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Abstract Background Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. Methods ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 μmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. Results ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. Conclusion ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.

Abstract Purpose We aimed to develop and evaluate a new diagnostic method, the 'chicken-wing muscle up test', to improve the accuracy of diagnosis of glenolabral articular disruption (GLAD) lesions compared to currently used clinical tests for injuries to the labrum. Methods Preoperative evaluations were conducted on 85 patients undergoing arthroscopic surgery at a single center between July 2021 to July 2022. The diagnostic performance of the preoperative clinical examinations (chicken-wing muscle up test, O'Brien test, crank test, and O'Driscoll test) were validated against the findings of arthroscopic examinations. Results 12 of the 85 patients in this study had arthroscopically confirmed GLAD lesions. The chicken-wing muscle up test demonstrated significantly higher sensitivity (83.33%) for GLAD lesions than the O'Brien test (33.33%), but not the crank test (50.00%) or O'Driscoll test (25.00%), and significantly higher specificity (95.89%) than the O'Brien test (75.34%), crank test (82.19%), and O'Driscoll test (71.23%). The chicken-wing muscle up test had the largest area under the receiver operating characteristic curve (AUC = 0.896, P 0.05; crank test AUC = 0.661, P > 0.05; O'Brien test AUC = 0.481, P > 0.05), indicating significantly better diagnostic efficacy for GLAD lesions than the other three tests. Conclusions The chicken-wing muscle up test is a reliable diagnostic method that improves the accuracy of diagnosis of GLAD lesions.

Abstract Background Alveolar hypercoagulation and fibrinolytic inhibition are mainly responsible for massive alveolar fibrin deposition, which are closely related with refractory hypoxemia in acute respiratory distress syndrome (ARDS). Our previous study testified runt-related transcription factor (RUNX1) participated in the regulation of this pathophysiology in this syndrome, but the mechanism is unknown. We speculate that screening the downstream genes associated with RUNX1 will presumably help uncover the mechanism of RUNX1. Methods Genes associated with RUNX1 were screened by CHIP-seq, among which the target gene was verified by Dual Luciferase experiment. Then the efficacy of the target gene on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS was explored in vivo as well as in vitro. Finally, whether the regulatory effects of RUNX1 on alveolar hypercoagulation and fibrinolytic in ARDS would be related with the screened target gene was also sufficiently explored. Results Among these screened genes, AKT3 was verified to be the direct target gene of RUNX1. Results showed that AKT3 was highly expressed either in lung tissues of LPS-induced rat ARDS or in LPS-treated alveolar epithelia cell type II (AECII). Tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) were increasingly expressed both in lung tissues of ARDS and in LPS-induced AECII, which were all significantly attenuated by down-regulation of AKT3. Inhibition of AKT3 gene obviously ameliorated the LPS-induced lung injury as well as the collagen I expression in ARDS. RUNX1 overexpression not only promoted the expressions of TF, PAI-1, but also boosted AKT3 expression in vitro. More importantly, the efficacy of RUNX1 on TF, PAI-1 were all effectively reversed by down-regulation of AKT3 gene. Conclusion AKT3 is an important target gene of RUNX1, through which RUNX1 exerted its regulatory role on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS. RUNX1/ATK3 signaling axis is expected to be a new target for the exploration of ARDS genesis and treatment.

Abstract Background Previous studies have traditionally attributed the initiation of cancer cells to genetic mutations, considering them as the fundamental drivers of carcinogenesis. However, recent research has shed light on the crucial role of epigenomic alterations in various cell types present within the tumor microenvironment, suggesting their potential contribution to tumor formation and progression. Despite these significant findings, the progress in understanding the epigenetic mechanisms regulating tumor heterogeneity has been impeded over the past few years due to the lack of appropriate technical tools and methodologies. Results The emergence of single-cell sequencing has enhanced our understanding of the epigenetic mechanisms governing tumor heterogeneity by revealing the distinct epigenetic layers of individual cells (chromatin accessibility, DNA/RNA methylation, histone modifications, nucleosome localization) and the diverse omics (transcriptomics, genomics, multi-omics) at the single-cell level. These technologies provide us with new insights into the molecular basis of intratumoral heterogeneity and help uncover key molecular events and driving mechanisms in tumor development. Conclusion This paper provides a comprehensive review of the emerging analytical and experimental approaches of single-cell sequencing in various omics, focusing specifically on epigenomics. These approaches have the potential to capture and integrate multiple dimensions of individual cancer cells, thereby revealing tumor heterogeneity and epigenetic features. Additionally, this paper outlines the future trends of these technologies and their current technical limitations.

Abstract Background Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising. Methods Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes. Results An integrated diagnostic model called “Combined method” was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.

