NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

Development and application of an efficient genomic mating method to maximize the production performances of three-way crossbred pigs.

Creating synthetic lines is the standard mating mode for commercial pig production. Traditional mating performance was evaluated through a strictly designed cross-combination test at the 'breed level' to maximize the benefits of production. The Duroc-Landrace-Yorkshire (DLY) three-way crossbred production system became the most widely used breeding scheme for pigs. Here, we proposed an 'individual level' genomic mating procedure that can be applied to commercial pig production with efficient algorithms for estimating marker effects and for allocating the appropriate boar-sow pairs, which can be freely accessed to public in our developed HIBLUP software at https://www.hiblup.com/tutorials#genomic-mating. A total of 875 Duroc boars, 350 Landrace-Yorkshire sows and 3573 DLY pigs were used to carry out the genomic mating to assess the production benefits theoretically. The results showed that genomic mating significantly improved the performances of progeny across different traits compared with random mating, such as the feed conversion rate, days from 30 to 120 kg and eye muscle area could be improved by -0.12, -4.64 d and 2.65 cm2, respectively, which were consistent with the real experimental validations. Overall, our findings indicated that genomic mating is an effective strategy to improve the performances of progeny by maximizing their total genetic merit with consideration of both additive and dominant effects. Also, a herd of boars from a richer genetic source will increase the effectiveness of genomic mating further.

HIBLUP: an integration of statistical models on the BLUP framework for efficient genetic evaluation using big genomic data.

Human diseases and agricultural traits can be predicted by modeling a genetic random polygenic effect in linear mixed models. To estimate variance components and predict random effects of the model efficiently with limited computational resources has always been of primary concern, especially when it involves increasing the genotype data scale in the current genomic era. Here, we thoroughly reviewed the development history of statistical algorithms used in genetic evaluation and theoretically compared their computational complexity and applicability for different data scenarios. Most importantly, we presented a computationally efficient, functionally enriched, multi-platform and user-friendly software package named 'HIBLUP' to address the challenges that are faced currently using big genomic data. Powered by advanced algorithms, elaborate design and efficient programming, HIBLUP computed fastest while using the lowest memory in analyses, and the greater the number of individuals that are genotyped, the greater the computational benefits from HIBLUP. We also demonstrated that HIBLUP is the only tool which can accomplish the analyses for a UK Biobank-scale dataset within 1 h using the proposed efficient 'HE + PCG' strategy. It is foreseeable that HIBLUP will facilitate genetic research for human, plants and animals. The HIBLUP software and user manual can be accessed freely at https://www.hiblup.com.

Both human diseases and agricultural traits can be predicted by incorporating phenotypic observations and a relationship matrix among individuals in a linear mixed model. Due to the great demand for processing massive data of genotyped individuals, the existing algorithms that require several repetitions of inverse computing on increasingly big dense matrices (e.g. the relationship matrix and the coefficient matrix of mixed model equations) have encountered a bottleneck. Here, we presented a software tool named 'HIBLUP' to address the challenges. Powered by our advanced algorithms (e.g. HE + PCG), elaborate design and efficient programming, HIBLUP can successfully avoid the inverse computing for any big matrix and compute fastest under the lowest memory, which makes it very promising for genetic evaluation using big genomic data.

IAnimal: a cross-species omics knowledgebase for animals.

With the exponential growth of multi-omics data, its integration and utilization have brought unprecedented opportunities for the interpretation of gene regulation mechanisms and the comprehensive analyses of biological systems. IAnimal (https://ianimal.pro/), a cross-species, multi-omics knowledgebase, was developed to improve the utilization of massive public data and simplify the integration of multi-omics information to mine the genetic mechanisms of objective traits. Currently, IAnimal provides 61 191 individual omics data of genome (WGS), transcriptome (RNA-Seq), epigenome (ChIP-Seq, ATAC-Seq) and genome annotation information for 21 species, such as mice, pigs, cattle, chickens, and macaques. The scale of its total clean data has reached 846.46 TB. To better understand the biological significance of omics information, a deep learning model for IAnimal was built based on BioBERT and AutoNER to mine 'gene' and 'trait' entities from 2 794 237 abstracts, which has practical significance for comprehending how each omics layer regulates genes to affect traits. By means of user-friendly web interfaces, flexible data application programming interfaces, and abundant functional modules, IAnimal enables users to easily query, mine, and visualize characteristics in various omics, and to infer how genes play biological roles under the influence of various omics layers.

