The cause of multiple sclerosis (MS), its driving pathogenesis at the earliest stages, and what factors allow the first clinical attack to manifest remain unknown. Some imaging studies suggest gray rather than white matter may be involved early, and some postulate this may be predictive of developing MS. Other imaging studies are in conflict. To determine if there was objective molecular evidence of gray matter involvement in early MS we used high-resolution mass spectrometry to identify proteins in the cerebrospinal fluid (CSF) of first-attack MS patients (two independent groups) compared to established relapsing remitting (RR) MS and controls. We found that the CSF proteins in first-attack patients were differentially enriched for gray matter components (axon, neuron, synapse). Myelin components did not distinguish these groups. The results support that gray matter dysfunction is involved early in MS, and also may be integral for the initial clinical presentation.
AIM: To examine transforming growth factor-β1 (TGF-β1) promoter methylation in gastric cancer and to determine if Helicobacter pylori (H. pylori) or interleukin (IL)-1β could induce TGF-β1 hypermethylation in vitro.
METHODS: We examined the frequency and extent of TGF-β1 promoter methylation using methylation-specific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects. H. pylori infection was confirmed by a positive result from either a serological test, histological analysis or C13 urea breath test. GES-1 and MKN-45 cells co-cultured with H. pylori or treated with IL-1β for 12, 24 and 48 h in vitro tested the effects of H. pylori or IL-1β on TGF-β1.
RESULTS: Twenty-four/forty-seven (51%) cases of gastric cancer (GC) tissues showed TGF-β1 promoter methylation, 15/47 (31.9%) cases of matched non-cancerous gastric mucosa tissues from the GC patients, and 11/39 (28%) case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation (51% vs 28%, P < 0.05). Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients (0.24 ± 0.06 vs 0.17 ± 0.04, P < 0.05) and normal gastric tissues from non-GC subjects (0.24 ± 0.06 vs 0.15 ± 0.03, P < 0.05). TGF-β1 methylation was found in 48.3% of H. pylori-positive gastric mucosal tissues whereas only 23.1% of H. pylori-negative gastric mucosal tissues showed TGF-β1 methylation (48.3% vs 23.1%, P < 0.05). IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h. Further studies showed that pre-treatment of GES-1 cells with 20 ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation. Infection of GES-1 cells by H. pylori was not found to induce significant TGF-β1 promoter methylation.
CONCLUSION: Our data revealed that TGF-β1 promoter is methylated in GC patients. IL-1β may be an important mediator for H. pylori induced gene methylation during GC development.
Transforming growth factor-β1; Interleukin-1β; Methylation; Helicobacter pylori; Gastric cancer
Aurora kinases are essential for regulation of chromosome segregation and cytokinesis during mitosis and play a role in growth and progression of human tumors, including ovarian cancer. Aurora A and Aurora B are frequently overexpressed in high-grade and low-grade ovarian cancers. Targeting Aurora kinases has great potential for improving the efficacy of chemotherapies of ovarian cancer. In this study, we investigated whether the Aurora kinase inhibitor, VE 465, can enhance the anti-tumor activity of carboplatin in human ovarian cancer cells. The antitumor activity of VE 465 was tested by MTT proliferative assay in multiple established human epithelial ovarian cancer cell lines of varying p53 status. VE 465 and carboplatin had a synergistic effect on cell viability in both platinum-sensitive and -resistant ovarian cancers. The growth-inhibitory effect was accompanied by reduction in expression of histone 3 and an increase in apoptosis. We conclude that VE 465 enhances the efficacy of carboplatin agents in ovarian carcinoma.
ovarian cancer; Aurora kinases; Aurora kinase inhibitors; chemosensitization
The utility of mass spectrometry (MS)-based proteomic analyses and their clinical applications have been increasingly recognized over the past decade due to their high sensitivity, specificity and throughput. MS-based proteomic measurements have been used in a wide range of biological and biomedical investigations, including analysis of cellular responses and disease-specific post-translational modifications. These studies greatly enhance our understanding of the complex and dynamic nature of the proteome in biology and disease. Some MS techniques, such as those for targeted analysis, are being successfully applied for biomarker verification, whereas others, including global quantitative analysis (for example, for biomarker discovery), are more challenging and require further development. However, recent technological improvements in sample processing, instrumental platforms, data acquisition approaches and informatics capabilities continue to advance MS-based applications. Improving the detection of significant changes in proteins through these advances shows great promise for the discovery of improved biomarker candidates that can be verified pre-clinically using targeted measurements, and ultimately used in clinical studies - for example, for early disease diagnosis or as targets for drug development and therapeutic intervention. Here, we review the current state of MS-based proteomics with regard to its advantages and current limitations, and we highlight its translational applications in studies of protein biomarkers.
biomarker; clinical proteomics; ion mobility separations; mass spectrometry; multiple reaction monitoring; selected reaction monitoring; shotgun proteomics; targeted proteomics; translational proteomics
Calcineurin inhibitors (CNIs) may promote post-transplantation cancer through altered expression of cytokines and chemokines in tumor cells. We found that there is a potential cross-talk among CNI-induced signaling molecules and mTOR. Here, we utilized a murine model of post-transplantation cancer to examine the effect of a combination therapy (CNI + mTOR-inhibitor rapamycin) on allograft survival and renal cancer progression. The therapy prolonged allograft survival; and significantly attenuated CNI-induced post-transplantation cancer progression, with down-regulation of mTOR and S6-kinase phosphorylation. Also, rapamycin inhibited CNI-induced over-expression of the angiogenic cytokine VEGF, and the chemokine receptor CXCR3 and its ligands in post-transplantation tumor tissues.
Renal cancer; Angiogenesis; VEGF; Chemokine; Transplantation
Our objective was to test the hypothesis that treatment for trichomoniasis among HIV-infected women not taking antiretrovirals in South Africa would be associated with decreased HIV genital shedding.
HIV-infected women presenting for routine HIV care were screened for trichomoniasis using self-collected vaginal swabs with a rapid point-of-care immunochromatographic antigen test. Women testing positive were offered enrollment into a prospective cohort study if they had documented HIV infection, were ages 18–50, and not receiving antiretroviral therapy. Recent use of post-exposure prophylaxis or antibiotic therapy, active genital ulcers, or systemic illness were exclusion criteria. Cervical swabs were collected for gonococcal and chlamydial testing and those testing positive were excluded. Women were treated with directly-observed oral therapy with 2 grams of oral metronidazole. A follow-up visit was scheduled one month after therapy and partner letters were provided. Paired cervical wicks and plasma were collected for viral load measurement.
557 women were screened. 60 tested positive for trichomoniasis, 10 subsequently met exclusion criteria, 4 were lost to follow-up. Of 46 women evaluated at follow-up, 37 were cured, 80.4%. Plasma viral load was not significantly different after therapy, p=0.93. Genital tract viral load decreased by 0.5 log10, p<0.01. The mean genital tract viral load (log10) decreased from 4.66 (<3.52 – 6.46) to 4.18 (<3.52 – 6.48), p<0.01 following therapy.
Screening and treatment of vaginal trichomoniasis decreases genital shedding of HIV among South African women not receiving antiretrovirals at one month following therapy.
HIV; trichomoniasis; women; genital shedding; metronidazole
The objective was to assess the relationship between alcohol use and misuse and patient sex among emergency department (ED) patients by comparing self-reported estimates of quantity and frequency of alcohol use; estimated blood alcohol concentrations (eBACs) when typically drinking, and during heavy episodic drinking (binging); and alcohol misuse severity, to understand sex differences in alcohol use and misuse for this population.
The authors surveyed a random sample of non-intoxicated, sub-critically ill or injured, 18 to 64 year-old English- or Spanish-speaking patients on randomly selected dates and times at two EDs during July 2009 and August 2009. Participants self-administered a questionnaire about their self-reported alcohol use during a typical month within the past 12 months, and the Alcohol Use Disorders Identification Test (AUDIT). Using the formulae by Matthews and Miller, sex-specific eBACs were calculated for participants according to their reported weight and the number of reported alcoholic drinks consumed on days when typically drinking, and on days of heavy episodic (binge) drinking (≥ 5 drinks/occasion for men, ≥ 4 drinks for women). Sex-specific alcohol misuse severity levels (low-risk, harmful, hazardous, and dependence) were calculated using AUDIT scores. Wilcoxon rank-sum and Pearson’s chi-square tests were used to compare outcomes by sex. Negative binomial regression was used to assess the relationship between sex and the number of drinks consumed on a typical day, the number of days spent drinking and binging, and estimated AUDIT scores. Logistic regression was used to assess the outcome of the presence of binging according to sex. Multinomial logistic regression was used to compare by sex the percentage of days spent drinking and binging in one month, eBACs when typically drinking and when binging, and AUDIT at-risk drinking levels. Incidence rate ratios (IRRs) and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were estimated. All models were adjusted for patient demographic characteristics.
