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Background Early identification of the occurrence of arrhythmia in patients with acute myocardial infarction plays an essential role in clinical decision-making. The present study attempted to use machine learning (ML) methods to build predictive models of arrhythmia after acute myocardial infarction (AMI). Methods A total of 2084 patients with acute myocardial infarction were enrolled in this study. (All data is available on Github: https://github.com/wangsuhuai/AMI-database1.git). The primary outcome is whether tachyarrhythmia occurred during admission containing atrial arrhythmia, ventricular arrhythmia, and supraventricular tachycardia. All data is randomly divided into a training set (80%) and an internal testing set (20%). Apply three machine learning algorithms: decision tree, random forest (RF), and artificial neural network (ANN) to learn the training set to build a model, then use the testing set to evaluate the prediction performance, and compare it with the model built by the Global Registry of Acute Coronary Events (GRACE) risk variable set. Results Three ML models predict the occurrence of tachyarrhythmias after AMI. After variable selection, the artificial neural network (ANN) model has reached the highest accuracy rate, which is better than the model constructed using the Grace variable set. After applying SHapley Additive exPlanations (SHAP) to make the model interpretable, the most important features are abnormal wall motion, lesion location, bundle branch block, age, and heart rate. Among them, RBBB (odds ratio [OR]: 4.21; 95% confidence interval [CI]: 2.42–7.02), ≥ 2 ventricular walls motion abnormal (OR: 3.26; 95% CI: 2.01–4.36) and right coronary artery occlusion (OR: 3.00; 95% CI: 1.98–4.56) are significant factors related to arrhythmia after AMI. Conclusions We used advanced machine learning methods to build prediction models for tachyarrhythmia after AMI for the first time (especially the ANN model that has the best performance). The current study can supplement the current AMI risk score, provide a reliable evaluation method for the clinic, and broaden the new horizons of ML and clinical research. Trial registration Clinical Trial Registry No.: ChiCTR2100041960.

What is known and objective Oral anticoagulants (OACs), including warfarin and newer direct-acting OACs (DOACs), have been used for decades to prevent thromboembolic diseases. A drug utilization study was performed to determine the prescribing patterns of OACs. Methods Data were extracted from the Cooperation Project of Hospital Prescription Analysis in China. A total of 455,490 prescription records from 43 tertiary hospitals in five cities of China (Beijing, Shanghai, Guangzhou, Hangzhou and Chengdu) were selected for inclusion. Quarterly trends of defined daily doses (DDDs) and defined daily dose cost (DDDC) from 1 January 2015 to 31 December 2019 were calculated. Results and discussion Warfarin was the most widely used OAC with DDDs between 189,982 and 176,323 from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2019, whereas the use of DOACs increased rapidly during this period. DDDs of rivaroxaban increased from 5409 in Q1 of 2015 to 125,800 in Q4 of 2019, whereas the DDDC declined from 160.5 to 45.7. From Q1 of 2018, rivaroxaban became the most prescribed OAC, surpassing warfarin, in patients diagnosed with deep vein thrombosis. In addition, the DDDs of rivaroxaban exceeded those of warfarin in patients diagnosed with non-valvular atrial fibrillation since the second quarter (Q2) of 2019. DDDs in outpatients and inpatients increased by 80.6% and 71.4%, respectively, and the DDDC for outpatients in Q4 of 2019 was 6.7-fold higher than that in Q1 of 2015. Among patients of all ages, the DDDs in elderly patients increased from 36.8% in Q1 of 2015 to 59.4% in Q4 of 2019. Moreover, the departments of cardiology and cardiothoracic surgery prescribed the majority of the OACs. What is new and conclusion In this study, we describe OAC prescription patterns in China. DOACs, especially rivaroxaban, contribute to the continuous increase in the use of OACs. In the investigated population of China, outpatients and elderly patients were observed to be administered the highest proportion of DOACs.

Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain. 1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity. 2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice. 3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.

Background: Immune checkpoint inhibitors targeting PD-1 and PD-L1 have noticeably improved the treatment landscape of advanced non-small-cell lung cancer, including lung squamous cell carcinoma (SCC). Although patients with immune checkpoint therapy can achieve long-term survival, acquired resistance has been recognized more frequently, while the underlying mechanisms are currently poorly understood. Materials and methods: Here, we report a patient with metastatic lung SCC treated with nivolumab as a first-line treatment for 28 months. Conclusion: The analysis of specimens prenivolumab and postnivolumab treatment suggests that genetic alterations in SOX2 and CDKN2A/CDKN2B and changes in the tumor microenvironment could be reasons for the acquired resistance to nivolumab observed in the lung SCC patient.

BackgroundProgestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial hyperplasia and cancer. Up to 30% of endometrial cancers fail to respond to progestin, a rate that has not significantly changed due to the lack of a detailed understanding of progestin resistance.MethodsCell Counting Kit-8 (CCK-8) assays were used to detect the synergistic effects of brusatol in combination with progestin. Using commercial kits, the conversion of progestin to 20α-dihydroxyprogesterone following btusatol treatment or AKR1C1 silence was investigated. The correlation betwwen AKR1C1 expression profile and prgestin response was further analyzed in paired endometrial hyperplasia and cancer samples from the same individuals before and after progestin therapy. The effects of brusatol-mediated reversal of progestin resistance was explored in both mouse xenograft and human organoid models. DNA dot blot, HMeDIP, and dural-luciferase reporter assays were performed to uncover the mechanism through which brusatol inhibits AKR1C1 and sensitizes endometrial hyperplasia and cancer to progestin.ResultsBrusatol sensitizes endometrial cancer cell to progestin by downregulating the expression of Nrf2 and its target AKR1C1. Increased AKR1C1 facilitated production of 20-α-dihydroxyprogeserone and was associated with declined progesterone. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Tet1 was identified as a novel Nrf2 target gene. It in turn upregulated AKR1C1 expression by increasing hydroxymethylation levels in its promoter regions. ConclusionsWe found that Nrf2-Tet1-AKR1C1 axis plays an essential role in progestin resistance, and brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing Nrf2-Tet1-AKR1C1-mediated progestin metabolism. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial hyperplasia and cancer .

The use of immune checkpoint inhibitors (ICIs) is rising exponentially in numerous cancers, but immune-related adverse events can occur. We report a rare case of high-grade drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome developed stepwise in a patient with gastric cancer after nivolumab treatment. Subclinical myocarditis was sensitively detected by cardiovascular magnetic resonance 3 weeks after initiating nivolumab. Eruption, eosinophilia, and interstitial pneumonitis occurred 1 week later. Corticosteroids were started and his condition improved. Four months later, when he was still on steroids tapering off, acute kidney injury and sequential herpes zoster virus activation developed. Severe acute tubulointerstitial nephritis (ATN) with an intense infiltration of lymphocytes was observed on renal biopsy. In blood, a substantial shift to Th2 response, an increase of Th17 cells, and strikingly enriched granzyme B+ and perforin+ CD8+ T cells were detected at ATN onset. Serum interleukin (IL)-5, IL-17, interferon gamma, and IL-6 levels were consistently elevated. Further molecular profiling identified a DRESS risk allele human leukocyte antigen (HLA)-A*31:01 in this patient. His ATN responded favorably to a high dose of corticosteroids. In parallel, complete antitumor response was observed during the clinical course of DRESS. This is the first ever case report of nivolumab-associated DRESS syndrome with exploration of the mechanisms from the histopathological, cellular and molecular aspects. Nivolumab-induced DRESS may result from type IV hypersensitivity-related ‘off-target effect’ and PD-1 block-mediated ‘on-target effect’. HLA risk alleles may constitute the genetic susceptible basis. HLA typing assay has the potential to screen susceptible individuals to avoid ICI-induced DRESS.

