Rubella remains a significant burden in mainland China. In this report, 667 viruses collected in 24 of 31 provinces of mainland China during 2010–2012 were sequenced and analyzed, significantly extending previous reports on limited numbers of viruses collected before 2010. Only viruses of genotypes 1E and 2B were found. Genotype 1E viruses were found in all 24 provinces. Genotype 1E viruses were likely introduced into mainland China around 1997 and endemic transmission of primarily one lineage became established. Viruses reported here from 2010–2012 are largely in a single cluster within this lineage. Genotype 2B viruses were rarely detected in China prior to 2010. This report documents a previously undetected 2B lineage, which likely became endemic in eastern provinces of China between 2010 and 2012. Bayesian analyses were performed to estimate the evolutionary rates and dates of appearance of the genotype 1E and 2B viral linages in China. A skyline plot of viral population diversity did not provide evidence of reduction of diversity as a result of vaccination, but should be useful as a baseline for such reductions as vaccination programs for rubella become widespread in mainland China.
Our study, conducted within a New York City-based cohort, identified novel interactions between maternal PAH exposure and maternal and newborn genetic haplotypes in key B[a]P metabolism genes on B[a]P-DNA adducts in paired cord blood samples.
Polycyclic aromatic hydrocarbons (PAH) are a class of chemicals common in the environment. Certain PAH are carcinogenic, although the degree to which genetic variation influences susceptibility to carcinogenic PAH remains unclear. Also unknown is the influence of genetic variation on the procarcinogenic effect of in utero exposures to PAH. Benzo[a]pyrene (B[a]P) is a well-studied PAH that is classified as a probable human carcinogen. Within our New York City-based cohort, we explored interactions between maternal exposure to airborne PAH during pregnancy and maternal and newborn haplotypes (and in one case, a single-nucleotide polymorphism) in key B[a]P metabolism genes on B[a]P-DNA adducts in paired cord blood samples. The study subjects included non-smoking African-American (n = 132) and Dominican (n = 235) women with available data on maternal PAH exposure, paired cord adducts and genetic data who resided in the Washington Heights, Central Harlem and South Bronx neighborhoods of New York City. We selected seven maternal and newborn genes related to B[a]P metabolism, detoxification and repair for our analyses: CYP1A1, CYP1A2, CYP1B1, GSTM3, GSTT2, NQO1 and XRCC1. We found significant interactions between maternal PAH exposure and haplotype on cord B[a]P-DNA adducts in the following genes: maternal CYP1B1, XRCC1 and GSTM3, and newborn CYP1A2 and XRCC1 in African-Americans; and maternal XRCC1 and newborn NQO1 in Dominicans. These novel findings highlight differences in maternal and newborn genetic contributions to B[a]P-DNA adduct formation, as well as ethnic differences in gene–environment interactions, and have the potential to identify at-risk subpopulations who are susceptible to the carcinogenic potential of B[a]P.
Noise exposure (NE) is a severe modern health hazard that induces hearing impairment. However, the noise-induced ultrastructural changes of blood-labyrinth barrier (BLB) and the potential involvements of tight junction proteins (TJP) remain inconclusive.
We investigated the effects of NE on not only the ultrastructure of cochlea and permeability of BLB but also the expression of TJP within the guinea pig cochlea.
Male albino guinea pigs were exposed to white noise for 4 h or 2 consecutive days (115 dB sound pressure level, 6 hours per day) and the hearing impairments and light microscopic change of BLB were evaluated with auditory brainstem responses (ABR) and the cochlear sensory epithelia surface preparation, respectively. The cochlear ultrastructure and BLB permeability after NE 2d were revealed with transmission electron microscope (TEM) and lanthanum nitrate-tracing techniques, respectively. The potential alterations of TJPs Claudin-5 and Occludin were quantified with immunohistochemistry and western blot. NE induced significant hearing impairment and NE 2d contributed to significant outer hair cell (OHC) loss that is most severe in the first row of outer hair cells. Furthermore, the loosen TJ and an obvious leakage of lanthanum nitrate particles beneath the basal lamina were revealed with TEM. Moreover, a dose-dependent decrease of Claudin-5 and Occludin was observed in the cochlea after NE.
