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ABSTRACT: Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder caused by heterozygous germline mutations in the exostonsin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we screened mutations in the EXT1/EXT2 genes in four Chinese MO kindreds by direct sequencing. Three point mutations were detected, including a nonsense mutation in the EXT2 gene (c.544C > T) and two splice site mutations in the EXT1 and EXT2 genes, respectively (EXT1: c.1883 + 1G > A and EXT2: c.1173 + 1G > T). Although splice site mutations constitute at least 10% of all mutations that cause MO, there has been limited research on their pathogenic effect on RNA processing due to poor availability of patient RNA samples. In this study, ex vivo and in vivo splicing assays were used to investigate the effect of EXT1 and EXT2 mutations on aberrant splicing at the mRNA level. Our results indicate that identified splice site mutations can cause either cryptic splice site usage or exon skipping. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res.
Journal of Orthopaedic Research 04/2013; · 2.81 Impact Factor
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ABSTRACT: Loss of heterozygosity of 1p35-pter, 4q, and 18q is frequent in gastric carcinoma, suggesting that these regions harbor tumor suppressor genes. However, the differences in these genetic alterations between adenocarcinoma of the gastric cardia and adenocarcinoma of the distal stomach remain unclear. In this study, loss of heterozygosity at chromosomes 1p35-pter, 4q, and 18q were analyzed in adenocarcinoma of the gastric cardia and adenocarcinoma of the distal stomach samples acquired by laser capture microdissection. The expression of several tumor suppressor gene proteins, runt-related transcription factor 3 (1p36), annexin A10 (4q33), SMAD family member 4 (18q21.1), and deleted in colorectal carcinoma (18q21.3), was evaluated immunohistochemically. The adenocarcinoma of the distal stomach and adenocarcinoma of the gastric cardia lesions had a similar trend in total deletion frequency for chromosomes 1p35-pter (36.5% for adenocarcinoma of the distal stomach and 32.5% for adenocarcinoma of the gastric cardia), 4q (42.3% for adenocarcinoma of the distal stomach and 47.5% for adenocarcinoma of the gastric cardia), and 18q (38.5% for adenocarcinoma of the distal stomach and 45% for adenocarcinoma of the gastric cardia). However, loss of heterozygosity patterns were clearly different in the 2 adenocarcinomas. Deletion mapping indicated that 4q32.2-4q34.3, 18q21.2-21.31, 18q22.3-23, and 1p35.2-1p36.13 were involved in adenocarcinoma of the distal stomach, whereas 4q13.3-4q22.3, 4q31.21-4q32.2, 18q21.31-18q22.1, and 1p35.2-1p36.13 were involved in adenocarcinoma of the gastric cardia. Expression of ANXA10 (P = .038), SMAD family member 4 (P = .028), and deleted in colorectal carcinoma (P = .004) was less common in adenocarcinoma of the distal stomach than in adenocarcinoma of the gastric cardia. Expression of runt-related transcription factor 3 (P = .795) showed no significant difference in the 2 tumors. The tumors differed in the profile of genetic alterations and protein expression of these well-known tumor suppressor genes. The deleted regions defined in this study may harbor tumor suppressor genes relevant to adenocarcinoma of the gastric cardia.
Human pathology 08/2012; · 3.03 Impact Factor
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ABSTRACT: To explore the value of combining high resolution melting (HRM) with multiplex ligation-dependent probe amplification (MLPA) for detecting mutations underlying phenylketonuria.
HRM was used for detecting small mutations in phenylalanine hydroxylase gene (PAH) of 26 phenylketonuria patients. The results were verified with DNA sequencing. MLPA was used for detecting potential deletions/duplications in the PAH gene. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed for additional potential mutations.
A total of 21 mutations were found in 44/52 alleles (84.62%), which included a dupEx4. Among the 21 types of mutation, 19 were reported previously, and the remaining two were novel mutations: c.584_585insA and IVS10+1G>T. In addition, the mutation of R243Q (25%) was the most common type in China.
