Objective Named entity recognition (NER) is one of the fundamental tasks in natural language processing. In the medical domain, there have been a numb

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineeredVHLgene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. TheVHLgene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL⁺) cells. Renal tumors with either VHL⁺or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL⁺cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL⁻) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

Alternative splicing (AS) represents a crucial method in mRNA level to regulate gene expression and contributes to the protein complexity. Abnormal splicing has been reported to play roles in several diseases, including cancers. We developed the OncoSplicing database for visualization of survival-associated and differential alternative splicing in 2019. Here, we provide an updated version of OncoSplicing for an integrative view of clinically relevant alternative splicing based on 122 423 AS events across 33 cancers in the TCGA SpliceSeq project and 238 558 AS events across 32 cancers in the TCGA SplAdder project. The new version of the database contains several useful features, such as annotation of alternative splicing-associated transcripts, survival analysis based on median and optimal cut-offs, differential analysis between TCGA tumour samples and adjacent normal samples or GTEx normal samples, pan-cancer views of alternative splicing, splicing differences and results of Cox’PH regression, identification of clinical indicator-relevant and cancer-specific splicing events, and downloadable splicing data in the SplAdder project. Overall, the substantially updated version of OncoSplicing (www.oncosplicing.com) is a user-friendly and registration-free database for browsing and searching clinically relevant alternative splicing in human cancers.

Kidney stone disease (KSD) is one of the earliest medical diseases known, but the mechanism of its formation and metabolic changes remain unclear. The formation of kidney stones is a extensive and complicated process, which is regulated by metabolic changes in various substances. In this manuscript, we summarized the progress of research on metabolic changes in kidney stone disease and discuss the valuable role of some new potential targets. We reviewed the influence of metabolism of some common substances on stone formation, such as the regulation of oxalate, the release of reactive oxygen species (ROS), macrophage polarization, the levels of hormones, and the alternation of other substances. New insights into changes in substance metabolism changes in kidney stone disease, as well as emerging research techniques, will provide new directions in the treatment of stones. Reviewing the great progress that has been made in this field will help to improve the understanding by urologists, nephrologists, and health care providers of the metabolic changes in kidney stone disease, and contribute to explore new metabolic targets for clinical therapy.