Olfactory regulation by dopamine and DRD2 receptor in the nose.

SignificanceDespite the identification of neural circuits and circulating hormones in olfactory regulation, the peripheral targets for olfactory modulation remain relatively unexplored. Here we show that dopamine D2 receptor (DRD2) is expressed in the cilia and somata of mature olfactory sensory neurons (OSNs), while nasal dopamine (DA) is mainly released from the sympathetic nerve terminals, which innervate the mouse olfactory mucosa (OM). We further demonstrate that DA-DRD2 signaling in the nose plays important roles in regulating olfactory function using genetic and pharmacological approaches. Moreover, the local DA synthesis in mouse OM is reduced during hunger, which contributes to starvation-induced olfactory enhancement. Altogether, we demonstrate that nasal DA and DRD2 receptor can serve as the potential peripheral targets for olfactory modulation.

Adolescent administration of ketamine impairs excitatory synapse formation onto parvalbumin-positive GABAergic interneurons in mouse prefrontal cortex.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.

Impact of Relative Improvement in Quantitative Flow Ratio on Clinical Outcomes After Percutaneous Coronary Intervention　- A Subanalysis of the PANDA III Trial.

BACKGROUND: The clinical impact of relative improvements in coronary physiology in patients receiving percutaneous coronary intervention (PCI) for coronary artery disease (CAD) remains undetermined.Methods and Results: The quantitative flow ratio (QFR) recovery ratio (QRR) was calculated in 1,424 vessels in the PANDA III trial as (post-PCI QFR-pre-PCI QFR)/(1-pre-PCI QFR). The primary endpoint was the 2-year vessel-oriented composite endpoint (VOCE; a composite of vessel-related cardiac death, vessel-related non-procedural myocardial infarction, and ischemia-driven target vessel revascularization). Study vessels were dichotomously stratified according to the optimal QRR cut-off value. During the 2-year follow-up, 41 (2.9%) VOCEs occurred. Low (<0.86) QRR was associated with significantly higher rates of 2-year VOCEs than high (≥0.86) QRR (6.6% vs. 1.4%; adjusted hazard ratio [aHR] 5.05; 95% confidence interval [CI] 2.53-10.08; P<0.001). Notably, among vessels with satisfactory post-procedural physiological results (post-PCI QFR >0.89), low QRR also conferred an increased risk of 2-year VOCEs (3.7% vs. 1.4%; aHR 3.01; 95% CI 1.30-6.94; P=0.010). Significantly better discriminant and reclassification performance was observed after integrating risk stratification by QRR and post-PCI QFR to clinical risk factors (area under the curve 0.80 vs. 0.71 [P=0.010]; integrated discrimination improvement 0.05 [P<0.001]; net reclassification index 0.64 [P<0.001]). CONCLUSIONS: Relative improvement of coronary physiology assessed by QRR showed applicability in prognostication. Categorical classification of coronary physiology could provide information for risk stratification of CAD patients.

Genome-centric metagenomics and methanogenic pathway analysis for acclimated anaerobic digestion of chicken manure with high ammonia stressed under thermophilic condition.

Thermophilic anaerobic digestion (AD) of animal manure offers various environmental benefits but the process requires a microbial community acclimatized to high ammonia. In current study, a lab-scale continuous stirred tank reactor (CSTR) fed with chicken manure was operated under thermophilic condition for 450 days in total. Results showed that the volumetric methane production decreased from 445 to 328 and sharply declined to 153 mL L-1·d-1 with feeding total solid (TS) step increased from 5% to 7.5% and 10%, respectively. While, after a long-term stop feeding for 80 days, highly disturbed reactor was able to recover methane generation to 739 mL L-1·d-1 at feeding TS of 10%. Isotope analysis indicted acetate converted to methane through the syntrophic acetate oxidation and hydrogenotrophic methanogenesis (SAO-HM) pathway increased from 33% to 63% as the concentration of ammonium increased from 2493 to 6258 mg L-1. Significant different in the genome expression of the SAO bacterial from 0.09% to 1.23%, combining with main hydrogenotrophic partners (Methanoculleus spp. and Methanothermobacter spp.) contented of 2.1% and 99.9% during inhibitory and recovery stages, respectively. The highly expressed KEGG pathway in level 3 (enzyme genes) for the Recovery sludge combining with the extraordinary high abundance of genera Halocella sp. suggested that Halocella sp. might be a highly efficient hydrolytic and acidogenic microorganism and enhance the process of SAO during carbon metabolic flow to methane. This report will be a basis for further study of AD studies on high nitrogen content of poultry manure.

