Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy

AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase(UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer(m CRC) patients treated with irinotecan-based chemotherapy(NCT01282658). Baseline serum bilirubin levels, including total bilirubin(TBil) and unconjugated bilirubin(UBil), were measured,and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve(ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as Co Bil, patients were classified into three groups. The classifier's performance of UGT1A1*28 and Co Bil for predicting treatment response was evaluated by ROC analysis. Associations between response and Co Bil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS: Among the 120 m CRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil(P = 0.018) and a higher UBil(P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on Co Bil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple(OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple(OR = 16.001; 95%CI: 2.802-91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28(TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous(TA)6 genotype in the simple(OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple(OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier's performance of Co Bil and UGT1A1*28 were comparable.CONCLUSION: Co Bil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of m CRC patients to irinotecan-based chemotherapy. After validation, Co Bil, an easily determinable index in the clinic, might be helpful in facilitating stratification of m CRC patients for individualized treatment options.

Investigation of gate oxide traps effect on NAND flash memory by TCAD simulation

The effects of gate oxide traps on gate leakage current and device performance of metal–oxide–nitride–oxide–silicon(MONOS)-structured NAND flash memory are investigated through Sentaurus TCAD. The trap-assisted tunneling(TAT)model is implemented to simulate the leakage current of MONOS-structured memory cell. In this study, trap position, trap density, and trap energy are systematically analyzed for ascertaining their influences on gate leakage current, program/erase speed, and data retention properties. The results show that the traps in blocking layer significantly enhance the gate leakage current and also facilitates the cell program/erase. Trap density ~10^(18) cm^(-3) and trap energy ~ 1 eV in blocking layer can considerably improve cell program/erase speed without deteriorating data retention. The result conduces to understanding the role of gate oxide traps in cell degradation of MONOS-structured NAND flash memory.

Genetic Variants in CHEK1 Gene Are Associated with the Prognosis of Thoracic Esophageal Squamous Cell Carcinoma Patients Treated with Radical Resection

CHEK1 gene is known to play an important role in tumor progression by cell cycle control.However,the association between CHEK1 and the prognosis of esophageal squamous cell carcinoma（ESCC） is unclear.In this study,we explored the association between genetic variants in CHEK1 gene and prognosis of ESCC patients treated with radical resection.A total of 131 thoracic ESCC patients who underwent radical resection were included in this retrospective study and genotyped using the Mass Array method.According to the univariate Cox hazard analysis,the GT/TT genotype of CHEK1 rs555752 was shown to be strongly related to a decreased overall survival（OS）（HR=2.560,95% CI：1.415–4.631,P=0.002） and disease-free survival（DFS）（HR=2.160,95% CI：1.258–3.710,P=0.005）.Furthermore,according to the multivariate Cox hazard analysis and multiple testing,patients with the GT/TT genotype of CHEK1 rs555752 had a notably decreased OS（HR=2.735,95% CI：1.468–5.096,P=0.002,Pc=0.006） and DFS（HR=2.282,95% CI：1.292–4.023,P=0.004,Pc=0.012）.In conclusion,genetic variants of the CHEK1 gene are significantly related to OS and DFS of ESCC patients,and may therefore be predictors of the prognosis of thoracic ESCC after surgery.

Critically dysregulated signaling pathways and clinical utility of the pathway biomarkers in lymphoid malignancies

Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the 'driver' oncogenic biomarkers, as well as to develop reliable and reproducible risk-stratification based on biomarkers will be challenging. Never-theless, pathway-based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine.