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Diabetic nephropathy (DN) is one of the most serious complications of advanced diabetes, and increases patient mortality. Recently, epigenetics-mediated hyperglycemic memory in pathological process of DN has received attention. The purpose of this study was to determine the underlying mechanism by which sirt7 modulates hyperglycemic memory in DN. In glomerular endothelial cells (GECs) cultured in high glucose and glomeruli of DN patients and rats, an increase in p65 phosphorylation and endothelial adhesion molecule levels persisted after glucose normalization but was reversed by glucose normalization associated with death-associated protein kinase-3 (DAPK3) knockout or DAPK3 inhibitor. High glucose-mediated decrease in sirt7, the deacetylase modulating H3K18-acetylation (H3K18ac), was sustained after normoglycemia. Sirt7 overexpression accompanied by glucose normalization suppressed DAPK3 expression and inflammation in GECs. Moreover, sh-sirt7-induced inflammation was inhibited by si-DAPK3. Furthermore, sirt7 and H3K18ac were located at the DAPK3 promoter region. ELK1 was found to combine with sirt7. si-ELK1 supplemented with normoglycemia inhibited high glucose-induced DAPK3 expression and inflammation in GECs. ELK1 overexpression-mediated inflammation was inhibited by si-DAPK3. In addition, ELK1 and sirt7 were located at the same promoter region of DAPK3. ELK1 overexpression enhanced DAPK3 promoter activity, which disappeared after specific binding site mutation. In vivo, sirt7 overexpression decreased inflammation and improved renal function during insulin treatment of DN rats, whereas insulin alone did not work. Our data demonstrated high glucose-mediated mutual inhibition between sirt7 and ELK1 induced DAPK3 transcription and inflammation despite normoglycemia in GECs, thus forming a vicious cycle and participating in the occurrence of hyperglycemic memory in DN.

Few studies have evaluated the short-term association between hospital admissions and individual exposure to ambient particulate matter (PM2.5). Particularly, no studies focused on hospital admissions for chronic obstructive pulmonary disease (COPD) at individual level. We assessed the short-term effects of PM2.5 on hospitalization admissions for COPD in Guangzhou, China, during 2014–2015, based on satellite-derived estimates of ambient PM2.5 concentrations at 1-km resolution near the residential address as individual-level exposure for each patient. 40,002 patients with COPD admitted to 110 hospitals were included in this study. A time-stratified case-crossover design with conditional logistic regression models was applied to assess the effects of PM2.5 based on 1-km grid data of aerosol optical depth provided by National Aeronautics and Space Administration on hospital admissions for COPD. Further, we performed stratified analyses by individual demographic characteristics and season of hospital admission. 10 µg/m3 increase in individual-level PM2.5 was associated with an increase of 1.6% (95% confidence interval [CI]: 0.6%, 2.7%) in hospitalization for COPD at lag of 0–5 days. The impact of PM2.5 on hospitalization for COPD was greater significantly in male and patients admitted in summer and accordingly the impacts may be exacerbated in the context of global warming. Our study strengthened the evidence for the adverse effect of PM2.5 based on satellite-based individual-level exposure data.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

The sensed data from infant sports and training programs are useful in analyzing their health conditions and forecasting any disorders or abnormalities. The sensed information is processed for providing errorless predictions for infant diseases/disorders, coupled with artificial intelligence and sophisticated healthcare technologies. The problem of noncongruent sensed data impacting the forecast occurs due to errors between consecutive training iterations. This problem is addressed using the deep learning (PEST-DL) proposed perceptible error segregation technique. The training process is halted between two consecutive iterations generating errors until a similarity verification based on infant history is performed. The similarity output determines the errors due to mismatching data observations, and therefore, the data augmentation is performed. The first perceptible error is mitigated by training the learning paradigm with all possible infant history data in the learning process. This prevents prediction lag and data omissions due to discrete availability. The learning is trained from the identified error with the precise detected disorder/abnormality data previously detected. Therefore, the first and consecutive training data segregate error instances from the actual training iterations. This improves the prediction accuracy and precision with controlled error and time complexity.

Background DNA 5-hydroxymethylcytosine (5hmC) is produced by dynamic 5mC oxidation process contributing to tissue specification, and loss of 5hmC has been reported in multiple cancers including genitourinary cancers. However, 5hmC is also cell-type specific, and its variability may exist between differentiated tumor cells and cancer stem cells. Thus, cancer-associated changes in 5hmC may be contributed by distinct sets of tumor cells within the tumor tissues. Results Here, we applied a sensitive immunoprecipitation-based method (hMeDIP-seq) to analyze 5hmC changes during genitourinary carcinogenesis (including prostate, urothelial and kidney). We confirmed the tissue-specific distribution of 5hmC in genitourinary tissues and identified regional gain and global loss of 5hmC coexisting in genitourinary cancers. The genes with gain of 5hmC during tumorigenesis were functionally enriched in regulating stemness and hypoxia, whereas were associated with poor clinical prognosis irrespective of their differences in tumor type. We identified that gain of 5hmC occurred in soft fibrin gel-induced 3D tumor spheres with a tumor-repopulating phenotype in two prostate cancer cell lines, 22RV1 and PC3, compared with conventional two-dimensional (2D) rigid dishes. Then, we defined a malignant signature derived from the differentially hydroxymethylated regions affected genes of cancer stem-like cells, which could predict a worse clinical outcome and identified phenotypically malignant populations of cells from prostate cancer tumors. Notably, an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, restored 5hmC and killed the cancer stem cell-like cells leading to apoptosis in prostate cancer cell lines. Conclusions Collectively, our study dissects the regional gain of 5hmC in maintaining cancer stem-like cells and related to poor prognosis, which provides proof of concept for an epigenetic differentiation therapy with vitamin C by 5hmC reprogramming. Graphic Abstract

Pyroptosis has profound impacts on tumor cell proliferation, invasion, and metastasis and is of great clinical significance for different cancers. However, the role of pyroptosis in the progression and prognosis of muscle invasive bladder cancer (MIBC) remains poorly characterized. Here, we collected multicenter MIBC data and performed integrated analysis to dissect the role of pyroptosis in MIBC and provide an optimized treatment for this disease. Based on transcriptomic data, we developed a novel prognostic model named the pyroptosis-related gene score (PRGScore), which summarizes immunological features, genomic alterations, and clinical characteristics associated with the pyroptosis phenotype. Samples with high PRGScore showed enhancement in CD8+ T cell effector function, antigen processing machinery and immune checkpoint and better response to immunotherapy by programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, which indicates that PRGScore is a valuable signature in the identification of populations sensitive to immune checkpoint inhibitors. Collectively, our study provides insights into further research targeting pyroptosis and its tumor immune microenvironment (TME) and offers an opportunity to optimize the treatment of MIBC.

This study was designed to critically evaluate the effect of music interventions on cancer-related fatigue (CRF) in cancer patients. Seven databases (Cochrane Library, PubMed, Embace, CBM, Wanfang, VIP, and CNKI) were systematically reviewed from inception to June 2020 for randomized controlled trials (RCTs). Two reviewers critically and independently assessed the risk of bias using Cochrane Collaboration criteria and extracted correlated data using the designed form. All analyses were performed with Review Manager 5.3. A total of 8 qualified studies that included 467 patients (music interventions: 235, control: 232) were included. Cancer patients who completed adjuvant therapy in the music intervention group, especially those with malignant hematological diseases, reported reduced CRF levels compared with patients undergoing routine care. Regardless of the frequencies, music interventions can relieve fatigue in cancer patients. Providing prerecorded music and participating in live music both can mitigate CRF. Music interventions can be considered as an alternative therapy for relieving fatigue in cancer patients who are undergoing active treatment or have completed treatment.

Purpose Children who are left behind when their parents migrate for work have a high prevalence of emotional and behavioral problems, which affect social function and increase family burden. To date, no national survey has been conducted on the emotional and behavioral problems of left-behind children (LBC) in China. This study aimed to investigate the emotional and behavioral outcomes of primary school LBC in the fourth grade in impoverished rural China and the possible influences of family environment and parenting practices. Methods A cross-sectional study was carried out in 27 rural counties in the central and western parts of China from November 2016 to January 2017. The method of quota sampling was adopted to achieve a representative sample using postweighting adjustment. The survey sample was distributed proportionately across each county. LBC were defined as children aged 17) was significantly higher in the LBC group than in the NLBC group (15.6% vs. 11.6%; p < .01). Binary regression analysis showed that high levels of insomnia (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.04–2.27), loneliness (OR 1.65, 95% CI 1.13–2.43), and self-harm (OR 1.92, 95% CI 1.17–3.16) may increase the risk of abnormal SDQ total scores in LBC. Conclusions LBC showed a higher prevalence of abnormal SDQ total scores than NLBC. Insomnia, loneliness, and self-harm behavior were associated with abnormal SDQ total scores in LBC.

Background Supraventricular tachycardia (SVT) with coronary sinus (CS) ostial atresia (CSA) or coronary sinus stenosis (CSS) causes difficulty in electrophysiological procedures, but its characteristics are poorly understood. Objective Study the anatomical and clinical features of SVT patients with CSA/CSS. Methods Of 6128 patients with SVT undergoing electrophysiological procedures, consecutive patients with CSA/CSS were enrolled, and the baseline characteristics, imaging materials, intraoperative data, and follow-up outcomes were analyzed. Results Thirteen patients, seven with CSA and six with CSS, underwent the electrophysiological procedure. Decapolar catheters were placed into the proximal CS in three cases, while the rest were placed at the free wall of the right atrium. Fourteen arrhythmias were confirmed: four atrioventricular nodal reentrant tachycardias, five left-sided accessory pathways, three paroxysmal atrial fibrillations, and two atrial flutters (AFLs). In addition to three patients who underwent only an electrophysiological study, the acute ablation success rate was 100% in 10 cases, with no procedure-related complications. After a median follow-up period of 59.6 months, only one case of atypical AFL recurred. For those cases (seven CSA and two CSS) with a total of 10 anomalous types of CS drainage, three types were classified: from the CS to the persistent left superior vena cava (n = 3), from an unroofed CS (n = 3), and from the CS to the small cardiac vein (n = 3) or Thebesian vein (n = 1). Conclusion Patients with CSA/CSS may develop different kinds of SVT. Electrophysiological procedures for such patients are feasible and effective. An individualized mapping strategy based on the three types of CS drainage will be helpful.

Background Percutaneous left atrial appendage (LAA) occlusion is effective for stroke prevention in patients with atrial fibrillation. LAA can have a complex anatomy, such as multiple lobes or a large orifice, which may render it unsuitable for occlusion using regular devices. We aimed to investigate the feasibility, safety, and short-term efficacy of the small-umbrella LAmbre device for morphologically complicated LAA. Methods We retrospectively enrolled 129 consecutive patients who underwent LAA occlusion using the LAmbre device; the small-umbrella LAmbre device was used in 30 of these patients. We analyzed patients’ characteristics, procedural details, and outcomes. Results Twenty-two patients (73.3%) had multilobed (≥ 2) LAA. The umbrella of the occluder was anchored in the branch in 9 patients and in the common trunks of branches in 13 patients. The landing zone and orifice diameters were 19.0 ± 4.39 mm and 27.4 ± 3.95 mm, respectively. The sizes of the umbrella and occluder cover were 22.0 ± 3.42 mm and 34.3 ± 2.75 mm, respectively. At 3-month follow-up transesophageal echocardiography in 24 patients, no peri-device residual flow was reported. Device thrombosis was detected in one patient at 3 months and disappeared after 3 months of anticoagulation. Ischemic stroke occurred in one patient; no other adverse events were reported. Conclusions Occlusion of morphologically complicated LAA using the small-umbrella LAmbre device was feasible, safe, and effective in patients with atrial fibrillation in this study. This occluder provides an alternative for patients who cannot be treated with regular-sized LAA occlusion devices.

Diabetic nephropathy (DN), which is a common microvascular complication with a high incidence in diabetic patients, greatly increases the mortality of patients. With further study on DN, it is found that epigenetics plays a crucial role in the pathophysiological process of DN. Epigenetics has an important impact on the development of DN through a variety of mechanisms, and promotes the generation and maintenance of metabolic memory, thus ultimately leading to a poor prognosis. In this review we discuss the methylation of DNA, modification of histone, and regulation of non-coding RNA involved in the progress of cell dysfunction, inflammation and fibrosis in the kidney, which ultimately lead to the deterioration of DN.

Objective. To investigate the efficacy of gamma globulin combined with azithromycin sequential therapy in the treatment of children with refractory mycoplasma pneumonia and its effect on Th1/Th2 cytokine levels. Method. From January 2021 to January 2022, 100 children diagnosed with refractory mycoplasma pneumonia were randomly divided into 2 groups (50 cases in each one), the control group was treated with azithromycin plus comprehensive basic treatment, and the treatment group was treated with combined treatment on the basis of the control group, gamma globulin therapy; the treatment effect and cytokine levels of the two groups were compared. Results. Th1, Th2, and Th1/Th2 before treatment were not significantly different between the two groups. Th1, Th2, and Th1/Th2 in the treatment group were significantly downregulated compared with those in the control group after treatment. The levels of IgG, IgA, and IgM in the treatment group were not significantly different from those in the control group before treatment but were significantly upregulated after treatment. IL-10, IL-6, and IL-2 levels were also significantly increased in the treatment group. The disappearance time of clinical symptoms such as fever, cough, and pulmonary rales in the treatment group was significantly shorter than that in the control group, and the cure rate in the treatment group was significantly better than that in the control group. Conclusion. The clinical effect of gamma globulin combined with azithromycin sequential therapy in the treatment of children with refractory mycoplasma pneumonia is remarkable, which can reduce inflammatory factors, improve patients’ immunity, and promote disease recovery.

With the rapid development and high therapeutic efficiency and biosafety of gas-involving theranostics, hydrogen medicine has been particularly outstanding because hydrogen gas (H2), a microbial-derived gas, has potent anti-oxidative, anti-apoptotic, and anti-inflammatory activities in many disease models. Studies have suggested that H2-enriched saline/water alleviates colitis in murine models; however, the underlying mechanism remains poorly understood. Despite evidence demonstrating the importance of the microbial hydrogen economy, which reflects the balance between H2-producing (hydrogenogenic) and H2-utilizing (hydrogenotrophic) microbes in maintaining colonic mucosal ecosystems, minimal efforts have been exerted to manipulate relevant H2–microbe interactions for colonic health. Consistent with previous studies, we found that administration of hydrogen-rich saline (HS) ameliorated dextran sulfate sodium–induced acute colitis in a mouse model. Furthermore, we demonstrated that HS administration can increase the abundance of intestinal-specific short-chain fatty acid (SCFA)–producing bacteria and SCFA production, thereby activating the intracellular butyrate sensor peroxisome proliferator–activated receptor γ signaling and decreasing the epithelial expression of Nos2, consequently promoting the recovery of the colonic anaerobic environment. Our results also indicated that HS administration ameliorated disrupted intestinal barrier functions by modulating specific mucosa-associated mucolytic bacteria, leading to substantial inhibition of opportunistic pathogenic Escherichia coli expansion as well as a significant increase in the expression of interepithelial tight junction proteins and a decrease in intestinal barrier permeability in mice with colitis. Exogenous H2 reprograms colonocyte metabolism by regulating the H2–gut microbiota–SCFAs axis and strengthens the intestinal barrier by modulating specific mucosa-associated mucolytic bacteria, wherein improved microbial hydrogen economy alleviates colitis.

Supplemental Digital Content is available in the text., Hepatocellular carcinoma (HCC) is a complicated and poor prognosis cancer, necessitating the development of a potential treatment strategy. In this study, we initially revealed that LukS-PV belonged to leukocidin family performs an anti-HCC action. Then, we used liquid chromatography-mass spectrometry (LC/MS) to compare protein expression profiles of the LukS-PV-treated human HCC cell lines HepG2 and the control cells. GO annotations and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out of differential expression followed by protein–protein interactome, to explore the underlying cancer suppressor mechanisms of LukS-PV for human HCC. A total of 88 upregulated proteins and 46 downregulated proteins were identified. The top 10 proteins identified by the MCC method are FN1, APP, TIMP1, nucleobindin-1, GOLM1, APLP2, CYR61, CD63, ENG, and CD9. Our observation on protein expression indicated that LukS-PV produces a signature affecting central carbon metabolism in cancer, galactose metabolism, and fructose and mannose metabolism pathways. The results give a functional effects and molecular mechanism insight, following LukS-PV treatment.

Cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) overexpression results in endothelial apoptosis, thus mediating vascular endothelial injury in hyperglycaemia. E26 transformation-specific sequence transcription factor-1 (ESE-1), which belongs to the E26 transformation-specific family of transcription factors, has been demonstrated to be involved in COX2 and iNOS gene transcription. Our previous study indicated that SET domain-containing protein 8 (SETD8) downregulation is involved in high glucose-mediated endothelial inflammation in human umbilical vein endothelial cells (HUVECs). Here, we report that SETD8 plays a major role in hyperglycaemia-induced COX2 and iNOS expression. In HUVECs, upregulation of ESE-1 expression was related to high glucose-mediated apoptosis and COX2 and iNOS expression. High glucose inhibited SETD8 expression, and overexpression of SETD8 diminished the effects of high glucose treatment. Consistently, RNA silencing of SETD8 led to the opposite effect. Furthermore, SETD8 was found to interact with specificity protein 1 (SP1). Blockade of SP1 protected against high glucose-mediated endothelial injury. Mechanistically, we showed that H4K20me1, a downstream target of SETD8, and SP1 were enriched at the ESE-1 promoter region by ChIP assay. Luciferase reporter assays indicated that SETD8 overexpression attenuated ESE-1 promoter activity and augmented the inhibitory effect of siSP1 on ESE-1 promoter activity. In general, our data indicate that SETD8 interacts with SP1 to coregulate ESE-1 expression, which is involved in hyperglycaemia-mediated endothelial apoptosis in HUVECs.

BACKGROUND Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity. METHODS We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients. RESULTS Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients. CONCLUSIONS Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.

Propofol is one of the most commonly used intravenous anesthetics and plays an important role in tumor suppression. In the present study, we aimed to investigate the mechanism by which propofol attenuates tumor endothelial cells (TECs) and tumor cell adhesion to inhibit tumor metastasis in vitro. Human umbilical vein endothelial cells (HUVECs) cultured in Dulbecco's modified Eagle's medium were treated with tumor conditioned medium for 24 h, followed by 4 h of treatment with or without 25 μM of propofol, 10 μM of KN93, 500 μM of MK801, or 20 μM of rapastinel. It was found that propofol inhibited TEC adhesion and the glycolysis level of TECs. Consistently, propofol inhibited the expressions of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and glycolysis proteins (GLUT1, HK2, and LDHA) in TECs. Moreover, propofol attenuated the expression of HIF-1α, the phosphorylation of AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the Ca2+ concentration in TECs. MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMKII, both inhibited the expressions of adhesion molecules and glycolysis proteins, in a manner similar to propofol. Additionally, rapastine, an activator of NMDA receptor, could counteract the effects of propofol. Our results indicated that propofol attenuates intracellular Ca2+ concentration, CaMKII and AKT phosphorylation, and HIF-1α expression, probably via inhibiting the NMDA receptor, thus inhibiting glycolysis and adhesion of tumor and endothelial cells.

Black rockfish is a viviparous teleost whose sperm could be stored in the female ovary for five months. We previously proposed that zona pellucida (ZP) proteins of black rockfish play a similar sperm-binding role as in mammals. In this study, SsZPB2a and SsZPB2c were identified as the most similar genes with human ZPA, ZPB1 and ZPB2 by Blastp method. Immunohistochemistry showed that ovary-specific SsZPB2a was initially expressed in the cytoplasm of oocytes at stage III. Then it gradually transferred to the region close to the cell membrane and zona pellucida of oocytes at stage IV. The most obvious protein signal was observed at the zona pellucida region of oocytes at stage V. Furthermore, we found that the recombinant prokaryotic proteins rSsZPB2a and rSsZPB2c could bind with the posterior end of sperm head and rSsZPB2a was able to facilitate the sperm survival in vitro. After knocking down Sszpb2a in ovarian tissues cultivated in vitro, the expressions of sperm-specific genes were down-regulated (p < 0.05). These results illustrated the regulatory role of ZP protein to the sperm in viviparous teleost for the first time, which could advance our understanding about the biological function of ZP proteins in the teleost.

Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined. Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130F/F-based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response. Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family–regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone. Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family–associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. Clin Cancer Res; 24(6); 1459–72. ©2018 AACR.

To compare the clinical effects of different anterior surgical methods in treating single segment cervical disc herniation.The clinical data of 46 patients with single-segment cervical disc herniation underwent surgical treatment from September 2013 to September 2018 were retrospectively analyzed. The patients were divided into three groups according to different surgical methods. Among them, 23 patients in the anterior percutanousendomic cervical dissection (APECD) group, there were 8 males and 15 females, aged (47±3) years old, prominent segments were CAll 46 patients were followed up for 12 to 24 (17.57±3.15)months. The follow-up time of APECD, CDR, ACDF groups were (17.30±3.25), (17.80±3.16), (17.85±2.88) months, and operation time were (95.48 ±13.85), (58.50±7.09), (76.00±15.72) min, respectively, there were no significant differences in follow-up time and operation time between two groups(The three anterior surgical approaches can achieve satisfactory clinical results for the treatment of single-segment cervical disc herniation. However, the improvement rate of the CDR group and the activity of the retained responsibility segment are better than those of the other two groups. APECD surgery may have recurrence.

Pyroptosis, a form of programmed cell death (PCD), has garnered increasing attention as it relates to innate immunity and diseases. However, the involvement of pyroptosis in the mechanism by which lobaplatin acts against colorectal cancer (CRC) is unclear. Our study revealed that treatment with lobaplatin reduced the viability of HT-29 and HCT116 cells in a dose-dependent manner. Morphologically, HT-29 and HCT116 cells treated with lobaplatin exhibited microscopic features of cell swelling and large bubbles emerging from the plasma membrane, and transmission electron microscopy (TEM) revealed multiple pores in the membrane. GSDME, rather than GSDMD, was cleaved in lobaplatin-induced pyroptosis in HT-29 and HCT116 cells due to caspase-3 activation. Knocking out GSDME switched lobaplatin-induced cell death from pyroptosis to apoptosis but did not affect lobaplatin-mediated inhibition of growth and tumour formation of HT-29 and HCT116 cells in vivo and in vitro. Further investigation indicates that lobaplatin induced reactive oxygen species (ROS) elevation and JNK phosphorylation. NAC, a ROS scavenger, completely reversed the pyroptosis of lobaplatin-treated HT-29 and HCT116 and JNK phosphorylation. Activated JNK recruited Bax to mitochondria, and thereby stimulated cytochrome c release to cytosol, followed by caspase-3/-9 cleavage and pyroptosis induction. Therefore, in colon cancer cells, GSDME mediates lobaplatin-induced pyroptosis downstream of the ROS/JNK/Bax-mitochondrial apoptotic pathway and caspase-3/-9 activation. Our study indicated that GSDME-dependent pyroptosis is an unrecognized mechanism by which lobaplatin eradicates neoplastic cells, which may have important implications for the clinical application of anticancer therapeutics.

Perioperative hyperglycemia is a common metabolic disorder in clinic settings. Hyperglycemia leads to endothelial inflammation, endothelial cell apoptosis, and dysfunction, thus resulting in endothelial injury. Propofol (2,6-diisopropylphenol) is a widely used intravenous anesthetic in clinic settings. Our previous study indicated that propofol inhibits mitochondrial reactive oxygen species (ROS) production via down-regulation of phosphatase A2 (PP2A) expression, inhibition of Ser36-p66shc dephosphorylation and mitochondrial translocation, thus improving high glucose-induced endothelial injury. The expression of p66shc was inhibited by propofol in hyperglycemic human umbilical vein endothelial cells (HUVECs). However, the mechanism by which propofol inhibits p66shc expression in hyperglycemic HUVECs is still obscure. In the present study, we mainly examined how propofol inhibited high glucose-induced p66shc expression in HUVECs. Compared with 5 mM glucose treatment, high glucose increased p66shc expression and decreased sirt1 expression, which was inhibited by propofol treatment. Moreover, EX527 (a sirt1 inhibitor) reversed the effect of propofol against high glucose-induced p66shc expression. However, EX527 did not reverse the effects of propofol against high glucose-induced ROS accumulation, endothelial inflammation, and apoptosis. Furthermore, when cells were incubated with propofol, EX527, and FTY720 (a PP2A activator) simultaneously, the effects of propofol against high glucose-induced ROS accumulation, inflammation, and apoptosis were reversed. Our results suggested that propofol inhibited high glucose-induced p66shc expression via upregulation of sirt1 expression in hyperglycemic HUVECs. Moreover, propofol protects against high glucose-mediated ROS accumulation and endothelial injury via both inhibition of p66shc expression and dephosphorylation of Ser36-p66shc.

Ivalin, an eudesmane-type sesquiterpene compound, was isolated from the Chinese herb Carpesium divaricatum in our chemistry group. In this study, we investigated the anti-migration and anti-invasion activities and underlying mechanisms of Ivalin in breast cancer cells in vitro. Cell viability was evaluated using the MTT assay, Western blotting was used to determine the expression of E-cadherin, N-cadherin, vimentin and ZEB1, and mRNA levels were analyzed by qPCR. The anti-migration and anti-invasion effects of Ivalin were measured by wound-healing and Transwell assays. In this connection, Ivalin treatment reduced the mRNA and protein expressions of ZEB1 as well as N-cadherin and vimentin expression in various breast cancer cells. E-cadherin expression was enhanced by Ivalin in the same cells, which implied that Ivalin depressed the process of epithelial-to-mesenchymal transition (EMT). Our results revealed that Ivalin significantly inhibited cell proliferation, migration and invasion in breast cancer cells in a dose-dependent manner in vitro. This study suggests that Ivalin may merit further investigation as a potential therapeutic leading compound for the treatment of breast cancer migration and invasion.

Bin Miao, Feng-Wu Li, Shu-Wen Zhang, Hong Wang, Wen-Jie Qi, Chao Wang Department of Infectious Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China Objective: To evaluate the efficacy and safety of Tongfu powder for external application on Shénquè (the umbilicus, hereafter, Tongfu powder) versus mosapride in acute pancreatitis (AP) patients with gastrointestinal dysfunction.Methods: A total of 102 AP patients were diagnosed using the latest Atlanta Criterion and recruited at the Department of Infectious Disease, Beijing Friendship Hospital (Beijing, People’s Republic of China) from August 2014 to December 2016. Patients were randomized into the Tongfu powder group and mosapride group using the random table. Information on scores (eg, the gastrointestinal function score) on days 1 and 7 of hospitalization, biochemical indicators (eg, interleukin [IL]-2 and IL-6), indicators for curative effects (eg, first defecation time, bowel sound recovery time, hospitalization costs, and duration) were collected and compared between the 2 groups.Results: The gastrointestinal function score decreased significantly after treatment, and the changes were significantly different between the Tongfu powder group and the mosapride group (P

This study is to assess the influences of climate, socio-economic determinants, and spatial distance on the confirmed cases and deaths in the raise phase of COVID-19 in China. The positive confirmed cases and deaths of COVID-19 over the population size of 100,000 over every 5 consecutive days (the CCOPSPTT and DOPSPTT for short, respectively) covered from 25th January to 29th February, 2020 in five city types (i.e., small-, medium-, large-, very large- and super large-sized cities), along with the data of climate, socio-economic determinants, spatial distance of the target city to Wuhan city (DW, for short), and spatial distance between the target city and their local province capital city (DLPC, for short) were collected from the official websites of China. Then the above-mentioned influencing factors on CCOPSPTT and DOPSPTT were analyzed separately in Hubei and other provinces. The results showed that CCOPSPTT and DOPSPTT were significantly different among five city types outside Hubei province (p < 0.05), but not obviously different in Hubei province (p > 0.05). The CCOPSPTT had significant correlation with socio-economic determinants (GDP and population), DW, climate and time after the outbreak of COVID-19 outside Hubei province (p < 0.05), while was only significantly related with GDP in Hubei province (p < 0.05). The DOPSPTT showed significant correlation with socio-economic determinants, DW, time and CCOPSPTT outside Hubei province (p < 0.05), while was significantly correlated with GDP and CCOPSPTT in Hubei province (p < 0.05). Compared with other factors, socio-economic determinants have the largest relative contribution to variance of CCOPSPTT in all studied cities (> 78%). The difference of DOPSPTT among cities was mainly affected by CCOPSPTT. Our results showed that influences of city types on the confirmed cases and death differed between Hubei and other provinces. Socio-economic determinants, especially GDP, have higher impact on the change of COVID-19 transmission compared with other factors.

Aspergillus niger is widely used for the efficient production of organic acids and enzyme preparations. However, this organism lacks basic genetic elements for dynamic control, especially inducible promoters that can respond to specific environmental signals. Since these are desirable for better adaptation of fermentation to large-scale industrial production, herein, we have identified the two first hypoxia-inducible promoters in A. niger, PsrbB and PfhbA. Their performance under high or low oxygen conditions was monitored using two reporter proteins, green fluorescent protein (EGFP) and β-glucuronidase (GUS). For comparison, basal expression of the general strong promoter PgpdA was lower than PsrbB but higher than PfhbA. However, under hypoxia, both promoters showed higher expression than under hyperoxia, and these values were also higher than those observed for PgpdA. For PsrbB, strength under hypoxia was ~2-3 times higher than under hyperoxia (for PfhbA, 3-9 times higher) and ~2.5-5 times higher than for PgpdA (for PfhbA, 2-3 times higher). Promoter truncation analysis showed that the PsrbB fragment -1024 to -588 bp is the core region that determines hypoxia response. KEY POINTS: The first identification of two hypoxia-inducible promoters in A. niger is a promising tool for modulation of target genes under hypoxia. Two reporter genes revealed a different activity and responsiveness to hypoxia of PfhbA and PsrbB promoters, which is relevant for the development of dynamic metabolic regulation of A. niger fermentation. PsrbB promoter truncation and bioinformatics analysis is the foundation for further research.

Introduction. Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes. Methods. This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified. Results. HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke. Conclusion. A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand–receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.

OBJECTIVE: To study the changes in metabolic markers and clinical outcome after treatment with different drug regimens in children with bipolar affective disorder. METHODS: A retrospective analysis was performed on the medical data of 220 children with bipolar affective disorder who attended the hospital from January 2017 to January 2020. According to the treatment method, 112 children treated with atypical antipsychotic drugs alone were enrolled as the control group, and 108 children treated with atypical antipsychotic drugs combined with mood stabilizer were enrolled as the study group. The two groups were compared in terms of baseline data, changes in related metabolic markers[fasting insulin (FIN), glycosylated hemoglobin (HbAlc), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)] after treatment, incidence rate of metabolic syndrome, and clinical outcome. RESULTS: There were no significant differences in the baseline data including age, sex, and course of disease between the two groups (P > 0.05). The study group had a significantly higher overall response than the control group (92.6% vs 82.1%, P < 0.05). Before treatment, there were no significant differences in the levels of FIN and HbAlc between the two groups (P > 0.05). After treatment, the control group had a significant increase in the level of FIN and a significantly higher level of FIN than the study group (P < 0.05). The study group showed no significant change in the level of FIN after treatment (P > 0.05). There was no significant difference in the level of HbAlc between the two groups before and after treatment (P > 0.05). Before treatment, there were no significant differences in the levels of TC, TG, HDL-C, and LDL-C between the two groups (P > 0.05), and after treatment, the control group had significant increases in TC and TG and significantly higher levels of TC and TG than the study group (P < 0.05). The study group showed no significant changes in TC and TG after treatment (P > 0.05). There were no significant differences in the levels of HDL-C and LDL-C between the two groups before and after treatment (P > 0.05). The study group had a significantly lower incidence rate of metabolic syndrome than the control group (2.8% vs 9.8%, P < 0.05). CONCLUSIONS: Atypical antipsychotic drugs combined with mood stabilizer in the treatment of bipolar disorder in children have little effect on the level of metabolic markers, and the curative effect is significant.

OBJECTIVE: To investigate the incidence rate of infectious diseases during hospitalization in late preterm infants in Beijing, China, as well as the risk factors for infectious diseases and the effect of breastfeeding on the development of infectious diseases. METHODS: Related data were collected from the late preterm infants who were hospitalized in the neonatal wards of 25 hospitals in Beijing, China, from October 23, 2015 to October 30, 2017. According to the feeding pattern, they were divided into a breastfeeding group and a formula feeding group. The two groups were compared in terms of general status and incidence rate of infectious diseases. A multivariate logistic regression analysis was used to investigate the risk factors for infectious diseases. RESULTS: A total of 1 576 late preterm infants were enrolled, with 153 infants in the breastfeeding group and 1 423 in the formula feeding group. Of all infants, 484 (30.71%) experienced infectious diseases. The breastfeeding group had a significantly lower incidence rate of infectious diseases than the formula feeding group (22.88% vs 31.55%, P=0.033). The multivariate logistic regression analysis showed that breastfeeding was an independent protective factor against infectious diseases (OR=0.534, P=0.004), while male sex, premature rupture of membranes, gestational diabetes mellitus, and asphyxia were risk factors for infectious diseases (OR=1.328, 5.386, 1.535, and 2.353 respectively, P < 0.05). CONCLUSIONS: Breastfeeding can significantly reduce the incidence of infectious diseases and is a protective factor against infectious diseases in late preterm infants. Breastfeeding should therefore be actively promoted for late preterm infants during hospitalization.

Background Patients with continuous multi-vertebral lumbar spine tuberculosis (CMLSTB) were subjected to single posterior debridement, interbody fusion, and fixation to explore their clinical outcomes. Methods Sixty-seven CMLSTB patients who underwent single posterior debridement interbody fusion and fixation between January 2008 to December 2017 were studied. The operation time, blood loss, perioperative complication rate, cure rate, Visual Analog Scale (VAS), Oswetry disability index (ODI), Japanese Orthopedic Association (JOA), Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), kyphotic Cobb’s angle and time of interbody fusion were analyzed to understand their therapeutic effects on CMLSTB patients. Results The patients were followed up for 20–48 months, with a mean of 24.3 months. The mean operation time was 215.5 min (range, 120–280 min), whereas 818.0 ml of blood was lost (range, 400–1500 ml) with a perioperative complication rate of 6.0% and a cure rate of 95.5%. During the last phase of follow-up, the mean preoperative VAS score (5.7) and ODI (72.0%) decreased significantly to 1.4 (t = 31.4, Pt = 48.4, PtESR = 39.7, PESRtCRP = 50.2, PCRPt = − 11.6, Pt = 14.0, Pt = − 0.476, P = 0.635). Furthermore, the mean of interbody fusion time was identified to be 8.8 months (range, 6–16 months). Conclusion Single posterior debridement, interbody fusion, and fixation may be one of the surgical choices for the treatment of CMLSTB patients.

Ceftazidime is a third-generation cephalosporin with high activity against many pathogens. But the ambiguity and diversity of the dosing regimens in neonates and young infants impair access to effective treatment. Thus, we conducted a population pharmacokinetic study of ceftazidime in this vulnerable population and recommended a model-based dosage regimen to optimize sepsis therapy. Totally 146 neonates and young infants (gestational age (GA): 36–43.4 weeks, postnatal age (PNA): 1–81 days, current weight (CW): 900–4500 g) were enrolled based on inclusion and exclusion criteria. Ceftazidime bloods samples (203) were obtained using the opportunistic sampling strategy and determined by the high-performance liquid chromatography. The population pharmacokinetic-pharmacodynamic analysis was conducted by nonlinear mixed effects model (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic data. Covariate analysis showed the significance of GA, PNA, and CW on developmental pharmacokinetics. Monte Carlo simulation was performed based on above covariates and minimum inhibitory concentration (MIC). In the newborns with PNA ≤ 3 days (MIC=8 mg/L), the dose regimen was 25 mg/kg twice daily (BID). For the newborns with PNA > 3 days (MIC=16 mg/L), the optimal dose was 30 mg/kg three times daily (TID) for those with GA ≤ 37 weeks and 40 mg/kg TID for those with GA > 37 weeks. Overall, on the basis of the developmental population pharmacokinetic-pharmacodynamic analysis covering the whole range of neonates and young infants, the evidence-based ceftazidime dosage regimens were proposed to optimize neonatal early-onset and late-onset sepsis therapy.

Background. Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods. We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results. Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1α, and both PGC1α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions. The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.

Breast cancer (BC) is currently one of the deadliest tumors worldwide. Cancer stem cells (CSCs) are a small group of tumor cells with self-renewal and differentiation abilities and high treatment resistance. One of the reasons for treatment failures is the inability to completely eliminate tumor stem cells. By using the edgeR package, we identified stemness-related differentially expressed genes in GSE69280. Via Lasso-penalized Cox regression analysis and univariate Cox regression analysis, survival genes were screened out to construct a prognostic model. Via nomograms and ROC curves, we verified the accuracy of the prognostic model. We selected 4 genes (PSMB9, CXCL13, NPR3, and CDKN2C) to establish a prognostic model from TCGA data and a validation model from GSE24450 data. We found that the low-risk score group had better OS than the high-risk score group, whether using TCGA or GSE24450 data. A prognostic model including four stemness-related genes was constructed in our study to determine targets of breast cancer stem cells (BCSCs) and improve the treatment effect.

Hyperglycemia-mediated reactive oxygen species (ROS) accumulation plays an important role in hyperglycemia-induced endothelial injury. Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway inhibition participates in hyperglycemia-induced ROS accumulation. Our previous study indicated that SET8 overexpression inhibits high glucose-mediated ROS accumulation in human umbilical vein endothelial cells (HUVECs). In the present study, we hypothesize that SET8 may play a major role in high glucose-induced ROS accumulation via modulation of Keap1/Nrf2/ARE pathway. Our data indicated that high glucose mediated cell viability reduction, ROS accumulation, and Nrf2/ARE signal pathway inhibition via upregulation of Keap1 expression in HUVECs. Moreover, high glucose inhibited the expressions of SET8 and H4K20me1 (a downstream target of SET8). SET8 overexpression improved high glucose-mediated Keap1/Nrf2/ARE pathway inhibition and endothelial oxidation. Consistently, the effects of sh-SET8 were similar to that of high glucose treatment and were reversed by si-Keap1. A mechanistic study found that H4K20me1 was enriched at the Keap1 promoter region. SET8 overexpression attenuated Keap1 promoter activity and its expression, while mutant SET8 R259G did not affect Keap1 promoter activity and expression. The results of this study demonstrated that SET8 negatively regulates Keap1 expression, thus participating in high glucose-mediated Nrf2/ARE signal pathway inhibition and oxidative injury in HUVECs.

MicroRNA (miR)-181a is a member of the miR-181 family that serves a key role in the pathogenesis of various cancer types. The present study aimed to investigate the interaction between miR-181a and Ras association domain family protein1 isoform A (RASSF1A), and their roles in gastric carcinogenesis. The interaction between miR-181a and RASSF1A was assessed in cell lines and cancer tissues. The direct binding of miR-181a and RASSF1A was identified using a luciferase reporting gene system. The effects of miR-181a and RASSF1A on gastric cancer cell growth, cell cycle and apoptosis were assessed with a Cell Counting Kit-8 assay and flow cytometry. The effects of miR-181a on cell division cycle 25A (CDC25A), cyclin A2, cyclin D1, p21, Bcl-2-associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) protein levels were assessed in gastric cancer cell lines. miR-181a directly interacted with the 3′-untranslated region of RASSF1A and downregulated RASSF1A protein expression. In tissues from patients with gastric cancer, the miR-181a level was significantly higher in the tumor tissues and was negatively correlated with the RASSF1A protein level. RASSF1A suppressed gastric cancer cell proliferation and G1/S transition, and promoted apoptosis; whereas miR-181a promoted cancer cell proliferation and G1/S transition, and suppressed apoptosis. RASSF1A knockdown attenuated the effects of miR-181a downregulation on cell proliferation and apoptosis. Furthermore, miR-181a upregulated CDC25A, cyclin A2 and Bcl-2, and downregulated Bax protein expression in gastric cancer cell lines. These data indicate that miR-181a promotes gastric carcinogenesis, possibly through a direct interaction with RASSF1A.

3β-Angeloyloxy-8β,10β-dihydroxyeremophila-7(11)-en-12,8α-lactone (FJ1) inhibited effectively paraquat (PQ)-induced injury in SH-SY5Y cells. In this way, FJ1 was shown to reverse the PQ-induced activation of caspase-9 and caspase-3, the increase in Bax/Bcl-2 ratio, and the release of cytochrome c. The mechanism was associated with a reduction of oxidative stress, including the decrease in the levels of ROS and MDA and maintaining the activity of SOD and GSH. Taken together, findings revealed that FJ1 had protective effects against PQ-induced injury via attenuating the oxidative stress in SH-SY5Y cells, which suggested that FJ1 might be a candidate for further evaluation against neurodegeneration in Parkinson's disease.

Marine organisms are commonly under threat from various pathogens. Edwardsiella tarda is one of the fish pathogens that can infect both cultured and wild fish species. E. tarda can also infect other vertebrates, including amphibians, reptiles, and mammals. Bacteremia caused by E. tarda can be a fatal disease in humans. Blood acts as a pipeline for the fish immune system. Generating blood transcriptomic resources from fish challenged by E. tarda is crucial for understanding molecular mechanisms underlying blood immune response process. In this study, we performed transcriptome-wide gene expression profiling of Japanese flounder ( Paralichthys olivaceus ) challenged by 8 and 48 h E. tarda stress. An average of 37 million clean reads per library was obtained, and approximately 85.6% of these reads were successfully mapped to the reference genome. In addition, 808 and 1265 differential expression genes (DEGs) were found at 8 and 48 h post-injection, respectively. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to search immune-related DEGs. A protein–protein interaction network was constructed to obtain the interaction relationship of immune genes during pathogens stress. Based on KEGG and protein association networks analysis, 30 hub genes were discovered and validated by quantitative RT-PCR. This study represents the first transcriptome analysis based on protein–protein interaction networks in fish and provides us with valuable gene resources for the research of fish blood immunity, which can significantly assist us to further understand the molecular mechanisms of humans and other vertebrates against E. tarda .

Existing temporary epicardial pacing wires (TPWs) are rigid and non-absorbable, such that they can cause severe complications after cardiac surgery. Here, a soft and absorbable temporary epicardial pacing wire (saTPW) for effectively correcting abnormal heart rates in a rabbit model, such as bradycardia and ventricular premature beat, is developed. The saTPW exhibits excellent conductivity, flexibility, cycling stability (>100 000 cycles), and less inflammatory response during two-month subcutaneous implantation in a rat model. The saTPW which consists of poly(l-lactide-co-e-caprolactone) and liquid metal, can degrade about 13% (mass loss) in the rats over a two-month subcutaneous implantation. It can be absorbed over time in the body. The cytocompatibility and absorbability avoid secondary injuries caused by remaining wires which are permanently left in the body. The saTPW will provide a great platform for diagnosis and treatments in cardiovascular diseases by delivering the physiological signal and applying electrical stimulation for therapy.

Loss of caudal type homeobox 2 (CDX2) is associated with the development of human colorectal cancer, while human telomerase reverse transcriptase (hTERT) frequently occurs in variety of human cancers. We investigated the effects of restoration of CDX2 expression using a hypoxia-inducible hTERT promoter-driven vector (pLVX-5HRE-hTERTp-CDX2-3FLAG) on colon cancer cell viability, cell cycle distribution, apoptosis, colony formation, invasion ability and xenograft tumor growth in nude mice. CDX2 overexpression significantly inhibited viability, colony formation, and the invasion and migration ability of LoVo cells, and induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. Overexpression of CDX2 under normoxic conditions significantly suppressed the expression of TGF-β, cyclin D1, uPA, MMP-9, MMP-2, and Bcl-2, and stimulated the expression of collagen IV, laminin-1, and Bax. Overexpression of CDX2 reduced colon cancer xenograft tumor formation in nude mice which was associated with downregulation of Ki-67. In conclusion, overexpression of CDX2 using a hypoxia-inducible hTERT promoter-driven vector suppressed malignant progression of colon cancer cells in vitro and in vivo. These results suggest that pLVX-5HRE-hTERTp-CDX2-3FLAG gene therapy may be a promising novel approach to treat colon cancer.

AIMS In this study, we investigated the characteristics and underlying mechanisms of the electrocardiographic (ECG) morphology during left bundle branch area pacing (LBBAP), which have not been systematically described. METHODS Patients with indications for permanent cardiac pacing underwent LBBAP attempts. The ECGs of patients with confirmed left bundle branch (LBB) capture were compared with those of individuals with right bundle branch block (RBBB) on 12-lead ECG. Intracardiac electrograms recorded during implantation were analyzed in all patients who underwent pacing. RESULTS LBBAP was successfully achieved in 87.5% (56/64) of patients. The QRS morphologies in lead V1 during LBBAP, which typically demonstrated Qr (60.7%), qR (19.6%), rSR' (7.1%), or QS (12.5%) patterns, differed from those of native RBBB, which featured rsR' (57.5%), M shape (23.7%), or monophasic R patterns (18.7%). The terminal R' wave duration in lead V1 was significantly shorter during LBBAP than during native RBBB (51 ± 12 ms vs 85 ± 19 ms, p

To evaluate the effectiveness of internal fixation with headless compression hollow embedding screws in the treatment of intraarticular fracture of elbow.Between March 2012 and September 2018, 12 patients with intraarticular fracture of elbow were treated with internal fixation with headless compression hollow embedding screws. There were 7 males and 5 females with an average age of 50.3 years (range, 22-65 years). Cause of injury included falling in 7 cases, falling from high places in 4 cases, and traffic accident in 1 case. Ten patients were distal humerus fractures which were classified as type 13-B3 in 8 cases and type 13-C3 in 2 cases according to the International Association of Internal Fixation Research (AO/ASIF). Two patients were radial head fractures which were classified as type Ⅲ according to the modified Mason classifications. The preoperative visual analogue scale (VAS) score was 8.25±0.83. The time from injury to operation was 3-5 days (mean, 3.7 days).All incisions healed by first intention. All 12 patients were followed up 6-15 months, with an average of 8.4 months. The results of X-ray films and CT examination showed that the fracture ends were anatomic reduction, and the fractures healed at 6-11 months after operation, with an average of 7.8 months. One patient had heterotopic ossification at 4 months after operation. The VAS scores were 5.17±0.79 at 2 weeks after operation and 0.50±0.50 at last follow-up. There were significant differences between the time points (The intraarticular fracture of elbow can be firmly fixed by the headless compression hollow embedding screw, which can allow the early functional training of the elbow joint, reduce the incidence of heterotopic ossification, and obtain good effectiveness.探讨无头加压中空埋入螺钉内固定治疗肘关节内骨折的疗效。.2012 年 3 月—2018 年 9 月，采用无头加压中空埋入螺钉内固定治疗 12 例肘关节内骨折。男 7 例，女 5 例；年龄 22～65 岁，平均 50.3 岁。致伤原因：摔伤 7 例，高处坠落伤 4 例，交通事故伤 1 例。肱骨远端骨折 10 例，按照国际内固定研究协会（AO/ASIF）分型 13-B3 型 8 例、13-C3 型 2 例；桡骨头骨折 2 例，按照改良 Mason 分型均为 Ⅲ 型。术前疼痛视觉模拟评分（VAS）为（8.25±0.83）分。受伤至手术时间为 3～5 d，平均 3.7 d。.术后切口均 Ⅰ 期愈合。12 例均获随访，随访时间 6～15 个月，平均 8.4 个月。X 线片及 CT 复查显示，骨折端解剖复位，术后 6～11 个月骨折均达骨性愈合，平均 7.8 个月；1 例术后 4 个月出现异位骨化。术后 2 周 VAS 评分为（5.17±0.79）分，末次随访时为（0.50±0.50）分，手术前后各时间点间比较差异均有统计学意义（采用无头加压中空埋入螺钉内固定肘关节内骨折牢固，允许术后早期肘关节功能训练，异位骨化发生率低，可获得较好疗效。.

Premature coronary artery disease (CAD) studies rarely involve coronary plaque characterization. We characterize coronary plaque tissue by radiofrequency intravascular ultrasound (IVUS) in patients with premature CAD. From July 2015 to December 2017, 220 patients from the Department of Cardiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine with first occurrence of angina or myocardial infarction within 3 months were enrolled. Patients with premature CAD (n = 47, males aged 3, p = 0.013] than the later CAD group. After the matching procedure, the premature CAD group appeared to be less plaque burden (72.69 ± 9.99 vs. 74.85 ± 9.80%, p = 0.005), and positive remodeling (1.03 ± 0.12 vs. 0.94 ± 0.18, p = 0.034), and lower high risk feature incidence (p = 0.006) than the later CAD group. At the plaque’s minimum lumen, premature CAD had more fibrotic (p

Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.

Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. Despite such a public health importance, efficient therapeutic agents are still lacking for this malignancy. Most tumor cells use aerobic glycolysis to sustain anabolic growth, including HCC, and the preference of glycolysis often leads to a close association with poorer clinical outcomes. The histone methyltransferase SET8 plays crucial roles in controlling cell-cycle progression, transcription regulation, and tumorigenesis. However, it remains largely undefined whether SET8 affects the glucose metabolism in HCC. Here, we report that upregulation of SET8 is positively correlated with a poor survival rate in HCC patients. Both in vitro and in vivo studies revealed that SET8 deficiency conferred an impaired glucose metabolism phenotype and thus inhibited the progression of HCC tumors. By contrast, SET8 overexpression aggravated the glycolytic alterations and tumor progression. Mechanistically, SET8 directly binds to and inactivates KLF4, resulting in suppression of its downstream SIRT4. We also provided further evidence that mutations in SET8 failed to restrain the transactivation of SIRT4 by KLF4. Our data collectively uncover a novel mechanism of SET8 in mediating glycolytic metabolism in HCC cells and may provide a basis for targeting SET8 as a therapeutic strategy in HCC.

Introduction Child emotional or behavioral problems and insufficient social development has been a heavy burden on family and society. However, currently large-scale studies on emotional and behavioral problems as well as social competence among school children in China are still lacking. This cross-sectional study analyzed the current status and risk factors of behavioral problems and social competences in Beijing students. Method A total of 9,295 students, with ages ranging from 6 to 16 years old, were enrolled in the study. The Child Behavior Checklist (CBCL) was used to screen emotional and behavioral problems, social competences of students. We then assessed significant predictors factors associated with children behavioral problems and social competences. Results The total detection rate of behavioral problems of this cohort was 16.7%. All kinds of social competence scores of boys were lower than girls (P

10-oxo-5-(3-(pyrrolidin-1-yl) propyl)-5,10-dihydroindeno [1,2-b] indol-9-yl propionate (LS-2-3j) is a new chemically synthesized indole compound and some related analogues are known to be inhibitors (such as alectinib and Ko143) of ATP-binding cassette (ABC) transporters, especially the ABC transporter subfamily B member 1 (ABCB1) and the ABC transporter subfamily G member 2 (ABCG2). This study aimed to evaluate the multidrug resistance (MDR) reversal effects and associated mechanisms of LS-2-3j in drug-resistant cancer cells. The inhibition of cell proliferation in tested agents was evaluated by the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Accumulation or efflux of chemotherapy drugs was analyzed by flow cytometry. The ATPase activity was measured using an ATPase activity assay kit. The mRNA transcripts and protein expression levels were detected by real-time PCR and Western blot, respectively. In this connection, LS-2-3j significantly enhanced the activity of chemotherapeutic drugs in MDR cells and could significantly increase the intracellular accumulation of doxorubicin (DOX) and mitoxantrone (MITX) by inhibiting the function of the efflux pumps in ABCB1- or ABCG2-overexpressing cells. Furthermore, reduced ATPase activity, mRNA transcription, and protein expression levels of ABCB1 and ABCG2 were observed in a concentration dependent manner in MDR cancer cells.

STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor α (ERR-α) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC.

Objectives There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has recently been brought back into use for treatment of infections in newborns; however, it is still used off-label in neonatal clinical practice due to the lack of an evidence-based dosing regimen. This study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants, and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD). Methods Opportunistic blood samples from newborns treated with latamoxef were collected to determine the latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range 28.4–46.1 weeks) were available for analysis. Results A two-compartment model with first-order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicated that the current dosing regimen (30 mg/kg q12h) is adequate with an MIC of 1 mg/L. For an MIC of 4 mg/L, 30 mg/kg q8h was required to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval. Conclusions Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen.