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author:("Zhao, jianji")
1.  Evaluation of the optimal dosage of S-1 in adjuvant SOX chemotherapy for gastric cancer 
Oncology Letters  2014;9(3):1451-1457.
Gastric cancer (GC) is the second leading cause of cancer-related mortality worldwide. The usual treatment of GC consists of surgery with additional adjuvant chemotherapy. In the present study, the feasibility and safety of adjuvant S-1 plus oxaliplatin (SOX) chemotherapy for patients with GC and the optimal dosage of S-1 were determined. Eligible patients were randomly assigned to either arm A (30 cases) receiving 70 mg/m2 S-1 (in two seperate half doses) daily or arm B (30 cases) receiving 80 mg/m2 S-1 (in two seperate half doses) daily. The S-1 was administered twice daily for 14 days followed by a 7-day rest period for the third week. A total of 130 mg/m2 oxaliplatin was administered on day 1 every 3 weeks for each arm. The cumulative rates of the relative total administration dose of S-1 at 100% in the 6th treatment course was 71.4% [95% confidence interval (CI), 56.5–90.3%] in arm A, which was significantly higher than 21.4% (95% CI, 10.5–43.6%) in arm B (P=0.001). The most common grade 3/4 toxicities were neutropenia (19.6%), thrombocytopenia (19.6%) and vomiting (16.1%). Grade 3/4 thrombocytopenia was observed in 7.1% of patients in arm A and in 32.1% of patients in arm B (P=0.019). With regard to the adverse events induced by S-1 administration, the incidence of diarrhea (3.6 vs. 42.9%; P<0.001) was significantly higher in arm B than in arm A, as anticipated. Collectively, adjuvant SOX therapy for GC is feasible and safe, and when combined with 130 mg/m2 oxaliplatin, 70 mg/m2/day S-1 appears to the optimal dose.
doi:10.3892/ol.2014.2821
PMCID: PMC4315063  PMID: 25663930
adjuvant chemotherapy; gastric cancer; S-1; oxaliplatin
2.  Morphology, Carbohydrate Composition and Vernalization Response in a Genetically Diverse Collection of Asian and European Turnips (Brassica rapa subsp. rapa) 
PLoS ONE  2014;9(12):e114241.
Brassica rapa displays enormous morphological diversity, with leafy vegetables, turnips and oil crops. Turnips (Brassica rapa subsp. rapa) represent one of the morphotypes, which form tubers and can be used to study the genetics underlying storage organ formation. In the present study we investigated several characteristics of an extensive turnip collection comprising 56 accessions from both Asia (mainly Japanese origin) and Europe. Population structure was calculated using data from 280 evenly distributed SNP markers over 56 turnip accessions. We studied the anatomy of turnip tubers and measured carbohydrate composition of the mature turnip tubers of a subset of the collection. The variation in 16 leaf traits, 12 tuber traits and flowering time was evaluated in five independent experiments for the entire collection. The effect of vernalization on flowering and tuber formation was also investigated. SNP marker profiling basically divided the turnip accessions into two subpopulations, with admixture, generally corresponding with geographical origin (Europe or Asia). The enlarged turnip tuber consists of both hypocotyl and root tissue, but the proportion of the two tissues differs between accessions. The ratio of sucrose to fructose and glucose differed among accessions, while generally starch content was low. The evaluated traits segregated in both subpopulations, with leaf shape, tuber colour and number of shoots per tuber explaining most variation between the two subpopulations. Vernalization resulted in reduced flowering time and smaller tubers for the Asian turnips whereas the European turnips were less affected by vernalization.
doi:10.1371/journal.pone.0114241
PMCID: PMC4256417  PMID: 25474111
3.  Variants Identified by Hepatocellular Carcinoma and Chronic Hepatitis B Virus Infection Susceptibility GWAS Associated with Survival in HBV-Related Hepatocellular Carcinoma 
PLoS ONE  2014;9(7):e101586.
