The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

Abstract: Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

Abstract: Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations

In silico-guided sequence modifications of K-ras epitopes improve immunological outcome against G12V and G13D mutant KRAS antigens

Background: Somatic point substitution mutations in the KRAS proto-oncogene primarily affect codons 12/13 where glycine is converted into other amino acids, and are highly prevalent in pancreatic, colorectal, and non-small cell lung cancers. These cohorts are non-responsive to anti-EGFR treatments, and are left with non-specific chemotherapy regimens as their sole treatment options. In the past, the development of peptide vaccines for cancer treatment was reported to have poor AT properties when inducing immune responses. Utilization of bioinformatics tools have since become an interesting approach in improving the design of peptide vaccines based on T- and B-cell epitope predictions. Methods: In this study, the region spanning exon 2 from the 4th to 18th codon within the peptide sequence of wtKRAS was chosen for sequence manipulation. Mutated G12V and G13D K-ras controls were generated in silico, along with additional single amino acid substitutions flanking the original codon 12/13 mutations. IEDB was used for assessing human and mouse MHC class I/II epitope predictions, as well as linear B-cell epitopes predictions, while RNA secondary structure prediction was performed via CENTROIDFOLD. A scoring and ranking system was established in order to shortlist top mimotopes whereby normalized and reducing weighted scores were assigned to peptide sequences based on seven immunological parameters. Among the top 20 ranked peptide sequences, peptides of three mimotopes were synthesized and subjected to in vitro and in vivo immunoassays. Mice PBMCs were treated in vitro and subjected to cytokine assessment using CBA assay. Thereafter, mice were immunized and sera were subjected to IgG-based ELISA. Results: In silico immunogenicity prediction using IEDB tools shortlisted one G12V mimotope (68-V) and two G13D mimotopes (164-D, 224-D) from a total of 1,680 candidates. Shortlisted mimotopes were predicted to promote high MHC-II and -I affinities with optimized B-cell epitopes. CBA assay indicated that: 224-D induced secretions of IL-4, IL-5, IL-10, IL-12p70, and IL-21; 164-D triggered IL-10 and TNF-α; while 68-V showed no immunological responses. Specific-IgG sera titers against mutated K-ras antigens from 164-D immunized Balb/c mice were also elevated post first and second boosters compared to wild-type and G12/G13 controls. Discussion: In silico-guided predictions of mutated K-ras T- and B-cell epitopes were successful in identifying two immunogens with high predictive scores, Th-bias cytokine induction and IgG-specific stimulation. Developments of such immunogens are potentially useful for future immunotherapeutic and diagnostic applications against KRAS(+) malignancies, monoclonal antibody production, and various other research and development initiatives

Vibroacoustic behavior and noise control of flax fiber-reinforced polypropylene composites

10.1080/15440478.2018.1433096Journal of Natural Fibers165729-74

Shock wave impact behavior of flax fiber reinforced polymer composites

AbstractNatural fibre based composites are garnering attention owing to their optimal trade-off between mechanical properties and environmental sustainability properties. It has been proposed that they could potentially replace synthetic and mineral fibre composites due to their minimized impact on human health and the natural environment. Though several studies have been dedicated to understanding certain mechanical properties like strength and fatigue life, fewer reported studies have focused on their response to impact or shock loads. In the present work, we have performed shock tests using a shock tube on flax/epoxy and flax/polypropylene unidirectional and cross-ply laminated composites. The objectives are, to compare the blast-resistance of polypropylene against epoxy in their use as matrix in flax–reinforced composites, and, secondly to assess the performance of cross-ply over unidirectional fiber orientation. The present results showed that the cross-ply samples retained their structural integrity at peak pressures that were sufficient to break unidirectional samples, indicating that cross-ply samples are superior candidates for applications where shock loading needs to be factored in. Furthermore, we also qualitatively assessed the failure modes predominant in each of the studied orientations

Highly Biodegradable and Tough Polylactic Acid–Cellulose Nanocrystal Composite

Poly­(l-lactide) cellulose nanocrystals-filled nanocomposites were fabricated by blending of cellulose nanocrystals-<i>g</i>-rubber-<i>g</i>-poly­(d-lactide) (CNC-rD-PDLA) and commercial PLLA, in which CNC-<i>g</i>-rubber was synthesized by ring opening polymerization (ROP) of d-lactide and a ε-caprolactone mixture to obtain CNC-P­(CL-DLA), followed by further polymerization of d-lactide to obtain CNC-rD-PDLA. X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and solubility tests confirmed successful grafting of the rubber segment and the PDLA segment onto CNC. Stereocomplexation between CNC-rD-PDLA nanofillers and PLLA matrix was confirmed by FT-IR, XRD, and differential scanning calorimetry (DSC) characterization. The PLLA/CNC-rD-PDLA nanocomposites exhibited greatly improved tensile toughness. With 2.5% CNC-rD-PDLA loading, strain at break of PLLA/CNC-rD-PDLA was increased 20-fold, and the composite shows potential to replace poly­(ethylene terephthalate). SEM and small-angle X-ray scattering (SAXS) investigations revealed that fibrillation and crazing during deformation of PLLA/CNC-rD-PDLA nanocomposites were the major toughening mechanisms in this system. The highly biodegradable and tough cellulose nanocrystals-filled PLLA nanocomposites could tremendously widen the range of industrial applications of PLA

A Community-enabled Readiness for first 1000 Days Learning Ecosystem (CRADLE) for first-time families: study protocol of a three-arm randomised controlled trial

10.1186/s13063-021-05144-5Trials22119

TP53 somatic mutations in Asian breast cancer are associated with subtype-specific effects

Abstract Background Recent genomics studies of breast cancer in Asian cohorts have found a higher prevalence of TP53 mutations in Asian breast cancer patients relative to Caucasian patients. However, the effect of TP53 mutations on Asian breast tumours has not been comprehensively studied. Methods Here, we report an analysis of 492 breast cancer samples from the Malaysian Breast Cancer cohort where we examined the impact of TP53 somatic mutations in relation to PAM50 subtypes by comparing whole exome and transcriptome data from tumours with mutant and wild-type TP53. Results We found that the magnitude of impact of TP53 somatic mutations appears to vary between different subtypes. TP53 somatic mutations were associated with higher HR deficiency scores as well as greater upregulation of gene expression pathways in luminal A and luminal B tumours compared to the basal-like and Her2-enriched subtypes. The only pathways that were consistently dysregulated when comparing tumours with mutant and wild-type TP53 across different subtypes were the mTORC1 signalling and glycolysis pathways. Conclusion These results suggest that therapies that target TP53 or other downstream pathways may be more effective against luminal A and B tumours in the Asian population