Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor.

Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.

Lifestyle factors on the long-term survival of gastric cancer patients after radical resection: A cohort study.

Background: This retrospective cohort study aimed to evaluate the effect of lifestyle factors (e.g., smoking, drinking, physical exercise, and sleep duration) on the long-term survival of gastric cancer (GC) patients after radical resection. Materials and Methods: GC patients after radical resection were enrolled from January 2016 to December 2017. Their baseline clinical data, lifestyle factors, and prognosis were collected. The primary endpoint was all-cause death. The relationship between the variables and survival was examined using the Cox proportional hazards model. Results: A total of 309 patients were enrolled and 296 patients were followed up for a median of 54.0 months, with 130 confirmed deaths. Older age (>60 years) (hazard ratio [HR]: 1.307, 95% confidence interval [CI]: 1.056-2.161, P = 0.006), advanced tumor, node, and metastasis stage (P < 0.05), poorly pathological differentiation (HR: 1.765, 95% CI: 1.080-2.884, P = 0.023), history of smoking (P < 0.001), never physical exercise (HR: 2.057, 95% CI: 1.170-3.617, P = 0.012), long sleep duration (≥8 h) (HR: 4.160, 95% CI: 1.501-11.533, P = 0.006), and short sleep duration (<6 h) (HR: 3.417, 95% CI: 1.312-8.900, P = 0.012) were independent indicators of a poor overall survival in GC patients after radical resection. Conclusion: Smoking cessation, proper sleep duration, and regular physical exercise habits can improve the long-term survival of GC patients after radical resection.

Dynamic changes in the gut microbiota during three consecutive trimesters of pregnancy and their correlation with abnormal glucose and lipid metabolism.

INTRODUCTION: During normal pregnancy, changes in the gut microbiota (GM) in response to physiological alterations in hormonal secretion, immune functions and homeostasis have received extensive attention. However, the dynamic changes in the GM during three consecutive trimesters of pregnancy and their relationship with glucose and lipid metabolism have not been reported. In this study, we aimed to investigate the dynamic changes in the diversity and species of the GM during three consecutive trimesters in women who naturally conceived, and their relationships with abnormal fasting blood glucose (FBG) and serum lipid levels. METHODS: A total of 30 pregnant women without any known chronic or autoimmune inflammatory disease history before pregnancy were enrolled during the first trimester. Serum and stool samples were collected during the first trimester, the second trimester, and the third trimester. Serum samples were tested for FBG and blood lipid levels, and stool specimens were analyzed by 16S rDNA sequencing. RESULTS: The abundance ratio of bacteroidetes/firmicutes showed an increasing tendency in most of the subjects (19/30, 63.3%) from the first to the third trimester. LEfSe analysis showed that the abundance of Bilophila was significantly increased from the first to the third trimester. In addition, at the genus level, the increased relative abundance of Mitsuokella, Clostridium sensu stricto and Weissella were potentially involved in the development of high FBG during pregnancy. The raised relative abundance of Corynebacterium, Rothia and Granulicatella potentially contributed to the occurrence of dyslipidemia during pregnancy. CONCLUSIONS: There are dynamic changes in the GM during the three trimesters, and the alterations in some bacterium abundance may contribute to the development of high FBG and dyslipidemia during pregnancy. Monitoring enterotypes and correcting dysbiosis in the first trimester may become new strategies for predicting and preventing glucolipid metabolism disorders during pregnancy.

Influencing factors of knowledge proficiency of general practitioners in rural China for esophageal cancer prevention and treatment: a cross-sectional study.

BACKGROUND: This study aims to investigate the knowledge of rural general practitioners (GPs) in esophageal cancer (EC) prevention and treatment in China and analyze relevant influencing factors, so as to improve the ability of rural GPs in EC prevention and treatment. METHODS: This cross-sectional study was conducted from November 5, 2021, to November 20, 2021. A self-designed questionnaire was used to conduct an online survey. Multivariable logistic regression models were used to identify the influencing factors of knowledge proficiency of GPs in rural China for EC prevention and treatment. RESULTS: This study included 348 participants from 12 rural areas in Hebei Province. The mean accuracy rate on all question items was 42.3% ± 10.67%. Sex (OR = 2.870, 95% CI: 1.519-5.423), educational level (OR = 3.256, 95% CI: 1.135-9.339), and comprehension of clinical practice guidelines for EC (OR = 4.305, 95% CI: 2.023-9.161) were significant predictors for GPs' knowledge proficiency of EC prevention and treatment (P < 0.05). CONCLUSIONS: The study indicated that knowledge proficiency of rural GPs of EC prevention and control still awaits to be improved. Sex, educational level, and comprehension of clinical practice guidelines for EC were significant predictors for their proficiency.

Environmental stimulus-responsive mesoporous silica nanoparticles as anticancer drug delivery platforms.

Currently, cancer poses a significant health challenge in the medical community. Traditional chemotherapeutic agents are often accompanied by toxic side effects and limited therapeutic efficacy, restricting their application and advancement in cancer treatment. Therefore, there is an urgent need for developing intelligent drug release systems. Mesoporous silica nanoparticles (MSNs) have many advantages, such as a large specific surface area, substantial pore volume and size, adjustable mesoporous material pore size, excellent biocompatibility, and thermodynamic stability, making them ideal carriers for drug delivery and release. Additionally, they have been widely used to develop novel anticancer drug carriers. Recently, MSNs have been employed to design responsive systems that react to the tumor microenvironment and external stimuli for controlled release of anticancer drugs. This includes factors within the intratumor environment, such as pH, temperature, enzymes, and glutathione as well as external tumor stimuli, such as light, magnetic field, and ultrasound, among others. In this review, we discuss the research progress on environmental stimulus-responsive MSNs in anticancer drug delivery systems, including internal and external environment single stimulus-responsive release and combined stimulus-responsive release. We also summarize the current challenges associated with environmental stimulus-responsive MSNs and elucidate future directions, providing a reference for the functionalization modification and practical application of these MSNs.

Comparative metabolomic and transcriptomic analysis of Saccharomyces cerevisiae W303a and CEN.PK2-1C.

Saccharomyces cerevisiae is a health microorganism closely related to human life, especially in food and pharmaceutical industries. S. cerevisiae W303a and CEN.PK2-1C are two commonly used strains for synthetic biology-based natural product production. Yet, the metabolomic and transcriptomic differences between these two strains have not been compared. In this study, metabolomics and transcriptomics were applied to analyze the differential metabolites and differential expression genes (DEGs) between W303a and CEN.PK2-1C cultured in YPD and SD media. The growth rate of W303a in YPD medium was the lowest compared with other groups. When cultured in YPD medium, CEN.PK2-1C produced more phenylalanine than W303a; when cultured in SD medium, W303a produced more phospholipids than CEN.PK2-1C. Transcriptomic analysis revealed that 19 out of 22 genes in glycolysis pathway were expressed at higher levels in CEN.PK2-1C than that in W303a no matter which media were used, and three key genes related to phenylalanine biosynthesis including ARO9, ARO7 and PHA2 were up-regulated in CEN.PK2-1C compared with W303a when cultured in YPD medium, whereas seven DEGs associated with phospholipid biosynthesis were up-regulated in W303a compared with CEN.PK2-1C when cultured in SD medium. The high phenylalanine produced by CEN.PK2-1C and high phospholipids produced by W303a indicated that CEN.PK2-1C may be more suitable for synthesis of natural products with phenylalanine as precursor, whereas W303a may be more appropriate for synthesis of phospholipid metabolites. This finding provides primary information for strain selection between W303a and CEN.PK2-1C for synthetic biology-based natural product production.

Dual effects of endogenous formaldehyde on the organism and drugs for its removal.

Endogenous formaldehyde (FA) is produced in the human body via various mechanisms to preserve healthy energy metabolism and safeguard the organism. However, endogenous FA can have several negative effects on the body through epigenetic alterations, including cancer growth promotion; neuronal, hippocampal and endothelial damages; atherosclerosis acceleration; haemopoietic stem cell destruction and haemopoietic cell production reduction. Certain medications with antioxidant effects, such as glutathione, vitamin E, resveratrol, alpha lipoic acid and polyphenols, lessen the detrimental effects of endogenous FA by reducing oxidative stress, directly scavenging endogenous FA or promoting its degradation. This study offers fresh perspectives for managing illnesses associated with endogenous FA exposure.

Preoperative monocyte to high-density lipoprotein ratio as a predictor of survival outcome of gastric cancer patients after radical resection.

Aim: This study aimed to verify the prognostic value of monocyte to high-density lipoprotein ratio (MHR) in gastric cancer patients after radical resection. Methods: The Cox proportional hazards model was used to determine the risk variables for survival. Results: Older age (>60 years) (hazard ratio [HR]: 1.832; 95% CI: 1.167-2.725; p = 0.009), advanced tumor node metastasis stage (p < 0.05), lymphatic invasion (HR: 1.639; 95% CI: 1.114-3.032; p < 0.05), vascular invasion (HR: 2.002; 95% CI: 1.246-5.453; p = 0.028) and high MHR (HR: 1.154; 95% CI: 1.062-2.315; p = 0.021) were independent poor prognostic factors for gastric cancer patients after radical resection. Conclusion: Older age, advanced tumor node metastasis stage, lymphatic invasion, vascular invasion and high MHR were independent poor prognostic factors for gastric cancer patients after radical resection.

A tracking work on how Sm4CL2 re-directed the biosynthesis of salvianolic acids and tanshinones in Salvia miltiorrhiza hairy roots.

KEY MESSAGE: Overexpression and antisense expression of Sm4CL2 re-directed the biosynthesis of salvianolic acids and tanshinones in Salvia miltiorrhiza hairy roots. Danshen (Salvia miltiorrhiza Bunge) is a widely used traditional Chinese medicine and its main active ingredients are water-soluble phenolic acids and lipophilic diterpenoids which are produced through the phenylpropanoid pathway and terpenoid pathway, respectively. 4-Coumaric acid: Coenzyme A ligase (4CL) is a key enzyme in the phenylpropanoid metabolism. We had obtained Sm4CL2-overexpressing (Sm4CL2-OE) and antisense Sm4CL2-expressing (anti-Sm4CL2) danshen hairy roots over ten years ago. In the follow-up study, we found that total salvianolic acids in Sm4CL2-OE-4 hairy roots increased to 1.35 times of the control-3, and that in anti-Sm4CL2-1 hairy roots decreased to 37.32% of the control-3, but tanshinones in anti-Sm4CL2-1 was accumulated to 1.77 ± 0.16 mg/g of dry weight, compared to undetectable in Sm4CL2-OE-4 and the control-3 hairy roots. Interestingly, Sm4CL2-OE-4 hairy roots contained more lignin, 1.36 times of the control-3, and enhanced cell wall and xylem lignification. Transcriptomic analysis revealed that overexpression of Sm4CL2 caused the upregulation of other phenylpropanoid pathway genes and antisense Sm4CL2 expression resulted in the downregulation of other phenylpropanoid pathway genes but activated the expression of terpenoid pathway genes like SmCYP76AK5, SmGPPS.SSUII.1 and SmDXS2. Protein-protein interaction analysis suggested that Sm4CL2 might interact with PAL, PAL4, CSE, CCoAOMT and SmCYP84A60, and appeared to play a key role in the interaction network. The tracking work in this study proved that Sm4CL2 could redirect both salvianolic acids and tanshinones biosynthesis possibly through synergistically regulating other pathway genes. It also indicated that genetic modification of plant secondary metabolism with biosynthetic gene might cause other responses through protein-protein interactions.

[Advances in traditional Chinese medicine treatment of non-alcoholic fatty liver disease via farnesoid X receptor].

Non-alcoholic fatty liver disease(NAFLD) is a chronic metabolic condition with rapidly increasing incidence, becoming a public health issue of worldwide concern. Studies have shown that farnesoid X receptor(FXR)-based modulation of downstream targets can improve liver function and metabolic status in the patients with NAFLD and may be a potential drug target for treating this di-sease. Great progress has been achieved in the development of drugs targeting FXR for the treatment of NAFLD. A number of studies have explored the traditional Chinese medicine and their active ingredients for the treatment of NAFLD via FXR considering the high safety and efficacy and mild side effects. This paper systematically describes the mechanism of traditional Chinese medicines in the treatment of NAFLD via FXR and the downstream targets, aiming to provide precise targets for the drug development and clinical treatment of NAFLD.

Genistein mitigates oxidative stress and inflammation by regulating Nrf2/HO-1 and NF-κB signaling pathways in hypoxic-ischemic brain damage in neonatal mice.

Background: Oxidative stress and neuroinflammation play crucial roles in the progression of neonatal hypoxic-ischemic brain damage (HIBD). Genistein, a natural phytoestrogen, has been found to protect against ischemic brain injury. However, its effects and potential mechanisms in HIBD have not yet been explored. Methods: A neonatal mouse model of hypoxia-ischemia (HI) and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) were employed. In the in vivo study, genistein (10 mg/kg; ip) was administered in mice once daily for 3 consecutive days before the operation and once immediately after HI. The effects of genistein treatment on acute brain damage and long-term responses were evaluated. Neuronal injury and apoptosis were estimated using hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. The expression of apoptosis-related proteins were also measured by Western blot analysis. Dihydroethidium (DHE) staining and glutathione (GSH) and malondialdehyde (MDA) production were determined to assess the extent of oxidative stress. The messenger RNA (mRNA) levels of proinflammatory cytokines were detected using real-time quantitative polymerase chain reaction (RT-qPCR) to evaluate the extent of neuroinflammation. In the in vitro study, cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays, as well as propidium iodide (PI) staining, were performed to analyse the neuroprotective effects of genistein on primary cortical neurons. Western blot assays were used to detect the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), phosphorylated inhibitor kappa B-α (p-IκB-α) and phosphorylated nuclear factor-kappa B (p-NF-κB) both in vivo and in vitro. Results: Our results showed that genistein treatment effectively reduced cerebral infarction, attenuated neuronal injury and apoptosis, and contributed to the long-term recovery of neurological outcomes and brain atrophy in neonatal HIBD mice. Moreover, genistein ameliorated HIBD-induced oxidative stress and neuroinflammation. Meanwhile, genistein significantly increased cell viability, reversed neuronal injury and decreased cell apoptosis after OGD/R injury. Finally, the activation of the Nrf2/HO-1 pathway and inhibition of the NF-κB pathway by genistein were verified in the brain tissues of neonatal mice subjected to HIBD and in primary cortical neurons exposed to OGD/R. Conclusions: Genistein exerted neuroprotective effects on HIBD by attenuating oxidative stress and neuroinflammation through the Nrf2/HO-1 and NF-κB signalling pathways.

Analysis of the Interaction Mechanism of the Risk Factors of Gas Explosions in Chinese Underground Coal Mines.

Gas explosion accidents easily cause severe casualties in Chinese underground coal mines. Systematic analysis of accident causation is crucial for the prevention of gas explosions. This study identifies the representative risk factors of gas explosions and determines the interrelationship among these risk factors to highlight weak links and develop countermeasures. A total of 21 representative risk factors of gas explosions were identified through 128 case studies and front-line investigations. On this basis, a five-level hierarchical structure model of gas explosions was established to explore the complex interrelationships among the representative risk factors based on a combination of the Decision-Making Trial and Evaluation Laboratory (DEMATEL) and Interpretive Structural Modeling (ISM) methods. Moreover, the Matrix of Cross Impact Multiplications Applied to Classification (MICMAC) method was applied to achieve risk factor classification into four clusters, namely, driving factors, linkage factors, dependent factors and autonomous factors. The results indicated that the interrelationships and emergence properties among the risk factors may cause gas explosions, which should give more attention to the interrelationships among multiple factors and multiple subsystems for coal enterprises. Meanwhile, the complex geological conditions, poor safety supervision, inadequate safety education and training, incomplete execution safety regulations and poor safety technology and input are the long-term focus of risk management for coal enterprises. Finally, 10 countermeasures were proposed to control these representative risk factors and interrelationships. The results are helpful to the development of gas explosion risk management policies and to the preferential allocation of limited resources to resolve these issues.

Sleep duration and risk of hyperlipidemia: a systematic review and meta-analysis of prospective studies.

PURPOSE: Current studies indicate that the association between sleep duration and risk of hyperlipidemia is uncertain. This systematic review aimed to evaluate relevant prospective studies and make a definite conclusion. METHODS: Three databases were searched for prospective studies on the relationship between sleep duration and hyperlipidemia risk from their inception to October 2020. RESULTS: We identified twelve studies involving 114,439 participants. Follow-up for incident hyperlipidemia ranged from 200 days to 10 years. Neither long (RR:1.00, 95%CI:0.90-1.11, P > 0.05) nor short (RR:0.99, 95%CI:0.94-1.05, P > 0.05) sleep duration had a significant association with increased hyperlipidemia risk in adults. However, long sleep duration was decidedly associated with low HDL-C (RR:0.19, 95%CI: - 0.03-0.40, P < 0.05) and high triglycerides (RR: - 0.20, 95%CI: - 0.43-0.03, P < 0.05) in children and adolescents. CONCLUSION: Long sleep duration has strong associations with risks of low HDL-C and high triglycerides in children and adolescents. The mechanisms underlying this association deserves to be explored in future studies.

Influencing factors for mental health of general practitioners in Hebei Province under the outbreak of COVID-19: A cross-sectional study.

OBJECTIVE: This study aimed to understand the mental health status of general practitioners (GPs) in Hebei Province during the outbreak of coronavirus disease 2019, analyse influencing factors, and establish and evaluate the risk prediction model. METHODS: During February 25-29, 2020, a self-designed questionnaire was used to conduct an online survey of GPs in Hebei Province. The survey included a questionnaire on GPs' basic information, a questionnaire on GPs' working hardware and software facilities, and a questionnaire on GPs' mental health condition. A total of 1040 participants returned the completely filled valid questionnaire, and the answers were analyzed using the χ2 test, Wilcoxon rank-sum test and logistic regression with SPSS 20.0 software. Based on the results of binary logistic regression analysis, a risk prediction model was established, and the receiver operating characteristic curve was used to evaluate the model. RESULTS: The results showed that 44.2% (460/1040) of GPs expressed anxiety after the outbreak. Absence of prescreening clinics, fever clinics or isolated observation rooms in primary medical institutions; persons in the administrative area required to be isolated; low sleep quality of GPs and less than 6 hours of sleep per day of GPs were risk factors affecting the mental health status of GPs. Also, epidemic-related training and adequate protective equipment were the protective factors for the mental health status of GPs. CONCLUSION: The government should strengthen the infrastructure construction of community institutions, equip them with sufficient epidemic protection equipment, ensure the rest time of GPs and strengthen mental health training to ensure the mental and physical health of GPs.

Metabolic syndrome and colorectal adenoma risk: A systematic review and meta­analysis.

OBJECTIVE: Whether metabolic syndrome is a risk factor of colorectal adenoma has spurred debate. We systematically meta-analyzed all clinical studies associated with metabolic syndrome (MetS)/metabolic components and colorectal adenoma risk and quantified the dose-response association between them, aiming to provide more clues for better decision-making. METHODS: We searched PubMed, EMBASE, and Cochrane Library through June 2020 for clinical studies of MetS and colorectal adenoma risk. RevMan 5.3 software and STATA 12.0 software were employed for meta-analysis. RESULTS: Seventeen studies representing 44,336 participants were eligible for analysis. The overall meta-analysis showed that MetS patients had increased risk of colorectal adenoma (OR: 1.39, 95% CI 1.24-1.57; P < 0.05). Dose-response analysis presented that every increased number of Mets components was associated with a 8% increment of colorectal adenoma risk(OR: 1.08; 95% CI: 1.04-1.11). Subgroup analysis by age revealed a higher colorectal adenoma risk in MetS patients 50 years or older (OR 1.46; 95% CI 1.21-1.76; P < 0.0001), rather than MetS patients younger than 50 years old (OR 1.23; 95% CI 0.95-1.59; P = 0.11).When stratified by sex, the analysis revealed a higher risk of colorectal adenoma in male MetS patients (OR 1.32; 95% CI 1.15-1.53; P = 0.0001), rather than females (OR 1.65; 95% CI 0.90-3.02; P = 0.10). The analysis split by adenoma location showed that the right colon (OR 1.35; 95% CI 1.04-1.75; P = 0.03), instead of the left colon (OR 1.16; 95% CI 0.84-1.59; P = 0.37) or rectum(OR 1.26; 95% CI 0.89-1.78; P = 0.20), was the predilection site associated with increased colorectal adenoma risk in MetS patients. CONCLUSIONS: Overall, our meta-analysis showed that MetS was associated with a higher risk of colorectal adenoma. MetS patients, especially old (≥50 years) male patients, should be a risk population for colorectal adenoma screening so that they can benefit from behavioural interventions that can help prevent the development of colorectal cancer.

TLR4 signalling via Piezo1 engages and enhances the macrophage mediated host response during bacterial infection.

TLR4 signaling plays key roles in the innate immune response to microbial infection. Innate immune cells encounter different mechanical cues in both health and disease to adapt their behaviors. However, the impact of mechanical sensing signals on TLR4 signal-mediated innate immune response remains unclear. Here we show that TLR4 signalling augments macrophage bactericidal activity through the mechanical sensor Piezo1. Bacterial infection or LPS stimulation triggers assembly of the complex of Piezo1 and TLR4 to remodel F-actin organization and augment phagocytosis, mitochondrion-phagosomal ROS production and bacterial clearance and genetic deficiency of Piezo1 results in abrogation of these responses. Mechanistically, LPS stimulates TLR4 to induce Piezo1-mediated calcium influx and consequently activates CaMKII-Mst1/2-Rac axis for pathogen ingestion and killing. Inhibition of CaMKII or knockout of either Mst1/2 or Rac1 results in reduced macrophage bactericidal activity, phenocopying the Piezo1 deficiency. Thus, we conclude that TLR4 drives the innate immune response via Piezo1 providing critical insight for understanding macrophage mechanophysiology and the host response.

Biphalin, a dimeric opioid peptide, reduces neonatal hypoxia-ischemia brain injury in mice by the activation of PI3K/Akt signaling pathway.

Previous studies have demonstrated that the activation of delta opioid receptors is neuroprotective against neonatal hypoxia-ischemia (HI) brain injury. The aim of this study was to investigate the neuroprotective effects of biphalin, a dimeric opioid peptide, in a mouse model of neonatal HI and the underlying mechanisms. On postnatal day 10, mouse pups were subjected to unilateral carotid artery ligation followed by 1 h of hypoxia (10 % O2 in N2). For treatment, biphalin (5 mg/kg, 10 mg/kg, 20 mg/kg) was administered intraperitoneally immediately after HI. The opioid antagonist naloxone or phosphatidylinositol-3-kinase inhibitor Ly294002 was administered to determine the underlying mechanisms. Infarct volume, brain edema, phosphorylated Akt and apoptosis-related proteins levels were evaluated by using a combination of 2,3,5-triphenyltetrazolium chloride staining, brain water content and Western blotting at 24 h after HI. The long-term effects of biphalin were evaluated by brain atrophy measurement, Nissl staining and neurobehavioral tests at 3 weeks post-HI. Biphalin (10 mg/kg) significantly reduced the infarct volume and ameliorated brain edema. Biphalin also had long-term protective effects against the loss of ipsilateral brain tissue and resulted in improvements in neurobehavioral outcomes. However, naloxone or Ly294002 abrogated the neuroprotective effects of biphalin. Furthermore, biphalin treatment significantly preserved phosphorylated Akt expression, increased Bcl-2 levels, and decreased Bax and cleaved caspase 3 levels after HI. These effects were also reversed by naloxone and Ly294002 respectively. In conclusion, biphalin protects against HI brain injury in neonatal mice, which might be through activation of the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.

Metabolic syndrome and esophageal cancer risk: a systematic review and meta­analysis.

OBJECTIVE: Many clinical studies evaluating the relationship between metabolic syndrome and esophageal cancer yielded uncertain results. The purpose of this study is to systematically assess the relationship between metabolic syndrome and esophageal cancer. METHODS: We searched clinical studies on metabolic syndrome and esophageal cancer risk in PubMed, Embase, and the Cochrane Library. Meta-analysis was conducted by RevMan 5.3 softwares. RESULTS: A total of four cohort studies and two case-control studies met eligibility criteria and were included in the meta-analysis. Meta-analysis using a fixed-effect model indicated that MetS was related with a higher risk of EC (OR: 1.16, 95% CI 1.08-1.25). Subgroup analyses grouped by pathological types showed that MetS was related with a higher risk of EAC (OR: 1.19, 95% CI 1.10-1.28). Subgroup analyses grouped by metabolic conditions showed hyperglycemia (OR: 1.12, 95% CI 1.03-1.21),hypertension (OR: 1.23, 95% CI 1.04-1.46), obesity (OR: 1.40, 95% CI 1.22-1.60, P < 0.05) were related with a higher risk of EAC. CONCLUSIONS: Overall, our meta-analysis provides high quality evidence that metabolic syndrome was related with a higher risk of EAC. Among the individual components of the metabolic syndrome, hyperglycemia, hypertension and obesity may be the key factors.

Effect of nonsteroidal anti-inflammatory drugs on Barrett's esophagus risk: a systematic review and meta-analysis.

OBJECTIVE: Conflicting evidence exists regarding the effect of NSAIDs on the risk of Barrett's esophagus. The purpose of this study is to systematically assess this effect through a meta-analysis. METHODS: Accordingly, clinical studies on NSAID use and Barrett's esophagus risk were searched on PubMed, Embase, and the Cochrane Library. Following this, meta-analyses were conducted using the RevMan 5.3 software. The pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were used as the effect size. RESULTS: Seven eligible studies (one cohort study and six case-control studies) were included for the present meta-analysis by adopting a fixed-effect model, which demonstrated that NSAIDs could reduce Barrett's esophagus risk (OR: 0.84, 95%CI:0.75-0.94, P＜0.05). Moreover, subgroup analyses done according to sex showed that NSAIDs could reduce Barrett's esophagus risk in females (OR 0.85; 95% CI 0.73-0.99; P = 0.04), without heterogeneity between studies (P = 1.00 and I2 = 0%). However, this relationship was not evident in males (OR 0.85; 95% CI 0.68-1.07; P = 0.16). CONCLUSIONS: Overall, this meta-analysis provided high quality evidence that use of NSAIDs is associated with a reduced risk of Barrett's esophagus. However, the presence of a sex-dependent difference remains to be clarified.

Toothbrushing frequency and gastric and upper aerodigestive tract cancer risk: A meta-analysis.

OBJECTIVE: Results of epidemiological studies evaluating the association between toothbrushing and gastric and upper aerodigestive tract (UADT) cancer risk showed inconsistent results. The purpose of this study was to evaluate the association between toothbrushing and gastric and UADT cancer risk and quantify the dose-response association between them. METHODS: We searched the PubMed, EMBASE and Cochrane Library databases to identify relevant studies on toothbrushing and gastric and UADT cancer risk. Statistical analyses were performed using STATA 12.0 software. RESULTS: A total of 30 studies of involving 1 194 017 participants met eligibility criteria and were included in the meta-analysis. Meta-analysis using a random-effect model showed that the high frequency of toothbrushing was associated with significantly reduced risk of gastric and UADT cancers (OR: 0.55, 95% CI 0.46-0.64, P < .05). Our dose-response analysis presented that every increased toothbrushing per day might reduce oral cavity cancer risk by 6%, pharyngeal cancer risk by 11%, laryngeal cancer risk by 3%, oesophageal cancer risk by 6% and gastric cancer risk by 4%. CONCLUSIONS: This meta-analysis suggested the negative relationship between frequency of toothbrushing and risk of gastric and UADT cancers. Toothbrushing may be a protective factor for gastric and UADT cancers. However, this association must be further validated through large prospective studies.