Renal thrombotic microangiopathy is associated with poor renal survival in children with immunoglobulin A nephropathy.

AIM: The aim of this study was to examine the clinical and pathological characteristics as well as the prognosis of immunoglobulin A nephropathy (IgAN) accompanied by renal thrombotic microangiopathy (rTMA) in paediatric patients. METHODS: After balancing epidemiological characteristics and pathological types between groups, 427 patients (rTMA group: 23, non-rTMA group: 46) were included. The clinical and pathological features, prognosis and clinical risk factors of the two groups were analysed. RESULTS: IgAN-rTMA children showed more severe clinical and pathological manifestations. The findings from the logistic regression analysis indicated that hypercellularity 1 (E1) (HR: 0.805, 95% CI: 0.763 ~ 1.452, P = .016), endocapillary proliferation (HR: 1.214, 95% CI: 0.093 ~ 4.815, P = .025) and C3 staining (HR: 7.554, 95% CI: 2.563 ~ 15.729, P = .037) were the risk factors for rTMA in children with IgAN. The renal survival in rTMA group was lower than non-rTMA group (χ2 = 18.467, P = .000). Cox regression analysis showed that E1 (HR: 7.441, 95% CI: 1.095 ~ 10.768, P = .037), C3 disposition (HR: 3.414, 95% CI: 0.834 ~ 11.578, P = .027) and rTMA (HR: 8.918, 95% CI: 1.032 ~ 16.754, P = .041) were identified as independent risk factors for the development of end-stage renal disease (ESRD). CONCLUSION: The presence of rTMA had a significant impact on the severity and prognosis of IgAN. And rTMA has been identified as an independent risk factor for the development of renal failure in children diagnosed with IgAN.

Efficacy of Botulinum Toxin in the Treatment of Facial and Cervical Hypertrophic Scar: A Meta-Analysis.

Objective: Maxillofacial-neck hyperplastic scars have long been a persistent concern among individuals in both Western and Eastern countries. These scars exhibit rapid growth within 3-6 months following wound healing, subsequently receding at a slower pace, leading to skin redness, tension, and potential itching. The lack of comprehensive understanding regarding the formation mechanism and biological attributes of these scars has made them a prominent subject of research both domestically and internationally. Methods: Research data from 2010 to 2023 was selected, and relevant literature on the efficacy of botulinum toxin in the treatment of facial and neck hypertrophic scars was searched until August 2023. The literature on the incidence of facial-neck hypertrophic scars included in PubMed, the Cochrane Library, EMbase, and Web of Science was searched. Two researchers independently screened and extracted the data according to strict inclusion and exclusion criteria.Risk bias in Review Manager 5.4, provided by the Cochrane Collaboration, was used for methodological quality assessment and meta-analysis of the included literature. In case of any disagreement, the decision shall be made through consultation with the third party. Scar width, patient satisfaction, and visual analogue scale (VAS) were evaluated. Weighted mean difference (WMD), odds ratio (OR), and 95% confidence interval (95%CI) were used for evaluation. Publication bias was intuitively determined by funnel plot, and sensitivity analysis was conducted by removing literatures one by one for risk assessment. Results: After reading the title, abstract, and full text, a total of 237 patients were included in 7 articles. Scar width was only studied in 6 literatures, and the heterogeneity test of the included studies (χ2 = 148.95, P < .001, I2 = 98%) showed significant heterogeneity among the studies. Therefore, the random effects model was used to merge the data. Combined effect value WMD =-2.85 [95% CI :(-6.51, 0.81), P < .001], the difference between the two groups was statistically significant. The combined OR of the random-effects model was 8.52 [95%CI: (7.96, 9.08), P < .001], and the difference between the two groups was statistically significant. Among them, the heterogeneity test (χ2 = 2.69, P = .44, I² = 0%) was carried out in two studies, indicating good homogeneity among the studies, so the combined WMD was 0.68 [95%CI: (0.38, 0.99), P < .001] by using the fixed-effect model. The median VAS was described in the other two literatures, and the mean scores in the experimental group were 8.9 and 8.25, respectively, while the mean scores in the control group were 7.2 and 6.28, respectively, indicating that local injection of botulinum A toxin at the early stage of wound healing can significantly improve scar quality. Sensitivity analysis suggested that the meta-analysis results were stable and reliable, and publication bias was not analyzed using funnel plots. Conclusion: Botulinum toxin has a positive effect on preventing hyperplastic scars in the maxillofacial and neck areas, and it can also help fade existing scars.