Hao Wang,1,2 Shanhao Chen,1 Die Meng,1,2 Chunyan Wu,3 Junjie Zhu,4 Minlin Jiang,1,2 Jing Ning,1,2 Shengyu Wu,1,2 Lijia Wu,5 Jingjie Li,5 Bin Chen,1 Sha Zhao,1 Wei Li,1 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Yayi He,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai, 200433, People’s Republic of China; 3Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 4Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 5Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People’s Republic of ChinaCorrespondence: Yayi He; Caicun ZhouDepartment of Medical Oncology, Shanghai Pulmonary Hospital, No. 507 Zhengmin Road, Shanghai, People’s Republic of ChinaTel +86 13818828623; Tel +86 13818828623Email 2250601@qq.com; caicunzhoudr@126.comIntroduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.Keywords: lung adenocarcinoma, EGFR mutation, tumor mutation burden, immune phenotype, immune checkpoint blockade

BackgroundTumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients.MethodsA total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed.ResultsAmong the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different.ConclusionsThis study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

Background: The clinical use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) in patients with COVID-19 infection remains controversial. Therefore, we performed a meta-analysis on the effects of ACEI/ARB on disease symptoms and laboratory tests in hypertensive patients infected with COVID-19 virus and those who did not use ACEI/ARB. Methods: We systematically searched the relevant literatures from Pubmed, Embase, EuropePMC, CNKI, and other databases during the study period of 31 December 2019 (solstice, 15 March 2020), and analyzed the differences in symptoms and laboratory tests between patients with COVID-19 and hypertension who used ACEI/ARB drugs and those who did not. All statistical analyses were performed with REVMAN5.3. Results: We included a total of 1808 patients with hypertension diagnosed with COVID-19 in six studies. Analysis results show that ACEI/ARB drugs group D-dimer is lower (SMD = −0.22, 95%CI: −0.36 to −0.06), and the chances of getting fever is lower (OR = 0.74, 95%CI: 0.55 to 0.98). Meanwhile, laboratory data and symptoms were not statistical difference, but creatinine tends to rise (SMD = 0.22, 95% CI: 0.04 to 0.41). Conclusion: We found that the administration of ACEI/ARB drugs had positive effect on reducing D-dimer and the number of people with fever. Meanwhile it had no significant effect on other laboratory tests (creatinine excepted) or symptoms in patients with COVID-19, while special attention was still needed in patients with renal insufficiency.

WHAT IS KNOWN AND OBJECTIVE Pregnancy after transplantation is a challenge owing to the high risk of adverse maternal and foetal outcomes, and immunosuppressants may further impact these outcomes. There are no head-to-head randomized controlled trials comparing influences of cyclosporin and tacrolimus on pregnancy outcomes. Thus, we systematically reviewed and meta-analysed observational studies assessing the comparative influences of these two drugs on pregnancy outcomes in liver/kidney transplant recipients. METHODS Relevant studies comparing pregnancy outcomes with tacrolimus and cyclosporin head-to-head were searched in PubMed, EMBASE and Web of Science (from 1 January 2000 to 20 March 2020). The weighted mean difference and odds ratio (OR) were calculated to compare continuous and dichotomous variables, respectively, with 95% confidence intervals (CIs). Publication bias was estimated using funnel plots. The study quality was assessed according to the modified Newcastle-Ottawa scale. RESULTS AND DISCUSSION Overall, 10 observational studies of low quality, including a total of 1080 post-liver or kidney transplant pregnancies, were identified. Tacrolimus-treated recipients experienced a lower risk of gestational hypertension (28.0%; OR: 1.74; 95% CI: 1.27-2.39; p

Purpose Difficult mask ventilation (DMV) is a potentially life-threatening situation that can arise during anesthesia. However, most clinical predictors of DMV are based on European and US populations. On the other hand, most predictive models consist of multiple factors and complicated assessments. Since obstructive sleep apnea (OSA) is among the most important risk factors associated with DMV, the apnea-hypopnea index (AHI) may play an important role in determining patient risk.The purpose of this study was to investigate the relationship between DMV and AHI, and to determine preoperative risk factors for DMV in Chinese patients. Methods A prospective cohort trial enrolled patients scheduled for elective surgery. After obtaining informed consent, patient demographic information was collected, and patients were tested with pre-operative polysomnography. The anesthesiologist who managed the airway graded the mask ventilation. The difficult mask ventilation was defined as the mask ventilation provided by an unassisted anesthesiologist without oral airway or other adjuvant. A logistic regression model was used to analyze the association between AHI and DMV. Results A total of 159 patients were analyzed. For both primary and secondary outcomes, the unadjusted and adjusted odds ratio for DMV showed significant increases by 5 AHI units. AHI, age, and the Mallampati classification were found to be independent predictive factors for DMV. Conclusions AHI is associated with DMV as a novel independent risk factor in Chinese patients. Along with age and Mallampati classification, AHI should be included in establishing a superior predictive strategy for DMV screening. Trial registration Chinese Clinical Trial Registry ChiCTR-DDD-17013076

Background Viral encephalitis is common in childhood. It is an acute brain parenchymal inflammation caused by a variety of viral infection, and enterovirus accounts for the majority. Due to atypical clinical manifestations, pathogenic testing is important for assisting clinical diagnosis. The purpose of this study was to evaluate the performance of the multiplex PCR assay compared with quantitative real‐time PCR for enterovirus detection. Methods A prospective case‐control study was performed involving 103 pediatric patients suspected for viral encephalitis and cerebrospinal fluid (CSF) samples were collected and tested for 9 pathogens using multiplex PCR assay during April to November in 2018. In parallel, an aliquot of samples was tested for enterovirus infection by real‐time PCR assay. Results There were 85.4% children were confirmed as viral encephalitis on discharge, the remaining ones were diagnosed as other CNS diseases, such as epilepsy. The specificity of the two methods was the same as that of the clinical diagnosis, but the sensitivity and consistency with clinical diagnosis of multiplex PCR were both higher than the real‐time PCR. Besides of enterovirus, multiplex PCR could also detect coinfection of enterovirus with Epstein‐Barr virus and mumps virus. Conclusion Results of multiplex PCR method are more consistent with the clinical diagnosis and are superior to real‐time PCR for detecting enterovirus in CSF., A comparison study between pathogen detection of viral encephalitis was conducted in a case‐control manner. The specificity of the two methods was the same as that of the clinical diagnosis, but the consensus value and sensitivity of the multiplex PCR were both higher than the real‐time PCR.

