A hybrid differential evolution based on gaining‑sharing knowledge algorithm and harris hawks optimization

Differential evolution (DE) is favored by scholars for its simplicity and efficiency, but its ability to balance exploration and exploitation needs to be enhanced. In this paper, a hybrid differential evolution with gaining-sharing knowledge algorithm (GSK) and harris hawks optimization (HHO) is proposed, abbreviated as DEGH. Its main contribution lies are as follows. First, a hybrid mutation operator is constructed in DEGH, in which the two-phase strategy of GSK, the classical mutation operator “rand/1” of DE and the soft besiege rule of HHO are used and improved, forming a double-insurance mechanism for the balance between exploration and exploitation. Second, a novel crossover probability self-adaption strategy is proposed to strengthen the internal relation among mutation, crossover and selection of DE. On this basis, the crossover probability and scaling factor jointly affect the evolution of each individual, thus making the proposed algorithm can better adapt to various optimization problems. In addition, DEGH is compared with eight state-of-the-art DE algorithms on 32 benchmark functions. Experimental results show that the proposed DEGH algorithm is significantly superior to the compared algorithms.

Classical versus non-classical EGFR mutations: Erlotinib response and impact of renal insufficiency

Introduction Erlotinib is an effective treatment option for EGFR-mutant non-small cell lung cancer. It is important to predict patients who will respond better to erlotinib. We designed this study to investigate the effect of renal insufficiency (RI) on erlotinib treatment outcomes. Methods All patients receiving erlotinib were stratified into 3 groups. Group 1 consisted of non-RI subjects with classical epidermal growth factor receptor (EGFR) mutations, Group 2 consisted of those with RI (Estimated glomerular filtration rate <60 mL/min) and classical EGFR mutations, and Group 3 consisted of those with non-classical EGFR mutations. Results 82 patients were included in the study. Median progression-free survival (PFS) in patients with classical mutation was approximately 6 months shorter in those with RI, although not statistically significant. Median overall survival (OS) in Group 1, 2 and 3 was 34.1 months, 35.2 months, and 15 months, respectively and although not statistically significant, median OS was 20 months shorter in Group 3. Univariate and multivariate cox-regression analysis revealed shorter PFS and OS in males and those with ECOG ≥2 while PFS and OS were longer in those with recurrent lung tumors and generating rash during erlotinib treatment. There was no difference between RI and non-RI patients in terms of adverse events except for fatigue and appetite loss. Conclusions This research showed OS in patients with and without RI was comparable. Although not statistically significant, PFS in patients with classical mutation was approximately 6 months shorter in those with RI patients.

Origin and functional differentiation of (E)-β-ocimene synthases reflect the expansion of monoterpenes in angiosperms

The acquisition of new metabolic activities is a major force driving evolution. We explored, from the perspectives of gene family expansion and the evolutionary adaptability of proteins, how new functions have arisen in which terpene synthases diverged. Monoterpenoids are diverse natural compounds that can be divided into cyclic and acyclic skeleton forms according to their chemical structure. We demonstrate, through phylogenetic reconstructions and genome synteny analyses, that the (E)-β-ocimene synthases, which are acyclic monoterpene synthases (mTPSs), appear to have arisen several times in independent lineages during plant evolution. Bioinformatics analyses and classical mutation experiments identified four sites (I388, F420, S446, and F485) playing important roles in the neofunctionalization of mTPSs. Incubation of neryl diphosphate with Salvia officinalis 1,8-cineole synthase (SCS) and mutated proteins show that these four sites obstruct the isomerization of geranyl diphosphate. Quantum mechanical/molecular mechanical molecular dynamics simulations of models of SCS, SCSY420F/I446S, and SCSN338I/Y420F/I446S/L485F with (3R)-linalyl diphosphate suggest that mutations changed the configuration of the intermediate to obtain new activities. These results provide new perspectives on the evolution of mTPSs, explain the convergent evolution of (E)-β-ocimene synthases at the molecular level, and identify key residues to control the specificity of engineered mTPSs.

Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia

Most genes associated with Acute Myeloid Leukemia (AML) are mutated in less than 10% of patients, suggesting alternative mechanisms for gene disruption contribute to this disease. Here we find a set of splicing events that disrupt the expression of a subset of AML-associated genes, including EZH2 and ZRSR2, independent of known somatic mutations. Most strikingly, in at least one cohort, aberrant splicing triples the number of patients with a reduction in functional EZH2 as compared to that predicted by somatic mutation of EZH2 alone. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlights the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.

