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1.  Fever Burden Is an Independent Predictor for Prognosis of Traumatic Brain Injury 
PLoS ONE  2014;9(3):e90956.
Objective
To evaluate fever burden as an independent predictor for prognosis of traumatic brain injury (TBI).
Methods
This retrospective study involved 355 TBI patients with Glasgow Coma Scale (GCS) ≤14, who presented at the emergency department of our hospital between November 2010 and October 2012. At 6 months follow-up, patients were divided into 5 groups based on Glasgow Outcome Scale (GOS) and dichotomized to GOS score (high (4 to 5) vs. low (1 to 3)). The relationship between fever burden and GOS was assessed.
Results
Fever burden increased as GOS scores decreased from 5 to 2, except for score 1 of GOS, which corresponded to a significant lower fever burden. Following dichotomization, patients in the high GOS group were younger, and showed less abnormal pupil reactivity (P<0.001), a higher median GCS score (P<0.001), and a lower median fever burden (P<0.001), compared with patients in the low GOS group. Univariate logistic regression analysis revealed that poor TBI prognosis was related to age, GCS, pupil reactivity, and fever burden (OR: 1.166 [95% CI: 1.117–1.217] P<0.0001). Multivariate logistic regression analysis identified fever burden as an independent predictor of poor prognosis after TBI (OR 1.098; 95% CI: 1.031–1.169; P = 0.003). These observations were confirmed by evaluation of the receiver operating characteristic (ROC) curve for fever burden (area under the curve [AUC] 0.73 [95% CI: 0.663–0.760]).
Conclusion
Fever burden might be an independent predictor for prognosis of TBI. High fever burden in the early stage of the disease course associated with TBI could increase the risk of poor prognosis.
doi:10.1371/journal.pone.0090956
PMCID: PMC3953326  PMID: 24626046
2.  Mutational landscape and significance across 12 major cancer types 
Nature  2013;502(7471):333-339.
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known(forexample, mitogen-activatedprotein kinase, phosphatidylinositol-3-OH kinase,Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the numberof driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
doi:10.1038/nature12634
PMCID: PMC3927368  PMID: 24132290
3.  THE GENOMIC LANDSCAPE OF HYPODIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA 
Nature genetics  2013;45(3):242-252.
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
doi:10.1038/ng.2532
PMCID: PMC3919793  PMID: 23334668
4.  Activating HER2 mutations in HER2 gene amplification negative breast cancer 
Cancer discovery  2012;3(2):224-237.
Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.
doi:10.1158/2159-8290.CD-12-0349
PMCID: PMC3570596  PMID: 23220880
Genomics; Breast Cancer; Receptor Tyrosine Kinase; Oncogene
5.  Re-sequencing Expands Our Understanding of the Phenotypic Impact of Variants at GWAS Loci 
PLoS Genetics  2014;10(1):e1004147.
Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20–30% of the heritable component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in >6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 [NFBC]) and a type 2 diabetes case-control sample (The Finland-United States Investigation of NIDDM Genetics [FUSION] study). By sequencing the coding sequence and 5′ and 3′ untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits (serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting both single-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotype associations at eight of these loci. At all eight of these loci, the identification of new associations provides significant evidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we found significant gene-level evidence of association to non-synonymous variants with MAF<1%. Additionally, two potentially deleterious variants that demonstrated significant associations (rs138726309, a missense variant in G6PC2, and rs28933094, a missense variant in LIPC) were considerably more common in these Finnish samples than in European reference populations, supporting our prior hypothesis that deleterious variants could attain high frequencies in this isolated population, likely due to the effects of population bottlenecks. Our results highlight the value of large, well-phenotyped samples for rare-variant association analysis, and the challenge of evaluating the phenotypic impact of such variants.
