Publications by authors named "Liang-Jun Wang"

33 Publications

Inhibition of Sp1-mediated survivin and MCL1 expression cooperates with SLC35F2 and myeloperoxidase to modulate YM155 cytotoxicity to human leukemia cells.

Biochem Pharmacol 2021 Apr 5;188:114544. Epub 2021 Apr 5.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Although YM155 is reported to suppress survivin (also known as BIRC5) expression in cancer cells, its cytotoxic mechanism in human acute myeloid leukemia (AML) cells has not been clearly resolved. In this study, we analyzed the mechanistic pathways that modulate the sensitivity of human AML U937 and HL-60 cells to YM155. YM155 induced apoptosis in AML cells, which was characterized by p38 MAPK phosphorylation and downregulation of survivin and MCL1 expression. Phosphorylated p38 MAPK causes autophagy-mediated Sp1 degradation, thereby inhibiting the transcription of survivin and MCL1. The reduction of survivin and MCL1 levels further facilitated Sp1 protein degradation through autophagy. The restoration of Sp1, survivin, or MCL1 expression protected U937 and HL-60 cells from YM155-mediated cytotoxicity. U937 and HL-60 cells were continuously exposed to hydroquinone (HQ) to generate U937/HQ and HL-60/HQ cells, which showed increased SLC35F2 expression. The increase in SLC35F2 expression led to an increase in the sensitivity of U937/HQ cells to YM155-mediated cytotoxicity, whereas no such effect was observed in HL-60/HQ cells. Of note, myeloperoxidase (MPO) activity in HL-60 and HL-60/HQ cells enhanced YM155 cytotoxicity in these cells, and the enforced expression of MPO also increased the sensitivity of U937 cells to YM155. Taken together, we conclude that p38 MAPK-modulated autophagy inhibits Sp1-mediated survivin and MCL1 expression, which, in turn, leads to the death of U937 and HL-60 cells following YM155 treatment. In addition, our data indicate that SLC35F2 increases the sensitivity of U937 cells to YM155-mediated cytotoxicity, whereas MPO enhances YM155 cytotoxicity in U937 and HL-60 cells.
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http://dx.doi.org/10.1016/j.bcp.2021.114544DOI Listing
April 2021

Modification of carboxyl groups converts α-lactalbumin into an active molten globule state with membrane-perturbing activity and cytotoxicity.

Int J Biol Macromol 2020 Nov 19;163:1697-1706. Epub 2020 Sep 19.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

We investigated whether the modification of the negatively charged carboxyl groups with semicarbazide could confer membrane-disrupting and cytotoxic properties to bovine α-lactalbumin (LA). MALDI-TOF analysis revealed that eighteen of the twenty-one carboxyl groups in LA were coupled with semicarbazide molecules. Measurement of circular dichroism spectra and Trp fluorescence quenching studies showed that semicarbazide-modified LA (SEM-LA) had a molten globule-like conformation that retained the α-helix secondary structure but lost the tertiary structure of LA. Compared to LA, SEM-LA had a higher structural flexibility in response to trifluoroethanol- and temperature-induced structural transitions. In sharp contrast to LA, SEM-LA exhibited membrane-damaging activity and cytotoxicity. Furthermore, SEM-LA-induced membrane permeability promoted the uptake of daunorubicin and thereby its cytotoxicity. The microenvironment surrounding the Trp residues of SEM-LA was enriched in positive charges, as revealed by iodide quenching studies. The binding of SEM-LA with lipid vesicles altered the positively charged cluster around Trp residues. Although LA and SEM-LA displayed similar lipid-binding affinities, the membrane interaction modes of SEM-LA and LA differed. Collectively, these results suggest that blocking of negatively charged residues enables the formation of a molten-globule conformation of LA with structural flexibility and increased positive charge, thereby generating functional LA with membrane-disrupting activity and cytotoxicity.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.09.095DOI Listing
November 2020

Blocking of negative charged carboxyl groups converts Naja atra neurotoxin to cardiotoxin-like protein.

Int J Biol Macromol 2020 Dec 23;164:2953-2963. Epub 2020 Aug 23.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Naja atra cobrotoxin and cardiotoxin 3 (CTX3) exhibit neurotoxicity and cytotoxicity, respectively. In the present study, we aimed to investigate whether the carboxyl groups of cobrotoxin play a role in structural constraints, thereby preventing cobrotoxin from exhibiting cytotoxic activity. Six of the seven carboxyl groups in cobrotoxin were conjugated with semicarbazide. Measurement of circular dichroism spectra and Trp fluorescence quenching showed that the gross conformation of semicarbazide-modified cobrotoxin (SEM-cobrotoxin) and cobrotoxin differed. In sharp contrast to cobrotoxin, SEM-cobrotoxin demonstrated membrane-damaging activity and cytotoxicity, which are feature more characteristic of CTX3. Furthermore, both SEM-cobrotoxin and CTX3 induced cell death through AMPK activation. Analyses of the interaction between polydiacetylene/lipid vesicles and fluorescence-labeled lipids revealed that SEM-cobrotoxin and cobrotoxin adopted different membrane-bound states. The structural characteristics of SEM-cobrotoxin were similar to those of CTX3, including trifluoroethanol (TFE)-induced structural transformation and membrane binding-induced conformational change. Conversely, cobrotoxin was insensitive to the TFE-induced effect. Collectively, the data of this study indicate that blocking negatively charged residues confers cobrotoxin with membrane-damaging activity and cytotoxicity. The findings also suggest that the structural constraints imposed by carboxyl groups control the functional properties of snake venom α-neurotoxins during the divergent evolution of snake venom neurotoxins and cardiotoxins.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.08.163DOI Listing
December 2020

GSK3β suppression inhibits MCL1 protein synthesis in human acute myeloid leukemia cells.

J Cell Physiol 2021 Jan 22;236(1):570-586. Epub 2020 Jun 22.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.

