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 4
Hypertrophic mouse heart displayed marked cardiac ultrastructural anomalies. Aspirin preserved the normal myocardial subcellular localization and reduced the hypertrophic injury.. (Courtesy of Dr. Baofeng Yang. See pages 444-456 by Samuel Chege Gitau et al. for more [Detail] ...
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REVIEW
Progress and perspectives of neural tissue engineering
Xiaosong Gu
Front. Med.. 2015, 9 (4): 401-411.  
https://doi.org/10.1007/s11684-015-0415-x

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Traumatic injuries to the nervous system lead to a common clinical problem with a quite high incidence and affect the patient’s quality of life. Based on a major challenge not yet addressed by current therapeutic interventions for these diseases, a novel promising field of neural tissue engineering has emerged, grown, and attracted increasing interest. This review provides a brief summary of the recent progress in the field, especially in combination with the research experience of the author’s group. Several important aspects related to tissue engineered nerves, including the theory on their construction, translation into the clinic, improvements in fabrication technologies, and the formation of a regenerative environment, are delineated and discussed. Furthermore, potential research directions for the future development of neural tissue engineering are suggested.

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Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse
Yuting Tan,Han Liu,Saijuan Chen
Front. Med.. 2015, 9 (4): 412-420.  
https://doi.org/10.1007/s11684-015-0423-x

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Genetic mutations are considered to drive the development of acute myeloid leukemia (AML). With the rapid progress in sequencing technologies, many newly reported genes that are recurrently mutated in AML have been found to govern the initiation and relapse of AML. These findings suggest the need to distinguish the driver mutations, especially the most primitive single mutation, from the subsequent passenger mutations. Recent research on DNA methyltransferase 3A (DNMT3A) mutations provides the first proof-of-principle investigation on the identification of preleukemic stem cells (pre-LSCs) in AML patients. Although DNMT3A mutations alone may only transform hematopoietic stem cells into pre-LSCs without causing the full-blown leukemia, the function of this driver mutation appear to persist from AML initiation up to relapse. Therefore, identifying and targeting preleukemic mutations, such as DNMT3A mutations, in AML is a promising strategy for treatment and reduction of relapse risk.

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Emerging roles of podoplanin in vascular development and homeostasis
Yanfang Pan,Lijun Xia
Front. Med.. 2015, 9 (4): 421-430.  
https://doi.org/10.1007/s11684-015-0424-9

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Podoplanin (PDPN) is a mucin-type O-glycoprotein expressed in diverse cell types, such as lymphatic endothelial cells (LECs) in the vascular system and fibroblastic reticular cells (FRCs) in lymph nodes. PDPN on LECs or FRCs activates CLEC-2 in platelets, triggering platelet activation and/or aggregation through downstream signaling events, including activation of Syk kinase. This mechanism is required to initiate and maintain separation of blood and lymphatic vessels and to stabilize high endothelial venule integrity within lymph nodes. In the vascular system, normal expression of PDPN at the LEC surface requires transcriptional activation of Pdpn by Prox1 and modification of PDPN with core 1-derived O-glycans. This review provides a comprehensive overview of the roles of PDPN in vascular development and lymphoid organ maintenance and discusses the mechanisms that regulate PDPN expression related to its function.

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Function of Slit/Robo signaling in breast cancer
Feng Gu,Yongjie Ma,Jiao Zhang,Fengxia Qin,Li Fu
Front. Med.. 2015, 9 (4): 431-436.  
https://doi.org/10.1007/s11684-015-0416-9

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Slit and Robo are considered tumor suppressors because they are frequently inactivated in various tumor tissue. These genes are closely correlated with CpG hypermethylation in their promoters. The Slit/Robo signaling pathway is reportedly involved in breast cancer development and metastasis. Overexpression of Slit/Robo induces its tumor suppressive effects possibly by inactivating the β-catenin/LEF/TCF and PI3K/Akt signaling pathways or by altering β-catenin/E-cadherin-mediated cell-cell adhesion in breast cancer cells. Furthermore, loss of Slit proteins or their Robo receptors upregulates the CXCL12/CXCR4 signaling axis in human breast carcinoma. In addition, this pathway regulates the distant migration of breast cancer cells not only by mediating the phosphorylation of the downstream molecules of CXCL12/CXCR4 and srGAPs, such as PI3K/Src, RAFTK/ Pyk2, and CDC42, but also by regulating the activities of MAP kinases. This review includes recent studies on the functions of Slit/Robo signaling in breast cancer and its molecular mechanisms.