Abstract Background and aims Although adjuvant transcatheter arterial chemoembolization (TACE) for resected hepatocellular carcinoma (HCC) may improve survival for some patients, identifying which patients can benefit remains challenging. The present study aimed to construct a survival prediction calculator for individualized estimating the net survival benefit of adjuvant TACE for patients with resected HCC. Methods From a multicenter database, consecutive patients undergoing curative resection for HCC were enrolled and divided into the developing and validation cohorts. Using the independent survival predictors in the developing cohort, two nomogram models were constructed for patients with and without adjuvant TACE, respectively, which predictive performance was validated internally and externally by measuring concordance index (C-index) and calibration. The difference between two estimates of the prediction models was the expected survival benefit of adjuvant TACE. Results A total of 2514 patients met the inclusion criteria for the study. The nomogram prediction models for patients with and without adjuvant TACE were, respectively, built by incorporating the same eight independent survival predictors, including portal hypertension, Child–Pugh score, alpha-fetoprotein level, tumor size and number, macrovascular and microvascular invasion, and resection margin. These two prediction models demonstrated good calibration and discrimination, with all the C-indexes of greater than 0.75 in the developing and validation cohorts. A browser-based calculator was generated for individualized estimating the net survival benefit of adjuvant TACE. Conclusions Based on large-scale real-world data, an easy-to-use online calculator can be adopted as a decision aid to predict which patients with resected HCC can benefit from adjuvant TACE.

Abstract Background Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. Methods Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. Results A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. Conclusions Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Abstract Background Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear. Methods We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing. Results We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13–15 region which encodes MDM2, CDK4 and HMGA2 is notable in DDLPS. Mutations in TP53, ATRX, PTEN, and RB1 are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression of MDM2, CDK4 and HMGA2 in DDLPS and down-regulation of TP53 and RB1 in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1, p = 0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS. Conclusions Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification of MDM2 and CDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment.

Abstract Purposes This study was designed to evaluate the effect of preoperative jaundice on long-term prognosis of gallbladder carcinoma (GBC) after radical resection (R0). Methods A total of 267 GBC patients who underwent R0 resection from January 2004 to December 2014 were enrolled, including 54 patients with preoperative jaundice and 213 patients without jaundice. The clinicopathological parameters between the two groups were compared, and the correlation between preoperative jaundice and the long-term prognosis was furtherly analyzed. Results Unilateral and multivariate analyses of 267 GBC patients showed that the depth of tumor invasion (pT stage), lymphatic metastasis, and hepatic invasion were independent prognostic factors. The univariate and multivariate analysis of 54 GBC patients with preoperative jaundice showed that only pT stage was an independent factor for prognosis. Furthermore, the intraoperative blood transfusion and pT stage were significant different between long-term survival (survive for more than 3 years) and those who died within 3 years (P

Abstract Background Krüppel-like factor 8 (KLF8), a cancer-promoting factor that regulates critical gene transcription and cellular cancer-related events, has been implicated in tumor development and progression. However, the functional role of KLF8 in the pathogenesis of hepatocellular carcinoma (HCC) remains largely unknown. Methods The gene expression patterns and genome-wide regulatory profiles of HCC cells after KLF8 knockout were analyzed by using RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) of histone H3 lysine 27 acetylation (H3K27ac) combined with bioinformatics analysis. Transcription factor-binding motifs that recognized by KLF8 were evaluated by motif analysis. For the predicted target genes, transcriptional changes were examined by ChIP, and loss of function experiments were conducted by siRNA transfection. Results KLF8 functioned as a transcription repressor in HCC and mainly regulated apoptotic-related genes directly. A total of 1,816 differentially expressed genes after KLF8 knockout were identified and significantly corresponded to global changes in H3K27ac status. Furthermore, two predicted target genes, high-mobility group AT-hook 2 (HMGA2) and matrix metalloproteinase 7 (MMP7), were identified as important participants in KLF8-mediated anti-apoptotic effect in HCC. Knockout of KLF8 enhanced cell apoptosis process and caused increase in the associated H3K27ac, whereas suppression HMGA2 or MMP7 attenuated these biological effects. Conclusions Our work suggests a novel role and mechanism for KLF8 in the regulation of cell apoptosis in HCC and facilitates the discovery of potential therapeutic targets for HCC treatment.

