To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts.
In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m2) and cytarabine (1 or 2 g/m2 twice a day if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design.
Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment.
Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings.
The aim of the study was to investigate the effect of icariin (ICA) on cardiac aging through its effects on the SIRT6 enzyme and on the NF-κB pathway. Investigating the effect of ICA on the enzymatic activity of histone deacetylase SIRT6 revealed a concentration of 10−8 mol/L ICA had a maximum activating effect on histone deacetylase SIRT6 enzymatic activity. Western analysis showed that ICA upregulated SIRT6 protein expression and downregulated NF-κB (p65) protein expression in animal tissues and cell models. ICA upregulated the expression of SIRT6 and had an inhibitory effect on NF-κB inflammatory signaling pathways as shown by decreasing mRNA levels of the NF-κB downstream target genes TNF-α, ICAM-1, IL-2, and IL-6. Those effects were mediated directly or indirectly by SIRT6. We provided evidence that inflammaging may involve a novel link between the effects of ICA on SIRT6 (a regulator of aging) and NF-κB (a regulator of inflammation).
Non-surgical bleeding (NSB) is a major complication among heart failure (HF) patients supported by CF-LVADs. Understanding the hemostatic defects contributing to NSB after CF-LVAD implantation is crucial for prevention of this adverse event. The aim of this study was to examine the link between platelet GPIbα ectodomain shedding and NSB in CF-LVAD recipients and to identify a potential biomarker of NSB.
Serial blood samples were collected from thirty five HF patients supported with CF-LVADs. Platelet function was evaluated by Platelet Function Analyzer 100® and thromboelastography (TEG). Platelet GPIbα shedding, von Villebrand factor (vWF) antigen and vWF collagen binding capacity were determined using enzyme-linked immunosorbent assays (ELISAs). The structural analysis of vWF was performed by gel electrophoresis. These platelet functional measures with vWF parameters of the patients who experienced NSB between 4 to 32 days after CF-LVAD implantation (bleeder) were analyzed against those without NSB (non-bleeder). Blood samples from seven healthy individuals were collected to obtain the healthy reference values for the laboratory assays.
Elevated GPIbα shedding was found to be a preexisting condition in all HF patients prior to CF-LVAD implantation. Post-operative level of GPIbα shedding increased and remained elevated in the bleeder group while a consistent decrease was found in the non-bleeder group. A receiver operating characteristic (ROC) analysis indicated that the level of GPIbα shedding has a predictive power of NSB in patients supported with CF-LVADs.
Platelet GPIbα ectodomain shedding which attenuates platelet reactivity is associated with NSB. Plasma GPIbα level may potentially be used to refine bleeding risk stratification in CF-LVAD patients.
heart failure; left ventricular assist device; non-surgical bleeding; platelet GPIbα shedding
Diabetes self-management often involves the interpretation and application of oral, written, or quantitative information. Numerous diabetes patients in China have limited health literacy, which likely leads to poorer clinical outcomes. This study is designed to examine the efficacy and cost-effectiveness of addressing health literacy to improve self-management skills and glycemic control in Chinese diabetes patients.
This is a cluster randomized controlled trial (RCT) conducted in 20 community healthcare sites in Shanghai, China. Overall, 800 diabetes patients will be randomized into intervention and control arms and will have a baseline hemoglobin A1c (HbA1c) assay and undergo a baseline survey which includes measures of health literacy and diabetes numeracy using revised Chinese versions of the Health Literacy Management Scale and Diabetes Numeracy Test Scale. During the 1-year period of intervention, while the control group will receive usual care, the intervention group will be supplemented with a comprehensive health literacy strategy which includes i) training healthcare providers in effective health communication skills that address issues related to low literacy, and ii) use of an interactive Diabetes Education Toolkit to improve patient understanding and behaviors. Assessments will be conducted at both patient and healthcare provider levels, and will take place upon admission and after 3, 6, 12, and 24 months of intervention. The primary outcome will be the improvement in HbA1c between Intervention group and Control group patients. Secondary outcomes at the patient level will include improvement in i) clinical outcomes (blood pressure, fasting lipids, body mass index, weight, smoking status), ii) patient reported self-management behaviors, and iii) patient-reported self-efficacy. Outcomes at the provider level will include: i) provider satisfaction and ii) intensity and type of care provided. The effects of the intervention will be examined in multivariable general linear models. Both cost-effectiveness and cost-utility analyses will be performed.