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RESEARCH ARTICLE
Outcome of Stretta radiofrequency and fundoplication for GERD-related severe asthmatic symptoms
Zhiwei Hu,Jimin Wu,Zhonggao Wang,Yu Zhang,Weitao Liang,Chao Yan
Front. Med.. 2015, 9 (4): 437-443.  
https://doi.org/10.1007/s11684-015-0422-y

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This study aimed to investigate the outcome of treatment with Stretta radiofrequency (SRF) or laparoscopic Nissen fundoplication (LNF). A total of 137 gastroesophageal reflux disease (GERD) patients with severe asthmatic symptoms who responded inadequately to medical treatment for asthma were investigated. The patients were followed up 1 year and 5 years after SRF (n = 82) or LNF (n = 55) treatment. A questionnaire covering 29 related symptoms and medication use was employed. Digestive, respiratory, and ear-nose-throat (ENT) symptom scores significantly decreased after antireflux treatment. Symptom scores respectively changed from 17.2±10.1, 31.9±6.6, and 21.1±11.8 to 5.0±6.2, 11.5±10.2, and 6.3±6.8 at 1 year and to 5.6±6.5, 13.1±10.1, and 7.8±7.2 at 5 years (P <0.001). The outcome of LNF was significantly better than that of SRF in terms of digestive (P <0.001, P = 0.001), respiratory (P = 0.006, P = 0.001), and ENT symptoms (P = 0.006, P = 0.003) at both 1 year and 5 years. SRF and LNF were both effective against the digestive symptoms of GERD as well as GERD-related severe asthmatic and ENT symptoms, with better outcomes exhibited by the LNF group. Severe asthmatic symptoms and GERD were closely associated, and this finding warrants further study.

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Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling
Samuel Chege Gitau,Xuelian Li,Dandan Zhao,Zhenfeng Guo,Haihai Liang,Ming Qian,Lifang Lv,Tianshi Li,Bozhi Xu,Zhiguo Wang,Yong Zhang,Chaoqian Xu,Yanjie Lu,Zhiming Du,Hongli Shan,Baofeng Yang
Front. Med.. 2015, 9 (4): 444-456.  
https://doi.org/10.1007/s11684-015-0421-z

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Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg−1·d−1); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L−1) was treated with the human equivalent of low (10 or 100 µmol·L−1) and high (1000 µmol·L−1) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.

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Evidence chain-based causality identification in herb-induced liver injury: exemplification of a well-known liver-restorative herb Polygonum multiflorum
Jiabo Wang,Zhijie Ma,Ming Niu,Yun Zhu,Qingsheng Liang,Yanling Zhao,Jingyuan Song,Zhaofang Bai,Yaming Zhang,Ping Zhang,Na Li,Yakun Meng,Qi Li,Lushan Qin,Guangju Teng,Junling Cao,Baosen Li,Shilin Chen,Yonggang Li,Zhengsheng Zou,Honghao Zhou,Xiaohe Xiao
Front. Med.. 2015, 9 (4): 457-467.  
https://doi.org/10.1007/s11684-015-0417-8

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Herbal medicines have recently been recognized as the second most common cause of drug-induced liver injury (DILI) in the United States. However, reliable methods to identify the DILI causality of some herbs, such as Heshouwu (dried root of Polygonum multiflorum), remain lacking. In this study, a total of 12 307 inpatients with liver dysfunction and 147 literature-reported cases of Heshouwu DILI were screened. A general algorithm indicated that only 22.5% (9/40) and 30.6% (45/147) of all hospitalization and literature case reports, respectively, demonstrate the high probability of DILI causality of Heshouwu. By contrast, 95% (19/20) of all cases prospectively investigated by pharmacognosy, phytochemistry, and metabolomic tests exhibited highly probable causality, including a patient who was previously incorrectly attributed and a case that was excluded from Heshouwu causality by pharmacognostic evidence. Toxin (heavy metals, pesticides, and mycotoxins) contamination was also excluded from Heshouwu DILI causality. The objectivity of these screening methods for Heshouwu DILI diagnosis addresses safety concerns regarding stilbene-containing herbal medicines and dietary supplements.

