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 3
Mice treated with p-cresyl sulfate (PCS) showed increased atherosclerotic plaque areas after eight weeks of PCS administration. The figure shows representative aortic images of en face staining with oil red O in vehicle-treated and PCS-treated mice. (Courtesy of Dr. Ruiyan Zhang. See pages 320?329 by Hui Han et al. for more information.)
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REVIEW
Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea
Muhammad Waqas,Shasha Zhang,Zuhong He,Mingliang Tang,Renjie Chai
Front. Med.. 2016, 10 (3): 237-249.  
https://doi.org/10.1007/s11684-016-0464-9

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Sensory hair cells in the inner ear are responsible for sound recognition. Damage to hair cells in adult mammals causes permanent hearing impairment because these cells cannot regenerate. By contrast, newborn mammals possess limited regenerative capacity because of the active participation of various signaling pathways, including Wnt and Notch signaling. The Wnt and Notch pathways are highly sophisticated and conserved signaling pathways that control multiple cellular events necessary for the formation of sensory hair cells. Both signaling pathways allow resident supporting cells to regenerate hair cells in the neonatal cochlea. In this regard, Wnt and Notch signaling has gained increased research attention in hair cell regeneration. This review presents the current understanding of the Wnt and Notch signaling pathways in the auditory portion of the inner ear and discusses the possibilities of controlling these pathways with the hair cell fate determiner Atoh1 to regulate hair cell regeneration in the mammalian cochlea.

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Alternative splicing of inner-ear-expressed genes
Yanfei Wang,Yueyue Liu,Hongyun Nie,Xin Ma,Zhigang Xu
Front. Med.. 2016, 10 (3): 250-257.  
https://doi.org/10.1007/s11684-016-0454-y

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Alternative splicing plays a fundamental role in the development and physiological function of the inner ear. Inner-ear-specific gene splicing is necessary to establish the identity and maintain the function of the inner ear. For example, exon 68 of Cadherin 23 (Cdh23) gene is subject to inner-ear-specific alternative splicing, and as a result, Cdh23(+68) is only expressed in inner ear hair cells. Alternative splicing along the tonotopic axis of the cochlea contributes to frequency tuning, particularly in lower vertebrates, such as chickens and turtles. Differential splicing of Kcnma1, which encodes for the α subunit of the Ca2+-activated K+ channel (BK channel), has been suggested to affect the channel gating properties and is important for frequency tuning. Consequently, deficits in alternative splicing have been shown to cause hearing loss, as we can observe in Bronx Waltzer (bv) mice and Sfswap mutant mice. Despite the advances in this field, the regulation of alternative splicing in the inner ear remains elusive. Further investigation is also needed to clarify the mechanism of hearing loss caused by alternative splicing deficits.

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Physiological functions and clinical implications of the N-end rule pathway
Yujiao Liu,Chao Liu,Wen Dong,Wei Li
Front. Med.. 2016, 10 (3): 258-270.  
https://doi.org/10.1007/s11684-016-0458-7

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The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein’s half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms.

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Anatomy and embryology of umbilicus in newborns: a review and clinical correlations
Abdelmonem A. Hegazy
Front. Med.. 2016, 10 (3): 271-277.  
https://doi.org/10.1007/s11684-016-0457-8

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Umbilicus is considered a mirror of the abdomen in newborns. Despite its importance, the umbilicus has been stated in literature and textbooks as discrete subjects with many body systems, such as the urinary, digestive, and cardiovascular ones. This article aimed to address the basic knowledge of the umbilicus in relation to clinical disorders under one integrated topic to aid physicians and surgeons in assessing newborns and infants. The umbilicus appears as early as the fourth week of fetal life when the folding of the embryonic plate occurs. The umbilicus appears initially as a primitive umbilical ring on the ventral aspect of the body. The primitive umbilicus contains the connecting stalk, umbilical vessels, vitelline duct and vessels, allantois, and loop of the intestine. Changes occur to form the definitive cord, which contains three umbilical vessels, namely, “one vein and two arteries,” embedded in Wharton’s jelly. After birth, the umbilical vessels inside the body obliterate and gradually form ligaments. Congenital disorders at the umbilicus include herniation, bleeding, and discharge of mucous, urine, or feces. Some of these disorders necessitate emergent surgical interference, whereas others may be managed conservatively. The umbilicus has many embryological remnants. Thus, the umbilicus is prone to various clinical disorders. Detecting these disorders as early as possible is essential to prevent or minimize possible complications.

