The dimensional overlap (DO) model proposes distinct mechanisms for stimulus-stimulus (S-S) and stimulus-response (S-R) conflict effects. Many studies have examined the independence of S-S and S-R conflict effects in the color-word Stroop and Simon tasks. However, confounds exist between the distinction of DO (i.e., S-S dimensional overlap compared with S-R dimensional overlap) and the distinction of stimulus attributes (e.g., color compared with spatial location; semantic compared with nonsemantic information), which may hinder interpretation of the independence of S-S and S-R conflicts. A spatial Stroop (word) task and a spatial Stroop (arrow) task were combined with a Simon task in Experiments 1 and 2, respectively to eliminate these confounds of stimulus attributes. The results showed that S-S and S-R conflicts affected performance additively. There was no significant correlation across participants. These findings lend further support to independent processing of S-S and S-R conflicts as it is outlined in the taxonomy of DO.
Quiescent fibroblasts possess unique genetic program and exhibit high metabolic activity distinct from proliferative fibroblasts. In response to inflammatory stimulation, quiescent fibroblasts are more active in expressing cyclooxygenase-2 and other proinflammatory genes than proliferative fibroblasts. The underlying transcriptional mechanism is unclear. Here we show that phorbol 12-myristate 13-acetate (PMA) and cytokines increased p300 histone acetyltransferase activity to a higher magnitude (> 2 fold) in quiescent fibroblasts than in proliferative fibroblasts. Binding of p300 to cyclooxygenase-2 promoter was reduced in proliferative fibroblasts. By ultrahigh-performance liquid chromatography coupled with a quadrupole time of flight mass spectrometer and enzyme-immunoassay, we found that production of 5-methoxytryptophan was 2–3 folds higher in proliferative fibroblasts than that in quiescent fibroblasts. Addition of 5-methoxytryptophan and its metabolic precursor, 5-hydroxytryptophan, to quiescent fibroblasts suppressed PMA-induced p300 histone acetyltransferase activity and cyclooxygenase-2 expression to the level of proliferative fibroblasts. Silencing of tryptophan hydroxylase-1 or hydroxyindole O-methyltransferase in proliferative fibroblasts with siRNA resulted in elevation of PMA-induced p300 histone acetyltransferase activity to the level of that in quiescent fibroblasts, which was rescued by addition of 5-hydroxytryptophan or 5-methoxytryptophan. Our findings indicate that robust inflammatory gene expression in quiescent fibroblasts vs. proliferative fibroblasts is attributed to uncontrolled p300 histone acetyltransferase activation due to deficiency of 5-methoxytryptophan production. 5-methoxytryptophan thus is a potential valuable lead compound for new anti-inflammatory drug development.
Abnormal trophoblast lineage proliferation and differentiation in early pregnancy have been associated with the pathogenesis of placenta diseases of pregnancy. However, there is still a gap in understanding the molecular mechanisms of early placental development due to the limited primary trophoblast cultures and fidelity of immortalized trophoblast lines. Trophoblasts stem (TS) cells, an in vitro model of trophectoderm that can differentiate into syncytiotrophoblasts and extravillous trophoblasts, can be an attractive tool for early pregnancy research. TS cells are well established in mouse but not in humans due to insufficient knowledge of which trophoblast lineage-specific transcription factors are involved in human trophectoderm (TE) proliferation and differentiation. Here, we applied induced pluripotent stem cell technique to investigate the human trophoblast lineage-specific transcription factors. We established human induced trophoblast progenitor (iTP) cells by direct reprogramming the fibroblasts with a pool of mouse trophoblast lineage-specific transcription factors consisting of CDX2, EOMES, and ELF5. The human iTP cells exhibit epithelial morphology and can be maintained in vitro for more than 2 months. Gene expression profile of these cells was tightly clustered with human trophectoderms but not with human neuron progenitor cells, mesenchymal stem cells, or endoderm cells. These cells are capable of differentiating into cells with an invasive capacity, suggesting extravillous trophoblasts. They also form multi-nucleated cells which secrete human chorionic gonadotropin and estradiol, suggesting syncytiotrophoblasts. Our results provide the evidence that transcription factors CDX2 and EOMES may play critical roles in human iTP cell generation.
