In the the title compound, C19H18BrNO3, the furanone ring is almost planar [maximum atomic deviation = 0.019 (3) Å] and is nearly perpendicular to the two phenyl rings, making dihedral angles of 88.96 (17) and 87.71 (17)°. Intermolecular C—H⋯O hydrogen bonding is present in the crystal structure.
The title compound, C19H30BrNO5, was obtained via a tandem asymmetric Michael addition–elimination reaction of 3,4-dibromo-5-[(S)-l-menthyloxy]furan-2(5H)-one and l-valine in the presence of potassium hydroxide. The molecular structure contains an approximately planar (r.m.s. deviation = 0.0204 Å) five-membered furanone ring and a six-membered menthyloxy ring adopting a chair conformation. The crystal packing is stabilized by intermolecular O—H⋯O and N—H⋯O hydrogen bonding.
The title compound, C19H30ClNO5, was obtained by the tandem asymmetric Michael addition–elimination reaction of (5S)-3,4-dichloro-5-(l-menthyloxy)furan-2(5H)-one and l-valine in the presence of potassium hydroxide. The furanone unit is approximately planar (r.m.s. deviation = 0.0204 Å) and the six-membered cyclohexane ring adopts a chair conformation. The crystal structure is stabilized by a network of O—H⋯O and N—H⋯O hydrogen bonds.
The title compound, C17H26ClNO5, was prepared via a tandem asymmetric Michael addition–elimination reaction of (5S)-3,4-dichloro-5-(l-menthyloxy)furan-2(5H)-one and l-alanine in the presence of potassium hydroxide. The five-membered furanone ring is approximately planar while the six-membered menthyloxy ring adopts a chair conformation. The crystal packing is stabilized by intermolecular O—H⋯O and N—H⋯O hydrogen bonds.
Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years prior to diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis and (1992–1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p<10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p= 4.84E-08) and rs3753519 (p= 0.0017) passed multiple testing adjustment at FDR q=1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p=0.019) did not, FDR q=0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V.
NNK; NNAL; tobacco specific nitrosamine; genetic polymorphism; HSD11B1
Genome-wide association studies (GWAS) have identified a number of genetic variants associated with lung cancer risk. However, these loci explain only a small fraction of lung cancer hereditability and other variants with weak effect may be lost in the GWAS approach due to the stringent significance level after multiple comparison correction. In this study, in order to identify important pathways involving the lung carcinogenesis, we performed a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using gene set enrichment analysis (GSEA) method. Predefined pathways by BioCarta and KEGG databases were systematically evaluated on Nanjing study (Discovery stage: 1,473 cases and 1,962 controls) and the suggestive pathways were further to be validated in Beijing study (Replication stage: 858 cases and 1,115 controls). We found that four pathways (achPathway, metPathway, At1rPathway and rac1Pathway) were consistently significant in both studies and the P values for combined dataset were 0.012, 0.010, 0.022 and 0.005 respectively. These results were stable after sensitivity analysis based on gene definition and gene overlaps between pathways. These findings may provide new insights into the etiology of lung cancer.
Holothurian glycosaminoglycan (hGAG) is a high-molecular-weight form of fucosylated chondroitin sulfate and has an antithrombotic effect. Our previous studies demonstrated that hGAG efficiently inhibited tumor cell metastasis. The interplays between thrombosis and tumor progression may have a major impact on hematogenous metastasis. In this study, we demonstrated that the mouse melanoma B16F10 cells treated with hGAG displayed a significant reduction of metastasis and coagulation capacity in vitro and in vivo. Mechanistic studies revealed that hGAG treatment in B16F10 cells remarkably inhibited the formation of fibrin through attenuating the generation of activated Factor Xa (FXa), without affecting the expression of urokinase (uPA) and plasminogen activator inhibitor 1 (PAI-1) that involved in fibrinolysis. Moreover, hGAG treatment downregulated the transcription and protein expression of tissue factor (TF). Promoter deletions, site mutations and functional studies identified that the nuclear transcription factor NF-κB binding region is responsible for hGAG-induced inhibition of TF expression. While the hGAG treatment of B16F10 cells was unable to inhibit NF-κB expression and phosphorylation, hGAG significantly prevented nuclear translocation of NF-κB from the cytosol, a potential mechanism underlying the transcriptional suppression of TF. Moreover, hGAG markedly suppressed the activation of p38MAPK and ERK1/2 signaling pathways, the central regulators for the expression of metastasis-related matrix metalloproteinases (MMPs). Consequently, hGAG exerts a dual function in the inhibition of metastasis and coagulation activity in mouse melanoma B16F10 cells. Our studies suggest hGAG to be a promising therapeutic agent for metastatic cancer treatment.
The one-sample-per-person problem has become an active research topic for face recognition in recent years because of its challenges and significance for real-world applications. However, achieving relatively higher recognition accuracy is still a difficult problem due to, usually, too few training samples being available and variations of illumination and expression. To alleviate the negative effects caused by these unfavorable factors, in this paper we propose a more accurate spectral feature image-based 2DLDA (two-dimensional linear discriminant analysis) ensemble algorithm for face recognition, with one sample image per person. In our algorithm, multi-resolution spectral feature images are constructed to represent the face images; this can greatly enlarge the training set. The proposed method is inspired by our finding that, among these spectral feature images, features extracted from some orientations and scales using 2DLDA are not sensitive to variations of illumination and expression. In order to maintain the positive characteristics of these filters and to make correct category assignments, the strategy of classifier committee learning (CCL) is designed to combine the results obtained from different spectral feature images. Using the above strategies, the negative effects caused by those unfavorable factors can be alleviated efficiently in face recognition. Experimental results on the standard databases demonstrate the feasibility and efficiency of the proposed method.
Gastroesophageal reflux symptoms (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma (EA). However, how angiogenic gene polymorphisms and environmental factors jointly affect EA development remains unclear.
Using a case-only design (n = 335), we examined interaction between 141 functional/tagging angiogenic SNPs and environmental factors (GERD, BMI, smoking) in modulating EA risk. Gene-environment interactions were assessed by a two-step approach. First, we applied random forest (RF) to screen for important SNPs that had either main or interaction effects. Second, we used case-only logistic regression (LR) to assess the effects of gene-environment interactions on EA risk, adjusting for covariates and false-discovery rate (FDR).
RF analyses identified three sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent LR analyses, interactions between 3 SNPs (rs2295778 of HIF1AN, rs133376 of TSC2, and rs2519757 of TSC1) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 (VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs3756309 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with EA development (all FDR ≤0.10). Moreover, these interactions tended to have a SNP dose-response effects for increased EA risk with increasing number of combined risk genotypes.
These findings suggest that genetic variations in angiogenic genes may modify EA susceptibility through interactions with environmental factors in a SNP dose-response manner.
Esophageal adenocarcinoma; angiogenesis pathway genes; gene-environment interaction; case-only analysis
Background and Aims
The pathogenesis of inflammatory bowel disease (IBD) has not been fully understood yet. Eosinophils (Eo) are one type of the major proinflammatory cells of the chronic inflammation in the intestine. CD98 is involved in the pathogenesis of a number of inflammations. This study aims to elucidate the role of CD98+ Eos in the initiation of intestinal inflammation.
The colon biopsies were collected from 60 patients with IBD. The expression of CD98 in the biopsies was examined by immunohistochemistry. The serum levels of the flagellin (FGN) antibody and Eo-derived mediators in the culture supernatants were assessed by enzyme-linked immunosorbent assay. The role of FGN on Eo activation was examined in a cell culture model. The role of FGN in the induction of colitis was observed in a mouse model.
Compared to normal controls, the frequency of CD98+ Eos was markedly increased in the IBD colon mucosa. FGN were detected in the colon biopsies and in the sera of IBD patients. Exposure to FGN induced the expression of galectin 3 (the ligand of CD98) in dendritic cells. The exposure to galectin 3 activated the CD98+ Eos. After treatment with FGN intrarectally, mice with eosinophilia showed severe inflammation in the colon.
The interaction of galectin 3 and CD98 can induce Eos to release chemical mediators that contributes to the initiation of the intestinal inflammation.
Mast cells play a significant role in the late stage of wound healing following burn injuries. In the present study, the possible role of mast cell chymase in burn wound healing was examined using a mast cell membrane stabilizer, ketotifen, in hamsters. A total of 28 hamsters were randomly divided into two groups (n=14), termed as the control and ketotifen groups. A deep partial-thickness burn injury was made on the back skin of the hamsters. The control group was orally administered physiological saline (1 ml) and the ketotifen group was orally administered ketotifen (4 mg/kg) once daily, two days prior to and two days subsequent to the burn. The results showed that concentrations of angiotensin II (Ang II), TGF-β1, collagens I and III and interleukin (IL)-1β were significantly decreased in the ketotifen group compared with those in the control group. However, there was no significant difference in fibroblast apoptosis between the two groups. The release of mast cell chymase was inhibited by the mast cell membrane stabilizer ketotifen. Taken together, these results suggest that mast cell chymase may participate in the process of burn wound healing. Chymase may therefore be a promising therapeutic target for the treatment of burn wounds.
chymase; mast cell; Ang II; TGF-β1; IL-1β
Obesity increases the risk of many diseases. However, there has been little literature about the epidemiology of obesity classified by body mass index (BMI) or waist (abdominal obesity) among urban Chinese adults. This study is to fill the gap by assessing the prevalence of obesity and associated risk factors among urban Chinese adults.
A representative sample of 25,196 urban adults aged 18 to 74 years in Northeast China was selected and measurements of height, weight and waist circumference (WC) were taken from 2009–2010. Definitions of overweight and obesity by the World Health Organization (WHO) were used.
The overall prevalence rates of general obesity and overweight classified by BMI were 15.0% (15.7% for men and 14.3% for women, p<0.01) and 19.2% (20.8% for men and 17.7% for women, p<0.01), respectively, and the overall prevalence rate of abdominal obesity was 37.6% (31.1% for men and women 43.9% for women, p<0.01). Multivariable logistic regression showed that the elderly and those who had a history of parental obesity, alcohol drinking, or former cigarette smoking were at high risk of obesity classified by BMI or WC, whereas those with a higher level of education, higher family income, or a healthy and balanced diet were at low risk of obesity. Analysis stratified by gender showed that men with a higher level education level, a white-collar job, a cadre job, or higher family income were the high risk group, and women with a higher level of education or higher family income were the low risk group.
Obesity and overweight have become epidemic in urban populations in China; associations of risk factors with obesity differ between men and women.
General obesity; Abdominal obesity; Risk factors; Gender difference; Chinese urban adults
Tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment. Variants in multiple genes in inflammation pathways may contribute to risk of lung cancer.
We therefore conducted a three-stage comprehensive pathway analysis (discovery, replication and meta-analysis) of inflammation gene variants in ever smoking lung cancer cases and controls. A discovery set (1096 cases; 727 controls) and an independent and non-overlapping internal replication set (1154 cases; 1137 controls) were derived from an ongoing case-control study. For discovery, we used an iSelect BeadChip to interrogate a comprehensive panel of 11737 inflammation pathway SNPs and selected nominally significant (p<0.05) SNPs for internal replication.
There were 6 SNPs that achieved statistical significance (p<0.05) in the internal replication dataset with concordant risk estimates for former smokers and 5 concordant and replicated SNPs in current smokers. Replicated hits were further tested in a subsequent meta-analysis using external data derived from two published GWAS and a case-control study. Two of these variants (a BCL2L14 SNP in former smokers and a SNP in IL2RB in current smokers) were further validated. In risk score analyses, there was a 26% increase in risk with each additional adverse allele when we combined the genotyped SNP and the most significant imputed SNP in IL2RB in current smokers and a 36% similar increase in risk for former smokers associated with genotyped and imputed BCL2L14 SNPs.
Before they can be applied for risk prediction efforts, these SNPs should be subject to further external replication and more extensive fine mapping studies.
Inflammation SNPS; lung cancer; smokers
The purpose of this study was to examine the main reasons for inpatient or outpatient visits after initiating duloxetine or pregabalin.
Commercially insured patients with fibromyalgia and aged 18–64 years who initiated duloxetine or pregabalin in 2006 with 12-month continuous enrollment before and after initiation were identified. Duloxetine and pregabalin cohorts with similar demographics, pre-index clinical and economic characteristics, and pre-index treatment patterns were constructed via propensity scoring stratification. Reasons for inpatient admissions, physician office visits, outpatient hospital visits, emergency room visits, and primary or specialty care visits over the 12 months post-index period were examined and compared. Logistic regression was used to assess the contribution of duloxetine versus pregabalin initiation to the most common reasons for visits, controlling for cross-cohort differences.
Per the study design, the duloxetine (n = 3711) and pregabalin (n = 4111) cohorts had similar demographics (mean age 51 years, 83% female) and health care costs over the 12-month pre-index period. Total health care costs during the 12-month post-index period were significantly lower for duloxetine patients than for pregabalin patients ($19,378 versus $27,045, P < 0.05). Eight of the 10 most common reasons for inpatient admissions and outpatient hospital (physician office, emergency room, primary or specialty care) visits were the same for both groups. Controlling for cross-cohort differences, duloxetine patients were less likely to be hospitalized due to an intervertebral disc disorder or major depressive disorder, to have a physician office visit due to nonspecific backache/other back/neck pain (NB/OB/NP) disorder, or to go to specialty care due to a soft tissue, NB/OP/NP, or intervertebral disc disorder. However, duloxetine patients were more likely to have a primary care visit due to a soft tissue disorder, essential hypertension, or other general symptoms.
Among similar commercially insured patients with fibromyalgia who initiated duloxetine or pregabalin, duloxetine patients had significantly lower health care costs over the 12-month post-index period. The leading reasons for inpatient or outpatient visits were also somewhat different.
duloxetine; pregabalin; inpatient admissions; physician office visits; outpatient hospital visits; emergency room; primary care visits; specialty care visits
Manipulation is an important issue for both developed and emerging stock markets. Many efforts have been made to detect manipulation in stock markets. However, it is still an open problem to identify the fraudulent traders, especially when they collude with each other. In this paper, we focus on the problem of identifying the anomalous traders using the transaction data of eight manipulated stocks and forty-four non-manipulated stocks during a one-year period. By analyzing the trading networks of stocks, we find that the trading networks of manipulated stocks exhibit significantly higher degree-strength correlation than the trading networks of non-manipulated stocks and the randomized trading networks. We further propose a method to detect anomalous traders of manipulated stocks based on statistical significance analysis of degree-strength correlation. Experimental results demonstrate that our method is effective at distinguishing the manipulated stocks from non-manipulated ones. Our method outperforms the traditional weight-threshold method at identifying the anomalous traders in manipulated stocks. More importantly, our method is difficult to be fooled by colluded traders.
GWAS has facilitated greatly the discovery of risk SNPs associated with complex diseases. Traditional methods analyze SNP individually and are limited by low power and reproducibility since correction for multiple comparisons is necessary. Several methods have been proposed based on grouping SNPs into SNP sets using biological knowledge and/or genomic features. In this article, we compare the linear kernel machine based test (LKM) and principal components analysis based approach (PCA) using simulated datasets under the scenarios of 0 to 3 causal SNPs, as well as simple and complex linkage disequilibrium (LD) structures of the simulated regions. Our simulation study demonstrates that both LKM and PCA can control the type I error at the significance level of 0.05. If the causal SNP is in strong LD with the genotyped SNPs, both the PCA with a small number of principal components (PCs) and the LKM with kernel of linear or identical-by-state function are valid tests. However, if the LD structure is complex, such as several LD blocks in the SNP set, or when the causal SNP is not in the LD block in which most of the genotyped SNPs reside, more PCs should be included to capture the information of the causal SNP. Simulation studies also demonstrate the ability of LKM and PCA to combine information from multiple causal SNPs and to provide increased power over individual SNP analysis. We also apply LKM and PCA to analyze two SNP sets extracted from an actual GWAS dataset on non-small cell lung cancer.
The purpose of this study was to assess select medication utilization prior to duloxetine initiation among patients with major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain associated with osteoarthritis or low back pain.
Commercially insured duloxetine initiators between January 1, 2007 and March 31, 2010 were identified from a large US administrative claims database. Disease subgroups were constructed based on diagnosis from medical claims during the 12 months prior to duloxetine initiation. Prior use of antidepressants, anticonvulsants, opioids, nonsteroidal anti-inflammatory drugs, and muscle relaxants was assessed during the 12-month preinitiation period.
This study identified 56,845 (2007), 44,838 (2008), and 65,840 (January 2009 to March 2010) duloxetine initiators. Among the 2009 initiators, utilization patterns were similar for patients with major depressive disorder and generalized anxiety disorder, with antidepressants being the most used (84% and 80%, respectively), followed by opioids (58% and 55%, respectively). Patients across pain-related conditions also had similar utilization patterns, with opioid use being the highest (76%–82%), followed by antidepressants (65%–72%). Use of other medication classes was common (29%–63%) but less frequent, and over 50% of the patients used any antidepressants, 70% used any antidepressants or anticonvulsants, and 90% used any antidepressants, anticonvulsants, or opioids. Trends in the use of these select medications were similar between 2007 and 2009.
Patients used several types of medications over the 12 months prior to initiating duloxetine across disease states, with antidepressants and opioids being the most frequently used medications. Trends of select medication use were similar over time.
duloxetine; medication utilization; commercial insurance
Bacterial transfer RNA can suppress the immunostimulatory activity of other bacterial tRNAs as a result of the presence of a guanosine modification.
Foreign RNA serves as pathogen-associated molecular pattern (PAMP) and is a potent immune stimulator for innate immune receptors. However, the role of single bacterial RNA species in immune activation has not been characterized in detail. We analyzed the immunostimulatory potential of transfer RNA (tRNA) from different bacteria. Interestingly, bacterial tRNA induced type I interferon (IFN) and inflammatory cytokines in mouse dendritic cells (DCs) and human peripheral blood mononuclear cells (PBMCs). Cytokine production was TLR7 dependent because TLR7-deficient mouse DCs did not respond and TLR7 inhibitory oligonucleotides inhibited tRNA-mediated activation. However, not all bacterial tRNA induced IFN-α because tRNA from Escherichia coli Nissle 1917 and Thermus thermophilus were non-immunostimulatory. Of note, tRNA from an E. coli knockout strain for tRNA (Gm18)-2′-O-methyltransferase (trmH) regained immunostimulatory potential. Additionally, in vitro methylation of this immunostimulatory Gm18-negative tRNA with recombinant trmH from T. thermophilus abolished its IFN-α inducing potential. More importantly, Gm18-modified tRNA acted as TLR7 antagonist and blocked IFN-α induction of influenza A virus–infected PBMCs.
Survival of airborne virus influences the extent of disease transmission via air. How environmental factors affect viral survival is not fully understood. We investigated the survival of a vaccine strain of Gumboro virus which was aerosolized at three temperatures (10°C, 20°C, and 30°C) and two relative humidities (RHs) (40% and 70%). The response of viral survival to four metrics (temperature, RH, absolute humidity [AH], and evaporation potential [EP]) was examined. The results show a biphasic viral survival at 10°C and 20°C, i.e., a rapid initial inactivation in a short period (2.3 min) during and after aerosolization, followed by a slow secondary inactivation during a 20-min period after aerosolization. The initial decays of aerosolized virus at 10°C (1.68 to 3.03 ln % min−1) and 20°C (3.05 to 3.62 ln % min−1) were significantly lower than those at 30°C (5.67 to 5.96 ln % min−1). The secondary decays at 10°C (0.03 to 0.09 ln % min−1) tended to be higher than those at 20°C (−0.01 to 0.01 ln % min−1). The initial viral survival responded to temperature and RH and potentially to EP; the secondary viral survival responded to temperature and potentially to RH. In both phases, survival of the virus was not significantly affected by AH. These findings suggest that long-distance transmission of airborne virus is more likely to occur at 20°C than at 10°C or 30°C and that current Gumboro vaccination by wet aerosolization in poultry industry is not very effective due to the fast initial decay.
Plasmodium spp. are pathogenic to their vertebrate hosts and also apparently, impose a fitness cost on their insect vectors. We show here, however, that Plasmodium-infected mosquitoes survive starvation significantly better than uninfected mosquitoes. This survival advantage during starvation is associated with higher energy resource storage that infected mosquitoes accumulate during period of Plasmodium oocyst development. Microarray analysis revealed that the metabolism of sated mosquitoes is altered in the presence of rapidly growing oocysts, including the down-regulation of several enzymes involved in carbohydrate catabolism. In addition, enhanced expression of several insulin-like peptides was observed in Plasmodium-infected mosquitoes. Blocking insulin-like signaling pathway resulted in impaired Plasmodium development. We conclude that Plasmodium infection alters metabolic pathways in mosquitoes, epitomized by enhanced insulin-like signaling – thereby conferring a survival advantage to the insects during periods of starvation. Manipulation of this pathway might provide new strategies to influence the ability of mosquitoes to survive and transmit the protozoa that cause malaria.
CCCH-type zinc finger proteins comprise a large protein family. Increasing evidence suggests that members of this family are RNA-binding proteins with regulatory functions in mRNA processing. Compared with those in animals, functions of CCCH-type zinc finger proteins involved in plant growth and development are poorly understood.
Here, we performed a genome-wide survey of CCCH-type zinc finger genes in maize (Zea mays L.) by describing the gene structure, phylogenetic relationships and chromosomal location of each family member. Promoter sequences and expression profiles of putative stress-responsive members were also investigated. A total of 68 CCCH genes (ZmC3H1-68) were identified in maize and divided into seven groups by phylogenetic analysis. These 68 genes were found to be unevenly distributed on 10 chromosomes with 15 segmental duplication events, suggesting that segmental duplication played a major role in expansion of the maize CCCH family. The Ka/Ks ratios suggested that the duplicated genes of the CCCH family mainly experienced purifying selection with limited functional divergence after duplication events. Twelve maize CCCH genes grouped with other known stress-responsive genes from Arabidopsis were found to contain putative stress-responsive cis-elements in their promoter regions. Seven of these genes chosen for further quantitative real-time PCR analysis showed differential expression patterns among five representative maize tissues and over time in response to abscisic acid and drought treatments.
The results presented in this study provide basic information on maize CCCH proteins and form the foundation for future functional studies of these proteins, especially for those members of which may play important roles in response to abiotic stresses.
Adherence to medication for the treatment of fibromyalgia (FM) is predictive of lower overall health-care costs, and thus a lower burden on both patients and providers. The objectives of this study were to examine the predictors of adherence to and persistence with duloxetine therapy among commercially insured FM patients, and to identify subgroups of patients with high duloxetine persistence and adherence.
This cross-sectional, retrospective study analyzed medical and pharmacy records over 1 year for patients in the US aged 18–64 years with FM who initiated (no prior 90-day use) duloxetine treatment in 2008.
Adherence to duloxetine was measured by medication possession ratio (MPR), with high adherence defined as MPR ≥ 0.8. Persistence was defined as the duration of therapy from the index date to the earliest of: the ending date of the last prescription, the date of the first gap of >15 days between prescriptions, or the end of the study period (12 months). Demographic and clinical predictors of adherence were examined via multiple logistic regression (MLR), and subgroups of duloxetine-persistent and -adherent patients were identified using classification and regression trees (CART).
Among 4660 duloxetine patients, 33% achieved high adherence. Factors associated with high adherence from MLR included older age, North Central and Northeast regions, prior venlafaxine, pregabalin, selective serotonin reuptake inhibitor (SSRI), or other antidepressant use, or comorbid dyslipidemia or osteoarthritis (all P < 0.05). CART analysis revealed that patients with prior antidepressant use, aged ≥46, or prior osteoarthritis had higher MPR (all P < 0.05), and patients aged ≥45 with a history of SSRI, venlafaxine, or anticonvulsant use had longer duration of therapy (all P < 0.05).
Patients with high adherence to and persistence with duloxetine were significantly older and had prior antidepressant use.
duloxetine; medication adherence; medication persistence; subgroup analysis; fibromyalgia
How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene–environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene–environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08–2.58 times [interaction odds ratio (ORi) = 2.08–2.58, adjusted P-value (Padj) = 0.02–0.04]. Compared with patients carrying ≤1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi = 1.89, Padj = 0.016) or ≥3 (ORi = 4.30, Padj < 0.0001) risk genotypes. Compared with cases with ≤1 risk genotype, smoking-associated EA risk increased by 3.15 times when ≥2 risk genotypes were present (ORi = 3.15, Padj < 0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development.
This study was designed to determine the levels of survivin expression and identify its clinical significance as a prognostic factor for stage III non-small cell lung cancer (NSCLC). A total of 210 cases of stage III NSCLC were collected and the expression levels of survivin and vascular endothelial growth factor A (VEGF-A) in tumor tissues were investigated using immunohistochemistry (IHC). The medical records of the patients were reviewed to determine the association with clinical course. Of the 210 NSCLC tissues, 112 (53.3%) cases demonstrated positive expression of survivin protein. Coexpression of survivin and VEGF-A was identified. The 5-year survival rate of patients with positive survivin expression was significantly lower compared with the survivin-negative cancer patients (P<0.05). The expression of survivin in NSCLC correlated with tumor size. Survivin and VEGF-A were independent prognostic factors of stage III NSCLC. Survivin protein is a valuable marker of prognosis in stage III NSCLC patients.
survivin; VEGF-A; immunohistochemistry; prognostic marker
Artemia eggs tend to develop ovoviviparously to yield nauplius larvae in good rearing conditions; while under adverse situations, they tend to develop oviparously and encysted diapause embryos are formed instead. However, the intrinsic mechanisms regulating this process are not well understood.
This study has characterized the function of cyclin K, a regulatory subunit of the positive transcription elongation factor b (P-TEFb) in the two different developmental pathways of Artemia. In the diapause-destined embryo, Western blots showed that the cyclin K protein was down-regulated as the embryo entered dormancy and reverted to relatively high levels of expression once development resumed, consistent with the fluctuations in phosphorylation of position 2 serines (Ser2) in the C-terminal domain (CTD) of the largest subunit (Rpb1) of RNA polymerase II (RNAP II). Interestingly, the cyclin K transcript levels remained constant during this process. In vitro translation data indicated that the template activity of cyclin K mRNA stored in the postdiapause cyst was repressed. In addition, in vivo knockdown of cyclin K in developing embryos by RNA interference eliminated phosphorylation of the CTD Ser2 of RNAP II and induced apoptosis by inhibiting the extracellular signal-regulated kinase (ERK) survival signaling pathway.
Taken together, these findings reveal a role for cyclin K in regulating RNAP II activity during diapause embryo development, which involves the post-transcriptional regulation of cyclin K. In addition, a further role was identified for cyclin K in regulating the control of cell survival during embryogenesis through ERK signaling pathways.