Author Summary
Abnormal serum levels of various metabolites, including measures relevant to cholesterol, other fats, and sugars, are known to be risk factors for cardiovascular disease and type 2 diabetes. Identification of the genes that play a role in generating such abnormalities could advance the development of new treatment and prevention strategies for these disorders. Investigations of common genetic variants carried out in large sets of research subjects have successfully pinpointed such genes within many regions of the human genome. However, these studies often have not led to the identification of the specific genetic variations affecting metabolic traits. To attempt to detect such causal variations, we sequenced genes in 17 genomic regions implicated in metabolic traits in >6,000 people from Finland. By conducting statistical analyses relating specific variations (individually and grouped by gene) to the measures for these metabolic traits observed in the study subjects, we added to our understanding of how genotypes affect these traits. Our findings support a long-held hypothesis that the unique history of the Finnish population provides important advantages for analyzing the relationship between genetic variations and biomedically important traits.
doi:10.1371/journal.pgen.1004147
PMCID: PMC3907339  PMID: 24497850
6.  Anatomy and transcript profiling of gynoecium development in female sterile Brassica napus mediated by one alien chromosome from Orychophragmus violaceus 
BMC Genomics  2014;15:61.
Background
The gynoecium is one of the most complex organs of angiosperms specialized for seed production and dispersal, but only several genes important for ovule or embryo sac development were identified by using female sterile mutants. The female sterility in oilseed rape (Brassica napus) was before found to be related with one alien chromosome from another crucifer Orychophragmus violaceus. Herein, the developmental anatomy and comparative transcript profiling (RNA-seq) for the female sterility were performed to reveal the genes and possible metabolic pathways behind the formation of the damaged gynoecium.
Results
The ovules in the female sterile Brassica napus with two copies of the alien chromosomes (S1) initiated only one short integument primordium which underwent no further development and the female gametophyte development was blocked after the tetrad stage but before megagametogenesis initiation. Using Brassica_ 95k_ unigene as the reference genome, a total of 28,065 and 27,653 unigenes were identified to be transcribed in S1 and donor B. napus (H3), respectively. Further comparison of the transcript abundance between S1 and H3 revealed that 4540 unigenes showed more than two fold expression differences. Gene ontology and pathway enrichment analysis of the Differentially Expressed Genes (DEGs) showed that a number of important genes and metabolism pathways were involved in the development of gynoecium, embryo sac, ovule, integuments as well as the interactions between pollen and pistil.
Conclusions
DEGs for the ovule development were detected to function in the metabolism pathways regulating brassinosteroid (BR) biosynthesis, adaxial/abaxial axis specification, auxin transport and signaling. A model was proposed to show the possible roles and interactions of these pathways for the sterile gynoecium development. The results provided new information for the molecular mechanisms behind the gynoecium development at early stage in B. napus.
doi:10.1186/1471-2164-15-61
PMCID: PMC3930543  PMID: 24456102
Brassica napus; Gynoecium; Ovule; Female sterility; Transcriptome
7.  Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts 
Cell reports  2013;4(6):10.1016/j.celrep.2013.08.022.
SUMMARY
To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.
doi:10.1016/j.celrep.2013.08.022
PMCID: PMC3881975  PMID: 24055055
8.  Pulmonary gangliocytic paraganglioma: a case report and review of the literature 
Gangliocytic paraganglioma (GP) is a rare histologic type of neuroendocrine tumors. We report a case of pulmonary GP in a 29-year-old male presenting with an asymptomatic endobronchial nodule. Grossly, the tumor showed a 4.0x3.8x3.5 cm well-defined nodule with yellowish cut surface. Microscopically, the tumor was composed of three distinct cellular types: epithelioid cells, ganglion-like cells and spindle cells. Meanwhile, transitional cells, having morphologic features between ganglion-like and epithelioid cells, were also presented. The epithelioid cells arranged in various morphologic architectures, including Zellballen, papillary, cystic and microcystic pattern. The epithelioid cells were positive for AE1/AE3, CAM 5.2, chromogranin A and synaptophysin. Ganglion-like cells showed immunoreactivity for chromogranin A and synaptophysin. A few ganglion-like cells were also positive for AE1/AE3 and/or CAM 5.2. The spindle cells were positive for S-100 protein and neurofilament. The transitional cells showed a similar immunohistochemical profile to the epithelioid cells. The authors believe stem cell theory is a reasonable explanation for the origin of GP. GP probably originate from some kind of mucosa associated stem cell which can differentiate into diverse cellular lineages.
