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A 5-year-old girl was admitted due to one episode of melena and one episode of hematemesis. Upon admission, gastroscopy revealed esophageal and gastric varices. Abdominal CT scan, MRI, and color Doppler ultrasound suggested cirrhosis, intrahepatic bile duct dilation, and bilateral kidney enlargement. Genetic testing identified compound heterozygous mutations in the PKHD1 gene: c.2264C>T (p.Pro755Leu) and c.1886T>C (p.Val629Ala). The c.2264C>T (p.Pro755Leu) mutation is a known pathogenic variant with previous reports, while c.1886T>C (p.Val629Ala) is a novel mutation predicted to have pathogenic potential according to Mutation Taster and PolyPhen2. The child was diagnosed with autosomal recessive polycystic kidney disease. In children presenting with gastrointestinal bleeding without obvious causes, particularly those with liver or kidney disease, consideration should be given to the possibility of autosomal recessive polycystic kidney disease, and genetic testing should be conducted for definitive diagnosis when necessary.

Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME T6E or GSDME T6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications., (© 2023. The Author(s).)

Introduction: The contribution of brain abnormalities in patients with Parkinson's disease (PD) to impaired functional status remains uncertain. Our study assessed whether global and regional brain structural abnormalities are associated with impaired performance of activities of daily living (ADL) in PD patients., Material and Methods: A retrospective analysis was conducted of 46 patients with PD, recruited prospectively from a movement disorder clinic. Motor impairment and disability were assessed using the Hoehn and Yahr (H-Y) scale and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Cognitive status was evaluated with Montreal Cognitive Assessment (MoCA). The performance of ADL was indexed by the sum score of the Physical Self-Maintenance Scale (PSMS) and Lawton Instrumental ADL scale. Brain magnetic resonance imaging (MRI) was performed to assess white matter hyperintensities and medial temporal lobe atrophy (MTLA). Global brain atrophy, indexed by the relative grey matter volume (RGM), relative white matter volume (RWM) and average cortical thickness of the whole brain, was quantified by voxel-based morphometry (VBM)., Results: The ADL score (where higher scores indicate poorer performance) negatively correlated with RWM (where greater volume indicates less severe atrophy; r = -0.41, p = 0.004) and RGM (where greater volume indicates less severe atrophy; r = -0.43, p = 0.003) but not with the average cortical thickness ( r = -0.16, p = 0.29). With ADL score as the dependent variable in a linear regression model, H-Y stage and RWM significantly correlated with the ADL score after adjusting for age and MoCA score, and together accounted for 51% of the variance therein. RGM was not significantly correlated with the ADL score after adjusting for age and MoCA score., Conclusions: Cerebral white matter atrophy may be associated with the performance of ADL in patients with PD, indicating an important role of white matter impairment in their functional status.

Background: Percutaneous coronary intervention (PCI), the most common method in treating coronary artery disease (CAD), has a variety of side effects. Yiqi Huoxue therapy (YQHX) can effectively alleviate the symptoms of patients and reduce the side effects. However, a reliable and systematic assessment of the methodologies is not available., Methods: Seven electronic databases were searched to identify randomized controlled trials of YQHX method for CAD after PCI. The quality assessment of the trials included was performed by employing the Cochrane Risk of Bias tool., Results: One thousand eight hundred sixty-eight patients from 23 randomized controlled trials were included in this review. The aggregated results showed that the experimental group got better effect in increasing ORR, TCMSRR, ECG, HDL-C, and in lowering the level of CRP, TC, and MACE in comparison with the control group., Conclusion: YQHX method is a valid complementary and alternative therapy in the management of CAD after PCI, and is an effective and safe therapy for CAD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Extracellular vesicles play crucial roles in intercellular communication in the tumor microenvironment. Here we demonstrate that in hepatic fibrosis, TGF-β stimulates the palmitoylation of hexokinase 1 (HK1) in hepatic stellate cells (HSCs), which facilitates the secretion of HK1 via large extracellular vesicles in a TSG101-dependent manner. The large extracellular vesicle HK1 is hijacked by hepatocellular carcinoma (HCC) cells, leading to accelerated glycolysis and HCC progression. In HSCs, the nuclear receptor Nur77 transcriptionally activates the expression of depalmitoylase ABHD17B to inhibit HK1 palmitoylation, consequently attenuating HK1 release. However, TGF-β-activated Akt functionally represses Nur77 by inducing Nur77 phosphorylation and degradation. We identify the small molecule PDNPA that binds Nur77 to generate steric hindrance to block Akt targeting, thereby disrupting Akt-mediated Nur77 degradation and preserving Nur77 inhibition of HK1 release. Together, this study demonstrates an overlooked function of HK1 in HCC upon its release from HSCs and highlights PDNPA as a candidate compound for inhibiting HCC progression., (© 2022. The Author(s).)

