GPEdit: the genetic and pharmacogenomic landscape of A-to-I RNA editing in cancers.

Altered A-to-I RNA editing has been widely observed in many human cancers and some editing sites are associated with drug sensitivity, implicating its therapeutic potential. Increasing evidence has demonstrated that a quantitative trait loci mapping approach is effective to understanding the genetic basis of RNA editing. We systematically performed RNA editing quantitative trait loci (edQTL) analysis in 33 human cancer types for >10 000 cancer samples and identified 320 029 edQTLs. We also identified 1688 ed-QTLs associated with patient overall survival and 4672 ed-QTLs associated with GWAS risk loci. Furthermore, we demonstrated the associations between RNA editing and >1000 anti-cancer drug response with ∼3.5 million significant associations. We developed GPEdit (https://hanlab.uth.edu/GPEdit/) to facilitate a global map of the genetic and pharmacogenomic landscape of RNA editing. GPEdit is a user-friendly and comprehensive database that provides an opportunity for a better understanding of the genetic impact and the effects on drug response of RNA editing in cancers.

Surgical Outcomes of Standardized Endoscopical Deep Medial Orbital Decompression in Dysthyroid Optic Neuropathy.

INTRODUCTION: The aim of the study was to standardize the endoscopic deep medial orbital decompression surgery for better relief of optic nerve compression in dysthyroid optic neuropathy (DON). METHODS: A total of 128 eyes from patients received the standardized endoscopic deep medial orbital decompression surgery were recruited in this study. The efficacy of the procedure was assessed at a 1-month follow-up by the best-corrected visual acuity (VA), visual field (VF), and visual evoked potential (VEP). Clinical data were collected to explore the factors that affected visual recovery. Oxygen saturation of retinal blood vessels, retinal thickness, and vessel density were measured to demonstrate the potential recovery mechanisms. RESULTS: After surgery, the ratio of extraocular muscle volume in the orbital apex to orbital apex volume significantly decreased from 44.32 ± 22.31% to 36.82 ± 12.02% (p < 0.001). 96.87% of eyes' final VA improved; average VA improved from 0.93 ± 0.73 to 0.50 ± 0.60 at 1 week (p < 0.001) and 0.40 ± 0.53 at 1 month (p < 0.001). Postoperatively, VF and VEP also improved, the oxygen saturation of retinal arteries increased, and the retinal thickness was reduced. Preoperative VA, visual impairment duration, and clinical activity score evaluation were associated with visual recovery. CONCLUSION: In this study, we standardized the endoscopic deep medial orbital decompression, of which key point was to relieve pressure in the orbital apex and achieved satisfactory visual recovery in DON patients.

A Multi-Omics Perspective of Quantitative Trait Loci in Precision Medicine.

Quantitative trait loci (QTL) analysis is an important approach to investigate the effects of genetic variants identified through an increasing number of large-scale, multidimensional 'omics data sets. In this 'big data' era, the research community has identified a significant number of molecular QTLs (molQTLs) and increased our understanding of their effects. Herein, we review multiple categories of molQTLs, including those associated with transcriptome, post-transcriptional regulation, epigenetics, proteomics, metabolomics, and the microbiome. We summarize approaches to identify molQTLs and to infer their causal effects. We further discuss the integrative analysis of molQTLs through a multi-omics perspective. Our review highlights future opportunities to better understand the functional significance of genetic variants and to utilize the discovery of molQTLs in precision medicine.

HeRA: an atlas of enhancer RNAs across human tissues.

Enhancer RNA (eRNA) is a type of long non-coding RNA transcribed from DNA enhancer regions. Despite critical roles of eRNA in gene regulation, the expression landscape of eRNAs in normal human tissue remains unexplored. Using numerous samples from the Genotype-Tissue Expression project, we characterized 45 411 detectable eRNAs and identified tens of thousands of associations between eRNAs and traits, including gender, race, and age. We constructed a co-expression network to identify millions of putative eRNA regulators and target genes across different tissues. We further constructed a user-friendly data portal, Human enhancer RNA Atlas (HeRA, https://hanlab.uth.edu/HeRA/). In HeRA, users can search, browse, and download the eRNA expression profile, trait-related eRNAs, and eRNA co-expression network by searching the eRNA ID, gene symbol, and genomic region in one or multiple tissues. HeRA is the first data portal to characterize eRNAs from 9577 samples across 54 human tissues and facilitates functional and mechanistic investigations of eRNAs.