PMCID: PMC3885502  PMID: 24427368
Gangliocytic paraganglioma; bronchial; histomorphology; immunohistochemistry; histogenesis
9.  Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas 
Nature genetics  2013;45(6):602-612.
The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.
doi:10.1038/ng.2611
PMCID: PMC3727232  PMID: 23583981
10.  An inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia 
Cancer cell  2012;22(5):683-697.
SUMMARY
To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
doi:10.1016/j.ccr.2012.10.007
PMCID: PMC3547667  PMID: 23153540
11.  Attomolar DNA detection with chiral nanorod assemblies 
Nature Communications  2013;4:2689.
Nanoscale plasmonic assemblies display exceptionally strong chiral optical activity. So far, their structural design was primarily driven by challenges related to metamaterials whose practical applications are remote. Here we demonstrate that gold nanorods assembled by the polymerase chain reaction into DNA-bridged chiral systems have promising analytical applications. The chiroplasmonic activity of side-by-side assembled patterns is attributed to a 7–9 degree twist between the nanorod axes. This results in a strong polarization rotation that matches theoretical expectations. The amplitude of the bisignate ‘wave’ in the circular dichroism spectra of side-by-side assemblies demonstrates excellent linearity with the amount of target DNA. The limit of detection for DNA using side-by-side assemblies is as low as 3.7 aM. This chiroplasmonic method may be particularly useful for biological analytes larger than 2–5 nm which are difficult to detect by methods based on plasmon coupling and ‘hot spots’. Circular polarization increases for inter-nanorod gaps between 2 and 20 nm when plasmonic coupling rapidly decreases. Reaching the attomolar limit of detection for simple and reliable bioanalysis of oligonucleotides may have a crucial role in DNA biomarker detection for early diagnostics of different diseases, forensics and environmental monitoring.
Nanoscale plasmonic assemblies are known to display exceptionally strong chiral optical activity. Here, the authors assemble gold nanorods into DNA-bridged chiral systems, and demonstrate their high efficiency for DNA detection at very low concentrations.
doi:10.1038/ncomms3689
PMCID: PMC3826651  PMID: 24162144
12.  Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns 
The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss.
doi:10.3892/etm.2013.1406
PMCID: PMC3861312  PMID: 24348793
newborn; hearing screening; gene screening; MassARRAY platform; mitochondrial 12S rRNA; GJB2 gene; SLC26A4 gene
13.  Effects of Zinc Supplementation on the Incidence of Mortality in Preschool Children: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(11):e79998.
Background
Previous trials have shown that zinc supplementation can decrease the risk of diarrhea, pneumonia, and malaria in children; however, the effects of zinc supplementation on mortality remain unclear. This study aimed at evaluating the benefits and risks of zinc supplementation on both total mortality and cause-specific mortality.
Methodology and Principal Findings
We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials in preschool children reporting total mortality or cause-specific mortality. Relative risk (RR) was used as a measure of the effect of zinc supplementation on the risk of mortality using a random effect model. Of the 1,520 identified articles, we included 8 trials reporting data on 87,854 children. Overall, zinc supplementation had no effect on total mortality (RR, 0.76; 95% CI: 0.56–1.04; P = 0.084), diarrhea-related mortality (RR, 0.80; 95% CI: 0.53–1.20; P = 0.276), pneumonia-related mortality (RR, 0.52; 95% CI: 0.11–2.39; P = 0.399), malaria-related mortality (RR, 0.90; 95% CI: 0.77–1.06; P = 0.196), or other causes of mortality (RR, 0.98; 95% CI: 0.67–1.44; P = 0.917). Subgroup analysis indicated that zinc supplementation was associated with a reduction in total mortality risk if the participants were boys, aged greater than 12 months, and the duration of the follow-up period was less than 12 months.
Conclusions/Significance
Zinc supplementation does not have an effect on total mortality, diarrhea-related mortality, pneumonia-related mortality, malaria-related mortality, or other causes of mortality. Subgroup analysis suggested that zinc supplementation can effectively reduce the risk of total mortality if the participants were boys, aged greater than 12 months, and the duration of the follow-up period was less than 12 months.
doi:10.1371/journal.pone.0079998
PMCID: PMC3823854  PMID: 24244591
14.  Comprehensive identification of mutational cancer driver genes across 12 tumor types 
Scientific Reports  2013;3:2650.