The study showed that the combination of HRM and MLPA could increase the detection rate for mutation in PKU. The study has added new information to the human mutation database of PAH and provided a basis for clinical diagnosis and prenatal counseling.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 12/2011; 28(6):649-53.
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ABSTRACT: This paper presents a general and rigorous transformation method to tailor planar conic reflectors. The proposed method enables the designed reflectors to scatter or reflect incident light in the same manner as a conic reflector while the whole device as well as the reflector would maintain planar profiles. In order to reduce the overall size, especially the aperture of the reflector, we further apply a set of compressed and folded spatial mapping to the planar reflectors. Planar reflectors with reduced sizes are finally obtained which may be useful in several optical and electromagnetic applications.
Phys. Rev. A. 08/2011; 84(2).
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Journal of Genetics 08/2011; 90(2):339-42. · 1.09 Impact Factor
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ABSTRACT: In this paper, we propose a kind of illusion cloak that does not provide invisibility but instead changes the scattering of a coated target to that of a totally different one. Different from other illusion cloaks such as those based on “anti-object” or active sources, the proposed one is independent of the information of concealed targets or incident waves and can reshape the scattering of any targets. In addition, we also provide a general method to imitate arbitrary conductor line segments, as a special case of conductor reshaper. Electromagnetic (EM) simulations by a finite-element solver on detailed examples have been carried to validate the design.
Phys. Rev. A. 04/2011; 83(4).
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ABSTRACT: The molecular genetic alterations leading to gastric malignancy are largely unknown. This study aimed to unravel the genomic DNA copy number aberrations (CNAs) profile during gastric tumorigenesis.
In this study, we performed genomic profiling in a set of 50 intestinal type gastric carcinomas by a PCR-based relative quantification method, multiple ligation-dependent probe amplification (MLPA) with 112 cancer-related gene loci selected throughout each human chromosome as probes of MLPA assay.
Numerous chromosomal DNA CNAs, including gains of 3p22, 4q25, 8q24, 11p13, and 20q13, and losses of 1p36 and 9p21, were identified by MLPA assay as recurrent DNA CNAs in gastric cancer. Moreover, we found the median numbers of gains, losses, and total CNAs were significantly higher in lymph node metastasis positive patients than in cases without metastasis. And gain of 11p13 and losses of 9p21.3, 11q13.3, 17q25.3, and 22q11.23 were associated with lymph node metastasis (P < 0.05). Finally, two major groups, including G1 + 2 with a large number of CNAs and G3 + 4 with a small number of CNAs, can be successfully distinguished by hierarchical cluster analysis.
Our results proved MLPA is a reliable and efficient method to evaluate DNA copy number changes in gastric cancers.
Journal of Surgical Oncology 02/2011; 103(2):124-32. · 2.10 Impact Factor
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ABSTRACT: This paper proposes a general method of extending the effective invisible regions for both the shell-like interior cloak and the complementary media exterior cloak, without affecting their original cloaking regions. The proposed method is based on layered spatial mapping instead of the intact mapping. Certain interior or exterior invisible regions can be obtained by properly using a compressed or folded transformation in each space layer. Therefore, the proposal enables the as-designed cloaks to provide multiple invisible regions of different types simultaneously. Thus objects can be hidden in the interior cavity and/or in the exterior space, or even be embedded between the cloaking shells.
Journal of optics 01/2011; 13(1):015105. · 1.57 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Our previous studies have revealed that miR-148a and miR-152 are significantly down-regulated in gastrointestinal cancers. Interestingly, miR-148b has the same "seed sequences" as miR-148a and miR-152. Although aberrant expression of miR-148b has been observed in several types of cancer, its pathophysiologic role and relevance to tumorigenesis are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in gastric cancer.