The main strengths of this study are its large sample size and RCT design, involvement of both patients and healthcare providers, and the long term follow-up (24-months). This project will help to demonstrate the value of addressing health literacy and health communication to improve self-management and clinical outcomes among Chinese diabetes patients.
ISRCTN76130594, Registration date: Sept 22, 2014.
Cost-effectiveness; Cost-utility; Diabetes self-management; Hemoglobin A1c; Literacy; Numeracy; Self-efficacy; Self-management behaviors
A concise thiolation of C(sp3)–H bond of cycloalkanes
with diaryl disulfides in the presence of oxidant of
di-tert-butylperoxide (DTBP) has been developed. This reaction
without using any of metal catalyst, tolerates varieties of disulfides and
cycloalkanes substrates, giving good to excellent chemical yields, which
provides a useful approach to cycloalkyl aryl sulfides from unactivated
metal-free; thiolation; oxidative; C(sp3)–H activation; cycloalkane
Gene expression microarray has been the primary biomarker platform ubiquitously applied in biomedical research, resulting in enormous data, predictive models, and biomarkers accrued. Recently, RNA-seq has looked likely to replace microarrays, but there will be a period where both technologies co-exist. This raises two important questions: Can microarray-based models and biomarkers be directly applied to RNA-seq data? Can future RNA-seq-based predictive models and biomarkers be applied to microarray data to leverage past investment?
We systematically evaluated the transferability of predictive models and signature genes between microarray and RNA-seq using two large clinical data sets. The complexity of cross-platform sequence correspondence was considered in the analysis and examined using three human and two rat data sets, and three levels of mapping complexity were revealed. Three algorithms representing different modeling complexity were applied to the three levels of mappings for each of the eight binary endpoints and Cox regression was used to model survival times with expression data. In total, 240,096 predictive models were examined.
Signature genes of predictive models are reciprocally transferable between microarray and RNA-seq data for model development, and microarray-based models can accurately predict RNA-seq-profiled samples; while RNA-seq-based models are less accurate in predicting microarray-profiled samples and are affected both by the choice of modeling algorithm and the gene mapping complexity. The results suggest continued usefulness of legacy microarray data and established microarray biomarkers and predictive models in the forthcoming RNA-seq era.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0523-y) contains supplementary material, which is available to authorized users.
To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis.
Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n=558), patients with SLE from the Hopkins Lupus Cohort (n=215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n=5,098) were evaluated. IgA anti-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity.
A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI and arterial thrombosis (p=0.0003) and all thrombosis (p=0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls.
Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids.
RNA-seq facilitates unbiased genome-wide gene-expression profiling. However, its concordance with the well-established microarray platform must be rigorously assessed for confident uses in clinical and regulatory application. Here we use a comprehensive study design to generate Illumina RNA-seq and Affymetrix microarray data from the same set of liver samples of rats under varying degrees of perturbation by 27 chemicals representing multiple modes of action (MOA). The cross-platform concordance in terms of differentially expressed genes (DEGs) or enriched pathways is highly correlated with treatment effect size, gene-expression abundance and the biological complexity of the MOA. RNA-seq outperforms microarray (90% versus 76%) in DEG verification by quantitative PCR and the main gain is its improved accuracy for low expressed genes. Nonetheless, predictive classifiers derived from both platforms performed similarly. Therefore, the endpoint studied and its biological complexity, transcript abundance, and intended application are important factors in transcriptomic research and for decision-making.
Objective. Vitamin D deficiency is common in SLE. Cardioprotective effects of vitamin D have been postulated due to modulation of inflammatory cytokines. However, the effects of vitamin D supplementation on inflammatory cytokines in trials have been inconsistent. We determined whether levels of vitamin D at baseline were associated with subclinical measures of atherosclerosis, or with changes in subclinical measures over 2 years.