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Clinical characteristics and prognostic factors of patients with mature T-cell lymphoid malignancies: a single-institution study of 225 cases
Wen Xue,Yan Sheng,Xiangqin Weng,Yongmei Zhu,Yan Zhao,Pengpeng Xu,Xiaochun Fei,Xiaoyan Chen,Li Wang,Weili Zhao
Front. Med.. 2015, 9 (4): 468-477.  
https://doi.org/10.1007/s11684-015-0419-6

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Mature T-cell lymphoid malignancies comprise a group of heterogeneous diseases that vary in clinicopathological features, biological behavior, treatment response, and prognosis. Bone marrow (BM) infiltration is more commonly present in mature T-cell lymphoid malignancies compared with their B-cell counterparts and hence important for differential diagnosis. In this study, clinical characteristics and prognostic factors were analyzed in 225 patients with mature T-cell lymphoid malignancies treated in a single institution. These included 29 cases of T-cell lymphoproliferative disorders (T-LPD, all with BM infiltration) and 196 cases of T-/natural-killer-cell lymphoma (T/NKCL, 56 with BM infiltration and 140 without BM infiltration). The estimated 5-year overall survival (OS) rates of T-LPD and T/NKCL were 96.6% and 37.3%, respectively. T-LPD patients were less likely to exhibit poor performance status, advanced disease stage, presence of B symptoms, or abnormal level of serum β-2 microglobulin. With similar pathological characteristics, T/NKCL patients with BM infiltration showed significantly lower response rates and shorter OS than those without BM infiltration (P = 0.0264 and P<0.0001, respectively). Multivariate analysis indicated that poor performance status, advanced disease stage, elevated serum lactate dehydrogenase level, and BM involvement were independent unfavorable prognostic factors. The Glasgow Prognostic Score may be more efficient than the International Prognostic Index in predicting disease outcome in T/NKCL. In conclusion, clinical characteristics may be useful in more effectively stratifying patients with mature T-cell lymphoid malignancies.

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U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population
Jiangbo Du,Wenjie Xue,Yong Ji,Xun Zhu,Yayun Gu,Meng Zhu,Cheng Wang,Yong Gao,Juncheng Dai,Hongxia Ma,Yue Jiang,Jiaping Chen,Zhibin Hu,Guangfu Jin,Hongbing Shen
Front. Med.. 2015, 9 (4): 478-486.  
https://doi.org/10.1007/s11684-015-0420-0

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Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TL-SNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P<0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P<0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84–3.14), 1.36 (1.03–1.79), 1.01 (0.76–1.35), and 1.37 (1.03–1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

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Temporal trend of mortality from major cancers in Xuanwei, China
Hualiang Lin,Bofu Ning,Jihua Li,Guangqiang Zhao,Yunchao Huang,Linwei Tian
Front. Med.. 2015, 9 (4): 487-495.  
https://doi.org/10.1007/s11684-015-0413-z

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Although a number of studies have examined the etiology of lung cancer in Xuanwei County, China, other types of cancer in this county have not been reported systematically. This study aimed to investigate the temporal trend of eight major cancers in Xuanwei County using data from three mortality surveys (1973–1975, 1990–1992, and 2004–2005). The Chinese population in 1990 was used as a standard population to calculate age-standardized mortality rates. Cancers of lung, liver, breast, brain, esophagus, leukemia, rectum, and stomach were identified as the leading cancers in this county in terms of mortality rate. During the three time periods, lung cancer remained as the most common type of cancer. The mortality rates for all other types of cancer were lower than those of the national average, but an increasing trend was observed for all the cancers, particularly from 1990–1992 to 2004–2005. The temporal trend could be partly explained by changes in risk factors, but it also may be due to the improvement in cancer diagnosis and screening. Further epidemiological studies are warranted to systematically examine the underlying reasons for the temporal trend of the major cancers in Xuanwei County.