The study aimed to investigate the individual and combined association of health-risk behaviors with mental health among Chinese children. A cross-sectional study was conducted in Wuhan, China, from May to June 2018. Participants self-reported the information on physical activity (PA), screen time (ST), fruit and vegetable (FV) intake, and sleep duration. Mental health, including depression, social anxiety and self-esteem, was assessed using standard questionnaires. A total of 1296 children (704 males and 592 females) aged 9.2 ± 0.4 years were included in the present study. The prevalence of low PA, high ST, low FV intake, and inadequate sleep duration was 45.6%, 18.0%, 69.7%, and 64.7%, respectively. Overall, significant associations were found between individual health-risk behavior and increased risks of mental health. Furthermore, children with three or four health-risk behaviors showed significantly increased risks of anxiety (OR: 3.18, 95%CI: 1.63-6.21), depression (OR: 4.55, 95%CI: 2.28-9.09) and low self-esteem (OR: 3.59, 95%CI: 2.20-5.88) compared with those without health-risk behavior. Results of this study revealed a high prevalence of health-risk behaviors among Chinese children. Furthermore, the clustering of health-risk behavior was associated with significantly increased risks of mental health in this population. Considering these findings, it is important to perform early interventions to reduce children's health-risk behavior and prevent mental health problems.

Child neglect robustly predicts many behavioral problems and adulthood mental disorders, but little is known about its association with daily lifestyles and psychological development during childhood, particularly in the longitudinal study. We aimed to examine the association of child neglect with physical activity (PA), screen time (ST), eating habits (EHs), and depression/self-esteem using a two-wave follow-up study of primary schoolchildren in Wuhan, China. Data of 1085 schoolchildren aged 8-10 years (boys: 53.5%) were analyzed. Child neglect, lifestyles, and depression/self-esteem were collected in 2018 (T1) and 2019 (T2). Autoregressive cross-lagged models (ARCLMs) were fitted to explore the interrelationships among these variables. In ARCLM including child neglect and lifestyles, higher child neglect at T1 was significantly associated with higher ST and more risky EHs at T2, while insignificantly associated with PA. In ARCLM including child neglect and depression/self-esteem, lower T1 child neglect significantly predicted a higher T2 depression, but insignificantly for T2 self-esteem. In ARCLM including all variables, child neglect still significantly predicted later ST and depression, but insignificantly predicted EHs. Our study underscores that child neglect is strongly intertwined with ST, EHs, and depression during childhood. The prevention of child neglect may promote some healthy lifestyles and depression in children., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Few studies have evaluated the long-term relationship between diet quality and cardiometabolic risk factor clustering among children. The moderating effect of socio-economic status (SES) is of interest., Objective: To investigate the association between diet quality with cardiometabolic risk among Chinese children and to explore the moderating effect of SES., Design: In this cohort study, 5 waves (1997-2009) of the China Health and Nutrition Survey were used. Diet quality was measured by a modified version of the Chinese Children Dietary Index (mCCDI) based on Dietary Guidelines for Chinese., Participants: Children between the ages of 7 and 17 (n = 2903) who completed at least 2 surveys were included. Those who missed measures or had hypertension or diabetes at baseline were excluded., Main Outcome Measures: The fasting blood samples were collected in 2009. Waist circumference (WC) and blood pressure (BP) were measured in each survey., Statistical Analysis Performed: A continuous cardiometabolic risk score (MetScore) was derived by a confirmatory factor analysis of 5 components: WC, BP, glucose, triglycerides, and high-density lipoprotein cholesterol. Considering the latency period of the effect of behaviors, the mCCDI was lagged by the period between surveys. Linear regression was used to analyze the association of mCCDI with MetScore and its components. Mixed effect linear regression and lagged mCCDI were used for WC and BP models., Results: Higher mCCDI was independently associated with a lower MetScore at follow-up (β: -.11; 95% CI: -.18 to -.04). Higher lagged mCCDI over time was associated with a lower WC z score overall (β: -.05; 95% CI: -.08 to -.01) and among children in the low SES group (β: -.09; 95% CI: -.14 to -.04) but not those in the high SES group. When examining the 15 mCDDI components separately, scores for 5 components: more grains, vegetables, soybeans and its products; less sugar-sweetened beverages; and more diet variety were significantly associated with a lower MetScore., Conclusions: Among Chinese children, higher diet quality measured by mCCDI was independently associated with a lower MetScore at follow-up., (Copyright © 2021 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Pyrotinib is a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor. Evidence of the efficacy of pyrotinib-based treatments for HER2-positive metastatic breast cancer (MBC) in patients exposed to lapatinib is limited. Methods: Ninety-four patients who received pyrotinib as a third- or higher-line treatment for HER2-positive MBC were included in this retrospective study. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were implemented to balance important patient characteristics between groups. Results: Thirty (31.9%) patients were pretreated with lapatinib and subsequently received pyrotinib as an anti-HER2 treatment, and 64 (68.1%) patients did not receive this treatment. The OS and PFS indicated a beneficial trend in lapatinib-naive group compared to lapatinib-treated group in either the original cohort (PFS: 9.02 vs 6.36 months, p = 0.05; OS: 20.73 vs 14.35 months, p = 0.08) or the PSM (PFS: 9.02 vs 6.08 months, p = 0.07; OS: 19.07 vs 18.00 months, p = 0.61) or IPTW (PFS: 9.90 vs 6.17 months, p = 0.05; OS: 19.53 vs 15.10 months, p = 0.08) cohorts. Subgroup analyses demonstrated lapatinib treatment-related differences in PFS in the premenopausal subgroup and the no prior trastuzumab treatment subgroup, but no significant differences were observed in OS. Conclusion: Pyrotinib-based therapy demonstrated promising effects in HER2-positive MBC patients in a real-world study, especially in lapatinib-naive patients, and also some activity in lapatinib-treated patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ouyang, Chen, Anwar, Xie, Ouyang, Fan, Qian, Chen, Zhou, Guo, Gu, Ding, Yang, Liu, Deng, Xiao, Li, Wang, Zeng, Wang and Yi.)

