Generation and identification of endothelial-specific Hrh2 knockout mice.

Histamine H2 receptor (HRH2) is closely associated with the development of cardiovascular and cerebrovascular diseases. However, systematic Hrh2 knockout mice did not exactly reflect the HRH2 function in specific cell or tissue types. To better understand the physiological and pathophysiological functions of endothelial HRH2, this study constructed a targeting vector that contained loxp sites flanking the ATG start codon located in Hrh2 exon 2 upstream and a neomycin (Neo) resistance gene flanked by self-deletion anchor sites within the mouse Hrh2 allele. The targeting vector was then electroporated into C57BL/6J embryonic stem (ES) cells, and positively targeted ES cell clones were micoinjected into C57BL/6J blastocysts, which were implanted into pseudopregnant females to obtain chimeric mice. The F1 generation of Hrh2flox/+ mice was generated via crossing chimeric mice with wild-type mice to excise Neo. We also successfully generated endothelial cell-specific knockout (ECKO) mice by crossing Hrh2flox/+ mice with Cdh5-Cre mice that specifically express Cre in endothelial cells and identified that Hrh2 deletion was only observed in endothelial cells. Hrh2flox/+ and Hrh2ECKO mice were normal, healthy and fertile and did not display any obvious abnormalities. These novel animal models will create new prospects for exploring roles of HRH2 during the development and treatment of related diseases.

The Associations Between CYP2D6*10 C188T Polymorphism and Pharmacokinetics and Clinical Outcomes of Tramadol: A Systematic Review and Meta-analysis.

BACKGROUND: Tramadol is one of the most extensively used centrally acting synthetic opioid analgesics. Recently, a number of studies have explored the associations of the CYP2D6*10 C188T polymorphism with pharmacokinetic and clinical outcomes of tramadol. However, the results of these previous reports remain controversial. Therefore, a meta-analysis was needed to reach a consensus. METHODS: PubMed, EMBASE, and the Cochrane Library were searched to identify eligible studies that explored the influence of the CYP2D6*10 C188T polymorphism on clinical outcomes of tramadol through April 2019. Articles meeting the inclusion criteria were comprehensively reviewed by two independent evaluators. A meta-analysis was performed using Review Manager 5.3. RESULTS: A total of nine studies involving 809 related subjects were included in this meta-analysis. Significant associations were found between CYP2D6*10 C188T mutation and longer serum tramadol half-lives, larger AUC0-∞, and the slower clearance rate of tramadol. In addition, we also found that CYP2D6*10 C188T had effects on the pharmacokinetic parameters of the metabolite of tramadol, O-desmethyltramadol, by sensitive analysis. Furthermore, CYP2D6*10 C188T polymorphism was associated with higher visual analog scale score, loading dose, and total consumption of tramadol. There was no significant association between CYP2D6*10 C188T polymorphism and postoperative nausea and vomiting. CONCLUSIONS: CYP2D6*10 C188T polymorphism had a significant influence on tramadol pharmacokinetics and analgesic effect, but there was insufficient evidence to demonstrate that this polymorphism was associated with incidence of nausea and vomiting.

The associations of HLA-DRB1 gene polymorphisms with late-onset myasthenia gravis: a meta-analysis.

BACKGROUND: Late-onset myasthenia gravis (LOMG) is one of the major subgroups of the MG. Intensive evidence suggested that polymorphisms in HLA-DRB1 gene were associated with LOMG risk, but the results remained inconsistent. Therefore, a meta-analysis is conducted to make a more precise evaluation between HLA-DRB1 alleles and LOMG. METHODS: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang and Technology of Chongqing (VIP) Database were searched for eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were applied to assess the association between HLA-DRB1 alleles and LOMG. RESULTS: A total of 11 studies involving 5513 people were included in our meta-analysis. The results showed that DRB1 07 and 0403 alleles were risk factors for LOMG (1.83 [1.12, 2.98], P = 0.02; 7.05 [2.62, 18.92], P = 0.0001, respectively), while DRB1 0301 and 1301 alleles were identified as protective factors for LOMG (0.44 [0.31, 0.62], P < 0.00001; 0.38 [0.23, 0.62], P = 0.0001, respectively). As for the HLA-DRB1 04 and 14 alleles, our subgroup analysis showed that there were significant associations between these alleles and LOMG in Caucasians (2.21 [1.14, 4.27], P = 0.02; 2.82 [1.29, 6.14], P = 0.009, respectively). CONCLUSIONS: These results confirmed the association of DRB1 alleles (0301, 04, 0403, 07, 1301, and 14) and LOMG, which might provide potential promising biomarkers for prediction of LOMG risk.

The associations of CYP19A1 rs700518 polymorphism with bone mineral density and risk of osteoporosis: a meta-analysis.

Osteoporosis is now a worldwide public health problem that seriously endangers human health, but its causes have not yet been fully clarified. Recently, increasing evidence suggested that polymorphisms in CYP19A1 gene were associated with osteoporosis risk and bone mineral density (BMD), but results remained conflicting. We herein performed a meta-analysis based on evidence currently available from the literature to make a more precise estimation of these relationships. The PubMed, Embase, Cochrane library, CNKI (China National Knowledge Infrastructure), and Wan Fang databases were searched for eligible studies. Odds ratio (OR), mean difference (MD), and 95% confidence interval (CI) were applied to assess the strength of these relationships. A total of 8 studies involving 2632 subjects were included in our meta-analysis. We observed that the AG genotype of CYP19A1 rs700518 was significantly associated with lower BMD values of lumbar spine and femoral neck (AG vs. GG: p = .001 and.01, respectively). However, this polymorphism had no obvious impacts on osteoporosis risk according to current available data. In conclusion, the present meta-analysis showed that CYP19A1 rs700518 polymorphism may be a potential candidate biomarker for osteoporosis screening, early diagnosis, and treatment, which will help improve individualized therapy of osteoporosis patients in clinics.

The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis.

BACKGROUND: The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. RESULTS: Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. CONCLUSIONS: CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA. METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA. CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer.

We previously demonstrated that histamine H4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.

Lack of Association between rs2067474 Polymorphism in Histamine Receptor H2 Gene and Breast Cancer in Chinese Han Population.

Histamine H2 receptor (HRH2) was previously suggested to affect the proliferation of breast cancer cells and disease-free survival of breast cancer patients. Furthermore, a common polymorphism, rs2067474, was identified in an enhancer element of the HRH2 gene promoter and was reported to be associated with various diseases including cancer. However, the relationship between this polymorphism and breast cancer risk and malignant degree remains unclear. The aim of this study was to clarify the clinical association of rs2067474 polymorphism with breast cancer. A total of 201 unrelated Chinese Han breast cancer patients and 238 ethnicity-matched health controls were recruited and rs2067474 polymorphism was genotyped. Logistic regression analyses were performed to calculate the odds ratios (ORs) as a measure of association of genotype with breast cancer according to 3 genetic models (dominant, recessive, and additive). Although the percentage of hormone receptor negative cases tended to be higher in AA genotypes, we did not find any significant associations of rs2067474 polymorphism with breast cancer risk or with related clinicopathological parameters in the present study, which indicates that rs2067474 polymorphism of HRH2 gene might not be a risk factor in the development of breast cancer in Chinese Han population.

Integrated analysis of differentially expressed genes and miRNA expression profiles in dilated cardiomyopathy.

Background: Although dilated cardiomyopathy (DCM) is a prevalent form of cardiomyopathy, the molecular mechanisms underlying its pathogenesis and progression remain poorly understood. It is possible to identify and validate DCM-associated genes, pathways, and miRNAs using bioinformatics analysis coupled with clinical validation methods. Methods: Our analysis was performed using 3 mRNA datasets and 1 miRNA database. We employed several approaches, including gene ontology (GO) analysis, KEGG pathway enrichment analysis, protein-protein interaction networks analysis, and analysis of hub genes to identify critical genes and pathways linked to DCM. We constructed a regulatory network for DCM that involves interactions between miRNAs and mRNAs. We also validated the differently expressed miRNAs in clinical samples (87 DCM ，83 Normal) using qRT-PCR.The miRNAs' clinical value was evaluated by receiver operating characteristic curves (ROCs). Results: 78 differentially expressed genes (DEGs) and 170 differentially expressed miRNAs (DEMs) were associated with DCM. The top five GO annotations were collagen-containing extracellular matrix, cell substrate adhesion, negative regulation of cell differentiation, and inflammatory response. The most enriched KEGG pathways were the Neurotrophin signaling pathway, Thyroid hormone signaling pathway, Wnt signaling pathway, and Axon guidance. In the PPI network, we identified 10 hub genes, and in the miRNA-mRNA regulatory network, we identified 8 hub genes and 15 miRNAs. In the clinical validation, we found 13 miRNAs with an AUC value greater than 0.9. Conclusion: Our research offers novel insights into the underlying mechanisms of DCM and has implications for identifying potential targets for diagnosis and treatment of this condition.

Effect of Histamine H2 Receptor Antagonists on All-Cause Mortality in Critically Ill Patients With Essential Hypertension: A Retrospective Cohort Study.

Previous studies found that histamine H2 receptor antagonists (H2RAs) had blood pressure lowering and cardioprotective effects, but the impact of H2RAs on the survival outcomes of critically ill patients with essential hypertension is still unclear. The aim of this study was to investigate the association of H2RAs exposure with all-cause mortality in patients with essential hypertension based on Medical Information Mart for Intensive Care III database. A total of 17,739 patients were included, involving 8482 H2RAs users and 9257 non-H2RAs users. Propensity score matching (PSM) was performed to improve balance between 2 groups that were exposed to H2RAs or not. Kaplan-Meier survival curves were used to compare the cumulative survival rates and multivariable Cox regression models were performed to evaluate the association between H2RAs exposure and all-cause mortality. After 1:1 PSM, 4416 pairs of patients were enrolled. The results revealed potentially significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortalities in multivariate analyses (HR = 0.783, 95% CI: 0.696-0.882 for 30-day; HR = 0.860, 95% CI: 0.778-0.950 for 90-day; and HR = 0.883, 95% CI: 0.811-0.961 for 1-year mortality, respectively). Covariate effect analyses showed that the use of H2RAs was more beneficial in essential hypertension patients with age ≥ 60, BMI ≥ 25 kg/m2, coronary arteriosclerosis, stroke, and acute kidney failure, respectively. In conclusion, H2RAs exposure was related to lower mortalities in critically ill patients with essential hypertension, which provided novel potential strategy for the use of H2RAs in essential hypertension patients.

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses.

Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta-analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty-six individual meta-analyses were identified, including 29 meta-analyses of observation studies with 32 unique outcomes and 19 meta-analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non-H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta-analyses showed that 4 of 46 meta-analyses were assigned as high scores, 3 were assigned as "moderate," and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as "moderate," 9 outcomes were rated as "low," and 17 outcomes were rated as "very low." We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.

Histamine H2 receptor antagonist exhibited comparable all-cause mortality-decreasing effect as ß-blockers in critically ill patients with heart failure: a cohort study.

Background: Our previous study reported that histamine H2 receptor antagonists (H2RAs) exposure was associated with decreased mortality in critically ill patients with heart failure (HF) through the same pharmacological mechanism as ß-blockers. However, population-based clinical study directly comparing the efficacy of H2RAs and ß-blockers on mortality of HF patients are still lacking. This study aims to compare the association difference of H2RAs and ß-blockers on mortality in critically ill patients with HF using the Medical Information Mart for Intensive Care III database (MIMIC-III). Methods: Study population was divided into 4 groups: ß-blockers + H2RAs group, ß-blockers group, H2RAs group, and Non-ß-blockers + Non-H2RAs group. Kaplan-Meier curves and multivariable Cox regression models were employed to evaluate the differences of all-cause mortalities among the 4 groups. Propensity score matching (PSM) was used to increase comparability of four groups. Results: A total of 5593 patients were included. After PSM, multivariate analyses showed that patients in H2RAs group had close all-cause mortality with patients in ß-blockers group. Furthermore, 30-day, 1-year, 5-year and 10-year all-mortality of patients in ß-blockers + H2RAs group were significantly lower than those of patients in ß-blockers group, respectively (HR: 0.64, 95%CI: 0.50-0.82 for 30-day; HR: 0.80, 95%CI: 0.69-0.93 for 1-year mortality; HR: 0.83, 95%CI: 0.74-0.93 for 5-year mortality; and HR: 0.85, 95%CI: 0.76-0.94 for 10-year mortality, respectively). Conclusion: H2RAs exposure exhibited comparable all-cause mortality-decreasing effect as ß-blockers; and, furthermore, H2RAs and ß-blockers had additive or synergistic interactions to improve survival in critically ill patients with HF.

Patients with multiple hepatocellular carcinomas within the UCSF criteria have outcomes after curative resection similar to patients within the BCLC early-stage criteria.

BACKGROUND: Surgical strategies for the treatment of multiple hepatocellular carcinomas (HCC) remain controversial. This study compared the prognostic power of the University of California, San Francisco (UCSF) criteria with the Barcelona Clinic Liver Cancer (BCLC) early-stage criteria. METHODS: Clinical and survival data of 162 multiple-HCC patients in Child-Pugh class A who underwent curative resection were retrospectively reviewed. Prognostic risk factors were analyzed using univariate and multivariate analyses. RESULTS: UCSF criteria were shown to independently predict overall and disease-free survival. In patients within the UCSF criteria, 3-year overall and disease-free survivals were significantly better than in those exceeding the UCSF criteria (68 vs. 34 % and 54 vs. 26 %, respectively; both p < 0.001). There were no significant differences in 3-year overall and disease-free survival between patients within the UCSF criteria but exceeding the BCLC early stage and patients with BCLC early-stage disease (71 vs. 66 %, p = 0.506 and 57 vs. 50 %, p = 0.666, respectively). Tumors within the UCSF criteria were associated with a lower incidence of high-grade tumor (p = 0.009), microvascular invasion (p = 0.005), 3-month death (p = 0.046), prolonged Pringle's maneuver (p = 0.005), and surgical margin <0.5 cm (p < 0.001) than those exceeding the UCSF criteria. Tumors within the UCSF criteria but exceeding the BCLC early stage had invasiveness and surgical difficulty similar to those within the BCLC early-stage criteria. CONCLUSIONS: Multiple HCC patients within the UCSF criteria benefit from curative resection. Expansion of curative treatment is justified.

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia.

Background: Pyroptosis is a novel inflammatory form of programmed cell death and a prospective target for cancer therapy. Nevertheless, little is known about the association between pyroptosis-related genes (PRGs) and acute myeloid leukemia (AML) prognosis. Herein, we systematically investigated the specific functions and clinical prognostic value of multiple PRGs in AML. Methods: Univariate and LASSO Cox regression analyses based on TCGA and GTEx databases were used to generate the PRG signature, whose predictive efficacy of survival was evaluated using survival analysis, ROC, univariate and multivariate Cox analyses as well as subgroup analysis. The BeatAML cohort was used for data validation. The association between risk score and immune cell infiltration, HLA, immune checkpoints, cancer stem cell (CSC), tumor mutation burden (TMB), and therapeutic drug sensitivity were also analyzed. Results: Six -PRG signatures, namely, CASP3, ELANE, GSDMA, NOD1, PYCARD, and VDR were generated. The high-risk score represented a poorer prognosis and the PRG risk score was also validated as an independent predictor of prognosis. A nomogram including the cytogenetic risk, age, and risk score was constructed for accurate prediction of 1-, 3-, and 5-year survival probabilities. Meanwhile, this risk score was significantly associated with the tumor immune microenvironment (TIME). A high-risk score is characterized by high immune cell infiltration, HLA, and immune checkpoints, as well as low CSC and TMB. In addition, patients with low-risk scores presented significantly lower IC50 values for ATRA, cytarabine, midostaurin, doxorubicin, and etoposide. Conclusion: Our findings might contribute to further understanding of PRGs in the prognosis and development of AML and provide novel and reliable biomarkers for its precise prevention and treatment.

Histamine H2 receptor antagonist exposure was related to decreased all-cause mortality in critical ill patients with heart failure: a cohort study.

AIMS: Previous studies reported that histamine H2 receptor antagonists (H2RAs) had cardioprotective effects. However, the effect of H2RAs on mortality of critical ill patients with heart failure (HF) remains unclear. The aim of this study was to clarify the association between H2RAs and all-cause mortality of critical ill patients with HF based on Medical Information Mart for Intensive Care III database (MIMIC-III). METHODS AND RESULTS: Propensity score matching (PSM) was applied to account for the baseline differences between two groups that were exposed to H2RAs or not. The study primary outcome was all-cause mortality. Kaplan-Meier curves and multivariable Cox regression models were employed to estimate the effects of H2RAs on mortality of critical ill patients with HF. A total of 10 387 patients were included, involving 4440 H2RAs users and 5947 non-H2RAs users. After matching, 3130 pairs of patients were matched between H2RAs users and non-H2RAs users. The results showed significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortality in both univariate analyses and multivariate analyses [hazard ratio (HR) = 0.73, 95% confidence interval (CI): 0.65-0.83 for 30-day; HR = 0.80, 95%CI: 0.72-0.89 for 90-day; and HR = 0.83, 95%CI: 0.76-0.90 for 1-year mortality, respectively] by Cox regression after PSM. Furthermore, stratified analyses revealed that the 30-day, 90-day, and 1-year mortality of ranitidine users were significantly lower than those of famotidine users, respectively. CONCLUSION: Histamine H2 receptor antagonists exposure was associated with lower mortality in critical ill patients with HF. Furthermore, ranitidine might be superior to famotidine in reducing mortality of critical ill patients with HF.

Proton Pump Inhibitors and Cancer Risk: An Umbrella Review and Meta-analysis of Observational Studies.

OBJECTIVES: Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews. METHODS: We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence. RESULTS: The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96). CONCLUSIONS: These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

Associations between CYP3A4, CYP3A5 and SCN1A polymorphisms and carbamazepine metabolism in epilepsy: A meta-analysis.

BACKGROUND AND OBJECTIVE: CYP3A4 (rs2242480), CYP3A5 (rs776746) and SCN1A (rs3812718 and rs2298771) gene polymorphisms were previously indicated to be associated with carbamazepine (CBZ) metabolism and resistance in epilepsy. However, previous studies regarding the effects of these polymorphisms still remain controversial. Therefore, we performed a meta-analysis to evaluate whether the four polymorphisms are associated with CBZ metabolism and resistance. METHODS: The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan Fang Database were searched up to January 2021 for appropriate studies regarding the association of rs2242480, rs776746, rs3812718 and rs2234922 polymorphisms with CBZ metabolism and resistance. The meta-analysis was conducted by Review Manager 5.3 software. RESULTS: Eighteen studies involving 2546 related epilepsy patients were included. We found that the G allele of CYP3A4 rs2242480 markedly decreased the plasma CBZ concentration in epilepsy. For CYP3A5 rs776746 polymorphism, the GG genotype (homozygote codominant model: GG vs. AA) and GG + GA genotype (dominant model: GG + GA vs. AA and recessive model: GG vs. GA + AA) were respectively found to be significantly associated with increased CBZ plasma concentration. Additionally, it was also found that the SCN1A rs3812718 A allele was significantly associated with decreased CBZ plasma concentration and increased CBZ resistance. However, no association was observed between SCN1A rs2298771 polymorphism and CBZ metabolism and resistance. CONCLUSION: The CYP3A4 rs2242480, CYP3A5 rs776746 and SCN1A rs3812718 polymorphisms may play important roles in CBZ metabolism and resistance, while SCN1A rs2298771 polymorphism is not associated with CBZ in epilepsy. These findings would improve the individualized therapy of epileptic patients in clinics.

Activation of histamine H4 receptor suppresses the proliferation and invasion of esophageal squamous cell carcinoma via both metabolism and non-metabolism signaling pathways.

Although dysregulation of histamine H4 receptor (H4R) has widely and frequently been documented in digestive carcinomas and correlates with the malignancy and proliferation of these tumors, the existence of H4R and its pathophysiological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In our present study, we explored the expression and function of H4R in human ESCC samples and cell lines. H4R was overexpressed in poorly differentiated ESCC samples and cell lines and correlated with the median survival of ESCC patients. H4R activation not only significantly blocked cell proliferation, cell cycle, and invasion but also inhibited the growth of TE-2 xenografts and increased the survival of xenograft-bearing mice. According to the mechanistic experiments, both metabolism (acetyl-coenzyme A synthetase 2 (ACSS2))- and non-metabolism (mitogen-activated protein kinase (MAPK))-related pathways were involved in the effect of H4R activation on suppressing tumor proliferation and invasion. Based on these findings, H4R was overexpressed in esophageal cancer and exerted antitumor effects on ESCC proliferation and invasion, suggesting that H4R may be a novel potential target of therapies for ESCC. KEY MESSAGES: The function of H4R in ESCC and the underlying mechanisms were investigated. H4R expression was correlated with ESCC cell differentiation and patients' survival. Both metabolism (ACSS2) and non-metabolism (MAPK)-related pathways were involved. This study provided new insight into the relationship between H4R and ESCC. H4R may be a novel potential therapeutic target for ESCC.

Cardioprotective effect of histamine H2 antagonists in congestive heart failure: A systematic review and meta-analysis.

BACKGROUND: Histamine H2 antagonists (H2RAs) have long been suggested to have beneficial effects on congestive heart failure (CHF). However, full agreement about the cardioprotective effects of H2RAs is still not reached yet. Therefore, this study aims to clarify the effects of H2RAs on myocardial function in CHF patients by meta-analysis. METHODS: Electronic databases including PubMed, Embase, and Cochrane Library were retrieved. Randomized controlled trials comparing the cardiac effects of H2RAs and placebo or other medicines were collected. Pooled mean differences (MDs) with 95% confidence intervals (CIs) were calculated and meta-analysis was performed using RevMan 5.3 software. RESULTS: A total of 10 studies (472 participants) were included in this meta-analysis. H2RAs exhibited significant negative inotropic and chronotropic effects to reduce heart rate (MD: -3.90; 95%CI: -7.07 to -0.73, P = .02). Furthermore, although H2RAs did not affect the blood pressure in health volunteers, they significantly decreased the blood pressure of CHF patients. Additionally, H2RAs were also associated with significant increase in pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time. CONCLUSION: In summary, these findings showed that H2RAs exerted negative inotropic and chronotropic effects to reduce heart rate and blood pressure, which, similar to beta-adrenergic receptor blockers, might decrease myocardial oxygen demand and eventually result in improvement of CHF symptoms. These data provided further evidence for the effect of H2RAs on cardiac function and novel potential strategy for treatment of CHF.