong
Front. Med.. 2015, 9 (3): 331-343.  
https://doi.org/10.1007/s11684-015-0409-8

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MicroRNAs (miRNAs), an important class of small non-coding RNAs, regulate gene expression at the post-transcriptional level. miRNAs are involved in a wide range of biological processes and implicated in different diseases, including cancers. In this study, miRNA profiling and qRT-PCR validation revealed that miR-142-3p and miR-142-5p were significantly downregulated in hepatocellular carcinoma (HCC) and their expression levels decreased as the disease progressed. The ectopic expression of miR-142 significantly reduced HCC cell migration and invasion. Overexpression of either miR-142-3p or miR-142-5p suppressed HCC cell migration, and overexpression of both synergistically inhibited cell migration, which indicated that miR-142-3p and miR-142-5p may cooperatively regulate cell movement. miR-142-3p and miR-142-5p, which are mature miRNAs derived from the 3′- and 5′-strands of the precursor miR-142, target distinct pools of genes because of their different seed sequences. Pathway enrichment analysis showed a strong association of the putative gene targets of miR-142-3p and miR-142-5p with several cell motility-associated pathways, including those regulating actin cytoskeleton, adherens junctions, and focal adhesion. Importantly, a number of the putative gene targets were also significantly upregulated in human HCC cells. Moreover, overexpression of miR-142 significantly abrogated stress fiber formation in HCC cells and led to cell shrinkage. This study shows that mature miR-142 pairs collaboratively regulate different components of distinct signaling cascades and therefore affects the motility of HCC cells.

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Pathogenesis sequences in Gejiu miners with lung cancer: an introduction
Li Bian,Yonghua Ruan,Liju Ma,Hairong Hua,Li Zhou,Xiaoyu Tuo,Zheyan Zhou,Ting Li,Shiyue Liu,Kewei Jin
Front. Med.. 2015, 9 (3): 344-349.  
https://doi.org/10.1007/s11684-015-0399-6

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Tin miners in Gejiu, Yunnan Province, China are at high risk of developing lung cancer with significant occupational characteristics. Tissue samples from these miners presented pathological characteristics, such as fibroplasia in carcinomas, peri-cancerous tissue in lung cancers, and hyperplasia and dysplasia of epithelial cells in peri-cancerous tissue. Carcinomas induced by Yunnan tin mine dust in the animal experiment underwent inflammation, fibroplasia, hyperplasia, dysplasia, and carcinogenesis of epithelial cells. A correlated and synergistic relationship was observed between bronchial epithelial cell transformation and fibroblast activation in vitro induced by mine dust. Fibroblast hyperplasia and activation are important factors that promote the transformation and carcinogenesis of epithelial cells. Our findings suggested that pulmonary fibrosis may increase the risk and promote the occurrence of lung cancer, which can lead to lung fiber hyperplasia.

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Exploring the diagnosis markers for gallbladder cancer based on clinical data
Lingqiang Zhang,Runchen Miao,Xiude Zhang,Wei Chen,Yanyan Zhou,Ruitao Wang,Ruiyao Zhang,Qing Pang,Xinsen Xu,Chang Liu
Front. Med.. 2015, 9 (3): 350-355.  
https://doi.org/10.1007/s11684-015-0402-2

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Presently, no effective markers are available to facilitate gallbladder cancer (GBC) diagnosis. This study aims to explore available markers for GBC diagnosis. Clinical data of 144 GBC and 116 cholelithiasis patients were retrospectively reviewed. Logistic regression analysis was performed to evaluate GBC risk factors. A receiver operating characteristic (ROC) curve was used to assess the diagnosis value of the risk factors. By comparing the characteristic of GBC and cholelithiasis patients, the following factors exhibited statistical difference: age, gender, gallstones, total bilirubin (TB), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count (PLT), CA125 (carcinoembryonic antigen 125), and CA199 (carbohydrate antigen 199). Logistic regression analysis indicated that age [odds ratio (OR), 1.032; 95% confidence interval (95% CI), 1.004 to 1.061; P = 0.024], gender (OR, 0.346; 95% CI, 0.167 to 0.716; P = 0.004), gallstones (OR, 0.027; 95% CI, 0.007 to 0.095; P<0.001), ALP (OR, 1.003; 95% CI, 1.000 to 1.006; P = 0.032), TB (OR, 1.004; 95% CI, 1.000 to 1.009; P = 0.042), and CA125 (OR, 1.007; 95% CI, 1.002 to 1.013; P = 0.011) were independent risk factors for GBC. According to the ROC curve, CA125 [area under curve (AUC), 0.720], ALP (AUC, 0.713), TB (AUC, 0.636), and age (AUC, 0.573) were valuable diagnosis markers. Additionally, based on the independent risk factors, the GBC diagnosis model was established. Age, TB, ALP, and CA125 can be used as auxiliary diagnosis factors of GBC. The diagnosis model provides a quantitative tool for GBC diagnosis when comprehensively considering various risk factors.