Objectives Cardiac injury is associated with poor prognosis of 2019 novel coronavirus disease 2019 (COVID-19), but the risk factors for cardiac injury have not been fully studied. In this study, we carried out a systematic analysis of clinical characteristics in COVID-19 patients to determine potential risk factors for cardiac injury complicated COVID-19 virus infection. Methods We systematically searched relevant literature published in Pubmed, Embase, Europe PMC, CNKI and other databases. All statistical analyses were performed using STATA 16.0. Results We analysed 5726 confirmed cases from 17 studies. The results indicated that compared with non-cardiac-injured patients, patients with cardiac injury are older, with a greater proportion of male patients, with higher possibilities of existing comorbidities, with higher risks of clinical complications, need for mechanical ventilation, ICU transfer and mortality. Moreover, C-reactive protein, procalcitonin, D-dimer, NT-proBNP and blood creatinine in patients with cardiac injury are also higher while lymphocyte counts and platelet counts decreased. However, we fortuitously found that patients with cardiac injury did not present higher clinical specificity for chest distress (P = 0.304), chest pain (P = 0.334), palpitations (P = 0.793) and smoking (P = 0.234). Similarly, the risk of concomitant arrhythmia (P = 0.103) did not increase observably either. Conclusion Age, male gender and comorbidities are risk factors for cardiac injury complicated COVID-19 infection. Such patients are susceptible to complications and usually have abnormal results of laboratory tests, leading to poor outcomes. Contrary to common cardiac diseases, cardiac injury complicated COVID-19 infection did not significantly induce chest distress, chest pain, palpitations or arrhythmias. Our study indicates that early prevention should be applied to COVID-19 patients with cardiac injury to reduce adverse outcomes.

A simple and sensitive LC-MS/MS method was established to quantify total and free mycophenolic acid (MPA) plasma concentrations during immunosuppressive medication for pediatric renal transplantation. The chromatographic separation was performed with the Hypersil GOLD C18 column, using a mobile phase consisting of 0.1% formic acid in water and acetonitrile (60:40, v/v) at an isocratic flow rate of 0.4 ml/min. An Agilent 6420 triple quadrupole mass spectrometer was operated via a positive electrospray ionization interface using the transitions m/z 321.14 → 206.9 for MPA and m/z 324.15 → 209.9 for MPA-d3 (internal standard). The linearity was 0.1-50 μg/ml for total MPA and 0.0025-0.5 μg/ml for free MPA. The within-run and between-run precisions were all

Affective personality traits have been associated with a risk of developing mental and cognitive disorders and can be informative for early detection and management of such disorders. However, conventional personality trait detection is often biased and unreliable, as it depends on the honesty of the subjects when filling out the lengthy questionnaires. In this paper, we propose a method for objective detection of personality traits using physiological signals. Subjects are shown affective images and videos to evoke a range of emotions. The electrical activity of the brain is captured using EEG during this process and the multi-channel EEG data is processed to compute the inter-hemispheric asynchrony of the brainwaves. The most discriminative features are selected and then used to build a machine learning classifier, which is trained to predict 16 personality traits. Our results show high predictive accuracy for both image and video stimuli individually, and an improvement when the two stimuli are combined, achieving a 95.49% accuracy. Most of the selected discriminative features were found to be extracted from the alpha frequency band. Our work shows that personality traits can be accurately detected with EEG data, suggesting possible use in practical applications for early detection of mental and cognitive disorders.

Airway compliance is an important index in the surgery of pediatric patients. This study aimed to explore factors affecting dynamic airway compliance (Cdyn) and airway resistance (Raw) after general anesthesia endotracheal intubation for adenotonsillectomy of pediatric patients. A prospective study was undertaken of 107 children who underwent adenotonsillectomy in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine between January and June 2018. The values of Cdyn and Raw were recorded at 5, 10, and 15 minute during general anesthesia endotracheal intubation. Univariate analysis and multiple linear regression analysis were performed for factors that affected Cdyn and Raw. Of the 107 patients aged 56.67 ± 18.28 months, 69 (64%) patients were male, and 26 (24%) and 12 (11%) had an upper respiratory infection in the past week and 1 to 2 weeks, respectively. During anesthesia, Cdyn showed a decreasing trend (P

Background Children who are exposed to anesthesia multiple times may undergo cognitive impairment during development. The underlying mechanism has been revealed as anesthesia-induced cognitive deficiency in young rodents and monkeys. However, the molecular mechanism of sevoflurane-induced neural development toxicity is unclear. Methods By combining RNA sequencing analysis of macaques' prefrontal cortex and human neural differentiation, this study investigates the mechanism of sevoflurane-induced neurotoxicity in primates. Results The level of dual specificity protein phosphatase 4 (Dusp4) was significantly downregulated in non-human primates after sevoflurane treatment. We further uncovered the dynamical expression of Dusp4 during the human neural differentiation of human embryonic stem cells and found that knockdown of Dusp4 could significantly inhibit human neural differentiation. Conclusion This study indicated that Dusp4 is critically involved in the sevoflurane-induced inhibition of neural differentiation in non-human primate and the regulation of human neural differentiation. It also suggested that Dusp4 is a potential therapeutic target for preventing the sevoflurane-induced neurotoxicity in primates.

Background Single nucleotide polymorphisms (SNPs) in 3′-untranslated region (UTR) of genes related with cell-matrix adhesions and migration might affect miRNA binding and potentially affect the risk of cancer. The present study aimed to screen SNPs in 3′ UTR of cancer-related genes and investigate their contribution to the susceptibility of lung cancer. Methods Seven SNPs were selected and genotyped in a case-control study (322 lung cancer patients and 384 controls) among Chinese Han population. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by logistic regression adjusted for age and gender in multiple genetic models. Results In stratified analyses by gender, three (rs1064607, rs3796283 and rs2378456) of LPP gene were associated with a significantly increased susceptibility for lung cancer among male population. Besides, LPP rs2378456 weakened lung cancer risk in female. LPP rs1064607 polymorphism was significantly correlated with increased risk of lung adenocarcinoma. Furthermore, AA genotype of TNS3 rs9876 polymorphism was associated with lymphatic metastasis. Conclusion Our results provides evidence for the impact of LPP polymorphisms on the susceptibility to lung cancer in Chinese population. Electronic supplementary material The online version of this article (10.1186/s12885-018-5241-5) contains supplementary material, which is available to authorized users.