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RESEARCH ARTICLE
iTRAQ-based quantitative analysis of cancer-derived secretory proteome reveals TPM2 as a potential diagnostic biomarker of colorectal cancer
Yiming Ma,Ting Xiao,Quan Xu,Xinxin Shao,Hongying Wang
Front. Med.. 2016, 10 (3): 278-285.  
https://doi.org/10.1007/s11684-016-0453-z

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Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. We aimed to find novel molecules as potential biomarkers for the early diagnosis of CRC. A serum-free conditioned medium was successfully collected from three pairs of CRC tissue and adjacent normal tissue. iTRAQ-based quantitative proteomic analysis was applied to compare the differences in secretome between primary CRC mucosa and adjacent normal mucosa. A total of 145 kinds of proteins were identified. Of these proteins, 29 were significantly different between CRC and normal tissue. Tropomyosin 2 β (TPM2) exhibited the most significant differences; as such, this protein was selected for further validation. Quantitative real-time PCR indicated that the mRNA expression of TPM2 significantly decreased in the CRC tissue compared with the paired adjacent normal tissue. Immunohistochemical analysis also confirmed that TPM2 was barely detected at protein levels in the CRC tissue. In summary, this study revealed potential molecules for future biomarker applications and provided an efficient approach for the differential analysis of cancer-associated secretome. TPM2 may be valuable for the early diagnosis of CRC.

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Influence of the intensity and loading time of direct current electric field on the directional migration of rat bone marrow mesenchymal stem cells
Xiaoyu Wang,Yuxuan Gao,Haigang Shi,Na Liu,Wei Zhang,Hongbo Li
Front. Med.. 2016, 10 (3): 286-296.  
https://doi.org/10.1007/s11684-016-0456-9

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Exogenic electric fields can effectively accelerate bone healing and remodeling through the enhanced migration of bone marrow mesenchymal stem cells (BMSCs) toward the injured area. This study aimed to determine the following: (1) the direction of rat BMSC (rBMSC) migration upon exposure to a direct current electric field (DCEF), (2) the optimal DCEF intensity and duration, and (3) the possible regulatory role of SDF-1/CXCR4 axis in rBMSC migration as induced by DCEF. Results showed that rBMSCs migrated to the positive electrode of the DCEF, and that the DCEF of 200 mV/mm for 4 h was found to be optimal in enhancing rBMSC migration. This DCEF strength and duration also upregulated the expression of osteoblastic genes, including ALP and OCN, and upregulated the expression of ALP and Runx2 proteins. Moreover, when CXCR4 was inhibited, rBMSC migration due to DCEF was partially blocked. These findings indicated that DCEF can effectively induce rBMSC migration. A DCEF of 200 mV/mm for 4 h was recommended because of its ability to promote rBMSC migration, proliferation, and osteogenic differentiation. The SDF-1/CXCR4 signaling pathway may play an important role in regulating the DCEF-induced migration of rBMSCs.

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Global transcriptome analysis for identification of interactions between coding and noncoding RNAs during human erythroid differentiation
Nan Ding,Jiafei Xi,Yanming Li,Xiaoyan Xie,Jian Shi,Zhaojun Zhang,Yanhua Li,Fang Fang,Sihan Wang,Wen Yue,Xuetao Pei,Xiangdong Fang
Front. Med.. 2016, 10 (3): 297-310.  
https://doi.org/10.1007/s11684-016-0452-0

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Studies on coding genes, miRNAs, and lncRNAs during erythroid development have been performed in recent years. However, analysis focusing on the integration of the three RNA types has yet to be done. In the present study, we compared the dynamics of coding genes, miRNA, and lncRNA expression profiles. To explore dynamic changes in erythropoiesis and potential mechanisms that control these changes in the transcriptome level, we took advantage of high throughput sequencing technologies to obtain transcriptome data from cord blood hematopoietic stem cells and the following four erythroid differentiation stages, as well as from mature red blood cells. Results indicated that lncRNAs were promising cell marker candidates for erythroid differentiation. Clustering analysis classified the differentially expressed genes into four subtypes that corresponded to dynamic changes during stemness maintenance, mid-differentiation, and maturation. Integrated analysis revealed that noncoding RNAs potentially participated in controlling blood cell maturation, and especially associated with heme metabolism and responses to oxygen species and DNA damage. These regulatory interactions were displayed in a comprehensive network, thereby inferring correlations between RNAs and their associated functions. These data provided a substantial resource for the study of normal erythropoiesis, which will permit further investigation and understanding of erythroid development and acquired erythroid disorders.

