RUNX1::ETO and CBFß::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core-binding factor-acute myeloid leukaemia.

Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFß::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFß::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.

Recurrent noncoding somatic and germline WT1 variants converge to disrupt MYB binding in acute promyelocytic leukemia.

Genetic alternations can occur at noncoding regions, but how they contribute to cancer pathogenesis is poorly understood. Here, we established a mutational landscape of cis-regulatory regions (CREs) in acute promyelocytic leukemia (APL) based on whole-genome sequencing analysis of paired tumor and germline samples from 24 patients and epigenetic profiling of 16 patients. Mutations occurring in CREs occur preferentially in active enhancers bound by the complex of master transcription factors in APL. Among significantly enriched mutated CREs, we found a recurrently mutated region located within the third intron of WT1, an essential regulator of normal and malignant hematopoiesis. Focusing on noncoding mutations within this WT1 intron, an analysis on 169 APL patients revealed that somatic mutations were clustered into a focal hotspot region, including one site identified as a germline polymorphism contributing to APL risk. Significantly decreased WT1 expression was observed in APL patients bearing somatic and/or germline noncoding WT1 variants. Furthermore, biallelic WT1 inactivation was recurrently found in APL patients with noncoding WT1 variants, which resulted in the complete loss of WT1. The high incidence of biallelic inactivation suggested the tumor suppressor activity of WT1 in APL. Mechanistically, noncoding WT1 variants disrupted MYB binding on chromatin and suppressed the enhancer activity and WT1 expression through destroying the chromatin looping formation. Our study highlights the important role of noncoding variants in the leukemogenesis of APL.

Hexaxial external fixator versus intramedullary nail in treating segmental tibial fractures: a retrospective study.

BACKGROUND: It's difficult to treat segmental tibial fractures (STFs), which are intricate injuries associated with significant soft tissue damage. The aim of this study was to compare the clinical effect of hexaxial external fixator (HEF) and intramedullary nail (IMN) in treatment of STFs. METHODS: A total of 42 patients with STFs were finally recruited between January 2018 and June 2022. There were 25 males and 17 females with age range of 20 to 60 years. All fractures were classified as type 42C2 using the Arbeitsgemeinschaftfür Osteosythese/Orthopaedic Trauma Association (AO/OTA) classification. 22 patients were treated with HEF and 20 patients were treated with IMN. The condition of vascular and neural injuries, time of full weight bearing, bone union time and infection rate were documented and analyzed between the two groups. The mechanical medial proximal tibial angle (mMPTA), mechanical posterior proximal tibial angle (mPPTA), mechanical lateral distal tibial angle (mLDTA), mechanical anterior distal tibial angle (mADTA), hospital for special surgery (HSS) knee joint score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle joint score, range of motion (ROM) of flexion of keen joint and ROM of plantar flexion and dorsal flexion of ankle joint were compared between the two groups at the last clinical visit. RESULTS: There were no vascular and neural injuries or other severe complications in both groups. All 22 patients in HEF group underwent closed reduction but 3 patients in IMN group were treated by open reduction. The time of full weight bearing was (11.3 ± 3.2) days in HEF group and (67.8 ± 5.8) days in IMN group(P < 0.05), with bone union time for (6.9 ± 0.8) months and (7.7 ± 1.4) months, respectively(P < 0.05). There was no deep infection in both groups. In the HEF group and IMN group, mMPTA was (86.9 ± 1.5)° and (89.7 ± 1.8)°(P < 0.05), mPPTA was (80.8 ± 1.9)° and (78.6 ± 2.0)°(P < 0.05), mLDTA was (88.5 ± 1.7)° and (90.3 ± 1.7)°(P < 0.05), while mADTA was (80.8 ± 1.5)° and (78.4 ± 1.3)°(P < 0.05). No significant differences were found between the two groups at the last clinical visit concerning HSS knee joint score and AOFAS ankle joint score, ROM of flexion of keen joint and ROM of plantar flexion of ankle joint (P > 0.05). The ROM of dorsal flexion of ankle joint in IMN group was (30.4 ± 3.5)°, better than (21.6 ± 2.8)° in HEF group (P < 0.05). CONCLUSION: In terms of final clinical outcomes, the use of either HEF or IMN for STFs can achieve good therapeutic effects. While HEF is superior to IMN in terms of completely closed reduction, early full weight bearing, early bone union and alignment. Nevertheless, HEF has a greater impact on the ROM of dorsal flexion of the ankle joint, and much more care and adjustment are needed for the patients than IMN.