Recent genome-wide association studies (GWAS) have identified several common susceptibility loci associated with the risk of hepatocellular carcinoma (HCC) or chronic hepatitis B infection (CHB). However, the relationship between these genetic variants and survival of patients with hepatitis B virus (HBV)-related HCC is still unknown. In this study, 22 single nucleotide polymorphisms (SNPs) were genotyped among 330 HBV-related HCC patients using the MassARRAY system from Sequenom. Cox proportional hazards regression was used to examine the effects of genotype on survival time under an additive model with age, sex, smoking status and clinical stage as covariates. We identified four SNPs on 6p21 (rs1419881 T>C, rs7453920 G>A,rs3997872 G>A and rs7768538 T>C), and two SNPs on 8p12 (rs2275959 C>T and rs7821974 C>T) significantly associated with survival time of HBV-related HCC patients. Our results suggest that HCC or CHB susceptibility loci might also affect the prognosis of patients with HBV-related HCC.
doi:10.1371/journal.pone.0101586
PMCID: PMC4079718  PMID: 24987808
4.  Prognosis of patients with hepatocellular carcinoma and hypersplenism after surgery: a single-center experience from the People’s Republic of China 
OncoTargets and therapy  2014;7:957-964.
Purpose
As prognosis of patients with hepatocellular carcinoma (HCC) and hypersplenism is rarely reported, this study examined prognostic factors for patients who underwent surgery for this condition.
Patients and methods
This study retrospectively analyzed prognostic factors in 181 consecutive HCC patients using univariate and multivariate analyses, as well as subgroup analyses for disease-free survival (DFS) and overall survival (OS) of two groups: one group who received splenectomies (Sp) and one group who did not (non-Sp).
Results
1, 3, and 5 year OS rates were 88.4%, 67.1%, and 52.8%, respectively; corresponding DFS rates were 67.0%, 43.8%, and 31.6%, respectively. Age ≥55 years old, cigarette smoking, tumor size ≥5 cm, microvascular invasion, and Child-Pugh grade B (versus A) correlated significantly with OS (P<0.05). Interestingly, in patients with tumor lymph node metastasis (TNM) stage I disease, DFS of the Sp-group (median DFS, 24.1 months; n=34) was significantly lower than that of the non-Sp group (median DFS, 62.1 months; n=74), P=0.034; whereas at TNM stage II, OS of the Sp-group (median OS, 79.1 months; n=21) was significantly better than that of the non-Sp group (median OS, 23.3 months; n=30), P=0.018.
Conclusion
Hepatectomy without concomitant splenectomy can contribute to improved DFS of TNM stage I HCC patients with hypersplenism, whereas simultaneous hepatectomy and splenectomy can prolong OS for patients at TNM stage II.
doi:10.2147/OTT.S64921
PMCID: PMC4061180  PMID: 24959082
hepatectomy; splenectomy; overall survival; disease-free survival
5.  Recent advances in the ARID family: focusing on roles in human cancer 
OncoTargets and therapy  2014;7:315-324.
The human AT-rich interaction domain (ARID) family contains seven subfamilies and 15 members characterized by having an ARID. Members of the ARID family have the ability to regulate transcription and are involved in cell differentiation and proliferation. Accumulating evidence suggests that ARID family members are involved in cancer-related signaling pathways, highly mutated or differentially expressed in tumor tissues, and act as predictive factors for cancer prognosis or therapeutic outcome. Here we review the molecular biology and clinical studies concerned with the role played by the ARID family in cancer. This may contribute to our understanding of the initiation and progression of cancer from a novel point of view, as well as providing potential targets for cancer therapy.
doi:10.2147/OTT.S57023
PMCID: PMC3933769  PMID: 24570593
AT-rich interaction domain; human cancer; cancer-related signaling pathway; therapy; potential targets
6.  Mechanisms underlying the beneficial effects of Kaiyu Granule for depression 
Neural Regeneration Research  2013;8(34):3241-3248.