APAatlas: decoding alternative polyadenylation across human tissues.

Alternative polyadenylation (APA) is an RNA-processing mechanism on the 3' terminus that generates distinct isoforms of mRNAs and/or other RNA polymerase II transcripts with different 3'UTR lengths. Widespread APA affects post-transcriptional gene regulation in mRNA translation, stability, and localization, and exhibits strong tissue specificity. However, no existing database provides comprehensive information about APA events in a large number of human normal tissues. Using the RNA-seq data from the Genotype-Tissue Expression project, we systematically identified APA events from 9475 samples across 53 human tissues and examined their associations with multiple traits and gene expression across tissues. We further developed APAatlas, a user-friendly database (https://hanlab.uth.edu/apa/) for searching, browsing and downloading related information. APAatlas will help the biomedical research community elucidate the functions and mechanisms of APA events in human tissues.

Visualizing Quantum Coherence Based on Single-Molecule Coherent Modulation Microscopy.

Massive magical phenomena in nature are closely related to quantum effects at the microscopic scale. However, the lack of straightforward methods to observe the quantum coherent dynamics in integrated biological systems limits the study of essential biological mechanisms. In this work, we developed a single-molecule coherent modulation (SMCM) microscopy by combining the superior features of single-molecule microscopy with ultrafast spectroscopy. By introducing the modem technology and defining the coherent visibility, we realized visualization and real-time observation of the decoherence process of a single molecule influenced by the microenvironment for the first time. In particular, we applied this technique to observe the quantum coherent properties of the entire chlorella cells and found the correlation between the coherent visibility and metabolic activities, which may have potential applications in molecular diagnostics and precision medicine.

One-step synthesis of N, S-doped carbon dots with orange emission and their application in tetracycline antibiotics, quercetin sensing, and cell imaging.

Water soluble N, S-doped carbon dots (N, S-CDs) with orange emission were synthesized from basic fuchsin and sulfosalicylic acid by the typical hydrothermal route. Based on the inner filter effect (IFE), the prepared N, S-CDs can be innovatively developed as an effective "signal-off" multifunctional sensing platform for sensitive determination of tetracycline antibiotics (for example, chlortetracycline (CTC)) and quercetin. The proposed sensor was utilized to realize the determination of CTC in water and milk samples and quercetin in beer sample (λex = 375 nm, λem = 605 nm) with satisfactory recoveries and relative standard deviations (RSD). The linear range and detection limit (LOD) of CTC is 1.24-165 µM and 32.36 nM, respectively. For quercetin, the linear ranges are 0.98-34 µM and 34-165 µΜ, and the LOD is 6.87 nM (3σ/m). By virtue of the good biocompatibility and long-wavelength emission, N, S-CDs were also used in the imaging of oocystis cells and yeast cells, which demonstrated promising applicability for bio-imaging and sensing. In this paper, N, S-doped carbon dots (N, S-CDs) with orange emission (λem = 605 nm) were synthesized from basic fuchsin and sulfosalicylic acid. Based on the inner filter effect (IFE), the prepared N, S-CDs can be innovatively developed as an effective "signal-off" multifunctional sensing platform for the sensing of tetracycline antibiotics (for example: chlortetracycline (CTC)) and quercetin. The sensor has been successfully applied to the determination of CTC in water and milk samples and quercetin in beer sample (λex = 375 nm, λem = 605 nm). The linear range and detection limit (LOD) of CTC is 1.24-165 µM and 32.36 nM respectively. For quercetin, the linear ranges are 0.98-34 µM and 34-165 µΜ, and the LOD is 6.87 nM (3σ/m). In addition, due to the characteristics of good biocompatibility and long-wavelength emission, the N, S-CDs were also used in the imaging of oocystis cells and yeast cells, which demonstrated promising applicability for bioimaging and sensing.

Defining the risk of liver failure after minor hepatectomy: a NSQIP analysis of 7029 patients.