Of the 513 participants, 52.1% were women, 55.8% were white non-Hispanic, and their median age was 34 years (IQR 25 to 46 years). Men reported greater mean alcohol consumption than women when typically drinking (4.3 vs. 3.3 drinks per day; p < 0.001), and during heavy episodic drinking (8.6 vs. 5.3/drinks per occasion; p < 0.001). Men spent more days drinking (IRR 1.41, 95% CI = 1.19 to 1.65) and engaging in heavy episodic drinking (IRR 1.68, 95% CI = 1.31 to 2.17) than women. Additionally, men were more likely to engage in heavy episodic drinking (AOR 1.72, 95% CI = 1.16 to 2.56) than women. However, the mean eBACs for men and women were similar when typically drinking (0.05 vs. 0.06; p < 0.13) and during heavy episodic drinking (0.13 vs. 0.12; p < 0.13). Mean AUDIT scores were greater for men than women (7.5 vs. 5.3; p < 0.001), although alcohol misuse severity levels were similar between men and women (24.4% vs. 26.6% for hazardous, 2.8% vs. 2.2% for harmful, and 6.5% vs. 3.4% for dependence; p < 0.38).
Although men drink more than women, women have similar eBACs with comparable levels of alcohol misuse. Women may benefit from recognizing that they are reaching similar levels of intoxication compared to men. Addressing these differences and possible health implications in future ED brief interventions may induce changes in problematic alcohol use among women.
To better understand how warming, increased precipitation and their interactions influence community structure and composition, a field experiment simulating hydrothermal interactions was conducted at an annual forb dominated desert steppe in northern China over 2 years. Increased precipitation increased species richness while warming significantly decreased species richness, and their effects were additive rather than interactive. Although interannual variations in weather conditions may have a major affect on plant community composition on short term experiments, warming and precipitation treatments affected individual species and functional group composition. Warming caused C4 grasses such as Cleistogenes squarrosa to increase while increased precipitation caused the proportions of non-perennial C3 plants like Artemisia capillaris to decrease and perennial C4 plants to increase.
The current study aimed to examine the effects of daily change of the Shenzhen Stock Exchange Index on cardiovascular mortality in Guangzhou and Taishan, China.
Daily mortality and stock performance data during 2006–2010 were collected to construct the time series for the two cities. A distributed lag non-linear model was utilized to examine the effect of daily stock index changes on cardiovascular mortality after controlling for potential confounding factors.
We observed a delayed non-linear effect of the stock index change on cardiovascular mortality: both rising and declining of the stock index were associated with increased cardiovascular deaths. In Guangzhou, the 15–25 lag days cumulative relative risk of an 800 index drop was 2.08 (95% CI: 1.38–3.14), and 2.38 (95% CI: 1.31–4.31) for an 800 stock index increase on the cardiovascular mortality, respectively. In Taishan, the cumulative relative risk over 15–25 days lag was 1.65 (95% CI: 1.13–2.42) for an 800 index drop and 2.08 (95% CI: 1.26–3.42) for an 800 index rising, respectively.
Large ups and downs in daily stock index might be important predictor of cardiovascular mortality.
Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18X per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from EPAS1, a transcription factor involved in response to hypoxia. One SNP at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.
The profiling of small RNAs by high throughput sequencing (smRNA-Seq) has revealed the complexity of the RNA world. Here, we describe a computational scheme for dissecting the plant smRNAome by integrating smRNA-Seq datasets in Arabidopsis thaliana. Our analytical approach first defines ab initio the genomic loci that produce smRNAs as basic units, then utilizes principal component analysis (PCA) to predict novel miRNAs. Secondary structure prediction of candidates’ putative precursors discovered a group of long hairpin double-stranded RNAs (lh-dsRNAs) formed by inverted duplications of decayed coding genes. These gene remnants produce miRNA-like small RNAs which are predominantly 21- and 22-nt long, dependent of DCL1 but independent of RDR2 and DCL2/3/4, and associated with AGO1. Additionally, we found two classes of transcription start site associated- (TSSa-) RNAs located at sense (+) and antisense (−) approximately 100 ~ 200 bp downstream of TSSs, but are differentially incorporated into AGO1 and AGO4, respectively.
High-throughput sequencing; small RNAs; Principal component analysis; TSS-associated RNAs
The objectives of this study were to 1) determine the correlation between osteoarthritis (OA) and Ihh expression, and 2) establish the effects of Ihh on expression of markers of chondrocyte hypertrophy and MMP-13 in human OA cartilage.
OA cartilage and synovial fluid samples were obtained during total knee arthroplasty. Normal cartilage samples were obtained from intra-articular tumor resections, and normal synovial fluid samples were obtained from healthy volunteers and the contralateral uninjured knee of patients undergoing anterior cruciate ligament reconstruction. OA was graded using the Mankin score. Expression of Ihh in synovial fluid was determined by western blot. Ihh, type X collagen and MMP-13 mRNA were determined by real time PCR. Protein expression of type X collagen and MMP-13 in cartilage samples were analyzed with immunohistochemistry. Chondrocyte size was measured using image analysis.
Ihh expression was increased 2.6 fold in OA cartilage and 37% in OA synovial fluid when compared to normal control samples. Increased expression of Ihh was associated with the severity of OA and expression of markers of chondrocyte hypertrophy: type X collagen and MMP-13, and chondocyte size. Chondrocytes were more spherical with increasing severity of OA. There was a significant correlation between Mankin score and cell size (r2= 0.80) and Ihh intensity (r2 = 0.89). Exogenous Ihh induced a 6.8 fold increase of type X collagen and 2.8 fold increase of MMP-13 mRNA expression in cultured chondrocytes. Conversely, knockdown of Ihh by siRNA and Hh inhibitor Cyclopamine had the opposite effect.
Ihh expression correlates with OA progression and changes in chondrocyte morphology and gene expression consistent with chondrocyte hypertrophy and cartilage degradation seen in OA cartilage. Thus, Ihh may be a potential therapeutic target to prevent OA progression.
Ihh; cartilage; osteoarthritis; chondrocyte hypertrophy; MMP-13
We investigated serum total immunoglobulin E (IgE), IgG, and IgG1 levels in patients with and without echinococcosis-induced anaphylactic shock. This was a case-control study of 11 patients with echinococcosis-induced anaphylactic shock and 22 echinococcosis patients with cyst rupture but without anaphylactic shock. Blood was collected before surgery (T0), at the time of cyst rupture (T1), and shock (Tx), 1 h (T2), 1 day (T3), and 1 week (T4) after cyst rupture. Serum IgE, IgG, and IgG1 were determined by enzyme-linked immunosorbent assay. Serum IgE, IgG, and IgG1 levels were significantly higher in patients who developed anaphylactic shock at all time points. Increased pre-surgical IgG and IgG1 levels were identified to be a significant risk factors for developing anaphylactic shock. The results showed that a serum IgG concentration of 312.25 μg/mL could be used as a cut-off point to predict whether an echinococcosis patient would develop anaphylactic shock.
There is increasing evidence that mesenchymal stem cells (MSCs) derived from different tissues could act as an alternative source of mature hepatocytes for treatment of acute liver failure (ALF). Human umbilical cord matrix stem cells (hUCMSCs) represent a novel source of MSCs. We examined the therapeutic potential and the different mechanisms of hUCMSCs by their transplantation into nonobese diabetic severe combined-immunodeficient (NOD-SCID) mice with carbon tetrachloride (CCl4)-induced ALF in comparison to adult human hepatocytes (AHHs). The characteristics of isolated hUCMSCs were determined from MSCs and hepatocyte marker expression, hepatic function, and differentiation. Native hUCMSCs constitutively expressed some hepatic markers, though weaker hepatocyte-specific functions were observed when compared to AHHs. When native hUCMSCs or AHHs were transplanted into livers of NOD-SCID mice with ALF induced by CCl4, both hUCMSCs and AHHs provided a significant survival benefit and prevented the release of liver injury biomarkers. hUCMSCs were found to engraft within the recipient liver and differentiated into functional hepatocytes, whereas the HepPar1-/albumin (ALB)-positive cells of the hUCMSC group were less than the AHH group in the recipient liver. Higher values of human ALB in the serum of mice-transplanted AHHs were determined in comparison with levels in mice-transplanted hUCMSCs. The analysis of mouse serum cytokine levels showed that hUCMSC transplantation was even more effective than treatment with AHHs and successfully downregulated the systemic inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-10, and IL-1 receptor antagonist (IL-1RA). Furthermore, paracrine effects produced by hUCMSCs were identified by indirect coculture with damaged mouse hepatocytes (MHs) induced by CCl4. Coculture with hUCMSCs significantly increased the viability, ALB secretion of damaged MHs, and greatly enhanced the regeneration of MHs in vitro when compared with AHHs. These data suggest that direct transplantation of native hUCMSCs can rescue ALF and repopulate livers of mice through paracrine effects to stimulate endogenous liver regeneration rather than hepatic differentiation for compensated liver function, which is the primary effect of AHHs. Thus, hUCMSCs can be a potential alternative source of AHHs for cell therapy of ALF and eliminate the shortage of hepatocytes.
Previous genome-wide association studies (GWAS) in multiple populations identified several genetic loci for coronary heart diseases (CHD). Here we utilized a 2-stage candidate gene association strategy in Chinese Han population to shed light on the putative association between several metabolic-related candidate genes and CHD. At the 1st stage, 190 patients with CHD and 190 controls were genotyped through the MassARRAY platform. At the 2nd stage, a larger sample including 400 patients and 392 controls was genotyped by the High Resolution Melt (HRM) method to confirm or rule out the associations with CHD. MLXIP expression level was quantified by the real time PCR in 65 peripheral blood samples. From the 21 studied single nucleotide polymorphisms (SNPs) of seven candidate genes: MLXIPL, MLXIP, MLX, ADIPOR1, VDR, SREBF1 and NR1H3, only one tag SNP rs4758685 (T→C) was found to be statistically associated with CHD (P-value = 0.02, Odds ratio (OR) of 0.83). After adjustment for the age, sex, lipid levels and diabetes, the association remained significant (P-value = 0.03). After adjustment for the hypertension, P-value became 0.20 although there was a significant difference in the allele distribution between the CHD patients with hypertension and the controls (P-value = 0.04, 406 vs 582). In conclusion, among the 21 tested SNPs, we identified a novel association between rs4758685 of MLXIP gene and CHD. The C allele of common variant rs4758685 interacted with hypertension, and was found to be protective against CHD in both allelic and genotypic models in Chinese Han population.
Many studies have shown that high temperatures or heat waves were associated with mortality and morbidity. However, few studies have examined whether temperature changes between neighboring days have any significant impact on human health.
A distributed lag non-linear model was employed to investigate the effect of temperature changes on mortality in summer during 2006–2010 in two subtropical Chinese cities. The temperature change was defined as the difference of the current day’s and the previous day’s mean temperature.
We found non-linear effects of temperature changes between neighboring days in summer on mortality in both cities. Temperature increase was associated with increased mortality from non-accidental diseases and cardiovascular diseases, while temperature decrease had a protective effect on non-accidental mortality and cardiovascular mortality in both cities. Significant association between temperature changes and respiratory mortality was only found in Guangzhou.
This study suggests that temperature changes between neighboring days might be an alternative temperature indicator for studying temperature-mortality relationship.
Sensitive and specific detection of liver cirrhosis is an urgent need for optimal individualized management of disease activity. Substantial studies have identified circulation miRNAs as biomarkers for diverse diseases including chronic liver diseases. In this study, we investigated the plasma miRNA signature to serve as a potential diagnostic biomarker for silent liver cirrhosis.
A genome-wide miRNA microarray was first performed in 80 plasma specimens. Six candidate miRNAs were selected and then trained in CHB-related cirrhosis and controls by qPCR. A classifier, miR-106b and miR-181b, was validated finally in two independent cohorts including CHB-related silent cirrhosis and controls, as well as non−CHB-related cirrhosis and controls as validation sets, respectively.
A profile of 2 miRNAs (miR-106b and miR-181b) was identified as liver cirrhosis biomarkers irrespective of etiology. The classifier constructed by the two miRNAs provided a high diagnostic accuracy for cirrhosis (AUC = 0.882 for CHB-related cirrhosis in the training set, 0.774 for CHB-related silent cirrhosis in one validation set, and 0.915 for non−CHB-related cirrhosis in another validation set).
Our study demonstrated that the combined detection of miR-106b and miR-181b has a considerable clinical value to diagnose patients with liver cirrhosis, especially those at early stage.
This study aimed to determine the effects and mechanisms of gardenia oil on bone density and bone biomechanics in ovariectomized female rats. An ovariectomized rat model was established and the rats were administered various doses of gardenia oil. Rats administered diethylstilbestrol or saline served as the positive and the untreated controls, respectively. All rats received the same surgery, with the exception of the ovariectomy in the sham group. The levels of serum 17β-estradiol, follicle-stimulating hormone, luteinizing hormone, alkaline phosphatase (ALP) and calcium, and the bone material density (BMD), maximum stress and maximum strain were determined. The expression of COX-2 was also determined by immunoblotting and quantitative PCR (qPCR). Gardenia oil increased the serum levels of 17β-estradiol, the BMD, and the maximum stress and maximum strain of bones. The levels of COX-2 protein and COX-2 mRNA were significantly increased in the gardenia oil-treated rats. In conclusion, gardenia oil increases estradiol levels and BMD in an ovariectomized rat model. The effects of gardenia oil are associated with upregulation of the expression of COX-2.
gardenia oil; hormone; bone material density; bone biomechanics
There are controversies on the association between interleukin-13 (IL-13) +1923C/T polymorphism (rs1295686) and the risk of asthma. We performed this study to assess the association by the method of meta-analysis. A systematic search current to October 16, 2012, was conducted using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) and identified ten studies comprising 13698 cases and 38209 controls. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. There was a significant association between IL-13 +1923C/T polymorphism and asthma risk in codominant model. When stratified by ethnicity, IL-13 +1923C/T polymorphism remained significantly associated with higher asthma risk in Asians and Caucasians. In the subgroup analysis by study quality, a significantly increased asthma risk was observed in high quality studies. Sensitivity analysis and cumulative analysis further strengthened the validity of the results. No publication bias was found in this meta-analysis. In conclusion, results from this meta-analysis suggested that IL-13 +1923C/T polymorphism was a risk factor of asthma.
Dynamic thermal management techniques employ a set of on-chip thermal sensors to measure runtime thermal behavior of microprocessors so as to prevent the on-set of high temperatures. Therefore, effective analysis of thermal behavior and determination of the best allocation and placement of thermal sensors directly impact the effectiveness of the dynamic thermal management mechanisms. In this paper, we propose systematic and effective techniques for determining the fewest number of thermal sensors and the optimal locations based on dual clustering to provide a high fidelity thermal monitoring. Initially, we utilize the dual clustering algorithm to devise method that can reduce the number of sensors to a great extent while satisfying an expected accuracy. Then we identify an optimal physical location for each sensor such that the sensor’s attraction towards steep thermal gradient is maximized. Experimental results indicate the superiority of our techniques and confirm that our proposed methods are capable of creating a sensor distribution for a given microprocessor architecture using the number of thermal sensors of 2, 8, 15, 24, 35, depending on different expected hot spot temperature error accuracy of 5%, 4%, 3%, 2%, 1%, respectively.
Dynamic thermal management; Thermal sensors; Allocation; Placement; Dual clustering; Thermal gradient
Emergency department (ED) patients comprise a high-risk population for alcohol misuse and sexual risk for HIV. In order to design future interventions to increase HIV screening uptake, we examined the interrelationship among alcohol misuse, sexual risk for HIV and HIV screening uptake among these patients.
A random sample of 18-64-year-old English- or Spanish-speaking patients at two EDs during July-August 2009 completed a self-administered questionnaire about their alcohol use using the Alcohol Use Questionnaire, the Alcohol Use Disorders Identification Test (AUDIT), and the HIV Sexual Risk Questionnaire. Study participants were offered a rapid HIV test after completing the questionnaires. Binging (≥ five drinks/occasion for men, ≥ four drinks for women) was assessed and sex-specific alcohol misuse severity levels (low-risk, harmful, hazardous, dependence) were calculated using AUDIT scores. Analyses were limited to participants who had sexual intercourse in the past 12 months. Multivariable logistic regression was used to assess the associations between HIV screening uptake and (1) alcohol misuse, (2) sexual risk for HIV, and (3) the intersection of HIV sexual risk and alcohol misuse. Adjusted odds ratios (AORs) with 95% confidence intervals (CIs) were estimated. All models were adjusted for patient demographic characteristics and separate models for men and women were constructed.