Methods. Of the 200 patients enrolled in the Lupus Atherosclerosis Prevention Study, complete baseline and follow-up data [including coronary artery calcium (CAC), carotid intima–media thickness (IMT), 25-hydroxy vitamin D [25(OH)D] and high-sensitivity CRP (hsCRP) levels] were available for 154 patients. Assessments were repeated 2 years later.
Results. 25(OH)D values ranged from 4 to 79 ng/ml. Among African American patients, 25(OH)D values ranged from 4 to 55 ng/ml. With low 25(OH)D (vitamin D <21 ng/ml), a higher proportion had a CAC score >100 (11%) compared with those with vitamin D insufficiency (21–32 ng/ml) (10%) and normal (≥32 ng/ml) 25(OH)D (3%), which was not statistically significant. 25(OH)D was neither associated with nor did it predict progression of CAC or carotid IMT over 2 years. The mean hsCRP decreased over 2 years.
Conclusion. 25(OH)D was not associated with any measure of subclinical atherosclerosis. 25(OH)D deficiency was associated with higher hsCRP at baseline, but did not predict a change in hsCRP over 2 years.
systemic lupus erythematosus; atherosclerosis; vitamin D
Accelerated atherosclerosis remains a major cause of death in late systemic lupus erythematosus (SLE). Omega-3 has been reported to have benefit for endothelial dysfunction, one of the earliest stages of atherosclerosis, and to reduce disease activity in SLE. We performed a randomized, double-blind placebo-controlled trial to examine the effect of Omega-3 on endothelial function, disease activity, inflammatory markers and lipids in SLE. SLE patients (n = 85, mean age 47, 55 % Caucasian, 38 % African-American, 94 % female) were randomly assigned to 3 g of Omega-3 (Lovaza, GSK) versus placebo for 12 weeks. Endothelial function was measured at baseline and at 12 weeks using flow-mediated dilation, calculated using high-resolution B-mode ultrasound of the brachial artery diameter in response to vasoactive stimuli (hyperemia). Disease activity was measured using the physician global assessment and SELENA-SLEDAI score. Inflammatory markers (sICAM-1, sVCAM-1, IL-6) and fasting lipid profile were done at baseline and 12-week follow-up. There was no difference between the treatment groups with respect to changes in flow-mediated dilation parameters or disease activity. An average increase in LDL cholesterol of 3.11 mg/dL (±21.99) was found with Omega-3 versus a decrease of 1.87 mg/dL (±18.29) with placebo (p = 0.0266). In this trial, Omega-3 did not improve endothelial function, disease activity, nor reduce inflammatory markers in SLE. Longer trials might be required if there are delayed clinical effects. There was evidence that Omega-3 may increase LDL cholesterol, but not the LDL/HDL ratio.
Omega-3; LDL cholesterol; Flow-mediated dilation; Systemic lupus erythematosus
Increasing evidence suggests that diabetes mellitus (DM) may be associated with an increased risk of bladder cancer. We performed an updated meta-analysis to examine the association between DM and risk of bladder cancer.
Materials and Methods
We systematically searched the EMBASE and Medline (PubMed) databases (from inception through February 1, 2013) and reviewed the reference lists of relevant publications to search for additional studies. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with random-effects models.
In total, 10 case-control and 14 cohort studies met the inclusion criteria. Analysis of all studies showed that DM was associated with an increased risk of bladder cancer (RR 1.30, 95% CI 1.18–1.43). There was heterogeneity among studies (Pheterogeneity <0.001, I2=81.5%). Cohort studies showed a lower risk (RR 1.23, 95% CI 1.09–1.37) than case-control studies (odds ratio 1.46, 95% CI 1.20–1.78). The positive association was significant only in women (RR 1.23, 95% CI 1.02–1.49), but not in men (RR 1.07, 95% CI 0.97–1.18). The combined RRs remained unchanged before and after the studies on type 1 diabetes were excluded from analysis. The association between DM and bladder cancer risk did not differ significantly by methods of DM ascertainment. The combined RRs were 1.17 (95% CI 1.03–1.34), 1.34 (95% CI 1.19–1.51), and 1.57 (95% CI 0.96–2.55), respectively, when restricting the analysis to the studies accounting for body mass index, cigarette smoking, or glucose-lowering drug use.