All these findings suggest that both decrease of Claudin-5 and Occludin and increased BLB permeability are involved in the pathologic process of noise-induced hearing impairment; however, the causal relationship and underlying mechanisms should be further investigated.
Electronic supplementary material
The online version of this article (doi:10.1186/s12868-014-0136-0) contains supplementary material, which is available to authorized users.
Blood-labyrinth barrier; Noise exposure; Tight-junction proteins
WebGLORE is a free web service that enables privacy-preserving construction of a global logistic regression model from distributed datasets that are sensitive. It only transfers aggregated local statistics (from participants) through Hypertext Transfer Protocol Secure to a trusted server, where the global model is synthesized. WebGLORE seamlessly integrates AJAX, JAVA Applet/Servlet and PHP technologies to provide an easy-to-use web service for biomedical researchers to break down policy barriers during information exchange.
Availability and implementation:
http://dbmi-engine.ucsd.edu/webglore3/. WebGLORE can be used under the terms of GNU general public license as published by the Free Software Foundation.
Tension-free hernia repairing techniques is a popular herniorrhaphy for open inguinal hernioplasty and the modified Kugel herniorrhaphy (MKH) is a kind of tension-free hernia repairing technique. The modified Kugel herniorrhaphy (MKH) is a minimally invasive, non-laparoscopic, conventional anterior approach, preperitoneal and sutureless technique. It is well accepted by most people because of few complications and low recurrence rate. A case of an 82-year-old man underwent MKH. After the third day of postoperation, a strange symptom of Grey-Turner’s sign appeared and maintained for 10 days.
Inguinal hernia; modified Kugel herniorrhaphy; preperitoneal approach; Grey-Turner’s sign; tension-free
Mink enteritis virus (MEV) is one of the most important pathogens in the mink industry. Recent studies have shed light into the role of microRNAs (miRNAs), small noncoding RNAs of length ranging from 18–23 nucleotides (nt), as critical modulators in the host-pathogen interaction networks. We previously showed that miRNA miR-181b can inhibit MEV replication by repression of viral non-structural protein 1 expression. Here, we report that two other miRNAs (miR-320a and miR-140) inhibit MEV entry into feline kidney (F81) cells by downregulating its receptor, transferrin receptor (TfR), by targeting the 3′ untranslated region (UTR) of TfR mRNA, while being themselves upregulated.
Mink enteritis virus (MEV); miR-320a; miR-140; Transferrin receptor (TfR)
We aim at developing a streamlined genome sequence compression algorithm to support alternative miniaturized sequencing devices, which have limited communication, storage, and computation power. Existing techniques that require heavy client (encoder side) cannot be applied. To tackle this challenge, we carefully examined distributed source coding theory and developed a customized reference-based genome compression protocol to meet the low-complexity need at the client side. Based on the variation between source and reference, our protocol will pick adaptively either syndrome coding or hash coding to compress subsequences of changing code length. Our experimental results showed promising performance of the proposed method when compared with the state-of-the-art algorithm (GRS).
genome compression; distributed source coding; graphical model
The orbitofrontal (OF) region is one of the least explored regions of the cerebral cortex. There are few studies on patients with electrophysiologically and surgically confirmed OF epilepsy and a negative MRI. We aimed to examine the neuroimaging characteristics of MRI-negative OF epilepsy with the focus on a voxel-based morphometric MRI post-processing technique.
We included 6 patients with OF epilepsy, who met the following criteria: surgical resection of the OF lobe with/without adjacent cortex, seizure-free for ≥ 12 months, invasive video-EEG monitoring showing ictal onset from the OF area, and pre-operative MRI regarded negative. Patients were investigated in terms of their image postprocessing and functional neuroimaging characteristics, electroclinical characteristics obtained from noninvasive and invasive evaluations, and surgical pathology. MRI postprocessing on T1-weighted high-resolution scans was implemented with a Morphometric Analysis Program (MAP) in MATLAB SPM5.