Efficacy of Dexamethasone in Reducing Pain and Inflammation and Accelerating Total Hip Arthroplasty Postoperative Recovery: A Randomized Controlled Trial.

PURPOSE: To evaluate the efficacy of dexamethasone in reducing pain and accelerating recovery after total hip arthroplasty (THA). DESIGN: A prospective randomized controlled trial. METHODS: A total of 98 patients who underwent THA received either low-dose (10 mg) dexamethasone (dexa group) or isotonic saline (placebo group). C-reactive protein and interleukin-6 levels were recorded at 24, 48, and 72 hours after surgery. Pain visual analog scale (VAS) score at rest and walking, the incidence of postoperative nausea and vomiting (PONV), nausea VAS score, postoperative identity-consequence fatigue scale rating, antiemetic use, postoperative length of stay (PLOS), and complications were also recorded and compared. FINDINGS: Inflammatory marker (C-reactive protein and interleukin-6) levels at 24, 48, and 72 hours postoperatively in the dexa group were lower than that in the placebo group (P < .05). After 24 hours of rest, the dynamic pain VAS scores in the dexa group were lower than those in the placebo group (P < .05). The incidence of PONV, nausea VAS score, and identity-consequence fatigue scale score in the dexa group were lower than those in the placebo group (P < .05), and the dosages of analgesics and antiemetics were also lower (P < .05). In addition, PLOS in the dexa group was shorter than that in the placebo group (P < .05). No significant difference in perioperative complications between the two groups was observed (P > .05). CONCLUSIONS: Low-dose dexamethasone in the THA perioperative period can effectively reduce inflammatory marker levels, pain, nausea, postoperative fatigue, opioid analgesic use, and shorten PLOS without increasing complications.

CCL3 secreted by hepatocytes promotes the metastasis of intrahepatic cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m6A) modification.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignant disease characterized by onset occult, rapid progression, high relapse rate, and high mortality. However, data on how the tumor microenvironment (TME) regulates ICC metastasis at the transcriptomic level remains unclear. This study aimed to explore the mechanisms and interactions between hepatocytes and ICC cells. METHODS: We analyzed the interplay between ICC and liver microenvironment through cytokine antibody array analysis. Then we investigated the role of N6-methyladenosine (m6A) modification and the downstream target in vitro, in vivo experiments, and in clinical specimens. RESULTS: Our study demonstrated that cytokine CCL3, which is secreted by hepatocytes, promotes tumor metastasis by regulating m6A modification via vir-like m6A methyltransferase associated (VIRMA) in ICC cells. Moreover, immunohistochemical analyses showed that VIRMA correlated with poor outcomes in ICC patients. Finally, we confirmed both in vitro and in vivo that CCL3 could activate VIRMA and its critical downstream target SIRT1, which fuels tumor metastasis in ICC. CONCLUSIONS: In conclusion, our results enhanced our understanding of the interaction between hepatocytes and ICC cells, and revealed the molecular mechanism of the CCL3/VIRMA/SIRT1 pathway via m6A-mediated regulation in ICC metastasis. These studies highlight potential targets for the diagnosis, treatment, and prognosis of ICC.

CDKN2B-AS1 mediates proliferation and migration of vascular smooth muscle cells induced by insulin.