This meta-analysis indicates a positive association between DM and risk of bladder cancer. Further studies are warranted to determine whether DM prevention and control can reduce risk of bladder cancer.
The FDA Adverse Event Reporting System (FAERS) is a database for post-marketing drug safety monitoring and influences FDA safety guidance documents, such as changes in drug labels. The number of cases in the FAERS has rapidly increased with the improvement of submission methods and data standard and thus has become an important resource for regulatory science. While the FAERS has been predominantly used for safety signal detection, this study explored its utility for disease monitoring.
Objective. The Medical Outcomes Short Form-36 Survey (SF-36) has been widely used as a measure of health-related quality of life (HRQOL) in different populations. SLE patients have consistently reported lower scores compared with the general population. The objective of our study was to identify predictors of HRQOL using SF-36 among patients with SLE enrolled in a 2-year randomized controlled trial (RCT).
Methods. We analysed 200 SLE patients enrolled in the Lupus Atherosclerosis Prevention Study (LAPS), an RCT of atorvastatin vs placebo, who completed SF-36 at qualifying, 12- and 24-month (final) visits.
Results. At baseline, mean SF-36 domain scores were lower than those of age- and gender-matched population norms. There was no statistical difference reported between Physical Component Summary (PCS), Mental Component Summary and eight domain scores in the atorvastatin vs placebo group at 2 years. In multiple regression analyses, African American patients reported significantly lower scores in Physical Functioning compared with Caucasians. The presence of FM was significantly associated with lower scores in physical functioning, role physical, bodily pain, general health, vitality, social functioning and lower overall mean PCS scores. The Physician’s Global Assessment of disease activity was associated with multiple SF-36 domains in univariate analysis.
Conclusion. This longitudinal study confirmed lower scores reported across all SF-36 domains. No one explanatory variable was independently associated with all domain scores. FM was independently associated with poorer HRQOL in most domains, underscoring the need for effective treatments for FM in SLE.
SLE; SF-36; HRQOL; fibromyalgia; statins; disease activity; PCS; MCS; disease activity indices; spydergram
Vulvovaginal-gingival syndrome is characterized by erosions and desquamation of the
vulva, vagina, and gingiva. We reported a case of a 32-year-old woman presenting with
an 8-year history of damage to the vulval and perianal anatomy and limitation of
mouth opening. The patient's symptoms were relieved after treatment with topical
Lichen planus; Tacrolimus; Therapeutics
The phenome represents a distinct set of information in the human population. It has been explored particularly in its relationship with the genome to identify correlations for diseases. The phenome has been also explored for drug repositioning with efforts focusing on the search space for the most similar candidate drugs. For a comprehensive analysis of the phenome, we assumed that all phenotypes (indications and side effects) were inter-connected with a probabilistic distribution and this characteristic may offer an opportunity to identify new therapeutic indications for a given drug. Correspondingly, we employed Latent Dirichlet Allocation (LDA), which introduces latent variables (topics) to govern the phenome distribution.
We developed our model on the phenome information in Side Effect Resource (SIDER). We first developed a LDA model optimized based on its recovery potential through perturbing the drug-phenotype matrix for each of the drug-indication pairs where each drug-indication relationship was switched to “unknown” one at the time and then recovered based on the remaining drug-phenotype pairs. Of the probabilistically significant pairs, 70% was successfully recovered. Next, we applied the model on the whole phenome to narrow down repositioning candidates and suggest alternative indications. We were able to retrieve approved indications of 6 drugs whose indications were not listed in SIDER. For 908 drugs that were present with their indication information, our model suggested alternative treatment options for further investigations. Several of the suggested new uses can be supported with information from the scientific literature.
The results demonstrated that the phenome can be further analyzed by a generative model, which can discover probabilistic associations between drugs and therapeutic uses. In this regard, LDA serves as an enrichment tool to explore new uses of existing drugs by narrowing down the search space.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-267) contains supplementary material, which is available to authorized users.