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Efficacy and safety of perioperative parecoxib for acute postoperative pain treatment in children: a meta-analysis
Xueshan Bu,Lei Yang,Yunxia Zuo
Front. Med.. 2015, 9 (4): 496-507.  
https://doi.org/10.1007/s11684-015-0414-y

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Perioperative parecoxib administration reduces postoperative pain, opioid consumption, and adverse events in adult patients. However, the efficacy and safety of parecoxib in children remain unclear. This meta-analysis included related published studies to address this concern. Eight databases in the literature until February 2015 were systematically explored to identify randomized controlled trials (RCTs) comparing perioperative parecoxib administration and placebo/standard treatments for acute postoperative pain in children. Primary outcomes were postoperative pain scores and adverse events. The Face, Legs, Activity, Crying, Consolability scale was used to score pain in children younger than 6 years, whereas the Visual Analog Scale was used in children older than 6 years. Secondary outcomes were sedation scores (measured using the Ramsay scale), agitation scores (measured using the Sedation-Agitation Scale), and opioid consumption. The methodological quality of RCTs was independently assessed in accordance with the “Risk of bias” of Cochrane Collaboration. Data were analyzed using Review Manager 5.2. Twelve RCTs involving 994 patients met the inclusion criteria. Compared with children who received placebo treatment, those who received parecoxib demonstrated lower early (2 h) and later (12 h) postoperative pain scores; lower incidence rates of postoperative nausea, vomiting, and agitation; higher early (1 h) postoperative sedation scores; and lower agitation scores. Similarly, children who received parecoxib had lower early (2 h) and later (12 h) postoperative pain scores, lower incidence rates of postoperative nausea and vomiting, and lower early (1 h) postoperative sedation scores compared with those who received standard treatments; however, these children showed no significant difference in agitation scores. Unfortunately, data on the effect of parecoxib on opioid consumption were insufficient. Overall, these results suggested that perioperative parecoxib administration was associated with less acute postoperative pain and fewer adverse events compared with placebo or standard treatments. Parecoxib administration also resulted in less emergence agitation compared with placebo treatment and less excessive sedation concern compared with standard treatments. However, the long-term effects, effects on opioid consumption, and patient satisfaction of parecoxib administration warrant further investigation.

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COMMENTARY
Bile duct injury repair — earlier is not better
Vinay K. Kapoor
Front. Med.. 2015, 9 (4): 508-511.  
https://doi.org/10.1007/s11684-015-0418-7

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Bile duct injury is a common complication of cholecystectomy. The timing of bile duct injury repair remains controversial. A recent review conducted in France reported 39% complications and 64% failure after immediate repair in 194 patients compared with 14% complications and 8% failure after late repair in 133 patients. A national review of 139 consecutive early repairs conducted at five hepatopancreaticobiliary centers in Denmark reported 4% mortality, 36% morbidity, and 42 restrictures (30%) at a median follow-up of 102 months, and only 64 patients (46%) demonstrated uneventful short-term and long-term outcomes. Most patients with bile duct injury present with bile leak and sepsis; thus, early repair is not recommended. Percutaneous drainage of bile and endoscopic stenting are the mainstays of treatment of bile leak because they convert acute bile duct injury into a controlled external biliary fistula. The ensuing benign biliary stricture should be repaired by a biliary surgeon after a delay of 4–6 weeks once the external biliary fistula has closed.

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LETTER TO FRONTIERS OF MEDICINE
Do not let precision medicine be kidnapped
Zhiping Yang
Front. Med.. 2015, 9 (4): 512-513.  
https://doi.org/10.1007/s11684-015-0425-8

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Obama’s precision medicine initiative made the medical community boil over after the initiative’s release. Precision medicine has been advocated by the majority of scientists and doctors. However, some experts have questioned this concept. This article does not oppose precision medicine. However, the incentive of vigorously promoting precision medicine at present is a concern.

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