Single MAP+ abnormalities were found in 4 patients; three were in the OF region and one in the ipsilateral mesial frontal area. These abnormalities were included in the resection. One patient had bilateral MAP+ abnormalities in the OF region, with the ipsilateral one completely removed. The MAP+ foci were concordant with invasive electrophysiological data in the majority of MAP+ patients (4 of 5). The localization value of FDG-PET and ictal SPECT is low in this cohort. Surgical pathology included focal cortical dysplasia, remote infarct, rosenthal fiber formation and gliosis.
Our study highlights the importance of MRI post-processing in the process of presurgical evaluation of patients with suspected orbitofrontal epilepsy and “normal” MRI. Using MAP, we were able to positively identify subtle focal abnormalities in the majority of the patients. MAP results need to be interpreted in the context of their electroclinical findings and can provide valuable targets in the process of planning invasive evaluation.
epilepsy; MRI; presurgical evaluation; MRI post-processing; MRI-negative epilepsy; voxel-based morphometry; orbitofrontal epilepsy; focal cortical dysplasia
The NLRP3 inflammasome plays key roles in inflammation and autoimmunity, and puriner-gic receptor P2X7 has been proposed to be upstream of NLRP3 activation. The aim of the present study, using murine models, was to investigate whether the P2X7/ NLRP3 inflammasome pathway contributes to the pathogenesis of lupus nephritis (LN).
MRL/lpr mice were treated with the selective P2X7 antagonist brilliant blue G (BBG) for 8 weeks. Following treatment, the severity of renal lesions, production of anti-double-stranded DNA (anti-dsDNA) antibodies, rate of survival, activation of the NLRP3/ ASC/caspase 1 inflammasome pathway, and ratio of Thl7 cells to Treg cells were evaluated. P2X7-targeted small interfering RNA (siRNA) was also used for in vivo intervention. Similar evaluations were carried out in NZM2328 mice, a model of LN in which the disease was accelerated by administration of adenovirus-expressing interferon-α (AdIFNα).
Significant up-regulation of P2X7/NLRP3 inflammasome signaling molecules was detected in the kidneys of MLR/lpr mice as compared with normal control mice. Blockade of P2X7 activation by BBG suppressed NLRP3/ASC/caspase 1 assembly and the subsequent release of interleukin-1β (IL-1β), resulting in a significant reduction in the severity of nephritis and circulating anti-dsDNA antibodies. The lifespan of the treated mice was significantly prolonged. BBG treatment reduced the serum levels of IL-1β and IL-17 and the Thl7:Treg cell ratio. Similar results were obtained by specific siRNA silencing of P2X7 in vivo. The effectiveness of BBG treatment in modulating LN was confirmed in NZM2328 mice with AdIFNα-accelerated disease.
Activation of the P2X7 signaling pathway accelerates murine LN by activating the NLRP3/ASC/caspase 1 inflammasome, resulting in increased IL-1β production and enhanced Thl7 cell polarization. Thus, targeting of the P2X7/NLRP3 pathway should be considered as a novel therapeutic strategy in patients with lupus.
The avian influenza virus (AIV) causes frequent disease with high morbidity and mortality. RNA interference (RNAi) has been shown to provide an effective antiviral defense in animals, and several studies have focused on harnessing small interfering RNAs (siRNAs) to inhibit viral infections. In addition, single chain variable fragments (scFvs) contain the complete antigen binding site, and specific scFvs can bind to and neutralize viruses.
Fourteen positive scFvs were selected by the yeast two-hybrid system. Using molecular docking technology, we selected the three highest affinity scFvs for further functional validation. Results of indirect ELISA and IFA showed that all three scFvs could bind to FJ13 strain and had neutralizing activity, decreasing the viral infectivity markedly. Chicken fibroblastic DF-1 cells were transfected with scFvs in combination with siRNA-NP604 (an siRNA of anti-AIV NP protein previously reported). Following infection with FJ13 virus, copy numbers of the virus were significantly reduced from 12 h to at least 60 h post-infection compared to that achieved in cells transfected with scFv or siRNA-NP604 separately.
A novel combination of antiviral siRNAs expressed in chicken cells and chicken antibody single-chain variable fragments (scFvs) secreted from the cells has a synergistic inhibitory effect on the avian influenza viral proliferation in vitro. Intracellular application of scFvs and anti-viral siRNA may provide a new approach to influenza prevention and treatment.
AIV H5N1; scFv; siRNA; Synergistic inhibitory effect
RABEX-5, a guanine-nucleotide exchange factor (GEF) for RAB-5, is implicated in tumorigenesis and in the development of certain human cancers. Here, we report that RABEX-5 promotes tumor growth and the metastatic ability of gastric cancer cells both in vitro and in vivo. Expression of RABEX-5 is significantly higher in gastric cancer tissues and is associated with tumor size and lymph node metastasis. In addition, targeted silencing of RABEX-5 reduced gastric cancer cell proliferation and colony formation in vitro via the induction of a G0/G1 phase arrest, and stimulated gastric cancer cell apoptosis. Knockdown of RABEX-5 also inhibited wound healing, migration and the invasive abilities of gastric cancer cells. The results of in vivo animal experiments were also consistent with these in vitro findings. Silencing of RABEX-5 led to decreased expression of VEGF. These results indicate that RABEX-5 is upregulated and plays an oncogenic role in gastric cancer development by activating the VEGF signaling pathway.
Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown previously to be neurotoxic.
In a prospective cohort study, we evaluated the relationship between Attention Deficit Hyperactivity Disorder behavior problems and prenatal polycyclic aromatic hydrocarbon exposure, adjusting for postnatal exposure.
Materials and Methods
Children of nonsmoking African-American and Dominican women in New York City were followed from in utero to 9 years. Prenatal polycyclic aromatic hydrocarbon exposure was estimated by levels of polycyclic aromatic hydrocarbon- DNA adducts in maternal and cord blood collected at delivery. Postnatal exposure was estimated by the concentration of urinary polycyclic aromatic hydrocarbon metabolites at ages 3 or 5. Attention Deficit Hyperactivity Disorder behavior problems were assessed using the Child Behavior Checklist and the Conners Parent Rating Scale- Revised.
High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously (N = 233). After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive (OR = 5.06, 95% CI [1.43, 17.93]) and DSM-IV Total (OR = 3.37, 95% CI [1.10, 10.34]) subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. In the smaller sample with cord adducts, the associations between outcomes and high cord adduct exposure were not statistically significant (N = 162).
The results suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood Attention Deficit Hyperactivity Disorder behavior problems.
Airborne polycyclic aromatic hydrocarbons (PAHs) are pollutants generated by combustion of fossil fuel and other organic material. Both prenatal PAH exposure and maternal psychological distress during pregnancy have each been associated with neurodevelopmental problems in children. The goal was to evaluate potential interactions between prenatal exposure to airborne PAHs and maternal psychological distress during pregnancy on subsequent behavioral problems in children.
In a longitudinal birth cohort study, 248 children of nonsmoking white women in the coal-burning region of Krakow, Poland, were followed from in utero until age 9. Prenatal PAH exposure was measured by personal air monitoring during pregnancy, maternal demoralization during pregnancy by the Psychiatric Epidemiology Research Instrument–Demoralization, and child behavior by the Child Behavior Checklist.
Significant interactions between maternal demoralization and PAH exposure (high versus low) were identified for symptoms of anxious/depressed, withdrawn/depressed, social problems, aggressive behavior, internalizing problems, and externalizing problems. The effects of demoralization on syndromes of anxious/depressed, withdrawn/depressed, rule-breaking, aggressive behavior, and the composite internalizing and externalizing scores were seen only in conjunction with high PAH exposure. Fewer significant effects with weaker effect sizes were observed in the low-PAH-exposure group.
Maternal demoralization during pregnancy appears to have a greater effect on child neurobehavioral development among children who experienced high prenatal PAH exposure. The results provide the first evidence of an interaction between prenatal exposure to maternal demoralization and air pollution on child neurobehavioral development, indicating the need for a multifaceted approach to the prevention of developmental problems in children.
prenatal; PAH; air pollution; child behavior; maternal psychological distress; demoralization
MicroRNAs (miRs) control cell growth, apoptosis and differentiation, and thus play a key role in carcinogenesis. Identification of a set of miRs that demonstrate differential expression in oral squamous cell carcinoma (OSCC) patients with poor prognosis has potential for utility as a prognostic marker. A retrospective study of miR expression was conducted in 20 tissue samples from early stage (Stages I & II) OSCC patients with known clinical outcome (10 from those who had 5-year disease free survival and 10 who died of disease within 5 years) using genome-wide deep sequencing analysis. The promising miR candidates were then validated in 80 tissue samples using quantitative real-time PCR (qRT-PCR). The deep sequencing and qRT-PCR analysis identified two promising miRs, miR-375 and miR-214-3p. Combining the two miRs as a panel with age and gender had a predictive value for the area under the curve (AUC) of 0.932, with a sensitivity of 87.5% and a specificity of 87.2% (p<0.0001) to identify patients with poor prognosis. A miR-based prognostic risk score model was constructed, which included the miR-214-3p, miR-375, age and gender, each weighed by relative contribution. The risk score model was able to identify high-risk individuals who had significantly shorter time to relapse (p<0.001) and time to death (p<0.001). The model consisting of a two-miR panel with age and gender may be useful in prognostication of early stage OSCC patients, which can aid in identifying patients with poor prognosis who will benefit from a subsequent aggressive treatment regimen.
microRNA; deep sequencing; qRT-PCR; prognosis; risk score; oral squamous cell carcinoma
The p42.3 gene was recently identified and characterized as having tumor-specific and mitosis phase-dependent expression in many types of cancer. This suggested that p42.3 antigen could be used as a target for vaccines against cancers. In this study, we immunized C57BL/6 mice with a DNA vaccine encoding p42.3. We used intramuscular injection with electroporation, either before or after challenge with tumor B16F10 cells. Vaccination with pcDNA3-p42.3 induced some degree of antitumor effect both therapeutically and prophylactically, as evaluated by the inhibition of tumor growth and decrease in tumor weight. Immunized mice showed a high level of specific cytotoxic activity against the p42.3 protein in vivo and had activated CD8 T cells that secreted IFN-γ, perforin, and granzyme B in response to stimulation with the antigen in vitro. Thus, this study presents the DNA vaccination against novel tumor target p42.3 as a promising antitumor modality.
cancer immunotherapy; p42.3; DNA vaccine; cytotoxic CD8+T cell; B16F10 melanoma
This paper describes ongoing work in analyzing sensor data logged in the homes of seniors. An estimation of relative energy expenditure is computed using motion density from passive infrared motion sensors mounted in the environment. We introduce a new algorithm for detecting visitors in the home using motion sensor data and a set of fuzzy rules. The visitor algorithm, as well as a previous algorithm for identifying time-away-from-home (TAFH), are used to filter the logged motion sensor data. Thus, the energy expenditure estimate uses data collected only when the resident is home alone. Case studies are included from TigerPlace, an Aging in Place community, to illustrate how the relative energy expenditure estimate can be used to track health conditions over time.
energy expenditure; motion density map; fuzzy logic; eldercare monitoring; visitor recognition
Several occupational stress studies of healthcare workers have predicted a high prevalence of anxiety symptoms, which can affect their quality of life and the care that they provide. However, few studies have been conducted among community healthcare workers in China. We attempted to explore whether burnout mediates the association between occupational stress and anxiety symptoms.
A cross-sectional survey was completed in Liaoning Province, China from November to December 2012. A total of 1,752 healthcare workers from 52 Community Health Centers participated in this study, and all participants were given self-administered questionnaires. These questionnaires addressed the following aspects: the Zung Self-Rating Anxiety Scale, the Chinese version of the effort-reward imbalance scale and the Maslach Burnout Inventory–General Survey. Finally, the study included 1,243 effective respondents (effective response rate, 70.95%). Hierarchical linear regression analysis, performed with SPSS 17.0, was used to estimate the effect of burnout.
The prevalence of anxiety symptoms among the community healthcare workers was 38.0%. After adjusting for demographic characteristics, the effort–reward ratio and overcommitment positively predicted anxiety symptoms. Meanwhile, the effort–reward ratio and overcommitment were positively related to the emotional exhaustion and cynicism subscales of burnout. In addition, the emotional exhaustion and cynicism subscales were positively related to anxiety symptoms. Thus, there is a link between burnout, occupational stress and anxiety symptoms.
Burnout mediates the effect of occupational stress on anxiety symptoms. To effectively reduce the impact of occupational stress on anxiety symptoms, burnout management should be considered.
A large number of long non-coding RNAs (lncRNAs) have been discovered by genome-wide transcriptional analyses. Emerging evidence has indicated that lncRNAs regulate gene expression at epigenetic, transcription, and post-transcription levels, are widely involved in various pathobiology of human diseases, and may play an important role in the biology of cancer stem cells. Alterations of specific lncRNAs have been revealed to interact with the major pathways of cell proliferation, apoptosis, differentiation, invasion and metastasis in many human malignancies, such as gastrointestinal cancer. This review summarizes the current understandings in biological functions and implications of lncRNAs in gastrointestinal cancer.
Long non-coding RNAs (lncRNAs); gastrointestinal cancer; tumor progression
Sweet potato chlorotic stunt virus (family Closteroviridae, genus Crinivirus) features a large bipartite, single-stranded, positive-sense RNA genome. To date, only three complete genomic sequences of SPCSV can be accessed through GenBank. SPCSV was first detected from China in 2011, only partial genomic sequences have been determined in the country. No report on the complete genomic sequence and genome structure of Chinese SPCSV isolates or the genetic relation between isolates from China and other countries is available.
The complete genomic sequences of five isolates from different areas in China were characterized. This study is the first to report the complete genome sequences of SPCSV from whitefly vectors. Genome structure analysis showed that isolates of WA and EA strains from China have the same coding protein as isolates Can181-9 and m2-47, respectively. Twenty cp genes and four RNA1 partial segments were sequenced and analyzed, and the nucleotide identities of complete genomic, cp, and RNA1 partial sequences were determined. Results indicated high conservation among strains and significant differences between WA and EA strains. Genetic analysis demonstrated that, except for isolates from Guangdong Province, SPCSVs from other areas belong to the WA strain. Genome organization analysis showed that the isolates in this study lack the p22 gene.
We presented the complete genome sequences of SPCSV in China. Comparison of nucleotide identities and genome structures between these isolates and previously reported isolates showed slight differences. The nucleotide identities of different SPCSV isolates showed high conservation among strains and significant differences between strains. All nine isolates in this study lacked p22 gene. WA strains were more extensively distributed than EA strains in China. These data provide important insights into the molecular variation and genomic structure of SPCSV in China as well as genetic relationships among isolates from China and other countries.
Background and Purpose
The relationship between right-to-left shunts (RLS) and migraine and cryptogenic stroke is not well understood. In this study, we investigated whether RLS are associated with impairment of dynamic cerebral autoregulation (dCA), which may play a role in migraine and cryptogenic stroke.
Sixty-six migraineurs were enrolled in the study, including 36 non-RLS patients and 30 RLS patients. Non-invasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each patient by using transcranial Doppler and servo-controlled plethysmograph, respectively. Transfer function analysis was applied to derive autoregulatory parameters of gain, phase difference (PD), and autoregulation index.
The PD in migraineurs with RLS was 50.6±22.9 degrees, which was significantly lower than that observed in the non-RLS group (67.2±18.2 degrees, P<0.001). The PD in the large RLS group (45.4±22.6 degrees) was significantly lower than that of the small RLS group (64.9±17.1 degrees, P<0.01) and non-RLS group (P<0.001); however, the PD in the small RLS group was similar to that of the non-RLS group. The PD in the permanent group (48.8±19.9 degrees) was similar to that of the latent group (52.6±26.1 degrees), and both were significantly lower than that of the non-RLS group (P<0.05). The autoregulation index results were similar to the PD findings.
dCA is impaired in migraineurs with large RLS, and this may represent a potential mechanism linking RLS, migraine, and cryptogenic stroke.
The Tongshu Capsule (TSC) is a prevalent form of traditional Chinese medicine widely used for its purported effects in treating mammary gland hyperplasia and inflammation. Though successful in several clinical studies, there is no clear evidence as to why TSC has a positive treatment effect, and little known about underlying mechanism that may account for it. In this study, we examined the effects of TSC and found that it has a comparatively strong growth inhibition on ERα positive breast cancer cells. TSC seems to cause G1 cell cycle arrest instead of apoptosis. Interestingly, TSC also down-regulated the expression of ERα and Cyclin D1. Consistently, TSC suppressed E2 mediated ERα downstream gene expression and cell proliferation in ERα positive breast cancer cell lines MCF7 and T47D. Depletion of ERα partially abolished the effects of TSC on the decrease of Cyclin D1 and cell viability. Our findings suggest that TSC may have therapeutic effects on ERα positive breast cancers and moreover that TSC may suppress breast epithelial cell proliferation by inhibiting the estrogen pathway.
GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2WT and NRASG12D in melanocytes and in melanoma cells increased anchorage independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1α and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non-linear and non-redundant in melanocytes and melanoma, and thus are acting independent of each other. Finally, we establish a link between GAB2 and angiogenesis in melanoma for the first time. In conclusion, our findings provide evidence that GAB2 is a novel regulator of tumor angiogenesis in NRAS-driven melanoma through regulation of HIF-1α and VEGF expressions mediated by RAS-RAF-MEK-ERK signaling.
oncogene; melanoma; angiogenesis; scaffold; adaptor
To demonstrate that subject selection based on sufficient laboratory results and medication orders in electronic health records can be biased towards sick patients.
Using electronic health record data from 10,000 patients who received anesthetic services at a major metropolitan tertiary care academic medical center, an affiliated hospital for women and children, and an affiliated urban primary care hospital, the correlation between patient health status and counts of days with laboratory results or medication orders, as indicated by the American Society of Anesthesiologists Physical Status Classification (ASA Class), was assessed with a Negative Binomial Regression model.
Higher ASA Class was associated with more points of data: compared to ASA Class 1 patients, ASA Class 4 patients had 5.05 times the number of days with laboratory results and 6.85 times the number of days with medication orders, controlling for age, sex, emergency status, admission type, primary diagnosis, and procedure.
Imposing data sufficiency requirements for subject selection allows researchers to minimize missing data when reusing electronic health records for research, but introduces a bias towards the selection of sicker patients. We demonstrated the relationship between patient health and quantity of data, which may result in a systematic bias towards the selection of sicker patients for research studies and limit the external validity of research conducted using electronic health record data. Additionally, we discovered other variables (i.e., admission status, age, emergency classification, procedure, and diagnosis) that independently affect data sufficiency.
Summary: MAGI is a web service for fast MicroRNA-Seq data analysis in a graphics processing unit (GPU) infrastructure. Using just a browser, users have access to results as web reports in just a few hours—>600% end-to-end performance improvement over state of the art. MAGI’s salient features are (i) transfer of large input files in native FASTA with Qualities (FASTQ) format through drag-and-drop operations, (ii) rapid prediction of microRNA target genes leveraging parallel computing with GPU devices, (iii) all-in-one analytics with novel feature extraction, statistical test for differential expression and diagnostic plot generation for quality control and (iv) interactive visualization and exploration of results in web reports that are readily available for publication.
Supplementary data are available at Bioinformatics online.