Studies have shown the difference appearing among the prognosis of patients in different age groups. However, the molecular mechanism implicated in this disparity have not been elaborated. In this study, expression profiles of female breast cancer (BRCA) associated mRNAs, lncRNAs and miRNAs were downloaded from the TCGA database. The sample were manually classified into three groups according to their age at initial pathological diagnosis: young (age ≤ 39 years), elderly (age ≥ 65 years), and intermediate (age 40-64 years). lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network was respectively constructed for different age BRCA. Then, the biological functions of differentially expressed mRNAs (DEmRNAs) in ceRNA network were further investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, survival analysis was used to identify prognostic biomarkers for different age BRCA patients. We identified 13 RNAs, 38 RNAs and 40 RNAs specific to patients aged ≤ 39 years, aged 40-64 years, and aged ≥ 65 years, respectively. Furthermore, the unique pathways were mainly enriched in cytokine-cytokine receptor interaction in patients aged 40-64 years, and were mainly enriched in TGF-beta signaling pathway in patients aged ≥ 65 years. According to the survival analysis, AGAP11, has-mir-301b, and OSR1 were respectively functioned as prognostic biomarkers in young, intermediate, and elderly group. In summary, our study identified the differences in the ceRNA regulatory networks and provides an effective bioinformatics basis for further understanding of the pathogenesis and predicting outcomes for different age BRCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Zhang, Jiang, Li, Chen and Luo.)

Background: The study aims to investigate the performance of a metagenomic next-generation sequencing (NGS)-based diagnostic technique for the identification of potential bacterial and viral infections and effects of concomitant viral infection on the survival rate of intensive care unit (ICU) sepsis patients., Methods: A total of 74 ICU patients with sepsis who were admitted to our institution from February 1, 2018 to June 30, 2019 were enrolled. Separate blood samples were collected from patients for blood cultures and metagenomic NGS when the patients' body temperature was higher than 38 °C. Patients' demographic data, including gender, age, ICU duration, ICU scores, and laboratory results, were recorded. The correlations between pathogen types and sepsis severity and survival rate were evaluated., Results: NGS produced higher positive results (105 of 118; 88.98%) than blood cultures (18 of 118; 15.25%) over the whole study period. Concomitant viral infection correlated closely with sepsis severity and had the negative effect on the survival of patients with sepsis. However, correlation analysis indicated that the bacterial variety did not correlate with the severity of sepsis., Conclusions: Concurrent viral load correlates closely with the severity of sepsis and the survival rate of the ICU sepsis patients. This suggests that prophylactic administration of antiviral drugs combined with antibiotics may be beneficial to ICU sepsis patients., Competing Interests: Conflicts of interest: The authors confirm that no conflict of interest or any financial relationship that relates to the content of the manuscript has been associated with this publication., (Copyright: © World Journal of Emergency Medicine.)

