Like other members of the γ-herpesvirus family, human herpes virus 8 (HHV-8), the etiologic agent of classic and HIV-related Kaposi’s sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including 7 cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84–3.92; Bonferroni-adjusted p= 9.9×10−3−2.6×10−4), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This “proof of concept” study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS
Kaposi’s sarcoma; Immunodeficiency; Herpes Virus 8; Multifactor Dimensionality Reduction; Polymorphism; Genetic association
Multiple MHC loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6,400 informative xMHC SNPs. When conditioned on HLA and non-genetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and non-classic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.
HIV-1; HLA; human MHC; SNP; viral load
This study aimed to investigate factors that influence antenatal care
utilization and their association with adverse pregnancy outcomes (defined as
low birth weight, stillbirth, preterm delivery or small for gestational age)
among pregnant women in Kumasi. A quantitative cross-sectional study was
conducted of 643 women aged 19-48 years who presented for delivery at selected
public hospitals and private traditional birth attendants from July-November
2011. Participants’ information and factors influencing antenatal
attendance were collected using a structured questionnaire and antenatal
records. Associations between these factors and adverse pregnancy outcomes were
assessed using chi-square and logistic regression.
Nineteen percent of the women experienced an adverse pregnancy outcome.
For 49% of the women, cost influenced their antenatal attendance. Cost
was associated with increased likelihood of a woman experiencing an adverse
outcome (adjusted OR = 2.15; 95% CI = 1.16-3.99;
p = 0.016). Also, women with >5 births had
an increased likelihood of an adverse outcome compared with women with single
deliveries (adjusted OR = 3.77; 95% CI = 1.50-9.53;
p = 0.005). The prevalence of adverse outcomes was
lower than previously reported (44.6% - 19%). Cost and distance
were associated with adverse outcomes after adjusting for confounders. Cost and
distance could be minimized through a wider application of the Ghana National
Health Insurance Scheme.
In 2005, the Ghana Health Service mandated malaria and helminths chemoprophylaxis during antenatal care visits. The aim of this study was to investigate the prevalence of malaria and helminth infections and their relationship with adverse birth outcomes (low birth weight, stillbirth, and preterm) following the implementation of these treatments.
A quantitative cross-sectional study.
The study was conducted on 630 women presenting for delivery in the Komfo Anokye Teaching Hospital and the Manhyia District Hospital from July to November 2011. Socio-demographic information and medical and obstetric history were collected. Laboratory analyses for the presence of malaria and helminths were performed. Association of malaria and helminths with birth outcomes was assessed using logistic regression to obtain odds ratios (ORs) and 95% confidence intervals.
The prevalence of malaria, helminths and adverse birth outcomes was 9.0%, 5.0% and 22.2%, respectively. Compared with women who received malaria prophylaxis, women without malaria prophylaxis were two times more likely to have malaria infection (aOR = 2.1; 95% CI = 1.06-4.17). Women who were not screened for helminths were twice as likely to be infected with helminths (aOR = 2.4; 95% CI = 1.15-5.12) than women who were screened for helminths. For women infected with hookworm or Schistosoma mansoni, the odds of having an adverse birth outcome (aOR = 3.9; 95% CI = 1.09-14.20) and stillbirth (aOR = 7.7; 95% CI = 1.21-36.38) were greater than for women who were not infected.
The prevalence of malaria, helminths and adverse birth outcomes was lower than previously reported 9.0% vs. 36.3, 5.0% vs. 25.7 and 22.2% vs. 44.6, respectively. Helminth but not malaria infection was found to be significantly associated with adverse birth outcomes.
Geohelminths; malaria; pregnancy outcomes; Kumasi
Motivation: Hidden Markov model, based on Li and Stephens model that takes into account chromosome sharing of multiple individuals, results in mainstream haplotype phasing algorithms for genotyping arrays and next-generation sequencing (NGS) data. However, existing methods based on this model assume that the allele count data are independently observed at individual sites and do not consider haplotype informative reads, i.e. reads that cover multiple heterozygous sites, which carry useful haplotype information. In our previous work, we developed a new hidden Markov model to incorporate a two-site joint emission term that captures the haplotype information across two adjacent sites. Although our model improves the accuracy of genotype calling and haplotype phasing, haplotype information in reads covering non-adjacent sites and/or more than two adjacent sites is not used because of the severe computational burden.
