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Pericentric heterochromatin serves as a fundamental component of eukaryotic chromosomes, endowing specialized genomic architecture with broad functional consequences. Although it is universally marked by H3K9me3 modification, the underlying pericentric DNA sequences diverge substantially across species. Here, by leveraging a transposition reporter system combined with a genome-wide RNA interference (RNAi) screen, we identified a specialized mechanism for recruiting SUV39H methyltransferase to initiate pericentric heterochromatin formation. This pathway depends on a highly ordered complex comprising the Puf68, pre-transfer RNAs (tRNAs), and the primer binding site (PBS). Puf68 binds with high affinity to poly-U tracts in pre-tRNA 3' trailer, forming a Puf68/pre-tRNA complex that subsequently base-pairs with the PBS of nascent long terminal repeat (LTR)-retrotransposons. Through direct interaction, Puf68 recruits Su(var)3-9 to these regions, catalyzing H3K9 trimethylation. Notably, Puf68 is sufficient to initiate de novo heterochromatin assembly both at pericentric and ectopically integrated LTR-retrotransposon regions. Our findings not only uncover a previously unrecognized mechanism of heterochromatin initiation but also resolve a long-standing question of how hosts harness nascent LTR-retrotransposon transcripts.
BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of sepsis. However, human genetic evidence linking mitochondria-related genes to sepsis susceptibility remains limited. This study aimed to identify mitochondria-related genes associated with sepsis risk using a multi-omics Mendelian randomization framework. METHODS: Summary-data-based Mendelian randomization (SMR) was applied using sepsis genome-wide association study (GWAS) summary statistics from the UK Biobank and FinnGen databases. Expression, methylation, single-cell, and protein quantitative trait loci (QTLs) were used as genetic instruments. Colocalization analyses were conducted to evaluate whether SMR associations were driven by shared genetic variants. Expression of prioritized candidate genes was further examined in clinical septic samples, and correlations with disease severity (SOFA scores) were assessed. RESULTS: SMR analysis prioritized 13 mitochondria-related genes associated with sepsis risk. Immune cell-specific eQTL analysis suggested that genetically predicted SURF1 expression in memory B cells and naïve T cells was associated with sepsis risk. Differential expression of 12 candidate genes was confirmed in septic patients by qPCR, and PPOX expression showed a negative correlation with SOFA scores. Integration of mQTL and eQTL data supported a regulatory relationship between methylation at cg06661924 and AK4 expression. Increased genetically predicted AK4 expression was associated with higher sepsis risk (OR = 1.21, 95% CI 1.02-1.42). Protein-level analysis identified DUT as a potential sepsis-associated candidate, with consistent evidence across streptococcal and pneumococcal septicemia subtypes. Subtype analyses also suggested heterogeneous genetic signals across different sepsis subtypes. CONCLUSION: This study prioritized several mitochondria-related genes associated with sepsis susceptibility based on human genetic evidence. These findings provide candidate targets for further mechanistic and translational investigation.
Nine-year-old brain tumor patient Gabriella Miller challenged members of Congress to "stop talking and start doing" when providing federal funding for research into cures for pediatric cancer and congenital anomalies. Though she ultimately lost her life to that cancer, her advocacy efforts resulted in the 2014 Gabriella Miller Kids First Research Act, launching the Gabriella Miller Kids First Pediatric Research Program at the National Institutes of Health (NIH). The overarching goal of the Gabriella Miller Kids First Pediatric Research Program is to help researchers uncover new insights into the biology of childhood cancer and congenital anomalies. Following the signing of the Gabriella Miller Kids First Research Act 2.0 in January 2025, the program has been extended at NIH through 2028 to advance the groundwork laid in the program's first ten years. The Gabriella Miller Kids First Data Resource Center has since honored her legacy by building a comprehensive data resource for genomic research into pediatric conditions. Data from more than 30,000 participants annotated with demographic and clinical information related to their diagnoses have been released for secondary research and analysis using the center's web-based platforms. This paper analyzes the outcomes of the initiative and highlights breakthroughs made by the larger research community resulting from the availability of this data resource. We explore the future expansion of the data resource to include new modalities and tools for supporting life-saving research for children like Gabriella Miller.