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Roles of integrin β3 cytoplasmic tail in bidirectional signal transduction in a trans-dominant inhibition model
Jiansong Huang,Yulan Zhou,Xiaoyu Su,Yuanjing Lyu,Lanlan Tao,Xiaofeng Shi,Ping Liu,Zhangbiao Long,Zheng Ruan,Bing Xiao,Wenda Xi,Quansheng Zhou,Jianhua Mao,Xiaodong Xi
Front. Med.. 2016, 10 (3): 311-319.  
https://doi.org/10.1007/s11684-016-0460-0

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We evaluated the roles of calpain cleavage-related mutations of the integrin β3 cytoplasmic tail in integrin αIIbβ3 bidirectional signaling using a trans-dominant inhibition model. Chimeric Tac-β3 proteins (i.e., Tac-β3, Tac-β3D741, Tac-β3D747, Tac-β3D754, Tac-β3D759, and Tac-β3DNITY) consisting of the extracellular and transmembrane domains of human IL-2 receptor (Tac) and the human integrin β3 cytoplasmic domain were stably expressed in the 123 CHO cells harboring human glycoprotein Ib-IX and wild-type integrin αIIbβ3. The different cells were assayed for stable adhesion and spreading on immobilized fibrinogen, and for binding soluble fibrinogen representing outside-in and inside-out signaling events, respectively. The chimeric protein Tac-β3 inhibited, and Tac-β3DNITY partially attenuated stable adhesion and spreading. Tac-β3, Tac-β3D759, Tac-β3DNITY, and Tac-β3D754, but not Tac-β3D747 or Tac-β3D741, impaired the soluble fibrinogen binding. Results indicated that the bidirectional signaling was significantly inhibited by Tac-β3 and Tac-β3DNITY, albeit to a much lesser extent. Moreover, only inside-out signaling was impaired in the 123/Tac-β3D759 and 123/Tac-β3D754 cells in contrast to an intact bidirectional signaling in the 123/Tac-β3D747 and 123/Tac-β3D741 cells. In conclusion, the calpain cleavage of integrin β3 resulted in the regulatory effects on signaling by interrupting its interaction with cytoplasmic proteins rather than altering its conformation, and may thus regulate platelet function.

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p-Cresyl sulfate promotes the formation of atherosclerotic lesions and induces plaque instability by targeting vascular smooth muscle cells
Hui Han,Yanjia Chen,Zhengbin Zhu,Xiuxiu Su,Jingwei Ni,Run Du,Ruiyan Zhang,Wei Jin
Front. Med.. 2016, 10 (3): 320-329.  
https://doi.org/10.1007/s11684-016-0463-x

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Coronary atherosclerosis is a major complication of chronic kidney disease. This condition contributes to the increased mortality in dialysis patients. p-Cresyl sulfate (PCS) is a prototype of protein-bound uremic toxins that cannot be efficiently removed through routine dialysis procedures. In the present study, ApoE−/− mice that underwent 5/6 nephrectomy were randomly divided into two groups, namely, vehicle-treated group (n = 20) and PCS-treated group (n = 20). Mice were sacrificed for en face and immunohistological analyses after 8 or 24 weeks of high-fat diet. Rat aortic vascular smooth muscle cells (VSMCs) were treated with phosphate buffer solution or 500 µmol/L PCS for in vitro evaluation. PCS-treated mice were observed to suffer increased atherosclerotic lesions after eight weeks of PCS administration. Moreover, 24 weeks of PCS administration also markedly increased the vulnerability index of aortic plaques. PCS was also observed to facilitate the migration and proliferation of VSMCs during the progression of the disease. Moreover, PCS disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques. Thus, PCS played a vital role in promoting atherogenesis and disturbing the stability of formed plaques probably by targeting VSMCs.

