Mixing Histopathology Prototypes into Robust Slide-Level Representations for Cancer Subtyping

Whole-slide image analysis via the means of computational pathology often relies on processing tessellated gigapixel images with only slide-level labels available. Applying multiple instance learning-based methods or transformer models is computationally expensive as, for each image, all instances have to be processed simultaneously. The MLP-Mixer is an under-explored alternative model to common vision transformers, especially for large-scale datasets. Due to the lack of a self-attention mechanism, they have linear computational complexity to the number of input patches but achieve comparable performance on natural image datasets. We propose a combination of feature embedding and clustering to preprocess the full whole-slide image into a reduced prototype representation which can then serve as input to a suitable MLP-Mixer architecture. Our experiments on two public benchmarks and one inhouse malignant lymphoma dataset show comparable performance to current state-of-the-art methods, while achieving lower training costs in terms of computational time and memory load. Code is publicly available at https://github.com/butkej/ProtoMixer.Comment: The final authenticated publication is available online at https://doi.org/10.1007/978-3-031-45676-3_1

A Biomechanical Approach to Investigate the Applicability of the Lake-Thomas Theory in Porcine Aorta

Robot-assisted surgeries are procedures where a physician performs surgical maneuvers by operating a robot. One of the main limitations is the difficulty in transferring the surgeon’s multiple skills onto the robotic system. Such skills include the ability to estimate the maximum applicable force before damaging the tissue. To implement this skill onto a robotic system, a mathematical model for tissue damage must be developed. The objective of this study is to measure the fracture characteristic in porcine aorta, to then investigate whether an existing fracture model can be applied onto biological tissues. Due to the similarity in the mechanical response between biological tissues and polymeric materials, the model chosen for this study was the Lake-Thomas model. This is the first paper with the aim of validating this model with biological tissues. Two main findings are reported in this investigation. We found that porcine thoracic aorta tears in a specific way which is directly correlated to the tensile direction. The second finding is that an anisotropic linear relationship exists between the critical tearing energy and the elastic modulus, and the elastic modulus to the -0.5th power. These results are discussed based on the elastin and collagen fibers, as well as established mathematical equations describing polymer mechanic

Identification of four genes as novel susceptibility loci for early‑onset type 2 diabetes mellitus, metabolic syndrome, or hyperuricemia

Given that early‑onset type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and hyperuricemia have been shown to have strong genetic components, the statistical power of a genetic association study may be increased by focusing on early‑onset subjects with these conditions. Although genome‑wide association studies have identified various genes and loci significantly associated with T2DM, MetS, and hyperuricemia, genetic variants that contribute to predisposition to these conditions in Japanese subjects remain to be identified definitively. We performed exome‑wide association studies (EWASs) for early‑onset T2DM, MetS, or hyperuricemia to identify genetic variants that confer susceptibility to these conditions. A total of 8,102 individuals aged ≤65 years were enrolled in the present study. The EWAS for T2DM was performed with 7,407 subjects (1,696 cases, 5,711 controls), that for MetS with 4,215 subjects (2,296 cases, 1,919 controls), and that for hyperuricemia with 7,919 subjects (1,365 cases, 6,554 controls). Single nucleotide polymorphisms (SNPs) were genotyped with Illumina Human Exome‑12 DNA Analysis BeadChip or Infinium Exome‑24 BeadChip arrays. The relationship of allele frequencies for 31,210, 31,521, or 31,142 SNPs that passed quality control for T2DM, MetS, or hyperuricemia, respectively, was examined with Fisher\u27s exact test. To compensate for multiple comparisons of genotypes with T2DM, MetS, or hyperuricemia, we applied Bonferroni\u27s correction for statistical significance of association. The EWAS of allele frequencies revealed that four, six, or nine SNPs were significantly associated with T2DM (P<1.60x10‑6), MetS (P<1.59x10‑6), or hyperuricemia (P<1.61x10‑6), respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that three, six, or nine SNPs were significantly related to T2DM (P<0.0031), MetS (P<0.0021), or hyperuricemia (P<0.0014). After examination of the association of identified SNPs to T2DM‑, MetS‑, or hyperuricemia‑related traits, linkage disequilibrium of the SNPs, and results of previous genome‑wide association studies, newly identified ZNF860 and OR4F6 were the susceptibility loci for T2DM, OR52E4 and OR4F6 for MetS, and HERPUD2 for hyperuricemia. Given that OR4F6 was significantly associated with both T2DM and MetS, we newly identified four genes (ZNF860, OR4F6, OR52E4, HERPUD2) that confer susceptibility to early‑onset T2DM, MetS, or hyperuricemia. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for T2DM, MetS, or hyperuricemia

Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study

DNA methylation is an important epigenetic modification that has been implicated in the pathogenesis of atherosclerosis. Although previous studies have identified various CpG sites and genes whose methylation is associated with atherosclerosis in populations with European or Mexican ancestry, the genome‑wide pattern of DNA methylation in the atherosclerotic human aorta is yet to be elucidated in Japanese individuals. In the present study, a genome‑wide analysis of DNA methylation at ~853,000 CpG sites was performed using 128 postmortem aortic intima specimens obtained from 64 Japanese patients. To avoid the effects of interindividual variation, intraindividual paired comparisons were performed between atheromatous plaque lesions and corresponding plaque‑free tissue for each patient. Bisulfite‑modified genomic DNA was analyzed using a specific microarray for DNA methylation. DNA methylation at each CpG site was calculated as the β value, where β = (intensity of the methylated allele)/(intensity of the methylated allele + intensity of the unmethylated allele + 100). Bonferroni\u27s correction for statistical significance of association was applied to compensate for multiple comparisons. The methylation of 2,679 CpG sites differed significantly (P0.15 (plaque lesion‑plaque‑free intima) and 11 had a β ratio of >1.50 (plaque/plaque‑free intima). A further 15 and 17 hypomethylated CpG sites in atheromatous plaques were observed to have a difference in β value of <‑0.15 or a β ratio of <0.67, respectively. According to these limits, a total of 16 novel genes that were significantly hyper‑ or hypomethylated in atheromatous plaque lesions compared with the plaque‑free intima were identified in the present study. The results of the present study suggest that the methylation of these genes may contribute to the pathogenesis of atherosclerosis in the Japanese population