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Chun-Yu Chen,
Ming-Shian Tsai,
Chien-Yu Lin,
I-Shing Yu,
You-Tzung Chen, Shu-Rung Lin,
Liang-Wen Juan,
Yuh-Tarng Chen,
Hua-Man Hsu,
Li-Jen Lee,
Shu-Wha Lin
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ABSTRACT: Mutation in CUL4B, which encodes a scaffold protein of the E3 ubiquitin ligase complex, has been found in patients with X-linked mental retardation (XLMR). However, early deletion of Cul4b in mice causes prenatal lethality, which has frustrated attempts to characterize the phenotypes in vivo. In this report, we successfully rescued Cul4b mutant mice by crossing female mice in which exons 4-5 of Cul4b were flanked by loxP sequences with Sox2-Cre male mice. In Cul4b-deficient (Cul4b(Δ)/Y) mice, no CUL4B protein was detected in any of the major organs, including the brain. In the hippocampus, the levels of CUL4A, CUL4B substrates (TOP1, β-catenin, cyclin E and WDR5) and neuronal markers (MAP2, tau-1, GAP-43, PSD95 and syn-1) were not sensitive to Cul4b deletion, whereas the number of parvalbumin (PV)-positive GABAergic interneurons was decreased in Cul4b(Δ)/Y mice, especially in the dentate gyrus (DG). Some dendritic features, including the complexity, diameter and spine density in the CA1 and DG hippocampal neurons, were also affected by Cul4b deletion. Together, the decrease in the number of PV-positive neurons and altered dendritic properties in Cul4b(Δ)/Y mice imply a reduction in inhibitory regulation and dendritic integration in the hippocampal neural circuit, which lead to increased epileptic susceptibility and spatial learning deficits. Our results identify Cul4b(Δ)/Y mice as a potential model for the non-syndromic model of XLMR that replicates the CUL4B-associated MR and is valuable for the development of a therapeutic strategy for treating MR.
Human Molecular Genetics 07/2012; 21(19):4270-85. · 7.64 Impact Factor
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Yu-Chen Hsu,
Hsiang-Po Huang,
I-Shing Yu,
Kang-Yi Su, Shu-Rung Lin,
Wei-Chou Lin,
Hua-Lin Wu,
Guey-Yueh Shi,
Mi-Hua Tao,
Cheng-Heng Kao,
Yao-Ming Wu,
Patricia E Martin,
Shih-Yao Lin,
Pan-Chyr Yang,
Shu-Wha Lin
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ABSTRACT: The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver, but has no known physiological functions. Here, we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin(-/-) ) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and antihepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin(-/-) mouse liver as a result of the retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective prohepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin(-/-) mice. Treatment of hepsin(-/-) mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes observed in hepsin(-/-) mice. Conclusion: Our findings show that the maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin-mediated changes in liver architecture significantly enhance tumor metastasis to the liver. (HEPATOLOGY 2012).
Hepatology 04/2012; · 11.66 Impact Factor
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Yung-Li Yang,
Chih-Cheng Hsiao,
Hsuan-Yu Chen,
Kai-Hsin Lin,
Shiann-Tarng Jou,
Jiann-Shiuh Chen,
Te-Kau Chang,
Jiunn-Ming Sheen,
Sung-Liang Yu,
Meng-Yao Lu,
Chao-Neng Cheng,
Kang-Hsi Wu,
Shih-Chung Wang,
Jiaan-Der Wang,
Hsiu-Hao Chang, Shu-Rung Lin,
Shu-Wha Lin,
Dong-Tsamn Lin
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ABSTRACT: The absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T-cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T-cell ALL.
Forty-five children with T-cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q-PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q-PCR was defined as a fold-change <0.35.
ABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23-53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10-16.42).
The absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T-cell ALL in Taiwan. Providing patients with T-cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials.
Pediatric Blood & Cancer 12/2011; 58(6):846-51. · 1.89 Impact Factor
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Yung-Li Yang,
Chia-Cheng Hung,
Jiann-Shiuh Chen,
Kai-Hsin Lin,
Shiann-Tarng Jou,
Chih-Cheng Hsiao,
Jiunn-Ming Sheen,
Chao-Neng Cheng,
Kang-Hsi Wu, Shu-Rung Lin,
Sung-Liang Yu,
Hsuan-Yu Chen,
Meng-Yao Lu,
Shih-Chung Wang,
Hsiu-Hao Chang,
Shu-Wha Lin,
Yi-Ning Su,
Dong-Tsamn Lin
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ABSTRACT: Despite current risk-directed therapy, approximately 15-20% of pediatric patients with acute lymphoblastic leukemia (ALL) have relapses. Recent genome-wide analyses have identified that an alteration of IKZF1 is associated with very poor outcomes in B-cell progenitor ALL. In this study, we determined the prognostic significance of IKZF1 deletions in patients with childhood ALL. This study analyzed 242 pediatric B-cell progenitor ALL patients in Taiwan. We developed a simple yet sensitive multiplex quantitative PCR coupled with capillary electrophoresis to accurately determine the allele dose of IKZF1, and high resolution melting was used for mutation screening for all coding exons of IKZF1. Twenty-six (10.7%) pediatric B-cell progenitor ALL patients were found to harbor these deletions. Most of the deletions were broader deletions that encompassed exon 3 to exon 6, consistent with previous reports. Genomic sequencing of IKZF1 was carried out in all cases and no point mutations were identified. Patients with IKZF1 deletions had inferior event-free survival (P < 0.001), and overall survival (P = 0.0016). The association between IKZF1 deletions and event-free survival was independent of age, leukocyte count at presentation, and cytogenetic subtype by multivariate Cox analysis (P = 0.003, hazard ratio = 2.45). This study indicates that detection of IKZF1 deletions upon diagnosis of B-cell progenitor ALL may help to identify patients at risk of treatment failure. IKZF1 deletions could be incorporated as a new high-risk prognostic factor in future treatment protocols. To the best of our knowledge, this is the first study to examine the poor prognosis of IKZF1 deletions in an Asian population.
Cancer Science 07/2011; 102(10):1874-81. · 3.33 Impact Factor
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ABSTRACT: TEM1 (endosialin) expression is increased in the stroma and tumor vasculature of several common human cancers. The exact physiological role of TEM1 is still unknown since Tem1-deficient mice are viable and show only a lower rate of abdominal site-specific tumor invasion in tumor transplantation experiments. Previous studies have reported Tem1 expression in mouse embryos and adults, but did not determine the timing or location of the earliest expression, and did not examine all organ systems. Using the highly sensitive Bluo-Gal staining method for detecting temporal and spatial Tem1-lacZ activity in lacZ knock-in (+/lacZ) mice, we found that Tem1 gene expression was initially detectable in the dorsal aortic wall, the heart, the umbilical vessels, the first branchial arch, and the cephalic mesenchyme at E9.5. From E10.5 to E14.5, Tem1 gene expression was additionally seen mainly in the genital tubercle, the mesonephros, the whisker follicles, the mesenchymal tissues around the eye, and the lung. Remarkably, the kidney expressed abundant Tem1-lacZ starting from E16.5. Postnatally, Tem1 expression decreased in most organs but elevated expression persisted in the renal glomerulus and the uterus, where the expression pattern varied at different estrous cycle stages. Co-localization studies indicated that most vimentin-positive cells co-expressed Tem1-lacZ, while a large portion of CD31- or desmin-positive cells were also positive for Tem1-lacZ. Taken together, our observations suggest that Tem1 is expressed throughout embryonic and adult development in several types of mesenchymal cells closely related to blood vessels.
Gene Expression Patterns 03/2011; 11(5-6):316-26. · 2.02 Impact Factor
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Yung-Li Yang, Shu-Rung Lin,
Jiann-Shiuh Chen,
Chih-Cheng Hsiao,
Kai-Hsin Lin,
Jiunn-Ming Sheen,
Chao-Neng Cheng,
Kang-Hsi Wu,
Shu-Wha Lin,
Sung-Liang Yu,
Hsuan-Yu Chen,
Meng-Yao Lu,
Hsiu-Hao Chang,
Ching-Tzu Yen,
Jing-Fang Lin,
Ying-Hui Su,
Ya-Ping Li,
Chien-Yu Lin,
Shiann-Tarng Jou,
Dong-Tsamn Lin
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ABSTRACT: The classification of B-lineage acute lymphoblastic leukemia (ALL) by specific chromosomal translocations has prognostic implications for risk-directed therapy. Reverse transcription-polymerase chain reaction (RT-PCR) assay is a useful tool for detecting fusion transcripts from common chromosomal translocations of ALL cells.