Previous studies have shown that glycogen synthase kinase 3β (GSK3β) suppression is a potential strategy for human acute myeloid leukemia (AML) therapy. However, the cytotoxic mechanism associated with GSK3β suppression remains unresolved. Thus, the underlying mechanism of N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418)-elicited GSK3β suppression in the induction of AML U937 and HL-60 cell death was investigated in this study. Our study revealed that AR-A014418-induced MCL1 downregulation remarkably elicited apoptosis of U937 cells. Furthermore, the AR-A014418 treatment increased p38 MAPK phosphorylation and decreased the phosphorylated Akt and ERK levels. Activation of p38 MAPK subsequently evoked autophagic degradation of 4EBP1, while Akt inactivation suppressed mTOR-mediated 4EBP1 phosphorylation. Furthermore, AR-A014418-elicited ERK inactivation inhibited Mnk1-mediated eIF4E phosphorylation, which inhibited MCL1 mRNA translation in U937 cells. In contrast to GSK3α, GSK3β downregulation recapitulated the effect of AR-A014418 in U937 cells. Transfection of constitutively active GSK3β or cotransfection of constitutively activated MEK1 and Akt suppressed AR-A014418-induced MCL1 downregulation. Moreover, AR-A014418 sensitized U937 cells to ABT-263 (BCL2/BCL2L1 inhibitor) cytotoxicity owing to MCL1 suppression. Collectively, these results indicate that AR-A014418-induced GSK3β suppression inhibits ERK-Mnk1-eIF4E axis-modulated de novo MCL1 protein synthesis and thereby results in U937 cell apoptosis. Our findings also indicate a similar pathway underlying AR-A014418-induced death in human AML HL-60 cells.
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http://dx.doi.org/10.1002/jcp.29884DOI Listing
January 2021

Albendazole-Induced SIRT3 Upregulation Protects Human Leukemia K562 Cells from the Cytotoxicity of MCL1 Suppression.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

Previous studies have shown that MCL1 stabilization confers cancer cells resistance to microtubule targeting agents (MTAs) and functionally extends the lifespan of MTA-triggered mitotically arrested cells. Albendazole (ABZ), a benzimidazole anthelmintic, shows microtubule-destabilizing activity and has been repositioned for cancer therapies. To clarify the role of MCL1 in ABZ-induced apoptosis, we investigated the cytotoxicity of ABZ on human leukemia K562 cells. Treatment with ABZ for 24 h did not appreciably induce apoptosis or mitochondrial depolarization in K562 cells, though it caused the mitotic arrest of K562 cells. ABZ-evoked p38 MAPK activation concurrently suppressed Sp1-mediated MCL1 expression and increased SIRT3 mRNA stability and protein expression. ABZ and A-1210477 (an MCL1 inhibitor) enhanced the cytotoxicity of ABT-263 (a BCL2/BCL2L1 inhibitor) to their effect on MCL1 suppression. Unlike ABZ, A-1210477 did not affect SIRT3 expression and reduced the survival of K562 cells. Overexpression of SIRT3 attenuated the A-1210477 cytotoxicity on K562 cells. ABZ treatment elicited marked apoptosis and ΔΨm loss in ABT-263-resistant K562 (K562/R) cells, but did not alter SIRT3 expression. Ectopic expression of SIRT3 alleviated the cytotoxicity of ABZ on K562/R cells. Collectively, our data demonstrate that ABZ-induced SIRT3 upregulation delays the apoptosis-inducing effect of MCL1 suppression on apoptosis induction in K562 cells.
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http://dx.doi.org/10.3390/ijms21113907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312678PMC
May 2020

Inhibition of EGFR pathway promotes the cytotoxicity of ABT-263 in human leukemia K562 cells by blocking MCL1 upregulation.

Biochem Pharmacol 2020 08 22;178:114047. Epub 2020 May 22.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

ABT-263 induces MCL1 upregulation in cancer cells, which confers resistance to the drug. An increased understanding of the mechanism underlying ABT-263-induced MCL1 expression may provide a strategy to improve its tumor-suppression activity. The present study revealed that ABT-263 reduced the turnover of MCL1 mRNA, thereby upregulating MCL1 expression in human K562 leukemia cells. Furthermore, ABT-263-induced EGFR activation promoted AGO2 phosphorylation at Y393 and reduced miR-125b maturation. Treatment with EGFR inhibitors mitigated MCL1 upregulation induced by ABT-263. Additionally, lithium chloride (LiCl) alleviated ABT-263-induced MCL1 upregulation through EGFR-AGO2 axis-modulated miR-125b suppression. Ectopic expression of dominant negative AGO2(Y393F) or transfection with miR-125b abolished ABT-263-induced upregulation of MCL1 mRNA and protein levels. Co-treatment with either EGFR inhibitors or LiCl collaboratively enhanced ABT-263 cytotoxicity, while MCL1 overexpression eliminated this synergistic effect. Collectively, our data reveal that ABT-263 increases EGFR-mediated AGO2 phosphorylation, which in turn suppresses miR-125b-mediated MCL1 mRNA degradation in K562 cells. The suppression of this signaling pathway results in the synergistic cytotoxic effect of EGFR inhibitors or LiCl and ABT-263.
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http://dx.doi.org/10.1016/j.bcp.2020.114047DOI Listing
August 2020

Status of Asp29 and Asp40 in the Interaction of Cardiotoxins with Lipid Bilayers.

Toxins (Basel) 2020 04 18;12(4). Epub 2020 Apr 18.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

It is widely accepted that snake venom cardiotoxins (CTXs) target the plasma membranes of cells. In the present study, we investigated the role of Asp residues in the interaction of cardiotoxin 1 (CTX1) and cardiotoxin 3 (CTX3) with phospholipid bilayers using chemical modification. CTX1 contains three Asp residues at positions 29, 40, and 57; CTX3 contains two Asp residues at positions 40 and 57. Compared to Asp29 and Asp40, Asp57 was sparingly modified with semi-carbazide, as revealed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass and mass/mass analyses. Thus, semi-carbazide-modified CTX1 (SEM-CTX1) mainly contained modified Asp29 and Asp40, while SEM-CTX3 contained modified Asp40. Compared to that of native toxins, trifluoroethanol easily induced structural transition of SEM-CTX1 and SEM-CTX3, suggesting that the structural flexibility of CTXs was constrained by Asp40. Modification of Asp29 and Asp40 markedly promoted the ability of CTX1 to induce permeability of cell membranes and lipid vesicles; CTX3 and SEM-CTX3 showed similar membrane-damaging activity. Modification of Asp residues did not affect the membrane-binding capability of CTXs. Circular dichroism spectra of SEM-CTX3 and CTX3 were similar, while the gross conformation of SEM-CTX1 was distinct from that of CTX1. The interaction of CTX1 with membrane was distinctly changed by Asp modification. Collectively, our data suggest that Asp29 of CTX1 suppresses the optimization of membrane-bound conformation to a fully active state and that the function of Asp40 in the structural constraints of CTX1 and CTX3 is not important for the manifestation of membrane-perturbing activity.
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http://dx.doi.org/10.3390/toxins12040262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232319PMC
April 2020

Arsenic trioxide-induced p38 MAPK and Akt mediated MCL1 downregulation causes apoptosis of BCR-ABL1-positive leukemia cells.