We showed significant down-regulation of miR-148b in 106 gastric cancer tissues and four gastric cancer cell lines, compared with their non-tumor counterparts by real-time RT-PCR. In situ hybridization of ten cases confirmed an overt decrease in the level of miR-148b in gastric cancer tissues. Moreover, the expression of miR-148b was demonstrated to be associated with tumor size (P = 0.027) by a Mann-Whitney U test. We also found that miR-148b could inhibit cell proliferation in vitro by MTT assay, growth curves and an anchorage-independent growth assay in MGC-803, SGC-7901, BGC-823 and AGS cells. An experiment in nude mice revealed that miR-148b could suppress tumorigenicity in vivo. Using a luciferase activity assay and western blot, CCKBR was identified as a target of miR-148b in cells. Moreover, an obvious inverse correlation was observed between the expression of CCKBR protein and miR-148b in 49 pairs of tissues (P = 0.002, Spearman's correlation).
These findings provide important evidence that miR-148b targets CCKBR and is significant in suppressing gastric cancer cell growth. Maybe miR-148b would become a potential biomarker and therapeutic target against gastric cancer.
Molecular Cancer 01/2011; 10:1. · 3.99 Impact Factor
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ABSTRACT: Arbitrary polygonal cloaks with multiple invisible regions are achieved by transformation optics. The original total space is divided into several layers. Choosing proper spatial mappings for these layers, a few empty layers in which objects can be hidden without bringing any scattering are available as extended invisible regions. Compared with the original polygonal cloaks the proposed one can provide multiple interior and/or exterior invisible regions simultaneously, and the objects can thus be hidden in the interior cavity and/or in the exterior space, or even be embedded into the gap between the cloaking shells.
Journal of Modern Optics 01/2011; 58(1):14-20. · 1.17 Impact Factor
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ABSTRACT: Two-dimensional nonsingular cloaks with internal and external invisible regions are presented. Objects can be hidden either in the internal cavity or the external concealment regions without being detected. Also in the latter case, the cloaked objects can receive incoming signals. In order to avoid the singularity (an infinitely large value of the constitutive parameters) which may appear at the inner boundary, the method of adjusting the principal stretches out of the cloaking plane is adopted. Detailed examples and their electromagnetic simulations are presented to validate the design. In addition, the effect of the material loss on the invisible property of the cloaks is also discussed.
Journal of optics 08/2010; 12(9):095705. · 1.57 Impact Factor
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ABSTRACT: Heparanase activity plays a decisive role in biological processes associated with remodeling of the extracellular matrix (e.g., cancer metastasis, angiogenesis, and inflammation). Heparanase gene overexpression has been associated with advanced stage and poor survival in several cancers. We investigated the potential association between single nucleotide polymorphisms (SNPs) of the HPSE-1 gene, tumor susceptibility, clinicopathological parameters, and survival with gastric cancer among the Han population in northern China.
In this case-control study, there were 155 patients with gastric cancer and 204 healthy controls. The genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Chi-square test was performed to exam differences of genotypes or alleles frequency between samples. The effect of various variables on outcome was investigated by multivariate analysis using the Cox proportional hazards model.
We identified four polymorphisms in the HPSE-1 gene. Polymorphisms in introns 2 and 3, exon8, and exon13 occurred at a minor allele frequency of >or=10%. There was an increase in frequency of individuals with a genotype that carried the intron3 (A), exon8 (A), exon13 (G) haplotype (AAG) in patients with gastric cancer compared with healthy individuals (P = 0.0001; OR = 7.467; 95% CI: 2.274-24.509). SNP rs11099592 variant genotypes AG/AA were associated with a Borrmann type classification (P = 0.015; OR = 0.182; 95% CI: 0.049-0.668) and invasion depth (P = 0.020; OR = 0.341; 95% CI: 0.134-0.866), whereas SNP rs4328905 AG genotype was correlated to Lauren diffuse grade (P = 0.027; OR = 0.419; 95% CI 0.191-0.917). SNP rs6856901 variant genotypes GC/CC were associated with a better tumor-related survival (P = 0.028; OR = 0.504; 95% CI: 0.273-0.930) compared with GG genotype.
HPSE-1 polymorphisms may contribute to gastric tumor characteristics. SNP rs6856901 may be helpful in identifying clinical outcome of patients with gastric cancer.