BACKGROUND: Post-hepatectomy liver failure (PHLF) remains a significant complication after hepatic resection. This study aims to determine the rate of PHLF in patients undergoing resection of 3 or fewer segments and analyze the association of PHLF with perioperative characteristics and postoperative complications. METHODS: The American College of Surgeons hepatectomy-targeted National Surgical Quality Improvement Program database was queried for patients undergoing left hemi-hepatectomy or partial resection from 2014 to 2018. The primary outcome was PHLF, defined by ISGLS. Multivariable logistic regression models assessed the association between PHLF, preoperative and operative variables and postoperative complications. RESULTS: Among 7029 patients, 187 (2.7%) experienced PHLF, with clinically significant (grade B/C) PHLF in 1.4%. PHLF was associated with older age, male gender, higher ASA classification, ascites, and elevated SGOT. Preoperative ascites (OR 4.94, 95%CI: 2.45-9.94, p < 0.001) had the strongest association with PHLF. There was no association between PHLF and concurrent colorectal resection, neoadjuvant therapy, or concurrent ablation. Surgical site infection (OR 3.64, 95%CI: 2.40-5.54, p < 0.001), sepsis (OR 3.78, 95%CI: 2.16-6.61, p < 0.001), postoperative invasive procedure (OR 6.92, 95%CI: 4.91-9.76, p < 0.001), and bile leak (OR 4.65, 95%CI: 3.04-7.12, p < 0.001) were associated with PHLF. CONCLUSION: PHLF after minor hepatectomy is rare and associated with signs of preoperative liver dysfunction. The association with infectious complications suggests a multifactorial etiology and provides targets for quality improvement.

The genetic and pharmacogenomic landscape of snoRNAs in human cancer.

Emerging evidence has revealed significant roles for small nucleolar RNAs (snoRNAs) in tumorigenesis. However, the genetic and pharmacogenomic landscape of snoRNAs has not been characterized. Using the genotype and snoRNA expression data from The Cancer Genome Atlas, we characterized the effects of genetic variants on snoRNAs across 29 cancer types and further linked related alleles with patient survival as well as genome-wide association study risk loci. Furthermore, we characterized the impact of snoRNA expression on drug response in patients to facilitate the clinical utility of snoRNAs in cancer. We also developed a user-friendly data resource, GPSno (http://hanlab.uth.edu/GPSno), with multiple modules for researchers to visualize, browse, and download multi-dimensional data. Our study provides a comprehensive genetic and pharmacogenomic landscape of snoRNAs, which will shed light on future clinical considerations for the development of snoRNA-based targeted therapies.

Novel Anthraquinone Compounds Inhibit Colon Cancer Cell Proliferation via the Reactive Oxygen Species/JNK Pathway.

A series of amide anthraquinone derivatives, an important component of some traditional Chinese medicines, were structurally modified and the resulting antitumor activities were evaluated. The compounds showed potent anti-proliferative activities against eight human cancer cell lines, with no noticeable cytotoxicity towards normal cells. Among the candidate compounds, 1-nitro-2-acyl anthraquinone-leucine (8a) showed the greatest inhibition of HCT116 cell activity with an IC50 of 17.80 µg/mL. In addition, a correlation model was established in a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using Comparative Molecular Field Analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). Moreover, compound 8a effectively killed tumor cells by reactive oxygen species (ROS)-JNK activation, causing an increase in ROS levels, JNK phosphorylation, and mitochondrial stress. Cytochrome c was then released into cytoplasm, which, in turn activated the cysteine protease pathway and ultimately induced tumor cell apoptosis, suggesting a potential use of this compound for colon cancer treatment.

Landscape of microRNA in the aqueous humour of proliferative diabetic retinopathy as assessed by next-generation sequencing.

BACKGROUND: The microRNAs (miRNA) have been found to play an important role in the pathogenesis of diabetic retinopathy. We try to explore the miRNA and piwi-interacting RNA (piRNA) profile in the aqueous humour of proliferative diabetic retinopathy (PDR) using next-generation sequencing (NGS). METHODS: Aqueous humour samples were collected from nine PDR eyes and nine cataract control eyes, and NGS was performed. Quantitative polymerase chain reaction (qPCR) was used to validate the sequencing results. An oxygen-induced retinopathy (OIR) model was used to validate the angiogenesis related miRNA. RESULTS: In total, 484 miRNAs were differently expressed between the PDR eyes and cataract control eyes, including 210 mature miRNAs and 274 novel miRNAs. Furthermore, eight miRNAs and 30 piRNAs were identified as the most differently expressed between the two groups (P > .85). This differential expression of miRNA was predicted to regulate Rho protein signal transduction, neurotransmitter uptake and histone lysine methylation. Relative expression patterns of miR-184, -150-5p and -93-5p were confirmed by qPCR. A reduced expression of miR-93-5p was confirmed in the OIR model. CONCLUSIONS: This study comprehensively demonstrated the miRNA and piRNA expression profile of the aqueous humour of PDR eyes, which may serve as a potential biomarker and involved in the pathogenesis of PDR.