Toxicol Appl Pharmacol 2020 Apr 17;397:115013. Epub 2020 Apr 17.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

In this study, we investigated the mechanisms underlying arsenic trioxide (ATO)-induced death of human BCR-ABL1-positive K562 and MEG-01 cells. ATO-induced apoptotic death in K562 cells was characterized by ROS-mediated mitochondrial depolarization, MCL1 downregulation, p38 MAPK activation, and Akt inactivation. ATO-induced BCR-ABL1 downregulation caused Akt inactivation but not p38 MAPK activation. Akt inactivation increased GSK3β-mediated MCL1 degradation, while p38 MAPK-mediated NFκB activation coordinated with HDAC1 suppressed MCL1 transcription. Inhibition of p38 MAPK activation or overexpression of constitutively active Akt increased MCL1 expression and promoted the survival of ATO-treated cells. Overexpression of MCL1 alleviated mitochondrial depolarization and cell death induced by ATO. The same pathway was found to be involved in ATO-induced death in MEG-01 cells. Remarkably, YM155 synergistically enhanced the cytotoxicity of ATO on K562 and MEG-01 cells through suppression of MCL1 and survivin. Collectively, our data indicate that ATO-induced p38 MAPK- and Akt-mediated MCL1 downregulation triggers apoptosis in K562 and MEG-01 cells, and that p38 MAPK activation is independent of ATO-induced BCR-ABL1 suppression.
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http://dx.doi.org/10.1016/j.taap.2020.115013DOI Listing
April 2020

Organic-inorganic Hybrid ([BrCH CH N(CH ) ] [CdBr ] ) with Unusual Ferroelectric and Switchable Dielectric Bifunctional Properties over Different Temperature Range.

Chem Asian J 2020 May 20;15(10):1621-1626. Epub 2020 Apr 20.

School of Chemistry and Chemical Engineering, The Key Laboratory of Coordination Chemistry of Jiangxi Province, Humic Acid Utilization Engineering Research Center of Jiangxi Province, Jinggangshan University, Ji'An, Jiangxi, 343009, P.R. China.

Both ferroelectric and switchable dielectric behaviors are of great academic value and practical significance, but they usually exist alone. If combine the two properties into one compound, it will be more valuable in practical application. In this paper, quasi-spherical (2-bromoethyl) trimethylammonium cation was used to match with [CdBr ] anion, and a new organic-inorganic hybrid compound ([BrCH CH N(CH ) ] [CdBr ] , BETABCdBr) was obtained and carefully characterized. The results indicate that this compound undergoes two continuous reversible phase transition around 342 K and 390 K. It could respectively exhibit ferroelectric and switchable dielectric properties over different temperature range. This work may provide a new clue to explore new types of bifunctional phase transition smart materials to meet various application requirements.
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http://dx.doi.org/10.1002/asia.202000241DOI Listing
May 2020

SIRT3, PP2A and TTP protein stability in the presence of TNF-α on vincristine-induced apoptosis of leukaemia cells.

J Cell Mol Med 2020 02 13;24(4):2552-2565. Epub 2020 Jan 13.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.

The contribution of vincristine (VCR)-induced microtubule destabilization to evoke apoptosis in cancer cells remains to be resolved. Thus, we investigated the cytotoxic mechanism of VCR on U937 and HL-60 human leukaemia cell lines. We discovered that VCR treatment resulted in the up-regulation of TNF-α expression and activation of the death receptor pathway, which evoked apoptosis of U937 cells. Moreover, VCR induced microtubule destabilization and mitotic arrest. VCR treatment down-regulated SIRT3, and such down-regulation caused mitochondrial ROS to initiate phosphorylation of p38 MAPK. p38 MAPK suppressed MID1-modulated degradation of the protein phosphatase 2A (PP2A) catalytic subunit. The SIRT3-ROS-p38 MAPK-PP2A axis inhibited tristetraprolin (TTP)-controlled TNF-α mRNA degradation, consequently, up-regulating TNF-α expression. Restoration of SIRT3 and TTP expression, or inhibition of the ROS-p38 MAPK axis increased the survival of VCR-treated cells and repressed TNF-α up-regulation. In contrast to suppression of the ROS-p38 MAPK axis, overexpression of SIRT3 modestly inhibited the effect of VCR on microtubule destabilization and mitotic arrest in U937 cells. Apoptosis of HL-60 cells, similarly, went through the same pathway. Collectively, our data indicate that the SIRT3-ROS-p38 MAPK-PP2A-TTP axis modulates TNF-α expression, which triggers apoptosis of VCR-treated U937 and HL-60 cells. We also demonstrate that the apoptotic signalling is not affected by VCR-elicited microtubule destabilization.
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http://dx.doi.org/10.1111/jcmm.14949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028858PMC
February 2020

Compound C induces autophagy and apoptosis in parental and hydroquinone-selected malignant leukemia cells through the ROS/p38 MAPK/AMPK/TET2/FOXP3 axis.

Cell Biol Toxicol 2020 08 3;36(4):315-331. Epub 2020 Jan 3.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.

