Yizhi Liu

Sun Yat-Sen University, Shengcheng, Guangdong, China

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Publications (87)326.23 Total impact

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    ABSTRACT: PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell determination during eye development. Defects of PAX6 cause aniridia and limbal stem cell deficiency in humans, and the Small eye (Sey) phenotype in mice. However, how PAX6 specifies limbal stem cell (LSC) and corneal fates during eye development is not well understood. Here we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, P63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors, and later on in LSCs. By using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs leads to an upregulation of skin epidermal specific keratins Concomitant with differentiation to a skin fate. Using gene expression analysis, we identified involvement of Notch, WNT and TGFb signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in keratin gene expression profile and by the appearance congenital dermoid tissue. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 06/2015; DOI:10.1074/jbc.M115.662940 · 4.60 Impact Factor
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    BMJ (online) 06/2015; 350(jun02 5):h2918. DOI:10.1136/bmj.h2918 · 16.38 Impact Factor
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    ABSTRACT: The purpose of the current study was to investigate the 11 bestrophin-1 (BEST1) exons in patients with best vitelliform macular dystrophy (BVMD), and to characterize the associated clinical features. Complete ophthalmic examinations were conducted on two families, and two family members were diagnosed with BVMD. Genomic DNA was extracted from the leukocytes of peripheral blood collected from the patients and their family members, in addition to 100 unrelated control subjects recruited from the same population. The polymerase chain reaction was used to amplify a total of 11 exons of the BEST1 gene, which were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination, fundus photography and fluorescein angiography imaging, as well as anterior segment analysis with Pentacam and optical coherence tomography, were conducted. The patients exhibited yellowish lesions in the macular area. A heterozygous mutation c.910_912delGAT (p.304del Asp) in exon 7 was identified in Case 1. A heterozygous BEST1 missense mutation c.685T>G (p.Trp229Gly) in exon 5 was identified in Case 2, but not in any of the unaffected family members or normal controls. Although BEST1 gene mutations and polymorphisms have previously been reported in various ethnic groups, the current study identified, for the first time to the best of our knowledge, two novel BEST1 gene mutations in patients with BVMD.
    Molecular Medicine Reports 04/2015; DOI:10.3892/mmr.2015.3711 · 1.48 Impact Factor
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    ABSTRACT: The mouse lens capsular injury model has been widely used in investigating the mechanisms of anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), and evaluating the efficacy of antifibrotic compounds. Nevertheless, there is no available protocol to quantitatively assess the treatment outcomes. Our aim is to describe a new method that can successfully quantify the wound and epithelial-mesenchymal transition (EMT) markers expression in vivo. In this model, lens anterior capsule was punctured with a hypodermic needle, which triggered lens epithelial cells (LECs) proliferation and EMT rapidly. Immunofluorescent staining of injured lens anterior capsule whole-mounts revealed the formation of ASC and high expression of EMT markers in the subcapsular plaques. A series of sectional images of lens capsule were acquired from laser scanning confocal microscopy (LSCM) three-dimensional (3D) scanning. Using LSCM Image Browser software, we can not only obtain high resolution stereo images to present the spatial structures of ASC, but also quantify the subcapsular plaques and EMT markers distribution sucessfully. Moreover, we also demonstrated that histone deacetylases (HDACs) inhibitor TSA significantly prevented injury-induced ASC using this method. Therefore, the present research provides a useful tool to study ASC and PCO biology as well as the efficacy of new therapies.
    Scientific Reports 02/2015; 5:8362. DOI:10.1038/srep08362 · 5.58 Impact Factor
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    ABSTRACT: To compare the efficacy and safety of the intraocular lens (IOL)-shell procedure versus conventional phacoemulsification for the surgical treatment of dense cataracts.