Association of stress hyperglycemia with clinical outcomes in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention: a cohort study.

BACKGROUND: In recent years, several studies have demonstrated that stress hyperglycemia is significantly associated with poor prognosis in patients diagnosed with acute coronary syndrome (ACS). In the present study, we aimed to investigate the potential associations between various markers of stress hyperglycemia, such as admission blood glucose (ABG), fasting blood sugar (FBS), and stress hyperglycemia ratio (SHR) with different definitions, and the occurrence of adverse cardiovascular events in patients diagnosed with ST-elevation myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI). METHODS: Our study enrolled a total of 1099 patients diagnosed with STEMI who underwent PCI from 2016 to 2021. The primary outcomes of this study were in-hospital death and all-cause mortality. RESULTS: Stress hyperglycemia was associated with a higher incidence of in-hospital death (ABG OR: 1.27 95% CI 1.19-1.36; FBS OR: 1.25 95% CI 1.16-1.35; SHR1 OR: 1.61 95% CI 1.21-2.14; SHR2 OR: 1.57, 95%CI 1.22-2.01; SHR3 OR: 1.59, 95%CI 1.24-2.05) and all-cause mortality (ABG HR: 1.10, 95% CI 1.07-1.14; FBS HR: 1.12, 95 CI 1.07-1.17; SHR1 HR: 1.19 95% CI 1.03-1.39; SHR2 HR: 1.28, 95%CI 1.14-1.44; SHR3 HR: 1.29, 95%CI 1.14-1.45) after adjusting for ischemic time, age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus (DM), current smoking history, chronic kidney disease (CKD), previous history of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, cancer, culprit vessel, multi-vessel disease. These associations exhibited a non-linear, J-shaped pattern, wherein the risk significantly increased when the ABG and FBS levels exceeded 5mmol/L. Moreover, the inflection point for SHR was estimated to be 1.2. CONCLUSIONS: Stress hyperglycemia was significantly associated with an increased risk of in-hospital death and all-cause mortality in STEMI patients treated with PCI. Stress hyperglycemia should be considered a high-risk prognostic marker in all STEMI patients, regardless of with or without diabetes.

Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients.

BACKGROUND: Stress hyperglycemia ratio (SHR), associated with adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI), has several definitions. This study aims to assess the prognostic value of SHR, derived from hemoglobin A1c (HbA1c) or glycated albumin (GA), to mortality. METHODS: The study comprised 1,643 STEMI patients who underwent percutaneous coronary intervention (PCI) in two centers. SHR1 was calculated using fasting blood glucose (FBG)/GA, while SHR2 was calculated using the formula FBG/(1.59*HbA1c-2.59). The primary endpoints were in-hospital death and all-cause mortality, with a median follow-up duration of 1.56 years. RESULTS: Higher SHR1 and SHR2 values are associated with increased risks of in-hospital death and all-cause mortality. Each standard deviation increase in SHR1 corresponded to a 39% and 22% escalation in in-hospital death and all-cause mortality, respectively. The respective increases for SHR2 were 51% and 26%. Further examinations validated these relationships as linear. Additionally, the areas under the curve (AUC) for in-hospital death were not significantly different between SHR1 and SHR2 (p > 0.05). Incorporating SHR1 or SHR2 into the base model significantly improved the discrimination and risk reclassification for in-hospital and all-cause mortality. A subgroup analysis revealed that the effects of SHR1 and SHR2 were more pronounced in patients with hypercholesteremia. CONCLUSION: SHR1 and SHR2 have emerged as robust and independent prognostic markers for STEMI patients undergoing PCI. The SHR calculation based on either HbA1c or GA can provide additional predictive value for mortality beyond traditional risk factors, helping to identify high-risk STEMI patients.

An Improved Projector Calibration Method by Phase Mapping Based on Fringe Projection Profilometry.

Aiming at the problem of the low accuracy of projector calibration in a structured light system, an improved projector calibration method is proposed in this paper. One of the key ideas is to estimate the sub-pixel coordinates in the projector image plane using local random sample consensus (RANSAC). A bundle adjustment (BA) algorithm is adopted to optimize the calibration parameters to further improve the accuracy and robustness of the projector calibration. After system calibration and epipolar rectification, the mapping relationship between the pixel coordinates and the absolute phase in the projector image plane is established by using cubic polynomial fitting, and the disparity is rapidly solved by using the mapping relationship, which not only ensures the measurement accuracy, but also improves the measurement efficiency. The experimental results demonstrated that the average re-projection error after optimization is reduced to 0.03 pixels, and the proposed method is suitable for high-speed 3D reconstruction without the time-consuming homogenous point searching.

