Pyroptotic-Spatiotemporally Selective Delivery of siRNA against Pyroptosis and Autoimmune Diseases.

Small-interfering RNAs (siRNAs) offer promising prospects for treating pyroptosis-related autoimmune diseases. However, poor stability and off-target effects during in vivo transportation hinder their practical clinical applications. Precision delivery and adaptive release of siRNAs into inflamed tissues and immune cells could unleash their full therapeutic potential. This study establishes a pyroptotic-spatiotemporally selective siRNA delivery system (PMRC@siGSDME) that selectively targets inflammatory tissues, responds to pyroptosis, and exhibits remarkable therapeutic efficacy against various autoimmune diseases. Novel hybrid nanovesicles (NVs) are designed as a combination of pyroptotic macrophage membranes (PMs) and R8-cardiolipin-containing nanovesicles (RC-NVs). Evidence provides that PM-derived proteins involved in cell-cell interactions and membrane trafficking may contribute to the specificity of NVs to inflammatory tissue. In addition, cardiolipin anchored in the hybrid NVs increases its affinity for activated gasdermin E (GSDME) and achieves pyroptosis-adaptive release of siGSDME for the spatiotemporally selective suppression of immune responses. More importantly, PMRC@siGSDME displays significant anti-inflammatory and therapeutic effects in multiple mouse autoimmune disease models, including arthritis and inflammatory bowel disease (IBD). Collectively, an innovative siRNA delivery strategy precisely tailored for pyroptotic cells has been developed, paving the way for new treatments for autoimmune inflammatory diseases with minimal side effects and wide clinical applicability.

Extend the benchmarking indel set by manual review using the individual cell line sequencing data from the Sequencing Quality Control 2 (SEQC2) project.

Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly enriched the known indel set by an additional 516 indels. The extended benchmarking indel set has a large range of variant allele frequencies (VAFs), with 87% of them having a VAF below 20% in reference Sample A. The reference Sample A and the indel set can be used for comprehensive benchmarking of indel calling across a wider range of VAF values in the lower range. Indel length was also variable, but the majority were under 10 base pairs (bps). Most of the indels were within coding regions, with the remainder in the gene regulatory regions. Although high confidence can be derived from the robust study design and meticulous human review, this extensive indel set has not undergone orthogonal validation. The extended benchmarking indel set, along with the indels in the previously published known-positive set, was the truth set used to benchmark indel calling pipelines in a community challenge hosted on the precisionFDA platform. This benchmarking indel set and reference samples can be utilized for a comprehensive evaluation of indel calling pipelines. Additionally, the insights and solutions obtained during the manual review process can aid in improving the performance of these pipelines.

Metagenomic association analysis of cognitive impairment in community-dwelling older adults.

The gut microbiota is reportedly involved in neurodegenerative disorders, and exploration of differences in the gut microbiota in different cognitive status could provide clues for early detection and intervention in cognitive impairment. Here, we used data from the Taizhou Imaging Study (N = 516), a community-based cohort, to compare the overall structure of the gut microbiota at the species level through metagenomic sequencing, and to explore associations with cognition. Interestingly, bacteria capable of producing short-chain fatty acids (SCFAs), such as Bacteroides massiliensis, Bifidobacterium pseudocatenulatum, Fusicatenibacter saccharivorans and Eggerthella lenta, that can biotransform polyphenols, were positively associated with better cognitive performance (p < 0.05). Although Diallister invisus and Streptococcus gordonii were not obviously related to cognition, the former was dominant in individuals with mild cognitive impairment (MCI), while the later was more abundant in cognitively normal (CN) than MCI groups, and positively associated with cognitive performance (p < 0.05). Functional analysis further supported a potential role of SCFAs and lactic acid in the association between the gut microbiota and cognition. The significant associations persisted after accounting for dietary patterns. Collectively, our results demonstrate an association between the gut microbiota and cognition in the general population, indicating a potential role in cognitive impairment. The findings provide clues for microbiome biomarkers of dementia, and insight for the prevention and treatment of dementia.

Molecular subtyping of esophageal squamous cell carcinoma by large-scale transcriptional profiling: Characterization, therapeutic targets, and prognostic value.

The tumor heterogeneity of the transcriptional profiles is independent of genetic variation. Several studies have successfully identified esophageal squamous cell carcinoma (ESCC) subtypes based on the somatic mutation profile and copy number variations on the genome. However, transcriptome-based classification is limited. In this study, we classified 141 patients with ESCC into three subtypes (Subtype 1, Subtype 2, and Subtype 3) via tumor sample gene expression profiling. Differential gene expression (DGE) analysis of paired tumor and normal samples for each subtype revealed significant difference among subtypes. Moreover, the degree of change in the expression levels of most genes gradually increased from Subtype 1 to Subtype 3. Gene set enrichment analysis (GSEA) identified the representative pathways in each subtype: Subtype 1, abnormal Wnt signaling pathway activation; Subtype 2, inhibition of glycogen metabolism; and Subtype 3, downregulation of neutrophil degranulation process. Weighted gene co-expression network analysis (WGCNA) was used to elucidate the finer regulation of biological pathways and discover hub genes. Subsequently, nine hub genes (CORO1A, CD180, SASH3, CD52, CD300A, CD14, DUSP1, KIF14, and MCM2) were validated to be associated with survival in ESCC based on the RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database. The clustering analysis of ESCC granted better understanding of the molecular characteristics of ESCC and led to the discover of new potential therapeutic targets that may contribute to the clinical treatment of ESCC.

Molecular features of pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor occurring mostly in children and young adults. Next-generation sequencing of 295 cancer-related genes was used to investigate the molecular profiles of 13 cases of PXA. We found that BRAF V600E (5/13; 38%), FANCA/D2/I/M (5/13; 38%), PRKDC (4/13; 31%), NF1 (3/13; 23%), and NOTCH2/3/4 (3/13; 23%) alterations were the most frequent somatic gene mutations. However, neither PTEN nor EGFR mutation, which is frequently present in glioblastoma, was detected. The KRAS mutation in PXA is reported for the first time in these tumors. Microsatellite stability was present in all cases. Because mutations of FANCA and BRAF and copy number variations of CDKN2A/B are more frequent in PXA than in glioblastoma, they might be used to distinguish the 2 tumors. The MAPK pathway is involved in the pathogenesis of PXA and may be an effective target for treatment.