Results: We develop a new probabilistic model for genotype calling and haplotype phasing from NGS data that incorporates haplotype information of multiple adjacent and/or non-adjacent sites covered by a read over an arbitrary distance. We develop a new hybrid Markov Chain Monte Carlo algorithm that combines the Gibbs sampling algorithm of HapSeq and Metropolis–Hastings algorithm and is computationally feasible. We show by simulation and real data from the 1000 Genomes Project that our model offers superior performance for haplotype phasing and genotype calling for population NGS data over existing methods.
Availability: HapSeq2 is available at www.ssg.uab.edu/hapseq/.
email@example.com or firstname.lastname@example.org
Supplementary data are available at Bioinformatics online.
To analyze the serum nicotinamide phosphoribosyltransferase (Nampt) level and its prognostic value in bladder cancer (BC).
The study included 131 patients with transitional cell BC and 109 healthy controls from the West China Hospital of Sichuan University in the period between 2007 and 2013. Nampt concentration in serum was measured by commercial ELISA kits for human Nampt.
The serum Nampt protein level in patients with BC (mean ± standard deviation, 16.02 ± 7.95 ng/mL) was significantly higher than in the control group (6.46 ± 2.08 ng/mL) (P < 0.001). Serum Nampt level was an independent prognostic marker of non-muscle-invasive BC, with a higher serum Nampt level (>14.74 ng/mL) indicating shorter recurrence-free survival rate (hazard ratio = 2.85, 95% confidence interval, 1.01-8.06; P = 0.048).
Our results suggest that serum Nampt level may serve as a biomarker of BC and an independent prognostic marker of non-muscle-invasive BC.
For most complex diseases, the fraction of heritability that can be explained by the variants discovered from genome-wide association studies is minor. Although the so-called ‘rare variants’ (minor allele frequency [MAF] < 1%) have attracted increasing attention, they are unlikely to account for much of the ‘missing heritability’ because very few people may carry these rare variants. The genetic variants that are likely to fill in the ‘missing heritability’ include uncommon causal variants (MAF < 5%), which are generally untyped in association studies using tagging single-nucleotide polymorphisms (SNPs) or commercial SNP arrays. Developing powerful statistical methods can help to identify chromosomal regions harboring uncommon causal variants, while bypassing the genome-wide or exome-wide next-generation sequencing. In this work, we propose a haplotype kernel association test (HKAT) that is equivalent to testing the variance component of random effects for distinct haplotypes. With an appropriate weighting scheme given to haplotypes, we can further enhance the ability of HKAT to detect uncommon causal variants. With scenarios simulated according to the population genetics theory, HKAT is shown to be a powerful method for detecting chromosomal regions harboring uncommon causal variants.
Similarity; Linkage disequilibrium; Rare variants; JAK2 gene; Body-mass index
An inverse relationship between body mass index (BMI) and circulating levels of N-terminal proB-type natriuretic peptide (NT-proBNP) has been demonstrated in subjects with and without heart failure. Obesity also has been linked with increased incidence of atrial fibrillation (AF), but its influence on NT-proBNP concentrations in AF patients remains unclear. This study aimed to investigate the effect of BMI on NT-proBNP levels in AF patients without heart failure.
A total of 239 consecutive patients with AF undergoing catheter ablation were evaluated. Levels of NT-proBNP and clinical characteristics were compared in overweight or obese (BMI≥25 kg/m2) and normal weight (BMI<25 kg/m2) patients.
Of 239 patients, 129 (54%) were overweight or obese. Overweight or obese patients were younger, more likely to have a history of nonparoxysmal AF, hypertension, and diabetes mellitus. Levels of NT-proBNP were significantly lower in overweight or obese than in normal weight subjects (P<0.05). The relationship of obesity and decreased NT-proBNP levels persisted in subgroup of hypertension, both gender and both age levels (≥65 yrs and <65 yrs).Multivariate linear regression identified BMI as an independent negative correlate of LogNT-proBNP level.
An inverse relationship between BMI and plasma NT-proBNP concentrations have been demonstrated in AF patients without heart failure. Overweight or obese patients with AF appear to have lower NT-proBNP levels than normal weight patients.