    PLoS ONE 11/2014; 9(11):e112663. DOI:10.1371/journal.pone.0112663 · 3.53 Impact Factor
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    ABSTRACT: Blood vessel degeneration is critically involved in nearly all types of degenerative diseases. Therefore strategies to enhance blood vessel protection and survival are highly needed. In this study, using different animal models and cultured cells, we show that PDGF-CC is a potent vascular protective and survival factor. PDGF-CC deficiency by genetic deletion exacerbated blood vessel regression/degeneration in various animal models. Importantly, treatment with PDGF-CC protein not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. Mechanistically, we revealed that heme oxygenase-1 (HMOX1) activity is critically required for the vascular protective/survival effect of PDGF-CC, because blockade of HMOX1 completely abolished the protective effect of PDGF-CC in vitro and in vivo. We further found that both PDGF receptors, PDGFR-β and PDGFR-α, are required for the vasoprotective effect of PDGF-CC. Thus our data show that PDGF-CC plays a pivotal role in maintaining blood vessel survival and may be of therapeutic value in treating various types of degenerative diseases.
    Proceedings of the National Academy of Sciences 09/2014; 111(41). DOI:10.1073/pnas.1404140111 · 9.81 Impact Factor
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    ABSTRACT: To assess the effect of provision of free glasses on academic performance in rural Chinese children with myopia.
    BMJ Clinical Research 09/2014; 349:g5740. DOI:10.1136/bmj.g5740 · 14.09 Impact Factor
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    ABSTRACT: To assess the bacterial contamination risk in cataract surgery associated with mechanical compression of the lid margin immediately after sterilization of the ocular surface.
    Journal of Cataract and Refractive Surgery 08/2014; 40(8):1377-81. DOI:10.1016/j.jcrs.2013.11.046 · 2.55 Impact Factor
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    ABSTRACT: The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non-transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.
    Nature 07/2014; 511(7509):358-61. DOI:10.1038/nature13465 · 42.35 Impact Factor
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    ABSTRACT: Congenital cataract (CC) is the primary cause of treatable childhood blindness. Population-based assessments of prevalence and surgery age of CC, which are critical for improving management strategies, have been unavailable in China until now. We conducted a hospital-based, cross-sectional study of the hospital charts of CC patients younger than 18 years old from January 2005 to December 2010 at Zhongshan Ophthalmic Center (ZOC) in Guangzhou, China. Residence, gender, age at surgery, hospitalization time, and the presence of other ocular abnormalities were extracted and statistically analyzed in different subgroups. The search identified 1314 patients diagnosed with CC from a total of 136154 hospitalizations, which accounted for 2.39% of all the cataract in-patients and 1.06% of the total in-patients over the six-year study period. Of the identified CC patients, 9.2% had ≥2 hospitalizations due to the necessity of additional surgeries, with a total ratio of boys to girls of 1.75∶1. Based on a subgroup analysis according to age, patients 2-6 years old constituted the highest proportion (29.22%) of all hospitalized CC patients, and those 13-18 years old constituted the lowest proportion (13.47%) of the total number. The average age at surgery was 27.62±23.36 months, but CC patients ≤6 years old (especially ≤6 months old) became increasingly prevalent throughout the 6-year study period. A total of 276 cases (20.93%) of CC were associated with one or more other ocular abnormalities, the highest incidence rates were observed for exotropia (6.24%), nystagmus (6.16%), and refractive error (3.65%). In conclusion, CC patients accounted for 2.39% of all cataract in-patients in a review of 6 years of hospitalization charts from ZOC. The age at the time of surgery decreased over the 6-year study period, which probably reflects the continuing improvement of public awareness of children's eye care in China.