Mizoribine (MZR) is an immunosuppressant for the prevention of allograft rejection in Asian countries, but the great variability in pharmacokinetics (PK) limits its clinical use. This study was to explore genetic and clinical factors that affect the MZR PK process. Blood samples and clinical data were collected from 60 Chinese renal transplant recipients. MZR plasma concentration was measured at pre-dose (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h post-dose by high performance liquid chromatography with an ultraviolet detector. PK parameters were calculated by non-compartmental analysis. High-throughput sequenced single nucleotide polymorphism was applied screening possible genetic factors. Extensive inter-individual MZR PK differences were reflected in the process of elimination (ke, CL/F, MRT and t1/2) and intestinal absorption (Cmax and Tmax), as well as in the dose-normalized exposure (AUC0–12h/D). From 146 SNPs within 39 genes screened, AUC0–12h/D was found higher in recipients with CREB1 rs11904814 TT than with G allele carriers (3.135 ± 0.928 versus 2.084 ± 0.379 μg h ml−1 mg−1, p = 0.007). Recipients with SLC28A3 rs10868138 TT had lower t1/2 as compared to C allele carriers (0.728 ± 0.189 versus 0.951 ± 0.196 h, p = 0.001). Serum creatinine (SCr) explained 35.5% of C0/D variability (p

Objective: The aim of this study was to explore the effects of NINJ2 polymorphisms on susceptibility of coronary heart disease (CHD).Methods: We conducted a case-control study with 499 CHD cases and 505 age- and sex- matched controls. Five single nucleotide polymorphisms (SNP) in NINJ2 (rs118050317, rs75750647, rs7307242, rs10849390 and rs11610368) were genotyped by Agena MassARRAY platform. Odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression to assess the association of NINJ2 polymorphism and CHD risk adjusting for age and gender..Results: NINJ2 rs118050317 significantly increased CHD risk among people older than 60 years old (allele: P = 0.010; heterozygote: P = 0.016; dominant: P = 0.015; additive: P = 0.021) and women (allele: P = 0.026; heterozygote: P = 0.015; dominant: P = 0.018; additive: P = 0.030). Rs118050317 and rs7307242 had strong relationship with hypertension risk in CHD patients. Additionally, rs75750647 significantly increased diabetes risk in multiple models among cases (allele: P = 0.014; homozygote: P = 0.037; heterozygote: P = 0.044; dominant: P = 0.019; additive: P = 0.013), whereas rs10849390 could protect CHD patients from diabetes in allele (P = 0.035), homozygote (P = 0.047) and additive (P = 0.037) models. We also observed two block (block 1: rs118050317 and rs75750647; block 2: rs7307242, rs10849390 and rs11610368) in NINJ2.Conclusion: Our results suggest that NINJ2 polymorphisms are associated with CHD risk.

Mizoribine (MZR) is an immunosuppressive agent with extensive inter-individual differences in pharmacokinetics (PK). Here, we investigated the PK characteristics of MZR in renal transplant recipients and gave equations for prediction of some critical PK parameters. A total of 40 renal transplant recipients participated in this prospective study and were administered MZR orally twice daily in the range of 1.1–8.9 mg kg−1 day−1. Steady-state concentrations of MZR were detected before (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h after administration by high-performance liquid chromatography method. Another 38 patients with newly detected trough concentration (C0) were enrolled to validate the obtained C0 predictive equation. Significant inter-individual differences in MZR PK parameters were observed. Patients with decreasing creatinine clearance rate (CCr) had significantly decreased terminal elimination rate constant (kel) and apparent total body clearance (Cl/F), while other PK parameters including apparent terminal half-life (t1/2), peak time (Tmax), peak concentration (Cmax), area under the curve (AUC0-12h), apparent volume of distribution (V/F), and mean residence time (MRT) were significantly increased. Correlation coefficients between AUC0-12h and C0/Cmax were 0.894 and 0.916, respectively (both p

BACKGROUND This study investigated the quality and quantity of eggs and embryos as well as the clinical pregnancy outcome in young infertile women with diminished ovarian reserve (DOR) after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). MATERIAL AND METHODS We retrospectively reviewed records of 4285 infertile women and divided them into 3 groups according to age and ovarian reserve: young women with normal ovarian reserve (n=1695), young women with DOR (n=1121), and older women with DOR (n=1469). RESULTS In young women with DOR, the proportion of high-quality embryos was significantly higher than in older women with DOR and lower than in young women with normal ovarian reserve (P

Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer., Highlights • WW437 is a novel HDACi, which displays potent anticancer activity in breast cancer. • HDACs-EphA2 signaling axis represents a novel target in breast cancer. • WW437 is a promising therapeutic agent for advanced breast cancer, alone or in combination with EphA2 inhibitor. Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL) and multiple myeloma (MM) treatment, which have also demonstrated clinical activities in solid tumors, including lung cancer and breast cancer. Herein we report a novel HDACi WW437, which displays potent anticancer activity in both cultured cancer cells and xenograft models. Importantly, our work reveals WW437 significantly blocked the HDACs-EphA2 signaling axis in breast cancer. WW437 exhibited significant inhibitory effects on tumor growth and metastases with little toxicity, and tumors from treated mice showed decreased EphA2 expression, suggesting that EphA2 may be a useful biomarker of response to WW437. We also found that EphA2 expression positively correlates with tumor progression in aggressive breast cancer.

In this study, we investigated the association between the polymorphisms of telomerase reverse transcriptase (TERT) gene and the risk of chronic hepatitis B (CHB) in a Chinese Han population. Four single nucleotide polymorphisms (SNPs) in TERT (rs10069690, rs2242652, rs2853677 and rs2853676) were genotyped from 224 CHB patients and 300 healthy controls using the Sequenom Mass-ARRAY platform. We used genetic model, haplotype analyses, chi-square test, logistic regression analysis to evaluate the association between SNPs and CHB risk. The relative risk was estimated by odd ratios (ORs) and 95% confidence intervals (CIs). We found that rs10069690 was significantly associated with an increased CHB risk in the dominant model (adjusted OR = 1.70, 95% CI: 1.06–2.71, P = 0.031) and additive model (adjusted OR = 1.62, 95% CI: 1.09–2.41, P = 0.018). The haplotype “TA” (rs10069690 and rs2242652) was found to be associated with an increased risk of CHB (adjusted OR = 1.58, 95% CI: 1.05–2.38, P = 0.027). Our results suggested potential genetic contributes for TERT in CHB development in a Chinese Han population. Future functional and association studies with larger sample sizes are required to confirm these findings.