Hydroquinone (HQ), a major metabolic product of benzene, causes acute myeloid leukemia (AML) elicited by benzene exposure. Past studies found that continuous exposure of human AML U937 cells to HQ selectively produces malignant U937/HQ cells in which FOXP3 upregulation modulates malignant progression. Other studies revealed that AMPK promotes TET2 activity on DNA demethylation and that TET2 activity is crucial for upregulating FOXP3 expression. This study was conducted to elucidate whether compound C, an AMPK inhibitor, blocked the AMPK-TET2-FOXP3 axis in AML and in HQ-selected malignant cells. We found higher levels of AMPKα, TET2, and FOXP3 expression in U937/HQ cells compared to U937 cells. Treatment of parental Original Article and HQ-selected malignant U937 cells with compound C induced ROS-mediated p38 MAPK activation, leading to a suppression of AMPKα, TET2, and FOXP3 expression. Moreover, compound C induced apoptosis and mTOR-independent autophagy. The suppression of the autophagic flux inhibited the apoptosis of compound C-treated U937 and U937/HQ cells, whereas co-treatment with rapamycin, a mTOR inhibitor, sensitized the two cell lines to compound C cytotoxicity. Overexpression of AMPKα1 or pretreatment with autophagic inhibitors abrogated compound C-induced autophagy and suppression of TET2 and FOXP3 expression. Restoration of AMPKα1 or FOXP3 expression increased cell survival after treatment with compound C. In conclusion, our results show that compound C suppresses AMPK/TET2 axis-mediated FOXP3 expression and induces autophagy-dependent apoptosis in parental and HQ-selected malignant U937 cells, suggesting that the AMPK/TET2/FOXP3 axis is a promising target for improving AML therapy and attenuating benzene exposure-induced AML progression.
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http://dx.doi.org/10.1007/s10565-019-09495-3DOI Listing
August 2020

Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells.

Toxicol Appl Pharmacol 2020 01 16;387:114857. Epub 2019 Dec 16.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

The aim of this study was to investigate the mechanism of YM155 cytotoxicity in human chronic myeloid leukemia (CML) cells. YM155-induced apoptosis of human CML K562 cells was characterized by ROS-mediated p38 MAPK activation, mitochondrial depolarization, and survivin and MCL1 downregulation. Moreover, YM155-induced autophagy caused degradation of HuR mRNA and downregulation of HuR protein expression, which resulted in destabilized survivin and MCL1 mRNA. Interestingly, survivin and MCL1 suppression contributed to autophagy-mediated HuR mRNA destabilization in YM155-treated cells. Pretreatment with inhibitors of p38 MAPK or autophagy alleviated YM155-induced autophagy and apoptosis in K562 cells, as well as YM155-induced downregulation of HuR, survivin, and MCL1. Ectopic overexpression of HuR, survivin, or MCL1 attenuated the cytotoxic effect of YM155 on K562 cells. Conversely, YM155 sensitized K562 cells to ABT-199 (a BCL2 inhibitor), and circumvented K562 cell resistance to ABT-199 because of its inhibitory effect on survivin and MCL1 expression. Overall, our data indicate that YM155-induced apoptosis is mediated by inducing autophagic HuR mRNA degradation, and reveal the pathway responsible for YM155-induced downregulation of survivin and MCL1 in K562 cells. Our findings also indicate a similar pathway underlying YM155-induced death in human CML MEG-01 cells.
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http://dx.doi.org/10.1016/j.taap.2019.114857DOI Listing
January 2020

Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca/PP2A/AMPK Axis.

Toxins (Basel) 2019 09 12;11(9). Epub 2019 Sep 12.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.
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http://dx.doi.org/10.3390/toxins11090527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784133PMC
September 2019

Naja atra cardiotoxins enhance the protease activity of chymotrypsin.

Int J Biol Macromol 2019 Sep 12;136:512-520. Epub 2019 Jun 12.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Snake venom cardiotoxins (CTXs) present diverse pharmacological functions. Previous studies have reported that CTXs affect the activity of some serine proteases, namely, chymotrypsin, subtilisin, trypsin, and acetylcholinesterase. To elucidate the mode of action of CTXs, the interaction of CTXs with chymotrypsin was thus investigated. It was found that Naja atra CTX isotoxins concentration-dependently enhanced chymotrypsin activity. The capability of CTX1 and CTX5 in increasing chymotrypsin activity was higher than that of CTX2, CTX3, and CTX4. Removal of the molecular beacon-bound CTXs by chymotrypsin, circular dichroism measurement, and acrylamide quenching of Trp fluorescence indicated that CTXs bound to chymotrypsin. Chemical modification of Lys, Arg, or Met residues of CTX1 attenuated its capability to enhance chymotrypsin activity without impairing their bond with chymotrypsin. Catalytically inactive chymotrypsin retained the binding affinity for native and modified CTX1. CTX1 and chemically modified CTX1 differently altered the global conformation of chymotrypsin and inactivated chymotrypsin. Moreover, CTX1 did not reduce the interaction of 2-(p-toluidino)-naphthalene-6-sulfonate (TNS) with chymotrypsin and inactivated chymotrypsin. Together with previous results revealing that TNS can bind at the hydrophobic region of active site in chymotrypsin, our data suggest that CTXs can enhance chymotrypsin activity by binding to the region outside the enzyme's active site.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.06.066DOI Listing
September 2019

Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation.

Biochem Pharmacol 2019 04 7;162:154-168. Epub 2018 Nov 7.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MAPK activation, TNF-α upregulation and activation of the death receptor-mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest. ABZ-induced SIRT3 degradation elicited ROS-mediated p38 MAPK activation, leading to pyruvate kinase M2-mediated tristetraprolin (TTP) degradation. Inhibition of TTP-mediated TNF-α mRNA decay elicited TNF-α upregulation in ABZ-treated cells. Either the overexpression of SIRT3 or abolishment of ROS/p38 MAPK activation suppressed TNF-α upregulation and rescued the viability of ABZ-treated cells. In contrast to the inhibition of ROS/p38 MAPK pathway, SIRT3 overexpression attenuated tubulin depolymerization and G2/M arrest in ABZ-treated cells. Treatment with a SIRT3 inhibitor induced TNF-α upregulation and cell death without the induction of G2/M arrest in U937 cells. Taken together, our data indicate that ABZ-induced SIRT3 downregulation promotes its microtubule-destabilizing effect, and that the non-mitotic effect of ABZ largely triggers apoptosis of U937 cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Notably, the same pathway is involved in the ABZ-induced death of HL-60 cells.
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http://dx.doi.org/10.1016/j.bcp.2018.11.003DOI Listing
April 2019

The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells.