With the ability to fully sequence tumor genomes/exomes, the quest for cancer driver genes can now be undertaken in an unbiased manner. However, obtaining a complete catalog of cancer genes is difficult due to the heterogeneous molecular nature of the disease and the limitations of available computational methods. Here we show that the combination of complementary methods allows identifying a comprehensive and reliable list of cancer driver genes. We provide a list of 291 high-confidence cancer driver genes acting on 3,205 tumors from 12 different cancer types. Among those genes, some have not been previously identified as cancer drivers and 16 have clear preference to sustain mutations in one specific tumor type. The novel driver candidates complement our current picture of the emergence of these diseases. In summary, the catalog of driver genes and the methodology presented here open new avenues to better understand the mechanisms of tumorigenesis.
doi:10.1038/srep02650
PMCID: PMC3788361  PMID: 24084849
15.  Serologic Reactivity to the Emerging Pathogen Granulibacter bethesdensis 
The Journal of Infectious Diseases  2012;206(6):943-951.
Background. Granulibacter bethesdensis is a recently described member of the Acetobacteraceae family that has been isolated from patients with chronic granulomatous disease (CGD). Its pathogenesis, environmental reservoir(s), and incidence of infection among CGD patients and the general population are unknown.
Methods. Detected antigens were identified by mass spectroscopy after 2-dimensional electrophoresis and immunoaffinity chromatography. The prevalence of Granulibacter immunoreactivity was assessed through immunoblotting and enzyme-linked immunosorbent assay (ELISA).
Results. Methanol dehydrogenase (MDH) and formaldehyde-activating enzyme were recognized during analysis of sera from infected patients. Unique patterns of immunoreactive bands were identified in Granulibacter extracts, compared with extracts of other Acetobacteraceae species. By use of criteria based on these specific bands, specimens from 79 of 175 CGD patients (45.1%) and 23 of 93 healthy donors (24.7%) reacted to all 11 bands. An ELISA that used native MDH to capture and detect immunoglobulin G was developed and revealed high-titer MDH seroreactivity in culture-confirmed cases and 5 additional CGD patients. Testing of samples collected prior to culture-confirmed infection demonstrated instances of recent seroconversion, as well as sustained seropositivity. Infection of CGD mice with G. bethesdensis confirmed acquisition of high-titer antibody-recognizing MDH.
Conclusions. These serologic tests suggest that Granulibacter immunoreactivity is more common among CGD patients and, perhaps, among healthy donors than was previously suspected. This finding raises the possibility that clinical presentations of Granulibacter infection may be underappreciated.
doi:10.1093/infdis/jis431
PMCID: PMC3501152  PMID: 22782953
16.  GENOMIC LANDSCAPE OF NON-SMALL CELL LUNG CANCER IN SMOKERS AND NEVER SMOKERS 
Cell  2012;150(6):1121-1134.
Summary
We report the results of whole genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and over 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatic modification and DNA repair pathways were identified along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions including ROS1 and ALK as well as novel metabolic enzymes. Cell cycle and JAK-STAT pathways are significantly altered in lung cancer along with perturbations in 54 genes that are potentially targetable with currently available drugs.
doi:10.1016/j.cell.2012.08.024
PMCID: PMC3656590  PMID: 22980976
17.  Fish intake and risk of heart failure: A meta-analysis of five prospective cohort studies 
The findings on the association between fish intake and the risk of heart failure (HF) have been inconsistent. The purpose of this study was to clarify this potential association. We searched for relevant studies in the PubMed database through January 2012 and manually reviewed references. Five independent prospective cohort studies involving 5,273 cases and 144,917 participants were included. The summary relative risk estimates (SRRE) based on the highest compared with the lowest category of fish consumption were estimated by variance-based meta-analysis. In addition, we performed sensitivity and dose-response analyses to examine the association. Overall, an absence of an association between fish intake and HF was observed (SRRE=1.00; 95% CI, 0.81–1.24). However, fried fish intake positively associated with HF (SRRE=1.40; 95% CI, 1.22–1.61). In addition, dose-response analysis of fried fish suggested that each increment of six fried fish per month corresponded to a 37% increase of HF rate (RR=1.37; 95% CI, 1.20–1.56). In conclusion, our findings suggest that there is no significant association between fish intake and risk of HF, with the exception of a possible positive correlation with individuals comsuming fried fish, based on a limited number of studies. Future studies are required to confirm these findings.