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Spatiotemporal expression of Ezh2 in the developing mouse cochlear sensory epithelium
Yan Chen,Wenyan Li,Wen Li,Renjie Chai,Huawei Li
Front. Med.. 2016, 10 (3): 330-335.  
https://doi.org/10.1007/s11684-016-0459-6

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The enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) is a histone-lysine N-methyltransferase enzyme that participates in DNA methylation. Ezh2 has also been reported to play crucial roles in stem cell proliferation and differentiation. However, the detailed expression profile of Ezh2 during mouse cochlear development has not been investigated. Here, we examined the spatiotemporal expression of Ezh2 in the cochlea during embryonic and postnatal development. Ezh2 expression began to be observed in the whole otocyst nuclei at embryonic day 9.5 (E9.5). At E12.5, Ezh2 was expressed in the nuclei of the cochlear prosensory epithelium. At E13.5 and E15.5, Ezh2 was expressed from the apical to the basal turns in the nuclei of the differentiating cochlear epithelium. At postnatal day (P) 0 and 7, the Ezh2 expression was located in the nuclei of the cochlear epithelium in all three turns and could be clearly seen in outer and inner hair cells, supporting cells, the stria vascularis, and spiral ganglion cells. Ezh2 continued to be expressed in the cochlear epithelium of adult mice. Our results provide the basic Ezh2 expression pattern and might be useful for further investigating the detailed role of Ezh2 during cochlear development.

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Clinical characteristics of pulmonary hypertension in bronchiectasis
Lan Wang,Sen Jiang,Jingyun Shi,Sugang Gong,Qinhua Zhao,Rong Jiang,Ping Yuan,Bigyan Pudasaini,Jing He,Zhicheng Jing,Jinming Liu
Front. Med.. 2016, 10 (3): 336-344.  
https://doi.org/10.1007/s11684-016-0461-z

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Pulmonary hypertension (PH), as a complication of bronchiectasis, is associated with increased mortality. However, hemodynamic characteristics and the efficacy of pulmonary arterial hypertension (PAH) therapies in patients with bronchiectasis and PH remain unknown. Patients with bilateral bronchiectasis and concurrent PH were included in the study. Patient characteristics at baseline and during follow-up, as well as survival, were analyzed. This observational study was conducted in 36 patients with a mean age of 51.5 years (range, 17?74 years). The 6 min walking distance was 300.8±93.3 m. The mean pulmonary arterial pressure (PAP) was 41.5±11.7 mmHg, cardiac output was 5.2±1.4 L/min, and pulmonary vascular resistance was 561.5±281.5 dyn·s·cm5. The mean PAP was>35 mmHg in 75% of the cases. Mean PAP was inversely correlated with arterial oxygen saturation values (r = −0.45, P = 0.02). In 24 patients who received oral PAH therapy, systolic PAP was reduced from 82.4±27.0 mmHg to 65.5±20.9 mmHg (P = 0.025) on echocardiography after a median of 6 months of follow-up. The overall probability of survival was 97.1% at 1 year, 83.4% at 3 years, and 64.5% at 5 years. Given the results, we conclude that PH with severe hemodynamic impairment can occur in patients with bilateral bronchiectasis, and PAH therapy might improve hemodynamics in such patients. Prospective clinical trials focusing on this patient population are warranted.

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Prevalence of asthma symptoms in Golestan schoolchildren aged 6–7 and 13–14 years in Northeast Iran
Fatemeh Mehravar,Soheil Rafiee,Behnaz Bazrafshan,Mahmoud Khodadost
Front. Med.. 2016, 10 (3): 345-350.  
https://doi.org/10.1007/s11684-016-0462-y

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Asthma is the most common chronic disease among children, and its incidences are often imminent among elementary schoolchildren. This study aimed to examine the prevalence of asthma symptoms in Golestan schoolchildren aged 6–7 and 13–14 years in Northeast Iran. The prevalence rate was compared according to age group (aged 6–7 years vs. aged 13–14 years) and gender (male vs. female). In this cross-sectional study, 1706 Iranian schoolchildren aged 6–7 and 13–14 years in Golestan Province were enrolled. Participants completed questionnaires between February and July 2014. Asthma symptoms were assessed using the questionnaire of the International Study of Asthma and Allergies in Childhood protocol in Persian. The logistic regression model was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the asthma symptoms for each of the gender and age groups. The prevalence rates of “current asthma” symptoms and “asthma ever” in all the children were estimated as 9.5% and 7.5%, respectively. The prevalence of asthma (“asthma ever” and “wheezing in the past 12 months”) in junior high schoolchildren (aged 13–14 years) is higher than that in elementary schoolchildren (aged 6–7 years) (P <0.05). The prevalence of the severity of wheezing in girls is lower than that in boys (OR= 1.7, 95%CI= 1.06–2.96, P = 0.02). Asthma is still a major public health problem. This study shows that the prevalence of the asthma symptoms in boys is lower than that in girls in both age groups, and the severity of asthma in girls is higher than that in boys aged 13–14 years.