Toxicol Appl Pharmacol 2018 11 10;358:43-55. Epub 2018 Sep 10.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Arsenic trioxide (ATO) has been reported to inhibit the activity of Ten-eleven translocation methylcytosine dioxygenase (TET). TET modulates FOXP3 expression, while dysregulation of FOXP3 expression promotes the malignant progression of leukemia cells. We examined the role of TET-FOXP3 axis in the cytotoxic effects of ATO on the human acute myeloid leukemia cell line, U937. ATO-induced apoptosis in U937 cells was characterized by activation of caspase-3/-9, mitochondrial depolarization, and MCL1 downregulation. In addition, ATO-treated U937 cells showed ROS-mediated inhibition of TET2 transcription, leading to downregulation of FOXP3 expression and in turn, suppression of FOXP3-mediated activation of Lyn and Akt. Overexpression of FOXP3 or Lyn minimized the suppressive effect of ATO on Akt activation and MCL1 expression. Promoter luciferase activity and chromatin immunoprecipitation assays revealed the crucial role of Akt-mediated CREB phosphorylation in MCL1 transcription. Further, ATO-induced Akt inactivation promoted GSK3β-mediated degradation of MCL1. Transfection of constitutively active Akt expression abrogated ATO-induced MCL1 downregulation. MCL1 overexpression lessened the ATO-induced depolarization of mitochondrial membrane and increased the viability of ATO-treated cells. Thus, our data suggest that ATO induces mitochondria-mediated apoptosis in U937 cells through its suppressive effect on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 transcription and protein stabilization. Our findings also indicate that the same pathway underlies ATO-induced death in human leukemia HL-60 cells.
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http://dx.doi.org/10.1016/j.taap.2018.09.008DOI Listing
November 2018

ABT-263-induced MCL1 upregulation depends on autophagy-mediated 4EBP1 downregulation in human leukemia cells.

Cancer Lett 2018 09 15;432:191-204. Epub 2018 Jun 15.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. Electronic address:

The present study aimed to investigate the pathway related to MCL1 expression in ABT-263-treated human leukemia U937 cells. ABT-263 upregulated MCL1 protein expression but did not affect its mRNA level and protein stability. Notably, ABT-263 increased 4EBP1 mRNA decay and thus reduced 4EBP1 expression. Overexpression of 4EBP1 abrogated ABT-263-induced MCL1 upregulation. ABT-263-induced activation of IKKα/β-NFκB axis elicited autophagy of U937 cells, leading to reduced mRNA stability of 4EBP1. Inhibition of the IKKα/β-NFκB axis or autophagy mitigated the effect of ABT-263 on 4EBP1 and MCL1 expression. Amsacrine enhanced the cytotoxicity of ABT-263 in human leukemia U937, HL-60, and Jurkat cells because of its inhibitory effect on the IKKα/β-NFκB-mediated pathway. Our data indicate that ABT-263 alleviates the inhibitory effect of 4EBP1 on MCL1 protein synthesis through IKKα/β-NFκB-mediated induction of autophagy, and suggest a promising strategy to improve anti-leukemia therapy with ABT-263.
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http://dx.doi.org/10.1016/j.canlet.2018.06.019DOI Listing
September 2018

A Turn-on Fluorescence Sensor for Heparin Detection Based on a Release of Taiwan Cobra Cardiotoxin from a DNA Aptamer or Adenosine-Based Molecular Beacon.

Molecules 2018 Feb 19;23(2). Epub 2018 Feb 19.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

This study presents two sensitive fluorescent assays for sensing heparin on the basis of the electrostatic interaction between heparin and cardiotoxin 3 (CTX3). Owing to CTX3-induced folded structure of an adenosine-based molecular beacon (MB) or a DNA aptamer against CTX3, a reduction in the fluorescent signal of the aptamer or MB 5'-end labeled with carboxyfluorescein (FAM) and 3'-end labeled with 4-([4-(dimethylamino)phenyl]azo)-benzoic acid (DABCYL) was observed upon the addition of CTX3. The presence of heparin and formation of the CTX3-heparin complex caused CTX3 detachment from the MB or aptamer, and restoration of FAM fluorescence of the 5'-FAM-and-3'-DABCYL-labeled MB and aptamer was subsequently noted. Moreover, the detection of heparin with these CTX3-aptamer and CTX3-MB sensors showed high sensitivity and selectivity toward heparin over chondroitin sulfate and hyaluronic acid regardless of the presence of plasma. The limit of detection for heparin in plasma was determined to be 16 ng/mL and 15 ng/mL, respectively, at a signal-to-noise ratio of 3. This study validates the practical utility of the CTX3-aptamer and CTX3-MB systems for determining the concentration of heparin in a biological matrix.
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http://dx.doi.org/10.3390/molecules23020460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017339PMC
February 2018

Membrane-damaging activities of mannosylated ovalbumin are involved in its antibacterial action.

Arch Biochem Biophys 2018 02 19;639:1-8. Epub 2017 Dec 19.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Mannosylated ovalbumin (Man-OVA) prepared by modification of carboxyl groups with p-aminophenyl α-d-mannopyranoside shows an increase of net positive charge, which may enhance its binding to bacterial membrane. Thus, we aimed to investigate whether Man-OVA exerts antibacterial activity on Escherichia coli and Staphylococcus aureus via membrane-perturbing effect. Man-OVA inhibited the growth of E. coli and S. aureus, whereas ovalbumin (OVA) did not show any antibacterial activity. Moreover, Man-OVA induced an increase in the membrane permeability of E. coli and S. aureus, which was positively correlated to its bactericidal action. Morphological examination using scanning electron microscopy revealed that Man-OVA disrupted the bacterial membrane integrity. Destabilization of the lipopolysaccharide (LPS) layer and inhibition of lipoteichoic acid (LTA) biosynthesis in the cell wall increased the bactericidal effect of Man-OVA. In contrast to OVA, Man-OVA also induced leakage of bacterial membrane-mimicking liposomes. Color transformation of phospholipid/polydiacetylene membrane assay revealed that the membrane-interaction mode of Man-OVA was distinct from that of OVA. LPS and LTA suppressed the membrane-damaging activity of Man-OVA, whereas an increase in the Man-OVA concentration attenuated the inhibitory action of LPS and LTA. Taken together, our data indicate that the bactericidal activity of Man-OVA depends strongly on its ability to induce membrane permeability.
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http://dx.doi.org/10.1016/j.abb.2017.12.006DOI Listing
February 2018

Quinacrine induces the apoptosis of human leukemia U937 cells through FOXP3/miR-183/β-TrCP/SP1 axis-mediated BAX upregulation.