The proprietary Chinese medicine preparation Kaiyu Granule is made of bupleurum, nutgrass galingale rhizome, szechwan lovage rhizome, turmeric root tuber, white peony alba, cape jasmine fruit, fried semen ziziphi jujubae, and prepared liquorice root. It is a common recipe for the clinical treatment of depression in China. In this study, after 21 days of unpredictable stress exposure, Wistar rats exhibited similar behavioral changes to patients with depression. Moreover, G-protein-coupled inwardly rectifying K+ channel 1 mRNA and protein expression were significantly reduced in rat hippocampal CA1 and CA3 regions. However, G-protein-coupled inwardly rectifying K+ channel 1 mRNA, protein expression, and rat behavior were clearly better after administration of 12, 8, or 4 g/kg of Kaiyu Granule when depression model rats underwent stress. 12 g/kg of Kaiyu Granule had the most obvious effects on the increased expression of G-protein-coupled inwardly rectifying K+ channel 1 mRNA and protein in rat hippocampal CA1 and CA3 regions. These results suggested that Kaiyu Granule improved depression by affecting G-protein-coupled inwardly rectifying K+ channel 1 expression in the rat hippocampus.
doi:10.3969/j.issn.1673-5374.2013.34.008
PMCID: PMC4146178  PMID: 25206645
neural regeneration; chronic stress; hippocampus; fluoxetine hydrochloride capsules; depression; neuropeptide; G-protein-coupled inwardly rectifying K+ channel 1; in situ hybridization; grants-supported paper; neuroregeneration
7.  Dose-finding study on adjuvant chemotherapy with S-1 plus oxaliplatin for gastric cancer 
Gastric cancer (GC) is the fourth most common type of cancer, accounting for an estimated one million new cases annually worldwide. Locally advanced GC often recurs, even following curative surgical resection. Therefore, there is a need for an effective adjuvant chemotherapy regimen. The aim of this trial was to investigate the maximum tolerated dose (MTD) of S-1 when administered in combination with oxaliplatin in postoperative GC patients. Oxaliplatin was administered at a fixed dose of 130 mg/m2 on day 1. S-1 was administered from day 1 to 14 of a 3-week cycle and escalated by 10 mg/m2/day from 60 to 80 mg/m2/day. A total of 15 patients were enrolled in this study. No dose-limiting toxicities (DLTs) occurred at level 1 (S-1, 60 mg/m2; n=3). One case of DLT (grade 3 vomiting) occurred at level 2 (S-1, 70 mg/m2; n= 6), whereas 2 cases of grade 3 vomiting were observed at level 3 (S-1, 80 mg/m2; n=6). Based on these results, the MTD of S-1 was initially determined to be 70 mg/m2. Furthermore, we observed that cytochrome P450 2A6 (CYP2A6) 41349640C>G was associated with severe neutropenia (C/C vs. C/G vs. G/G = 0 vs. 33.33 vs. 100%; P=0.03297, Fisher’s exact test) during the entire course of the treatment.
doi:10.3892/mco.2013.191
PMCID: PMC3915807  PMID: 24649314
S-1; oxaliplatin; adjuvant chemotherapy; maximum-tolerated dose; cytochrome P450 2A6
8.  Poxue Huayu and Tianjing Busui Decoction for cerebral hemorrhage (Upregulation of neurotrophic factor expression): Upregulation of neurotrophic factor expression 
Neural Regeneration Research  2013;8(22):2039-2049.