Defining the Intrinsic Cardiac Risks of Operations to Improve Preoperative Cardiac Risk Assessments.

BACKGROUND: Current preoperative cardiac risk stratification practices group operations into broad categories, which might inadequately consider the intrinsic cardiac risks of individual operations. We sought to define the intrinsic cardiac risks of individual operations and to demonstrate how grouping operations might lead to imprecise estimates of perioperative cardiac risk. METHODS: Elective operations (based on Common Procedural Terminology codes) performed from January 1, 2010 to December 31, 2015 at hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program were studied. A composite measure of perioperative adverse cardiac events was defined as either cardiac arrest requiring cardiopulmonary resuscitation or acute myocardial infarction. Operations' intrinsic cardiac risks were derived from mixed-effects models while controlling for patient mix. Resultant risks were sorted into low-, intermediate-, and high-risk categories, and the most commonly performed operations within each category were identified. Intrinsic operative risks were also examined using a representative grouping of operations to portray within-group variation. RESULTS: Sixty-six low, 30 intermediate, and 106 high intrinsic cardiac risk operations were identified. Excisional breast biopsy had the lowest intrinsic cardiac risk (overall rate, 0.01%; odds ratio, 0.11; 95% CI, 0.02 to 0.25) relative to the average, whereas aorto-bifemoral bypass grafting had the highest (overall rate, 4.1%; odds ratio, 6.61; 95% CI, 5.54 to 7.90). There was wide variation in the intrinsic cardiac risks of operations within the representative grouping (median odds ratio, 1.40; interquartile range, 0.88 to 2.17). CONCLUSIONS: A continuum of intrinsic cardiac risk exists among operations. Grouping operations into broad categories inadequately accounts for the intrinsic cardiac risk of individual operations.

Trends in perioperative outcomes of hospitals performing major cancer surgery.

BACKGROUND AND OBJECTIVES: Cancer surgery outcomes at National Cancer Institute-designated cancer centers (NCI-CCs) have been shown to vary, and have not been uniformly better than outcomes among non-NCI-CCs. We aimed to assess whether NCI-CCs have improved their short-term outcomes over time and whether variation across these centers has changed. METHODS: Patients who underwent colectomy, esophagectomy, hepatectomy, pancreatectomy, and proctectomy for cancer were identified from the 2010 to 2016 American College of Surgeons' National Surgical Quality Improvement Program registry. Hospital trends in risk-adjusted, smoothed observed-to-expected ratios were assessed to evaluate improvement and variation in perioperative complications, stratified by NCI-CC status. RESULTS: Complications occurred in 18.8% of 204 732 patients who underwent major cancer operations at 645 hospitals, and complications occurred in 19.9% of 60,903 patients at 54 NCI-CCs studied. More NCI-CCs than non-NCI-CCs improved over the period (85.2% vs 58.4%, P < 0.001; relative risk [RR] 1.46, 95% confidence interval [CI], 1.28-1.66); this remained significant after adjusting for years of participation (RR 1.33, 95% CI, 1.17-1.51). Variation in performance remained unchanged over time. CONCLUSION: NCI-CCs were detected to have improved over a contemporary seven-year period and to have improved more than non-NCI-CCs. However, NCI-CCs do not uniformly outperform non-NCI-CCs, and variation in perioperative outcomes remains, warranting continued quality improvement efforts targeting cancer-specific operations.

Outcomes of Concurrent Operations: Results From the American College of Surgeons' National Surgical Quality Improvement Program.

OBJECTIVE: To determine whether concurrently performed operations are associated with an increased risk for adverse events. BACKGROUND: Concurrent operations occur when a surgeon is simultaneously responsible for critical portions of 2 or more operations. How this practice affects patient outcomes is unknown. METHODS: Using American College of Surgeons' National Surgical Quality Improvement Program data from 2014 to 2015, operations were considered concurrent if they overlapped by ≥60 minutes or in their entirety. Propensity-score-matched cohorts were constructed to compare death or serious morbidity (DSM), unplanned reoperation, and unplanned readmission in concurrent versus non-concurrent operations. Multilevel hierarchical regression was used to account for the clustered nature of the data while controlling for procedure and case mix. RESULTS: There were 1430 (32.3%) surgeons from 390 (77.7%) hospitals who performed 12,010 (2.3%) concurrent operations. Plastic surgery (n = 393 [13.7%]), otolaryngology (n = 470 [11.2%]), and neurosurgery (n = 2067 [8.4%]) were specialties with the highest proportion of concurrent operations. Spine procedures were the most frequent concurrent procedures overall (n = 2059/12,010 [17.1%]). Unadjusted rates of DSM (9.0% vs 7.1%; P < 0.001), reoperation (3.6% vs 2.7%; P < 0.001), and readmission (6.9% vs 5.1%; P < 0.001) were greater in the concurrent operation cohort versus the non-concurrent. After propensity score matching and risk-adjustment, there was no significant association of concurrence with DSM (odds ratio [OR] 1.08; 95% confidence interval [CI] 0.96-1.21), reoperation (OR 1.16; 95% CI 0.96-1.40), or readmission (OR 1.14; 95% CI 0.99-1.29). CONCLUSIONS: In these analyses, concurrent operations were not detected to increase the risk for adverse outcomes. These results do not lessen the need for further studies, continuous self-regulation and proactive disclosure to patients.