Abstract Background It has been confirmed that NF-κB p65 signaling pathway is involved in the regulation of alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS). Whether SN50, a NF-κB cell permeable inhibitor, could attenuate alveolar hypercoagulation and fibrinolysis inhibition in ARDS remains to be elucidated. Purpose We explored the efficacy and potential mechanism of SN50 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS in mice. Materials and methods Mouse ARDS was made by 50 μl of lipopolysaccharide (LPS) (4 mg/ml) inhalation. Male BALB/c mice were intraperitoneally injected with different does of SN50 1 h before LPS inhalation. Lung tissues were collected for hematoxylin-eosin (HE) staining, wet/dry ratio. Pulmonary expressions of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), collagen III, as well as phosphorylated p65 (p-p65), p65 in nucleus (p’-p65), IκBα and IKKα/β were measured. Bronchoalveolar lavage fluid (BALF) was gathered to test the concentrations of TF, PAI-1, activated protein C (APC) and thrombinantithrombin complex (TAT). DNA binding activity of NF-κB p65 was also determined. Results After LPS stimulation, pulmonary edema and exudation and alveolar collapse occured. LPS also stimulated higher expressions of TF and PAI-1 in lung tissues, and higher secretions of TF, PAI-1, TAT and low level of APC in BALF. Pulmonary collagen III expression was obviously enhanced after LPS inhalation. At same time, NF-κB signaling pathway was activated with LPS injury, shown by higher expressions of p-p65, p’-p65, p-IKKα/β, p-Iκα in pulmonary tissue and higher level p65 DNA binding activity. SN50 dose-dependently inhibited TF, PAI-1 and collagen IIIexpressions, and decreased TF, PAI-1, TAT but increased APC in BALF. SN50 treatment attenuated pulmonary edema, exudation and reduced lung tissue damage as well. SN50 application significantly reduced p’-p65 expression and weakened p65 DNA binding activity, but expressions of p-p65, p-IKKα/β, p-Iκα in cytoplasm of pulmonary tissue were not affected. Conclusions SN 50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in ARDS via inhibition of NF-κB p65 translocation. Our data demonstrates that NF-κB p65 pathway is a viable new therapeutic target for ARDS treatment.

Abstract Background Risk factors for unfavorable surgical outcomes are dependent on the definitions of the unfavorable surgical outcomes. The aims of this study were to compare risk factors for each unfavorable surgical outcome according to two different definitions of “unfavorable” surgical outcomes after surgery for lumbar spinal stenosis (LSS) as well as compare the clinical course from the preoperative period to 3 years postoperatively between cases with favorable and unfavorable outcomes according to the two different definitions. Methods Overall, 295 patients who underwent spine surgery for LSS and a follow-up evaluation at 3 years postoperatively were enrolled and divided into favorable and unfavorable groups, based on two different definitions for unfavorable surgical outcomes, as evaluated at 12 months postoperatively: the patient-reported outcome (PRO) and minimal clinically important difference (MCID) methods. In the PRO method, patients with a postoperative Oswestry Disability Index (ODI) score > 22 were considered as having an “unfavorable” outcome, whereas in the MCID method, those with a postoperative ODI score that changed 22 after surgery for LSS. It may also be associated with higher odds for improvements in the ODI score of > 12.8.

Abstract Background Specialized Institution-Based Rehabilitation (SIBR) is the cornerstone of care and treatment for individuals with spinal cord injury, but most people with chronic spinal cord injury (CSCI) living in China have no SIBR experience after acute care hospital discharge. In 2009, an SIBR facility was set up in Shanghai (China) to fill this important gap in care. The purpose of the study was to evaluate the effectiveness of an integrated rehabilitation training program among individuals with CSCI living in Shanghai. Methods A within-subject pre-posttest design was used to evaluate the SIBR. The sample included 455 individuals ≥1 year post-SCI, who were older than 18 years of age and were enrolled in a rehabilitation center in Shanghai, China, between 2013 and 2019. The data included individuals’ sociodemographic and injury characteristics, and twenty-three indicators were used as outcome measurements to evaluate basic life skills and their applications in family and social life. Multivariate linear regression was conducted to determine which factors might have influenced the effectiveness of the SIBR. Results All basic life skills and their applications in family and social life were improved, but with variations across socio-demographics. Female individuals with CSCI had better outcomes in basic life skills than did males. In terms of basic life skills and their applications in family and social life, individuals with a low level (thoracic or lumbosacral) of injury achieved more significant functional gains than those with a higher level (cervical). The baseline score was also a relevant factor in functional outcome. Conclusions Even for individuals with a long SCI history, SIBR training can improve basic life skills and the applications of those skills in family and social life settings.

Abstract Background More and more cases of human infections with avian influenza A H7N9 have been reported since it was first mentioned in 2013 in China, but concurrence of influenza A H7N9 with Mycoplasma pneumoniae, however, has never been described. Here, we reported the case of a woman co-infected by influenza A H7N9 and Mycoplasma pneumoniae, whose treatment process was a little bit longer and a little bit complicated as well. Case presentation Our patient was an 80-year-old Chinese woman who presented with fever, cough, chest tightness, and shortness of breath. A computed tomography scan showed obvious infiltrations at lower parts of both lungs. Arterial blood gas analysis confirmed a severe respiratory failure (type I). Her sputum and throat swabs were checked for nucleic acid of influenza A and the result was positive for influenza A H7N9. She was diagnosed as having severe influenza A H7N9 and acute respiratory distress syndrome, and was admitted to an intensive care unit. She was given comprehensive treatment, including oseltamivir, methylprednisolone, immunoglobulin, gastric protection, and noninvasive mechanical ventilation. Her condition improved 4 days later. However, some symptoms exacerbated again 2 days later with ground-glass changes appearing in upper area of right lung and the titer of antibody to Mycoplasma pneumoniae rising from 1:80 to 1:640. She was reasonably considered to be infected with Mycoplasma pneumoniae as well, and azithromycin and moxifloxacin were added to her treatment. Oseltamivir was discontinued because of three consecutive negative results of nucleic acid for influenza A H7N9, but anti-Mycoplasma treatment was continued. Although her symptoms and abnormal changes on computed tomography scan slowly went away, she finally recovered from the mixed infection after a total of 33 days of management. Conclusion In patients with confirmed influenza A H7N9 infection whose condition worsens again, especially with new infiltration or lung ground-glass infiltration, one should suspect infection by other pathogens such as Mycoplasma pneumoniae.