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Controversy exists around the locoregional management of the primary tumor for breast cancer associated with synchronous ipsilateral supraclavicular lymph node metastasis (sISLM) due to the rarity of the disease and limited available data. This study aimed to compare outcomes of patients in the Surveillance, Epidemiology, and End Results (SEER) database with sISLM who underwent surgical resection and radiation of the primary tumor with those who did not., Methods: This population-based retrospective study included breast cancer patients with sISLM without distant metastases from 2004 to 2016 in the SEER database. In this study, patients had been stratified by operative management, and propensity score matching (PSM) had been successfully applied., Results: A total of 1172 breast cancer patients with sISLM were included in the study: 863 (73.6%) of patients underwent the primary tumor resection, and 309 (26.4%) patients did not undergo surgery. The median survival time in the surgery group was longer compared to the nonsurgery group in the overall cohort and the PSM cohort. We concluded that the primary tumor resection was associated with improved survival. Subgroup analysis further demonstrated that local surgery was not inferior to radical surgery., Conclusion: For selected breast cancer patients with sISLM, surgery is a promising local intervention which may improve the survival.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.

Background: Fruit and vegetable intake (FVI) has been inversely associated with the risk of depression. However, there is a gap in evidence from low- and middle-income countries (LMICs) and among adolescents. Further, little is known about FVI in relation to the risk of anxiety. Therefore, we examined these associations among adolescents in 25 LMICs., Methods: Data from the Global School-based Student Health Survey were analyzed in 65267 adolescents aged 12-15 years (mostly nationally representative). Depressive and anxiety symptoms during the past 12 months were self-reported. Frequencies of FVI during the past 30 days were collected. Multivariable logistic regression and meta-analyses of country-wise estimates were undertaken., Results: The prevalence of depressive and anxiety symptoms were 30.3% and 9.8%, respectively. A meta-analysis indicated that FVI of <5 times/d (vs. higher) was associated with an increased risk of depressive symptoms (OR = 1.10; 95% CI = 1.02-1.18). The pooled estimate for anxiety symptoms was insignificant. When examined separately, fruit intake was significantly associated with both lower risks of depressive and anxiety symptoms; vegetable intake was significantly associated with a lower risk of depressive symptoms, but not with anxiety., Limitations: Only adolescents attending school were included; the cross-sectional design cannot reveal causality; outcomes were not measured against the gold-standard diagnostic criteria., Conclusions: Our study provides multi-national evidence of the protective effect of FVI against depressive and anxiety symptoms among adolescents in LMICs, enabling key stakeholders to address mental health issues among adolescents globally., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Endometrial cancer (EC) is one of the most common malignant diseases worldwide. Although many studies have been performed on EC, a systems analysis between transcription factors (TFs) and EC relationship remains poorly characterized. Here, we present a systems bioinformatics analysis of TFs in EC patient samples to identify key TFs in EC. First, dysregulated and survival-related TFs were identified in EC using data from The Cancer Genome Atlas database and Gene Expression Omnibus. Second, we investigated the mechanisms of dysregulated TFs and tested whether their expression is correlated with prognosis of EC. Finally, we addressed new perspectives in EC biomarker research, including comprehensive knowledge of previously suggested candidate biomarkers in conjunction with novel mass spectrometry-based proteomic technologies with enhanced sensitivity and specificity not yet applied to EC studies, enabling a directed clinical perspective of the study design. Our study identified three promising TFs, E2F1, HMGA1, and PGR, which closely correlate with EC. Although treatments targeting TFs are not always efficient, these TFs may be useful as biomarkers for the diagnosis and prognosis of EC. Furthermore, we found that these dysregulated TFs and their target genes are primarily involved in the cell cycle and may promote endometrial carcinoma occurrence and development. Using integrated bioinformatic analysis, we identified candidate genes and pathways in EC, which could improve our understanding of the etiology and underlying molecular events of EC. Furthermore, these candidate genes and pathways could be therapeutic targets for EC., (© 2019 Wiley Periodicals, Inc.)