doi:10.3892/etm.2012.605
PMCID: PMC3503629  PMID: 23181122
fish; nutrition; heart failure; meta-analysis
18.  OptiVol fluid index predicts acute decompensation of heart failure with a high rate of unexplained events 
Background
Intrathoracic impedance monitoring has emerged as a promising new technique for the detection of impending heart failure (HF). Although false positive episodes have been reported in case reports and clinical trials, the efficacy and false positive rate in real-world practice remain unclear.
Objective
The aim of this study is to investigate the utility and reliability of the OptiVol alert feature in clinical practice.
Methods
We continuously recruited patients who underwent implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (CRT-D) implantation with feature of intrathoracic impedance monitoring system in our center from Sep. 2010 to Oct. 2012. Regular in-office follow-up were required of all patients and the following information was collected at each visit: medical history, device interrogation, N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement and an echocardiogram. Worsening HF was defined as hospitalization or the presentation of signs or symptoms of HF.
Results
Forty three patients (male: 76.7%, mean age: 57 ± 15 years, left ventricular ejection fraction (LVEF): 33% ± 14%) were included in this observational study. Fifty four alert events and 14 adjudicated worsening HF were detected within 288 ±163 days follow-up. Eleven (20.4%) alert episodes were associated with acute cardiac decompensation in 9 patients with a positive predictive value of 78.6%. Forty three audible alerts showed no connection to worsening HF. The unexplained alerts rate was 79.6% and 1.27 per person-year. Thirty seven alarm alerts were detected in patients with EF < 45%, among which 9 accompanied with HF, 17 alerts detected in patients with LVEF ≥ 45% and 2 associated with HF. There was no significant difference between the two groups (9/37 vs. 2/17; P = 0.47).
Conclusions
Patients with normal or nearly normal left ventricular systolic function also exhibited considerable alert events. The OptiVol fluid index predicted worsening cardiac events with a high unexplained detection rate, and any alert must therefore be analyzed with great caution. Efforts to improve the specificity of this monitoring system represent a significant aspect of future studies.
doi:10.3969/j.issn.1671-5411.2013.03.012
PMCID: PMC3796699  PMID: 24133513
Heart failure; Intrathoracic impedance measurement; OptiVol fluid index; Left ventricular ejection fraction
19.  Intrathoracic Nontuberculous Mycobacterial Infections in Otherwise Healthy Children 
Pediatric pulmonology  2009;44(11):1051-1056.
Background
Nontuberculous mycobacterial (NTM) infection is typically associated with lymphadenitis in immune competent children, and disseminated disease in children with immune deficiencies. Isolated pulmonary NTM disease is seen in cystic fibrosis, and is increasingly recognized in immunocompetent elderly women, where it is associated with an increased incidence of cystic fibrosis transmembrane regulator (CFTR) mutations. Thoracic NTM infection has been reported rarely in otherwise healthy children. We aimed to determine whether otherwise healthy children with pulmonary NTM disease had immunologic abnormalities or CFTR mutations.
Study Design
Clinical presentations of five otherwise healthy children with pulmonary NTM were reviewed. Immunologic studies were performed including a complete blood cell count (CBC), flow cytometric lymphocyte phenotyping and IFN-gamma receptor expression, in vitro cytokine stimulation, and serum immunoglobulin levels. Mutational analysis was performed for CFTR.
Results
The children ranged in age from 12 months to 2.5 years at diagnosis. Four presented with new onset wheezing or stridor failing bronchodilator therapy. One child was asymptomatic. Endobronchial lesions and/or hilar lymph nodes causing bronchial obstruction were identified in all patients. Mycobacterium avium complex was cultured from four patients, and M. abscessus from one patient. All patients were successfully treated with anti-mycobacterial therapy with or without surgery. No definitive immunologic abnormalities were identified. No clinically significant mutations were found in CFTR.
