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Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. Therapeutic targeting of osteosarcoma has been unsuccessful; therefore, identifying novel osteosarcoma pathogenesis could offer new therapeutic options. CDK7 is a subunit within the general transcription factor TFIIH. We aim to explore the new mechanism by which CDK7 regulates osteosarcoma and our studies may provide new theoretical support for the use of CDK7 inhibitors in the treatment of osteosarcoma. Here, we investigate the molecular mechanism underlying the association between CDK7 and GRP78 in osteosarcoma. Specifically, we find that an E3 ubiquitin ligase TRIM21 binds and targets GRP78 for ubiquitination and degradation, whereas CDK7 phosphorylates GRP78 at T69 to inhibit TRIM21 recruitment, leading to GRP78 stabilization. Notably, a CDK7-specific inhibitor, THZ1, blunts osteosarcoma growth and metastasis. Combination treatment with CDK7 and GRP78 inhibitors yield additive effects on osteosarcoma growth and progression inhibition. Thus, simultaneous suppression of CDK7 and GRP78 activity represents a potential new approach for the treatment of osteosarcoma. In conclusion, the discovery of this previously unknown CDK7/GRP78 signaling axis provides the molecular basis and the rationale to target human osteosarcoma.

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.

Background and aimsGrowing studies have focused on the effect of lead exposure on human circulatory system, while the relationship between lead exposure and subclinical myocardial injury (SC-MI) is still poorly known. Therefore, this study was to explore the effect of lead exposure on SC-MI.MethodsThe study included 6,272 individuals aged 40 and older without cardiovascular disease (CVD) from the third National Health and Nutrition Examination Survey. Blood lead was used as an alternative marker of lead exposure. Multivariable logistic regression models, restricted cubic spline and threshold effect analyses were performed to investigate the effect of blood lead on SC-MI.ResultsAfter adjusting for age, sex, race, diabetes, hypertension, systolic blood pressure, body mass index, waist-to-hip ratio, triglycerides, total cholesterol, creatinine, fasting plasma glucose and hemoglobin Alc, higher blood lead level was independently related to higher risk of SC-MI (OR 1.047, 95% CI [1.018, 1.077]; P = 0.003). Restricted cubic spline curve showed that there was a non-linear correlation between blood lead and SC-MI. Threshold effect analysis determined that the inflection point of blood lead was 3.8 ug/dl. When the blood lead level was higher than 3.8 ug/dl, there was an independent positive correlation between blood lead level and the risk of SC-MI (OR 1.031, 95% CI [1.009, 1.053]; P < 0.01). And similar associations were also observed among subgroups of male, ≤60 years, >60 years, never smoker, non-Hispanic White, non-Hispanic Black or without hypertension and diabetes.ConclusionsBlood lead was non-linearly related to SC-MI in population free from CVD.

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.

Background and aims A novel non–insulin-based metabolic score for insulin resistance (METS‐IR) index has been proposed as a simple and reliable alternative insulin resistance (IR) marker, but its the predictive value in asymptomatic adults with coronary artery calcification (CAC) remains unclear. Methods and results We enrolled 1576 participants without cardiovascular disease (CVD), who underwent multidetector computed tomography. Logistic regression, restricted cubic spline models and receiver operating characteristic (ROC) curves were used to examine the association between METS-IR, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride glucose index (TyG index) and CAC. In multivariate logistic regression analysis, the increase in METS-IR was independently associated with a higher prevalence of CAC (all P Conclusion Compared with other IR indexes, METS-IR may have better discrimination ability in predicting the incidence of CAC in asymptomatic adults without CVD.

BackgroundAlthough studies have shown that higher waist-hip ratio (WHR) is closely related to higher risk of metabolism-related diseases, the relationship between WHR and subclinical myocardial injury (SC-MI) is unknown. This study was to evaluate the effect of WHR on SC-MI in the general population free from cardiovascular disease.MethodsThe cross-sectional study included 6253 participants without cardiovascular disease (CVD) from the third National Health and Nutrition Examination Survey (NHANES III) for further analysis. Restricted cubic spline, multivariable logistic regression models and subgroup analyses were performed to assess the association between WHR and SC-MI.ResultsThe multivariate logistic regression showed that after adjusting for potential confounding factors, participants in the higher quartiles had higher risk of developing SC-MI than those in the first quartile of WHR [Q3, OR (95% CI): 1.523 (1.159, 2.000), P = 0.002; Q4, OR (95% CI): 1.719 (1.279, 2.311), P < 0.001], and this relationship was robust among the participants aged ≥ 50 years, with hypertension and without diabetes. Every 0.1 unit increase in WHR, as a continuous variable, increased the risk of SC-MI by more than 20% [OR (95% CI): 1.233 (1.092, 1.392), P = 0.001]. And restricted cubic spline analysis showed that there was a linear positive correlation between WHR and the risk of SC-MI.ConclusionsWHR may be an independent risk factor for SC-MI in the general population free from CVD.

BackgroundGrowing studies have shown that insulin resistance (IR) is associated with cardiovascular disease (CVD), while the association between IR and subclinical myocardial injury (SC-MI) remains unclear. Hence we aimed to assess the association between IR and SC-MI.MethodsIn this cross-sectional study, we enrolled 6043 individuals (age: 58.43 ± 13.08 years; 46.2% men) free from CVD from the third National Health and Nutrition Examination Survey. A novel metabolic score for insulin resistance (METS-IR) was used as alternative markers of IR. Multivariate logistic regression and restricted cubic spline were performed to evaluate the associations between METS-IR and SC-MI.ResultsThe multivariate logistic regression analysis showed that after adjusting for cardiovascular metabolic risk factors, higher METS-IR was independently correlated with higher risk of SC-MI [as a quartile variable, Q4 vs Q1, OR (95% CI): 1.395 (1.147, 1.698), P = 0.001, P for trend < 0.001; as a continuous variable, per 10-unit increment, OR (95% CI): 1.869 (1.524, 2.292), P < 0.001]. Restricted cubic spline indicated that there was a J-curve connection between METS-IR and SC-MI. Threshold effect analysis ascertained an inflection point of 37 of METS-IR. The ORs (95% CIs) of per 10-unit increase of METS-IR for SC-MI were 0.707 (0.538, 0.928) and 1.327 (1.210, 1.456) on the left and right sides of the inflection point (P < 0.05), respectively. Subgroup analysis showed that the association between METS-IR and SC-MI was only statistically significant in participants without diabetes.ConclusionsMETS-IR was nonlinearly related to SC-MI in the general population without CVD.

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.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication during ovarian stimulation. Even though the incidence of OHSS was relatively low in clinical practice, the consequence can be potentially devastating and life-threatening. Abnormal lipid metabolism may relate to the pathological development of OHSS, but there is still a research gap in the lipidomic research. So here in our study, an ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS) based lipidomic analysis was performed using follicular fluid samples obtained from 17 patients undergoing OHSS. The lipid profiles of OHSS patients were characterized by increased cholesterol ester (ChE) and decreased lysophosphatidylcholine (LPC), phosphatidylinositol (PI), sphingomyelin (SM), dimethylphosphatidylethanolamine (dMePE) and lysodimethylphosphatidylethanolamine (LdMePE). Totally 10 lipids including LPC(18:0), SM(d18:1/16:0), PC(18:0/18:1), PC(20:2/20:5), PC(16:0/18:1), TG(16:0/18:1/18:1), TG(16:0/18:2/18:2), TG(16:0/16:1/18:1), ChE(20:4) and TG(8:0/8:0/10:0) were selected as differential lipids. In conclusion, this study demonstrated the alteration of various lipids in OHSS patients, which suggested the key role of lipids during the development of OHSS and shed light on the further pathophysiological research of OHSS.

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.

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.

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.

To delineate the nature and origin of a chromosomal aberration detected in a boy with mental retardation.The proband and his parents were subjected to routine G-banded chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) analysis.The karyotype of the proband was determined as 46, XX, add(8)(p23). No karyotypic abnormality was detected in either of his parents. SNP-array has identified a 34.9 Mb duplication at 8p23.1q11.1 and a 6.78 Mb microdeletion at 8p23.1pter in the proband. No copy number variation was detected in either parent.The child was diagnosed with 8p inverted duplication deletion syndrome, which might be induced by non-allelic homologous recombination between olfactory genes in the 8p23.1 region.

OBJECTIVE: To investigate the relevant influencing factors for perioperative airway events of infantile subglottic hemangioma, and to further discuss the strategies of perioperative airway management. METHODS: A total of 36 infants with subglottic hemangioma that had no response to the drug therapy and underwent surgical treatment from July 2007 to April 2017 were enrolled. The relevant influencing factors, including gender, age, birth weight, age of onset, degree of tracheal stenosis and histories of underlying diseases(congenital heart disease and respiratory disease), were also recorded simultaneously. Intraoperative SpO(2) decline, intraoperative emergency tracheal intubation, intraoperative emergency tracheotomy, whether preserving tracheal intubation after operation or not, and postoperative emergency tracheal intubation were included in the perioperative airway events of infantile subglottic hemangioma. The relevant influencing factors of perioperative airway events were analyzed so that meaningful statistical indicators were selected for grouped logistic regression analysis, and the correlation was evaluated based on OR value and 95% confidence interval(CI). Based on the correlation between influencing factors and airway events, perioperative airway management was discussed. RESULTS: ① The degree of tracheal stenosis was a risk factor for SpO(2) decline(95%CI[2.121-33.818]); ②The degree of airway stenosis, history of comorbid cardiovascular disease and respiratory disease were the influencing factors for intraoperative emergency tracheal intubation(95%CI[0.863-21.692], [0-+∞] and [1.741-232.403], respectively); ③The degree of airway stenosis was the influencing factor for postoperative emergency tracheal intubation(95%CI[1.277-20.421]); ④The degree of airway stenosis was a risk factor for whether preserving postoperative tracheal intubation or not(95%CI[1.523-13.296]). CONCLUSION: ① Infants with a history of preoperative underlying diseases are more likely to present with intraoperative airway instability and SpO(2) decline, which deserves more preoperative and postoperative attention. Tracheal intubation should be performed timely in case of intraoperative SpO(2) decline. ②Preoperative tracheotomy should be performed in infants with preoperative grade Ⅲ airway stenosis, especially those with comorbid heart diseases or respiratory diseases. ③The degree of airway stenosis is an extremely important influencing factor for perioperative airway management of infantile subglottic hemangioma. For infants whose airway stenosis were greater than 60% of airway diameter, the airway maintenance should be closely monitored. Once SpO(2)decreases, tracheal intubation should be performed immediately. It's recommended to preserve tracheal intubation so as to ensure the airway stability. The tracheal intubation could be prolonged to 48-72 hours postoperatively. ④The surgical approach has no significant effect on perioperative airway management.

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.

Background: As genetic inheritance is an inevitable risk factor in the development of coronary heart disease (CHD), it is critical to identify the single-nucleotide polymorphism (SNP) locus of CHD risk. This case-control study exported whether the NPAS4 polymorphisms are related to the CHD risk in the Chinese Han population. Methods: The Agena MassARRAY platform was used to genotype the five SNPs in NPAS4 from 499 CHD patients and 500 healthy controls. We used χ2 test to compare the distributions of gender, allele and genotypes frequencies between cases and controls. The logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: The rs4466842 in NPAS4 was found to be correlated with an increased risk of CHD in overall, males and age ≤ 60. The rs117186164 and rs12785321 in NPAS4 were significantly related to an increased risk of CHD in the male and the age ≤ 60, respectively. Moreover, the haplotype AC (rs117186164 and rs4466842) in NPAS4 was significantly correlated with an increased risk of CHD. Conclusions: Our results indicated that polymorphisms (rs117186164, rs12785321, and rs4466842) in NPAS4 were significantly correlated with increased the risk of CHD in the Chinese Han population. Further association and functional studies are required to confirm the results and investigate the role of this SNP in the development of CHD.

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

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

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

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.

// 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.

To analyze the clinical and molecular genetic characteristics of patient with Kleefstra syndrome 1.Clinical data, chromosomal karyotype and whole genome copy number variations (CNVs) of the patient were analyzed.The patient was found to have a karyotype of 45,XX,-9[4]/46,XX,r(9)(p24q34)[56]. Whole-genome CNVs detection revealed that she has carried a heterozygous deletion of approximately 670 kb at 9q34.3, which encompassed the entire EHMT1 gene. The region is strongly associated with Kleefstra syndrome (1/9q telomere deletion). In addition, the patient also had heterozygous deletion of 9pter, which may predispose to formation of ring chromosome 9.The child was diagnosed with Kleefstra syndrome type 1 in conjunct with ring chromosome 9.

To analyze the clinical and molecular genetics features of a family affected with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS).High-throughput sequencing was used to detect copy number variations (CNVs) and pathogenic variant within the whole exome of the affected child.No pathogenic CNV was found in the child, while exome sequencing identified a heterozygous c.3367_c.3370delAGAA (p.Arg1123Argfs*6) frameshifting variant in the exon 16 of the KAT6B gene. The same variant was not found in either parent.The c.3367_c.3370delAGAA (p.R1123Rfs*6) probably underlies the disease in the affected child. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.

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.

Background: Adequate thickness of the endometrium has been well recognized as a critical factor for embryo implantation. This was a prospective cohort study to investigate the benefits of platelet-rich plasma (PRP) for women with thin endometrium who received frozen embryo transfer (FET) program in a larger number of patients and explore the underlying mechanism. Methods: In this study, we investigated the effects of PRP in women with thin endometrium in FET program. 64 patients with thin endometrium (

// 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.

// Qingbin Zhao 1 , Shudan Liao 2 , Huiyi Wei 1 , Dandan Liu 3 , Jingjie Li 4,5 , Xiyang Zhang 5 , Mengdan Yan 4,5 and Tianbo Jin 4,5 1 Department of Geratology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China 2 Department of Cardiology, Xi’an Center Hospital, Xi’an, Shaanxi, China 3 Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China 4 Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi’an, Shaanxi, China 5 Xi’an Tiangen Precision Medical Institute, Xi’an, Shaanxi, China Correspondence to: Qingbin Zhao, email: // Keywords : coronary heart disease; single nucleotide polymorphisms; CDKN2BAS; case-control,Gerotarget Received : September 01, 2016 Accepted : October 05, 2016 Published : October 11, 2016 Abstract The goal of our study was to determine whether CDKN2BAS polymorphisms are associated with coronary heart disease (CHD) risk in a Han Chinese population. Eight SNPs were genotyped in 676 men and 465 women. We used χ 2 tests and genetic model analyses to evaluate associations between the SNPs and CHD risk. We found that rs10757274 was associated with an increased risk of CHD in both men (allele G: Odds ratio [OR] = 1.30, 95% confidence interval [CI]: 1.05-1.61, P = 0.018; codominant model: P = 0.042; recessive model: OR = 1.70, 95% CI: 1.10-2.62, P = 0.016; log-additive model: OR = 1.34, 95% CI: 1.05-1.71, P = 0.019) and women (dominant model: OR = 2.26, 95% CI: 1.28-3.99, P = 0.004). In addition, rs7865618 was associated with an 8.10-fold increased risk of CHD in women under a recessive model (OR = 8.10, 95% CI: 1.74-37.68, P = 0.006). Interestingly, the haplotype AA (rs10757274 and rs1333042) of CDKN2BAS was associated with decreased the risk of CHD in men (OR = 0.72, 95% CI: 0.55 - 0.95, P = 0.022).

// Bin Li 1, 2, * , Wenhui Zhao 3, * , Jingjie Li 1, 2 , Mengdan Yan 1, 2 , Zhilan Xie 2 , Yuanyuan Zhu 2 , Chao Chen 1, 2 , Tianbo Jin 1, 2, 4 1 School of Life Sciences, Northwest University, Xi’an, Shaanxi, 710069, China 2 National Engineering Research Center for Miniaturized Detection Systems, Xi’an, Shaanxi, 710069, China 3 Department of Anesthesiology, Shaanxi Provincial Tumor Hospital, Xi’an, Shaanxi, 710061, 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 Chao Chen, email: cchen898@nwu.edu.cn Keywords: EGFR, glioma, polymorphism, prognosis Received: March 17, 2016 Accepted: May 29, 2016 Published: July 18, 2016 ABSTRACT Previous studies suggested that single nucleotide polymorphisms (SNPs) in epidermal growth factor receptor ( EGFR ) are associated with risk of glioma. However, the associations between these SNPs and glioma patient prognosis have not yet been fully investigated. Therefore, the present study was aimed to evaluate the effects of EGFR polymorphisms on the glioma patient prognosis. We retrospectively evaluated 269 glioma patients and investigated associations between EGFR SNPs and patient prognosis using Cox proportional hazard models and Kaplan-Meier curves. Univariate analysis revealed that age, gross-total resection and chemotherapy were associated with the prognosis of glioma patients ( p < 0.05). In addition, four EGFR SNPs (rs11506105, rs3752651, rs1468727 and rs845552) correlated with overall survival (OS) (Log-rank p = 0.011, 0.020, 0.008, and 0.009, respectively) and progression-free survival PFS (Log-rank p = 0.026, 0.024, 0.019 and 0.009, respectively). Multivariate analysis indicated that the rs11506105 G/G genotype, the rs3752651 and rs1468727 C/C genotype and the rs845552 A/A genotype correlated inversely with OS and PFS. In addition, OS among patients with the rs730437 C/C genotype ( p = 0.030) was significantly lower OS than among patients with A/A genotype. These data suggest that five EGFR SNPs (rs11506105, rs3752651, rs1468727, rs845552 and rs730437) correlated with glioma patient prognosis, and should be furthered validated in studies of ethnically diverse patients.

Schizophrenia (SCZ) is a complex and severe mental disorder with highly heritability (80%). Several large genome-wide association studies have identified that the transcription factor 4 (TCF4) polymorphisms were strongly associated with SCZ. Therefore, the present study was to replicate the potential relationships between the TCF4 polymorphisms and SCZ. Furthermore, the study also investigated whether other variants were associated with SCZ in the Han Chinese. We conducted a case-control study including 499 patients and 500 healthy controls. Five SNPs were successfully genotyped and evaluated the association with SCZ by using χ2 test and genetic model analysis. We found that the genotype "AG" of rs9320010 and "GA" of rs7235757 decreased SCZ risk (OR = 0.70, 95%CI = 0.50-0.99, P = 0.041; OR = 0.69, 95%CI = 0.49-0.97, P = 0.034, respectively). In the genetic model analysis, we also observed that the allele "A" of rs9320010 and "G" of rs7235757 were inversely related with the risk of SCZ in the dominant model (OR = 0.72, 95%CI = 0.52-0.98, P = 0.039; OR = 0.69, 95%CI = 0.50-0.96, P = 0.025, respectively). Further interaction and stratification analysis suggested that rs1452787 was notably correlated with increased SCZ risk in males (OR = 2.77, 95%CI = 1.43-5.35, P = 0.002). Our study indicated that rs9320010, rs7235757, and rs1452787 were prominently associated with SCZ. Further studies are required to verify our findings and focus on determining the biological functions of the SNPs. © 2016 Wiley Periodicals, Inc.

An outbreak of echovirus 18 encephalitis/meningitis in children in Hebei Province, China, 2015

Background/Aims: The identification of new compound candidates for endometriosis treatment is needed. Cyclooxygenase-2 (COX-2) is considered a crucial target to control the progress and recurrence of endometriosis. Here, we identified ursolic acid (UA) as a natural inhibitor of COX-2 and investigated its effects on endometriosis progression. Methods: Primary human endometriotic stromal cells isolated from patients with endometriosis were exposed to UA at concentrations of 15, 30, 45, and 60 μM. 3-(4,5-Dimethylthiaziazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, 5′-bromo-2’-deoxy-uridine assays, and Caspase-3 activity measurements were performed to detect cell growth and apoptosis. Enzyme-linked immunosorbent assays were used to detect COX-2 and vascular endothelial growth factor (VEGF) protein expression and prostaglandin E2 (PGE2) levels. Capillary-tubule formation assays using human umbilical vein endothelial cells were also carried out to determine angiogenesis. Results: UA significantly decreased cell viability, inhibited proliferation, and increased caspase-3 activity in a dose-dependent manner. COX-2 protein expression and the subsequent PGE2 production were both reduced by UA. Meanwhile, UA exposure decreased VEGF secretion in the stromal cells and the capillary-tubule formation assay confirmed the inhibitory effect of UA on angiogenesis. Furthermore, UA increased the phosphorylation of c-Jun N-terminal kinase and p38. Conclusions: Our data suggest that UA plays a role as a natural inhibitor of COX-2 to control the survival of human endometriotic stromal cells by inhibiting proliferation and angiogenesis and promoting apoptosis.

Breast cancer is one of the most lethal cancers in women when it reaches the metastatic stage. Here, we screen a library of small molecules for inhibitors of breast cancer cell invasion, and use structure/activity relationship studies to develop a series of small molecules with improved activity. We find WJ460 as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in breast cancer cells. Proteomic and biochemical studies identify myoferlin (MYOF) as the direct target of WJ460. In parallel, loss of MYOF or pharmacological inhibition of MYOF by WJ460 reduces breast cancer extravasation into the lung parenchyma in an experimental metastasis mouse model, which reveals an essential role of MYOF in breast cancer progression. Our findings suggest that MYOF can be explored as a molecular target in breast cancer metastasis and that targeting MYOF by WJ460 may be a promising therapeutic strategy in MYOF-driven cancers.

SCOPE The objective of the present study is to evaluate the effects of milk powder co-supplemented with inulin and resistant dextrin (MPCIR) on elderly patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS A randomized, double-blind, placebo-controlled clinical trial is carried out among elderly T2DM patients. The subjects recruited from the community are randomly assigned to either the MPCIR group or placebo group for 12 weeks intervention. Each group receives 45 g milk powder with or without inulin and resistant dextrin. Anthropometric and metabolic variables are measured. For the MPCIR group, systolic blood pressure (BP) and diastolic BP are reduced significantly by 5.45 and 4.56 mm Hg (p < 0.001, vs placebo group), respectively. Compared with the placebo group, the fasting and 2-h postprandial plasma glucose levels, glycosylated serum protein, and insulin resistance index of the MPCIR group are significantly decreased by 0.96 mmol L-1 , 1.47 mmol L-1 , 16.33 μmol L-1 , and 0.65 respectively (p < 0.001). The MPCIR group shows an increase by 7.09 μIU mL-1 and 20.43 in 2-h postprandial insulin (p = 0.016) and β-cell function index (p < 0.001), respectively. CONCLUSION MPCIR supplementation helps to improve glycemic control, insulin resistance, and blood pressure.

Background Chromatin modification at mitosis is closely related to transcriptional reactivation in the subsequent cell cycle. We reasoned this process is deregulated by oncogenic signals, which would contribute to mitotic stress resistance in pancreatic cancer. Here, we show DMAP1/Bub3 complex mediates mitotic stress-induced cellular apoptosis, while this effect is counteracted by c-Src in pancreatic cancer cells. Our study aims to uncover an unidentified mechanism underlying the distinct response to mitotic stress between normal cells and pancreatic cancer cells. Methods The interaction between Bub3 and DMAP1 upon mitotic stress signaling was determined through molecular and cell biological methods. The inhibitory effect of c-Src on DMAP1/Bub3-mediated DNA methylation and gene transcription profile was investigated. The association between c-Src-mediated DMAP1 phosphorylation and paclitaxel activity in vivo and clinicopathologic characteristics were analyzed. Results Mitotic arrest induced p38-dependent phosphorylation of Bub3 at Ser211, which promotes DMAP1/Bub3 interaction. DMAP1/Bub3 complex is recruited by TAp73 to the promoter of anti-apoptotic gene BCL2L1, thus mediates the DNA methylation and represses gene transcription linked to cell apoptosis. Meanwhile, DMAP1 was highly phosphorylated at Tyr 246 by c-Src in pancreatic cancer cells, which impedes DMAP1/Bub3 interaction and the relevant cellular activites. Blocking DMAP1 pTyr-246 potentiates paclitaxel-inhibited tumor growth. Clinically, DMAP1 Tyr 246 phosphorylation correlates with c-Src activity in human pancreatic cancer specimens and poor prognosis in pancreatic cancer patients. Conclusions Our findings reveal a regulatory role of Bub3 in DMAP1-mediated DNA methylation upon mitotic stress and provide the relevance of DMAP1 pTyr-246 to mitotic stress resistance during pancreatic cancer treatment. Electronic supplementary material The online version of this article (10.1186/s12943-018-0919-5) contains supplementary material, which is available to authorized users.

Background The sensitivity and specificity of non-invasive diagnostic methods for endometriosis, especially at early stages, are not optimal. The clinical diagnostic indicator cancer antigen 125 (CA125) performs poorly in the diagnosis of minimal endometriosis, with a sensitivity of 24%. Therefore, it is urgent to explore novel diagnostic biomarkers. We evaluated the metabolomic profile variation of the eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS). Methods Our study comprised 29 patients with laparoscopically confirmed endometriosis at stages I-II and 37 infertile women who underwent diagnostic laparoscopy combined with hysteroscopy from January 2014 to January 2015. Eutopic endometrium samples were collected by pipelle endometrial biopsy. The metabolites were quantified by UHPLC-ESI-HRMS. The best combination of biomarkers was then selected by performing step-wise logistic regression analysis with backward elimination. Results Twelve metabolites were identified as endometriosis-associated biomarkers. The eutopic endometrium metabolomic profile of the endometriosis patients was characterized by a significant increase in the concentration of hypoxanthine, L-arginine, L-tyrosine, leucine, lysine, inosine, omega-3 arachidonic acid, guanosine, xanthosine, lysophosphatidylethanolamine and asparagine. In contrast, the concentration of uric acid was decreased. Metabolites were filtered by step-wise logistic regression with backward elimination, and a model containing uric acid, hypoxanthine, and lysophosphatidylethanolamine was constructed. Receiver-operating characteristic (ROC) analysis confirmed the prognostic value of these parameters for the diagnosis of minimal/mild endometriosis with a sensitivity of 66.7% and a specificity of 90.0%. Conclusions Metabolomics analysis of the eutopic endometrium in endometriosis was effectively characterized by UHPLC-ESI-HRMS-based metabolomics. Our study supports the importance of purine and amino acid metabolites in the pathophysiology of endometriosis and provides potential biomarkers for semi-invasive diagnosis of early-stage endometriosis.