[Analysis the influence factors of treatment free remission outcome with chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitors].

Objective: To explore the related factors affecting the outcome of treatment free remission (TFR) in patients with chronic myeloid leukemia (CML). Methods: Clinical data of CML patients with automatic discontinuation of tyrosine kinase inhibitor (TKI) from the CML cooperative organization of Henan province between June 2, 2013 to March 27, 2021 and the follow-up time was ≥ 6 months were retrospectively analyzed. Log-rank test was used for univariate analysis and Cox proportional risk regression model was used for multivariate analysis. Results: A total of 135 patients were enrolled, and 69 patients (51.1%) were femal and 66 patients (48.9%)were male. Median age was[M(Q1,Q3)] 49 years (38, 58)at discontinuation.Before discontinuation, 72 patients (53.3%) were on treatment with second-generation TKI, 63 patients (46.7%) were on treatment with IM, 17patients (12.6%) had a history of TKI reduction/withdrawal;median duration of treatment was months 84 (68, 108) for all patients;median time of TKI treatment to DMR was months 12(8, 26);median duration of DMR was months 65 (54, 84), and 9 patients (6.7%) had unsustained DMR.The median follow-up time was months 16(6-96), 35 patients (25.9%) lost MMR at a median months 3(1-22), overall estimated TFR was 74.1%.The univariate analysis results showed that:second-generation TKI was used, the time of TKI treatment to DMR was ≤12 months, DMR duration time ≥48 months, had sustained DMR, without TKI reduction/withdrawal history were favorable factors affecting of TFR in patients with TKI discontinuation (all P<0.05).The TFR rate of the second-generation TKI therapy group was significantly higher than the IM therapy group (81.9% vs 65.1%, P=0.019).The multivariate analysis results showed that second-generation TKI treatment[RR=0.451, 95%CI (0.227-0.896), P=0.023] and had sustained DMR [RR=0.120, 95%CI (0.053-0.271), P<0.001] were the protective factors of TFR in patients with TKI discontinuation. Conclusions: Treated with second-generation TKI and had sustained DMR are the protective factors of TFR in patients with TKI discontinuation.The CML patients who had sustained DMR more≥48 months before TKI discontinuation showed a better TFR.

The application of computational methods to the study of enzyme catalysis by triose-phosphate isomerase and stabilities of variants of bacteriophage T4 lysozyme.

We review our research on triose-phosphate isomerase and bacteriophage T4 lysozyme. In our studies over the last ten years we have used electrostatic potentials, computer graphics, quantum mechanics, molecular mechanics, molecular dynamics and free energy calculations to try to understand why triose-phosphate isomerase is such an efficient enzyme and why its efficiency is dramatically decreased by several site-specific mutations. For T4 lysozyme we have used free energy methods to analyse and try to understand why Thr-157----Val and Thr-157----Ala mutations decrease protein stability by about 1-2 kcal/mol.

Why do A.T base pairs inhibit Z-DNA formation?

We have carried out free energy perturbation calculations on DNA double-stranded hexanucleotides. The sequence d(CGCGCG)2 has been "mutated" into d(CGTGCG).d(CGCACG) with the oligonucleotide in the A, B, and Z structural forms, both in vacuo and in aqueous solution. In addition, model free energy calculations have been carried out in which the electrostatic charges of the H-bonding groups of the bases in the major and minor grooves of the DNA are reduced to zero as a way of assessing the relative solvation effects of these groups in the different structural forms of DNA. Finally, energy component analyses have been carried out to assess the relative roles of different intranucleotide interactions on the B----Z equilibrium as a function of base sequence. In vacuo, the free energy for changing a G.C to an A.T base pair is largest in the Z conformation; in the A and B conformations, the free energy cost is approximately 2 kcal/mol lower (1 cal = 4.184 J). The results are similar when the simulations are run in explicit solvent: the change costs 3 kcal/mol more in the Z conformation than in the B form. These results are consistent with experimental data, where it is clear that A.T sequences are significantly more "Z-phobic" than G.C sequences. The calculations indicate that both intranucleotide and solvation interactions contribute to this Z-phobicity.