Conclusions
Pulmonary NTM infection should be considered in otherwise healthy young children presenting with refractory stridor or wheezing with endobronchial lesions or hilar lymphadenopathy. It does not appear to be associated with recognized underlying immune deficiency or CFTR mutations.
doi:10.1002/ppul.21069
PMCID: PMC3746060  PMID: 19824053
nontuberculous mycobacteria; intrathoracic infection; hilar lymphadenopathy; endobronchial granuloma
20.  Pulmonary mixed squamous cell and glandular papilloma mimicking adenocarcinoma: a case study and literature review 
Journal of Thoracic Disease  2013;5(4):E129-E132.
Mixed squamous cell and glandular papilloma of the lung is an extremely rare benign neoplasm. Here we present another case of mixed squamous cell and glandular papilloma in a 64-year-old female nonsmoker. Histologically, the tumor was composed of mainly papillary structures covered with squamous, glandular and transitional epithelium. Some glandular structures extending into adjacent bronchiolar and alveolar spaces with mucus were similar to adenocarcinoma. Immunohistochemical analysis showed the different kinds of epithelia had similar immunophenotype. The different components were positive for cytokeratin (CK)7, CK19, CAM5.2, CK5/6, CK34βE12, and TTF-1, but negative for CK20. The transitional morphology and immunohistochemistry indicate the different components likely come from a same kind of progenitor in the bronchiolar wall.
doi:10.3978/j.issn.2072-1439.2013.07.38
PMCID: PMC3755688  PMID: 23991321
Lung; pulmonary; mixed squamous cell and glandular papilloma
21.  Aberrant Expression of Beclin-1 and LC3 Correlates with Poor Prognosis of Human Hypopharyngeal Squamous Cell Carcinoma 
PLoS ONE  2013;8(7):e69038.
Background
Beclin-1, a key regulator of autophagy. Microtubule-associated protein 1 light chain 3 (LC3), is involved in autophagsome formation during autophagy. The autophagic genes beclin-1 and LC3 paly an important role in the development and progression of tumor. This study was designed to investigate the expression of beclin-1 and LC3 and to clarify their clinical significance in hypopharyngeal squamous cell carcinoma (HSCC).
Methods
Eighty-two surgical hypopharyngeal squamous cell carcinoma specimens and fifty-four adjacent non-cancerous mucosal epithelial tissues were obtained. Beclin-1 and LC3-II expression was examined by immunohistochemistry, real-time RT-PCR and Western blotting assays. Correlations with patient clinical characteristics and overall survival were evaluated.
Results
Beclin-1 was positively expressed in 42.7% (35/82) of HSCC specimens (adjacent non-cancerous tissues, 79.6%, 43/54; P<0.0001). Furthermore, 41.5% (34/82) of HSCC specimens exhibited high LC3 immunoreactivity (adjacent non-cancerous tissues, 74.1%, 40/54; P=0.0002). Beclin-1 and LC3-II mRNA transcript levels were significantly lower in HSCCs than in paired non-cancerous tissues (P<0.0001, P=0.0001, respectively). Similarly, western blotting assays showed that beclin-1 and LC3-II were markedly decreased in HSCCs (P=0.02, P=0.004, respectively). A positive correlation was observed between the mRNA transcript levels of beclin-1 and LC3-II in HSCCs (r=0.51, P<0.0001; 95%CI: 0.273 to 0.689). Beclin-1 and LC3 expression were significantly correlated with T categories, differentiation and lymph node metastasis. Negative beclin-1 immuoreactivity and low LC3 expression were associated with poorer overall survival in HSCC patients (P<0.0001, P=0.0145, respectively). Multivariate analysis revealed that beclin-1 was an independent prognositic factor for overall survival.
Conclusion
Beclin-1 and LC3-II are downregulated in HSCCs and their aberrant expression correlates with poor prognosis of HSCCs.
doi:10.1371/journal.pone.0069038
PMCID: PMC3723780  PMID: 23935917
22.  BreakFusion: targeted assembly-based identification of gene fusions in whole transcriptome paired-end sequencing data 
Bioinformatics  2012;28(14):1923-1924.