The majority of killer cell immunoglobin-like receptor (KIR) genes are detected as either present or absent using locus-specific genotyping technology. Ambiguity arises from the presence of a specific KIR gene since the exact copy number (one or two) of that gene is unknown. Therefore, haplotype inference for these genes is becoming more challenging due to such large portion of missing information. Meantime, many haplotypes and partial haplotype patterns have been previously identified due to tight linkage disequilibrium (LD) among these clustered genes thus can be incorporated to facilitate haplotype inference. In this paper, we developed a hidden Markov model (HMM) based method that can incorporate identified haplotypes or partial haplotype patterns for haplotype inference from present-absent data of clustered genes (e.g., KIR genes). We compared its performance with an expectation maximization (EM) based method previously developed in terms of haplotype assignments and haplotype frequency estimation through extensive simulations for KIR genes. The simulation results showed that the new HMM based method outperformed the previous method when some incorrect haplotypes were included as identified haplotypes and/or the standard deviation of haplotype frequencies were small. We also compared the performance of our method with two methods that do not use previously identified haplotypes and haplotype patterns, including an EM based method, HPALORE, and a HMM based method, MaCH. Our simulation results showed that the incorporation of identified haplotypes and partial haplotype patterns can improve accuracy for haplotype inference. The new software package HaploHMM is available and can be downloaded at http://www.soph.uab.edu/ssg/files/People/KZhang/HaploHMM/haplohmm-index.html.
Hidden Markov model; haplotype; haplotype inference; KIR genes; haplotype patterns
Population stratification is a growing concern in genetic-association studies. Averaged ancestry at the genome level (global ancestry) is insufficient for detecting the population substructures and correcting population stratifications in association studies. Local and phase stratification are needed for human genetic studies, but current technologies cannot be applied on the entire genome data due to various technical caveats. Here we developed a novel approach (aMAP, ancestry of Modern Admixed Populations) for inferring local phased ancestry. It took about 3 seconds on a desktop computer to finish a local ancestry analysis for each human genome with 1.4-million SNPs. This method also exhibits the scalability to larger datasets with respect to the number of SNPs, the number of samples, and the size of reference panels. It can detect the lack of the proxy of reference panels. The accuracy was 99.4%. The aMAP software has a capacity for analyzing 6-way admixed individuals. As the biomedical community continues to expand its efforts to increase the representation of diverse populations, and as the number of large whole-genome sequence datasets continues to grow rapidly, there is an increasing demand on rapid and accurate local ancestry analysis in genetics, pharmacogenomics, population genetics, and clinical diagnosis.
The influenza A H7N9 virus outbreak in Eastern China in the spring of 2013 represented a novel, emerging avian influenza transmission to humans. While clinical and microbiological features of H7N9 infection have been reported in the literature, the current study investigated acute cytokine and antibody responses in acute H7N9 infection. Between March 27, 2013 and April 23, 2013, six patients with confirmed H7N9 influenza infection were admitted to Drum Tower Hospital, Nanjing, China. Acute phase serum cytokine profiles were determined using a high-throughput multiplex assay. Daily H7 hemagglutinin (HA)-specific IgG, IgM, and IgA responses were monitored by ELISA. Neutralizing antibodies specific for H7N9 viruses were determined against a pseudotyped virus expressing the novel H7 subtype HA antigen. Five cytokines (IL-6, IP-10, IL-10, IFNγ, and TNFα) were significantly elevated in H7N9-infected patients when compared to healthy volunteers. Serum H7 HA-specific IgG, as well as IgM and IgA responses, were detected within 8 days of disease onset and increased in a similar pattern during acute infection. Neutralizing antibodies developed shortly after the appearance of binding antibody responses and showed similar kinetics as a fraction of the total H7 HA-specific IgG responses. H7N9 infection resulted in hallmark serum cytokine increases, which correlated with fever and disease persistence. The novel finding of simultaneous development of IgG, IgM, and IgA responses in acute H7N9 infection points to the potential for live influenza viruses to elicit fast and potent protective antibodies to limit the infection.
In this paper, based on the coupled social networks (CSN), we propose a hybrid algorithm to nonlinearly integrate both social and behavior information of online users. Filtering algorithm, based on the coupled social networks, considers the effects of both social similarity and personalized preference. Experimental results based on two real datasets, Epinions and Friendfeed, show that the hybrid pattern can not only provide more accurate recommendations, but also enlarge the recommendation coverage while adopting global metric. Further empirical analyses demonstrate that the mutual reinforcement and rich-club phenomenon can also be found in coupled social networks where the identical individuals occupy the core position of the online system. This work may shed some light on the in-depth understanding of the structure and function of coupled social networks.