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CASE REPORT
Right coronary occlusion following transcatheter aortic valve implantation: two case reports
Gang Zhang,Jun Luo,Guo Chen
Front. Med.. 2016, 10 (3): 351-355.  
https://doi.org/10.1007/s11684-016-0465-8

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This paper discusses two male patients with severe aortic stenosis, whose right coronary arteries (RCA) were completely occluded during transcatheter aortic valve implantation (TAVI), leading to fatal hemodynamic disorder. Occlusions of RCA complicated by TAVI are rare. In addition, emergency cardiopulmonary bypass (CPB) played a critical role in rescuing our second patient. Both patients were admitted for “severe aortic stenosis,” and TAVIs were performed. The first patient’s blood pressure immediately dropped to 70/40 mmHg after the balloon expansion and did not increase much after the administration of aramine or fluid therapy. He did not receive emergency surgery and died after 1.5 h of resuscitation. The second patient’s blood pressure fluctuated greatly for several minutes after the valve implantation, ranging from 170/100 mmHg to 60/40 mmHg. Angiography revealed a total occlusion of RCA. Thoracic surgery with CPB was performed, and the patient survived.

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A rare chronic constrictive pericarditis with localized adherent visceral pericardium and normal parietal pericardium: a case report
Qingqiang Ni,Lin Yun,Rui Xu,Guohua Li,Yucai Yao,Jiamin Li
Front. Med.. 2016, 10 (3): 356-359.  
https://doi.org/10.1007/s11684-016-0467-6

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Classic constrictive pericarditis (CP) is characterized by fibrous scarring and adhesion of both the visceral pericardium and the parietal pericardium, which leads to restricted cardiac filling. However, diagnosing CP with normal thickness pericardium and without calcification is still a challenge. The predominant cause in the developed world is idiopathic or viral pericarditis, followed by post-cardiac surgery and post-radiation. Tuberculosis still remains a common cause of CP in developing countries. In this report, we describe a rare case of idiopathic localized constrictive visceral pericardium with normal thickness of the parietal pericardium in a middle-aged man. The patient presented with unexplained right heart failure and echocardiography showed moderate bi-atrial enlargement which should be?identified with the restrictive cardiomyopathy.?After 10 months of conservative treatment, the progression of right heart failure was remaining. A pericardiectomy was performed and the patient recovered. This case serves as a reminder to consider CP in patients with unexplained right heart failure, so that timely investigation and treatment can be initiated.

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COMMENTARY
Barriers and countermeasures in developing traditional Chinese medicine in Europe
Yunfang Liu,Zhiping Yang,Jing Cheng,Daiming Fan
Front. Med.. 2016, 10 (3): 360-376.  
https://doi.org/10.1007/s11684-016-0455-x

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Traditional Chinese medicine (TCM) is one of the unique cultural treasures of Chinese; it represents a significant feature and prominent advantage of the healthcare cause in China. Data in this paper were from World Health Organization, Chinese Bureau of Statistics, China National Knowledge Infrastructure, and PubMed. In recent years, TCM has established a solid foundation in Europe, which made great strides in legislation, education, research, and international exchange, and has enjoyed a vast development space in the continent. Now, TCM is embracing unprecedented development opportunities in Europe. At the same time, the stiff international competition poses a grave threat to China’s TCM industry. With multiple cultural, legal, and institutional challenges, as well as talent shortages in the way, TCM is now facing many difficulties in Europe. To fully prepare and enact active and vigorous steps to seize opportunities, we should have a clear picture about the serious challenges hampering TCM development in Europe. The TCM development at overseas markets has shifted from a spontaneous trade activity into a national strategy spearheaded by the government and participated in by multiple stakeholders. We should make a systematic, comprehensive, and sustainable push in fields such as TCM therapy, healthcare, education, research, culture, and industry development. The ultimate goal is to bring TCMs to the global market and allow them to play a role in safeguarding public health along with modern medicines.

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15 articles