The cardiac sympathetic nerves distribute across cardiac tissues with uneven density. Yet, to what extent this anatomical heterogeneity affects electrical activity of the left ventricle is largely unknown. Dogs were randomized into non-stimulation control (NC), posterior basal-stimulation (PB), anterior superior-stimulation (AS), apical part-stimulation (AP) group. The epicardial sympathetic nerves at different sites along their distribution were with electrical stimulation (ES) for 4 hours except in the NC group. The myocardial effective refractory period (ERP), ventricular fibrillation threshold (VFT) and density of sympathetic nerves were recorded. Compared with ES at other places, the stimulation at PB site significantly shortened ERP (left ventricular anterior and posterior walls; PB group, 118 ± 4 ms, 106 ± 2 ms; Versus NC group, 155 ± 3.5 ms, 160 ± 3 ms; p p

The study was aimed to explore whether the TERT and TERC polymorphisms are associated with the lung cancer risk. Five TERC and TERT polymorphisms were genotyped from 554 lung cancer patients and 603 healthy controls. We used χ2 test, genetic model, linkage disequilibrium (LD) and haplotype analyses to evaluate the association between the polymorphisms and lung cancer risk. We found that the allele "C" of rs10936599 (TERC) and the allele "T" of rs10069690 (TERT) were associated with increased risk of lung cancer (OR = 1.32, 95% CI: 1.12-1.55, P = 0.001; OR = 1.41, 95% CI: 1.14-1.76, P = 0.002, respectively). The genotype of "CC" of rs10936599, genotype "CT" of rs10069690 and genotype "GG and "AG" of rs2853677 were also associated with increased the risk of lung cancer. In addition, rs10936599 under the dominant, recessive and log-additive models; rs10069690 under the dominant, overdominant and log-additive models; rs2853677 under the dominant and log-additive models were found to be associated with increased lung cancer risk. The SNP rs2242652 was found to be associated with an increased lung cancer risk under the dominant and overdominant models without adjustment. The haplotype "TA" of TERT was also associated with an increased risk of lung cancer. Our study indicated that rs10936599 (TERC) and rs10069690, rs2242652 and rs2853677 in TERT and haplotype "TA" of TERT were revealed as risk factors of lung cancer in a Chinese Han population. However, it required to verify our result and investigate the function genetic variants and mechanism of lung cancer.

// Yanbin Song 1, 2, 3 , Mengdan Yan 1, 2 , Jing Li 1, 2 , Jingjie Li 1, 2 , Tianbo Jin 1, 2 and Chao Chen 1, 2 1 Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi’an, Shaanxi 710069, China 2 School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 3 Department of Cardiovascular, Yanan University Affiliated Hospital, Yanan, Shaanxi 716000, China Correspondence to: Tianbo Jin, email: tianbojin1973@163.com Chao Chen, email: chaochenxd@gmail.com Keywords: coronary artery disease (CAD), polymorphisms, ZNF208, TNIP1, MPHOSPH6 Received: May 18, 2017 Accepted: June 24, 2017 Published: August 24, 2017 ABSTRACT Introduction: Coronary artery disease (CAD) is a common disease and among the leading cause of death in the general population. Inherited factors are involved in the pathogenesis of CAD. Aims: Our study examined whether SNPs in TNIP1, MPHOSPH6, ZNF208 to be associated with CAD risk in a Chinese Han population. We recruited 596 CAD patients, 603 controls and genotyping fifteen SNPs using Sequenom MassARRAY. For association analysis between TNIP1, MPHOSPH6 and ZNF208 and CAD was determined by Odds ratios (ORs) with 95% confidence intervals (CIs) using Logistic Regression. Results: The results indicated in allel model, the rs960709 in TNIP1 was associated with CAD risk (OR = 0.78, 95%CI = 0.65-0.94, P=0.010). The genetic model results showed that the rs960709 (A/G) polymorphism was associated with the risk of developing CAD in codominant, Dominant and Log-additive. The rs1056654 A/A allele and CAD patients compared to the healthy controls in recessive model (OR = 0.55, 95%CI = 0.34-0.90; P = 0.018). We also found that three SNPS in ZNF208 associated with CAD, respectively, rs2188971, rs8103163 and rs7248488. Linkage disequilibrium (LD) and haplotype analyses of the SNPs found that the CTA haplotype (rs1056675, rs1056654, rs11859599) and rs2188972A/rs2188971T/rs8103163A/rs7248488A (ATAA) were associated with CAD. Conclusion: In conclusion, the present study provided evidence that SNPs in the TNIP1, ZNF208 and MPHOSPH6 were associated with CAD in Chinese Han population. It is possible that these SNPs are CAD risk factors and these data can provide.

// Zhong Chen 1 , Yu Sun 2 , Zhenxiong Xu 2 , Junnv Xu 3 , Jingjie Li 4 , Mengdan Yan 4 , Jing Li 4 , Tianbo Jin 4, 5 and Haifeng Lin 3 1 Department of Thoracic Surgery, Second People’s Hospital of Hainan Province, Hainan, 572200, China 2 Department of General Surgery, Second People’s Hospital of Hainan Province, Hainan, 572200, China 3 Department of Internal Medicine-Oncology, Agricultural Reclamation General Hospital of Hainan Province, Hainan, 570311, China 4 Key Laboratory of Resource Biology and Biotechnology in Western China, Northwest University, Ministry of Education, School of Life Sciences, Northwest University, Shaanxi, 710069, China 5 Xi’an Tiangen Precision Medical Institute, Shaanxi, 710075, China Correspondence to: Haifeng Lin, email: 13322060949@163.com Keywords: ACYP2, polymorphism, liver cancer, case-control, Han Chinese population Received: October 24, 2016 Accepted: April 05, 2017 Published: June 19, 2017 ABSTRACT We explored the association between single nucleotide polymorphisms (SNPs) in ACYP2 and liver cancer risk. Thirteen SNPs were genotyped in 473 cases and 564 controls. Genetic model, linkage disequilibrium, and haplotype analyses were performed to evaluate the association between ACPY2 SNPs and liver cancer risk. We found that rs6713088 (G allele: odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.07−1.52, P = 0.007; GG vs. CC: OR = 1.49, 95% CI: 1.02−2.1, P = 0.038), rs843711 (T allele: OR = 1.29, 95% CI: 1.09−1.54, P = 0.004; TT vs. CC: OR = 1.62, 95% CI: 1.13−2.31, P = 0.008), rs843706 (A allele: OR = 1.30, 95% CI: 1.09−1.55, P = 0.003; AA vs. CC: OR = 1.62, 95% CI: 1.13−2.31, P = 0.008), and rs843645 (GG vs. AG: OR = 1.40, 95% CI: 1.07−1.82, P = 0.014) were associated with an increased risk of liver cancer. In contrast, rs1682111 (A allele: OR = 0.77, 95% CI: 0.640−0.94, P = 0.007; AT vs. TT: OR = 0.69, 95% CI: 0.53−0.91, P = 0.007), rs843720 (additive model: OR = 0.82, 95% CI: 0.68−1.00, P = 0.049), ATATCGCC and CG haplotypes (OR = 0.76, 95% CI: 0.62−0.92, P = 0.006; OR = 0.78, 95% CI: 0.65−0.93, P = 0.006, respectively) were significantly decreased liver cancer risk. Our results confirmed that rs6713088, rs843645, rs843711 and rs843706 were significantly increased liver cancer risk, but rs1682111, rs843720 and haplotypes (ATATCGCC and CG) were significantly decreased liver cancer risk in a Han Chinese population.