This study established a rat model of cerebral hemorrhage by injecting autologous anticoagulated blood. Rat models were intragastrically administered 5, 10, 20 g/kg Poxue Huayu and Tianjing Busui Decoction, supplemented with Hirudo, raw rhubarb, raw Pollen Typhae, gadfly, Fructrs Trichosanthis, Radix Notoginseng, Rhizoma Acori Talarinowii, and glue of tortoise plastron, once a day, for 14 consecutive days. Results demonstrated that brain water content significantly reduced in rats with cerebral hemorrhage, and intracerebral hematoma volume markedly reduced after treatment. Immunohistochemical staining revealed that brain-derived neurotrophic factor, tyrosine kinase B and vascular endothelial growth factor expression noticeably increased around the surrounding hematoma. Reverse transcription-PCR revealed that brain-derived neurotrophic factor and tyrosine kinase B mRNA expression significantly increased around the surrounding hematoma. Neurologic impairment obviously reduced. These results indicated that Poxue Huayu and Tianjing Busui Decoction exert therapeutic effects on cerebral hemorrhage by upregulating the expression of brain-derived neurotrophic factor.
doi:10.3969/j.issn.1673-5374.2013.22.003
PMCID: PMC4146063  PMID: 25206512
neural regeneration; traditional Chinese medicine; cerebral hemorrhage; brain-derived neurotrophic factor; tyrosine kinase B; vascular endothelial growth factor; Poxue Huayu and Tianjing Busui; grants-supported paper; neuroregeneration
9.  Angiotensin-converting enzyme gene polymorphism and middle cerebral artery stenosis in a Chinese Han population★ 
Neural Regeneration Research  2013;8(15):1410-1417.
The angiotensin-converting enzyme gene is a candidate gene of stroke. The present study involved 62 healthy volunteers and 148 patients with middle cerebral artery stenosis as confirmed by brain color ultrasound from a Han population in North China, and determined the peripheral blood angiotensin-converting enzyme genotype using PCR-restriction fragment length polymorphism analysis. The results showed that the frequencies of the DD genotype and D allele were increased in patients with middle cerebral artery stenosis, but the difference was not statistically significant compared with healthy controls. The findings of this study on the relationship between stroke genes and middle cerebral artery stenosis indicate no significant correlation between the frequencies of the DD genotype and D allele of angiotensin-converting enzyme and middle cerebral artery stenosis in this Han population from North China. In the future, studies will be carried out to investigate correlations between multiple stroke candidate gene synergy and middle cerebral artery stenosis to provide a foundation for the development of gene therapy.
doi:10.3969/j.issn.1673-5374.2013.15.008
PMCID: PMC4107760  PMID: 25206436
neural regeneration; brain injury; stroke; angiotensin-converting enzyme; gene; polymorphism; middle cerebral artery; angiostenosis; North China; Han population; neuroregeneration
10.  Different Roles of the Mevalonate and Methylerythritol Phosphate Pathways in Cell Growth and Tanshinone Production of Salvia miltiorrhiza Hairy Roots 
PLoS ONE  2012;7(11):e46797.
Salvia miltiorrhiza has been widely used in the treatment of coronary heart disease. Tanshinones, a group of diterpenoids are the main active ingredients in S. miltiorrhiza. Two biosynthetic pathways were involved in tanshinone biosynthesis in plants: the mevalonate (MVA) pathway in the cytosol and the methylerythritol phosphate (MEP) pathway in the plastids. The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme of the MVA pathway. The 1-deoxy-D-xylulose 5-phosphate synthase (DXS) and 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) are the key enzymes of the MEP pathway. In this study, to reveal roles of the MVA and the MEP pathways in cell growth and tanshinone production of S. miltiorrhiza hairy roots, specific inhibitors of the two pathways were used to perturb metabolic flux. The results showed that the MVA pathway inhibitor (mevinolin, MEV) was more powerful to inhibit the hairy root growth than the MEP pathway inhibitor (fosmidomycin, FOS). Both MEV and FOS could significantly inhibit tanshinone production, and FOS was more powerful than MEV. An inhibitor (D, L-glyceraldehyde, DLG) of IPP translocation strengthened the inhibitory effects of MEV and FOS on cell growth and tanshinone production. Application of MEV resulted in a significant increase of expression and activity of HMGR at 6 h, and a sharp decrease at 24 h. FOS treatment resulted in a significant increase of DXR and DXS expression and DXS activity at 6 h, and a sharp decrease at 24 h. Our results suggested that the MVA pathway played a major role in cell growth, while the MEP pathway was the main source of tanshinone biosynthesis. Both cell growth and tanshinone production could partially depend on the crosstalk between the two pathways. The inhibitor-mediated changes of tanshinone production were reflected in transcript and protein levels of genes of the MVA and MEP pathways.
