Characteristics and Clinical Implication of UGT1A1 Heterozygous Mutation in Tumor

Background:The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1 A1 homozygous mutations,but the impact of UGT1 A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.Methods:A total of 107 patients with UGT1 A1 heterozygous mutation or wild-type,who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital,were retrospectively enrolled.The adverse reaction spectra of patients with UGT1 A1*6 and UGT1 A1*28 mutations were analyzed.Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE) 5.0.The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors(RECIST) 1.1.The genotypes of UGT1 A1*6 and UGT1 A1*28 were detected by digital fluorescence molecular hybridization.Results:There were 43 patients with UGT1 A1*6 heterozygous mutation,26 patients with UGT1 A1*28 heterozygous mutation,8 patients with UGT1 A1*6 and UGT1 A1*28 double heterozygous mutations,61 patients with heterozygous mutation at any gene locus of UGT1 A1*6 and UGT1 A1*28.Logistic regression analysis showed that the presence or absence of vomiting(P=0.013) and mucositis(P=0.005) was significantly correlated with heterozygous mutation of UGT1 A1*28,and the severity of vomiting(P<0.001) and neutropenia(P=0.021) were significantly correlated with heterozygous mutation of UGT1 A1*6.In colorectal cancer,UGT1 A1*6 was significantly correlated to diarrhea(P=0.005),and the other adverse reactions spectrum was similar to that of the whole patient cohort,and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.Conclusion:In clinical use,heterozygous mutations of UGT1 A1*6 and UGT1 A1*28 are related to the risk and severity of vomiting,diarrhea,neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy.In colorectal cancer,UGT1 A1*6 is significantly related to diarrhea post CPT-11 use,efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.

Many-objective Optimization Method Based on Dimension Reduction for Operation of Large-scale Cooling Energy Systems

Large-scale cooling energy system has developed well in the past decade.However,its optimization is still a problem to be tackled due to the nonlinearity and large scale of existing systems.Reducing the scale of problems without oversimplifying the actual system model is a big challenge nowadays.This paper proposes a dimension reduction-based many-objective optimization(DRMO)method to solve an accurate nonlinear model of a practical large-scale cooling energy system.In the first stage,many-objective and many-variable of the large system are pre-processed to reduce the overall scale of the optimization problem.The relationships between many objectives are analyzed to find a few representative objectives.Key control variables are extracted to reduce the dimension of variables and the number of equality constraints.In the second stage,the manyobjective group search optimization(GSO)method is used to solve the low-dimensional nonlinear model,and a Pareto-front is obtained.In the final stage,candidate solutions along the Paretofront are graded on many-objective levels of system operators.The candidate solution with the highest average utility value is selected as the best running mode.Simulations are carried out on a 619-node-614-branch cooling system,and results show the ability of the proposed method in solving large-scale system operation problems.