The Use of DNA Methylation Profiling to Assess the Significance of Different Types of Mutations in CEBPA-Mutated AML

In AML, the favorable prognosis associated with mutations in the CEBPA gene is restricted to those cases with double CEBPA mutations (CEBPADM), consistent with the loss of normal CEBP/alpha activity from both alleles. Current recommendations are that CEBPADM-mutated patients should not receive a stem cell transplant in first remission. In general, these cases have 2 ‘classical’ mutations, an N-terminal out-of-frame insertion/deletion that leads to loss of the full-length p42 protein and increased levels of the p30 isoform translated from an internal start site, coupled with a C-terminal in-frame insertion/deletion in the DNA binding domain (DBD) or leucine zipper domain (LZD) that interferes with DNA binding or dimerization. However, in our study of 1427 younger adult patients, 26% of mutations did not fit this classical description due to either the location or type of mutation. Furthermore, of the CEBPADM cases, 20% had a classical plus a ‘non-classical’ mutation or a homozygous non-classical mutation. It will be important to understand the functional consequences of these atypical mutations if CEBPA genotype is to be used to determine patient management. As methylation profiling has shown that CEBPADM cases form a distinct hypermethylated cluster, we investigated whether this can provide information about non-classical cases. A test set of 40 diagnostic samples were analyzed on the Illumina Infinium 27K Human Methylation Array, all normal karyotype with wild type (WT) NPM1, FLT3ITD and FLT3TKD; 10 were CEBPADM, 30 CEBPAWT. Unsupervised cluster analysis showed that the 10 CEBPADM cases clustered within a group of 16 hypermethylated cases that separated from 24 hypomethylated cases. A methylation signature was created from the 25 most-differentially methylated CpG sites between the CEBPADM and CEBPAWT cases and used to examine a validation set of 95 samples analyzed on the Illumina Infinium 450K Human Methylation Array (31 CEBPADM, 38 single-mutated CEBPA [CEBPASM], 26 CEBPAWT). This included 38 cases with non-classical mutations, 14 of them CEBPADM. On unsupervised cluster analysis, most CEBPADM cases (81%) fell in a hypermethylated group that was distinct from CEBPASM and CEBPAWT cases, with no segregation between the latter. We derived a genotype predictor by comparing the % methylation in a sample at each of the 25 CpG sites with that in the CEBPADM and CEBPAWT signatures to determine which signature the sample data most approximated. This correctly predicted 25/31 (81%) of the CEBPADM cases, including 2 with missense DBD/LZD mutations (A295P, N321S) coupled with a classic N or C mutation, 2 with homozygous classic C mutations, indicating that presence of the p30 isoform is not required for the methylation profile, and 5 with a classic N mutation coupled with a truncating mutation in the middle of the gene, consistent with the presence of the p30 isoform alone. This data was supported by functional evaluation of mutant constructs in a luciferase reporter assay to assess DNA binding and transactivation activity (TA). Classic CEBPADM constructs all had significantly lower TA than CEBPAWT (mean 12%, 27%, 15% of CEBPAWT for homozygous N, homozygous C and N+C constructs). Combination of a classic N mutation with missense DBD mutations (A295P, R297P, R300P), a LZD truncation (K313fs) or a middle region truncation (Q209fs, A238fs), all led to ≤15% activity consistent with almost complete loss of CEBP/alpha activity. Of the 6 CEBPADM cases that did not cluster as expected, 1 with classic N+C mutations had a lower mutant level (mean 28% for the 2 mutations compared to 45% for 9 other pairs with available data) and 1 had a homozygous missense LZD mutation that did not show reduced TA that could explain the discrepancy. The other 4 all had high mutant level (mean level ≥39%) and biallelic mutations as assessed by cloning, and relevant constructs showed low TA (≤19%). The reason for their misclassification is therefore not apparent, although we cannot exclude the possibility of other coincident mutations influencing methylation. These data indicate that the hypermethylated profile associated with CEBPADM cases holds true for most of the CEBPA mutations identified in patients and can be used to support predicted functional consequence of the mutations. This may be particularly useful in determining management in CEBPADM cases with non-classical mutations. Disclosures No relevant conflicts of interest to declare.