Programmed cell death 6 (PDCD6) participates in T cell receptor, Fas, and glucocorticoid—induced programmed cell death. To test the relationship between PDCD6 polymorphisms and uterine leiomyomas (UL) risk, we investigated the association of two SNPs (rs4957014 and rs3756712) in PDCD6 with UL risk in a case–control study of 295 unrelated premenopausal UL patients and 436 healthy postmenopausal control subjects in a population of China. Genotypes of the two SNPs were determined with the use of PCR-restriction fragment length polymorphism assay. Significantly increased UL risks were found to be associated with the T allele of rs4957014 and the T allele of rs3756712 (p=0.016, odds ratio [OR]=1.325, 95% confidence intervals [CI]=1.053–1.668 for rs4957014; p<0.0001, OR=1.898, 95% CI=1.457–2.474 for rs3756712, respectively). Increased UL risks were associated with them in different genetic models. The present study provided evidence that rs4957014 and rs3756712 are associated with UL risk, the results indicated that genetic polymorphisms in PDCD6 may contribute to the development of UL.
DNA variants in the tumor necrosis factor-α (TNF) and linked lymphotoxin-α genes, and specific alleles of the highly polymorphic human leukocyte antigen B (HLA-B) gene have been implicated in a plethora of immune and infectious diseases. However, the tight linkage disequilibrium characterizing the central region of the human major histocompatibility complex (MHC) containing these gene loci has made difficult the unequivocal interpretation of genetic association data.
To alleviate these difficulties and facilitate the design of more focused follow-up studies, we investigated the structure and distribution of HLA-B-specific MHC haplotypes reconstructed in a European population from unphased genotypes at a set of 25 single nucleotide polymorphism sites spanning a 66 kilobase-long region across TNF.
Consistent with the published data, we found limited genetic diversity across the so-called TNF block, with the emergence of seven common MHC haplotypes, termed TNF block super-haplotypes. We also found that the ancestral haplotype 8.1 shares a TNF block haplotype with HLA-B*4402. HLA-B*5701, a known protective allele in HIV-1 pathogenesis, occurred in a unique TNF block haplotype.
SNPs; TNF; LTA; HLA-B
Klebsiella pneumoniae is a frequent nosocomial pathogen, with the multidrug-resistant (MDR) K. pneumoniae being a major public health concern, frequently causing difficult-to-treat infections worldwide. The aim of this study was to investigate the molecular characterization of clinical MDR Klebsiella pneumoniae isolates.
A total of 27 non-duplicate MDR K. pneumoniae isolates with a CTX-CIP-AK resistance pattern were investigated for the prevalence of antimicrobial resistance genes including extended spectrum β-lactamase genes (ESBLs), plasmid-mediated quinolone resistance (PMQR) genes, 16S rRNA methylase (16S-RMTase) genes, and integrons by polymerase chain reaction (PCR) amplification and DNA sequencing. Plasmid replicons were typed by PCR-based replicon typing (PBRT). Multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were carried out to characterize the strain relatedness.
All the isolates co-harbored 3 or more resistance determinants. OqxAB, CTX-M-type ESBLs and RmtB were the most frequent determinants, distributed among19 (70.4%),18 (66.7%) and 8 (29.6%) strains. Fourteen isolates harbored class 1 integrons, with orfD-aacA4 being the most frequent gene cassette array. Class 3 integrons were less frequently identified and contained the gene cassette array of blaGES-1-blaOXA-10-aac(6′)-Ib. IncFII replicon was most commonly found in this collection. One cluster was observed with ≥80% similarity among profiles obtained by PFGE, and one sequence type (ST) by MLST, namely ST11, was observed in the cluster.
K. pneumoniae carbapenemase (KPC)–producing ST11 was the main clone detected. Of particular concern was the high prevalence of multiple resistance determinants, classs I integrons and IncFII plasmid replicon among these MDR strains, which provide advantages for the rapid development of MDR strains.
Multidrug resistance; Resistance determinants; Multi-locus sequence typing; Pulsed-field gel electrophoresis; Plasmid replicons
Sedation or anesthesia is used to facilitate many cases of an estimated 45 million diagnostic and therapeutic medical procedures in the United States. Preclinical studies have called attention to the possibility that sedative hypnotic drugs can increase pain perception but it remains unclear whether this observation holds true in humans and whether pain-modulating effects are agent specific or characteristic of intravenous sedation in general.
To study this important clinical question, we recruited 86 healthy volunteers and randomly assigned them to receive one of three sedative drugs; midazolam, propofol or dexmedetomidine. We asked participants to rate their pain in response to four experimental pain tasks (cold, heat, ischemic or electrical pain) before and during moderate sedation.
Midazolam increased cold, heat and electrical pain perception significantly (10-point pain rating scale change = 0.82 ± 0.29, mean ± SEM). Propofol reduced ischemic pain and dexmedetomidine reduced both cold and ischemic pain significantly (−1.58 ± 0.28, mean ± SEM). We observed a gender-by-race interaction for dexmedetomidine. In addition to these drug specific effects, we observed gender effects on pain perception; females rated identical experimental pain stimuli higher than males. We also noted racedrug interaction effects for dexmedetomidine with higher doses of drug needed to sedate Caucasians when compared to African-Americans.
The results of our study call attention to the fact that intravenous sedatives may increase pain perception. The effect of sedation on pain perception is agent and pain type specific. Knowledge of these effects provides a rational basis for analgesia and sedation to facilitate medical procedures.
Genetic alterations could be responsible lung cancer, the leading cause of worldwide cancer death.
This study investigated gene mutations in a Han Chinese family of lung cancer using the whole genome exome sequencing and subsequent Sanger sequencing validation and then confirmed alteration of prominin 1(PROM1) and cyclic AMP-response element binding protein-regulated transcription co-activator2 (CRTC2) in blood samples of 343 sporadic lung cancer patients vs. 280 healthy controls as well as in 200 pairs of lung cancer and the corresponding normal tissues using PCR-restriction fragment length polymorphism and directed DNA sequencing of PCR products.
The data showed PROM1 (p. S281R) and CRTC2 (p. R379C) mutations, in 5 and 2 cases of these 343 sporadic lung cancer patients, respectively. Notably, these mutations were absent in the healthy controls. Furthermore, in the 200 lung cancer and the matched normal tissues, PROM1 mutation occurred in 3 patients (i.e., one squamous cell carcinoma and two adenocarcinomas) with a mutation frequency of 1.5%, while CRTC2 mutation occurred in 5 patients (two squamous cell carcinomas and three adenocarcinomas) with a mutation frequency of 2.5%.
The data from the current study demonstrated novel PROM1 and CRTC2 mutations, which could promote lung cancer development.
Lung cancer; Gene mutation; PROM1; CRTC2; Whole genome exome sequencing
Novel avian influenza A(H7N9) virus was isolated in fatal patients in Yangtze River Delta of China in March 2013. We aimed to screen the virus in febrile patients in a tertiary hospital in an area with confirmed cases. Throat-swab specimens collected from consecutive patients with fever (≥38°C) and flu-like symptoms from April 15 to April 25, 2013 were subjected to detect novel avian influenza A(H7N9) virus with real-time PCR. The clinical outcomes in the patients and close contacts were followed up. Of total 200 patients screened, one (0.5%) was positive for avian influenza A(H7N9) virus and 199 others were negative. The infected patient experienced respiratory failure and had diffuse infiltrates in the right lower lobe in chest CT images. He received symptomatic and antibacterial treatments as well as oseltamivir. His condition was substantially improved within three days after admission; avian influenza A(H7N9) virus was not detected after 5 days' antiviral therapy. The hemagglutinin inhibition test showed that the serum titers against avian influenza A(H7N9) virus increased from <1∶20 at the early phase to 1∶80 at the convalescent phase. Follow-up of 23 close contacts showed that none of them developed fever and other symptoms within two weeks. Our findings suggest that although the infection rate of avian influenza A(H7N9) virus in patients with fever and flu-like symptoms is rare, the screening is valuable to rapidly define the infection, which will be critical to improve the clinical outcomes.