// Mengdan Yan 1,2 , Jingjie Li 1,2 , Na He 1,2 , Xugang Shi 2 , Shuli Du 2 , Bin Li 1,2,3 and Tianbo Jin 1,2 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Northwest University, Ministry of Education, Xi’an, China 2 Xi’an Tiangen Precision Medical Research Institute, Xi’an, China 3 Department of Neurosurgery, Xi’an First Hospital, Xi’an, China Correspondence to: Bin Li, email: // Tianbo Jin, email: // Keywords : glioma, EGFR gene, tag single nucleotide polymorphism, case-control study Received : July 13, 2016 Accepted : December 07, 2016 Published : April 07, 2017 Abstract The Epidermal Growth Factor Receptor gene has been reported to be involved in the progression of gliomas which is one of the deadliest primary brain tumors in humans. To determine potential association between EGFR and glioma risk, we performed a case-control study with 394 glioma patients and 298 cancer-free controls in which captured a total of 8 tag single nucleotide polymorphisms of EGFR gene from Xi’an, China. SPSS 19.0 statistical packages, χ 2 test, genetic model analysis and SHEsis software platform were analyzed s the variants in EGFR gene associations with glioma risk. For five different inheritance models analyzed, the following genotypes were associated with increased glioma risk. In the codominant model, genotype CC (rs730437, OR = 1.93, p = 0.024; rs1468727, OR = 2.02, p = 0.007); In the dominant model, genotype CA and CC (rs730437, OR = 1.45, p = 0.026), genotype GA and AA (rs845552, OR = 1.40, p = 0.044); In the recessive model, genotype CC (rs730437, OR = 1.64, p = 0.026; rs1468727, OR = 1.87, p = 0.002); In the additive model, genotype CC (rs730437, OR = 1.32, p = 0.006; rs1468727, OR = 1.39, p = 0.005), genotype GG (rs11506105, OR = 1.32, p = 0.02) and genotype AA (rs845552, OR = 1.27, p = 0.04). Our study indicated that 8 mutants located in EGFR gene were risk-conferring factors, larger and different populations with EGFR polymorphisms are required to verify these associations.

// Jing Fang 1, * , Ying Li 2, * , Jiayi Zhang 3, 4 , Mengdan Yan 3, 4 , Jingjie Li 3, 4 , Shan Bao 5 and Tianbo Jin 3, 4 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China 2 Department of Radiology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710077, China 3 Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 4 Xi’an Tiangen Precision Medical Institute, Xi’an, Shaanxi 710075, China 5 Clinic of Gynecology and Obstetrics, Hainan Provincial People’s Hospital, Haikou 570102, China * These authors have contributed equally to this work and should be considered as joint first authors Correspondence to: Shan Bao, email: shanbaohainan@163.com Tianbo Jin, email: jintianbo@gmail.com Keywords: association study, cervical cancer, MicroRNA gene, single nucleotide polymorphisms (SNPs) Received: November 14, 2016 Accepted: February 15, 2017 Published: March 07, 2017 ABSTRACT We explored the correlation between single nucleotide polymorphisms (SNPs) and susceptibility to cervical cancer (CC) in a Xinjiang Uygur population. Ten SNPs in eight miRNA-regulated genes were selected for analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used to detect correlations between SNPs and CC. We found that minor allele “C” of rs512715 in NEAT1 was associated with an increased risk of CC in the allele, codominant, dominant, overdominant and log-additive models. Minor allele “C” of rs4777498 in CELF6 was associated with an increased risk of CC in the recessive model. Minor allele “C” of rs3094 in RNASE4 was associated with increased risk of CC in the allele, dominant and log-additive models. In clinical stage III/IV CC patients, minor allele “C” of rs3094 in RNASE4 and minor allele “C” of rs8004334 in JDP2 were associated with increased risk. In subtype squamous carcinoma CC patients, minor allele “C” of rs512715 in NEAT1 and minor allele “C” of rs3094 in RNASE4 were associated with increased risk. In subtype adenocarcinoma CC patients, minor allele “C” of rs3094 in RNASE was associated with increased risk.

// Nan Wang 1, * , Qing Qiao 1, * , Guoqiang Bao 1 , Tao Wu 1 , Yizhou Li 2 , Jingjie Li 3 , Jianguo Lu 1 , Xianli He 1 1 Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, China 2 Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010050, China 3 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi, 710069, China * These authors have contributed equally to this work Correspondence to: Jianguo Lu, email: lujianguoLJG123@163.com Xianli He, email: wanghe@fmmu.edu.cn Keywords: gastric cancer, colorectal cancer, single-nucleotide polymorphism, susceptibility, case-control Received: September 26, 2016 Accepted: January 10, 2017 Published: February 26, 2017 ABSTRACT Here, we genotyped eleven single-nucleotide polymorphisms (SNPs) and evaluated their association with the risk of developing gastric cancer (GC) or colorectal cancer (CRC) in 1,790 Han Chinese participants (588 GC patients, 499 CRC patients, and 703 healthy controls). Statistically analysis showed that the “C” allele of rs2689154 in MIPEPP2 was associated with a decreased risk of GC (odds ratio [OR] = 0.81, 95 % confidence interval [CI]: 0.66-0.99, P = 0.041), whereas the “T” allele of rs12615966 in LOC284998 was associated with a 1.29-fold increase in the risk of GC (OR = 1.29, 95% CI: 1.03-1.63, P = 0.029). Additionally, genetic model analyses showed that rs2689154 was associated with a reduced risk of GC under the recessive model (adjusted OR = 0.46, 95% CI: 0.22-0.98, P = 0.037), and rs12615966 in FOXF1 was associated with an increased risk of GC in both the dominant and log-additive models after adjusted for age and gender (adjusted OR = 1.36, 95% CI: 1.02-1.81, P = 0.033; adjusted OR = 1.36, 95% CI: 1.05-1.75, P = 0.018, respectively). We also observed that rs2178146 in FOXF1 was associated with an increased risk of CRC in the recessive model (adjusted OR = 1.90, 95% CI: 1.05-3.45, P = 0.034). Our results confirmed that rs2689154 in MIPEPP2 was significantly decreased GC risk, but rs12615966 in LOC284998 was significantly increased GC risk, and rs2178146 in FOXF1 was associated with increased CRC risk in the Han Chinese population.

// Lijun Liu 1, 2, 3 , Jingjie Li 4 , Mengdan Yan 4 , Jing Li 4 , Junyu Chen 5 , Yi Zhang 5 , Xikai Zhu 1, 2, 3 , Li Wang 1, 2, 3 , Longli Kang 1, 2, 3 , Dongya Yuan 1, 2, 3 , Tianbo Jin 1, 2, 3, 4 1 Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 2 Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 3 Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 4 Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 5 Inner Mongolia Medical University, Hohhot, Inner Mongolia, 010050, China Correspondence to: Dongya Yuan, email: dongyayuanxzmz@gmail.com Tianbo Jin, email: jintianbo@gmail.com Keywords: TCF7L2 , schizophrenia, SNP, case-control Received: September 06, 2016 Accepted: January 04, 2017 Published: February 22, 2017 ABSTRACT Single nucleotide polymorphisms (SNPs) in TCF7L2 (Transcription Factor 7-Like 2) reportedly affect susceptibility to schizophrenia (SCZ). We examined the association between TCF7L2 polymorphisms and SCZ susceptibility in a Chinese Han population. Six SNPs were genotyped in 499 SCZ patients and 500 healthy individuals, after which their associations with SCZ were evaluated using the Chi-squared test and genetic model analyses. We observed that the allele A of rs12573128 is associated with an increased SCZ risk (odds ratio [OR] = 1.33, 95% confidence interval [CI]: 1.08-1.63, P = 0.006, adjusted P = 0.030). The AA genotype of rs12573128 was associated with a higher SCZ risk than the GG genotype, before and after adjustment for sex and age (adjusted OR = 2.97, 95% CI: 1.49-5.92, P = 0.002). In addition, SNP rs12573128 was associated with 1.47-fold, 2.64-fold and 1.50-fold increases in SCZ risk of in dominant, recessive and additive model, respectively (adjusted OR = 1.47, 95% CI = 1.09-1.99, P = 0.012; Bonferroni adjusted P = 0.030). adjusted OR = 2.64, 95% CI = 1.34-5.18, P = 0.005 and adjusted OR = 1.50, 95% CI = 1.17-1.93, P = 0.002, respectively). These results suggest rs12573128 is significantly associated with an increased risk of SCZ in the Chinese Han population.

Following publication of the work [1], authors reported the “flow cytometery plots” panel in Fig. 4e contained an inter-duplication in error.

Background Laryngeal squamous cell carcinoma (LSCC) is one of the most prevalent malignant neoplasms of the upper respiratory tract. Studies have confirmed that an unstable chromosome constitution promotes the progress of laryngeal tumorigenesis, and ACYP2 has been confirmed as a telomere length‐related gene. However, to date, the association between ACYP2 polymorphisms and LSCC susceptibility has not been investigated. Methods We performed this study to explore the effect of 11 single‐nucleotide polymorphisms (SNPs) in ACYP2 on LSCC susceptibility in Chinese Han males. Unconditional logistic regression analysis adjusted for age was used to calculate the odds ratios and 95% confidence intervals. Results Based on allele and genotype models, our results showed that rs1682111 variant was significantly associated with a decreased LSCC susceptibility (p

Chromatin-associated fumarase (FH) affects histone methylation via its metabolic activity. However, whether this effect is involved in gene transcription remains to be clarified. In this study, we show that under glucose deprivation conditions, AMPK phosphorylates FH at Ser75, which in turn forms a complex with ATF2 and participates in promoter activation. FH-catalysed fumarate in promoter regions inhibits KDM2A demethylase activity, and thus maintains the H3K36me2 profile and facilitates gene expression for cell growth arrest. On the other hand, FH is found to be O-GlcNAcylated at the AMPK phosphorylation site; FH-ATF2-mediated downstream events are impeded by FH O-GlcNAcylation, especially in cancer cells that display robust O-GlcNAc transferase (OGT) activity. Consistently, the FH-Ser75 phosphorylation level inversely correlates with the OGT level and poor prognosis in pancreatic cancer patients. These findings uncover a previously uncharacterized mechanism underlying transcription regulation by FH and the linkage between dysregulated OGT activity and growth advantage of cancer cells under glucose deficiency.

GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) are sequentially responsible for de novo synthesis of tetrahydrobiopterin (BH4), a known co-factor for nitric oxide synthase (NOS). The implication of BH4-biosynthesis process in tumorigenesis remains to be investigated. Here, we show that PTPS, which is highly expressed in early-stage colorectal cancer, is phosphorylated at Thr 58 by AMPK under hypoxia; this phosphorylation promotes PTPS binding to LTBP1 and subsequently drives iNOS-mediated LTBP1 S-nitrosylation through proximal-coupling BH4 production within the PTPS/iNOS/LTBP1 complex. In turn, LTBP1 S-nitrosylation results in proteasome-dependent LTBP1 protein degradation, revealing an inverse relationship between PTPS pT58 and LTBP1 stability. Physiologically, the repressive effect of PTPS on LTBP1 leads to impaired transforming growth factor β (TGF-β) secretion and thereby maintains tumor cell growth under hypoxia. Our findings illustrate a molecular mechanism underlying the regulation of LTBP1-TGF-β signaling by the BH4-biosynthesis pathway and highlight the specific requirement of PTPS for tumor growth.

Context Late follicular phase elevation in serum progesterone (P) during controlled ovarian hyperstimulation negatively affects the outcome of assisted reproductive technology by contributing to endometrial-embryo asynchrony. There are still no data on lipid metabolite alterations during this process. Objectives To investigate alterations in the lipid profile during the window of implantation in patients with premature P rise. Design Lipidomic variations in the endometrium were evaluated by ultrahigh-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry. Setting University assisted reproductive medicine unit. Patients or Other Participants Forty-three patients undergoing in vitro fertilization/intracytoplasmic sperm injection because of a tubal factor or male factor infertility were included in this study. The patients were divided into a high P group (P ≥ 1.5 ng/mL, 15 patients) and a normal P group (P < 1.5 ng/mL, 28 patients) on the day of human chorionic gonadotropin administration. Interventions The endometrial tissues were obtained by Pipelle biopsy 7 days after human chorionic gonadotropin administration. Main Outcome Measures Alterations in lipid metabolites. Results A total of 1026 ions were identified, and 25 lipids were significantly upregulated. The endometrial lipid profile was characterized by substantial increases in the concentrations of phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, diacylglycerol, ceramide, phosphatidylinositol, and phosphatidylserine in patients with a premature P rise at the end of the follicular phase. The correlation analysis between P levels and lipids showed a stronger negative correlation between phosphatidylethanolamine or phosphatidylserine and P levels. Conclusions Premature P elevation disrupts the lipid homeostasis of the endometrium during the peri-implantation period. The altered lipid levels may impair endometrial receptivity and early embryo implantation.

// Huijie Wang 1 , Jianzhong Yu 2 , Yanling Guo 1 , Zhengxing Zhang 1 , Guoqi Liu 1 , Jingjie Li 3 , Xiyang Zhang 4 , Tianbo Jin 3 , Zhaoxia Wang 1 1 Department of Intergrated Traditional Chinese and Western Medicine in Oncology, Affiliated Luoyang Central Hospital, Zhengzhou University, Luoyang 471000, China 2 Department of Neurology, Haikou People’s Hospital, Haikou 570208, Hainan, China 3 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 4 Xi’an Tiangen Precision Medical Institute, Xi’an, Shaanxi 710075, China Correspondence to: Zhaoxia Wang, email: wangzhaoxia_a@163.com Keywords: ZNF208, esophageal cancer, single nucleotide polymorphisms (SNPs), association study Received: July 05, 2016 Accepted: October 29, 2016 Published: November 19, 2016 ABSTRACT Previous studies showed an association between the ZNF208 gene and gastric cancer. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in ZNF208 and the risk of esophageal cancer in a Chinese Han population. We conducted a case-control study that included 386 cases and 495 controls. Five SNPs were selected from previous genome-wide association studies and genotyped using the Sequenom MassARRAY platform. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals after adjustment for age and gender. Logistic regressionl analysis showed that two SNPs (rs8103163 and rs7248488) were associated with an increased risk of esophageal cancer under different inheritance models after Bonferroni correction. Haplotype analysis suggested that the four variants comprised one block, and that the G rs2188972 C rs2188971 C rs8103163 C rs7248488 haplotype was significantly correlated with an increased risk of esophageal cancer. Our data indicate that variants in ZNF208 are contribute to the susceptibility to esophageal cancer in a Chinese Han population.