Abstract Background Posterior occipitocervical fixation and fusion are often required to address occipitocervical instability. Safe, stable internal fixation with screws is vital for the success of such surgery. Thus, poor selection of an internal fixation technique may cause fixation and fusion failure, possibly leading to neurovascular injury. Hence, in certain cases, such as in patients with severe instability of an occipitocervical deformity or osteoporosis, we hypothesized that having a third anchor point (a screw in C2) could enhance the stability of the occipitocervical fixation. Case presentation A 31-year-old man with occipitocervical deformity and spinal cord edema underwent a traditional occipitocervical fixation procedure but with the addition of a spinous process screw in C2 as a third anchor point. The procedure included posterior internal fixation and fusion. The occipitocervical fixation was completed by inserting occipital screws, bilateral C2 pedicle screws, C3 lateral mass screws, and a spinous process screw in C2 as a third anchor point. There were no neurovascular complications or incision-site infections. Postoperatively, radiography and computed tomography showed that the occipitocervical reduction and internal fixation had resulted in good spinal alignment, and magnetic resonance imaging showed no obvious spinal cord compression. At 4 months after the surgery, fusion was observed, and the occipitocervical screws remained well positioned. The patient continued to be monitored for 24 months postoperatively. At the 24-month follow-up visit, the muscle strength of the limbs was grade 5, and the patient’s sensation function had improved over his preoperative condition. Conclusions Use of a C2 spinous process screw as a third anchor point may enhance the stability of occipitocervical fixation. Further biomechanical and clinical studies are needed to validate this result.

Abstract Objective The incidence of recurrent hernia after radical resection of prostate cancer is high, so this article discusses the incidence and risk factors of inguinal hernia after radical resection of prostate cancer. Methods This case control study was conducted in The First People’s Hospital of Huzhou clinical data of 251 cases underwent radical resection of prostate cancer in this hospital from March 2019 to May 2021 were retrospectively analyzed. According to the occurrence of inguinal hernia, the subjects were divided into study group and control group, and the clinical data of each group were statistically analyzed, Multivariate Logistic analysis was performed to find independent influencing factors for predicting the occurrence of inguinal hernia. The Kaplan-Meier survival curve was drawn according to the occurrence and time of inguinal hernia. Results The overall incidence of inguinal hernia after prostate cancer surgery was 14.7% (37/251), and the mean time was 8.58 ± 4.12 months. The average time of inguinal hernia in patients who received lymph node dissection was 7.61 ± 4.05 (month), and that in patients who did not receive lymph node dissection was 9.16 ± 4.15 (month), and there was no significant difference between them (P > 0.05). There were no statistically significant differences in the incidence of inguinal hernia with age, BMI, hypertension, diabetes, PSA, previous abdominal operations and operative approach (P > 0.05), but there were statistically significant differences with surgical method and pelvic lymph node dissection (P

Abstract Objective To investigate the association between circulating secretoneurin (SN) and angiographic coronary collateralization in stable angina patients with chronic coronary total occlusion (CTO). Methods SN concentrations in serum were measured in 641 stable angina patients with CTO by radioimmunoassay. The status of coronary collaterals from the contra-lateral vessel was visually estimated using the Rentrop grading system, and was categorized into poor (grade 0 or 1) or good (grade 2 or 3) collateralization. Results Serum SN levels were significantly higher in patients with good coronary collaterals compared to those with poor collaterals (175.23 ± 52.09 pmol/L vs. 143.29 ± 42.01 pmol/L, P

Abstract Background In designing genome-wide association (GWA) studies it is important to calculate statistical power. General statistical power calculation procedures for quantitative measures often require information concerning summary statistics of distributions such as mean and variance. However, with genetic studies, the effect size of quantitative traits is traditionally expressed as heritability, a quantity defined as the amount of phenotypic variation in the population that can be ascribed to the genetic variants among individuals. Heritability is hard to transform into summary statistics. Therefore, general power calculation procedures cannot be used directly in GWA studies. The development of appropriate statistical methods and a user-friendly software package to address this problem would be welcomed. Results This paper presents GWAPower, a statistical software package of power calculation designed for GWA studies with quantitative traits, where genetic effect is defined as heritability. Based on several popular one-degree-of-freedom genetic models, this method avoids the need to specify the non-centrality parameter of the F-distribution under the alternative hypothesis. Therefore, it can use heritability information directly without approximation. In GWAPower, the power calculation can be easily adjusted for adding covariates and linkage disequilibrium information. An example is provided to illustrate GWAPower, followed by discussions. Conclusions GWAPower is a user-friendly free software package for calculating statistical power based on heritability in GWA studies with quantitative traits. The software is freely available at: http://dl.dropbox.com/u/10502931/GWAPower.zip

Abstract Background It is well established in E. coli and Vibrio cholerae that strains harboring mutations in the ferric uptake regulator gene (fur) are unable to utilize tricarboxylic acid (TCA) compounds, due to the down-regulation of key TCA cycle enzymes, such as AcnA and SdhABCD. This down-regulation is mediated by a Fur-regulated small regulatory RNA named RyhB. It is unclear in the γ-proteobacterium S. oneidensis whether TCA is also regulated by Fur and RyhB. Results In the present study, we showed that a fur deletion mutant of S. oneidensis could utilize TCA compounds. Consistently, expression of the TCA cycle genes acnA and sdhA was not down-regulated in the mutant. To explore this observation further, we identified a ryhB gene in Shewanella species and experimentally demonstrated the gene expression. Further experiments suggested that RyhB was up-regulated in fur mutant, but that AcnA and SdhA were not controlled by RyhB. Conclusions These cumulative results delineate an important difference of the Fur-RyhB regulatory cycle between S. oneidensis and other γ-proteobacteria. This work represents a step forward for understanding the unique regulation in S. oneidensis.

Abstract Ubiquitin-specific-processing protease 7 (USP7) is a promising target protein for cancer therapy, and great attention has been given to the identification of USP7 inhibitors. Traditional virtual screening methods have now been successfully applied to discover USP7 inhibitors aiming at reducing costs and speeding up time in several studies. However, due to their unsatisfactory accuracy, it is still a difficult task to develop USP7 inhibitors. In this study, multiple supervised learning classifiers were built to distinguish active USP7 inhibitors from inactive ligands. Physicochemical descriptors, MACCS keys, ECFP4 fingerprints and SMILES were first calculated to represent the compounds in our in-house dataset. Two deep learning (DL) models and nine classical machine learning (ML) models were then constructed based on different combinations of the above molecular representations under three activity cutoff values, and a total of 15 groups of experiments (75 experiments) were implemented. The performance of the models in these experiments was evaluated, compared and discussed using a variety of metrics. The optimal models are ensemble learning models when the dataset is balanced or severely imbalanced, and SMILES-based DL performs the best when the dataset is slightly imbalanced. Meanwhile, multimodal data fusion in some cases can improve the performance of ML and DL models. In addition, SMOTE, unbiased decoy selection and SMILES enumeration can improve the performance of ML and DL models when the dataset is severely imbalanced, and SMOTE works the best. Our study established highly accurate supervised learning classification models, which would accelerate the development of USP7 inhibitors. Some guidance was also provided for drug researchers in selecting supervised models and molecular representations as well as handling imbalanced datasets. Graphical Abstract

Abstract Background The formation of advanced glycation end-products (AGEs) is a crucial risk factor for the pathogenesis of cardiovascular diseases in diabetes. We investigated whether N-epsilon-carboxymethyllysine (CML), a major form of AGEs in vivo, was associated with poor coronary collateral vessel (CCV) formation in patients with type 2 diabetes mellitus (T2DM) and chronic total occlusion (CTO) of coronary artery. Methods This study consisted of 242 T2DM patients with coronary angiographically documented CTO. Blood samples were obtained and demographic/clinical characteristics were documented. The coronary collateralization of these patients was defined according to Rentrop or Werner classification. Serum CML levels were evaluated using ELISA assay. Receiver operating characteristic curve and multivariable regression analysis were performed. Results 242 patients were categorized into poor CCV group or good CCV group (107 vs. 135 by the Rentrop classification or 193 vs. 49 by the Werner classification, respectively). Serum CML levels were significantly higher in poor CCV group than in good CCV group (110.0 ± 83.35 vs. 62.95 ± 58.83 ng/ml by the Rentrop classification and 94.75 ± 78.29 ng/ml vs. 40.37 ± 28.69 ng/ml by Werner classification, both P

Abstract Background Labor represents a period of significant physical activity. Inefficient energy supply may delay labor process and even lead to cesarean delivery. Herein we investigated whether ingestion of a carbohydrate-rich beverage could reduce cesarean delivery in laboring women with epidural analgesia. Methods This multicenter randomized trial was conducted in obstetrician-led maternity units of nine tertiary hospitals in China. Primigravidae with single term cephalic pregnancy who were preparing for vaginal birth under epidural analgesia were randomized to intake a carbohydrate-rich beverage or commercially available low-carbohydrate beverages during labor. The primary outcome was the rate of cesarean delivery. Secondary outcomes included maternal feeling of hunger, assessed with an 11-point scale where 0 indicated no hunger and 10 the most severe hunger, and maternal and neonatal blood glucose after childbirth. Results Between 17 January 2018 and 20 July 2018, 2008 women were enrolled and randomized, 1953 were included in the intention-to-treat analysis. The rate of cesarean delivery did not differ between the two groups (11.3% [111/982] with carbohydrate-rich beverage vs. 10.9% [106/971] with low-carbohydrate beverages; relative risk 1.04, 95% CI 0.81 to 1.33; p = 0.79). Women in the carbohydrate-rich beverage group had lower subjective hunger score (median 3 [interquartile range 2 to 5] vs. 4 [2 to 6]; median difference − 1; 95% CI − 1 to 0; p

Abstract Background We investigated whether glycemic control affects the relation between endothelial dysfunction and coronary artery disease in patients with type 2 diabetes mellitus (T2DM). Methods In 102 type 2 diabetic patients with stable angina, endothelial function was evaluated using brachial artery flow-mediated dilation (FMD) with high-resolution ultrasound, and significant stenosis of major epicardial coronary arteries (≥ 50% diameter narrowing) and degree of coronary atherosclerosis (Gensini score and SYNTAX score) were determined. The status of glycemic control was assessed by blood concentration of glycated hemoglobin (HbA1c). Results The prevalence of significant coronary artery stenosis (67.9% vs. 37.0%, P = 0.002) and degree of coronary atherosclerosis (Gensini score: 48.99 ± 48.88 vs. 15.07 ± 21.03, P 0.05). Conclusion Poor glycemic control negatively influences the association of endothelial dysfunction and coronary artery disease in T2DM patients.

Abstract Background Patients with type 2 diabetes mellitus (T2DM) are predisposed to poor cardiovascular outcomes after ST-segment elevation myocardial infarction (STEMI). Left ventricular adverse remodeling (LVAR) triggered upon myocardial infarction is recognized as the predominant pathological process in the development of heart failure. In the present study, we sought to investigate whether visit-to-visit fasting plasma glucose (FPG) variability is a potential predictor of LVAR in T2DM patients after STEMI. Methods From January 2014 to December 2018 in Ruijin Hospital, T2DM patients with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for ~ 12 months. The changes in left ventricular geometric and functional parameters between baseline and 12-month follow-up were assessed by echocardiography. The incidence of LVAR, defined as 20% increase in indexed left ventricular end-diastolic volume (LVEDV), and its relationship with visit-to-visit FPG variability were analyzed. Multivariate regression models were constructed to test the predictive value of FPG variability for post-infarction LVAR. Results A total of 437 patients with type 2 diabetes and STEMI were included in the final analysis. During a mean follow-up of 12.4 ± 1.1 months, the incidence of LVAR was 20.6% and mean enlargement of indexed LVEDV was 3.31 ± 14.4 mL/m2, which was significantly increased in patients with higher coefficient variance (CV) of FPG (P = 0.002) irrespective of baseline glycemic levels. In multivariate analysis, FPG variability was independently associated with incidence of post-infarction LVAR after adjustment for traditional risk factors, baseline HbA1c as well as mean FPG during follow-up (OR: 3.021 [95% CI 1.081–8.764] for highest vs. lowest tertile of CV of FPG). Assessing FPG variability by other two measures, including standard deviation (SD) and variability independent of the mean (VIM), yielded similar findings. Conclusions This study suggests that visit-to-visit FPG variability is an independent predictor of incidence of LVAR in T2DM patients with STEMI. Trial registration Trials number, NCT02089360; registered on March 17,2014.

Abstract Background Patients with type 2 diabetes are under substantially higher risk of in-stent restenosis (ISR) after coronary stent implantation. We sought to investigate whether visit-to-visit HbA1c variability is a potential predictor of ISR in diabetic patients after stent implantation. Methods We consecutively enrolled type 2 diabetic patients who underwent successful elective percutaneous coronary intervention and performed follow-up coronary angiography after around 12 months. The incidence of ISR and its relationship with visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), standard deviation (SD) and variability independent of the mean (VIM), were studied. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of HbA1c variability for ISR. Results From September 2014 to July 2018 in Ruijin Hospital, a total of 420 diabetic patients (688 lesions) after stent implantation were included in the final analysis. During a mean follow-up of 12.8 ± 1.3 months, the incidence of ISR was 8.6%, which was significantly increased in patients with higher CV of HbA1c (P = 0.001). The mean diameter stenosis (DS), net luminal loss and net luminal gain were 22.9 ± 16.8%, 0.42 ± 0.88 mm and 1.66 ± 0.83 mm, respectively. Greater DS was observed in subjects with higher tertiles of CV of HbA1c (P

