Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

CRISPR-based targeted haplotype-resolved assembly of a megabase region.

Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved assembly of the targeted genomic region with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assembly, our targeted approach achieved comparable completeness and accuracy with reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal MHC haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses of the MHC region. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.

Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis.

BACKGROUND: Thoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation landscape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis. RESULTS: Ascending aortic tissues from TAD patients (Stanford type A; n = 6) and healthy controls (n = 6) were first examined via whole-genome bisulfite sequencing (WGBS). While no obvious global methylation shift was observed, numerous differentially methylated regions (DMRs) were identified, with associated genes enriched in the areas of vasculature and heart development. We further confirmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfite pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were significantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n = 7) and healthy controls (n = 4) were examined by WGBS. A prediction model was built using DMRs identified previously from aortic tissues on methylation data from cfDNA. Both high sensitivity (86%) and specificity (75%) were achieved in patient classification (AUC = 0.96). CONCLUSIONS: These findings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regulation and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specific, which can be used as a non-invasive biomarker for disease prediction.

DNA methylation in human diseases.

Even though the importance of epigenetics was first recognized in light of its role in tissue development, an increasing amount of evidence has shown that it also plays an important role in the development and progression of many common diseases. We discuss some recent findings on one representative epigenetic modification, DNA methylation, in some common diseases. While many new risk factors have been identified through the population-based epigenetic epidemiologic studies on the role of epigenetics in common diseases, this relatively new field still faces many unique challenges. Here, we describe those promises and unique challenges of epigenetic epidemiological studies and propose some potential solutions.

Generalized Two-Temperature Model for Coupled Phonons in Nanosized Graphene.

The design of graphene-based composite with high thermal conductivity requires a comprehensive understanding of phonon coupling in nanosized graphene. We extended the two-temperature model to coupled groups of phonons. The study give new physical quantities, the phonon-phonon coupling factor and length, to characterize the couplings quantitatively. Besides, our proposed coupling length has an obvious dependence on system size. Our studies can not only observe the nonequilibrium between different groups of phonons but explain theoretically the thermal resistance inside nanosized graphene.

A Revisit to High Thermoelectric Performance of Single-layer MoS2.

Both electron and phonon transport properties of single layer MoS2 (SLMoS2) are studied. Based on first-principles calculations, the electrical conductivity of SLMoS2 is calculated by Boltzmann equations. The thermal conductivity of SLMoS2 is calculated to be as high as 116.8 Wm(-1) K(-1) by equilibrium molecular dynamics simulations. The predicted value of ZT is as high as 0.11 at 500 K. As the thermal conductivity could be reduced largely by phonon engineering, there should be a high possibility to enhance ZT in the SLMoS2-based materials.

Nutrients and contaminants in tissues of five fish species obtained from Shanghai markets: Risk-benefit evaluation from human health perspectives.

Shanghai is a Chinese megacity in the Yangtze River Delta area, one of the most polluted coastal areas in China. The inhabitants of Shanghai have very high aquatic product consumption rates. A risk-benefit assessment of the co-ingestion of fish nutrients and contaminants has not previously been performed for Shanghai residents. Samples of five farmed fish species (marine and freshwater) with different feeding habits were collected from Shanghai markets in winter and summer. Fatty acids, protein, mercury, cadmium, lead, copper, polychlorinated biphenyls, hexachlorocyclohexanes, and dichlorodiphenyltrichloroethanes were measured in liver, abdominal fat, and dorsal, abdominal, and tail muscles from fish. Tolerable daily intakes and benefit-risk quotients were calculated to allow the benefits and risks of co-ingesting n-3 long-chain polyunsaturated fatty acids and contaminants to be assessed according to the cancer slope factors and reference doses of selected pollutants. All of the contaminant concentrations in the muscle tissues were much lower than the national maximum limits, but the livers generally contained high Hg concentrations, exceeding the regulatory limit. The organic pollutant and n-3 long-chain polyunsaturated fatty acid concentrations correlated with the lipid contents of the fish tissues, and were higher in carnivorous marine fish than in omnivorous and herbivorous freshwater fish. The tolerable daily intakes, risk-benefit quotients, and current daily aquatic product intakes for residents of large Chinese cities indicated that the muscle tissues of most of the fish analyzed can be consumed regularly without significant contaminant-related risks to health. However, attention should be paid to the potential risks posed by dichlorodiphenyltrichloroethane in large yellow croaker and Hg in tilapia. Based on the results of this study, we encourage people to consume equal portions of marine and freshwater fish.