The structure-based cancer-related single amino acid variation prediction

Single amino acid variation (SAV) is an amino acid substitution of the protein sequence that can potentially influence the entire protein structure or function, as well as its binding affinity. Protein destabilization is related to diseases, including several cancers, although using traditional experiments to clarify the relationship between SAVs and cancer uses much time and resources. Some SAV prediction methods use computational approaches, with most predicting SAV-induced changes in protein stability. In this investigation, all SAV characteristics generated from protein sequences, structures and the microenvironment were converted into feature vectors and fed into an integrated predicting system using a support vector machine and genetic algorithm. Critical features were used to estimate the relationship between their properties and cancers caused by SAVs. We describe how we developed a prediction system based on protein sequences and structure that is capable of distinguishing if the SAV is related to cancer or not. The five-fold cross-validation performance of our system is 89.73% for the accuracy, 0.74 for the Matthews correlation coefficient, and 0.81 for the F1 score. We have built an online prediction server, CanSavPre (http://bioinfo.cmu.edu.tw/CanSavPre/), which is expected to become a useful, practical tool for cancer research and precision medicine.

Paradoxical clade- and age-specific vaccine effectiveness during the 2018/19 influenza A(H3N2) epidemic in Canada: potential imprint-regulated effect of vaccine (I-REV)

Introduction The Canadian Sentinel Practitioner Surveillance Network reports vaccine effectiveness (VE) for the 2018/19 influenza A(H3N2) epidemic. Aim To explain a paradoxical signal of increased clade 3C.3a risk among 35–54-year-old vaccinees, we hypothesise childhood immunological imprinting and a cohort effect following the 1968 influenza A(H3N2) pandemic. Methods We assessed VE by test-negative design for influenza A(H3N2) overall and for co-circulating clades 3C.2a1b and 3C.3a. VE variation by age in 2018/19 was compared with amino acid variation in the haemagglutinin glycoprotein by year since 1968. Results Influenza A(H3N2) VE was 17% (95% CI: −13 to 39) overall: 27% (95% CI: −7 to 50) for 3C.2a1b and −32% (95% CI: −119 to 21) for 3C.3a. Among 20–64-year-olds, VE was −7% (95% CI: −56 to 26): 6% (95% CI: −49 to 41) for 3C.2a1b and −96% (95% CI: −277 to −2) for 3C.3a. Clade 3C.3a VE showed a pronounced negative dip among 35–54-year-olds in whom the odds of medically attended illness were > 4-fold increased for vaccinated vs unvaccinated participants (p < 0.005). This age group was primed in childhood to influenza A(H3N2) viruses that for two decades following the 1968 pandemic bore a serine at haemagglutinin position 159, in common with contemporary 3C.3a viruses but mismatched to 3C.2a vaccine strains instead bearing tyrosine. Discussion Imprinting by the first childhood influenza infection is known to confer long-lasting immunity focused toward priming epitopes. Our findings suggest vaccine mismatch may negatively interact with imprinted immunity. The immunological mechanisms for imprint-regulated effect of vaccine (I-REV) warrant investigation.