Clinical efficacy of apatinib in treating metastatic gastric cancer and its effect on the levels of serum IL-17 were investigated. A retrospective analysis was performed on 129 patients who had metastatic gastric cancer after first-line chemotherapy and were treated in Xiangyang No. 1 People's Hospital from February 2012 to February 2015. Of these patients, 78 received oral apatinib and were assigned to experimental group; and 51 received oral tegafur-gimeracil-oteracil and were assigned to control group. Clinical efficacy was compared between the two groups, and the levels of serum IL-17 were measured for all the patients. The treatment response rate in the experimental group was 52.56% and in the control group 31.37%. Apparently, the treatment response rate in the experimental group was higher than that in the control group, and the difference was statistically significant (P<0.05). The incidence of adverse drug reactions in the experimental group was significantly lower than that in the control group (P<0.05). The serum level of IL-17 after one course of medication was significantly lower than that before medication in both groups (P<0.05). In comparison between groups, the serum level of IL-17 after one course of medication was clearly lower in the experimental group than that in the control group (P<0.05). Apatinib regimen was demonstrated to have less toxic side-effects in the treatment of metastatic gastric cancer than tegafur-gimeracil-oteracil regimen, indicating that apatinib has favorable safety. In addition, apatinib can downregulate IL-17 expression, which is helpful in attenuating tumor proliferation and improving the clinical efficacy. Therefore, apatinib has potential use in a wide range of clinical applications.

BACKGROUND Currently, proton pump inhibitors (PPIs) are the first-line treatment for ulcers resulting from endoscopic submucosal dissection (ESD). Vonoprazan is a new oral potassium-competitive acid blocker (P-CAB). The aim of this systematic review and meta-analysis was to compare the efficacy, safety, and tolerance of vonoprazan with PPIs in the treatment of peptic ulcers resulting from ESD. MATERIAL AND METHODS Published results of randomized clinical trials (RCTs) comparing vonoprazan with PPIs in the treatment of ulcers resulting from ESD were identified up to March 2018. The main clinical endpoints evaluated were healing rate and adverse events. The meta-analysis included quality assessment of the studies, statistical analysis of endpoints, and sensitivity analysis using Revman version 5.3 meta-analysis software. RESULTS Systematic literature review identified seven published studies that included 548 patients. Five studies were published as full-text manuscripts, and two studies were published as abstracts. Meta-analysis of the vonoprazan treatment, compared with PPI treatment, for ESD showed that the pooled relative risk (RR) of healing rate was 0.64 (95% CI, 0.33-1.22) for the 4-week study group and 0.98 (95% CI, 0.84-1.15) for the 8-week study group. The RR for adverse events was 0.65 (95% CI, 0.31-1.38) (P>0.05). No statistical evidence of publication bias was found. CONCLUSIONS The findings of the systematic review and meta-analysis showed that the efficacy of vonoprazan was comparable with PPIs for the treatment of peptic ulcers following ESD. Further studies are required to support the safety and efficacy of vonoprazan compared with different types of PPIs.

p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here, we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded the development of mammary tumors in PyVT mice. FliI induced p62-recruited cargoes into Triton X-100 insoluble fractions (TI) to form aggregates, thereby blocking p62 recognition of LC3 and hindering p62-dependent selective autophagy. This function of Flil was reinforced by Akt-mediated phosphorylation at Ser436 and inhibited by phosphorylation of Ulk1 at Ser64. Obstruction of autophagic clearance of p62-recruited cargoes by FliI was associated with the accumulation of oxidative damage on proteins and DNA, which could contribute to the development of cancer. Heterozygous knockout of FliI facilitated selectively autophagic clearance of aggregates, abatement of ROS levels, and protein oxidative damage, ultimately retarding mammary cancer progression. In clinical breast cancer samples, Akt-mediated phosphorylation of FliI at Ser436 negatively correlated with long-term prognosis, while Ulk1-induced FliI phosphorylation at Ser64 positively correlated with clinical outcome. Together, this work demonstrates that FliI functions as a checkpoint protein for selective autophagy in the crosstalk between FliI and p62-recruited cargoes, and its phosphorylation may serve as a prognostic marker for breast cancer. Significance: Flightless-I functions as a checkpoint protein for selective autophagy by interacting with p62 to block its recognition of LC3, leading to tumorigenesis in breast cancer. Cancer Res; 78(17); 4853-64. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Critically ill patients can benefit from enteral nutrition with postpyloric feeding tubes, but the low success rate limits its wide use. Erythromycin could elevate the success rate of tube insertion, but its clinical efficiency still remains controversial., Methods: Included studies must be RCTs which assessed the success rate of postpyloric feeding tube insertion using erythromycin., Results: 284 patients were enrolled in six studies. Meta-analysis showed that erythromycin significantly increases the rate of successful postpyloric feeding tube placement (RR 1.45, 95% CI (1.12, 1.86)) and did not increase the risk of adverse effects (RR 2.15, 95% CI (0.20, 22.82)). Subgroup analysis showed that unweighted feeding tubes (RR 1.47, 95% CI (1.03, 2.11)) could significantly increase the success rate. Country of study, intravenous route of erythromycin, and year of participant enrollment did not influence these results., Conclusions: Erythromycin significantly increases the success rate of postpyloric feeding tube placement. This suggests that erythromycin can be used as an auxiliary method to improve the success rate of bedside insertion.