Toxicol Appl Pharmacol 2017 11 1;334:35-46. Epub 2017 Sep 1.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Quinacrine, which is clinically used as an antimalarial drug, has anti-cancer activity. However, mechanism underlying its cytotoxic effect remains to be completely elucidated. In the present study, we investigated the cytotoxic effect of quinacrine on human leukemia U937 cells. Quinacrine-induced apoptosis of U937 cells was accompanied with ROS generation, mitochondrial depolarization, and BAX upregulation. Quinacrine-treated U937 cells showed ROS-mediated p38 MAPK activation and ERK inactivation, which in turn upregulated FOXP3 transcription. FOXP3-mediated miR-183 expression decreased β-TrCP mRNA stability and suppressed β-TrCP-mediated SP1 degradation, thus increasing SP1 expression in U937 cells. Upregulated SP1 expression further increased BAX expression. BAX knock-down attenuated quinacrine-induced mitochondrial depolarization and increased the viability of quinacrine-treated cells. Together, our data indicate that quinacrine-induced apoptosis of U937 cells is mediated by mitochondrial alterations triggered by FOXP3/miR-183/β-TrCP/SP1 axis-mediated BAX upregulation.
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http://dx.doi.org/10.1016/j.taap.2017.08.019DOI Listing
November 2017

Introducing Upfront Money Can Decrease Discounting in Intertemporal Choices with Losses.

Front Psychol 2016 22;7:1256. Epub 2016 Aug 22.

College of Economics and Management, Zhejiang University of Technology Hangzhou, China.

People generally tend to advance gains and postpone losses in intertemporal choice. Jiang et al. (2014) recently showed that adding upfront losses or gains to both smaller and sooner (SS) and larger and later (LL) rewards can decrease people's discounting. To account for this decrease, they proposed the salience hypothesis, which states that introducing upfront losses or gains makes the money dimension more salient than not, thus increasing people's preference for LL rewards. Considering that decreasing the discounting of delayed losses is imperative and that most previous studies have focused on intertemporal choices with gains, in the current paper we conducted two experiments and used hypothetical money outcomes to examine whether the effect of upfront money could be extended to intertemporal choices with losses. The results showed that when both SS and LL intertemporal losses were combined with an upfront loss or gain, people's discounting rate decreased and the preference for the SS option increased. This finding further supports the salience account.
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http://dx.doi.org/10.3389/fpsyg.2016.01256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992676PMC
September 2016

Response of Potato Tuber Number and Spatial Distribution to Plant Density in Different Growing Seasons in Southwest China.

Front Plant Sci 2016 8;7:365. Epub 2016 Apr 8.

Agronomy, Sichuan Agricultural University Chengdu, China.

The aim of this study was to explore the effects of different density treatments on potato spatial distribution and yield in spring and fall. Plant density influenced yield and composition, horizontal, and vertical distribution distances between potato tubers, and spatial distribution position of tuber weights. The results indicated that: (1) Spring potato yield had a convex quadratic curve relationship with density, and the highest value was observed at 15.75 × 10(4) tubers per hectare. However, the yield of fall potatoes showed a linear relationship with plant density, and the highest value was observed at 18 × 10(4) tubers per hectare; (2) Density had a greater influence on the tuber weight of spring potatoes and fruit number of single fall potatoes; (3) The number of potato tubers in the longitudinal concentration exhibited a negative linear relationship with density, whereas the average vertical distribution distance of tubers exhibited a positive incremental hyperbolic relationship. For spring and fall potato tubers, the maximum distances were 8.4152 and 6.3316 cm, and the minimum distances 8.7666 and 6.9366 cm, respectively; and (4) Based on the artificial neural network model of the spatial distribution of tuber weight, density mainly affected the number and spatial distribution of tubers over 80 g. Tubers over 80 g were mainly distributed longitudinally (6-10 cm) and transversely (12-20 cm) within the high density treatment, and the transverse distribution scope and number of tubers over 80 g were reduced significantly. Spring potato tubers over 80 g grown at the lowest density were mainly distributed between 12 and 20 cm, whereas those at the highest density were primarily distributed between 10 and 15 cm.
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http://dx.doi.org/10.3389/fpls.2016.00365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824783PMC
April 2016

[Surgical treatment of bilateral thoracotomy in patients with lesions of left main bronchus invading carina].

Zhonghua Yi Xue Za Zhi 2010 Jan;90(3):205-7

Department of Thoracic Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.

Objective: To investigate the outcome for surgical treatment of bilateral thoracotomy in patients with lesions of left main bronchus invading carina by bilateral thoracotomy.

Methods: The clinical data of 4 patients with lesions of left main bronchus invading carina undergoing bilateral thoracotomy were retrospectively reviewed.

Results: There were two male and two female patients with a median age of 37.5 (range: 27 - 55) years old. Four patients were all accessed by bilateral thoracotomy, and received carinal reconstruction. Of these 4 patients, three patients received left pneumonectomy and one patient received carinal resection without concomitant pulmonary resection. Pathological results showed that one patient had tuberculosis. And other three patients were of 1 squamous cell carcinoma and 2 adenoid cystic carcinomas. Three patients received mechanical ventilation for a period of 3 - 21 days. one patient died of anastomotic dehiscence at 5 days postoperatively.

Conclusion: Bilateral thoracotomy is an alternative approach for relatively young patients with decent cardiopulmonary functions with lesions of left main bronchus invading carina. Operation type should be based on histopathological type and length of involved left main bronchus.
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January 2010

[The study on the chromosome aneuploidy in human lung cancer].