On-demand Reporting of Risk-adjusted and Smoothed Rates for Quality Profiling in ACS NSQIP.

BACKGROUND: Surgical quality improvement depends on hospitals having accurate and timely information about comparative performance. Profiling accuracy is improved by risk adjustment and shrinkage adjustment to stabilize estimates. These adjustments are included in ACS NSQIP reports, where hospital odds ratios (OR) are estimated using hierarchical models built on contemporaneous data. However, the timeliness of feedback remains an issue. STUDY DESIGN: We describe an alternative, nonhierarchical approach, which yields risk- and shrinkage-adjusted rates. In contrast to our "Traditional" NSQIP method, this approach uses preexisting equations, built on historical data, which permits hospitals to have near immediate access to profiling results. We compared our traditional method to this new "on-demand" approach with respect to outlier determinations, kappa statistics, and correlations between logged OR and standardized rates, for 12 models (4 surgical groups by 3 outcomes). RESULTS: When both methods used the same contemporaneous data, there were similar numbers of hospital outliers and correlations between logged OR and standardized rates were high. However, larger differences were observed when the effect of contemporaneous versus historical data was added to differences in statistical methodology. CONCLUSIONS: The on-demand, nonhierarchical approach provides results similar to the traditional hierarchical method and offers immediacy, an "over-time" perspective, application to a broader range of models and data subsets, and reporting of more easily understood rates. Although the nonhierarchical method results are now available "on-demand" in a web-based application, the hierarchical approach has advantages, which support its continued periodic publication as the gold standard for hospital profiling in the program.

Improved Surgical Outcomes for ACS NSQIP Hospitals Over Time: Evaluation of Hospital Cohorts With up to 8 Years of Participation.

BACKGROUND: The American College of Surgeons, National Surgical Quality Improvement Program (ACS NSQIP) surgical quality feedback models are recalibrated every 6 months, and each hospital is given risk-adjusted, hierarchical model, odds ratios that permit comparison to an estimated average NSQIP hospital at a particular point in time. This approach is appropriate for "relative" benchmarking, and for targeting quality improvement efforts, but does not permit evaluation of hospital or program-wide changes in quality over time. We report on long-term improvement in surgical outcomes associated with participation in ACS NSQIP. STUDY DESIGN: ACS NSQIP data (2006-2013) were used to create prediction models for mortality, morbidity (any of several distinct adverse outcomes), and surgical site infection (SSI). For each model, for each hospital, and for year of first participation (hospital cohort), hierarchical model observed/expected (O/E) ratios were computed. The primary performance metric was the within-hospital trend in logged O/E ratios over time (slope) for mortality, morbidity, and SSI. RESULTS: Hospital-averaged log O/E ratio slopes were generally negative, indicating improving performance over time. For all hospitals, 62%, 70%, and 65% of hospitals had negative slopes for mortality, morbidity, and any SSI, respectively. For hospitals currently in the program for at least 3 years, 69%, 79%, and 71% showed improvement in mortality, morbidity, and SSI, respectively. For these hospitals, we estimate 0.8%, 3.1%, and 2.6% annual reductions (with respect to prior year's rates) for mortality, morbidity, and SSI, respectively. CONCLUSIONS: Participation in ACS NSQIP is associated with reductions in adverse events after surgery. The magnitude of quality improvement increases with time in the program.

Identification and characterization of two CYP9A genes associated with pyrethroid detoxification in Locusta migratoria.

Cytochrome P450s (CYPs) constitute one of the largest gene super families and distribute widely in all living organisms. In this study, the full-length cDNA sequences of two LmCYP9A genes (LmCYP9AQ1 and LmCYP9A3) were cloned from Locusta migratoria. We analyzed the expression patterns of two LmCYP9A genes in various tissues and different developmental stages using real-time quantitative PCR. Then we evaluated the detoxification functions of the two LmCYP9A genes by testing mortalities with four kinds of pyrethroid treatment after RNA interference (RNAi), respectively. Combining with docking structure of two LmCYP9A genes, their detoxification properties were extensively analyzed. The full-length cDNAs of LmCYP9AQ1 and LmCYP9A3 putatively encoded 525 and 524 amino acid residues, respectively. Both LmCYP9A genes were expressed throughout the developmental stages. The expression of LmCYP9AQ1 in the brain was higher than that in other examined tissues, whereas the LmCYP9A3 was mainly expressed in the fat body. The mortalities of nymphs exposed to deltamethrin and permethrin increased from 27.7% to 77.7% and 27.7% to 58.3%, respectively, after dsLmCYP9A3 injection. While the mortalities of nymphs exposed to fluvalinate increased from 29.8% to 53.0% after LmCYP9AQ1 was silenced using RNA interference. Our results suggested that the two LmCYP9A genes may be involved in different pyrethroid insecticide detoxification in L. migratoria.

Magnetic Phase Transition-Induced Modulation of Ferroelectric Properties in Hexagonal RFeO3 (R = Tb and Ho).

Hexagonal rare-earth iron oxides (h-RFeO3) exhibit spontaneous magnetization and room-temperature ferroelectricity simultaneously. However, achieving a large magnetoelectric coupling necessitates further exploration. Herein, we report the impact of the magnetic phase transition on the ferroelectric properties of epitaxial h-RFeO3 (R = Tb and Ho) films prepared by pulsed laser deposition. The metastable h-RFeO3 phase is successfully stabilized with high crystallinity and low leakage current due to the ITO buffer layer, making it possible to investigate the ferroelectric properties. The h-TbFeO3 film exhibits a magnetic-field-induced transition from antiferromagnetic (AFM) to weak ferromagnetic (wFM) phases below 30 K, while also exhibiting ferroelectricity at 300 K. The dielectric constants change with the magnetic phase transition, demonstrating hysteresis in the magnetocapacitance. In contrast, the h-HoFeO3 film exhibits antiferroelectric-like behavior and an AFM-wFM phase transition. Notably, the h-HoFeO3 film shows a rapid increase in the remnant polarization during the AFM-wFM phase transition accompanied by an increase in the ferroelectric component. Considering the strong connection between the antiferroelectric behavior in the h-RFeO3 system and the ferroelectric domain wall motion, this considerable modification of ferroelectric properties during the magnetic phase transition is probably due to the faster movement of the ferroelectric domain walls in the wFM phase induced by the clamping effect. Our findings indicate the effectiveness of magnetic phase transitions in enhancing the magnetoelectric coupling, particularly when utilizing domain wall clamping properties.

National Multi-Institutional Validation of a Surgical Transfusion Risk Prediction Model.

BACKGROUND: Accurate estimation of surgical transfusion risk is important for many aspects of surgical planning, yet few methods for estimating are available for estimating such risk. There is a need for reliable validated methods for transfusion risk stratification to support effective perioperative planning and resource stewardship. STUDY DESIGN: This study was conducted using the American College of Surgeons NSQIP datafile from 2019. S-PATH performance was evaluated at each contributing hospital, with and without hospital-specific model tuning. Linear regression was used to assess the relationship between hospital characteristics and area under the receiver operating characteristic (AUROC) curve. RESULTS: A total of 1,000,927 surgical cases from 414 hospitals were evaluated. Aggregate AUROC was 0.910 (95% CI 0.904 to 0.916) without model tuning and 0.925 (95% CI 0.919 to 0.931) with model tuning. AUROC varied across individual hospitals (median 0.900, interquartile range 0.849 to 0.944), but no statistically significant relationships were found between hospital-level characteristics studied and model AUROC. CONCLUSIONS: S-PATH demonstrated excellent discriminative performance, although there was variation across hospitals that was not well-explained by hospital-level characteristics. These results highlight the S-PATH's viability as a generalizable surgical transfusion risk prediction tool.

Deciphering metabolic heterogeneity in retinoblastoma unravels the role of monocarboxylate transporter 1 in tumor progression.

BACKGROUND: Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. METHODS: The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. RESULTS: Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. CONCLUSIONS: This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.