Gluconeogenesis, an essential metabolic process for hepatocytes, is downregulated in hepatocellular carcinoma (HCC). Here we show that the nuclear receptor Nur77 is a tumour suppressor for HCC that regulates gluconeogenesis. Low Nur77 expression in clinical HCC samples correlates with poor prognosis, and a Nur77 deficiency in mice promotes HCC development. Nur77 interacts with phosphoenolpyruvate carboxykinase (PEPCK1), the rate-limiting enzyme in gluconeogenesis, to increase gluconeogenesis and suppress glycolysis, resulting in ATP depletion and cell growth arrest. However, PEPCK1 becomes labile after sumoylation and is degraded via ubiquitination, which is augmented by the p300 acetylation of ubiquitin-conjugating enzyme 9 (Ubc9). Although Nur77 attenuates sumoylation and stabilizes PEPCK1 via impairing p300 activity and preventing the Ubc9-PEPCK1 interaction, Nur77 is silenced in HCC samples due to Snail-mediated DNA methylation of the Nur77 promoter. Our study reveals a unique mechanism to suppress HCC by switching from glycolysis to gluconeogenesis through Nur77 antagonism of PEPCK1 degradation.

Background: Metformin is a first-line drug for treating type 2 diabetes mellitus, yet its mechanism remains only partially understood and controversial. In this study we assessed a global gene expression profiling in liver of KKAy mice affected by metformin. This study aimed to identify the novel anti-diabetic mechanisms of metformin., Methods: After KKAy mice were administered metformin for 5 weeks, the gene changes profile in the livers of KKAy mice were assessed by using the Agilent whole mice genome oligo microarray., Results: Metformin altered the gene expression profiles in liver of KKAy mice. To our best knowledge, some genes have not been reported until now, such as Anxa2, Atf6, and so on. These genes were involved in many pathways, such as peroxisome proliferator activated receptor signaling pathway., Conclusions: Gene expression changes induced by metformin were in support of the improvement of glucolipid metabolism and insulin resistance in KKAy mice. These findings expanded our knowledge of pharmacological action of metformin, and provided the potential novel insights and interesting information about the molecules involved in the antidiabetic effects of metformin., (Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.)

Mammalian tachykinins are a family of neuropeptides which are potent modulators of smooth muscle function with a significant contractile effect on human smooth muscle preparations. Tachykinins act via three distinct G protein-coupled neurokinin (NK) receptors, NK1, NK2 and NK3, coded by the genes TACR1, TACR2 and TACR3 respectively. The purpose of this paper was to measure the mRNA and protein expression of these receptors and their isoforms in the clasp and sling fibers of the human lower esophageal sphincter complex and circular muscle from the adjacent distal esophagus and proximal stomach. We found differences in expression between the different receptors within these muscle types, but the rank order of the receptor expression did not differ between the different muscle types. The rank order of the mRNA expression was TACR2 (α isoform)>TACR2 (β isoform)>TACR1 (short isoform)>TACR1 (long isoform)>TACR3. The rank order of the protein expression was NK2>NK1>NK3. This is the first report of the measurement of the transcript and protein expression of the tachykinin receptors and their isoforms in the muscles of the human lower esophageal sphincter complex. The results provide evidence that the tachykinin receptors could contribute to the regulation of the human lower esophageal sphincter, particularly the TACR2 α isoform which encodes the functional isoform of the tachykinin NK2 receptor was the most highly expressed of the tachykinin receptors in the muscles associated with the lower esophageal sphincter., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Coating a layer of PEG functionalized porous silica shell onto doxorubicin-conjugated Fe(3)O(4) nanoparticles, we demonstrated, provides a number of combined advantages in view of the magnetic carrier's therapeutic functionality to treat tumors.