The TIM-3 Rs10053538 Polymorphism Is Associated with Clinical Prognosis of Colorectal Cancer.

BACKGROUND: Genetic variants in the T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) gene have been reported to be associated with the risk of cancers and patients' outcomes. The aims of this study were to explore the role of TIM-3 polymorphisms in the risk of colorectal cancer (CRC) and the prognosis of CRC patients in a northern Chinese population. METHODS: Two polymorphisms of TIM-3 were genotyped using polymerase chain reaction and ligase detection reaction in 364 CRC patients and 372 healthy control subjects. The levels of TIM-3 mRNA were investigated in 65 CRC tissues by quantitative real-time PCR. RESULTS: The results showed that neither rs10053538 nor rs10515746 was associated with susceptibility to CRC. However, the CA+AA genotypes of rs10053538 were related to an advanced clinical stage and increased risk of lymph nodemetastasis (P = .046 and 0.024, respectively). Multivariate analyses performed after adjusting for clinical variables showed that patients with the CA+AA genotypes of rs10053538 exhibited a significantly shorter disease-free survival (DFS) and overall survival (OS) time compared with those carrying the CC genotype (HR = 1.91, 95% CI = 1.04-3.51; HR = 2.61, 95% CI = 1.35-5.03). In addition, the expression of TIM-3 mRNA was significantly increased in the CRC tissues of patients carrying the rs10053538 CA+AA genotypes compared with patients carrying the CC genotype (P = .019). CONCLUSION: The rs10053538 may serve as an independent molecular marker for predicting the clinical outcome of CRC patients in the study population.

Screening and identification of a novel FHL2 mutation by whole exome sequencing in twins with familial Waldenström macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is a rare chronic B-cell lymphoma. Familial clustering of WM has been observed over the years. However, little is known about the contribution of inherited genetic variants to familial WM cases. METHODS: The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Bioinformatics analysis of public biological databases was used to identify the most relevant familial WM candidate from WES. Transcript expression and protein levels of the familial WM candidate were evaluated in the WM patient and 2 unaffected members of the kindred. RESULTS: Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM-associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings. CONCLUSIONS: Taken together, these findings indicate that an FHL2g226a mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases. LAY SUMMARY: Familial clustering in Waldenström macroglobulinemia (WM) has been observed over the years. The authors performed whole exome sequencing of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Among the 10 shared candidate mutations in the twins, a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) was identified as the most relevant familial WM candidate through bioinformatics analysis of a public database. Also, messenger RNA and protein expression of FHL2 was significantly lower in peripheral blood mononuclear cells of the WM patient in comparison with the healthy siblings, and this suggested that the function of FHL2 was impaired when mutated.

circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells.

NF-κB-mediated inflammatory phenotypic switching of vascular smooth muscle cells (VSMCs) plays a central role in atherosclerosis and neointimal formation. However, little is known about the roles of circRNAs in the regulation of NF-κB signaling. Here, we identify the involvement of circ-Sirt1 that was one of transcripts of SIRT1 host gene in VSMC inflammatory response and neointimal hyperplasia. First, in the cytoplasm, circ-Sirt1 directly interacts with and sequesters NF-κB p65 from nuclear translocation induced by TNF-α in a sequence-dependent manner. The inhibitory complex of circ-Sirt1-NF-κB p65 is not dependent on IκBα. Second, circ-Sirt1 binds to miR-132/212 that interferes with SIRT1 mRNA, and facilitates the expression of host gene SIRT1. Increased SIRT1 results in deacetylation and inactivation of the nuclear NF-κB p65. These findings illustrate that circ-Sirt1 is a novel non-coding RNA regulator of VSMC phenotype.

Circ_cse1l Inhibits Colorectal Cancer Proliferation by Binding to eIF4A3.