doi:10.1371/journal.pone.0046797
PMCID: PMC3510226  PMID: 23209548
11.  Efficacy of Chuanxiong Ding Tong Herbal Formula Granule in the Treatment and Prophylactic of Migraine Patients: A Randomized, Double-Blind, Multicenter, Placebo-Controlled Trial 
Objective. To evaluate the efficacy of traditional Chinese herbal ChuanXiong Ding Tong herbal formula granule (CXDT-HFG) for migraine patients with “the Syndrome of Liver Wind and Blood Stasis.” Methods. 150 migraine patients were recruited and assigned randomly in a double-blind, placebo-controlled study to receive CXDT-HFG (n = 99) plus necessary analgesics, or placebo (n = 51) plus necessary analgesics for 16 weeks (12 weeks' intervention and 4 weeks' follow up). Outcome measures included migraine days, frequency of migraine attacks, analgesics consumption for acute treatment, and the proportion of responders as well as the visual analogue scale (VAS) scores and intensity for pain. Results. Compared with the placebo group, the CXDT-HFG group showed significant reduction in migraine days and attacks frequency at week 12 and follow-up period (P < 0.05) as well as in the reduction of VAS scores at follow-up period.There was significant difference in the proportion of responders between the two groups at follow-up period (P = 0.014). However there were no significant differences between the two groups in analgesics consumption (P > 0.05). Conclusion. CXDT-HFG was more effective than placebo in decreasing days of migraine attacks, frequency, VAS scores, and relieving pain intensity for migraine patients.
doi:10.1155/2012/967968
PMCID: PMC3525331  PMID: 23304233
12.  A naturally occurring InDel variation in BraA.FLC.b (BrFLC2) associated with flowering time variation in Brassica rapa 
BMC Plant Biology  2012;12:151.
Background
Flowering time is an important trait in Brassica rapa crops. FLOWERING LOCUS C (FLC) is a MADS-box transcription factor that acts as a potent repressor of flowering. Expression of FLC is silenced when plants are exposed to low temperature, which activates flowering. There are four copies of FLC in B. rapa. Analyses of different segregating populations have suggested that BraA.FLC.a (BrFLC1) and BraA.FLC.b (BrFLC2) play major roles in controlling flowering time in B. rapa.
Results
We analyzed the BrFLC2 sequence in nine B. rapa accessions, and identified a 57-bp insertion/deletion (InDel) across exon 4 and intron 4 resulting in a non-functional allele. In total, three types of transcripts were identified for this mutated BrFLC2 allele. The InDel was used to develop a PCR-based marker, which was used to screen a collection of 159 B. rapa accessions. The deletion genotype was present only in oil-type B. rapa, including ssp. oleifera and ssp. tricolaris, and not in other subspecies. The deletion genotype was significantly correlated with variation in flowering time. In contrast, the reported splicing site variation in BrFLC1, which also leads to a non-functional locus, was detected but not correlated with variation in flowering time in oil-type B. rapa, although it was correlated with variation in flowering time in vegetable-type B. rapa.