INTRODUCTION: Advances in cancer diagnostics raise questions about when and how to de-implement traditional approaches; however, these processes remain poorly described. At St. Jude Children's Research Hospital (SJCRH), routine conventional cytogenetics for pediatric acute lymphoblastic leukemia (ALL) diagnosis was de-implemented in 2018 following adoption of clinical genomics. This study aimed to map this process to inform future diagnostic de-implementation initiatives. METHODS: Interviews were conducted with SJCRH staff involved or impacted by cytogenetics de-implementation. Data were analyzed using thematic and rapid qualitative analysis informed by the Consolidated Framework for Implementation Research. Member-checking was used to verify and refine process maps, which were subsequently reviewed by an external expert panel, representing diverse settings, through focus group discussions. RESULTS: Thirteen SJCRH clinicians participated. De-implementation was described as successful, with no negative impact on patient outcomes. Decision-making began with internal correlation studies that demonstrated superior diagnostic performance of clinical genomics. De-implementation was viewed as a natural evolution that improved molecular classification, resource allocation, and workflow efficiency. Perceived risks included loss of cytogenetics competency, delayed turnaround time, and career insecurity, all addressed institutionally. Lessons learned highlighted the importance of deliberate discussion about logic and evidence supporting de-implementation. Fifteen external experts offered suggestions to improve process map generalizability, highlighting institutional- and system-level considerations. CONCLUSION: De-implementation of cytogenetics in ALL in favor of clinical genomics was successful at SJCRH. This study offers an example of diagnostic de-implementation in cancer care and proposes a structured approach to guide future efforts. De-implementation should be considered alongside introduction of novel diagnostic approaches.
Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD) and is closely associated with cellular senescence. Previous studies have demonstrated the efficacy of luteolin in treating aging-related symptoms. This study aims to elucidate the therapeutic potential of luteolin against CS-induced cellular senescence. Using a CS-exposed mouse model and cigarette smoke extract (CSE) treated mouse lung epithelial cells (TC-1), we demonstrate that luteolin significantly attenuates CS-induced histopathological alterations and inflammatory cytokine release while alleviating cellular senescence. Transcriptome sequencing suggests that NQO1 and Fos may serve as a common molecular target for both CS-induced pathology and luteolin treatment. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment analysis and pathway validation experiments revealed that the cAMP agonist Forskolin inhibits senescence marker expression by activating the CREB pathway, exhibiting a mechanism similar to that of luteolin. Notably, luteolin activation of this pathway may not depend on PKA activation. Ultimately, the study found that luteolin mitigates inflammatory responses and prevents lung epithelial cell senescence via the CREB/c-Fos/NQO1 pathway. These findings not only suggest the pivotal role of NQO1 in regulating CS-induced cellular senescence but also underscore the potential of luteolin as a therapeutic drug.
BACKGROUND: RecQ-like helicase (RECQL), a member of the RecQ-like DNA helicase family, plays a crucial role in maintaining genomic stability. However, its relevance in gastric cancer (GC) has not been fully investigated. This study aimed to explore the clinical significance, biological functions, and potential role of RECQL in the tumor immune microenvironment of GC through comprehensive bioinformatics analyses and in vitro experiments. METHODS: Weighted gene co-expression network analysis (WGCNA), differential expression analysis, and least absolute shrinkage and selection operator (LASSO) regression were performed using public datasets [The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD), GSE150290] to identify key genes associated with GC progression. Subsequently, key pathways were identified through functional enrichment analysis, while immune infiltration and spatial transcriptomic analyses were conducted to characterize RECQL expression and its association with the tumor immune microenvironment. Finally, the effects of RECQL knockdown on the biological function of GC cells were assessed through Cell Counting Kit-8 (CCK-8), colony formation, scratch, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: RECQL was significantly upregulated in GC tissues and correlated with advanced clinical stage and poor prognosis. Gene set enrichment analysis (GSEA) revealed a strong association between high RECQL expression and DNA repair pathway. Immune infiltration analysis indicated significant enrichment of M2 macrophages in the high-RECQL group, along with upregulation of immune checkpoint molecules including PDCD1, CTLA4, and CD274. Spatial transcriptomics further demonstrated co-localization of RECQL with myeloid cell-enriched regions in tumor parenchymal areas. Furthermore, in vitro experimental results indicated that RECQL was highly expressed in GC cell lines, and its knockdown effectively inhibited the viability, proliferation, and migration capabilities of HGC-27 cells, while enhancing their apoptosis. CONCLUSIONS: RECQL serves as a promising biomarker and potential therapeutic target in GC.
Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg = 0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX. These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively. Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus. We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.
Mesenchymal stem cells-derived exosomes (MSCs-Exo) constitute critical mediators of intercellular communication between stem cells and other cell types. Among these, exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs-Exo) have attracted considerable attention owing to their potent immunomodulatory capacity, low surface antigenicity, and favorable biosafety profile. Accumulating evidence indicates that HUMSCs-Exo can attenuate ferroptosis in target tissues across a spectrum of pathological conditions, including inflammatory bowel disease and viral cardiomyopathy, thereby mitigating tissue injury, improving organ function, and prolonging host survival. Nevertheless, the regulatory effects of HUMSCs-Exo on sepsis-associated liver injury (SALI) and hepatocellular ferroptosis, as well as the underlying molecular mechanisms, remain largely undefined. In this study, we identified pronounced differential gene expressions between control and septic mice hepatocytes, particularly within pathways related to iron metabolism, lipid metabolism, and ferroptosis. Building on these findings, we systematically characterized the dynamic progression of hepatocyte ferroptosis in septic mice through integrated in vivo and in vitro experiments, demonstrating a strong positive correlation between ferroptotic activity and the severity of liver injury. Using wild-type male C57BL/6J mice and the murine normal hepatocyte cell line NCTC1469, we further demonstrated that HUMSCs-Exo markedly upregulate the expression of FPN, xCT, GPX4, and FTH1 while concomitantly downregulating ACSL4 and TFRC. These molecular alterations reduced intracellular lipid peroxidation and labile iron accumulation, thereby robustly attenuating sepsis-induced hepatocyte ferroptosis and conferring significant hepatoprotective effects. Finally, these findings were validated in the immortalized human normal hepatocyte cell line THLE-2, in which HUMSCs-Exo similarly suppressed lipopolysaccharide-induced ferroptosis and cellular injury by modulating intracellular lipid peroxide and free iron levels. Collectively, our results demonstrate that HUMSCs-Exo exert potent inhibitory effects on sepsis-induced hepatocyte ferroptosis and confer protection against liver injury, primarily through the restoration of intracellular iron homeostasis and the suppression of lipid peroxidation. This study provides a novel therapeutic strategy for the treatment of SALI and ferroptosis.
BACKGROUND: This study aims to assess the efficacy and safety of a triplet adjuvant regimen consisting of tislelizumab, lenvatinib, and capecitabine following radical resection in patients with biliary tract cancer (BTC). METHODS: In this open-label, single-arm trial, patients with histologically confirmed BTC who had undergone curative resection were enrolled to receive adjuvant therapy within 4-16 weeks postoperatively. The treatment regimen consisted of tislelizumab (200 mg), lenvatinib (8 mg), and capecitabine (1250 mg/m2). The primary endpoint was the 1-year disease-free survival (DFS) rate. Secondary endpoints included median DFS, 2-year DFS rate, and 1- and 3-year overall survival (OS) rates, as well as safety profiles. Exploratory analyses were conducted to evaluate genomic alterations and prognostic biomarkers associated with clinical outcomes. RESULTS: Between February 24 and December 31, 2022, a total of 50 patients underwent treatment. As of the data cutoff (April 30, 2025), the median follow-up duration was 29.3 months (95% CI: 27.2-30.4). Intrahepatic cholangiocarcinoma constituted 78% of cases, with TNM stage III or IV observed in 40% of patients and poorly differentiated tumors identified in another 40%. The median DFS was calculated at 12.7 months (95% CI: 6.4-19.0), with DFS rates being reported as 55.5% (95% CI: 51.4%-57.6%) at 1 year and 30.8% (95% CI: 28.6%-32.9%) at 2 years, respectively. Median OS was not reached; however, the 1-year OS rate stood at an impressive figure of 93.8% (95% CI: 91.7%-95.9%) while the 3-year OS rate declined to 54.4% (95% CI: 50.0%-58.4%). By the exploratory analyses, FSIP2 mutation was associated shorter DFS (P < 0.001). Treatment-related grade 3 adverse events occurred in 20% of patients, with no treatment-related deaths or grade ≥ 4 toxicities reported. CONCLUSIONS: Adjuvant tislelizumab, lenvatinib, and capecitabine demonstrated clinical activity and tolerable safety in patients with resected BTC. Despite not meeting the primary endpoint, continued follow-up and further evaluation are warranted to better define the potential role of this combination regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05254847; registered prospectively on February 15, 2022.
PURPOSE: The purpose of the study was to design a pan-cancer gene panel for childhood malignancies and validate it using clinically characterized patient samples. EXPERIMENTAL DESIGN: In addition to 5,275 coding exons, SJPedPanel also covers 297 introns for fusions/structural variations and 7,590 polymorphic sites for copy-number alterations. Capture uniformity and limit of detection are determined by targeted sequencing of cell lines using dilution experiment. We validate its coverage by in silico analysis of an established real-time clinical genomics (RTCG) cohort of 253 patients. We further validate its performance by targeted resequencing of 113 patient samples from the RTCG cohort. We demonstrate its power in analyzing low tumor burden specimens using morphologic remission and monitoring samples. RESULTS: Among the 485 pathogenic variants reported in RTCG cohort, SJPedPanel covered 86% of variants, including 82% of 90 rearrangements responsible for fusion oncoproteins. In our targeted resequencing cohort, 91% of 389 pathogenic variants are detected. The gene panel enabled us to detect ∼95% of variants at allele fraction (AF) 0.5%, whereas the detection rate is ∼80% at AF 0.2%. The panel detected low-frequency driver alterations from morphologic leukemia remission samples and relapse-enriched alterations from monitoring samples, demonstrating its power for cancer monitoring and early detection. CONCLUSIONS: SJPedPanel enables the cost-effective detection of clinically relevant genetic alterations including rearrangements responsible for subtype-defining fusions by targeted sequencing of ∼0.15% of human genome for childhood malignancies. It will enhance the analysis of specimens with low tumor burdens for cancer monitoring and early detection.
BACKGROUND: Respiratory Syncytial Virus (RSV) disease in young children ranges from mild cold symptoms to severe symptoms that require hospitalization and sometimes result in death. Studies have shown a statistical association between RSV subtype or phylogenic lineage and RSV disease severity, although these results have been inconsistent. Associations between variation within RSV gene coding regions or residues and RSV disease severity has been largely unexplored. METHODS: Nasal swabs from children (< 8 months-old) infected with RSV in Rochester, NY between 1977-1998 clinically presenting with either mild or severe disease during their first cold-season were used. Whole-genome RSV sequences were obtained using overlapping PCR and next-generation sequencing. Both whole-genome phylogenetic and non-phylogenetic statistical approaches were performed to associate RSV genotype with disease severity. RESULTS: The RSVB subtype was statistically associated with disease severity. A significant association between phylogenetic clustering of mild/severe traits and disease severity was also found. GA1 clade sequences were associated with severe disease while GB1 was significantly associated with mild disease. Both G and M2-2 gene variation was significantly associated with disease severity. We identified 16 residues in the G gene and 3 in the M2-2 RSV gene associated with disease severity. CONCLUSION: These results suggest that phylogenetic lineage and the genetic variability in G or M2-2 genes of RSV may contribute to disease severity in young children undergoing their first infection.
Various biological agents have been developed to target tumor necrosis factor alpha (TNF-α) and its receptor TNFR1 for the rheumatoid arthritis (RA) treatment, whereas small molecules modulating such cytokine receptors are rarely reported in comparison to the biologicals. Here, by revealing the mechanism of action of vinigrol, a diterpenoid natural product, we show that inhibition of the protein disulfide isomerase (PDI, PDIA1) by small molecules activates A disintegrin and metalloprotease 17 (ADAM17) and then leads to the TNFR1 shedding on mouse and human cell membranes. This small-molecule-induced receptor shedding not only effectively blocks the inflammatory response caused by TNF-α in cells, but also reduces the arthritic score and joint damage in the collagen-induced arthritis mouse model. Our study indicates that targeting the PDI-ADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a promising strategy for alleviating RA.