BACKGROUND Circular RNAs (circRNAs) are involved in the growth of many tumors. However, the expression and possible role of circ_cse1l (hsa_circ_0060745) in colorectal cancer (CRC) are unclear. The present study was designed to explore the role of circ_cse1l in CRC. MATERIAL AND METHODS The levels of circ_cse1l expression in cancer tissues and serum samples of 50 patients with CRC and in control subjects were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). CCK-8, colony formation, transwell and wound healing assays were performed to assess the functions of circ_cse1l in CRC cell lines after overexpression. The relationship between circ_cse1l and eIF4A3 during cell proliferation was analyzed by western blotting and RNA-binding protein immunoprecipitation (RIP). RESULTS qRT-PCR assays showed that the levels of expression of circ_cse1l were lower in CRC cell lines and in tissue and serum samples from patients with CRC than in control samples. The expression of circ_cse11 in CRC tissues had clinical significance, as its level of expression was inversely associated with the depth of tumor invasion. Overexpression of circ_cse1l in HT29 and HCT116 cells markedly reduced cell proliferation and metastasis. Western blotting showed that circ_cse1l overexpression dowregulated the expression of PCNA protein. RIP results demonstrated that circ_cse1l inhibited the proliferation of CRC cells by binding to eIF4A3. CONCLUSIONS The expression of circ_cse1l is downregulated in CRC. Furthermore, circ_cse1l downregulated PCNA expression by binding to eIF4A3, inhibiting the proliferation of CRC cells.

Study on the Correlation between Metabolism, Insulin Sensitivity and progressive weight loss change in Type-2 Diabetes.

OBJECTIVE: To observe the changes of lipid metabolism, blood glucose level and insulin sensitivity in patients with Type-2 diabetes after progressive weight loss of their body weight, so as to lay a theoretical foundation for diabetes treatment and education in the future. METHODS: One hundred obese patients with Type-2 diabetes (BMI ≥ 25 kg/m2) who visited the endocrinology department of our hospital from April 2017 to April 2018 were given diabetes health education, diabetic diet, exercise and other measures to control their weight. The changes of blood glucose, blood lipid, insulin level and insulin release test before weight loss (T1), and at the time points of weight loss reached 5% (T2), 10% (T3) and 15% (T4) were recorded respectively to understand the influence of progressive weight loss on relevant indexes of patients. RESULTS: With the decrease of body weight, the differences of TC, TG, LDL-C and HDL-C at different weight loss points were significant (p < 0.05), and the changes of fasting blood glucose in 5% and 10% weight loss were significant (p = 0.02). The 2h postprandial blood glucose showed the most significant difference when the weight loss reached 15% (p = 0.00). There was no statistical difference in the change of glycosylated hemoglobin among different weight loss points (p = 0.08). When the weight loss reached 10%, the blood insulin level was significantly lower than that before the weight loss, while the insulin level was not significantly changed when the weight loss reached 15%, but the peak of secretion was shifted forward. It is suggested that insulin sensitivity gradually increases with weight loss. CONCLUSION: Obese patients with Type-2 diabetes can benefit from weight loss, with abnormal blood glucose and lipid metabolism improved, insulin resistance relieved, and insulin sensitivity increased.

LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells.

Our study aimed to investigate the effects of lncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-axis on prostate cancer (PCa) progression. Microarray analysis was conducted to determine differentially expressed lncRNAs and mRNAs. Gene Set Enrichment analysis was implemented for verification of dys-regulated signaling pathways between DU-145 cells and doxorubicin-resistant prostate cancer DU-145 cells. Relative expression of lncRNA LOXL1-AS1 in doxorubicin-resistant prostate cancer DU-145 cells was analyzed by qRT-PCR. CCK-8 assay and flow cytometry analysis were employed to detect cell proliferation and apoptosis, respectively. Cell migration was performed by transwell assay. Furthermore, targeted relationships between lncRNA LOXL1-AS1 and miR-let-7a-5p, as well as miR-let-7a-5p and EGFR were predicted using bioinformatics analysis and validated by dual-luciferase reporter gene assay. Besides, tumor xenograft assay was utilized for verification of the roles of LOXL1-AS1 in PCa progression in vivo. Microarray analysis showed that lncRNA LOXL1-AS1 and EGFR were both downregulated, while miR-let-7a-5p was upregulated in doxorubicin-resistant prostate cancer DU-145 cells. MiR-let-7a-5p could target both lncRNA LOXL1-AS1 and EGFR to affect PCa progression. Upregulation of lncRNA LOXL1-AS1 promoted cell proliferation and migration, while suppressed cell apoptosis. Besides, it was further confirmed that EGFR was downregulated in drug-resistant PCa cells and negatively correlated with miR-let-7a-5p. Tumor xenograft assay verified that silence of lncRNA LOXL1-AS1 inhibited the tumor growth in vivo in DU-145 cells. Our results demonstrated that the lncRNALOXL1-AS1/miR-let-7a-5p/EGFR axis significantly affected proliferation, migration, and apoptosis of drug-resistant DU-145 Cells, which may provide us with a potential treatment strategy for drug-resistant PCa patients. © 2019 IUBMB Life, 2019.