// Jing Li 1, * , Jiachen Wei 2, * , Pengcheng Xu 3 , Mengdan Yan 1, 4 , Jingjie Li 1, 4 , Zhengshuai Chen 1, 4 , Tianbo Jin 1, 4 1 Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 2 Department of Endocrinology, Xi’an NO.1 Hospital, Xi’an 710002, China 3 Inner Mongolia Medical University, Inner Mongolia, Hohhot 010010, China 4 Xi’an Tiangen Precision Medical Institute, Xi’an, Shaanxi, 710075, China * These authors have contributed equally to this work Correspondence to: Tianbo Jin, email: jintianbo@gmail.com Keywords: type2 diabetes, single nucleotide polymorphism, case-control, genetic Received: August 19, 2016 Accepted: October 19, 2016 Published: November 16, 2016 ABSTRACT We investigated the correlation between type 2 diabetes (T2D)-related genes and the clinical characteristics of T2D in the Chinese Han population. Our study included 319 patients and 387 controls. Age, gender, clinical features, medications intake and biochemical blood profiles were analyzed. Genotyping was performed on a total of 18 single nucleotide polymorphisms previously reported to be associated with T2D. Our analyses revealed that the CT genotype of ARHGAP22 rs4838605 is associated with T2D risk. Upon analyzing the subjects’ clinical characteristics, we found that for rs2811893, the TT genotype correlated with high creatinine levels, while the AA genotype of rs17045754 and the TT genotype of rs4838605 correlated with elevated triglyceride levels. In addition, the AA genotype of rs17376456 and the TT genotype of rs6214 ( p = 0.006) correlated with elevated hemoglobin A1c levels. Lastly, those carrying the TT genotype of rs7772697 and the CA genotype of rs3918227 exhibited higher mean body mass index and Cystatin C than controls. Our results showing that the ARHGAP22 gene is associated with an increased risk of T2D, and that seven SNPs in MYSM1 , PLXDC2 , ARHGAP22 and HS6ST3 promote T2D progression and could help predict the clinical course of T2D in patients at risk.

// Xiaojuan Guo 1 , Yani Zhang 1 , Jieli Du 2 , Hua Yang 3 , Yini Ma 3 , Jingjie Li 3 , Mengdan Yan 3 , Tianbo Jin 3, 4, 5, 6 , Xianyang Liu 1 1 Xi'an Mental Health Center, Xi’an, Shaanxi 710061, China 2 Inner Mongolia Medical University Hohhot 010010, Inner Mongolia, China 3 School of Life Sciences, Northwest University, Xi’an 710069, China 4 Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 5 Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China 6 Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China Correspondence to: Xianyang Liu, email: liuxianyang2016@126.com Keywords: ANK3, schizophrenia risk, association, case-control study, Chinese Han population Received: September 18, 2016 Accepted: October 28, 2016 Published: November 03, 2016 ABSTRACT Schizophrenia is a chronic, severely debilitating mental disorder. Many studies have suggested that genetic factors play an important role in the onset and development of schizophrenia. In our study, we conducted a case-control study in a northern Chinese Han population of 499 schizophrenia patients and 500 controls to investigate the effect of variant genotypes of 13 SNPs in ANK3 on schizophrenia risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using the chi-squared test, genetic model analysis, and haplotype analysis. Four ANK3 SNPs were associated with schizophrenia risk. The minor allele of rs958852 in ANK3 was associated with a 0.75-fold reduction in schizophrenia risk in an allelic model. In the genetic model, rs958852 was associated with a reduced schizophrenia risk, and rs10994336, rs10994338 and rs4948418 were associated with an increased schizophrenia risk (rs10994336, OR = 2.00, 95%CI: 1.01–3.94, p = 0.047; rs10994338, OR = 1.99, 95%CI: 1.01–3.93, p = 0.047; rs4948418, OR = 2.00, 95%CI: 1.01–3.94, p = 0.047). In addition, haplotype “TTC” of ANK3 was associated with a 0.73-fold reduced schizophrenia risk (95%CI: 0.54–0.99; p = 0.044). To our knowledge, this is the first to report of an association between ANK3 rs10994336, rs10994338, rs4948418 and rs958852 and schizophrenia risk in a northern Chinese Han population.

// Zhen Shen 1, * , Wanli Ren 1, * , Yanxia Bai 1 , Zhengshuai Chen 3, 4 , Jingjie Li 3, 4 , Bin Li 3, 4 , Tianbo Jin 3, 4 , Peilong Cao 2 , Yuan Shao 1 1 Department of Otolaryngology & head neck, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China 2 Department of Pathology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China 3 School of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China 4 National Engineering Research Center for Miniaturized Detection Systems, Xi’an 710069, China * These authors have contributed equally to this work Correspondence to: Peilong Cao, email: peilonggao@163.com Yuan Shao, email: jiaodashaoyuan@163.com Keywords: laryngeal squamous cell carcinoma, NABP1, DIRC3, biomarker, polymorphism Received: August 11, 2016 Accepted: October 14, 2016 Published: October 25, 2016 ABSTRACT Laryngeal squamous cell carcinoma (LSCC) is one of the most common and aggressive malignancies of the upper digestive tract. The present study is a retrospective analysis of data from a prospective longitudinal study. A total of 170 male LSCC patients (average age, 60.75±10.082) at the First Affiliated Hospital of Xi’an Jiaotong University School of Medicine were recruited between January 2002 and April 2013 for this study. We assessed correlations between patient characteristics and survival, and sequenced genomic DNA from patient peripheral blood samples. We found that the single nucleotide polymorphisms (SNPs), rs11903757, with closest proximity to NABP1 and SDPR , and rs966423 in DIRC3 , were associated with survival in LSCC patients. Median follow-up was 38 months (range 3–122) and median survival time was 48 months. LSCC patients with total laryngectomy, poor differentiation, T3-T4 stage, N1-N2 stage or III-IV TNM stage had reduced survival. This is the first study to demonstrate that the rs11903757 GT (HR=2.036; 95% CI, 1.071–3.872; p =0.030) and rs966423 TT (HR=11.677; 95% CI, 3.901–34.950; p =0.000) genotypes predict poor patient outcome. These polymorphisms may serve as useful clinical markers to predict patient survival, and to guide individual patient therapeutic decisions.