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the intimal hyperplasia in type 2 diabetes mellitus (T2DM) patients after percutaneous coronary intervention. We aimed to investigate the role of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in VSMC proliferation and migration, as well as the underlying mechanism. T2DM model mice with carotid balloon injury were used in vivo and mouse aortic vascular smooth muscle cells (MOVAS) stimulated by insulin were used in vitro to assess the role of CDKN2B-AS1 in VSMC proliferation and migration following vascular injury in T2DM state. To investigate cell viability and migration, MTT assay and Transwell assay were conducted. To elucidate the underlying molecular mechanisms, the methylation-specific polymerase chain reaction, RNA immunoprecipitation, RNA-pull down, co-immunoprecipitation, and chromatin immunoprecipitation were performed. In vivo, CDKN2B-AS1 was up-regulated in common carotid artery tissues. In vitro, insulin treatment increased CDKN2B-AS1 level, enhanced MOVAS cell proliferation and migration, while the promoting effect was reversed by CDKN2B-AS1 knockdown. CDKN2B-AS1 forms a complex with enhancer of zeste homolog 2 (EZH2) and DNA methyltransferase (cytosine-5) 1 (DNMT1) to regulate smooth muscle 22 alpha (SM22α) methylation levels. In insulin-stimulated cells, SM22α knockdown abrogated the inhibitory effect of CDKN2B-AS1 knockdown on cell viability and migration. Injection of lentivirus-sh-CDKN2B-AS1 relieved intimal hyperplasia in T2DM mice with carotid balloon injury. Up-regulation of CDKN2B-AS1 induced by insulin promotes cell proliferation and migration by targeting SM22α through forming a complex with EZH2 and DNMT1, thereby aggravating the intimal hyperplasia after vascular injury in T2DM.

Identification of ORM1, vWF, SPARC, and PPBP as immune-related proteins involved in immune thrombocytopenia by quantitative LC-MS/MS.

BACKGROUND: Immune thrombocytopenia (ITP) is a common autoimmune disease characterized by loss of immune tolerance to platelet autoantigens leading to excessive destruction and insufficient production of platelets. METHOD: Quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect the differentially expressed proteins in bone marrow samples from active ITP patients and normal controls. RESULT: Our bioinformatic analysis identified two upregulated proteins (ORM1 and vWF) and two downregulated proteins (PPBP and SPARC) related to immune function. The four proteins were all found to be related to the tumor necrosis factor (TNF) -α signalling pathway and involved in the pathogenesis of ITP in KEGG pathway analysis. CONCLUSION: Bioinformatics analysis identified differentially expressed proteins in bone marrow that are involved in the TNF-α signalling pathway and are related to the activation of immune function in ITP patients. These findings could provide new ideas for research on the loss of immune tolerance in ITP patients.

Intensified glycemic control by HbA1c for patients with coronary heart disease and Type 2 diabetes: a review of findings and conclusions.

The occurrence and development of coronary heart disease (CHD) are closely linked to fluctuations in blood glucose levels. While the efficacy of intensified treatment guided by HbA1c levels remains uncertain for individuals with diabetes and CHD, this review summarizes the findings and conclusions regarding HbA1c in the context of CHD. Our review showed a curvilinear correlation between regulated level of HbA1c and therapeutic effectiveness of intensified glycemic control among patients with type 2 diabetes and coronary heart disease. It is necessary to optimize the dynamic monitoring indicators of HbA1c, combine genetic profiles, haptoglobin phenotypes for example and select more suitable hypoglycemic drugs to establish more appropriate glucose-controlling guideline for patients with CHD at different stage of diabetes.

High triglyceride-glucose index and stress hyperglycemia ratio as predictors of adverse cardiac events in patients with coronary chronic total occlusion: a large-scale prospective cohort study.