Of 524 participants (55.0% female), 58.4% identified as white, non-Hispanic, and 72% reported previous HIV testing. Approximately 75% of participants reported drinking alcohol within the past 30 days and 74.5% of men and 59.6% of women reported binge drinking. A relationship was found between reported sexual risk for HIV and alcohol use among men (AOR 3.31 [CI 1.51-7.24]) and women (AOR 2.78 [CI 1.48-5.23]). Women who reported binge drinking were more likely to have higher reported sexual risk for HIV (AOR 2.55 [CI 1.40-4.64]) compared to women who do not report binge drinking. HIV screening uptake was not higher among those with greater alcohol misuse and sexual risk among men or women.
The apparent disconnection between HIV screening uptake and alcohol misuse and sexual risk for HIV among ED patients in this study is concerning. Brief interventions emphasizing these associations should be evaluated to reduce alcohol misuse and sexual risk and increase the uptake of ED HIV screening.
Emergency services; Hospital; Ethanol/blood; Questionnaires; Sexual behavior risk; HIV; Intervention
Regulatory T cell (Treg)-mediated immunosuppression represents one of the crucial tumor immune evasion mechanisms and is a main obstacle for successful tumor immunotherapy. Hypoxia, a common feature of solid tumors, has been associated with potentiated immunosuppression, decreased therapeutic response, malignant progression and local invasion. Unfortunately, the link between hypoxia and Treg-mediated immune tolerance in gastric cancer remains poorly understood. In our study, Tregs and hypoxia inducible factor-1α were found to be positively correlated with each other and were increased with the tumor progression. A subsequent in vitro study indicated that supernatants derived from gastric cancer cells under hypoxic condition, could induce the expression of Foxp3 via TGF-β1. These findings confirmed the crucial role of Tregs as a therapeutic target in gastric cancer therapy and provided helpful thoughts for the design of immunotherapy for gastric cancer in the future.
Summary: Transcription and chromatin regulators, and histone modifications play essential roles in gene expression regulation. We have created CistromeMap as a web server to provide a comprehensive knowledgebase of all of the publicly available ChIP-Seq and DNase-Seq data in mouse and human. We have also manually curated metadata to ensure annotation consistency, and developed a user-friendly display matrix for quick navigation and retrieval of data for specific factors, cells and papers. Finally, we provide users with summary statistics of ChIP-Seq and DNase-Seq studies.
Availability: Freely available on the web at http://cistrome.dfci.harvard.edu/pc/
Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a stress-induced p53-target gene whose expression is modulated by transcription factors such as p53, p73, and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. In association with homeodomain-interacting protein kinase-2 (HIPK2), TP53INP1 phosphorylates p53 protein at Serine-46. This enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53-target genes such as p21 and PIG3, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1 has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumorigenesis, whereas TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53-independent pathways, as well as the elements which repress TP53INP1 expression, hence highlighting its potential as a therapeutic target in cancer treatment.
TP53INP1; p53; protein phosphorylation; apoptosis; autophagy
Semaphorin 5A, a member of the semaphorin family, was originally identified as an axonal guidance factor functioning during neuronal development. Previously, we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer. However, less information is currently available as to the involvement of uPA in the semaphorin 5A-induced metastasis and invasion of gastric cancer cells.
The present study was designed to test whether semaphorin 5A mediates the invasion and metastasis of gastric cancer via PI3K/Akt/uPA signaling.
The semaphorin 5A-overexpressing cell was established from the gastric cancer cell line AGS. The effect of semaphorin 5A on the expression of uPA was evaluated by ELISA and Western blotting as well as RT-PCR assays, respectively. Synthetic or natural inhibitors and dominant-negative mutants were used to determine the hierarchical relationship between semaphorin 5A, PI3K/Akt and uPA in the invasion and metastasis of gastric cancer.
Overpression of semaphorin 5A enhanced the expression of uPA, and synthetic or natural inhibitors of uPA abolished semaphorin 5A-induced cell migration and invasion. Semaphorin 5A overexpression promoted the phosphorylation of Akt. Blocking effects of PI3K/Akt using pharmacologic inhibitors, dominant-negative mutants abolished the ability of semaphorin 5A to induce uPA expression and cell invasion and migration.
Semaphorin 5A could promote invasion and metastasis of gastric cancer through the PI3K/Akt/uPA signal transduction pathway. Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy.
Semaphorin 5A; Gastric cancer; Urokinase-type plasminogen activator (uPA); Phosphoinositide 3-kinase (PI3K); Protein kinase B (Akt)