Multiplex RT-PCR and nested-PCR assays were used to detect ALL-type BCR-ABL1 transcripts of the t(9;22), TCF-PBX1 transcripts of t(1;19), the MLL-AF4 transcripts of t(4;11), and 2 variants of ETV6-RUNX1 of the cryptic t(12;21) in 148 leukemic samples upon diagnosis. The patients received risk-directed protocols of the Taiwan Pediatric Oncology Group-ALL-2002 that consisted of multiple chemotherapeutic agents of different intensities. Event-free survival (EFS) and overall survival (OS) rates were analyzed for genetic abnormalities detected by multiplex PCR and conventional cytogenetic analysis by the Kaplan-Meier method, and compared with the Mantel-Haenszel test. The Cox proportional hazards model was implemented to identify independent prognostic factors for EFS and OS.
In this cohort of Taiwanese children, the relative frequencies of the 4 translocations of B-lineage ALL were 8% with ALL-type t(9;22)/BCR-ABL1, 4% with (1;19)/TCF-PBX1, 2% with t(4;11)/MLL-AF4, and 17.6% with t(12;21)/ETV6-RUNX1. Patients with t(12;21)/ETV6-RUNX1 fusion, hyperdiploidy, and t(1;19)/TCF-PBX1 fusion had the most favorable outcomes, whereas those with the t(9;22)/BCR-ABL1 fusion or t(4;11) and other MLL gene rearrangement had poor prognosis (P<0.001 for EFS and OS). BCR-ABL1, MLL gene rearrangement, and very high-risk group were independent prognostic factors after Cox regression analysis.
The biological factors of leukemia cells are associated with treatment outcomes in childhood ALL. Multiplex RT-PCR assay is an efficient and sensitive diagnostic tool that may improve the ability to accurately and rapidly risk-stratify children with ALL.
Journal of Pediatric Hematology/Oncology 10/2010; 32(8):e323-30. · 1.16 Impact Factor
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Yung-Li Yang, Shu-Rung Lin,
Jiann-Shiuh Chen,
Shu-Wha Lin,
Sung-Liang Yu,
Hsuan-Yu Chen,
Ching-Tzu Yen,
Chien-Yu Lin,
Jing-Fang Lin,
Kai-Hsin Lin,
Shiann-Tarng Jou,
Chung-Yi Hu,
Sheng-Kai Chang,
Meng-Yao Lu,
Hsiu-Hao Chang,
Wan-Hui Chang,
Kuo-Sin Lin,
Dong-Tsamn Lin
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ABSTRACT: Improved treatment of childhood acute lymphoblastic leukemia (ALL) depends on the identification of new molecular markers that are able to predict treatment response and clinical outcome. The development of impaired apoptosis in leukemic cells is one factor that may influence their response to treatment. We investigated the expression of three apoptosis related genes, BCL2L13, CASP8AP2, and Livin, as well as their prognostic significance, in a retrospective study of 90 pediatric ALL patients diagnosed between 1996 and 2007 in Taiwan. Univariant analysis revealed that high expression of BCL2L13 was associated with inferior event-free survival and overall survival (p<0.001 and 0.005, respectively). Multivariate analysis for EFS and OS demonstrated that high expression of BCL2L13 was an independent prognostic factor for childhood ALL in this ethnic group.
Leukemia research 01/2010; 34(1):18-23. · 2.36 Impact Factor
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Yung-Li Yang,
Dong-Tsamn Lin,
Sheng-Kai Chang, Shu-Rung Lin,
Shu-Wha Lin,
Rong-Jing Chiou,
Ching-Tzu Yen,
Kai-Hsin Lin,
Shiann-Tarng Jou,
Meng-Yao Lu,
Hsiu-Hao Chang,
Wan-Hui Chang,
Kuo-Sin Lin,
Chung-Yi Hu
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ABSTRACT: This retrospective study evaluates the role of pharmacogenomic determinants in the treatment of childhood acute lymphoblastic leukemia (ALL) in the Taiwanese population.
A total of 105 childhood ALL patients received combined chemotherapy of different intensities based on risk-directed Taiwan Pediatric Oncology Group (TPOG)-ALL-93 protocols. Seventeen genetic polymorphisms in 13 pharmacogenomic targets were analyzed by PCR-based restriction fragment length polymorphism (RFLP) and sequence-specific oligonucleotide (SSO) probe hybridization. Pharmacogenomic polymorphisms were correlated with event-free survival (EFS) of patients, with confounding effects adjusted by multivariate regression.
Three polymorphic alleles in the multi-drug resistance 1 (MDR1) ABCB1 gene, and homozygotic MDR1 2677GG, 3435CC, and 2677G-3435C genotypes were highly associated with a significant reduction in EFS in those patients treated by the standard risk (SR) protocol (TPOG-ALL-93-SR). The hazard ratios were 6.8 (p = 0.01), 21.7 (p = 0.009), and 6.8 (p = 0.01), respectively.