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Robotic distal pancreatectomy versus conventional laparoscopic distal pancreatectomy: a comparative study for short-term outcomes
Eric C. H. Lai,Chung Ngai Tang
Front. Med.. 2015, 9 (3): 356-360.  
https://doi.org/10.1007/s11684-015-0404-0

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Robotic system has been increasingly used in pancreatectomy. However, the effectiveness of this method remains uncertain. This study compared the surgical outcomes between robot-assisted laparoscopic distal pancreatectomy and conventional laparoscopic distal pancreatectomy. During a 15-year period, 35 patients underwent minimally invasive approach of distal pancreatectomy in our center. Seventeen of these patients had robot-assisted laparoscopic approach, and the remaining 18 had conventional laparoscopic approach. Their operative parameters and perioperative outcomes were analyzed retrospectively in a prospective database. The mean operating time in the robotic group (221.4 min) was significantly longer than that in the laparoscopic group (173.6 min) (P = 0.026). Both robotic and conventional laparoscopic groups presented no significant difference in spleen-preservation rate (52.9% vs. 38.9%) (P = 0.505), operative blood loss (100.3 ml vs. 268.3 ml) (P = 0.29), overall morbidity rate (47.1% vs. 38.9%) (P = 0.73), and post-operative hospital stay (11.4 days vs. 14.2 days) (P = 0.46). Both groups also showed no perioperative mortality. Similar outcomes were observed in robotic distal pancreatectomy and conventional laparoscopic approach. However, robotic approach tended to have the advantages of less blood loss and shorter hospital stay. Further studies are necessary to determine the clinical position of robotic distal pancreatectomy.

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Immunohistochemical measurement and expression of Mcl-1 in infertile testes
Raafat Hegazy,Abdelmonem Hegazy,Mustafa Ammar,Emad Salem
Front. Med.. 2015, 9 (3): 361-367.  
https://doi.org/10.1007/s11684-015-0395-x

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The diagnosis of azoospermia represents a major challenge to andrologists as this condition may occur despite normal spermatogenesis and genital tracts. Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins involved in regulation of apoptosis in various cell types. This study aimed to investigate the immunohistochemical expression of Mcl-1 in testicular biopsies of subjects with azoospermia. Eighty-six cases with azoospermia were obtained from 509 infertile patients admitted to the Andrology Unit of the Zagazig University Hospitals from January 2010 to December 2011. Biopsies were diagnosed and classified using H&E-stained slide sections. The specimens were subjected to immunohistochemical staining for Mcl-1 and examined through light microscopy. Forty-five cases of maturation arrest (25 at spermatids and 20 at the spermatocytes), 31 cases of hypospermatogenesis (20 moderate and 11 severe), 5 cases of Sertoli?cell-only syndrome, 2 cases of basement membrane hyalinization, and 1 case of tubular and peritubular sclerosis were observed. Normal spermatogenesis was detected in 2 cases. A strong positive immunoreaction in Leydig cells was observed among all investigated specimens. A moderate reaction was detected in spermatocytes and spermatozoa in cases of normal spermatogenesis and hypospermatogenesis, but a negative reaction was detected in cases of maturation arrest and germ cell aplasia. Apoptosis was found to be associated with decreased rate of spermatogenesis. High apoptosis rates may result in azoospermia, which can occur despite normal spermatogenesis and absence of duct obstruction.

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Glucagon-like peptide-2 exhibits protective effect on hepatic ischemia-reperfusion injury in rats
Naci Topaloğlu,Adem Küçük,Şule Yıldırım,Mustafa Tekin,Havva Erdem,Mustafa Deniz
Front. Med.. 2015, 9 (3): 368-373.  
https://doi.org/10.1007/s11684-015-0403-1

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Glucagon-like peptide-2 (GLP-2) has potent anti-inflammatory effects and protects against experimental ischemia/reperfusion (I/R) injury in pulmonary, intestinal, and myocardial tissue. However, its protective abilities against I/R injury in the liver are unknown. We investigated the potential role of GLP-2 pretreatment on hepatic I/R injury in rats. A total of 24 rats were randomly divided into three groups (n = 8). The first group was the control group; the second group was the vehicle-treated hepatic ischemia/reperfusion (HIR, vehicle saline-treated) group; and the third group was the GLP-2 pretreated I/R (GLP2-IR) group. Each rat in the third group was intraperitoneally administered 5 μg GLP-2 for 5 d before the procedure. A portal triad was created to induce ischemia with a vascular atraumatic clamp. After 40 min, the clamp was released to initiate hepatic reperfusion for 6 h. Blood samples and tissue specimens from the liver were obtained. Alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels significantly increased in the saline-treated HIR group (P<0.001), whereas GLP-2 pretreatment significantly decreased their levels (P<0.01). Our data suggested that GLP-2 pretreatment may have a protective effect on liver I/R injury. However, dose-response studies are necessary to determine the most effective dose.

