Browsing by Author "Luo, Yuan"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells
    (American Association for the Advancement of Science, 2025) Eduardo, Mariana Bustamante; Cottone, Gannon; McCloskey, Curtis W.; Liu, Shiyu; Palma, Flavio R.; Zappia, Maria Paula; Islam, Abul B. M. M. K.; Gao, Peng; Setya, Joel; Dennis, Saya; Gao, Hongyu; Zhang, Qian; Xuei, Xiaoling; Luo, Yuan; Locasale, Jason; Bonini, Marcelo G.; Khokha, Rama; Frolov, Maxim V.; Benevolenskaya, Elizaveta V.; Chandel, Navdeep S.; Khan, Seema A.; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.
  • Thumbnail Image
    Item
    Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock
    (Wolters Kluwer, 2023) Sanchez-Pinto, L. Nelson; Bennett, Tellen D.; Stroup, Emily K.; Luo, Yuan; Atreya, Mihir; Bubeck Wardenburg, Juliane; Chong, Grace; Geva, Alon; Faustino, E. Vincent S.; Farris, Reid W.; Hall, Mark W.; Rogerson, Colin; Shah, Sareen S.; Weiss, Scott L.; Khemani, Robinder G.; Pediatrics, School of Medicine
    Objectives: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies. Design: Multicenter observational cohort study. Setting: Thirteen PICUs in the United States. Patients: Patients admitted with suspected infections to the PICU between 2012 and 2018. Interventions: None. Measurements and main results: We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS. Conclusions: We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.
  • Thumbnail Image
    Item
    External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock
    (Research Square, 2023-08-02) Atreya, Mihir R.; Bennett, Tellen D.; Geva, Alon; Faustino, E. Vincent S.; Rogerson, Colin M.; Lutfi, Riad; Cvijanovich, Natalie Z.; Bigham, Michael T.; Nowak, Jeffrey; Schwarz, Adam J.; Baines, Torrey; Haileselassie, Bereketeab; Thomas, Neal J.; Luo, Yuan; Sanchez-Pinto, L. Nelson; Novel Data-Driven Sepsis Phenotypes in Children Study and the Genomics of Pediatric Septic Shock Investigators; Pediatrics, School of Medicine
    Objective: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. Data-driven phenotyping approaches that leverage electronic health record (EHR) data hold promise given the widespread availability of EHRs. We sought to externally validate the data-driven 'persistent hypoxemia, encephalopathy, and shock' (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk-strata. Design: We trained and validated a random forest classifier using organ dysfunction subscores in the EHR dataset used to derive the PHES phenotype. We used the classifier to assign phenotype membership in a test set consisting of prospectively enrolled pediatric septic shock patients. We compared biomarker profiles of those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk-strata. Setting: 25 pediatric intensive care units (PICU) across the U.S. Patients: EHR data from 15,246 critically ill patients sepsis-associated MODS and 1,270 pediatric septic shock patients in the test cohort of whom 615 had biomarker data. Interventions: None. Measurements and main results: The area under the receiver operator characteristic curve (AUROC) of the new classifier to predict PHES phenotype membership was 0.91(95%CI, 0.90-0.92) in the EHR validation set. In the test set, patients with the PHES phenotype were independently associated with both increased odds of complicated course (adjusted odds ratio [aOR] of 4.1, 95%CI: 3.2-5.4) and 28-day mortality (aOR of 4.8, 95%CI: 3.11-7.25) after controlling for age, severity of illness, and immuno-compromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and overlapped with high risk-strata based on PERSEVERE biomarkers predictive of death and persistent MODS. Conclusions: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlap with higher risk-strata based on validated biomarker approaches.
  • Thumbnail Image
    Item
    Somatic genetic aberrations in benign breast disease and the risk of subsequent breast cancer
    (Nature, 2020-06-12) Zeng, Zexian; Vo, Andy; Li, Xiaoyu; Shidfar, Ali; Saldana, Paulette; Blanco, Luis; Xuei, Xiaoling; Luo, Yuan; Khan, Seema A.; Clare, Susan E.; Medical and Molecular Genetics, School of Medicine
    It is largely unknown how the development of breast cancer (BC) is transduced by somatic genetic alterations in the benign breast. Since benign breast disease is an established risk factor for BC, we established a case-control study of women with a history of benign breast biopsy (BBB). Cases developed BC at least one year after BBB and controls did not develop BC over an average of 17 years following BBB. 135 cases were matched to 69 controls by age and type of benign change: non-proliferative or proliferation without atypia (PDWA). Whole-exome sequencing (WES) was performed for the BBB. Germline DNA (available from n = 26 participants) was utilized to develop a mutation-calling pipeline, to allow differentiation of somatic from germline variants. Among the 204 subjects, two known mutational signatures were identified, along with a currently uncatalogued signature that was significantly associated with triple negative BC (TNBC) (p = 0.007). The uncatalogued mutational signature was validated in 109 TNBCs from TCGA (p = 0.001). Compared to non-proliferative samples, PDWA harbors more abundant mutations at PIK3CA pH1047R (p < 0.001). Among the 26 BBB whose somatic copy number variation could be assessed, deletion of MLH3 is significantly associated with the mismatch repair mutational signature (p < 0.001). Matched BBB-cancer pairs were available for ten cases; several mutations were shared between BBB and cancers. This initial study of WES of BBB shows its potential for the identification of genetic alterations that portend breast oncogenesis. In future larger studies, robust personalized breast cancer risk indicators leading to novel interception paradigms can be assessed.