Objectives. To verify the relationship between Egr-1 and vein graft restenosis and investigate the related mechanisms. Methods. Mouse vein graft models were established in Egr-1 knockout (KO) and wild-type (WT) mice. The vein grafts in the mice were taken for pathological examination and immunohistochemical analysis. The endothelial cells (ECs) were stimulated by using a computer-controlled cyclic stress unit. BrdU staining and PCR were used to detect ECs proliferation activity and Egr-1 and ICAM-1 mRNA expression, respectively. Western-blot analysis was also used to detect expression of Egr-1 and intercellular adhesion molecule-1 (ICAM-1) proteins. Results. The lumens of vein grafts in Egr-1 KO mice were wider than in WT mice. ECs proliferation after mechanical stretch stimulation was suppressed by Egr-1 knockout (P < 0.05). Both in vein grafts and ECs from WT mice after mechanical stretch stimulation, mRNA expression and protein of Egr-1 and ICAM-1 showed increases (P < 0.05). However, ICAM-1 expression was significantly suppressed in ECs from Egr-1 knockout mice (P < 0.05). Conclusions. Egr-1 may promote ECs proliferation and result in vein graft restenosis by upregulating the expression of ICAM-1. As a key factor of vein graft restenosis, it could be a target for the prevention of restenosis after CABG surgery.
Phosphorylated AKT (p-AKT), constitutive activation of AKT, is a potentially interesting prognostic marker and therapeutic target in non-small cell lung cancer (NSCLC). However, the available results of p-AKT expression in NSCLC are heterogeneous. Therefore, a meta-analysis of published researches investigating the prognostic relevance of p-AKT expression in patients with NSCLC was performed.
Materials and Methods
A literature search via PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases was conducted. Data from eligible studies were extracted and included into meta-analysis using a random effects model.
A total of 1049 patients from nine studies were included in the meta-analysis. Nine studies investigated the relationship between p-AKT expression and overall survival using univariate analysis, and five of these undertook multivariate analysis. The pooled hazard ratio (HR) for overall survival was 1.49 (95% confidence interval (CI): 1.01-2.20) by univariate analysis and 1.02 (95% CI: 0.54-1.95) by multivariate analysis.
Our study shows that positive expression of p-AKT is associated with poor prognosis in patients with NSCLC. However, adequately designed prospective studies need to perform.
The scavenger receptor class B type 1 (SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggested that the SCARB1 gene may contribute to variation in plasma lipid levels at the fasting; however, the results have been inconsistent and it is unclear if SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with post-fenofibrate change for triglyceride (TG) (P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response as well as response to fenofibrate intervention.
Scavenger receptor class B type 1; lipid; genetics; fenofibrate; postprandial
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
HLA class I; Allele frequency; HIV-1 control; African American
To determine the prevalence of male circumcision (MC) among men in the western region of Jamaica, and to identify factors associated with acceptability of MC for self, infants (<1 year) and older sons (1-17 years).
A cross-sectional, interviewer-administered questionnaire survey of 549 men aged 19-54 years was conducted in the western region of Jamaica. The survey included questions about the acceptance of MC for self, infants, and sons before and after an information session about the benefits of MC in preventing HIV/STI transmission. Logistic regression models were used to identify factors that were associated with acceptability of MC. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated from the models.
Fourteen percent of the men reported that they were circumcised. In the multivariable model, which adjusted for age, education, religion and income, there were increased odds of accepting MC for infants/sons among uncircumcised men who accepted MC for self (AOR=8.1; 95% CI = 4.1-15.9), believed they would experience more pleasure during sex if circumcised (AOR=4.0; 95% CI = 2.0-8.2), and reported having no concerns regarding MC (AOR=3.0; 95% CI = 1.8-4.8). Similarly, uncircumcised men who reported no concerns about MC or who believed that they would experience more pleasure during sex if circumcised were more likely to accept MC for self.
Providing men with information about MC increased acceptance of MC for self, infants (<17 years) and sons (1-17 years). Since targeted education on the benefits of male circumcision for prevention of HIV/STI can be effective in increasing acceptability of MC, health professionals should be trained, and willing to discuss MC with men in healthcare facilities and in the community.
Rationale: DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF).
Objectives: To determine the DNA methylation changes in IPF and their effects on gene expression.
Methods: Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels.
Measurements and Main Results: DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression.
Conclusions: Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.
idiopathic pulmonary fibrosis; DNA methylation; gene expression; microarray