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Factors related to compliance with oral analgesic treatment of inpatients with chronic pain
Hong Zhu,Yuzhu Zheng,Hui Gao,Li Liu,Lie Yang
Front. Med.. 2015, 9 (3): 374-379.  
https://doi.org/10.1007/s11684-015-0411-1

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This study aimed to determine the relationship between the different factors of analgesic therapy and the compliance of chronic pain inpatients. We prospectively investigated 100 consecutive inpatients with non-cancer chronic pain who were hospitalized to receive oral analgesic treatment in the Pain Department of West China Hospital from May 2013 to October 2013. Patients who completed the treatment plan were recorded as good compliance, whereas patients who partly completed or even refused the treatment were recorded as moderate or non-compliance, respectively. A total of 73 (73.7%), 17 (17.1%), and 9 (9.2%) patients showed good, moderate, and non-compliance, respectively. Univariate analyses showed significantly better compliance among farmers, patients educated in college or above, with family income of<3000 CNY, and with severe or moderate pain than those employed and unemployed (P=0.02), patients educated below college (P=0.013), with family income of≥3000 CNY (P=0.025), and with mild pain (P<0.001), respectively. Logistic regression analysis showed that the family income of≥3000 CNY (OR: 2.50, 95%CI: 1.65–4.51, P=0.021) and mild pain (OR: 1.27, 95%CI: 1.03–3.31, P=0.016) were associated with moderate or non-compliance with oral analgesic treatment. In conclusion, the low compliance with oral treatment of analgesics was found in Chinese inpatients with chronic pain and compliance was negatively associated with family income and degree of pain of patients.

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CASE REPORT
Cushing’s syndrome during pregnancy caused by adrenal cortical adenoma: a case report and literature review
Wei Wang,Fengyi Yuan,Dan Xu
Front. Med.. 2015, 9 (3): 380-383.  
https://doi.org/10.1007/s11684-015-0407-x

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Cushing’s syndrome (CS) during pregnancy is a rare condition with significant maternal and fetal complications. A case of CS during the third trimester of pregnancy secondary to adrenocortical adenoma was reported. Literature review revealed the disadvantages of different treatments in this period. Besides the conservative treatment, surgery is recommended for CS during the third trimester of pregnancy secondary to adrenal adenoma, if an experienced surgeon is available.

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Small cell carcinoma of the urinary bladder without gross hematuria: a case report
Wanqiu Huang,Yang Luan,Lu Jin,Tao Wang,Ruibao Chen,Zheng Liu,Zhiqiang Chen,Ruzhu Lan
Front. Med.. 2015, 9 (3): 384-387.  
https://doi.org/10.1007/s11684-015-0405-z

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Small cell carcinoma of the urinary bladder (SCCB) is a rare and aggressive form of bladder cancer with poor prognosis. Hematuria is the main symptom of this malignancy, and most patients have a history of smoking. The disease incidence of malignant bladder tumors in China is approximately 0.74%. Early and accurate diagnosis of SCCB can ensure timely and appropriate treatment of this malignant disease. Oncologic surgery is the standard treatment; however, it may not be a curative approach. Chemotherapy and/or radiotherapy should be performed following surgical removal. This case report describes a patient with a single neoplasm diagnosed as SCCB that arose because of recurrence of bladder cancer after bladder tumor resection. In contrast to previously reported cases, this patient had no gross hematuria and no history of smoking.

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Severe hepatoxicity caused by aspirin overdose: a case report
Zhuping Cao,Shiqi Liu,Jianhua Niu,Bing Wei,Jie Xu
Front. Med.. 2015, 9 (3): 388-391.  
https://doi.org/10.1007/s11684-015-0398-7

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We report here the rare case of a 61-year-old man with multiple organ dysfunction caused by an aspirin overdose (4 g orally). The patient presented with a fever that reached 39.2 °C, a peptic ulcer, and massive upper gastrointestinal bleeding. His blood test results were as follows: white blood cell count, 1.8×109/L; absolute lymphocytes, 0.4×109/L; absolute neutrophils, 1.2×109/L; and electrolyte disturbances. A computed tomography (CT) scan showed evidence of bilateral inferior pulmonary infection and acute pancreatitis. Thick dark bile with visible floccule was drawn via a percutaneous transhepatic cholangiodrainage (PTCD). Klebsiella pneumoniae was detected in microbiological bile tests. Two years later, the patient died of chronic liver failure.

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COMMENTARY
Ambient air pollution and lung disease in China: health effects, study design approaches and future research
Jeffrey H. Mandel,Christine Wendt,Charles Lo,Guangbiao Zhou,Marshall Hertz,Gurumurthy Ramachandran
Front. Med.. 2015, 9 (3): 392-400.  
https://doi.org/10.1007/s11684-015-0397-8

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Ambient air pollution in China has worsened following dramatic increases in industrialization, automobile use and energy consumption. Particularly bothersome is the increase in the PM2.5 fraction of pollutants. This fraction has been associated with increasing rates of cardio-respiratory disease in China and elsewhere. Ambient pollutant levels have been described in many of China’s cities and are comparable to previous levels in southern California. Lung cancer mortality in China has increased since the 1970s and has been higher in men and in urban areas, the exact explanation for which has not been determined. The estimation of individual risk for Chinese citizens living in areas of air pollution will require further research. Occupational cohort and case-control designs each have unique attributes that could make them helpful to use in this setting. Other important future research considerations include detailed exposure assessment and the possible use of biomarkers as a means to better understand and manage the threat posed by air pollution in China.

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17 articles