Summary: Despite recent progress, computational tools that identify gene fusions from next-generation whole transcriptome sequencing data are often limited in accuracy and scalability. Here, we present a software package, BreakFusion that combines the strength of reference alignment followed by read-pair analysis and de novo assembly to achieve a good balance in sensitivity, specificity and computational efficiency.
Availability: http://bioinformatics.mdanderson.org/main/BreakFusion
Contact: kchen3@mdanderson.org; lding@genome.wustl.edu
Supplementary information: Supplementary data are available at Bioinformatics online
doi:10.1093/bioinformatics/bts272
PMCID: PMC3389765  PMID: 22563071
23.  Massively Parallel Sequencing Approaches for Characterization of Structural Variation 
The emergence of next-generation sequencing (NGS) technologies offers an incredible opportunity to comprehensively study DNA sequence variation in human genomes. Commercially available platforms from Roche (454), Illumina (Genome Analyzer and Hiseq 2000), and Applied Biosystems (SOLiD) have the capability to completely sequence individual genomes to high levels of coverage. NGS data is particularly advantageous for the study of structural variation (SV) because it offers the sensitivity to detect variants of various sizes and types, as well as the precision to characterize their breakpoints at base pair resolution. In this chapter, we present methods and software algorithms that have been developed to detect SVs and copy number changes using massively parallel sequencing data. We describe visualization and de novo assembly strategies for characterizing SV breakpoints and removing false positives.
doi:10.1007/978-1-61779-507-7_18
PMCID: PMC3679911  PMID: 22228022
Next-generation sequencing; Paired-end sequencing; 454; Illumina; Solexa; Abi solid; Insertions; Deletions; Duplications; Inversions; Translocations; Indels; Copy number variants
24.  Adaptability and Persistence of the Emerging Pathogen Bordetella petrii 
PLoS ONE  2013;8(6):e65102.
The first described, environmentally isolated, Bordetella petrii was shown to undergo massive genomic rearrangements in vitro. More recently, B. petrii was isolated from clinical samples associated with jaw, ear bone, cystic fibrosis and chronic pulmonary disease. However, the in vivo consequences of B. petrii genome plasticity and its pathogenicity remain obscure. B. petrii was identified from four sequential respiratory samples and a post-mortem spleen sample of a woman presenting with bronchiectasis and cavitary lung disease associated with nontuberculous mycobacterial infection. Strains were compared genetically, phenotypically and by antibody recognition from the patient and from inoculated mice. The successive B. petrii strains exhibited differences in growth, antibiotic susceptibility and recognition by the patient’s antibodies. Antibodies from mice inoculated with these strains recapitulated the specificity and strain dependent response that was seen with the patient’s serum. Finally, we characterize one strain that was poorly recognized by the patient’s antibodies, due to a defect in the lipopolysaccharide O-antigen, and identify a mutation associated with this phenotype. We propose that B. petrii is remarkably adaptable in vivo, providing a possible connection between immune response and bacterial evasion and supporting infection persistence.
doi:10.1371/journal.pone.0065102
PMCID: PMC3672207  PMID: 23750235
25.  BreakDancer: An algorithm for high resolution mapping of genomic structural variation 
Nature methods  2009;6(9):677-681.
Detection and characterization of genomic structural variation are important for understanding the landscape of genetic variation in human populations and in complex diseases such as cancer. Recent studies demonstrate the feasibility of detecting structural variation using next-generation, short-insert, paired-end sequencing reads. However, the utility of these reads is not entirely clear, nor are the analysis methods under which accurate detection can be achieved. The algorithm BreakDancer predicts a wide variety of structural variants including indels, inversions, and translocations. We examined BreakDancer's performance in simulation, comparison with other methods, analysis of an acute myeloid leukemia sample, and the 1,000 Genomes trio individuals. We found that it substantially improved the detection of small and intermediate size indels from 10 bp to 1 Mbp that are difficult to detect via a single conventional approach.
doi:10.1038/nmeth.1363
PMCID: PMC3661775  PMID: 19668202

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