Journal of Surgical Oncology 07/2010; 102(1):68-72. · 2.10 Impact Factor
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ABSTRACT: Hereditary multiple exostoses (HME) is an autosomal dominant bone disorder characterized by growth of benign multiple exostoses. In our present study, we describe a four-generation Han Chinese kindred with eight members affected by HME. Haplotyping analysis and mutation detection was performed. The results linked the disease-causing gene to the EXT1 locus on chromosome 8. A novel mutation in EXT1, c.1897delC, which cosegregated with the disease phenotype, was detected. To further confirm this mutation, a mismatch primer was designed to introduce a ScaI restriction site into the normal allele by polymerase chain reaction, and the following restriction fragment length polymorphism analysis demonstrated that the mutation was not detected in any unaffected individuals of the family or 100 unrelated Han Chinese control individuals. This mutation leads to a frameshift from codon 633, resulting in a premature termination at codon 642 and loss of the highly conserved C terminal region of the protein. Therefore, this heterozygous mutation must be classified as pathogenic and can be regarded as the cause of HME in this Chinese family.
Genetic Testing and Molecular Biomarkers 06/2010; 14(3):371-6. · 1.11 Impact Factor
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Yaran Wen,
Yang Liu,
Yiming Xu,
Yiwei Zhao,
Rui Hua,
Kaibo Wang,
Miao Sun,
Yuanhong Li,
Sen Yang,
Xue-Jun Zhang, [......],
Jack Green,
Dandan Shang,
Qing Liu, Yang Luo,
Li Jiang,
Hong-Duo Chen,
Wilson H Y Lo,
W H Irwin McLean,
Chun-Di He,
Xue Zhang
Nature Genetics 07/2009; 41(6):762. · 35.53 Impact Factor
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Miao Sun,
Ning Li,
Wu Dong,
Zugen Chen,
Qing Liu,
Yiming Xu,
Guang He,
Yongyong Shi,
Xin Li,
Jiajie Hao, [......],
Yaran Wen,
Lihua Cao,
Alan D Irvine,
W H Irwin McLean,
Qi Dong,
Ming-Rong Wang,
Jun Yu,
Lin He,
Wilson H Y Lo,
Xue Zhang
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ABSTRACT: Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.
The American Journal of Human Genetics 07/2009; 84(6):807-13. · 10.60 Impact Factor
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ABSTRACT: Mutations in ROR2, encoding the receptor tyrosine kinase-like orphan receptor 2, cause two distinct skeletal diseases: autosomal dominant brachydactyly type B1 (BDB1) and autosomal recessive Robinow syndrome. In a large Chinese family with a limb phenotype, consisting of atypical BDB1 and cutaneous syndactyly of varying degrees, we performed a two-point linkage analysis using microsatellite markers on 2q33-q37 and 9q22.31, and found a significant linkage to the ROR2 locus. We identified a novel single-base deletion in ROR2, c.2243delC (p.W749fsX24), and confirmed its segregation with the limb phenotype in the family. This deletion is predicted to produce a truncated ROR2 protein with an additional C-terminal polypeptide of 24 amino-acid residues. To the best of our knowledge, the deletion represents the second ROR2 mutation associated with a BDB1-syndactyly phenotype.