Drug repositioning; Bayesian methods; Latent dirichlet allocation; Data mining; Phenome; Side effects; Indications
We investigated whether an increase in vitamin D levels in patients with systemic lupus erythematosus was associated with improvement in disease activity.
1006 SLE patients were followed over 128 weeks. SLE patients with low levels of 25-hydroxy Vitamin D (<40 ng/mL) were supplemented with 50,000 units Vitamin D2 weekly, with Ca/D3 200 units twice daily. Longitudinal regression models were used to estimate the association between levels of vitamin D and various measures of disease activity.
The SLE patients were 91% female, mean age 49.6, 54% Caucasian, 37% African-American and 8% other ethnicity. For those with low 25-hydroxy Vitamin D (<40 ng/mL), a 20 unit increase in 25-hydroxy Vitamin D was associated with a decrease in mean SELENA-SLEDAI by 0.22 (CI: −0.41, −0.02) (p= 0.032). This corresponded with a 21% decrease in the odds of having a SELENA-SLEDAI higher than 4 (CI: 1%, 37%). Mean urine protein-to-creatinine ratio decreased 2% (CI: −0.03, −0.01) (p=0.009), corresponding to a 15% decrease in the odds of having a ratio of 0.5 or greater (CI: 2%, 27%).
We found that a 20 ng/mL increase in vitamin D was associated with a 21% decrease in the odds of having a high activity score and a 15% decrease in the odds of having clinically important proteinuria. Though these associations were statistically significant, the clinical importance is relatively modest. There was no evidence of additional benefit beyond a level of 40 ng/mL.
Vitamin D; Disease activity; Proteinuria; Systemic lupus Erythematosus
Background. Childhood obesity has become a global public health problem in recent years. This study aimed to explore the association of genetic variants in INSIG-SCAP-SREBP pathway with obesity in Chinese children. Methods. A case-control study was conducted, including 705 obese cases and 1,325 nonobese controls. We genotyped 15 single nucleotide polymorphisms (SNPs) of five genes in INSIG-SCAP-SREBP pathway, including insulin induced gene 1 (INSIG1), insulin induced gene 2 (INSIG2), SREBP cleavage-activating protein gene (SCAP), sterol regulatory element binding protein gene 1 (SREBP1), and sterol regulatory element binding protein gene 2 (SREBP2). We used generalized multifactor dimensionality reduction (GMDR) and logistic regression to investigate gene-gene interactions. Results. Single polymorphism analyses showed that SCAP rs12487736 and rs12490383 were nominally associated with obesity. We identified a 3-locus interaction on obesity in GMDR analyses (P = 0.001), involving 3 genetic variants of INSIG2, SCAP, and SREBP2. The individuals in high-risk group of the 3-locus combinations had a 79.9% increased risk of obesity compared with those in low-risk group (OR = 1.799, 95% CI: 1.475–2.193, P = 6.61 × 10−9). Conclusion. We identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect.
We performed a meta-analysis of 2 genome-wide association studies of
coronary artery disease comprising 1,515 cases with coronary artery disease and
5,019 controls, followed by de novo replication studies in
15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully
identified four new loci for coronary artery disease reaching genome-wide
significance (P < 5 × 10−8),
which mapped in or near TTC32-WDR35, GUCY1A3,
C6orf10-BTNL2 and ATP2B1. We also
replicated four loci previously identified in European populations
(PHACTR1, TCF21, CDKN2A/B
and C12orf51). These findings provide new insights into
biological pathways for the susceptibility of coronary artery disease in Chinese
Protein farnesylation is an important tosttranslational modification in fungi. We evaluated the antifungal activity of two farnesyltransferase inhibitors against clinical isolates of Aspergillus and Candida.
Disk diffusion assay and broth microdilution assay were used to determine the antifungal susceptibility of two farnesyltransferase inhibitors (manumycin A and tipifarnib) against clinical isolates of Aspergillus and Candida.
Disk diffusion assay demonstrated both agents had activity against Aspergillus and Candida. The minimal inhibitory concentration (MIC) ranges for manumycin A against Aspergillus and Candida were 200 to 400 μM and 13 to >25 μM, respectively. Unfortunately, the MIC were vastly higher than the concentrations that inhibit the proliferation and viability of mammalian cells. The MICs of tipifarnib against Aspergillus and Candida were >1600 μM.
The outcome of present study showed that farnesyltransferase inhibitors have activity against Aspergillus and Candida. This suggests that farnesyltransferase may be used as anifungal target in designing and developing new drugs.
Aspergillus; Candida; Farnesyltransferase inhibitors; Antifungal susceptibility testing
The SLICC/ACR Damage Index (SDI) is the accepted measure of permanent organ damage in SLE. We analyzed data from a large SLE cohort to identify variables associated with rates of damage accrual as measured by the SDI.
2054 SLE patients (92% female, 56% Caucasian, 37% African-American, mean age at diagnosis 33 years) were included. The SDI was calculated retrospectively at the time of cohort entry, and prospectively during follow-up. The relationships between time-invariant patient characteristics and rates of damage accrual were assessed based on the damage score at last available follow-up. The relationships between time-varying patient characteristics and damage accrual were assessed based on the timing of damage accrual during cohort participation..
Overall, the SDI increased at a rate of 0.13 per year. Higher rates of damage were observed for those who were older, male, African American, low income, low education, hypertensive, had lupus anticoagulant, or who had proteinuria. During follow-up, the risk of damage was higher for those who were older with more disease activity, low complement, anti-dsDNA, satisfied more ACR-11 criteria, and using corticosteroids. Lower risk was observed among those using hydroxychloroquine. After adjustment for other variables, age, hypertension, and use of corticosteroids emerged as the most important predictors of damage accrual.
Rates of damage vary in demographic subgroups, but much variation appears to be explained by hypertension and corticosteroid use. These data clearly point to the need for tight control of disease activity without reliance on corticosteroids.
SLICC/ACR Damage index (SDI); SLE
Objective(s): Protein kinase C (PKCα) is involved in modulating articular chondrocytes apoptosis induced by nitric oxide (NO). Hyaluronic acid (HA) inhibits nitric oxide-induced apoptosis of articular chondrocytes by protecting PKCα, but the mechanism remains unclear. The present study was performed to investigate the effects and mechanisms of PKCα regulate protective effect of hyaluronic acid.
Materials and Methods The ratio of apoptotic cell and cell viability was surveyed by PCNA and MTT assay. The expression of caspase-3 was determined by real-time PCR and western blot.
Results: It was showed that HA was able to reduce the nuclei fragment and PCNA expression, and NO-induced articular apoptosis blocked by HA, pretreated chondrocytes with PMA, HA significantly inhibits the activation of caspase-3 induced by NO, but pretrement with CHR, HA significantly incresed the expression of caspase-3.
Conclusion: The results may be showed that PKCa regulate the expresion of caspase-3, which contribute to the apoptosis of chondrocytes induced by NO. PKC α agonists enhance the protective effect of hyaluronic acid on nitric oxide-induced articular chondrocytes apoptosis.
Apoptosis; Nitric Oxide; PKC-α; PMA
High Content Screening (HCS) has become an important tool for toxicity assessment, partly due to its advantage of handling multiple measurements simultaneously. This approach has provided insight and contributed to the understanding of systems biology at cellular level. To fully realize this potential, the simultaneously measured multiple endpoints from a live cell should be considered in a probabilistic relationship to assess the cell's condition to response stress from a treatment, which poses a great challenge to extract hidden knowledge and relationships from these measurements.
In this work, we applied a text mining method of Latent Dirichlet Allocation (LDA) to analyze cellular endpoints from in vitro HCS assays and related to the findings to in vivo histopathological observations. We measured multiple HCS assay endpoints for 122 drugs. Since LDA requires the data to be represented in document-term format, we first converted the continuous value of the measurements to the word frequency that can processed by the text mining tool. For each of the drugs, we generated a document for each of the 4 time points. Thus, we ended with 488 documents (drug-hour) each having different values for the 10 endpoints which are treated as words. We extracted three topics using LDA and examined these to identify diagnostic topics for 45 common drugs located in vivo experiments from the Japanese Toxicogenomics Project (TGP) observing their necrosis findings at 6 and 24 hours after treatment.