Objective: To test the Piezoelectric property of novel biological piezoelectric ceramic HALNK and its effect on the proliferation and differentiation of rat osteoblast cells., Methods: The biological piezoelectric ceramic HALNK1/9 and HALNK5/5 were prepared by mixing Hydroxyapatite (HA) with lithium sodium potassium niobate (LNK) piezoelectric ceramic at a ratio of 1/9 and 5/5 (wt/wt), respectively. After poling treatment, the piezoelectric constants were measured. The osteoblast cells were then seeded on the surfaces of HALNK. The proliferation and differentiation activities of the osteoblast cells were evaluated by MTT assays, ALP activities and scanning electron microscopy examinations., Results: Cells grown on the surfaces of HALNK showed normal morphology, and had better proliferation and differentiation activities than the control. The growth of osteoblastic cells on the surface of HALNK1/9 was significantly better than others., Conclusion: The surface of HALNK 1/9 possesses better piezoelectric property and osteogenesis potential than HALNK5/5.

Objective: Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) belong to neurological diseases caused by a defect in the energy-producing system of mitochondria, and are known to be associated with a deletion in the mitochondrial genome. This study was aimed to understand with greater clearness the characteristics of mitochondrial DNA (mtDNA) mutations in 11 Chinese patients with CPEO (7 cases) or KSS (4 cases)., Methods: Densitometry of the bands on Southern blot, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing were performed to search large scale deletions and A3243G point mutation in patients' muscle mtDNA., Results: Large deletions in mtDNA were detected in 2 CPEO and 3 KSS patients, the size of deletion ranged from 3.0 kb to 8.0 kb. Moreover, mtDNA A3243G point mutation was identified in 1 KSS patient. The proportion of mutant mtDNA was 37.6%-87.0%. Direct sequencing of the PCR products revealed 5 novel large deletions not reported by others., Conclusion: The findings in this study being consistent with the reports by others, large scale deletions of mtDNA are frequently found in Chinese patients with KSS and CPEO. mtDNA A3243G mutation may also exist in some patients with KSS and CPEO.

Biochemical property of L-arginine (L-Arg)/nitric oxide synthase (NOS)/nitric oxide (NO) system was observed in rat brain mitochondria. The results showed that there existed L-Arg transporters of high-affinity, low-transport and saturability in mitochondria membrane of normal rat brain. The maximum transport velocity (V(max)) and Michaelis constant (Km) were 5.87+/ -0.46 nmol/mg pro x min(-1) and 7.8+/- 0.56 micromol/L respectively. In normal condition, endothelium-type NOS was expressed in the mitochondria of rat brain, with its V(max) and Km being 2.7+/-0.3 nmol/mg pro x min(- 1) and 20.85+/-3.27 micromol/L, respectively. NO production was increased in a time-dependent manner and reached a maximum value at 60 min. These results suggest that the L-Arg transporters in MT membrane of normal rat brain were similar with Y(+) type amino acid transporters in cellullar membrane. Furthermore the NOS of mitochondria belongs to eNOS, whereas the L-Arg/NOS/NO system may be a source of NO.

Aim: The approximate entrophy was applied to study EEG in different brain functional states., Methods: EEG were recorded in 40 cases healthy volunteers, who are in five functions states (1. resting conscious with eye-close. 2. resting conscious with eye-opened. 3. closed eyes and listening pure tone. 4. staring at picture. 5. closed eyes and counting numbers). ApEn were calculated in these EEG., Results: The ApEn of frontal was the highest and ApEn of occipital was the lowest in resting conscious with eye-closed. ApEn in every brain area were higher than that in resting conscious with eye-opened. ApEn were changed in different physiological functions. Variation of frontal EEG ApEn value were highest., Conclusions: The ApEn may reflect characteristic of EEG non-linear dynamical. It is a stable parameter. The dates of its requirement were fewer. It may be a useful parameter in studying EEG time series.

