SUMMARY To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

The molecular foundations of Hürthle cell carcinoma (HCC) are poorly understood. Here we describe a comprehensive genomic characterization of 56 primary HCC tumors that span the spectrum of tumor behavior. We elucidate the mutational profile and driver mutations and show that these tumors exhibit a wide range of recurrent mutations. Notably, we report a high number of disruptive mutations to both protein-coding and tRNA-encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole-chromosomal duplications of chromosomes 5 and 7 and widespread loss of heterozygosity arising from haploidization and copy-number-neutral uniparental disomy. We also identify fusion genes and disrupted signaling pathways that may drive disease pathogenesis.

We aim to investigate the mutation types of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Chinese Han children in eastern Fujian Province.A total of 904 Chinese Han neonates (male: 733 with positive G6PD deficiency and 28 with weakly positive deficiency; female: 73 with positive G6PD deficiency and 70 with weakly positive deficiency) received G6PD screening in our center from January 2014 to December 2016 were included in this study. Additionally, 904 age-matched normal Chinese Han individuals (male: 761; female: 143) were selected as control. Neonatal G6PD deficiency screening was performed through blood sample collection from the heels, using the commercial kits. Multicolor melting curve analysis (MMCA) method was used to determine the G6PD mutation type in the 904 cases. If it failed to detect mutations in the cases with abnormal enzyme activity, the polymerase chain reaction (PCR) and gene sequencing were used to determine the mutation sites. PCR and gene sequencing were used to determine the mutation sites in the 904 individuals with normal enzyme activity. Three most common mutation types in Chinese population were compared between Fujian and other provinces.Among the 904 neonates with abnormal G6PD enzyme activity, 17 mutation types were detected including 15 single point mutations and 7 complex mutations. Three most common mutation types were c.1376G > T, c.1388G > A, and c.95A > G accounted for 72.6% of the total mutations in eastern Fujian.The proportion of mutational types in G6PD and the degree of enzyme activity change in various mutational types were found in the neonates of Fujian Province. Our study may enrich the molecular diagnosis of G6PD deficiency meaning Fujian Province.

BackgroundClear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer type with a high mortality rate. Due to a diverse range of biochemical alterations and a high level of tumor heterogeneity, it is crucial to select highly validated prognostic biomarkers to be able to identify subtypes of ccRCC early and apply precision medicine approaches.MethodsTranscriptome data of ccRCC and clinical traits of patients were obtained from the GSE126964 dataset of Gene Expression Omnibus and The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database. Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening were applied to detect common differentially co-expressed genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, survival analysis, prognostic model establishment, and gene set enrichment analysis were also performed. Immunohistochemical analysis results of the expression levels of prognostic genes were obtained from The Human Protein Atlas. Single-gene RNA sequencing data were obtained from the GSE131685 and GSE171306 datasets.ResultsIn the present study, a total of 2,492 DEGs identified between ccRCC and healthy controls were filtered, revealing 1,300 upregulated genes and 1,192 downregulated genes. Using WGCNA, the turquoise module was identified to be closely associated with ccRCC. Hub genes were identified using the maximal clique centrality algorithm. After having intersected the hub genes and the DEGs in GSE126964 and TCGA-KIRC dataset, and after performing univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, ALDOB, EFHD1, and ESRRG were identified as significant prognostic factors in patients diagnosed with ccRCC. Single-gene RNA sequencing analysis revealed the expression profile of ALDOB, EFHD1, and ESRRG in different cell types of ccRCC.ConclusionsThe present results demonstrated that ALDOB, EFHD1, and ESRRG may act as potential targets for medical therapy and could serve as diagnostic biomarkers for ccRCC.

Proteostasis declines with age, characterized by the accumulation of unfolded or damaged proteins. Recent studies suggest that proteins constituting pathological inclusions in neurodegenerative diseases also enter and accumulate in mitochondria. How unfolded proteins are managed within mitochondria remains unclear. Here, we found that excessive unfolded proteins in the mitochondrial matrix of yeast cells are consolidated into solid-phase inclusions, which we term deposits of unfolded mitochondrial proteins (DUMP). Formation of DUMP occurs in mitochondria near endoplasmic reticulum–mitochondria contact sites and is regulated by mitochondrial proteins controlling the production of cytidine 5′-diphosphate–diacylglycerol. DUMP formation is age dependent but accelerated by exogenous unfolded proteins. Many enzymes of the tricarboxylic acid cycle were enriched in DUMP. During yeast cell division, DUMP formation is necessary for asymmetric inheritance of damaged mitochondrial proteins between mother and daughter cells. We provide evidence that DUMP-like structures may be induced by excessive unfolded proteins in human cells.

Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs. Emerging findings from laboratory studies indicate that SGLT2 inhibitors can improve liver function and suppress the proliferation of hepatocellular carcinoma (HCC) cells. The aim of this study was to test the hypothesis that initiation of SGLT2 inhibitors improves HCC prognosis in a human population. Methods We used National Surveillance, Epidemiology and End Results (SEER)—Medicare linked data in the United States to evaluate the role of SGLT2 inhibitor initiation on the survival of HCC patients. 3,185 HCC patients newly diagnosed between 2014 and 2017 aged 66 years or older with pre-existing type 2 diabetes were included and followed to the end of 2019. Information on SGLT2 inhibitor initiation was extracted from the Medicare Part D file. Results SGLT2 inhibitor initiation was associated with significantly lower mortality risk after adjusting for potential confounders (HR = 0.68, 95% CI = 0.54–0.86) with stronger association for longer duration of use (HR = 0.60, 95% CI = 0.41–0.88). Further, we found that SGLT2 inhibitor initiation was associated with a lower risk mortality risk ranging from 14% to 60% regardless of patient demographic variables, tumor characteristics, and cancer treatments. Conclusion Our large SEER-Medicare linked data study indicates that SGLT2 inhibitor initiation was associated with improved overall survival of HCC patients with pre-existing type 2 diabetes compared with no SGLT2 inhibitor use. Further studies are needed to confirm our findings and elucidate the possible mechanisms behind the association.

These results suggest that radiotherapy offers a noninvasive approach in controlling adrenal metastasis from HCC with promising local control and acceptable tolerability.

Keratoconus (KTCN), characterized by the steeper curvature of the cornea and the thinner central corneal thickness, was a degenerative corneal ectasia with ambiguous etiology and mechanism. We aim to reveal underlying pathological mechanisms of KTCN by multi-level transcriptomic, integrative omics analyses. We performed RNA-sequencing on corneal epithelial samples from seven patients and seven control donors, as well as peripheral matched blood samples from three of the patients and three control donors. After RNA extraction, library construction, and sequencing, differentially expressed genes and splicing events were identified, followed by over-representation analysis. In total, 547 differential expressed genes were identified in KTCN corneal epithelial samples, which were mainly enriched in immune responses and inflammatory processes. WGCNA module analysis, the transcriptomic analysis of peripheral blood samples, multiple omics data, and the meta-analysis of GEO samples confirmed the involvement of immune and inflammatory factors. Besides, 190 and 1,163 aberrant splicing events were identified by rMATS combined with CASH methods in corneal epithelial and blood samples with KCTN. In conclusion, this comprehensive transcriptome analysis of KTCN patients based on patients’ tissue and blood samples uncovered a significant association between immune-inflammatory genes and pathways with KCTN, highlighting the contribution of the perturbed immune signaling to the pathogenesis of KCTN. Our study suggested the importance of measures to control inflammation in the treatment of KCTN.