We have demonstrated that T lymphoma invasion and metastasis 1 (Tiam1) gene is associated with the poor prognosis of patients with hepatocellular carcinoma (HCC), and we used a computational approach to identify miR-141 as a Tiam1-targeting microRNA (miRNA). Here, we explored the function of miR-141 and the relationship between miR-141 and Tiam1 gene in HCC.
The miR-141 expression in HCC tissues and cell lines was detected and its roles in regulation of HCC cell proliferation, migration and invasion and target gene expression was investigated. Tiam1 was identified as a novel target of miR-141. Ethics statement: our study was approved by the Nanfang Hospital Medical Ethics Committee Ethics statement. Written informed consent was obtained before collection.
Based on in situ hybridization (ISH) analysis, miR-141 was down-regulated in the same HCC samples. Kaplan-Meier analysis demonstrated that patients with low miR-141 expression had poorer overall survival rate than that of the patients with high miR-141 expression. Furthermore, multivariate Cox regression analysis indicated that miR-141 could serve as an independent prognostic factor in HCC. MiR-141 significantly inhibited in vitro cell proliferation, migration and invasion as proved by gain- and loss- of function studies, while the mRNA and protein levels of Tiam1 were reduced in cells over-expressing miR-141. Moreover, Tiam1 treatment antagonized this effect, while knockdown of Tiam1 by Tiam1 short hairpin RNA (shTiam1) induced inhibitory effects.
These findings indicated that miR-141 functions as a tumor suppressor and inhibits the migration and invasion of HCC cells by targeting Tiam1, which may provide novel prognostic and treatment strategies for HCC patients.
Advances in DNA information extraction techniques have led to huge sequenced genomes from organisms spanning the tree of life. This increasing amount of genomic information requires tools for comparison of the nucleotide sequences. In this paper, we propose a novel nucleotide sequence alignment method based on sparse coding and belief propagation to compare the similarity of the nucleotide sequences. We used the neighbors of each nucleotide as features, and then we employed sparse coding to find a set of candidate nucleotides. To select optimum matches, belief propagation was subsequently applied to these candidate nucleotides. Experimental results show that the proposed approach is able to robustly align nucleotide sequences and is competitive to SOAPaligner  and BWA .
We have demonstrated a proof-of-principle experiment of reference-frame-independent phase coding quantum key distribution (RFI-QKD) over an 80-km optical fiber. After considering the finite-key bound, we still achieve a distance of 50 km. In this scenario, the phases of the basis states are related by a slowly time-varying transformation. Furthermore, we developed and realized a new decoy state method for RFI-QKD systems with weak coherent sources to counteract the photon-number-splitting attack. With the help of a reference-frame-independent protocol and a Michelson interferometer with Faraday rotator mirrors, our system is rendered immune to the slow phase changes of the interferometer and the polarization disturbances of the channel, making the procedure very robust.
A reasonable compromise of privacy and utility exists at an “appropriate” resolution of the data. We proposed novel mechanisms to achieve privacy preserving data publishing (PPDP) satisfying ε-differential privacy with improved utility through component analysis. The mechanisms studied in this article are Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA). The differential PCA-based PPDP serves as a general-purpose data dissemination tool that guarantees better utility (i.e., smaller error) compared to Laplacian and Exponential mechanisms using the same “privacy budget”. Our second mechanism, the differential LDA-based PPDP, favors data dissemination for classification purposes. Both mechanisms were compared with state-of-the-art methods to show performance differences.
differential privacy; data publishing; principal component analysis; linear discriminant analysis
Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ≥ 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ≥ 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.