Zhonghua Yi Xue Za Zhi 2007 Jun;87(24):1701-3

Department of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China.

Objective: To study the feasibility of interphase fluorescence in situ hybridization (FISH) in detection of chromosomal aneuploidy in touch preparations of lung carcinoma and its clinic significance.

Methods: We examined 46 touch preparations of lung carcinomas by FISH with DNA specific for chromosomes 7, 8, 9 and 12 to detect chromosomal aneuploidy.

Results: Aneuploidy, mainly featured in gains of chromosomes 7, 8 and 12 and loss of chromosome 9 were observed in all of the touch preparations of the 46 cases with lung cancer. The rates of chromosomal aneuploidy detected by FISH were 67.4% (31/46), 60.9% (28/46), 28.3% (13/46) and 56.5% (26/31) respectively.

Conclusion: Interphase FISH is feasible in detecting aneuploidy in touch preparations of lung cancer. These alterations may be applied to early diagnosis and predicting prognosis of lung cancer.
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June 2007

[Postoperative respiratory failure in patients with cancer of esophagus and gastric cardia].

Zhonghua Zhong Liu Za Zhi 2005 Dec;27(12):753-6

Department of Thoracic Surgical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical University, Beijing 100021, China.

Objective: We retrospectively analyzed the cause and death risk of 114 postoperative respiratory failure patients found in 3519 patients with esophageal cancer and 1495 patients with carcinoma of gastric cardia surgically treated between January 1992 and May 2003.

Methods: To analyze the reasons causing postoperative respiratory failure in surgically treated esophageal or gastric cardia cancer patients, and the correlation between the death risk of postoperative respiratory failure and preoperative pulmonary function tests, postoperative complications, operation modes, history of preoperative accompanying diseases and so on using Binary Logistic Regression analysis and Chi-square tests (chi(2)) in SSPS statistics software.

Results: In this series, postoperative respiratory failure developed in 97 of 3519 (2.76%) esophageal cancer patients and 17 of 1495 (1.14%) gastric cardia cancer patients, which were mainly caused by severe respiratory tract infection (37.7%, 43/114) and operative complications (35.1%, 40/114) such as: anastomotic leakage or perforation of thoracic stomach, extensive bleeding during operation, chylothorax, etc, totally accounting for 72.8% (83/114). In contrast with lung cancer patients, most of the postoperative respiratory failure (69.3%) occurred in the patients who had perioperative complications but almost always normal preoperative pulmonary function tests. Other reasons to cause postoperative respiratory failure were: extubation in unconscious patients at the end of general anesthesia; over-infusion during operation; pulmonary artery embolism; severe arrhythmia and so on. All patients except 2 were treated in ICU by mechanic ventilation through intubation and/or tracheotomy. Eighty patients (70.2%) were intubated and/or had tracheotomy within 3 days postoperatively. Seventy patients (61.4%) were rescued successfully, whereas 44 cases (38.6%) died of postoperative respiratory failure and/or other postoperative complications. Univariate analysis and multivariate analysis by binary logistic regression indicated that: severe perioperative complications, more postoperative complications, poor preoperative pulmonary function, radical preoperative radiotherapy, intubation and/or tracheotomy after the second postoperative day and long period of mechanic ventilation were the major risk factors leading to death once the postoperative respiratory failure developed. The former 3 factors were independent risk factors leading to death with OR of 2.50, 2.37, 1.68, respectively. Age, sex, operation modes, history of preoperative accompanying disease, prophylactic antibiotics were not demonstrated as statistically significant risk factors correlated with death.

Conclusion: Severe perioperative complications and respiratory tract infection are the two major causes of postoperative respiratory failure in patients with cancer of esophagus and gastric cardia. Patients with severe perioperative complications or poor preoperative pulmonary function or association with more than two kinds of postoperative complications have much higher death risk than other patients when they develop postoperative respiratory failure. Careful manipulation during operation and effective perioperative management are the most important measures to avoid postoperative respiratory failure and high mortality.
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December 2005

[Clinicopathological features and prognosis of thymic carcinoma].

Zhonghua Zhong Liu Za Zhi 2004 Apr;26(4):223-5

Department of Thoracic Surgical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.

Objective: To investigate the clinicopathologic features of thymic carcinoma and assess its prognostic factors.

Methods: A retrospective analysis was performed in 54 patients with thymic carcinoma who underwent surgical resection. Eighteen patients were treated by total resection of the tumor, 17 partial resection and 10 exploratory thoracotomy. The clinical stage was determined according to Masaoka's classification. The survival time and prognostic factors were evaluated by the log-rank and Cox multivariate analysis model.

Results: The overall 5-year survival rate was 44.4%. Being located in anterior mediastinum and noncalcification in the tumor pathognomonically played an important role in the differential diagnosis. According to the multivariate analysis, tumor maximum diameter (OR = 1.84), histological subtype (OR = 1.70), completeness of resection (OR = 1.37), tumor invasion of peritumoral organs (OR = 1.32) and postoperative recurrence (OR = 1.26) were significant prognostic factors. Compared with other subtypes, carcinoid tumor had the characteristics of earlier lesion, better resection rate and better prognosis.

Conclusion: The most important prognostic variables for thymic carcinoma are tumor maximum diameter, histological subtype, completeness of resection, tumoral invasion and postoperative recurrence. Complete resection followed by chemoradiotherapy should be considered as favorable on the basis of a definitive pathologic diagnosis.
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April 2004

[Myasthenia gravis occurring after resection of thymoma].

Zhonghua Wai Ke Za Zhi 2004 May;42(9):540-2

Department of Thoracic Surgery, Cancer Hospital (Institute), Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.

Objective: The aim of this study was to analyses the clinicopathologic features of the patient with myasthenia gravis (MG) occurring after resection of thymoma.

Methods: Data of 15 patients were collected. The follow-up range from 8 to 178 (average 76.7) months. A retrospective analysis was performed through comparison with data of all 112 cases without MG, which had not occurred MG during our average 5.5 years follow-up, operated for thymoma in same period. The statistics analysis adopted chi(2) and t test.