Abstract Background To assess the prognostic role of coronary collaterals in patients with type 2 diabetes mellitus (T2DM) after successful percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). Methods Coronary collateralization was graded according to Rentrop scoring system in 198 type 2 diabetic patients and 335 non-diabetics with stable angina undergoing PCI for at least one CTO lesion. Left ventricular ejection fraction (LVEF) was determined and major adverse cardio-cerebral events (MACCE) were recorded during follow-up. Results Poor collateralization was more common in patients with T2DM than in non-diabetics (40% vs 29%, p = 0.008). At 13.5 ± 4.1 months, the rate of composite MACCE (17.3% vs 27.6%, p = 0.034) and repeat revascularization (15.2% vs 25.5%, p = 0.026) was lower and the increase in LVEF (3.10% vs 1.80%, p = 0.024) was greater in patients with good collaterals than in those with poor collaterals for non-diabetic group. The associations were in the same direction for T2DM group (35% vs 44%; 30% vs 36%; 2.14% vs 1.65%, respectively) with a higher all-cause mortality in diabetic patients with poor collaterals (p = 0.034). Multivariable Cox proportional hazards analysis showed that coronary collateralization was an independent factor for time to MACCE (HR 2.155,95% CI 1.290–3.599, p = 0.003) and repeat revascularization (HR 2.326, 95% CI 1.357–3.986, p = 0.002) in non-diabetic patients, but did not enter the model in those with T2DM. Conclusions T2DM is associated with reduced coronary collateralization. The effects of the status of coronary collateralization on long-term clinical outcomes and left ventricular function appear to be similar in size in type 2 diabetic patients and non-diabetics after successful recanalization of CTO.

Abstract Background Bladder cancer is the most common cancer in the urinary system and the fourth most common cancer in males. This study aimed to examine differences in the survival of bladder cancer patients of different ethnicities. Method We used the SEER database to obtain data pertaining to bladder cancer patients from 2010 to 2015. Univariate and multivariate Cox proportional hazards regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ethnicity and death. Kaplan–Meier survival and nomogram analyses were used to compare survival differences among patients with different ethnicities. Results Among 101,364 bladder cancer patients, 90,910 were white, 5893 were black, 337 were American Indian/Alaska Native (AIAN), and 4224 were Asian or Pacific Islander (API). Our multivariate analysis identified differences between different ethnicities. Compared to the API group, the AIAN (HR = 1.31, 95% CI = 1.09–1.57, P

Abstract Background Metabolic syndrome (MS) has abruptly increased in China in the past two decades, gradually representing an important public health threat over the years. Here, we firstly reported the prevalence and associated factors of metabolic syndrome in Jiangxi province, China. Methods A population-based cross-sectional survey was performed in Jiangxi province, China, from April to August 2015. MS was diagnosed by International Diabetes Federation (IDF) and Chinese Diabetes Society (CDS) criteria, respectively. Factors associated with MS were investigated by multivariate logistic regression. Results A total of 2665 residents aged over 18 years were enrolled, and 2580 effectively participated. According to IDF and CDS criteria, age-standardized prevalence of MS were 21.1 and 15.2% in all participants, respectively; prevalence were 19.6% or 17.1% in men, and 22.7% or 13.0% in women, based on these respective criteria. Rural participants had a significantly higher prevalence than urban individuals, so did rural females. Prevalence in males did not differ between rural and urban participants. Factors independently associated with MS were low education level and menopausal state. Conclusions To the best of our knowledge, this was the latest study on MS prevalence in Jiangxi province. In conclusion, MS prevalence is high in Jiangxi province. Considering the unhealthy lifestyle, education is urgently needed to prevent the rapid increase of MS prevalence.

Abstract Background Although enhanced recovery after surgery (ERAS) has made great progress in the field of surgery, the guidelines point to the lack of high-quality evidence in upper gastrointestinal surgery. Methods Randomized controlled trials in four electronic databases that involved ERAS protocols for upper gastrointestinal surgery were searched through December 12, 2018. The primary endpoints were lung infection, urinary tract infection, surgical site infection, postoperative anastomotic leakage and ileus. The secondary endpoints were postoperative length of stay, the time from end of surgery to first flatus and defecation, and readmission rates. Subgroup analysis was performed based on the type of surgery. Results A total of 17 studies were included. The results of the meta-analysis indicate that there was a decrease in rates of lung infection (RR = 0.50, 95%CI: 0.33 to 0.75), postoperative length of stay (MD = -2.53, 95%CI: − 3.42 to − 1.65), time until first postoperative flatus (MD = -0.64, 95%CI: − 0.84 to − 0.45) and time until first postoperative defecation (MD = -1.10, 95%CI: − 1.74 to − 0.47) in patients who received ERAS, compared to conventional care. However, other outcomes were not significant difference. There was no significant difference between ERAS and conventional care in rates of urinary tract infection (P = 0.10), surgical site infection (P = 0.42), postoperative anastomotic leakage (P = 0.45), readmissions (P = 0.31) and ileus (P = 0.25). Conclusions ERAS protocols can reduce the risk of postoperative lung infection and accelerating patient recovery time. Nevertheless, we should also consider further research ERAS should be performed undergoing gastrectomy and esophagectomy.