Conclusions
Our results suggest that the naturally occurring deletion mutation across exon 4 and intron 4 in BrFLC2 gene contributes greatly to variation in flowering time in oil-type B. rapa. The observed different relationship between BrFLC1 or BrFLC2 and flowering time variation indicates that the control of flowering time has evolved separately between oil-type and vegetable-type B. rapa groups.
doi:10.1186/1471-2229-12-151
PMCID: PMC3487953  PMID: 22925611
13.  ARID2: A new tumor suppressor gene in hepatocellular carcinoma 
Oncotarget  2011;2(11):886-891.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, however, genetic-environmental interactions and mechanisms associated with the development of HCC remains largely unclear. Our recent work described novel inactivating mutations of ARID2 (AT-rich interactive domain 2) in four major subtypes of HCC through exomic sequencing of ten HCV-associated HCCs and subsequent evaluation of the tumors from additional affected individuals. Here, we summarize the current knowledge about the relevance of ARID2 in HCC and the implication in future patient care.
PMCID: PMC3259997  PMID: 22095441
Hepatocellular Carcinoma; Hepatitis C Virus; ARID2; Tumor Suppressor; Interferon
14.  Differentiation of canine distemper virus isolates in fur animals from various vaccine strains by reverse transcription-polymerase chain reaction-restriction fragment length polymorphism according to phylogenetic relations in china 
Virology Journal  2011;8:85.
In order to effectively identify the vaccine and field strains of Canine distemper virus (CDV), a new differential diagnostic test has been developed based on reverse transcription-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). We selected an 829 bp fragment of the nucleoprotein (N) gene of CDV. By RFLP analysis using BamHI, field isolates were distinguishable from the vaccine strains. Two fragments were obtained from the vaccine strains by RT-PCR-RFLP analysis while three were observed in the field strains. An 829 nucleotide region of the CDV N gene was analyzed in 19 CDV field strains isolated from minks, raccoon dogs and foxes in China between 2005 and 2007. The results suggest this method is precise, accurate and efficient. It was also determined that three different genotypes exist in CDV field strains in fur animal herds of the north of China, most of which belong to Asian type. Mutated field strains, JSY06-R1, JSY06-R2 and JDH07-F1 also exist in Northern China, but are most closely related to the standard virulent strain A75/17, designated in Arctic and America-2 genetype in the present study, respectively.
doi:10.1186/1743-422X-8-85
PMCID: PMC3056815  PMID: 21352564
15.  BrFLC2 (FLOWERING LOCUS C) as a candidate gene for a vernalization response QTL in Brassica rapa 
Journal of Experimental Botany  2010;61(6):1817-1825.
Flowering time is an important agronomic trait, and wide variation exists among Brassica rapa. In Arabidopsis, FLOWERING LOCUS C (FLC) plays an important role in modulating flowering time and the response to vernalization. Brassica rapa contains several paralogues of FLC at syntenic regions. BrFLC2 maps under a major flowering time and vernalization response quantitative trait locus (QTL) at the top of A02. Here the effects of vernalization on flowering time in a double haploid (DH) population and on BrFLC2 expression in selected lines of a DH population in B. rapa are descibed. The effect of the major flowering time QTL on the top of A02 where BrFLC2 maps clearly decreases upon vernalization, which points to a role for BrFLC2 underlying the QTL. In all developmental stages and tissues (seedlings, cotyledons, and leaves), BrFLC2 transcript levels are higher in late flowering pools of DH lines than in pools of early flowering DH lines. BrFLC2 expression diminished after different durations of seedling vernalization in both early and late DH lines. The reduction of BrFLC2 expression upon seedling vernalization of both early and late flowering DH lines was strongest at the seedling stage and diminished in subsequent growth stages, which suggests that the commitment to flowering is already set at very early developmental stages. Taken together, these data support the hypothesis that BrFLC2 is a candidate gene for the flowering time and vernalization response QTL in B. rapa.
doi:10.1093/jxb/erq048
PMCID: PMC2852669  PMID: 20231331
Brassica rapa; FLOWERING LOCUS C; flowering time; quantitative trait loci; vernalization

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