genome-wide; DNA methylation; alterations; hepatocellular carcinoma; 450K BeadChips
Several studies have brought about increasing evidence to support the hypothesis that miRNAs play a pivotal role in multiple processes of carcinogenesis, including cell growth, apoptosis, differentiation, and metastasis. In this study, we investigated the potential role of miR-31 in colorectal cancer (CRC) aggressiveness and its underlying mechanisms. We found that miR-31 increased in CRC cells originated from metastatic foci and human primary CRC tissues with lymph node metastases. Furthermore, the high-level expression of miR-31 was significantly associated with a more aggressive and poor prognostic phenotype of patients with CRC (p < 0.05). The stable over-expression of miR-31 in CRC cells was sufficient to promote cell proliferation, invasion, and migration in vitro. It facilitated tumor growth and metastasis in vivo too. Further studies showed that miR-31 can directly bind to the 3’untranslated region (3’UTR) of SATB2 mRNA and subsequently repress both the mRNA and protein expressions of SATB2. Ectopic expression of SATB2 by transiently transfected with pCAG-SATB2 vector encoding the entire SATB2 coding sequence could reverse the effects of miR-31 on CRC tumorigenesis and progression. In addition, ectopic over-expression of miR-31 in CRC cells induced epithelial-mesenchymal transition (EMT). Our results illustrated that the up-regulation of miR-31 played an important role in CRC cell proliferation, invasion, and metastasis in vitro and in vivo through direct repressing SATB2, suggesting a potential application of miR-31 in prognosis prediction and therapeutic application in CRC.
Mutations in the PRRT2 gene have been identified as the major cause of benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with paroxysmal choreoathetosis/dyskinesias (ICCA). Here, we analyzed the phenotypes and PRRT2 mutations in Chinese families with BFIE and ICCA.
Clinical data were collected from 22 families with BFIE and eight families with ICCA. PRRT2 mutations were screened using PCR and direct sequencing.
Ninety-five family members were clinically affected in the 22 BFIE families. During follow-up, two probands had one seizure induced by diarrhea at the age of two years. Thirty-one family members were affected in the eight ICCA families, including 11 individuals with benign infantile epilepsy, nine with PKD, and 11 with benign infantile epilepsy followed by PKD. Two individuals in one ICCA family had PKD or ICCA co-existing with migraine. One affected member in another ICCA family had experienced a fever-induced seizure at 7 years old. PRRT2 mutations were detected in 13 of the 22 BFIE families. The mutation c.649_650insC (p.R217PfsX8) was found in nine families. The mutations c.649delC (p.R217EfsX12) and c.904_905insG (p.D302GfsX39) were identified in three families and one family, respectively. PRRT2 mutations were identified in all eight ICCA families, including c.649_650insC (p.R217PfsX8), c.649delC (p.R217EfsX12), c.514_517delTCTG (p.S172RfsX3) and c.1023A > T (X341C). c.1023A > T is a novel mutation predicted to elongate the C-terminus of the protein by 28 residues.
Our data demonstrated that PRRT2 is the major causative gene of BFIE and ICCA in Chinese families. Site c.649 is a mutation hotspot: c.649_650insC is the most common mutation, and c.649delC is the second most common mutation in Chinese families with BFIE and ICCA. As far as we know, c.1023A > T is the first reported mutation in exon 4 of PRRT2. c.649delC was previously reported in PKD, ICCA and hemiplegic migraine families, but we further detected it in BFIE-only families. c.904_905insG was reported in an ICCA family, but we identified it in a BFIE family. c.514_517delTCTG was previously reported in a PKD family, but we identified it in an ICCA family. Migraine and febrile seizures plus could co-exist in ICCA families.
Benign familial infantile epilepsy; Infantile convulsions with paroxysmal choreoathetosis; Phenotype; PRRT2; Mutation
Mink enteritis virus (MEV) is one of the most important viral pathogens in the mink industry. Recent studies have showed that microRNAs (miRNAs), small noncoding RNAs of length ranging from 18–23 nucleotides (nt) participate in host-pathogen interaction networks; however, whether or not miRNAs are involved in MEV infection has not been reported. Our study revealed that miRNA miR-181b inhibited replication of MEV in the feline kidney (F81) cell line by targeting the MEV non-structural protein 1 (NS1) messenger RNA (mRNA) coding region, resulting in NS1 translational repression, while MEV infection reduced miR-181b expression. This is the first description of cellular miRNAs modulating MEV infection in F81 cells, providing further insight into the mechanisms of viral infection, and may be useful in development of naturally-occurring miRNAs antiviral strategies.
In a growing interdisciplinary field like biomedical informatics, information dissemination and citation trends are changing rapidly due to many factors. To understand these factors better, we analyzed the evolution of the number of articles per major biomedical informatics topic, download/online view frequencies, and citation patterns (using Web of Science) for articles published from 2009 to 2012 in JAMIA. The number of articles published in JAMIA increased significantly from 2009 to 2012, and there were some topic differences in the last 4 years. Medical Record Systems, Algorithms, and Methods are topic categories that are growing fast in several publications. We observed a significant correlation between download frequencies and the number of citations per month since publication for a given article. Earlier free availability of articles to non-subscribers was associated with a higher number of downloads and showed a trend towards a higher number of citations. This trend will need to be verified as more data accumulate in coming years.
Genome data are becoming increasingly important for modern medicine. As the rate of increase in DNA sequencing outstrips the rate of increase in disk storage capacity, the storage and data transferring of large genome data are becoming important concerns for biomedical researchers. We propose a two-pass lossless genome compression algorithm, which highlights the synthesis of complementary contextual models, to improve the compression performance. The proposed framework could handle genome compression with and without reference sequences, and demonstrated performance advantages over best existing algorithms. The method for reference-free compression led to bit rates of 1.720 and 1.838 bits per base for bacteria and yeast, which were approximately 3.7% and 2.6% better than the state-of-the-art algorithms. Regarding performance with reference, we tested on the first Korean personal genome sequence data set, and our proposed method demonstrated a 189-fold compression rate, reducing the raw file size from 2986.8 MB to 15.8 MB at a comparable decompression cost with existing algorithms. DNAcompact is freely available at https://sourceforge.net/projects/dnacompact/for research purpose.
Pain is a common but significant problem that is considered a high priority area of care. Although there are many pain assessment scales that can be applied to patients who can communicate, either verbally or non-verbally, pain assessment for minimally responsive patients is limited. In this preliminary work, we developed a novel approach for assessing pain in such patients using a principal component analysis (PCA)-based local detector. Our algorithm produce a single index to indicate the increase in pain level based on unsynchronized, sparse and noisy time series data collected from electronic flowsheets. Among 8032 patient cases collected, 53 cases that satisfied the data requirements for PCA were used in this experiment. Our preliminary results indicate high potential in this approach by yielding an average AUC of 0.76 for the 53 cases.
Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.
HCC; genome-wide; host gene; microRNA; DNA methylation
Epilepsy; Seizure; Intracranial electrodes; Epilepsy surgery; Epileptogenic zone; Cortical localization
China experienced several large measles outbreaks in the past two decades, and a series of enhanced control measures were implemented to achieve the goal of measles elimination. Molecular epidemiologic surveillance of wild-type measles viruses (MeV) provides valuable information about the viral transmission patterns. Since 1993, virologic surveillnace has confirmed that a single endemic genotype H1 viruses have been predominantly circulating in China. A component of molecular surveillance is to monitor the genetic characteristics of the hemagglutinin (H) gene of MeV, the major target for virus neutralizing antibodies.
Analysis of the sequences of the complete H gene from 56 representative wild-type MeV strains circulating in China during 1993–2009 showed that the H gene sequences were clustered into 2 groups, cluster 1 and cluster 2. Cluster1 strains were the most frequently detected cluster and had a widespread distribution in China after 2000. The predicted amino acid sequences of the H protein were relatively conserved at most of the functionally significant amino acid positions. However, most of the genotype H1 cluster1 viruses had an amino acid substitution (Ser240Asn), which removed a predicted N-linked glycosylation site. In addition, the substitution of Pro397Leu in the hemagglutinin noose epitope (HNE) was identified in 23 of 56 strains. The evolutionary rate of the H gene of the genotype H1 viruses was estimated to be approximately 0.76×10−3 substitutions per site per year, and the ratio of dN to dS (dN/dS) was <1 indicating the absence of selective pressure.
Although H genes of the genotype H1 strains were conserved and not subjected to selective pressure, several amino acid substitutions were observed in functionally important positions. Therefore the antigenic and genetic properties of H genes of wild-type MeVs should be monitored as part of routine molecular surveillance for measles in China.
While exposures to urban fine particulate matter (PM2.5) and soot-black carbon (soot-BC) have been associated with asthma exacerbations, there is limited evidence on whether these pollutants are associated with the new development of asthma or allergy among young inner city children. We hypothesized that childhood exposure to PM2.5 and the soot-BC component would be associated with the report of new wheeze and development of seroatopy in an inner city birth cohort.
As part of the research being conducted by the Columbia Center of Children’s Environmental Health (CCCEH) birth cohort study in New York City, two-week integrated residential monitoring of PM2.5, soot-BC (based on a multi-wavelength integrating sphere method), and modified absorption coefficient (Abs*; based on the smoke stain reflectometer) was conducted between October 2005 and May 2011 for 408 children at age 5–6 years old. Residential monitoring was repeated 6 months later (n=262) to capture seasonal variability. New wheeze was identified through the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires during up to 3 years of follow-up and compared to a reference group that reported never wheeze, remitted wheeze, or persistent wheeze. Specific immunoglobulin (Ig) E against cockroach, mouse, cat, and dust mite and total IgE levels were measured in sera at ages 5 and 7 years.
PM2.5, soot-BC, and Abs* measured at the first visit were correlated moderately with those at the second visit (Pearson r > 0.44). Using logistic regression models, a positive association between PM2.5 and new wheeze was found with adjusted odds ratio [95% confidence intervals] of 1.51 [1.05–2.16] per interquartile range (IQR). Positive but nonsignificant association was found between the development of new wheeze and soot-BC and (OR 1.40 [0.96–2.05]), and Abs* (OR 1.57 [0.91–2.68]); Significantly positive associations were found between air pollutant measurements and new wheeze when restricting to those participants with repeat home indoor measurements 6 months apart. Associations between pollutants and IgE levels were not detected.
Our findings suggest that childhood exposure to indoor air pollution, much of which penetrated readily from outdoor sources, may contribute to the development of wheeze symptoms among children age 5 to 7 years.
indoor air pollution; long-term exposure; PM2.5; black carbon; wheeze; asthma; young children
For many cancers, features of the metabolic syndrome, such as diabetes and obesity, have been associated with both increased risk of cancer development and poor outcomes.
Materials and Methods
We examined a large retrospective cohort of 342 consecutive patients who underwent liver transplantation for hepatocellular carcinoma between January, 1999 and July, 2010 at our institution. We evaluated the relationship between diabetes, obesity, HCC recurrence, and overall survival.
We found that a body mass index (BMI)>30 was an independent predictor of poor overall survival in a multivariable Cox model, approximately doubling the risk of death after transplant. BMI>30 was also a predictor of recurrent HCC, although this was of borderline statistical significance (HR for recurrence 1.9, 95% CI 0.9–4.1). We also found increased BMI to be an independent predictor of microvascular invasion (MVI) within HCC tumors, lending a possible explanation to these results. Those with diabetes had worsened overall survival compared to those without diabetes in univariate, but not multivariable analysis, possibly related to longer wait times.
Our findings suggest a relationship between higher BMI, tumor vascular invasion, increased recurrence, and worsened overall survival. These findings may help explain why those with high BMI have worse outcomes from their cancers. A better understanding of the role of obesity and diabetes in patients with cancer should help develop better predictors of outcome and improved treatment options for patients with HCC.
Liver transplantation; hepatocellular carcinoma; diabetes; obesity; outcomes
DNA methylation changes have been implicated in many common chronic diseases leading to the hypothesis that environmental and age-related DNA methylation changes within individuals are involved in disease etiology. Few studies have examined DNA methylation changes within an individual over time and all of these studies have been conducted in adults. Here, we aim to characterize how global DNA methylation changes from birth to age three within a longitudinal birth cohort study and to determine whether there are consistent predictors of DNA methylation levels measured three years apart. We measured global DNA methylation in the same children at birth (cord blood) and again at three years of age among 165 children, using an immunoassay. We found that on average, DNA methylation was significantly higher in blood at age 3-years than in cord blood (p<0.01). However, for any individual child, the difference was less than would be expected by chance. We found that pre-pregnancy BMI was negatively predictive of both cord and three-year DNA methylation, even after statistical adjustment to account for the correlation between cord blood and three-year DNA methylation. The biologic implications of small changes in global DNA methylation are unknown. However, the observation that global DNA methylation levels persist within an individual from birth to age three supports the belief that factors that influence global DNA methylation, including pre-pregnancy BMI, may confer long-term effects.
Reduction of glutamine synthetase (GS) function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl), a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated). It was found that low doses of MSO (5 or 10 µg) significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg) aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×106 TU/2 µl) of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.
Ocular drug transport barriers pose a challenge for drug delivery comprising the ocular surface epithelium, the tear film and internal barriers of the blood-aqueous and blood-retina barriers. Ocular drug delivery efficiency depends on the barriers and the clearance from the choroidal, conjunctival vessels and lymphatic. Traditional drug administration reduces the clinical efficacy especially for poor water soluble molecules and for the posterior segment of the eye. Nanoparticles (NPs) have been designed to overcome the barriers, increase the drug penetration at the target site and prolong the drug levels by few internals of drug administrations in lower doses without any toxicity compared to the conventional eye drops. With the aid of high specificity and multifunctionality, DNA NPs can be resulted in higher transfection efficiency for gene therapy. NPs could target at cornea, retina and choroid by surficial applications and intravitreal injection. This review is concerned with recent findings and applications of NPs drug delivery systems for the treatment of different eye diseases.
nanoparticles; eye; drug delivery
Nanoscale functional structures are indispensable elements in many fields of modern science. In this paper, nanopillar array with a pillar diameter far smaller than Abbe's diffraction limit is realized by a new kind of continuous wave (CW) laser direct lithography technology. With atomic force microscopy technology, the average diameter of nanopillars on thin OIR906 photoresist film is about 65 nm and the smallest diameter is 48 nm, which is about 1/11 of the incident laser wavelength. Also, the influences of coma and astigmatism effects to the shape and size of nanopillar are numerically simulated by utilizing vector integral. As far as we know, it is the first time that nanopillar array is implemented by a donut-shaped 532-nm visible CW laser. The study presents a new, simple, inexpensive, and effective approach for nanopillar/pore array fabrication.
Nanopillar; Diffraction limit; Lithography; Coma; Astigmatism
Distributed video coding (DVC) is rapidly increasing in popularity by the way of shifting the complexity from encoder to decoder, whereas no compression performance degrades, at least in theory. In contrast with conventional video codecs, the inter-frame correlation in DVC is explored at decoder based on the received syndromes of Wyner-Ziv (WZ) frame and side information (SI) frame generated from other frames available only at decoder. However, the ultimate decoding performances of DVC are based on the assumption that the perfect knowledge of correlation statistic between WZ and SI frames should be available at decoder. Therefore, the ability of obtaining a good statistical correlation estimate is becoming increasingly important in practical DVC implementations. Generally, the existing correlation estimation methods in DVC can be classified into two main types: pre-estimation where estimation starts before decoding and on-the-fly (OTF) estimation where estimation can be refined iteratively during decoding. As potential changes between frames might be unpredictable or dynamical, OTF estimation methods usually outperforms pre-estimation techniques with the cost of increased decoding complexity (e.g., sampling methods). In this paper, we propose a low complexity adaptive DVC scheme using expectation propagation (EP), where correlation estimation is performed OTF as it is carried out jointly with decoding of the factor graph-based DVC code. Among different approximate inference methods, EP generally offers better tradeoff between accuracy and complexity. Experimental results show that our proposed scheme outperforms the benchmark state-of-the-art DISCOVER codec and other cases without correlation tracking, and achieves comparable decoding performance but with significantly low complexity comparing with sampling method.
Belief propagation; Expectation propagation; Distributed video coding; Adaptive decoding
Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). We have previously demonstrated that hypermethylation in candidate genes can be detected in plasma DNA prior to HCC diagnosis. To identify with a genome-wide approach additional genes hypermethylated in HCC that could be used for more accurate analysis of plasma DNA for early diagnosis, we analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor compared to non-tumor tissues. Array data were validated with pyrosequencing in a subset of 5 of these genes; correlation coefficients ranged from 0.92 to 0.97. Analysis of plasma DNA from 38 cases demonstrated that 37% to 63% of cases had detectable hypermethylated DNA (≥5% methylation) for these 5 genes individually. At least one of these genes was hypermethylated in 87% of cases, suggesting that measurement of DNA methylation in plasma samples is feasible. The panel of methylated genes indentified in the current study will be further tested in large cohort of prospectively collected samples to determine their utility as early biomarkers of hepatocellular carcinoma.
Genome-wide; DNA mehtylation; Hepatocellular Carcinoma
Patients with hepatocellular carcinoma (HCC) have a poor prognosis if their tumors are not diagnosed early. The authors investigated factors associated with the receipt of liver transplant among patients with HCC and evaluated the effects of these differences on survival.
The authors reviewed records from consecutive patients diagnosed with HCC at Columbia University Medical Center from January 1, 2002 to September 1, 2008. We compared patient clinical and demographic characteristics, developed a multivariable logistic regression model of predictors of transplant, and used a Cox model to analyze predictors of mortality.
Of 462 HCC patients, 175 (38%) received a transplant. Black patients were much less likely than whites to receive a transplant (odds ratio [OR], 0.03; 95% confidence interval [CI], 0.0–0.37). Hispanics and Asians were also less likely to undergo transplantation, but the differences were not statistically significant. Patients with private insurance were more likely to receive a transplant than those with Medicaid (odds ratio [OR], 22.07; 95% confidence interval [CI], 2.67–182.34). Black and Hispanic patients, and Medicaid recipients, presented with more advanced disease than whites and privately insured patients, and had poorer survival. In a Cox model, those who did not receive a transplant were 3 times as likely as transplant recipients to die, but race and insurance were not independently predictive of mortality.
Race and insurance status were strongly associated with receipt of transplantation and with more advanced disease at diagnosis, but transplantation was the most important determinant of survival. Improved access to care for non-white and Medicaid patients may allow more patients to benefit from transplant.
hepatocellular carcinoma; liver transplant; disparities; race; insurance
Motivation: DNA methylation is a molecular modification of DNA that plays crucial roles in regulation of gene expression. Particularly, CpG rich regions are frequently hypermethylated in cancer tissues, but not methylated in normal tissues. However, there are not many methodological literatures of case-control association studies for high-dimensional DNA methylation data, compared with those of microarray gene expression. One key feature of DNA methylation data is a grouped structure among CpG sites from a gene that are possibly highly correlated. In this article, we proposed a penalized logistic regression model for correlated DNA methylation CpG sites within genes from high-dimensional array data. Our regularization procedure is based on a combination of the l1 penalty and squared l2 penalty on degree-scaled differences of coefficients of CpG sites within one gene, so it induces both sparsity and smoothness with respect to the correlated regression coefficients. We combined the penalized procedure with a stability selection procedure such that a selection probability of each regression coefficient was provided which helps us make a stable and confident selection of methylation CpG sites that are possibly truly associated with the outcome.
Results: Using simulation studies we demonstrated that the proposed procedure outperforms existing main-stream regularization methods such as lasso and elastic-net when data is correlated within a group. We also applied our method to identify important CpG sites and corresponding genes for ovarian cancer from over 20 000 CpGs generated from Illumina Infinium HumanMethylation27K Beadchip. Some genes identified are potentially associated with cancers.
Supplementary data are available at Bioinformatics online.
No studies on the risk factors of 2009 pandemic influenza A (H1N1) in China have been reported. We aimed to investigate the risk factors for severe manifestations of 2009 pandemic H1N1 influenza in China
A case–control study with 343 severe hospitalized patients and 343 randomly selected mild controls was conducted. The diagnosis was established by assessment of clinical symptoms and confirmed by the real-time reverse-transcriptase-polymerase chain reaction assay. Severe or mild patients were classified by uniform criteria issued by the Ministry of Health in China.
The multivariable logistic regression analysis showed that the overweight or obese subjects admitted to hospital with H1N1 influenza were more likely to experience severe manifestations. The ORs were 3.70 (95% CI: 2.04-6.72) and 35.61 (95% CI: 7.96-159.21) respectively. Subjects at age less than 5 years or older than 60 years had an increased risk of severe manifestations (OR = 21.14, 95% CI: 7.79-57.33). We also observed increased risk among subjects with longer time interval from symptom onset to hospital admission (OR = 3.26, 95% CI: 2.08-5.11) or peasants (OR = 9.79, 95% CI: 5.11-18.78). Those with chronic disorders had increased risk of severe manifestations of H1N1 influenza.
We provide evidence on the risk factors associated with severe manifestations of 2009 pandemic H1N1 influenza in a study of hospitalized subjects in China.
Severe manifestation; Novel influenza A; Risk factor