CDX2; EOMES; transcription factors; human induced trophoblast progenitor cells
Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in intrauterine fetal death.
Structural and gene expression changes in the microvasculature of the human choroid occur during normal aging and age-related macular degeneration (AMD). In this study, we sought to determine the impact of aging and AMD on expression of the endothelial cell glycoprotein CD34. Sections from 58 human donor eyes were categorized as either young (under age 40), age-matched controls (> age 60 without AMD), or AMD affected (>age 60 with early AMD, geographic atrophy, or choroidal neovascularization). Dual labeling of sections with Ulex europaeus agglutinin-I lectin (UEA-I) and CD34 antibodies was performed, and the percentage of capillaries labeled with UEA-I but negative for anti-CD34 was determined. In addition, published databases of mouse and human retinal pigment epithelium-choroid were evaluated and CD34 expression compared between young and old eyes. Immunohistochemical studies revealed that while CD34 and UEA-I were colocalized in young eyes, there was variable loss of CD34 immunoreactivity in older donor eyes. While differences between normal aging and AMD were not significant, the percentage of CD34 negative capillaries in old eyes, compared to young eyes, was highly significant (p = 3.8×10−6). Endothelial cells in neovascular membranes were invariably CD34 positive. Published databases show either a significant decrease in Cd34 (mouse) or a trend toward decreased CD34 (human) in aging. These findings suggest that UEA-I and endogenous alkaline phosphatase activity are more consistent markers of aging endothelial cells in the choroid, and suggest a possible mechanism for the increased inflammatory milieu in the aging choroid.
Snail and Slug play critical roles in the epithelial to mesenchymal transition (EMT), the mesenchymal to epithelial transition (MET) and in the maintenance of mesenchymal morphology. In this research, we investigated the correlation of DNA methylation with the transcriptional level of these two genes during the EMT/MET process. First, we used several cell lines associated with EMT/MET processes of induced pluripotent stem cell generation and differentiation, trophoblast invasion, as well as cancer progression to examine the association between DNA methylation and transcription levels of these two genes. We found an inverse correlation between DNA methylation of first intron regions and transcription levels of Snail and Slug genes in these EMT/METs. To further verify the results, we treated two trophoblast cell line BeWo and HTR8/SVneo and one induced pluripotent stem cell line with 5-aza-2′-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferase, which caused increased expression of these two genes. Lastly, we cloned the promoters of both Snail and Slug into pGL3-Basic vector, after in vitro DNA methylation and transfection into IMR90 and HTR8/SVneo cells; we observed the significant reduction of their promoter activity due to DNA methylation. In summary, based on these results, DNA methylation is one of the molecular mechanisms regulating Snail and Slug genes during EMT/MET process.
Stem cell differentiation; epithelial-to-mesenchymal transition; DNA methylation
Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.
Genomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).
The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.
The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.
Spindle cell neoplasm; Sarcoma; KIAA1549-BRAF; BRAF; Targeted therapy; Sorafenib; mTOR; Bevacizumab; Next generation sequencing; N = 1 trial
InPBi thin films have been grown on InP by gas source molecular beam epitaxy. A maximum Bi composition of 2.4% is determined by Rutherford backscattering spectrometry. X-ray diffraction measurements show good structural quality for Bi composition up to 1.4% and a partially relaxed structure for higher Bi contents. The bandgap was measured by optical absorption, and the bandgap reduction caused by the Bi incorporation was estimated to be about 56 meV/Bi%. Strong and broad photoluminescence signals were observed at room temperature for samples with xBi < 2.4%. The PL peak position varies from 1.4 to 1.9 μm, far below the measured InPBi bandgap.
InPBi; HRXRD; Absorption; Photoluminescence; Molecular beam epitaxy
Background: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients.
Methods: The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP).
Results: Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients ≥60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50.
Conclusions: Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients.