Journal of Human Genetics 06/2009; 54(7):422-5. · 2.57 Impact Factor
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Tianxiao Zhang,
Rui Hua,
Wei Xiao,
Kathryn P Burdon,
Shomi S Bhattacharya,
Jamie E Craig,
Dandan Shang,
Xiuli Zhao,
David A Mackey,
Anthony T Moore, Yang Luo,
Jinsong Zhang,
Xue Zhang
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ABSTRACT: Congenital cataracts (CCs) are clinically and genetically heterogeneous. Mutations in the same gene may lead to CCs differing in inheritance, morphology and severity. Loci for autosomal dominant posterior polar CC and total CC have both been mapped to the chromosomal 1p36 region harboring the EPHA2 receptor tyrosine kinase gene. Here, we report mutations of EPHA2 in three CC families from different ancestral groups. In a Chinese family with posterior polar CC, we identified a missense mutation, c.2819C>T (p.T940I), replacing a critical amino acid that functions at the receptor oligomerization interface. In a British family with posterior polar CC and an Australian family with total CC, we found a frameshift mutation (c.2915_2916delTG) and a splicing mutation (c.2826-9G>A), respectively. These two mutations are predicted to produce novel C-terminal polypeptides with 39 identical amino acids. Yeast two-hybrid analysis showed stronger interaction between the total CC-associated mutant EPHA2 and low molecular weight protein-tyrosine phosphatase, a negative regulator of EPHA2 signaling. Our results implicate the Eph-ephrin signaling system in development of human cataract and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCs.
Human Mutation 04/2009; 30(5):E603-11. · 5.69 Impact Factor
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ABSTRACT: Midkine (MDK), a heparin-binding growth factor, modulates the proliferation and migration of various cells, is often highly expressed in many malignant tumors, and may act as an oncoprotein. We found that MDK is overexpressed in clinical human gastric cancer tissues relative to its expression in adjacent noncancerous tissues. To further investigate the biological activities of MDK in gastric cancer, we introduced the MDK gene into human SGC7901 gastric cancer cells, where it contributed to the proliferation of SGC7901 cells in vitro and in vivo. Conversely, the knockdown of MDK expression by siRNA resulted in significantly reduced proliferation of BGC823 cells. Our study also shows that MDK activates both the Akt and ERK1/2 pathways and upregulates the expression of several cell-cycle-related proteins, including cyclin A, cyclin D1, Cdk2, Cdk4, and Cdk6, which in part explains the contribution of MDK to gastric cancer cell survival and growth. These results demonstrate that MDK contributes to gastric cancer cell proliferation and suggest that it plays an important role in the development of human gastric cancer.
Cancer letters 03/2009; 279(2):137-44. · 4.86 Impact Factor
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Yaran Wen,
Yang Liu,
Yiming Xu,
Yiwei Zhao,
Rui Hua,
Kaibo Wang,
Miao Sun,
Yuanhong Li,
Sen Yang,
Xue-Jun Zhang, [......],
Jack Green,
Dandan Shang,
Qing Liu, Yang Luo,
Li Jiang,
Hong-Duo Chen,
Wilson H-Y Lo,
W H Irwin McLean,
Chun-Di He,
Xue Zhang
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ABSTRACT: Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34-amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.
Nature Genetics 02/2009; 41(2):228-33. · 35.53 Impact Factor
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ABSTRACT: To explore whether cyclooxygenase 2 (COX-2) -765G>C polymorphism is associated with susceptibility of colorectal cancer (CRC) and to evaluate the risk of colorectal cancer in relation to environmental exposures and polymorphism.
We conducted a case-control study of 137 patients with colorectal cancer and 199 cancer-free controls in northeast China. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI).
The -765G>C polymorphism was not independently associated with CRC risk. However, risk associated with the polymorphism differed by smoking and body mass index (BMI). Smoking and BMI associated risks were stronger among those with -765GG genotype, showing that smokers had a 2.682-fold greater risk of CRC than nonsmokers (51/43 vs 68/126, P = 0.006). Compared to those with a normal body mass index (BMI 18.5-22.9), those with overweight (BMI 23-24.9) had a 3.909-fold higher risk of CRC (OR = 3.909, 95% CI = 2.081-7.344; P < 0.001), while those with obesity (BMI > 25) had a 2.031- fold higher risk of CRC (OR = 1.107, 95% CI = 1.107-3.726; P = 0.022).
Although COX-2 -765G>C polymorphism is not associated with an increased risk of CRC, -765GG genotype appears to be related to an increased risk in the presence of smoking and higher BMI.
World Journal of Gastroenterology 03/2008; 14(11):1785-9. · 2.47 Impact Factor