Association between intake of red and processed meat and the risk of heart failure: a meta-analysis.

BACKGROUND: Many studies have assessed the association between consumption of red and processed meat and the risk of heart failure, but the results are not consistent. This meta-analysis aimed to comprehensively evaluate the relationship between intake of red and processed meat and the risk of heart failure. METHODS: Databases of Web of Knowledge, PubMed, and Wan Fang Med Online were retrieved up to date of August 31st, 2017. Suitable publications were identified through using the defined inclusion criteria. The summarized relative risk (RR) with the corresponding 95% confidence interval (CI) was calculated. RESULTS: Six scientific literatures were included in this study. In comparison with the lowest category, the summarized RR and 95% CI of the highest category of processed meat intake for heart failure risk was 1.23 (95% CI = 1.07-1.41, I2 = 58.9%, P = 0.045). A significant connection between processed meat intake and heart failure was identified among the Europeans (RR = 1.33, 95% CI = 1.15-1.54), but not the Americans. Yet few of essential association was found between heart failure risk and red meat intake (RR = 1.04, 95% CI = 0.96-1.12). CONCLUSIONS: Findings of this meta-analysis indicated that the highest category of processed meat intake, other than red meat intake, correlated with an increased risk of heart failure.

V2Te2O: A Two-Dimensional van der Waals Correlated Metal.

A metastable vanadium oxytelluride V2Te2O is prepared via a topochemical deintercalation of interlayer Rb+ cations in Rb1-δV2Te2O. The new ternary mixed-anion compound crystallizes in a body-centered tetragonal lattice with a = 3.9282(1) Å and c = 13.277(5) Å, containing V2O square nets that are sandwiched by Te-atomic sheets. The charge-neutral [V2OTe2] block layers stack along the c axis with van der Waals forces, which shows a metallic behavior with a dominant T2 dependence for resistivity at low temperatures. The electronic specific-heat coefficient reaches 33.9 mJ K-2 mol-1, ∼4 times that of the electronic structure calculations, suggesting a significant electron-mass renormalization. The electron correlation effect is concurrently demonstrated by the Wilson and Kadowaki-Woods ratios. Neither charge/spin-density wave nor superconductivity was observed down to 0.03 K.

[Retracted] MicroRNA­30a suppresses the proliferation, migration and invasion of human renal cell carcinoma cells by directly targeting ADAM9.

[This retracts the article DOI: 10.3892/ol.2018.8999.].

Agreement of ejection fraction measured by coronary computed tomography (CT) and cardiac ultrasound in evaluating patients with chronic heart failure: an observational comparative study.

Background: Cardiac ultrasound is one of the most important examinations in cardiovascular medicine, but the technical requirements for the operator are relatively high, which to some extent affects the scope of its use. This study was dedicated to investigating the agreement of ejection fraction between coronary computed tomography (CT) and cardiac ultrasound and diagnostic performance in evaluating the clinical diagnosis of patients with chronic heart failure. Methods: We conducted a single-center-based retrospective study including 343 consecutive patients enrolled between January 2019 to April 2020, all of whom presented with suspected symptoms of heart failure within one month. All enrolled cases performed cardiac ultrasound and coronary CT scans. The CT images were analyzed using accurate left ventricle (AccuLV) artificial intelligence (AI) software to calculate the ejection fraction-computed tomography (EF-CT) and it was compared with the ejection fraction (EF) obtained based on ultrasound. Cardiac insufficiency was determined if the EF measured by ultrasound was below 50%. Diagnostic performance analysis, correlation analysis and Bland-Altman plot were used to compare agreement between EF-CT and CT. Results: Of the 319 successfully performed patients, 220 (69%) were identified as cardiac insufficiency. Quantitative consistency analysis showed a good correlation between EF-CT and EF values in all cases (R square =0.704, r=0.837). Bland-Altman analysis showed mean bias of 6.6%, mean percentage error of 27.5% and 95% limit of agreement of -17% to 30% between EF and EF-CT. The results of the qualitative diagnostic study showed that the sensitivity and specificity of EF measured by coronary CT reached a high level of 91% [95% confidence interval (CI): 86-94%], and the positive diagnostic value was up to 96% (95% CI: 92-98%). Conclusions: The EF-CT and EF have excellent agreement, and AccuLV-based AI left ventricular function analysis software perhaps can be used as a clinical diagnostic reference.

Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.