Independent pharmacogenomic determinants associated with treatment outcome were identified in subsets of Taiwanese ALL patients.
Pediatric Blood & Cancer 09/2009; 54(2):206-11. · 1.89 Impact Factor
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Kang-Yi Su,
Wei-Lin Chien,
Wen-Mei Fu,
I-Shing Yu,
Hsiang-Po Huang,
Pei-Hsing Huang, Shu-Rung Lin,
Jin-Yuan Shih,
Yi-Ling Lin,
Yi-Ping Hsueh,
Pan-Chyr Yang,
Shu-Wha Lin
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ABSTRACT: Collapsing response mediator protein-1 (CRMP-1) was initially identified in brain and has been implicated in plexin-dependent neuronal function. The high amino acid sequence identity among the five CRMPs has hindered determination of the functions of each individual CRMP. We generated viable and fertile CRMP-1 knock-out (CRMP-1(-/-)) mice with no evidence of gross abnormality in the major organs. CRMP-1(-/-) mice exhibited intense microtubule-associated protein 2 (MAP2) staining in the proximal portion of the dendrites, but reduced and disorganized MAP2 staining in the distal dendrites of hippocampal CA1 pyramidal cells. Immunoreactivity to GAP-43 (growth-associated protein-43) and PSD95 (postsynaptic density-95) (a postsynaptic membrane adherent cytoskeletal protein) was also decreased in the CA1 region of the knock-out mice. These changes were consistent with the mutant mice showing a reduction in long-term potentiation (LTP) in the CA1 region and impaired performance in hippocampal-dependent spatial learning and memory tests. CRMP-1(-/-) mice showed a normal synapsin I labeling pattern in CA1 and normal paired-pulse facilitation. These findings provide the first evidence suggesting that CRMP-1 may be involved in proper neurite outgrowth in the adult hippocampus and that loss of CRMP-1 may affect LTP maintenance and spatial learning and memory.
Journal of Neuroscience 04/2007; 27(10):2513-24. · 7.11 Impact Factor
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I-Shing Yu, Shu-Rung Lin,
Chin-Chin Huang,
Hui-Yu Tseng,
Pei-Hsing Huang,
Guey-Yueh Shi,
Hua-Lin Wu,
Chi-Lu Tang,
Pao-Hsien Chu,
Lee-Ho Wang,
Kenneth K Wu,
Shu-Wha Lin
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ABSTRACT: Besides its well-recognized role in hemostasis and thrombosis, thromboxane A(2) synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte differentiation. To evaluate its various physiologic roles, we generated TXAS-deleted mice by gene targeting. TXAS(-/-) mice had normal bone marrow megakaryocytes, normal blood platelet counts, and normal CD4 and CD8 lymphocyte counts in thymus and spleen. Platelets from TXAS(-/-) mice failed to aggregate or generate thromboxane B(2) in response to arachidonic acid (AA) but produced increased prostaglandin-E(2) (PGE(2)), PGD(2), and PGF(2 alpha). AA infusion caused a progressive drop of mean arterial pressure (MAP), cardiac arrest, and death in wild-type (WT) mice but did not induce shock in TXAS(-/-) mice or in WT and TXAS(-/-) mice treated with antagonist to the thromboxane-prostanoid (TP) receptor. The TXAS(-/-) mice were able to maintain normal MAP upon AA insult when TP was present but were unable to do so when TP was blocked by an antagonist, suggesting a role of endoperoxide accumulation in influencing MAP. We conclude that TXAS is not essential for thrombopoiesis and lymphocyte differentiation. Its deficiency causes a mild hemostatic defect and protects mice against arachidonate-induced shock and death. The TXAS-deleted mice will be valuable for investigating the roles of arachidonate metabolic shunt in various pathophysiologic processes.
Blood 08/2004; 104(1):135-42. · 9.90 Impact Factor
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ABSTRACT: We describe the identification of a new CA dinucleotide repeat marker for the diagnosis of haemophilia A carriers. The marker (CA-6) is present in intron 6 as a single copy 5 kb upstream of exon 7. Of 195 and 118 X chromosomes from normal individuals and haemophilia A patients, respectively, we observed three alleles of CA-6 with 12–14 repetitions [(CA)12−14]. The frequencies were 0·5% and 0% for (CA)12, 99% and 95·8% for (CA)13, and 0·5% and 4·2% for (CA)14 in normals and patients respectively. We conclude that the low polymorphism of the CA-6 marker renders it less useful for the diagnosis of Chinese haemophilia A carriers.
British Journal of Haematology 11/2000; 111(4):1256 - 1259. · 4.94 Impact Factor
