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The immunity potency upon natural infection or vaccination is the main concern for the vaccine strategy of severe acute respiratory syndrome coronavirus 2 (SARS COV-2 variant), especially the recently reported Omicron variant (B.1.1.529). In this study, 200 recipients immunized with three doses of a COVID-19-inactivated vaccine were enrolled, whose serum samples were collected within 2 months after the third immunization. The neutralizing activity of sera against the pseudotyped Omicron variant, prototype, and Delta variant was determined. Our results demonstrated that the positive neutralization activity was 95.5% for the Omicron variant, 99.5% for the prototype, and 98.5% for the Delta variant. The geometric mean titers (GMT) for the Omicron variant was 49 and maintained sustained immune levels for 2 months, which decreased by 4.9-fold and 3.0-fold compared with the prototype (GMT, 239) and Delta variant (GMT, 148), respectively. In summary, our study demonstrated that three doses of a COVID-19-inactivated vaccine effectively yielded potent cross-neutralizing activity against the Omicron variant at 2 months after the third vaccination.

The “replication crisis” is a methodological problem in which many scientific research findings have been difficult or impossible to replicate. Because the reproducibility of empirical results is an essential aspect of the scientific method, such failures endanger the credibility of theories based on them and possibly significant portions of scientific knowledge. An instance of the replication crisis, analytic replication, pertains to reproducing published results through computational reanalysis of the authors’ original data. However, direct replications are costly, time-consuming, and unrewarded in today’s publishing standards. We propose that bioinformatics and computational biology students replicate recent discoveries as part of their curriculum. Considering the above, we performed a pilot study in one of the graduate-level courses we developed and taught at our University. The course is entitled Intro to R Programming and is meant for students in our Master’s and PhD programs who have little to no programming skills. As the course emphasized real-world data analysis, we thought it would be an appropriate setting to carry out this study. The primary objective was to expose the students to real biological data analysis problems. These include locating and downloading the needed datasets, understanding any underlying conventions and annotations, understanding the analytical methods, and regenerating multiple graphs from their assigned article. The secondary goal was to determine whether the assigned articles contained sufficient information for a graduate-level student to replicate its figures. Overall, the students successfully reproduced 39% of the figures. The main obstacles were the need for more advanced programming skills and the incomplete documentation of the applied methods. Students were engaged, enthusiastic, and focused throughout the semester. We believe that this teaching approach will allow students to make fundamental scientific contributions under appropriate supervision. It will teach them about the scientific process, the importance of reporting standards, and the importance of openness.

BACKGROUND The majority of surgical patients aged 65 years and over are accompanied with underlying conditions, making them susceptible to perioperative cerebral complications. Here, we investigated the clinical value of continuous cerebral autoregulation (CA) monitoring in protecting against cerebral dysfunction in elderly patients undergoing surgery. METHODS This study enrolled 40 elderly patients (aged ≥65 years) and 40 middle-aged patients (aged 45 to 64 years) selected to undergo robotic-assisted laparoscopic radical prostatectomy. Cerebral oxygenation was assessed by regional cerebral oxygen saturation (rScO2) using near-infrared spectroscopy (NIRS). CA function was estimated using the cerebral oximetry index (COX), which is the rolling correlation between rScO2 and the mean arterial pressure (MAP). With the patient in the Trendelenburg position, the rScO2, MAP, calculated COX, HR, end-tidal CO2, and sevoflurane concentrations were continuously recorded. Standardized anesthesia was administered to all patients (sevoflurane, propofol, remifentanil, and rocuronium). Postoperative delirium (POD) was screened for daily using the Confusion Assessment Method (CAM). The primary outcome was the difference in periods of CA dysfunction between the elderly and middle-aged groups. Secondary outcomes included the incidence of POD and the optimal MAP range in the 2 groups. RESULTS Taking positive COX values (cutoff ≥0.3) to reflect periods of CA dysfunction, we found that the cumulative duration of CA dysfunction in the Trendelenburg position was longer in elderly patients than in middle-aged patients [ratio of cumulative time of CA dysfunction: middle-aged group, 32.8% (26.3%, 43.1%) vs. elderly group, 42.2% (33.1%, 51.2%)] (P

Apoptosis and clearance of dead cells is highly evolutionarily conserved from nematode to humans, which is crucial to the growth and development of multicellular organism. Fail to remove apoptotic cells often lead to homeostasis imbalance, fatal autoimmune diseases, and neurodegenerative diseases. Small ubiquitin-related modifiers (SUMOs) modification is a post-translational modification of ubiquitin proteins mediated by the sentrin-specific proteases (SENPs) family. SUMO modification is widely involved in many cellular biological process, and abnormal SUMO modification is also closely related to many major human diseases. Recent researches have revealed that SUMO modification event occurs during apoptosis and clearance of apoptotic cells, and plays an important role in the regulation of apoptotic signaling pathways. This review summarizes some recent progress in the revelation of regulatory mechanisms of these pathways and provides some potential researching hotpots of the SUMO modification regulation to apoptosis.

The emerging new VOC B.1.1.529 (Omicron) variant has raised serious concerns due to multiple mutations, reported significant immune escape, and unprecedented rapid spreading speed. Currently, studies describing the neutralization ability of different homologous and heterologous booster vaccination against Omicron are still lacking. In this study, we explored the immunogenicity of COVID-19 breakthrough patients, BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group against SARS-CoV-2 pseudotypes corresponding to the prototype, Beta, Delta, and the emergent Omicron variant. Notably, at 14 days post two-dose inactivated vaccines, pVNT titre increased to 67.4 GMTs against prototype, 8.85 against Beta and 35.07 against Delta, while neutralization activity against Omicron was below the lower limit of quantitation in 80% of the samples. At day 14 post BBIBP-CorV homologous booster vaccination, GMTs of pVNT significantly increased to 285.6, 215.7, 250.8, 48.73 against prototype, Beta, Delta, and Omicron, while at day 14 post ZF2001 heterologous booster vaccination, GMTs of pVNT significantly increased to 1436.00, 789.6, 1501.00, 95.86, respectively. Post booster vaccination, 100% samples showed positive neutralization activity against Omicron, albeit illustrated a significant reduction (5.86- to 14.98-fold) of pVNT against Omicron compared to prototype at 14 days after the homologous or heterologous vaccine boosters. Overall, our study demonstrates that vaccine-induced immune protection might more likely be escaped by Omicron compared to prototypes and other VOCs. After two doses of inactivated whole-virion vaccines as the “priming” shot, a third heterologous protein subunit vaccine and a homologous inactivated vaccine booster could improve neutralization against Omicron.

BackgroundDespite wide usage across all areas of medicine, it is uncertain how useful standard reference ranges of laboratory values are for critically ill patients.ObjectivesThe aim of this study is to assess the distributions of standard laboratory measurements in more than 330 selected intensive care units (ICUs) across the USA, Amsterdam, Beijing and Tarragona; compare differences and similarities across different geographical locations and evaluate how they may be associated with differences in length of stay (LOS) and mortality in the ICU.MethodsA multi-centre, retrospective, cross-sectional study of data from five databases for adult patients first admitted to an ICU between 2001 and 2019 was conducted. The included databases contained patient-level data regarding demographics, interventions, clinical outcomes and laboratory results. Kernel density estimation functions were applied to the distributions of laboratory tests, and the overlapping coefficient and Cohen standardised mean difference were used to quantify differences in these distributions.ResultsThe 259 382 patients studied across five databases in four countries showed a high degree of heterogeneity with regard to demographics, case mix, interventions and outcomes. A high level of divergence in the studied laboratory results (creatinine, haemoglobin, lactate, sodium) from the locally used reference ranges was observed, even when stratified by outcome.ConclusionStandardised reference ranges have limited relevance to ICU patients across a range of geographies. The development of context-specific reference ranges, especially as it relates to clinical outcomes like LOS and mortality, may be more useful to clinicians.

RRS1 is a chromosome 8q oncogene that couples ribosome biogenesis to RPL11-MDM2-p53 signaling in hepatocellular carcinoma., Hepatocellular carcinomas (HCCs) are characterized by frequent somatic genomic copy number alterations (CNAs), with most of them biologically unexplored. Here, we performed integrative analyses combining CNAs with the transcriptomic data to reveal the cis- and trans-effects of CNAs in HCC. We identified recurrent genomic gains of chromosome 8q, which exhibit strong trans-effects and are broadly associated with ribosome biogenesis activity. Furthermore, 8q gain–driven overexpression of ribosome biogenesis regulator (RRS1) promotes growth of HCC cells in vitro and in vivo. Mechanistically, RRS1 attenuates ribosomal stress through retaining RPL11 in the nucleolus, which, in turn, potentiates MDM2-mediated ubiquitination and degradation of p53. Clinically, higher RRS1 expression levels predict poor clinical outcomes for patients with HCC, especially in those with intact p53. Our findings established that the chromosome 8q oncogene RRS1 promotes HCC development through attenuating the RPL11-MDM2-p53 pathway and provided new potential targets for treatment of this malignancy.

To identify hepatocellular carcinoma (HCC)-implicated long noncoding RNAs (lncRNAs), we performed an integrative omics analysis by integrating mRNA and lncRNA expression profiles in HCC tissues. We identified a collection of candidate HCC-implicated lncRNAs. Among them, we demonstrated that an lncRNA, which is named as p53-stabilizing and activating RNA (PSTAR), inhibits HCC cell proliferation and tumorigenicity through inducing p53-mediated cell cycle arrest. We further revealed that PSTAR can bind to heterogeneous nuclear ribonucleoprotein K (hnRNP K) and enhance its SUMOylation and thereby strengthen the interaction between hnRNP K and p53, which ultimately leads to the accumulation and transactivation of p53. PSTAR is down-regulated in HCC tissues, and the low PSTAR expression predicts poor prognosis in patients with HCC, especially those with wild-type p53. Conclusion: This study sheds light on the tumor suppressor role of lncRNA PSTAR, a modulator of the p53 pathway, in HCC.

Background Although major advances have been made in the histopathological diagnosis of high-grade astrocytoma (HGA), methods for effective and noninvasive diagnosis remain largely unknown. Exosomes can cross the blood–brain barrier and are readily accessible in human biofluids, making them promising biomarkers for HGA. Circular RNAs (circRNAs) have potential as tumor biomarkers owing to their stability, conservation, and tissue specificity. However, the landscape and characteristics of exosome circRNAs in HGA remain to be studied. Methods CircRNA deep sequencing and bioinformatics approaches were used to generate a circRNA profiling database and analyze the features of HGA cell circRNAs and HGA cell-derived exosome circRNAs. Exosome circRNA expression in the serum and tissues of healthy individuals and patients with HGA was detected using reverse transcription-quantitative PCR. Additionally, the receiver operating characteristic curve and overall survival curves were analyzed. Results By investigating the characteristics of HGA cell-derived exosome circRNAs and HGA cell circRNAs, we observed that exosomes were more likely to enrich short-exon and suppressor circRNAs than HGA cells. Moreover, a serum exosome circRNA panel including hsa_circ_0075828, hsa_circ_0003828, and hsa_circ_0002976 could be used to screen for HGA, whereas a good prognosis panel comprised high concentrations of hsa_circ_0005019, hsa_circ_0000880, hsa_circ_0051680, and hsa_circ_0006365. Conclusions This study revealed a comprehensive circRNA landscape in HGA exosomes and cells. The serum exosome circexosome circRNA panel and tissue circRNAs are potentially useful for HGA liquid biopsy and prognosis monitoring. Exosome circRNAs as novel targets should facilitate further biomarker discovery and aid in HGA diagnosis and therapy monitoring.

More efficient biomarkers are needed to facilitate the early detection of hepatocellular carcinoma (HCC). We aimed to identify candidate biomarkers for HCC detection by proteomic analysis. First, we performed a global proteomic analysis of 10 paired HCC and non-tumor tissues. Then, we validated the top-ranked proteins by targeted proteomic analyses in another tissue cohort. At last, we used enzyme-linked immunosorbent assays to validate the candidate biomarkers in multiple serum cohorts including HCC cases (HCCs), cirrhosis cases (LCs), and normal controls (NCs). We identified and validated 33 up-regulated proteins in HCC tissues. Among them, eight secretory or membrane proteins were further evaluated in serum, revealing that aldo–keto reductase family 1 member B10 (AKR1B10) and cathepsin A (CTSA) can distinguish HCCs from LCs and NCs. The area under the curves (AUCs) were 0.891 and 0.894 for AKR1B10 and CTSA, respectively, greater than that of alpha-fetoprotein (AFP; 0.831). Notably, combining the three proteins reached an AUC of 0.969, which outperformed AFP alone (P

Physiological signals can contain abundant personalized information and indicate health status and disease deterioration. However, in current medical practice, clinicians working in the general wards are usually lack of plentiful means and tools to continuously monitor the physiological signals of the inpatients. To address this problem, we here presented a medical-grade wireless monitoring system based on wearable and artificial intelligence technology. The system consists of a multi-sensor wearable device, database servers and user interfaces. It can monitor physiological signals such as electrocardiography and respiration and transmit data wirelessly. We highly integrated the system with the existing hospital information system and explored a set of processes of physiological signal acquisition, storage, analysis, and combination with electronic health records. Multi-scale information extracted from physiological signals and related to the deterioration or abnormality of patients could be shown on the user interfaces, while a variety of reports could be provided daily based on time-series signal processing technology and machine learning to make more information accessible to clinicians. Apart from an initial attempt to implement the system in a realistic clinical environment, we also conducted a preliminary validation of the core processes in the workflow. The heart rate veracity validation of 22 patient volunteers showed that the system had a great consistency with ECG Holter, and bias for heart rate was 0.04 (95% confidence interval: −7.34 to 7.42) beats per minute. The Bland-Altman analysis showed that 98.52% of the points were located between Mean ± 1.96SD. This system has been deployed in the general wards of the Hyperbaric Oxygen Department and Respiratory Medicine Department and has collected more than 1000 cases from the clinic. The whole system will continue to be updated based on clinical feedback. It has been demonstrated that this system can provide reliable physiological monitoring for patients in general wards and has the potential to generate more personalized pathophysiological information related to disease diagnosis and treatment from the continuously monitored physiological data.

Objective The traditional approaches for diagnosing catheter-related bloodstream infection(CRBSI) is time consuming, which could not meet the clinical requirement. Our aim was to investigate the value of serum procalcitonin(PCT) in predicting CRBSI in first-ever acute ischemic stroke patients with central venous catheters (CVCs). Methods This was a retrospective study. First-ever acute ischemic stroke patients hospitalized in neurological intensive care unit(NICU) of Aerospace Center Hospital and NICU of Beijing Chaoyang Hospital during January 2010 and December 2017 with clinically suspected CRBSI were enrolled. Peripheral blood white blood cell (WBC) count, neutrophils percentage(NE%), the levels of serum PCT, dwell time of catheterization and outcome of the patients were collected. According to the diagnosis of CRBSI or not, they were divided into CRBSI group and no CRBSI group. We used receiver operating characteristic curve (ROC) to evaluate the value of serum PCT levels in predicting CRBSI in patients with clinically suspected CRBSI. Results Forty-five patients with suspected CRBSI were included in this study, and 13 patients were diagnosed with CRBSI. Comparing to those in no CRBSI group, the maximum body temperature (Tmax) (p = 0.036) and the PCT levels (P = 0.013) in CRBSI group were both significantly higher. The area under ROC of the serum PCT levels and the Tmax to predict the CRBSI were 0.803 (0.95CI,0.660–0.946) and 0.680 (0.95CI,0.529–0.832) respectively. The PCT cut-off value was 0.780 ng/ml, with the sensitivity 69.23%, specificity 87.50%, positive predictive values 69.23% and negative predictive values 87.50%. Conclusion It could be helpful to adopt PCT as a rapid diagnostic biomarker for first-ever acute stroke patients with suspected CRBSI.

Ectopic epigenetic mechanisms play important roles in facilitating tumorigenesis. Here, we first demonstrated that ANKDD1A is a functional tumor suppressor gene, especially in the hypoxia microenvironment. ANKDD1A directly interacts with FIH1 and inhibits the transcriptional activity of HIF1α by upregulating FIH1. In addition, ANKDD1A decreases the half-life of HIF1α by upregulating FIH1, decreases glucose uptake and lactate production, inhibits glioblastoma multiforme (GBM) autophagy, and induces apoptosis in GBM cells under hypoxia. Moreover, ANKDD1A is highly frequently methylated in GBM. The tumor-specific methylation of ANKDD1A indicates that it could be used as a potential epigenetic biomarker as well as a possible therapeutic target.

Background SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Methods Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. Results SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. Conclusion SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0483-2) contains supplementary material, which is available to authorized users.

Objectives This study demonstrated the prognostic value of the residual SYNTAX score (rSS) for patients with chronic renal insufficiency (CRI). Background The rSS has been proposed as a useful tool for quantifying and stratifying the degree and complexity of residual stenosis and predicting long‐term clinical outcomes following percutaneous coronary intervention (PCI). However, it has never been validated for patients with CRI. Methods A total of 2,468 consecutive patients with an estimated glomerular filtration rate 0 were defined as having incomplete revascularization and were stratified into the reasonable incomplete revascularization (RICR; 0 8) group. Their outcomes were compared to those of the complete revascularization (CR) group. Results During follow‐up (median, 3 years; range, 1.5–5 years), the ICR group had the highest incidence of all‐cause death, cardiac death, myocardial infarction (MI), unplanned revascularization, stroke, and major adverse cardiovascular and cerebrovascular events (MACCE). Despite having higher rates of unplanned revascularization and MACCE, RICR group had comparable all‐cause mortality, cardiac mortality, MI, and stroke with CR group. A multivariable Cox analysis indicated that rSS was an independent predictor of cardiac death, MI, unplanned revascularization, stroke, and MACCE. Furthermore, compared with baseline SYNTAX score, rSS had stronger prognostic accuracy when predicting the risk of unplanned revascularization, stroke, and MACCE at the 3‐year follow‐up. Conclusions The rSS is a powerful indicator of clinical outcomes and may help determine reasonable levels of revascularization for patients with CRI following PCI.

The analysis of big data in medical field cannot be isolated from the high quality clinical database, and the construction of first aid database in our country is still in the early stage of exploration. This paper introduces the idea and key technology of the construction of multi-parameter first aid database. By combining emergency business flow with information flow, an emergency data integration model was designed with reference to the architecture of the Medical Information Mart for Intensive Care III (MIMIC-III), created by Computational Physiology Laboratory of Massachusetts Institute of Technology (MIT), and a high-quality first-aid database was built. The database currently covers 22 941 medical records for 19 814 different patients from May 2015 to October 2017, including relatively complete information on physiology, biochemistry, treatment, examination, nursing, etc. And based on the database, the first First-Aid Big Data Datathon event, which 13 teams from all over the country participated in, was launched. The First-Aid database provides a reference for the construction and application of clinical database in China. And it could provide powerful data support for scientific research, clinical decision making and the improvement of medical quality, which will further promote secondary analysis of clinical data in our country.医疗大数据的分析利用离不开高质量的临床数据库，我国在急救数据库建设方面尚处于起步和探索阶段。本文介绍了多参数急救数据库的构建思路和关键技术，参考麻省理工学院（MIT）计算生理学实验室创建的重症监护医学信息数据库（MIMIC-III）的架构设计，并结合急诊业务流和信息流，设计了急诊数据整合模型，完成了高质量急救数据库的建设。该数据库目前涵盖了 2015 年 5 月至 2017 年 10 月共 19 814 名不同患者的 22 941 次抢救医疗数据，包含相对完整的生理、生化、治疗、检查、护理等信息，并基于该数据库开展了首届急救大数据 Datathon 活动，全国有 13 个队伍参赛。急救数据库的建设为国内临床数据库的构建和应用提供了参考，为科学研究、临床决策和改善医疗服务质量提供了有力的数据支撑，将进一步推动我国临床数据的二次分析利用工作。.

// Yunchao Li 1 , Chunhua Zhao 2 , Zhibin Yu 2 , Jiarui Chen 3 , Xiaoling She 4 , Peiyao Li 2 , Changhong Liu 2 , Yan Zhang 2 , Jianbo Feng 2 , Haijuan Fu 2 , Bing Wang 1 , Lei Kuang 1 , Lei Li 1 , Guohua Lv 1 , Minghua Wu 2 1 Department of Spinal Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China 2 Cancer Research Institute, School of Basic Medical Science, Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, Changsha, Hunan, China 3 Xiangya Nursing School, Central South University, Changsha, Hunan, China 4 Pathology Department, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China Correspondence to: Guohua Lv, email: spinelv@163.com Minghua Wu, email: wuminghua554@aliyun.com Keywords: miR-381, osteosarcoma, LRRC4, chemosensitivity Received: April 09, 2016 Accepted: August 24, 2016 Published: September 06, 2016 ABSTRACT Osteosarcoma (OS) is the most common primary bone malignancy with a poor prognosis for all races and both sexes. In this study, we found that miR-381 is a positive prognosis factor for OS patients that OS patients with a low expression of miR-381 had a longer survival time after surgical intervention, and miR-381 expression promotes MG-63 cell proliferation and cell invasion ability. Our results also showed a strong negative correlation between the expression of miR-381 and LRRC4 (brain relative specific expression gene) in OS tissues. This demonstrated that LRRC4 is a direct target gene of miR-381, and suppressing the expression of miR-381 increases the sensitivity of OS cells to chemotherapeutic drugs through the LRRC4-mediated mTOR pathway. In summary, miR-381 is an important biomarker in directing therapeutic intervention and predicting prognosis in OS patients.

Ion channel subunits typically assemble in the endoplasmic reticulum. α-SNAP orchestrates a unique assembly and calcium selectivity of Orai1 subunits into functional multimers. Dynamic assembly of Orai1 and its dependence on α-SNAP could enable localization of calcium signals and regulation of rate and amount of calcium influx., Orai1 forms a highly calcium-selective pore of the calcium release activated channel, and α-SNAP is necessary for its function. Here we show that α-SNAP regulates on-site assembly of Orai1 dimers into calcium-selective multimers. We find that Orai1 is a dimer in resting primary mouse embryonic fibroblasts but displays variable stoichiometry in the plasma membrane of store-depleted cells. Remarkably, α-SNAP depletion induces formation of higher-order Orai1 oligomers, which permeate significant levels of sodium via Orai1 channels. Sodium permeation in α-SNAP–deficient cells cannot be corrected by tethering multiple Stim1 domains to Orai1 C-terminal tail, demonstrating that α-SNAP regulates functional assembly and calcium selectivity of Orai1 multimers independently of Stim1 levels. Fluorescence nanoscopy reveals sustained coassociation of α-SNAP with Stim1 and Orai1, and α-SNAP–depleted cells show faster and less constrained mobility of Orai1 within ER-PM junctions, suggesting Orai1 and Stim1 coentrapment without stable contacts. Furthermore, α-SNAP depletion significantly reduces fluorescence resonance energy transfer between Stim1 and Orai1 N-terminus but not C-terminus. Taken together, these data reveal a unique role of α-SNAP in the on-site functional assembly of Orai1 subunits and suggest that this process may, in part, involve enabling crucial low-affinity interactions between Orai1 N-terminus and Stim1.

N-methyl-d-aspartate receptors (NMDARs) play a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. NMDARs activation has been recently implicated in Alzheimer’s disease (AD) related to synaptic dysfunction. Synaptic NMDARs are neuroprotective, whereas overactivation of NMDARs located outside of the synapse cause loss of mitochondrial membrane potential and cell death. NMDARs dysfunction in the glutamatergic tripartite synapse, comprising presynaptic and postsynaptic neurons and glial cells, is directly involved in AD. This review discusses that both beta-amyloid (Aβ) and tau perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of NMDARs as a possible convergence point for Aβ and tau toxicity and possible reversible stages of the AD through preventive and/or disease-modifying therapeutic strategies.

To study the distribution of diseases in Medical Information Mart for Intensive Care (MIMIC-III) database in order to provide reference for clinicians and engineers who use MIMIC-III database to solve clinical research problems.The exploratory data analysis technologies were used to explore the distribution characteristics of diseases and emergencies of patients (excluding newborns) in MIMIC-III database were explored; then, neonatal gestational age, weight, length of hospital stay in intensive care unit (ICU) were analyzed with the same method.In the MIMIC-III database, 46 428 patients were admitted for the first time, and 49 214 ICU records were recorded. There were 26 076 males and 20 352 females; the median age was 60.5 (38.6, 75.6) years, and most patients were between 60 and 80 years old. The first diagnosis in the disease spectrum analysis was firstly ranked by circulatory diseases (32%), followed by injury and poisoning (14%), digestive system disease (8%), tumor (7%), respiratory disease (6%) and so on. Patients with ischemic heart disease accounted for the largest proportion of circulatory disease (42%), the proportion of these patients gradually increased with age of 60-70 years old, then decreased. However, the proportion of patients with cerebrovascular disease declined first and then increased with age, which was the main cause of death of circulatory system disease (ICU mortality was 22.5%). Injury and poisoning patients showed a significant decrease with age. Digestive system diseases were younger than the general population (most people aged between 50 to 60 years), and non-infectious enteritis and colitis were the main causes of death (ICU mortality was 18.3%). Respiratory infections were predominant in infected patients (34%), but circulatory system infections were the main cause of death (ICU mortality was 25.6%). Secondly, in the neonatal care unit, premature infants accounted for the vast majority (82%). As the gestational age increased, the duration of ICU was decreased, and the mortality was decreased.The diseases distribution of patients can be provided by MIMIC-III database, which helps to grasp the overview of the volume and age distribution of the target patients in advance, and carry out the next step of research. Meanwhile, it points out the important role of exploratory data analysis in electronic health records analysis.

Background Despite the overwhelming number of investigations on AKT, little is known about lncRNA on AKT regulation, especially in GBM cells. Methods RNA-binding protein immunoprecipitation assay (RIP) and RNA pulldown were used to confirm the binding of LINC00470 and fused in sarcoma (FUS). Confocal imaging, co-immunoprecipitation (Co-IP) and GST pulldown assays were used to detect the interaction between FUS and AKT. EdU assay, CCK-8 assay, and intracranial xenograft assays were performed to demonstrate the effect of LINC00470 on the malignant phenotype of GBM cells. RT-qPCR and Western blotting were performed to test the effect of LINC00470 on AKT and pAKT. Results In this study, we demonstrated that LINC00470 was a positive regulator for AKT activation in GBM. LINC00470 bound to FUS and AKT to form a ternary complex, anchoring FUS in the cytoplasm to increase AKT activity. Higher pAKT activated by LINC00470 inhibited ubiquitination of HK1, which affected glycolysis, and inhibited cell autophagy. Furthermore, higher LINC00470 expression was associated with GBM tumorigenesis and poor patient prognosis. Conclusions Our findings revealed a noncanonical AKT activation signaling pathway, i.e., LINC00470 directly interacts with FUS, serving as an AKT activator to promote GBM progression. LINC00470 has an important referential significance to evaluate the prognosis of patients. Electronic supplementary material The online version of this article (10.1186/s13045-018-0619-z) contains supplementary material, which is available to authorized users.

The study on complexity of glucose fluctuation not only helps us understand the regulation of the glucose homeostasis system but also brings us a new insight of the research methodology on glucose regulation. In the experiments, we analyzed the complexity of the temporal structure of the 72 hours continuous glucose time series from a group of 93 subjects with type Ⅱ diabetes mellitus using the multi-scale entropy method. We adapted the most recently improved refined composite multi-scale entropy(RCMSE) algorithm which could overcome the shortcomings on the 72 hours short time series analysis. We then quantified and compared the complexity of continuous glucose time series between groups with type Ⅱ diabetes mellitus with different mean absolute glycemic excursion(MAGE) and glycated hemoglobin(Hb A1c). The results implied that the complexity of glucose time series decreased on lower MAGE group compared to high MAGE group, and the entropy on scale 1 to 6 which corresponded to 5 to 30 min had significant differences between these two groups; the complexity of glucose time series decreased with the increasing Hb A1 c level but the entropy had no statistical difference among groups at different scales. Therefore, RCMSE provided us with a new prospect to analyze the glucose time series and it was proved that less complexity of glucose dynamics could indicate the impaired gluco-regulation function from the MAGE point of view or Hb A1 c for patients, and the glucose complexity had the potential to become a new biomarker to reflect the fluctuation of the glucose time series.

Membrane-bound transcription factors (MTFs) are transcription factors (TFs) that are anchored in membranes in a dormant state. Activated by external or internal stimuli, MTFs are released from parent membranes and are transported to the nucleus. Existing research indicates that some plasma membrane (PM)-bound proteins and some endoplasmic reticulum (ER) membrane-bound proteins have the ability to enter the nucleus. Upon specific signal recognition cues, some PM-bound TFs undergo proteolytic cleavage to liberate the intracellular fragments that enter the nucleus to control gene transcription. However, lipid-anchored PM-bound proteins enter the nucleus in their full length for depalmitoylation. In addition, some PM-bound TFs exist as full-length proteins in cell nucleus via trafficking to the Golgi and the ER, where membrane-releasing mechanisms rely on endocytosis. In contrast, the ER membrane-bound TFs relocate to the nucleus directly or by trafficking to the Golgi. In both of these pathways, only the fragments of the ER membrane-bound TFs transit to the nucleus. Several different nuclear trafficking modes of MTFs are summarized in this review, providing an effective supplement to the mechanisms of signal transduction and gene regulation. Moreover, targeting intracellular movement pathways of disease-associated MTFs may significantly improve the survival of patients.

Neuronal polarization is pivotal for neural network formation during brain development. Axon differentiation is a hallmark of initial neuronal polarization. Here, we report that the leucine-rich repeat-containing protein netrin-G ligand-2 (NGL-2) as a polarity regulator that localizes asymmetrically in rat hippocampal neurons and is required for differentiation of the future axon. NGL-2 was associated with PAR complex, and this interaction resulted in local stabilization of axonal microtubules. Further study showed that the C terminal of NGL-2 binds to the PDZ domain of PAR6, and NGL-2 interacts with PAR3 and atypical PKCζ (aPKCζ), with PAR6 acting as a bridge or modifier. Then, NGL-2 regulates the local stabilization of microtubules and promotes axon differentiation by the aPKCζ/microtubule affinity-regulating kinase 2 pathway. These findings reveal the critical role of NGL-2 in regulating axon differentiation in rat hippocampal neurons and reveal a novel partner of the PAR complex.

Circular RNAs, a novel class of endogenous noncoding RNAs, are characterized by their covalently closed loop structures without a 5′ cap or a 3′ Poly A tail. Although the mechanisms of circular RNAs’ generation and function are not fully clear, recent research has shown that circular RNAs may function as potential molecular markers for disease diagnosis and treatment and play an important role in the initiation and progression of human diseases, especially in tumours. This review summarizes some information about categories, biogenesis, functions at the molecular level, properties of circular RNAs and the possibility of circular RNAs as biomarkers in cancers.

The transcription factor TWIST1 is a highly evolutionally conserved basic Helix-Loop-Helix (bHLH) transcription factor that functions as a master regulator of gastrulation and mesodermal development. Although TWIST1 was initially associated with embryo development, an increasing number of studies have shown TWIST1 role in the regulation of tissue homeostasis, primarily as a regulator of inflammation. More recently, TWIST1 has been found to be involved in the process of tumor metastasis through the regulation of Epithelial Mesenchymal Transition (EMT). The objective of this review is to examine the normal functions of TWIST1 and its role in tumor development, with a particular focus on ovarian cancer. We discuss the potential role of TWIST1 in the context of ovarian cancer stem cells and its influence in the process of tumor formation.

Glucose variability provides detailed information on glucose control and fluctuation. The aim of this study is to investigate the glucose variability by multi-scale analysis approach on 72-h glucose series captured by continuous glucose monitoring system (CGMS), gaining insights into the variability and complexity of the glucose time series data. Ninety-eight type 2 DM patients participated in this study, and 72-h glucose series from each subject were recorded by CGMS. Subjects were divided into two subgroups according to the mean amplitude of glycemic excursions (MAGE) value threshold at 3.9 based on Chinese standard. In this study, we applied two types of multiple scales analysis methods on glucose time series: ensemble empirical mode decomposition (EEMD) and refined composite multi-scale entropy (RCMSE). With EEMD, glucose series was decomposed into several intrinsic mode function (IMF), and glucose variability was examined on multiple time scales with periods ranging from 0.5 to 12 h. With RCMSE, complexity of the structure of glucose series was quantified at each time scale ranging from 5 to 30 min. Subgroup with higher MAGE value (>3.9) presented higher glycemic baseline and variability. There were significant differences in glycemic variability on IMFs3–5 between subgroups with MAGE>3.9 and MAGE

Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 x 10(-18)). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

Background Argonaute 2 (AGO2), a central component of RNA-induced silencing complex, plays critical roles in cancer. We examined whether the single nucleotide polymorphisms (SNPs) of AGO2 were related to the risk of nasopharyngeal carcinoma (NPC). Methods Twenty-five tag SNPs within AGO2 were genotyped in Guangxi population consisting of 855 NPC patients and 1036 controls. The SNPs significantly associated with NPC were further replicated in Guangdong population consisting of 996 NPC patients and 972 controls. Functional experiments were conducted to examine the biologic roles of AGO2 in NPC. Results A significantly increased risk of advanced lymph node metastasis of NPC was identified for the AGO2 rs3928672 GA + AA genotype compared with GG genotype in both the Guangxi and Guangdong populations (combined odd ratio = 2.08, 95 % confidence interval = 1.44-3.01, P = 8.60 × 10−5). Moreover, the AGO2 protein expression levels of rs3928672 GA + AA genotype carriers were higher than the GG genotype carriers in the NPC tissues (P = 0.041), and AGO2 was significantly over-expressed in NPC tissues compared with non-cancerous nasopharyngeal tissues (P = 0.011). In addition, AGO2 knockdown reduced cell proliferation, induced apoptosis, and inhibited migration of NPC cells. Furthermore, gene expression microarray showed that genes altered following AGO2 knockdown were clustered in tumorigenesis and metastasis relevant pathways. Conclusions Our findings suggest that the genetic polymorphism in AGO2 may be a risk factor for the advanced lymph node metastasis of NPC in Chinese populations, and AGO2 acts as an oncogene in the development of NPC. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1895-4) contains supplementary material, which is available to authorized users.

Our previous report identified PR domain containing 16 (PRDM16), a member of the PR-domain gene family, as a new methylation associated gene in astrocytoma cells. This previous study also reported that miR-101 is a tumor suppressor in glioma. The present study confirms that PRDM16 is a hypomethylated gene that can be overexpressed in astrocytoma patients and demonstrates that the hypomethylation status of the PRDM16 promoter can predict poor prognoses for astrocytoma patients. The results reported herein show that PRDM16 was inhibited by miR-101 directly and also through epigenetic regulation. PRDM16 was confirmed as a new target of miR-101 and shown to be directly inhibited by miR-101. miR-101 also decreased the expression of PRDM16 by altering the methylation status of the PRDM16 promoter. miR-101 was associated with a decrease in the methylation-related histones H3K4me2 and H3K27me3 and an increase in H3K9me3 and H4K20me3 on the PRDM16 promoter. In addition, EZH2, EED and DNMT3A were identified as direct targets of miR-101, and miR-101 suppressed PRDM16 expression by targeting DNMT3A which decreases histone H3K27me3 and H3K4me2 at the PRDM16 core promoter. The results reported here demonstrate that miR-101 disrupted cellular mitochondrial function and induced cellular apoptosis via the mitochondrial pathway; for example, MMP and ATP levels decreased, while there was an increase in ADP/ATP ratios and ROS levels, levels of cleaved Caspase-9 and cleaved-PARP, the Bax/Bcl-2 ratios, and Smac release from the mitochondria to the cytoplasm. Knockdown of PRDM16 reversed the anti-apoptotic effect of miR-101 inhibition. In summary, miR-101 reversed the hypomethylation of the PRDM16 promoter which suppressed the expression of PRDM16, disrupted cellular mitochondrial function, and induced cellular apoptosis.

// Yang Zhang 1, 2, * , Xiaoai Zhang 1, 3, * , Hongxing Zhang 1 , Yun Zhai 1 , Zhifu Wang 1, 2 , Peiyao Li 1 , Lixia Yu 1 , Xia Xia 1 , Ying Zhang 1 , Yixin Zeng 4 , Fuchu He 1 , Gangqiao Zhou 1 1 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 3 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China 4 Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China * These authors contributed equally to this work Correspondence to: Fuchu He, e-mail: hefc@nic.bmi.ac.cn Gangqiao Zhou, e-mail: zhougq114@126.com Keywords: TERT, CLPTM1L, polymorphism, nasopharyngeal carcinoma Received: April 28, 2015 Accepted: November 14, 2015 Published: November 26, 2015 ABSTRACT Associations between single nucleotide polymorphisms (SNPs) at 5p15 ( TERT-CLPTM1L ) and multiple cancer types have been reported. We examined whether polymorphisms in the TERT-CLPTM1L locus were related to the risk of developing nasopharyngeal carcinoma (NPC) among Chinese populations. In the first stage, 26 tag SNPs were genotyped in a Guangxi population (855 patients and 1036 controls). In the second stage, the SNPs, which showed significant association, were further genotyped in a Guangdong population (997 patients and 972 controls). Functional analyses were conducted to verify the biological relevance of the associated polymorphism. In the 1st stage, four SNPs (rs2736098, rs2735845, rs402710, and rs401681) were significantly associated with the risk of developing NPC. After the 2nd stage validation, rs2735845 and rs401681 were independently associated with the risk of developing NPC in the additive model (rs2735845, OR = 1.19, 95% CI = 1.04–1.37, P = 0.011; rs401681, OR = 0.85, 95% CI = 0.74–0.99, P = 0.034). Furthermore, we observed higher CLPTM1L messenger RNA levels in fetal mesenchymal stem cells from the rs2735845 G allele carriers compared with that from non-carriers. In addition, using an immunohistochemistry assay, we observed higher TERT and CLPTM1L levels in NPC tissues compared with that in non-cancerous nasopharyngeal tissues. Our findings suggest that polymorphisms in the TERT-CLPTM1L locus may play a role in mediating the susceptibility to NPC in Chinese populations.

LRRC4/NGL-2 (Leucine rich repeat containing 4/Netrin-G ligand-2), a relatively specific expressed gene in brain tissue, is a member of the LRRC4/ NGL (netrin-G ligand) family and belongs to the superfamily of LRR proteins. LRRC4/NGL-2 regulates neurite outgrowth and lamina-specific dendritic segmentation, suggesting that LRRC4/NGL-2 is important for the development of the nervous system. In addition, LRRC4/NGL-2 has been identified as a tumor suppressor gene. The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. LRRC4/NGL-2 also has the ability to form multiphase loops with miRNA, transcription factors and gene methylation modification; the loss of LRRC4/NGL-2 function may be an important event in multiple biological processes in gliomas. In summary, LRRC4/NGL-2 is a critical gene in the normal development and tumorigenesis of the nervous system.

miR-101 has been suggested as a tumor suppressor, but the promoter methylation and loss of heterozygosity didn’t contribute to its low expression in astrocytoma. We investigated the role of a new long non-coding RNA CASC2c binding with miR-101. High CASC2c was positively correlated with astrocytoma progression, and an unfavorable prognosis factor for patients. Knockdown CASC2c inhibited proliferation and tumorgenesis. Overexpression of CASC2c promotes the malignant characteristic of astrocytoma cells.CASC2c directly bound miR-101 and mediated pre-miR-101 processing into mature miR-101, and functions as a competitor of miR-101 target genes such as CPEB1. Patients who possessed both low CASC2c and high miR-101 had a longer survival than those of low CASC2c alone or high miR-101 alone. In summary, CASC2c plays the onco-RNA role in the tumorgenesis of astrocytoma by acting as a decoy miR-101 sponge. Combination of low expression of CASC2c and high expression of miR-101 has an important referential significance to evaluate the prognosis of patients.

p73, a structural and functional homolog of p53, plays an important role in modulating cell cycle control and apoptosis. We examined whether the p73 G4C14-to-A4T14 polymorphism was related to the risk of nasopharyngeal carcinoma (NPC) among Chinese populations. The G4C14-to-A4T14 polymorphism was genotyped in 593 NPC cases and 480 controls, and in 102 NPC trios. Logistic regression analysis and transmission/disequilibrium tests (TDT) were performed to evaluate whether there was an association between the polymorphism and NPC, respectively. Functional analyses were conducted to verify the biological relevance of the polymorphism. We observed that compared with the GC/GC genotype, the genotypes containing AT allele (GC/AT + AT/AT genotypes) were associated with significantly increased susceptibility to NPC [odds ratio (OR) = 1.51; 95% confidence interval (CI) = 1.16-1.95; P = 0.002]. Furthermore, compared with the GC/GC genotype, the GC/AT + AT/AT genotypes were significantly associated with the advanced lymph node metastasis (OR = 1.47; 95% CI = 1.02-2.11; P = 0.041). A significantly greater than expected transmission of the AT allele from heterozygous parents to offspring was also observed (P = 0.049) using the TDT. By using the TdT-mediated dUPT-biotin nick end labeling assay, we observed lower apoptosis in NPC tissues from the AT allele carriers compared with that from non-carriers. Furthermore, the relative TAp73 RNA levels of the AT allele were lower than those of the GC allele in heterozygous cells. Our findings suggest that the p73 G4C14-to-A4T14 polymorphism may play a role in mediating the susceptibility to NPC in Chinese populations.

Sepsis represents a systemic inflammatory response to infection and its sequelae include severe sepsis, septic shock, multiple organ dysfunction syndrome (MODS) and death. Studies in mice and humans indicate that the inducible nitric oxide synthase (iNOS, NOS2) plays an important role in the development of sepsis and its sequelae. It was reported that several single nucleotide polymorphisms (SNPs) within NOS2 could influence the production or activity of NOS2. In this study, we assessed whether SNPs within NOS2 gene were associated with severity of sepsis in Chinese populations. A case–control study was conducted, which included 299 and 280 unrelated patients with sepsis recruited from Liaoning and Jiangsu provinces in China, respectively. Six SNPs within NOS2 were genotyped using Sequenom MassARRAY system. The associations between the SNPs and risk of sepsis complications were estimated by a binary logistic regression model adjusted for confounding factors. Functional assay was performed to assess the biological significance. The GA + AA genotype of a non-synonymous SNP in the exon 16 of NOS2 (rs2297518: G>A) was significantly associated with increased susceptibility to septic shock compared with GG genotype in Liaoning population (OR = 3.29, 95 % CI = 1.40–7.72, P = 0.0047). This association was confirmed in the Jiangsu population (OR = 3.49, 95 % CI = 1.57–7.79, P = 0.0019). Furthermore, the functional assay performed in the immortalized lymphocyte cell lines indicated that the at-risk GA genotype had a tendency of higher NOS2 activity than the GG genotype (P = 0.32). Our findings suggest that the NOS2 rs2297518 may play a role in mediating the susceptibility to septic shock in patients with sepsis in Chinese populations.

Background Increases in human telomerase reverse transcriptase (TERT) expression and telomerase activity are frequently seen in nasopharyngeal carcinoma (NPC). Recently, a variable tandem-repeats polymorphism, MNS16A, located in the downstream region of the TERT gene, was identified and reported to have an effect on TERT expression and telomerase activity. We examined whether the functional MNS16A was related to the risk of occurrence or progression of NPC in the Chinese population. Methods We genotyped the MNS16A polymorphism in a case-control study of 855 patients with NPC and 1036 cancer-free controls using PCR, and determined genotype by classifying the DNA band of 243 or 272 base pairs (bp) as the short (S) allele and 302 or 333 bp as the long (L) allele. The genetic associations with the risk of NPC were analyzed by logistic regression. Results The MNS16A genotype was not associated with the progression of NPC. However, individuals carrying the S alleles (SL + SS genotype) had a significantly reduced risk of NPC occurrence compared with those carrying the LL genotype (odds ratio (OR) = 0. 71, 95% confidence interval (CI) = 0. 52 to 0. 96, P = 0. 025). Using a immunohistochemical assay on the NPC tissues, the SL genotype carriers were found to have lower TERT expression than the LL genotype carriers (P = 0. 035). Conclusions Our study indicates that the TERT MNS16A polymorphism may contribute to the risk of NPC onset in Chinese population.

Background Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin) is a member of the inhibitor of apoptosis protein (IAP) family, which plays an important role in the occurrence and progression of cancer. Recently, a polymorphism in the promoter of BIRC5, -31C/G (rs9904341), was shown to influence BIRC5 expression. Methods We examined whether the -31C/G was related to the risk of developing nasopharyngeal carcinoma (NPC) in a case-control population from Guangxi province in southern China, which consists of 855 patients with NPC and 1036 controls. This polymorphism was genotyped by TaqMan assay. The genetic associations with the occurrence and progression of NPC were estimated by logistic regression. Results We observed a statistically significant increased occurrence of NPC associated with the CC genotype (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.13–1.73; P = 0.0020) compared with the genotypes containing G allele (CG + GG genotype). However, no significant association was observed for the -31C/G with the severity of NPC (as measured by tumor-node-metastasis staging system). Conclusion Our findings suggest that the functional polymorphism -31C/G in the promoter of BIRC5 gene may play a role in mediating the susceptibility to NPC among Chinese.

Background The balance between endothelial cell survival and apoptosis during stress is an important cellular process for vessel integrity and vascular homeostasis, and it is also pivotal in angiogenesis during the development of many vascular diseases. However, the underlying molecular mechanisms remain largely unknown. Although both transcription and alternative splicing are important in regulating gene expression in endothelial cells under stress, the regulatory mechanisms underlying this state and their interactions have not yet been studied on a genome-wide basis. Results Human umbilical vein endothelial cells (HUVECs) were treated with cobalt chloride (CoCl2) both to mimic hypoxia and to induce cell apoptosis and alternative splicing responses. Cell apoptosis rate analysis indicated that HUVECs exposed to 300 μM CoCl2 for 24 hrs were initially counterbalancing apoptosis with cell survival. We therefore used the Affymetrix exon array system to determine genome-wide transcript- and exon-level differential expression. Other than 1583 differentially expressed transcripts, 342 alternatively spliced exons were detected and classified by different splicing types. Sixteen alternatively spliced exons were validated by RT-PCR. Furthermore, direct evidence for the ongoing balance between HUVEC survival and apoptosis was provided by Gene Ontology (GO) and protein function, as well as protein domain and pathway enrichment analyses of the differentially expressed transcripts. Importantly, a novel molecular module, in which the heat shock protein (HSP) families play a significant role, was found to be activated under mimicked hypoxia conditions. In addition, 46% of the transcripts containing stress-modulated exons were differentially expressed, indicating the possibility of combinatorial regulation of transcription and splicing. Conclusion The exon array system effectively profiles gene expression and splicing on the genome-wide scale. Based on this approach, our data suggest that transcription and splicing not only regulate gene expression, but also carry out combinational regulation of the balance between survival and apoptosis of HUVECs under mimicked hypoxia conditions. Since cell survival following the apoptotic challenge is pivotal in angiogenesis during the development of many vascular diseases, our results may advance the knowledge of multilevel gene regulation in endothelial cells under physiological and pathological conditions.

Phosphatase and tensin homolog (PTEN), v-akt murine thymoma viral oncogene homolog 1 (AKT1), mouse double minute 2 (MDM2) and p53 play important roles in the development of cancer. We examined whether the single nucleotide polymorphisms (SNPs) in the PTEN, AKT1, MDM2 and p53 genes were related to the risk and severity of nasopharyngeal carcinoma (NPC) in the Chinese population. Seven SNPs [p53 rs1042522, PTEN rs11202592, AKT1 SNP1-5 (rs3803300, rs1130214, rs3730358, rs1130233 and rs2494732)] were genotyped in 593 NPC cases and 480 controls by PCR direct sequencing or PCR-RFLP analysis. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). None of the polymorphisms alone was associated with the risk or severity of NPC. However, haplotype analyses indicated that a two-SNP core haplotype (SNP4-5, AA) in AKT1 was associated with a significantly increased susceptibility to NPC risk (adjusted OR = 3.87, 95% CI = 1.96-7.65; P

Background As a well-characterized key player in various signal transduction networks, extracellular-signal-regulated kinase (ERK1/2) has been widely implicated in the development of many malignancies. We previously found that Leucine-rich repeat containing 4 (LRRC4) was a tumor suppressor and a negative regulator of the ERK/MAPK pathway in glioma tumorigenesis. However, the precise molecular role of LRRC4 in ERK signal transmission is unclear. Methods The interaction between LRRC4 and ERK1/2 was assessed by co-immunoprecipitation and GST pull-down assays in vivo and in vitro. We also investigated the interaction of LRRC4 and ERK1/2 and the role of the D domain in ERK activation in glioma cells. Results Here, we showed that LRRC4 and ERK1/2 interact via the D domain and CD domain, respectively. Following EGF stimuli, the D domain of LRRC4 anchors ERK1/2 in the cytoplasm and abrogates ERK1/2 activation and nuclear translocation. In glioblastoma cells, ectopic LRRC4 expression competitively inhibited the interaction of endogenous mitogen-activated protein kinase (MEK) and ERK1/2. Mutation of the D domain decreased the LRRC4-mediated inhibition of MAPK signaling and its anti-proliferation and anti-invasion roles. Conclusions Our results demonstrated that the D domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells. These findings identify a new mechanism underlying glioblastoma progression and suggest a novel therapeutic strategy by restoring the activity of LRRC4 to decrease MAPK cascade activation. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0355-1) contains supplementary material, which is available to authorized users.