Results: (1) According to Masaoka's classification of thymoma, stage I in 7 cases, stage II in 4, stage III in 4. Histologic Bernatz's classification: lymphocyte predominant type in 4, epithelial type in 3, mixed type in 7, unknown in 1. According to Osserman's classification of MG, grade I in 7, IIa in 4, IIb in 3, III in 1. The MG onset times was the postoperative narcotic waking duration-137 (average 33.9) months, and the average remission time was 30.9 (0.5 - 120) months. (2) 4 cases who occur MG as soon as pull up narcotic tube, all adopted nondepolarizing muscular relaxants. (3) MG was discovered in 3 cases (3/67) during postoperative radiotherapy until a average dosage of 36 Gy was received in average 24 days. (4) The tendency of occurring MG following resection was found in female patients with longer duration of disease, mixed type, larger and later stage thymoma as compared with the thymoma group.

Conclusions: The factors including the operation, relatively using overdose relaxation control, choosing unfavorable muscle relaxant and postoperative radiotherapy could induce postoperative MG. An intensive care should be put on the cases with the tendency of occurring postoperative MG.
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May 2004

[Clinical analysis of surgical treatment of primary tracheal tumors].

Zhonghua Wai Ke Za Zhi 2003 Nov;41(11):823-6

Department of Thoracic Surgical, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100021, China.

Objective: To summarize the clinical experiences in treating primary tracheal tumors by surgery.

Methods: The clinical data concerning 70 surgically treated patients between 1968 and 2001 were retrospectively analyzed.

Results: There were 39 sleeve tracheal resections, 13 carinal resections, 10 lateral tracheal wall resections, 5 local enucleations, and 1 pneumonectomy. The tumors in 2 patients were unresectable. The morbidity rate was 31% (22/70) and operative 30-day mortality for resection with primary reconstruction was 8% (4/52). The tumors were benign in 14 and malignant in 56 cases. The most common malignant tumors were adenoidcystic carcinoma (45%) and squamous cell carcinoma (23%). The cases of benign tracheal tumors were followed up for an average of 5.7 years. After resection for malignant tumors, the overall 5- and 10-year survival rates were 64% (21/33) and 54% (14/26), respectively.

Conclusions: Surgical resection is the most effective treatment of tracheal tumors. Tracheal resection and reconstruction is the treatment of choice for primary tracheal tumors. Benign tumors should be resected conservatively with preservation of tracheal parenchyma. The reduction of operative complications are key points of good surgical results.
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November 2003

[Poly(AT) polymorphism in DNA repair gene XPC and lung cancer risk].

Zhonghua Zhong Liu Za Zhi 2003 Nov;25(6):555-7

Department of Surgical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China.

Objective: It has been shown that suboptimal DNA repair capacity is associated with cancer risk and that a poly(AT) polymorphism in XPC gene (XPC PAT) may influence DNA capacity. This study was designed to assess the relationship between XPC PAT polymorphism and susceptibility to lung cancer in the Chinese population.

Methods: XPC genotypes were determined by PCR methods in 509 healthy controls and 597 patients with lung cancer. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariate logistic regression model.

Results: Genotype frequencies of XPC PAT among controls were 37.9% (PAT-/-), 49.7% (PAT+/-) and 12.4% (PAT+/+), respectively. They were not significantly different from those among lung cancer patients (42.1%, 46.7% and 11.2%, respectively; P = 0.37). Individuals carrying XPC PAT+/+ genotype were not at increased risk for lung cancer as compared with those with PAT+/- or PAT-/- genotype (adjusted OR, 0.8; 95% CI, 0.55 approximately 1.16). No interaction between XPC genotype and smoking was observed.

Conclusion: Our findings indicate that the XPC PAT polymorphism may not be associated with risk of lung cancer in the Chinese population.
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November 2003

[Significance of CEA, SCC and Cyfra21-1 serum test in esophageal cancer].

Zhonghua Zhong Liu Za Zhi 2003 Sep;25(5):457-60

Department of Thoracic Surgical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China.

Objective: To study the clinical significance of serum CEA, SCC and Cyfra21-1 test in the diagnosis, prediction of prognosis and postoperative monitor of recurrence in esophageal cancer.

Methods: The concentration of serum CEA and Cyfra21-1 was measured by electrochemiluminescence immunoassay (ECLIA) using Elecsys 2010, CEA kit and Cyfra21-1 kit. Serum SCC was measured by microparticle enzyme immunoassay (MEIA) using IMx System and SCC kit. Serum of 206 patients with esophageal cancer (203 squamous cell carcinoma, 2 small cell carcinoma and 1 adenosquamous carcinoma) was measured preoperatively, 71 of whom also measued 8 to 12 days after resection.

Results: The cut-off value of CEA and Cyfra21-1 was < or = 3.25 ng/ml and < or = 2.61 ng/ml, which were determined by the data of 45 healthy Chinese measured during the same period. The positive ratios of serum CEA and Cyfra21-1 in 206 cases were 29.1% and 45.1%. The combined positive ratio of CEA and Cyfra21-1 was 57.3%. The CEA positive ratios, according to the pathological stage of 165 resectable patients, were 16.6% (stage I), 26.8% (II) and 30.8% (III). For Cyfra21-1, they were 27.8%, 37.5% and 50.5%. For CEA combined with Cyfra21-1, they were 38.9%, 50.0% and 63.7%. The mean value of CEA, SCC and Cyfra21-1 (especially SCC and Cyfra21-1) was found to be well correlated with the tumor volume, TNM stage and depth of tumor invasion. Patient with bulky tumor or advanced tumor (T4) usually had much higher mean value than those with early stage tumors. One week after radical resection, the level of the three tumor markers fell to normal level in 92.9% of 71 patients. The level of serum CEA and Cyfra21-1 varied greatly in a small part of the patients. Extremely elevated serum CEA and Cyfra21-1 usually indicated advanced lesion or tumor metastasis.

Conclusion: Preoperative and postoperative measurement of serum CEA, SCC and Cyfra21-1 (especially Cyfra21-1) is helpful in the diagnosis, prediction of prognosis and monitor of postoperative recurrence in patients with esophageal cancer.
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September 2003