BACKGROUND: The triglyceride-glucose (TyG) index and the stress hyperglycaemia ratio (SHR) are both positively associated with cardiovascular (CV) risk in patients with coronary heart disease. However, the prognostic value of these two biomarkers has not been well elucidated in patients with chronic total occlusion (CTO). Therefore, this study aims to evaluate the association of the TyG index and the SHR with long-term prognosis in patients with CTO. METHODS: This prospective cohort study consecutively included 2740 angina patients with CTO from January 2017 to December 2018 at Fuwai Hospital. The outcomes are a composite of CV death and target vessel myocardial infarction (TVMI) and major CV cerebrovascular adverse events (MACCEs, including all-cause death, nonfatal MI, ischaemia-driven target vessel revascularization, and stroke). The association between biomarkers and prognosis was analysed by multivariable Cox proportional hazard models, and the predictive value was determined by a receiver-operating characteristic (ROC) curve. RESULTS: During the follow-up with a median time of 3 years, 179 (6.5%) cases of MACCEs and 47 (1.7%) cases of CV death or TVMI were recorded. Patients with a high TyG index (> 9.10) and a high SHR (> 0.87) showed a significantly increased risk of CV death/TVMI (TyG index: HR 4.23, 95% CI 1.58-11.37; SHR: HR 5.14, 95% CI 1.89-13.98) and MACCEs (TyG index: HR 2.47, 95% CI 1.54-3.97; SHR: HR 2.91, 95% CI 1.84-4.60) compared with those with a low Tyg index and a low SHR (TyG < 8.56, SHR < 0.76). The area under the curve (AUC) values were 0.623 (TyG index) and 0.589 (SHR) for CV death/TVMI and 0.659 (TyG index) and 0.624 (SHR) for MACCEs. Furthermore, patients with both a high TyG index and a high SHR showed the highest risk of clinical outcomes among patients with different levels of these two biomarkers, and the AUC for the TyG-SHR combination was larger than the TyG index alone in predicting MACCE risk. CONCLUSIONS: The study revealed that a high TyG index and a high SHR were significantly correlated with poor prognosis in patients with CTO and suggested that these two biomarkers are reliable in predicting long-term prognosis in CTO patients.

The impact of fasting stress hyperglycemia ratio, fasting plasma glucose and hemoglobin A1c on in-hospital mortality in patients with and without diabetes: findings from the China acute myocardial infarction registry.

BACKGROUND: Stress hyperglycemia was positively associated with poor prognosis in individuals with acute myocardial infarction (AMI). However, admission glucose and stress hyperglycemia ratio (SHR) may not be the best indicator of stress hyperglycemia. We performed this study to evaluate the comparative prognostic value of different measures of hyperglycemia (fasting SHR, fasting plasma glucose [FPG], and hemoglobin A1c [HbA1c]) for in-hospital mortality in AMI patients with or without diabetes. METHODS: In this prospective, nationwide, multicenter China Acute Myocardial Infarction (CAMI) registry, 5,308 AMI patients including 2081 with diabetes and 3227 without diabetes were evaluated. Fasting SHR was calculated using the formula [(first FPG (mmol/l))/(1.59×HbA1c (%)-2.59)]. According to the quartiles of fasting SHR, FPG and HbA1c, diabetic and non-diabetic patients were divided into four groups, respectively. The primary endpoint was in-hospital mortality. RESULTS: Overall, 225 (4.2%) patients died during hospitalization. Individuals in quartile 4 had a significantly higher rate of in-hospital mortality compared with those in quartile 1 in diabetic cohort (9.7% vs. 2.0%; adjusted odds ratio [OR] 4.070, 95% CI 2.014-8.228) and nondiabetic cohort (8.8% vs. 2.2%; adjusted OR 2.976, 95% CI 1.695-5.224). Fasting SHR was also correlated with higher in-hospital mortality when treated as a continuous variable in diabetic and nondiabetic patients. Similar results were observed for FPG either as a continuous variable or a categorical variable. In addition, fasting SHR and FPG, rather than HbA1c, had a moderate predictive value for in-hospital mortality in patients with diabetes (areas under the curve [AUC] for fasting SHR: 0.702; FPG: 0.689) and without diabetes (AUC for fasting SHR: 0.690; FPG: 0.693). The AUC for fasting SHR was not significantly different from that of FPG in diabetic and nondiabetic patients. Moreover, adding fasting SHR or FPG to the original model led to a significant improvement in C-statistic regardless of diabetic status. CONCLUSIONS: This study indicated that, in individuals with AMI, fasting SHR as well as FPG was strongly associated with in-hospital mortality regardless of glucose metabolism status. Fasting SHR and FPG might be considered as a useful marker for risk stratification in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01874691.

Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma.

To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.

WITHDRAWN: Novel subgroups of patients with left ventricular thrombus and their differential effects with anticoagulation: a data-driven cluster analysis.

UNSTRUCTURED: Ahead of Print article withdrawn by the publisher.