We found that assay endpoints assigned to particular topics were in concordance with the histopathology observed. Drugs showing necrosis at 6 hour were linked to severe damage events such as Steatosis, DNA Fragmentation, Mitochondrial Potential, and Lysosome Mass. DNA Damage and Apoptosis were associated with drugs causing necrosis at 24 hours, suggesting an interplay of the two pathways in these drugs. Drugs with no sign of necrosis we related to the Cell Loss and Nuclear Size assays, which is suggestive of hepatocyte regeneration.
The evidence from this study suggests that topic modeling with LDA can enable us to interpret relationships of endpoints of in vitro assays along with an in vivo histological finding, necrosis. Effectiveness of this approach may add substantially to our understanding of systems biology.
Pulsed field gel electrophoresis (PFGE) is currently the most widely and routinely used method by the Centers for Disease Control and Prevention (CDC) and state health labs in the United States for Salmonella surveillance and outbreak tracking. Major drawbacks of commercially available PFGE analysis programs have been their difficulty in dealing with large datasets and the limited availability of analysis tools. There exists a need to develop new analytical tools for PFGE data mining in order to make full use of valuable data in large surveillance databases.
In this study, a software package was developed consisting of five types of bioinformatics approaches exploring and implementing for the analysis and visualization of PFGE fingerprinting. The approaches include PFGE band standardization, Salmonella serotype prediction, hierarchical cluster analysis, distance matrix analysis and two-way hierarchical cluster analysis. PFGE band standardization makes it possible for cross-group large dataset analysis. The Salmonella serotype prediction approach allows users to predict serotypes of Salmonella isolates based on their PFGE patterns. The hierarchical cluster analysis approach could be used to clarify subtypes and phylogenetic relationships among groups of PFGE patterns. The distance matrix and two-way hierarchical cluster analysis tools allow users to directly visualize the similarities/dissimilarities of any two individual patterns and the inter- and intra-serotype relationships of two or more serotypes, and provide a summary of the overall relationships between user-selected serotypes as well as the distinguishable band markers of these serotypes. The functionalities of these tools were illustrated on PFGE fingerprinting data from PulseNet of CDC.
The bioinformatics approaches included in the software package developed in this study were integrated with the PFGE database to enhance the data mining of PFGE fingerprints. Fast and accurate prediction makes it possible to elucidate Salmonella serotype information before conventional serological methods are pursued. The development of bioinformatics tools to distinguish the PFGE markers and serotype specific patterns will enhance PFGE data retrieval, interpretation and serotype identification and will likely accelerate source tracking to identify the Salmonella isolates implicated in foodborne diseases.
Data mining; Salmonella; PFGE; bioinformatics tools; data analysis.
An important mechanism of endocrine activity is chemicals entering target cells via transport proteins and then interacting with hormone receptors such as the estrogen receptor (ER). α-Fetoprotein (AFP) is a major transport protein in rodent serum that can bind and sequester estrogens, thus preventing entry to the target cell and where they could otherwise induce ER-mediated endocrine activity. Recently, we reported rat AFP binding affinities for a large set of structurally diverse chemicals, including 53 binders and 72 non-binders. However, the lack of three-dimensional (3D) structures of rat AFP hinders further understanding of the structural dependence for binding. Therefore, a 3D structure of rat AFP was built using homology modeling in order to elucidate rat AFP-ligand binding modes through docking analyses and molecular dynamics (MD) simulations.
Homology modeling was first applied to build a 3D structure of rat AFP. Molecular docking and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) scoring were then used to examine potential rat AFP ligand binding modes. MD simulations and free energy calculations were performed to refine models of binding modes.
A rat AFP tertiary structure was first obtained using homology modeling and MD simulations. The rat AFP-ligand binding modes of 13 structurally diverse, representative binders were calculated using molecular docking, (MM-GBSA) ranking and MD simulations. The key residues for rat AFP-ligand binding were postulated through analyzing the binding modes.
The optimized 3D rat AFP structure and associated ligand binding modes shed light on rat AFP-ligand binding interactions that, in turn, provide a means to estimate binding affinity of unknown chemicals. Our results will assist in the evaluation of the endocrine disruption potential of chemicals.