    PLoS ONE 07/2014; 9(7):e101781. DOI:10.1371/journal.pone.0101781 · 3.53 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells is a major pathologic change in the development of proliferative vitreoretinopathy (PVR), which leads to severe visual impairment. ERK1/2 pathway has been reported to play a key role in the carcinogenesis, cancer metastasis, and multiple fibrotic diseases. We hypothesized that ERK1/2 signaling could cross-interact with transforming growth factor β2 (TGFβ2)/Smad and Notch signaling pathways in the regulation of EMT in RPE cells. Here, we demonstrated that ERK1/2 signaling was activated in TGFβ2-induced EMT in human RPE cells, while blockade of the canonical TGFβ2/Smad2/3 signaling with SB431542 could not inhibit TGFβ2-induced the activation of ERK1/2. Meanwhile, blockade of ERK1/2 signaling with a specific MEK/ERK1/2 inhibitor U0126 strongly prevented TGFβ2-induced the downregulation of P-cadherin, and the upregulation of α-SMA, collagen type IV, N-cadherin and fibronectin in RPE cells. In addition, we also identified that blockade of ERK1/2 signaling could inhibit not only the canonical TGFβ/Smad signaling, but also the Jagged/Notch pathway. Finally, we found that blockade of Notch pathway with a specific inhibitor DAPT could inhibit TGFβ2-induced the activation of ERK1/2 pathway conversely. Therefore, our study provides evidence that ERK1/2 signaling can cross-interact with the canonical TGFβ/Smad and the Jagged/Notch signaling pathways in RPE cells EMT. ERK1/2 inhibitor may have therapeutic value in the prevention and treatment of PVR and other fibrotic diseases.
    PLoS ONE 05/2014; 9(5):e96365. DOI:10.1371/journal.pone.0096365 · 3.53 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is the major pathological mechanism in anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Extracellular signal-regulated kinase (ERK)1/2 pathway has been reported to play a major role in carcinogenesis, cancer metastasis and various fibrotic diseases. We hypothesized that ERK1/2 signaling can cross-interact with canonical transforming growth factor β (TGFβ)/Smad signaling and the Notch pathway, which subsequently contributes to LECs EMT. In this study, we demonstrated that ERK1/2 signaling was activated in TGFβ2‑induced EMT in human LECs, whereas the blockade of TGFβ2/Smad2/3 signaling with SB431542 did not inhibit the activation of ERK1/2 induced by TGFβ2. In addition, inactivation of ERK1/2 signaling with a specific MEK/ERK1/2 inhibitor, U0126, completely prevented the TGFβ2-induced upregulation of α-SMA, collagen type I, collagen type IV and fibronectin. We also demonstrated that inactivation of ERK1/2 signaling inhibited canonical TGFβ/Smad signaling, as well as the Jagged/Notch pathway. By contrast, blockade of the Notch pathway by DAPT inhibited the TGFβ2‑induced activation of ERK1/2 pathway in LECs. Thus, results of this study provide evidence for the complex interplay between ERK1/2, TGFβ/Smad, and Jagged/Notch signaling pathways in the regulation of EMT in LECs. Inhibition of the ERK1/2 pathway may therefore have therapeutic value in the prevention and treatment of ASC and PCO.
    International Journal of Molecular Medicine 04/2014; 33(6). DOI:10.3892/ijmm.2014.1723 · 1.88 Impact Factor
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    ABSTRACT: The epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays a key role in proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), both of which lead to severe loss of vision. Recently, microRNAs (miRNAs) have been found to be involved in the regulation of various physiological and pathological processes, such as embryogenesis, organ development, oncogenesis and angiogenesis. However, the expression profile and function of miRNAs in the EMT of RPE cells remain to be clarified. In this study, human miRNA expression profiles were identified using microarrays and 304 miRNAs were found to be differentially expressed in TGFβ2-induced EMT in human RPE cells. Of these differentially expressed miRNAs, 185 miRNAs were downregulated and 119 miRNAs were upregulated at least 2-fold in TGFβ2 treatment samples. Similar alterations of miRNA expression were validated for 35 representative miRNAs by quantitative polymerase chain reaction analysis. Therefore, these results suggested that differentially expressed miRNAs play potential roles in TGFβ2-induced EMT in RPE cells. This is an essential step in the identification of miRNAs associated with PVR and PDR progression, and in the identification of potential therapeutic targets for these diseases.