Abstract Background Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex. Methods With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease. Results The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP

Abstract Background Adverse cardiac remodeling after ST-segment elevation myocardial infarction (STEMI) is a major cause for poor cardiovascular outcomes such as heart failure. The predisposing factors and underlying mechanisms remain not fully understood. This study investigates the association of insulin resistance and dysglycemia with left ventricular (LV) remodeling after STEMI in non-diabetic patients. Methods A total of 485 non-diabetic subjects with STEMI who underwent primary percutaneous coronary intervention were consecutively enrolled and followed up for 12 months. Relation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and glucose levels to changes in echocardiography parameters was studied. Results Left ventricular dilation was detected in 49.1% of subjects at 12-month follow-up after STEMI, and was more severe in subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and high HOMA-IR levels. HOMA-IR remained correlated to changes in LV dimensions after adjusting for confounding risk factors. Multivariate regression analysis demonstrated that higher HOMA-IR was independently associated with greater LV dilation after STEMI. A significant interaction term was present between HOMA-IR and IGT in the model (P = 0.001). Conclusions Our study reveals that insulin resistance and dysglycemia are prevalent in non-diabetic patients with STEMI and are predictors of the post-infarction LV dilation. Trial registration Trials number, NCT02089360; registered on March 17, 2014

Abstract Background We investigated whether or to what extent the interaction of lipoprotein (a) [Lp(a)] with cholesterol-containing lipids was associated with angiographic coronary collateralization in type 2 diabetic patients with chronic total occlusion. Methods Serum levels of Lp(a), total cholesterol, low-density lipoprotein–cholesterol (LDL-C), high-density lipoprotein–cholesterol (HDL-C), and triglyceride were determined and non-HDL-C was calculated in 706 type 2 diabetic and 578 non-diabetic patients with stable coronary artery disease and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3). Results For diabetic and non-diabetic patients, Lp(a), total cholesterol, LDL-C, and non-HDL-C levels were higher in patients with poor coronary collateralization than in those with good collateralization, whereas HDL-C and triglyceride levels were similar. After adjustment for potential confounding factors, tertiles of Lp(a), total cholesterol, LDL-C and non-HDL-C remained independent determinants for poor collateralization. A significant interaction between Lp(a) and total cholesterol, LDL-C or non-HDL-C was observed in diabetic patients (all P interaction

Abstract Background Gestational diabetes mellitus is strongly related to the risk of pancreatic cancer in pregnant women, but gestational diabetes can precede a diagnosis of pancreatic cancer by many years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1. Pancreatic adenocarcinoma is one of the most common malignancies associated with thromboembolic events. A clinical study showed that thromboembolic events were detected in 36% of patients diagnosed as having pancreatic cancer. Studies showed that gestational diabetes mellitus could be one of the important risk factors for pancreatic cancer. Case presentation Gestational diabetes mellitus is associated with increased risk of breast and pancreatic cancer. This case report describes a 29-year-old Chinese woman who presented with: gestational diabetes mellitus; International Society on Thrombosis and Haemostasis criteria suggested disseminated intravascular coagulation with a score of 5; hemolysis, elevated liver enzymes, low platelet count syndrome; and pulmonary hypertension. After an intravenous injection of fibrinogen, she gave birth to a normal baby and following delivery, her blood pressure reached 180/110 mmHg. Laboratory analysis results showed elevated lactic dehydrogenase, decreased platelets and fibrinogen, and urine protein was positive. She was transfused with fresh frozen plasma, blood coagulation factor, and fibrinogen. Subsequently, she was transferred to a maternity intensive care unit, where magnesium sulfate seizure prophylaxis was continued for 24 hours to keep her magnesium level at a low therapeutic range. However, continuous oxygen therapy was needed to maintain her oxygenation. Further laboratory investigations revealed elevated carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4. Positron emission tomography-computed tomography showed malignant carcinoma in the head of her pancreas with lymph node involvement along with bone, peritoneal, and left adrenal metastasis, as well as double lung lymphangitic carcinomatosis. Conclusion A differential diagnosis of digestive system neoplasm should be considered when a pregnant patient presents with gestational diabetes mellitus and disseminated intravascular coagulation, where the disseminated intravascular coagulation has no specific cause and cannot be readily resolved.

Abstract Background Negative coronary artery remodeling is frequent in patients with diabetes, but its mechanism remains unclear. We here evaluated the association of serum levels of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) with coronary artery remodeling in type 2 diabetic patients. Methods Serum levels of GA and esRAGE were measured and intravascular ultrasound was performed in 136 consecutive diabetic patients with 143 coronary intermediate lesions. The remodeling index (RI) was calculated as the ratio between external elastic membrane (EEM) area at the lesion site and EEM area at the reference segment. Negative remodeling (NR) was defined as an RI

Abstract Background We investigated whether and to what extent stenosis of predominant collateral donor artery (PCDA) affects coronary collateral flow in relation to blood pressure (BP) in type 2 diabetic patients with chronic total occlusion (CTO). Methods Collateral flow index (CFI) as derived from intracoronary pressure distal to occluded segment and mean aortic pressure in 220 type 2 diabetic patients and 220 propensity score matched non-diabetic controls undergoing percutaneous coronary intervention for CTO. The severity of PCDA stenosis was graded according to lumen diameter narrowing. Results CFI decreased stepwise from mild to severe stenosis of the PCDA and was lower in diabetic patients with moderate or severe PCDA stenosis than in non-diabetic controls (0.36 ± 0.10 vs. 0.45 ± 0.08, P

Abstract Background The extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear. Methods With the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO). Results Diffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation. Conclusions T2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM.