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Y.S. Chang
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-074 - Increased AIMP2-DX2/AIMP2 Autoantibody Ratio is Associated with Poor Prognosis in Lung Cancer (ID 4874)
14:30 - 14:30 | Author(s): Y.S. Chang
- Abstract
Background:
Aminoacyl t-RNA synthetase-interacting multi-functional proteins (AIMPs) are scaffolding protein required for the assembly of the t-RNA synthetase complex, forming multisynthetase complex. Besides their inherent roles, AIMPs translocate to the other cellular compartments and involve in various cellular pathways. On the other hands, its alternative spliced form lacking exon2 (AIMP2-DX2) compromises the tumor suppressive activity of AIMP2. Recently, presence of autoantibodies against AIMP2-DX2 and AIMP2 were identified in the human blood but its clinical implication is unknown.
Methods:
The diagnostic usefulness of blood autoantibody against AIMP2-DX2 and AIMP2 was investigated in 80 lung cancer cases and 1:1 age, gender and smoking status matched control cases using ROC curve. To exploit their clinical implication, blood level of autoantibody against AIMP2-DX2, AIMP2 and AIMP2-DX2/AIMP2 ratio was analyzed with clinical parameters in 165 lung cancer patients.
Results:
There was no statistically significant difference in the blood autoantibody level against AIMP2-DX2 and AIMP2 between lung cancer and control cases. However AIMP2-DX2/AIMP2 ratio was higher in lung cancer patients (30.7±12.6 vs. 39.1±18.4, P=0.001, t-test). When their diagnostic usefulness was evaluated by ROC curve generation, the AUC of auto-antibody level of AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 ratio were 0.416, 0.579 and 0.357 respectively, suggesting their diagnostic value in lung cancer is limited. A total 165 lung cancer patients were classified into 2 groups, high and low group, on the basis of median value of AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 ratio, respectively, and then further analyzed. There was no statistical difference in the gender, smoking, pathologic diagnosis and stage between high and low group of AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 ratio. But AIMP2-DX2 high group was older than those with lower AIMP2-DX2 group (66.8±8.4 vs. 63.8±10.1 years, P-value=0.040, t-test). When the relationship with CEA and CYFRA-21 was evaluated, the AIMP2-DX2/AIMP2 high group showed higher CYFRA-21 level (7.9±12.1 vs. 4.3±4.3 ng/mL, P-value=0.020, χ[2]-test). There was no significant relationship between AIMP2-DX2 and AIMP2 concentration with progression free survival and overall survival. But the patients with high AIMP2-DX2/AIMP2 ratio showed significant short overall survival (18.6 (95% CI: 15.19~22.00) vs. 48.9 (95% CI: 14.89~82.91 months), P-value=0.021, Log-Rank Test).
Conclusion:
Autoantibodies against AIMP2-DX2 and AIMP2 exist at detectable level in human blood. Increased AIMP2-DX2/AIMP2 ratio is closely related to the poor clinical outcome of lung cancer patents, indicating those are warranted for further study for development as biomarkers in lung cancer.
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-004 - ABT-737, a BH3 Mimetic, Enhances Therapeutic Effect of Ionizing Radiation in Murine Lung Cancer Model (ID 5895)
14:30 - 14:30 | Author(s): Y.S. Chang
- Abstract
Background:
Radiotherapy is one of the main treatment modalities of lung cancer, but its effectiveness is often hampered because of dose dependent radiation toxicity. Aberration of apoptotic pathway after irradiation is another mechanism attenuating therapeutic effect of radiation. ABT-737, a ‘first-in-class’ of BH3 mimetics, disrupts the BCL-2/BAK complex and initiates BAK-dependent intrinsic apoptotic pathway. In this study, we sought that ABT-737 is able to maximize the therapeutic effects of radiation in experimental animal models.
Methods:
Kras:p53[fl/fl] double mutant mice were obtained by genotyping of offspring from LSL Kras G12D and p53[fl/fl ]mouse. Lung cancer was induced by inhalation of 5 X 10[7] PFU AdCre viral particles at 8 weeks age. After 12 (± 2) weeks of inhalation, the mice were randomized and treated with either vehicle or ABT-737 (50 mg/kg, i.p., daily) for 3 days. Then mice underwent microCT and were irradiated in the left lung at a dose of 20 Gy using X-rad 320. In 2 weeks, 2[nd] round microCT was performed and lungs were harvested for histological analysis.
Results:
When the changes in the expression of pro-apoptotic and anti-apoptotic molecules after 20 Gy of irradiation were evaluated by immunoblotting, the decrease of BCL2-like 11 (BCL2L11) was most prominent in the irradiated lung. The tumor area was decreased in the irradiated lung of both vehicle and ABT-737 pretreated mice and inhibitory effect was remarkable when the mice were pretreated with ABT-737. Disputed tumor structure with apoptotic bodies were most frequently observed in the irradiated lung of ABT-737 pretreated mice. To quantify the apoptotic effect of this combination, immunohistochemical analysis against activated caspase-3 was performed. Counts of activated caspase-3 were significantly higher in the irradiated lung with ABT-737 pretreatment, suggesting ABT-737 possesses radiosensitizing property.
Conclusion:
Decrease of BCL2L11 expression in the irradiated lung is one of prominent findings, which might compromise therapeutic effect of radiation. Pretreatment of ABT-737 enhanced anti-tumor effect of ionizing radiation in Kras:p53[fl/fl] lung cancer model, suggesting BH3 mimetics would be a good candidate of radiosensitizer in lung cancer. Further studies are warranted for identification of optimal dosing and schedule of this combination treatment.