    International Journal of Molecular Medicine 03/2014; 33(5). DOI:10.3892/ijmm.2014.1688 · 1.88 Impact Factor
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    ABSTRACT: The proliferation and epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells are the major pathological changes in development of proliferative vitreoretinopathy (PVR), which leads to severe visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanisms play important roles in controlling various physiological and pathological events. However, whether HDACs are involved in the regulation of proliferation and EMT in PRE cells remains unidentified. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that some of class I and class II HDACs were up-regulated in transforming growth factor-β2 (TGF-β2)/TGF-β1-stimulated RPE cells. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of RPE cells by G1 phase cell cycle arrest through inhibition of cyclin/CDK/p-Rb and induction of p21 and p27. In the meantime, TSA strongly prevented TGF-β2-induced morphological changes and the up-regulation of α-SMA, collagen type I, collagen type IV, fibronectin, Snail and Slug. We also demonstrated that TSA affected not only the canonical Smad signalling pathway but also the non-canonical TGF-β/Akt, MAPK and ERK1/2 pathways. Finally, we found that the underlying mechanism of TSA affects EMT in RPE cells also through down-regulating the Jagged/Notch signalling pathway. Therefore, this study may provide a new insight into the pathogenesis of PVR, and suggests that epigenetic treatment with HDAC inhibitors may have therapeutic value in the prevention and treatment of PVR.
    Journal of Cellular and Molecular Medicine 01/2014; 18(4). DOI:10.1111/jcmm.12212 · 3.70 Impact Factor
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    ABSTRACT: Congenital cataract is a major cause of visual impairment and childhood blindness. The solubility and stability of crystallin proteins play critical roles in maintaining the optical transparency of the lens during the life span. Previous studies have shown that approximately 8.3%∼25% of congenital cataracts are inherited, and mutations in crystallins are the most common. In this study, we attempted to identify the genetic defect in a four-generation family affected with congenital cataracts. The congenital cataract phenotype of this four-generation family was identified as membranous cataract by slit-lamp photography. Mutation screening of the candidate genes detected a heterozygous c.465G→C change in the exon6 of the βB2-crystallin gene (CRYBB2) in all family members affected with cataracts, resulting in the substitution of a highly conserved Tryptophan to Cystine (p.W151C). The mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis and found that the transition res
    PLoS ONE 11/2013; 8(11-11):e81290. DOI:10.1371/journal.pone.0081290 · 3.53 Impact Factor
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    ABSTRACT: Recent advances in stem cell research have raised the possibility of stem cells repairing or replacing retinal photoreceptor cells that are either dysfunctional or lost in many retinal diseases. Various types of stem cells have been used to replace retinal photoreceptor cells. Recently, peripheral blood stem cells, a small proportion of pluripotent stem cells, have been reported to mainly exist in the peripheral blood mononuclear cells (PBMCs). In this study, the effects of pre-induced adult human PBMCs (hPBMCs) on the degenerative retinas of rd1 mice were investigated. Freshly isolated adult hPBMCs were pre-induced with the use of the conditioned medium of rat retinas for 4 days and were then labeled with chloromethyl-benzamidodialkylcarbocyanine (CM-DiI) and then transplanted into the subretinal space of the right eye of rd1 mice through a trans-scleral approach. The right eyes were collected 30 days after transplantation. The survival and migration of the transplanted cells in host retinas were investigated by whole-mount retinas, retinal frozen sections and immunofluorescent staining. After subretinal transplantation, pre-induced hPBMCs were able to survive and widely migrate into the retinas of rd1 mice. A few CM-DiI-labeled cells migrated into the inner nuclear layer and the retinal ganglion cell layer. Some transplanted cells in the subretinal space of rd1 host mice expressed the human photoreceptor-specific marker rhodopsin. This study suggests that pre-induced hPBMCs may be a potential cell source of cell replacement therapy for retinal degenerative diseases.
    Cytotherapy 11/2013; 15(11):1416-1425. DOI:10.1016/j.jcyt.2013.05.025 · 3.10 Impact Factor
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    ABSTRACT: Monitoring intraocular pressure (IOP) is essential for pediatric cataract treatment but always difficult due to lack of cooperation in young children. We present the baseline characteristics and the first-year results of a long-term prospective cohort study, which are aimed to determine the relationship of the incidence of ocular hypertension (OH) in children after cataract surgery during the first-year period and the risk of developing late-onset glaucoma. Children were included with the following criteria: they were≤10 years old and scheduled to undergo cataract surgery with/without intraocular lens implantation; they were compliant with our follow-up protocol, which included monitoring IOP using a Tono-Pen under sedation or anesthesia. Incidence of OH, peak OH value, OH onset time and OH duration within a 12-month period following surgery were measured. In brief, 206 patients (379 eyes) were included and OH developed in 66 of 379 (17.4%) eyes. The mean follow-up period was 14.0±3.2 months (med
    PLoS ONE 07/2013; 8(7-7):e69867. DOI:10.1371/journal.pone.0069867 · 3.53 Impact Factor
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    ABSTRACT: Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E(-/-) [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.
    Cell metabolism 07/2013; 18(1):118-29. DOI:10.1016/j.cmet.2013.06.003 · 16.75 Impact Factor
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    ABSTRACT: It is well established that the tumor suppressor p53 plays major roles in regulating apoptosis and cell cycle progression. In addition, recent studies have demonstrated that p53 is actively involved in regulating cell differentiation in muscle, the circulatory system and various carcinoma tissues. We have recently shown that p53 also controls lens differentiation. Regarding the mechanism, we reveal that p53 directly regulates c-Maf and Prox1, two important transcription factors to control cell differentiation in the ocular lens. In the present study, we present further evidence to show that p53 can regulate lens differentiation by controlling expression of the differentiation genes coding for the lens crystallins. First, the aA and bA3/A1 gene promoters or introns all contain putative p53 binding sites. Second, gel mobility shifting assays revealed that the p53 protein in nuclear extracts from lens epithelial cells directly binds to the p53 binding sites found in these crystallin gene promoters or introns. Third, exogenous wild type p53 induces dose-dependent expression of the luciferase reporter gene driven by different crystallin gene promoters and the exogenous dominant negative mutant p53 causes dose-dependent inhibition of the same crystallin genes. Fourth, ChIP assays revealed that p53 binds to crystallin gene promoters in vivo. Finally, in the p53 knockout mouse lenses, expression levels of various crystallins were found down-regulated in comparison with those from the wild type mouse lenses. Together, our results reveal that p53 directly regulates expression of different sets of genes to control lens differentiation.
    Current Molecular Medicine 06/2013; DOI:10.2174/15665240113139990052 · 3.61 Impact Factor
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    ABSTRACT: Congenital cataract is the main cause of blindness in children, with significantly varying treatment effects. The development of axial length is an important factor that affects the prognosis of these children. However, when compared with the eyes of normal children, the mechanism of growth of the axial length is so complicated that the reported findings differ significantly in terms of the measuring apparatus, assessment methods, and statistical outcome, making the rule of axial length development still unclear. In this paper, we first review the process of axial length development in normal healthy children and compare different hypotheses about certain factors that could affect the development of axial length. The results of some current research about the characteristics of axial length development in congenital cataract children are then reviewed. Lastly, the advantages and disadvantages of current axial length measurements methods are compared and analyzed. The purpose of this review is to improve our understanding of the complexity and importance of axial length development and to suggest better use of axial length monitoring measurements in congenital cataract children for pediatric ophthalmologists, with the hope of offering assistance that will enhance long-term therapeutic effects for these children.

Publication Stats

780 Citations
326.23 Total Impact Points

Institutions

  • 2002–2015
    • Sun Yat-Sen University
      • State Key Laboratory of Oncology
      Shengcheng, Guangdong, China
  • 2014
    • Sun Yat-Sen University Cancer Center
      Shengcheng, Guangdong, China
  • 2012
    • Jinan University (Guangzhou, China)
      Shengcheng, Guangdong, China
  • 2006
    • Harvard University
      Cambridge, Massachusetts, United States