Biomedical subjects

Chi-Ming Chang

Publications and source records attributed to Chi-Ming Chang.

3 recordsLinked to original sources

PubMed2005

Computer-aided disease prediction system: development of application software with SAS component language.

AIMS: The intricacy of predictive models associated with prognosis and risk classification of disease often discourages medical personnel who are interested in this field. The aim of this study was therefore to develop a computer-aided disease prediction model underpinning a step-by-step statistics-guided approach including five components: (1) data management; (2) exploratory analysis; (3) type of predictive model; (4) model verification; (5) interactive mode of disease prediction using SAS 8.02 Windows 2000 as a platform. METHODS: The application of this system was illustrated by using data from the Swedish Two-County Trial on breast cancer screening. The effects of tumour size, node status, and histological grade on breast cancer death using logistic regression model or survival models were predicted. A total of 20 questions were designed to exemplify the usefulness of each component. We also evaluated the system using a controlled randomized trial. Times to finish the above 20 questions were used as endpoint to evaluate the performance of the current system. User satisfaction with the current system such as easy to use, the efficiency of risk prediction, and the reduction of barrier to predictive model was also evaluated. RESULTS: The intervention group not only performed more efficiently than the control group but also satisfied with this application software. CONCLUSIONS: The MD-DP-SOS system characterized by menu-driven style, comprehensiveness, accuracy and adequacy assessment, and interactive mode of disease prediction is helpful for medical personnel who are involved in disease prediction.

Decision Support Techniques↗

PubMed2004

Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin.

Amplification and mutation of the epidermal growth factor receptor (EGFR) are common features of malignant gliomas. The most frequent mutation seen in these tumors involves deletion of exon 2-7 resulting in a constitutively active form of the receptor (EGFRvIII, or deltaEGFR). Since EGFRvIII is found primarily in gliomas and has not been reported in sarcomas, we compared the effects of this altered receptor in immortalized primary astrocytes and fibroblasts. While EGFRvIII displayed ligand-independent autophosphorylation in both cell types, downstream signaling differed. While EGFRvIII increased the proliferative capacity of both astrocytes and fibroblasts consistent with activation of ERK in these cells, EGFRvIII activated AKT only in the immortalized astrocytes. EGFRvIII expression in astrocytes also led to increased radioresistance in that cell type. Furthermore, specific inhibition of phosphotidylinositol-3 kinase (PI-3K) with LY294002 reverted the radioresistant phenotype in the immortalized astrocytes. Thus, selective activation of PI-3K/AKT in astrocytes expressing EGFRvIII appears to be responsible for the observed increase in radioresistance. EGFRvIII's differential ability to activate the PI-3K downstream signal may explain why this mutant receptor is such a prominent lesion in malignant gliomas but less often seen in other tumor types, even those where EGFR signaling has a prominent role.

Astrocytes↗

PubMed2003

Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas.

Epidermal growth factor (EGF) receptor (EGFR) is commonly amplified and/or mutated in high-grade gliomas. Abnormal signaling from this receptor tyrosine kinase is believed to contribute to the malignant phenotypes seen in these tumors. Highly specific small molecule inhibitors of this receptor tyrosine kinase have been developed and may potentially improve the treatment of these highly aggressive brain tumors. A glioma cell line overexpressing EGFR was developed to mimic the situation of a malignant glioma with amplified EGFR, and this line was used to characterize the response to specific EGFR inhibitors. Treatment of our in vitro glioma model with the EGFR kinase inhibitors ZD1839 (Iressa) or PD153035, synthetic anilinoquinazolines with high specificity for EGFR, resulted in significant suppression of EGFR autophosphorylation even with very low levels of drug. However, significantly higher levels of drug were required to fully inhibit signaling through the phosphatidylinositol 3'-kinase/AKT and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathways. Interestingly, not all downstream signaling pathways displayed this resistance to inhibition. EGF-dependent activation of signal transducers and activators of transcription-3 occurred at low doses of EGFR inhibitors. The uncoupling of EGFR autophosphorylation and signaling through AKT and ERK was not dependent on EGFR overexpression. In addition, although this response was seen in other glioma and the SK-BR3 breast cancer cell lines, it was not universally present. The SQ20B head and neck squamous carcinoma cell line demonstrated loss of EGF-dependent AKT and ERK activation even at low doses of inhibitor. Despite significant loss of EGF-dependent autophosphorylation, the inability of low levels of EGFR inhibitor to suppress some downstream signaling pathways in our model glioma cell line permitted continued EGF-responsive decreases in the expression of the cyclin-dependent kinase inhibitor p27KIP and EGF-dependent proliferation/cell cycle progression. Although the mechanism responsible for the differential sensitivity of the various signal transduction pathways to EGFR inhibitors remains unclear, signaling through erbB2 does not appear to be involved. The ability of certain tumor cells to maintain signaling through AKT and ERK under EGFR inhibition may represent a potential mechanism of resistance by which a tumor cell may escape the antiproliferative activity of this new class of drugs.

Antineoplastic Agents↗