Fecal culture for Campylobacter jejuni with the method of Skirrow and serum class specific antibodies (IgG, IgM, IgA) against Campylobacter jejuni using a solid phase enzyme linked immunosorbent assay were performed in 17 cases of Guillain-Barre Syndrome, 17 other neurological disease controls, and 33 normal controls. The results revealed: 1. the incidence of Campylobacter jejuni infection, especially the recent one in Guillain-Barre Syndrome was much higher than in the other two groups; 2. the recent incidence of infection in those below 30 years old and those within the period of summer and autumn was higher than that above 30 years old and that in the other seasons. The results suggested that Campylobacter jejuni infection might be one of the important precipitating factors of Guillain-Barre syndrome and might play an important role in the epidemiological pattern of Guillain-Barre Syndrome in China.

The article concentrated on the study of skeletal muscles of four extremities in 12 cases of different kinds of neuromuscular diseases and 4 volunteers with MRI. The results revealed: MRI could clearly display individual muscle, muscle groups or abnormal muscles morphologically. It could also demonstrate the difference between the neurogenic and myogenic changes. In patients with progressive muscular dystrophy (PMD), the gracilis m. and sartorius m. were relatively intact. In patients with primary myopathies, the severity of MRI changes was consistent with the severity of the illness and the EMG changes. The results indicated that MRI examination was helpful in the diagnosis of neuromuscular disorders. It can define the distribution and the severity of impaired muscles. In addition, MRI could be used to select the appropriate muscles for EMG examinations or muscle biopsies. Selective muscular impairments might be the characteristics of patients with PMD.

A strain of fungus (CZ408) was isolated from white piedra of a female child. Mycological identification showed that it is the first case in the world. Asymptomatic white nodules were noted on the hair of the scalp, and they were distributed irregularly along the shaft 4-10 cm from the scalp. The nodules, hard, not easily broken or removed, consist of hyphae, spores and metabolic materials around the hair. Oral antimycotic drugs are effective in treating this disease.

Two autopsy cases of uremic neuropathy were reported. The chief clinical features were progressive peripheral sensory impairment, especially of the deep sensation, and the distal weakness of the four extremities. Histopathological findings revealed not only marked segmental demyelination and axonal degeneration of the peripheral nerves, but also severe damage of the skeletal muscles, including the necrosis of the myofibers, streaming of the Z-band, aggregation of glycogen, and the presence of membranous bodies under the electron microscope. It indicated that both the peripheral nerves and the skeletal muscles were involved in some metabolic diseases.

To study the long-term prognosis of stroke, we performed annual follow-up examinations on 306 patients who had survived cerebrovascular accidents. All patients had been admitted to the Neurology Service, First Teaching Hospital, Beijing Medical College from January 1, 1976, to December 31, 1978, and were followed up for 1 to 4 years. The series included 217 cases of cerebral thrombosis, 54 of cerebral hemorrhage, and 35 of TIA. The life-table method was used to determine the cumulative survival rate (CSR), cumulative marked improvement rate (CMIR), and cumulative recurrence rate (CRR), for each of these three types of stroke. The main results were the following: 1. The prognosis was not significantly influenced by sex, BP level on admission, or type of cerebrovascular accident. 2. Age was an important prognostic factor. The survival rate decreased significantly in each successive age group. However, age was not a risk factor for recurrence or poor improvement. 3. The cumulative survival rate, cumulative marked improvement rate, and cumulative recurrence rate did not differ significantly among cerebral thrombosis, cerebral hemorrhage, and TIA.

To study the long-term prognosis, we performed annual follow-up examinations on 414 patients who had survived cerebrovascular accidents, including 334 cases of cerebral infarction and 80 cases of cerebral hemorrhage. All patients had been admitted to the Neurological Service of our hospital from January 1, 1976 to December 31, 1980, and were followed up for 3-6 years. The life-table method, the log rank test, and the rank sum test were used to determine the cumulative marked improvement rate, the cumulative recovery rate of pathological reflexes, the cumulative survival rate, and the cumulative recurrence rate. The results revealed the marked improvement rate in cerebral infarction was 81.98%, while in cerebral hemorrhage 89.87% at the end of 3 years after discharge. The recovery rate of pathological reflexes was 52.59% in cerebral infarction, 54.75% in cerebral hemorrhage at the end of 4 years. The cumulative survival rate was 58.67% in cerebral infarction, 53.36% in cerebral hemorrhage at the end of 6 years. The cumulative recurrence rate was 49.39% in cerebral infarction, 49.81% in cerebral hemorrhage at the end of 6 years.