TGR5; DNA methylation; Hepatocellular carcinoma; MSP; serum
Gastric carcinoma is one of the major causes of cancer-related mortality worldwide. Early detection and treatment leads to an excellent prognosis in patients with early gastric cancer (EGC), whereas the prognosis of patients with advanced gastric cancer (AGC) remains poor. It is unclear whether EGCs and AGCs are distinct entities or whether EGCs are the beginning stages of AGCs. We performed whole exome sequencing of four samples from patients with EGC and compared the results with those from AGCs. In both EGCs and AGCs, a total of 268 genes were commonly mutated and independent mutations were additionally found in EGCs (516 genes) and AGCs (3104 genes). A higher frequency of C>G transitions was observed in intestinal-type compared to diffuse-type carcinomas (P = 0.010). The DYRK3, GPR116, MCM10, PCDH17, PCDHB1, RDH5 and UNC5C genes are recurrently mutated in EGCs and may be involved in early carcinogenesis.
Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression.
A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed.
Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (CDKN2A, GADD45y, FGFR2, caspase-8, and PTAG) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (CDKN2A; DAPK; Rb1), sex (MAGE-A3), tumor size (GNAS1), and histopathological subtype (CDKN2A; MEG3; p27; RASSF1A; Rb1).
Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.
AIM: To construct normal values for the tests of the psychometric hepatic encephalopathy score (PHES) and to evaluate its usefulness in the diagnosis of minimal hepatic encephalopathy (MHE) among Chinese individuals with cirrhosis.
METHODS: The five tests of PHES, number connection test-A (NCT-A), number connection test-B, serial dotting test, line tracing test and digit symbol test (DST), were administered to all enrolled subjects in a quiet room with sufficient light. Cirrhotic subjects with overt HE were excluded by the West-Haven criteria and a detailed neurological examination. Based on the nomograms of healthy volunteers, the patients were classified as having MHE when their PHES was less than -4.
RESULTS: In total, 146 healthy volunteers completed all the PHES tests. Age and education years were confirmed to be predictors of all five tests. In total, 53 patients with liver cirrhosis completed the PHES. Of the patients with liver cirrhosis, 24 (45.3%), 22(41.5%) and 7(13.2%) had Child-Pugh grades A, B and C, respectively. MHE was diagnosed in 26 patients (49.1%). Compared with compensated cirrhotic patients (Child A), decompensated cirrhotic patients (Child B and C) had a higher proportion of MHE (65.5% vs 29.2%). No differences in age and education years were found between the MHE and non-MHE groups. NCT-A and DST were able to diagnose MHE with a sensitivity of 76.9% and a specificity of 96.3% (AUC = 0.866, K = 0.735).
CONCLUSION: The proportion of MHE is associated with liver function. NCT-A and DST are simple tools that can be used for the diagnosis of MHE in China.
Cirrhosis; Minimal hepatic encephalopathy; Neuropsychological tests; Psychometric hepatic encephalopathy score; Number connection test; Digit symbol test
Hierarchical Li4Ti5O12/TiO2 tubes composed of ultrathin nanoflakes have been successfully fabricated via the calcination of the hydrothermal product of a porous amorphous TiO2 precursor and lithium hydroxide monohydrate. The hierarchical tubes are characterized by powder X-ray diffraction, nitrogen adsorption/desorption, scanning electron microscopy and transmission electron microscopy techniques. These nanoflakes exhibit a quite complex submicroscopic structure with regular structural imperfection, including a huge number of grain boundaries and dislocations. The lithium ion storage property of these tubes is evaluated by galvanostatic discharge/charge experiment. The product shows initial discharge capacities of 420, 225, and 160 mAh g−1 at 0.01, 0.1, and 1.0 A g−1, respectively. After 100 cycles, the discharge capacity is 139 mAh g−1 at 1.0 A g−1 with a capacity retention of 87%, demonstrating good high-rate performance and good cycleability. The high electrochemical performance is attributed to unique structure and morphology of the tubes. The regular structural imperfection existed in the nanoflakes also benefit to lithium ion storage property of these tubes. The hierarchical Li4Ti5O12/TiO2 tubes are a promising anode material for lithium-ion batteries with high power and energy densities.
Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 5-fluoro-2-(3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain the benzothiazole pharmacophore and possess potent and selective in vitro antitumor properties. Prior studies suggested the involvement of cytochrome P450 (P450) 1A1 and 2W1-mediated bioactivation in the antitumor activities and P450 2S1-mediated deactivation of 5F 203 and GW 610. In the present study, the biotransformation pathways of 5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated and the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation were determined in steady-state kinetic studies. The oxidations of 5F 203 catalyzed by P450s 1A1 and 2W1 yielded different products, and formation of a hydroxylamine was observed for the first time in the latter process. Liquid chromatography-mass spectrometry (LC-MS) analysis with the synthetic hydroxylamine and also a P450 2W1/5F 203 incubation mixture indicated the formation of dGuo adduct via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation of GW 610 was 5-fold more efficient than the P450 1A1-catalyzed reaction. GW 610 underwent a two-step oxidation process catalyzed by P450 1A1 or 2W1: a regiospecific O-demethylation and a further hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610, presumably through a quninoneimine and a 1,2-quinone intermediate, respectively, were detected. These results demonstrate that human P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive intermediates and lead to GSH conjugates and a dGuo adduct, which may account for the antitumor activities of 5F 203 and GW 610 and also be involved in cell toxicity. P450 2S1 can catalyze the reduction of the hydroxylamine to the amine 5F 203 under anaerobic conditions and, to a lesser extent, under aerobic conditions, thus attenuating the anticancer activity.
The body area network (BAN) is an emerging branch of wireless sensor networks for personalized applications. The services in BAN usually have a high requirement on security, especially for the medical diagnosis. One of the fundamental directions to ensure security in BAN is how to provide node authentication. Traditional research using cryptography relies on prior secrets shared among nodes, which leads to high resource cost. In addition, most existing non-cryptographic solutions exploit out-of-band (OOB) channels, but they need the help of additional hardware support or significant modifications to the system software. To avoid the above problems, this paper presents a proximity-based node authentication scheme, which only uses wireless modules equipped on sensors. With only one sensor and one control unit (CU) in BAN, we could detect a unique physical layer characteristic, namely, the difference between the received signal strength (RSS) measured on different devices in BAN. Through the above-mentioned particular difference, we can tell whether the sender is close enough to be legitimate. We validate our scheme through both theoretical analysis and experiments, which are conducted on the real Shimmer nodes. The results demonstrate that our proposed scheme has a good security performance.
authentication; body area network; sensor; RSS ratio
DYT1 dystonia is the most common hereditary form of primary torsion dystonia. This autosomal-dominant disorder is characterized by involuntary muscle contractions that cause sustained twisting and repetitive movements. It is caused by an in-frame deletion in the TOR1A gene, leading to the deletion of a glutamic acid residue in the torsinA protein. Heterozygous knock-in mice, which reproduce the genetic mutation in human patients, have abnormalities in synaptic transmission at the principal GABAergic neurons in the striatum, a brain structure that is involved in the execution and modulation of motor activity. However, whether this mutation affects the excitability of striatal GABAergic neurons has not been investigated in this animal model. Here, we examined the excitability of cultured striatal neurons obtained from heterozygous knock-in mice, using calcium imaging as indirect readout. Immunofluorescence revealed that more than 97% of these neurons are positive for a marker of GABAergic neurons, and that more than 92% are also positive for a marker of medium spiny neurons, indicating that these are mixed cultures of mostly medium spiny neurons and a few (~5%) GABAergic interneurons. When these neurons were depolarized by field stimulation, the calcium concentration in the dendrites increased rapidly and then decayed slowly. The amplitudes of calcium transients were larger in heterozygous neurons than in wild-type neurons, resulting in ~15% increase in cumulative calcium transients during a train of stimuli. However, there was no change in other parameters of calcium dynamics. Given that calcium dynamics reflect neuronal excitability, these results suggest that the mutation only slightly increases the excitability of striatal GABAergic neurons in DYT1 dystonia.
Motivation: In modern sequencing studies, one can improve the confidence of genotype calls by phasing haplotypes using information from an external reference panel of fully typed unrelated individuals. However, the computational demands are so high that they prohibit researchers with limited computational resources from haplotyping large-scale sequence data.
Results: Our graphics processing unit based software delivers haplotyping and imputation accuracies comparable to competing programs at a fraction of the computational cost and peak memory demand.
Mendel-GPU, our OpenCL software, runs on Linux platforms and is portable across AMD and nVidia GPUs. Users can download both code and documentation at http://code.google.com/p/mendel-gpu/.
Supplementary data are available at Bioinformatics online.
Solubility data were measured for omeprazole sulfide in ethanol, 95 mass-% ethanol, ethyl acetate, isopropanol, methanol, acetone, n-butanol and n-propanol in the temperature range from 280.35 to 319.65 K by employing the gravimetric method. The solubilities increase with temperature and they are in good agreement with the calculated solubility of the modified Apelblat equation and the λh equation. The experimental solubility and correlation equation in this work can be used as essential data and model in the purification process of omeprazole sulfide. The thermodynamic properties of the solution process, including the Gibbs energy, enthalpy, and entropy were calculated using the van’t Hoff equation.
Omeprazole sulfide; Solubility; Gravimetric method; Purification; Solution thermodynamics
The MYC proto-oncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. While MYC constitutes a formidable therapeutic target, it also plays an essential role in normal physiology, thus creating the need for context--specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase-activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor (BCR) activation, while its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC addicted tumors in vivo thus providing a novel viable target for treating these malignancies.
STK38; MYC post-translational modifications; protein turnover; transcriptional activity; protein-protein interaction
AIM: To assess diagnostic accuracy of Ras association domain family 1A (RASSF1A) promoter methylation in body fluids (serum, plasma and whole blood) for hepatocellular carcinoma (HCC).
METHODS: Relative information about study characteristics and incidence of RASSF1A methylation was collected. Quality of all included studies was evaluated by Quality Assessment of Diagnostic Accuracy Studies-2. Sensitivity and specificity were pooled using a random-effect model, and a summary receiver operating characteristic curve was used to demonstrate the overall diagnostic performance. Positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with 95%CI were also calculated. Meta-regression was applied to analyze observed heterogeneity, and Deeks’ test was performed to detect publication bias.
RESULTS: After a systematic literature review, seven studies with a total of 302 cases of HCC and 250 cases of chronic liver diseases were included in the analysis. The pooled sensitivity and specificity were 0.70 (95%CI: 0.49-0.85) and 0.72 (95%CI: 0.54-0.85), respectively. The PLR was 2.51 (95%CI: 1.64-3.86), NLR was 0.41 (95%CI: 0.25-0.68), and DOR was 6.13 (95%CI: 3.17-11.84). The χ2 values of sensitivity, specificity, PLR, NLR and DOR were 59.41 (P < 0.001), 50.50 (P < 0.001), 17.40 (P = 0.010), 31.24 (P < 0.001) and 80.51 (P < 0.001), respectively. The area under the curve was 0.77 (95%CI: 0.73-0.81). Three factors were analyzed by univariate meta-regression and none was significant to interpret the observed heterogeneity (P > 0.05). No significant publication bias was detected by Deeks’ test (P = 0.346).
CONCLUSION: We showed the potential diagnostic value of RASSF1A methylation in body fluids in HCC patients and it may improve diagnostic accuracy combined with the α-fetoprotein test.
Methylation; Ras association domain family 1A; Hepatocellular carcinoma; Biomarker; Diagnostic sensitivity; Diagnostic specificity
The zinc finger-homeodomain transcription factor, δ-crystallin enhancer factor 1 (δEF1) has been identified as a regulatory factor involved in the promotion of breast cancer cell proliferation via the downregulation of p21 and the upregulation of cyclin-dependent kinase-2 (CDK2) and CDK4 expression. However, the molecular mechanisms underlying the regulation of CDK4 expression by δEF1 have not yet been elucidated. The present study demonstrated that the ectopic expression of δEF1 in MDA-MB-231 breast cancer cells significantly increased the activity of the CDK4 promoter. Deletion of the E2-box (CACGTG), which is located at position -197/-191 on the human CDK4 promoter, significantly attenuated the activation of CDK4 transcription by δEF1. In addition, a CDK4 promoter-M construct was generated via site-directed mutagenesis of the E2-box on the human CDK4 promoter. Luciferase assay showed that the activation of CDK4 promoter-M activity by δEF1 was markedly decreased compared with the CDK4-promoter-0.4k promoter. Knockdown of δEF1 using RNA interference resulted in the inhibition of CDK4 promoter activity. These observations suggest that δEF1 upregulates CDK4 transcription via the E2-box element on the CDK4 promoter.
δ-crystallin enhancer factor 1; cyclin-dependent kinase 4; promoter; E2-box
The title compound, C4H6ClNO3, crystallizes with two independent molecules (A and B) in the asymmetric unit. In each molecule, there are N—H⋯O and N—H⋯Cl hydrogen bonds. Both molecules are relatively planar, with the mean plane of the acetamide [N—C(=O)C] group being inclined to the mean plane of the acetate group [C—C(=O)O] by 9.23 (13)° in molecule A and 6.23 (12)° in molecule B. In the crystal, adjacent molecules are linked by O—H⋯O hydrogen bonds and weak C—H⋯O contacts forming –A–A–A– and –B–B–B– parallel chains propagating along the a-axis direction.
One of the fundamental goals of genetics is to understand gene functions and their associated phenotypes. To achieve this goal, in this study we developed a computational algorithm that uses orthology and protein-protein interaction information to infer gene-phenotype associations for multiple species. Furthermore, we developed a web server that provides genome-wide phenotype inference for six species: fly, human, mouse, worm, yeast, and zebrafish. We evaluated our inference method by comparing the inferred results with known gene-phenotype associations. The high Area Under the Curve values suggest a significant performance of our method. By applying our method to two human representative diseases, Type 2 Diabetes and Breast Cancer, we demonstrated that our method is able to identify related Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. The web server can be used to infer functions and putative phenotypes of a gene along with the candidate genes of a phenotype, and thus aids in disease candidate gene discovery. Our web server is available at http://jjwanglab.org/PhenoPPIOrth.
Glaucoma is a common cause of visual disability and affects ∼1.6% of individuals over 40 years of age (
1). Non-synonymous coding sequence variations in the ankyrin repeat and SOCS box containing gene 10 (ASB10) were recently associated with 6.0% of cases of primary open angle glaucoma (POAG) in patients from Oregon and Germany. We tested a cohort of POAG patients (n= 158) and normal control subjects (n= 82), both from Iowa, for ASB10 mutations. Our study had 80% power to detect a 4.9% mutation frequency in POAG patients. A total of 11 non-synonymous coding sequence mutations were detected in the cohort, but no association with POAG was detected when analyzed individually or as a group (P > 0.05). Furthermore, a survey of the National Heart, Lung, and Blood Institute's (NHLBI's) Exome Sequencing Project revealed that non-synonymous ASB10 mutations are present in the general population at a far higher frequency than the prevalence of POAG. These data suggest that non-synonymous mutations in ASB10 do not cause Mendelian forms of POAG.
The current study aims to develop a stable pH-sensitive drug delivery system. First, cleavable polyethylene glycol-α-tocopherol hemisuccinate (PEG-THS) was synthesized. Conventional pH-sensitive vesicles composed of the Tris salt of α-tocopherol hemisuccinate (THST) were then prepared using the detergent removal technique. The vesicles had a mean particle size of (163.8 ± 5.5) nm and a zeta potential of −74.5 ± 6.4 mV. The THST vesicles were then modified using PEG-THS or uncleavable PEG-cholesterol (PEG-CHOL) (THST/PEG-lipids, 100:6 molar ratio). The mean vesicle particle size and absolute zeta potential decreased with increasing PEG-THS proportion. When the pH was decreased, the vesicle particle size and calcein release rate increased. The THST vesicles were initially Ca2+-unstable but exhibited significantly improved stability after modification with PEG-THS, especially at PEG-lipid ratios above 6%. Incubation in an acid serum increased the calcein release rate of conventional THST vesicles to 45 ± 1.98% at 10 min. However, the release rate of the PEG-CHOL vesicles remained low. The calcein release rate of PEG-THS vesicles was between those of conventional and PEG-CHOL-V. Therefore, PEG-THS can protect vesicles in serum and reconstitute their pH sensitivity in acidic conditions. Cleavable PEG-THS can be used in stable pH-sensitive preparations without loss of pH sensitivity. Free calcein and conventional vesicles eliminated from the plasma soon after injection, as well as the half-life (t1/2) and area under the curve of PEG-THS-V encapsulating calcein, were dramatically increased. This phenomenon indicates that the use of PEG-lipid derivatives has gained a favorably long circulation effect in mice.
cleavage; long circulation; PEG-α-tocopherol hemisuccinate; pH-sensitive; vesicles