The present study aimed to explore the safety profile and clinical efficacy of CT-guided radioactive seed implantation in treating local recurrent rectal carcinoma.
Materials and methods
CT-guided 125I seed implantation was carried out in 20 patients with locally recurrent rectal carcinoma. 14 of the 20 patient had prior adjuvant external-beam radiation therapy (EBRT). The treatment planning system (TPS) was used preoperatively to reconstruct three dimensional images of the tumor and to calculate the estimated seed number and distribution. The median matched peripheral dose (MPD) was 120 Gy (range, 100-160 Gy).
Of the 20 patients, 12 were male, 8 were female, and ages ranged from 38 to 78, with a median age of 62. Duration of follow-up was 3-34 months. The response rate of pain relief was 85% (17/20). Repeat CT scan 2 months following the procedure revealed complete response (CR) of the tumor in 2 patients, partial response (PR) in 13 patients, stable disease (SD) in 3 patients, and progressive disease (PD) in 2 patients. 75% of patients had either CR or PR. Median survival time was 18.8 months (95% CI: 3.5-22.4 months). 1 and 2 year survival rates were 75% and 25%, respectively. 4 patients died of recurrent tumor; 4 patients died of distant metastases; 9 patients died of recurrent tumor and distant metastases. 3 patients survived after 2 year follow up. Two patients were found to have mild hematochezia, which was reversible with symptomatic management.
CT-guided 125I seed implantation appeared to be a safe, useful and less complicated interventional treatment option for local recurrent rectal carcinoma.
Toward an understanding of the protein interaction network of the human liver
An extensive interaction network of human liver-expressed proteins is described, composed of 3484 interactions among 2582 proteins. Proteins associated with liver disease tend to be central and highly connected in the network.
Proteome-scale protein interaction maps are available for many organisms, ranging from bacteria, yeast, worms and flies to humans. These maps provide substantial new insights into systems biology, disease research and drug discovery. However, only a small fraction of the total number of human protein–protein interactions has been identified. In this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins. The data set has a validation rate of over 72% as determined by three independent biochemical or cellular assays. The network includes metabolic enzymes and liver-specific, liver-phenotype and liver-disease proteins that are individually critical for the maintenance of liver functions. The liver enriched proteins had significantly different topological properties and increased our understanding of the functional relationships among proteins in a liver-specific manner. Our data represent the first comprehensive description of a HLPN, which could be a valuable tool for understanding the functioning of the protein interaction network of the human liver.
human liver; network; protein–protein interaction; yeast two hybrid
The ChIP-chip and ChIP-seq techniques enable genome-wide mapping of in vivo protein-DNA interactions and chromatin states. The cross-platform and between-laboratory variation poses a challenge to the comparison and integration of results from different ChIP experiments. We describe a novel method, MM-ChIP, which integrates information from cross-platform and between-laboratory ChIP-chip or ChIP-seq datasets. It improves both the sensitivity and the specificity of detecting ChIP-enriched regions, and is a useful meta-analysis tool for driving discoveries from multiple data sources.
Our previous studies showed that tetraspanin CD151 promotes neovascularization in rat hindlimb and myocardial ischemia models. This study is to assess whether CD151 induces arteriogenesis and promotes functional neovascularization in a pig myocardial infarction model, and to determine the signaling pathways involved. CD151 cDNA and antiCD151 sequence were constructed into a recombinant adeno-associated virus (rAAV) vector. All 26 pigs used either were subjected to coronary artery ligation or did not undergo surgery. Eight wks after viral administration, the expression of CD151 protein was measured by Western blot. The densities of capillaries and arterioles were determined using immunohistochemistry. Regional myocardial perfusion and other myocardial functions were evaluated by 13N-labeled NH3 positron emission computed tomography (13N-NH3 PET) and echocardiography. Western blot was performed for assessing the signaling mechanisms. Overexpression of CD151 markedly increased the densities of capillaries and arterioles, significantly enhanced the regional myocardial perfusion, reduced myocardial ischemia, and improved the myocardial contraction, wall motion, and wall thickness. Conversely, antiCD151 gene delivery reversed the above changes. In addition, CD151 activated focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), c-Jun N-teminal kinase (JNK), phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and endothelial nitric-oxide synthase (eNOS), and increased nitric oxide (NO) level. These findings demonstrate a robust role of CD151 in inducing and/or upregulating neovascularization. CD151-dependent neovascularization correlates with the activations of FAK, mitogen activated protein kinases (MAPKs), and PI3K signaling, suggesting that CD151 may promote neovascularization via MAPKs and PI3K pathways.
AIM: To examine transforming growth factor-β1 (TGF-β1) promoter methylation in gastric cancer and to determine if Helicobacter pylori (H. pylori) or interleukin (IL)-1β could induce TGF-β1 hypermethylation in vitro.
METHODS: We examined the frequency and extent of TGF-β1 promoter methylation using methylation-specific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects. H. pylori infection was confirmed by a positive result from either a serological test, histological analysis or C13 urea breath test. GES-1 and MKN-45 cells co-cultured with H. pylori or treated with IL-1β for 12, 24 and 48 h in vitro tested the effects of H. pylori or IL-1β on TGF-β1.
RESULTS: Twenty-four/forty-seven (51%) cases of gastric cancer (GC) tissues showed TGF-β1 promoter methylation, 15/47 (31.9%) cases of matched non-cancerous gastric mucosa tissues from the GC patients, and 11/39 (28%) case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation (51% vs 28%, P < 0.05). Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients (0.24 ± 0.06 vs 0.17 ± 0.04, P < 0.05) and normal gastric tissues from non-GC subjects (0.24 ± 0.06 vs 0.15 ± 0.03, P < 0.05). TGF-β1 methylation was found in 48.3% of H. pylori-positive gastric mucosal tissues whereas only 23.1% of H. pylori-negative gastric mucosal tissues showed TGF-β1 methylation (48.3% vs 23.1%, P < 0.05). IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h. Further studies showed that pre-treatment of GES-1 cells with 20 ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation. Infection of GES-1 cells by H. pylori was not found to induce significant TGF-β1 promoter methylation.
CONCLUSION: Our data revealed that TGF-β1 promoter is methylated in GC patients. IL-1β may be an important mediator for H. pylori induced gene methylation during GC development.
Transforming growth factor-β1; Interleukin-1β; Methylation; Helicobacter pylori; Gastric cancer
Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18X per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from EPAS1, a transcription factor involved in response to hypoxia. One SNP at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.
The profiling of small RNAs by high throughput sequencing (smRNA-Seq) has revealed the complexity of the RNA world. Here, we describe a computational scheme for dissecting the plant smRNAome by integrating smRNA-Seq datasets in Arabidopsis thaliana. Our analytical approach first defines ab initio the genomic loci that produce smRNAs as basic units, then utilizes principal component analysis (PCA) to predict novel miRNAs. Secondary structure prediction of candidates’ putative precursors discovered a group of long hairpin double-stranded RNAs (lh-dsRNAs) formed by inverted duplications of decayed coding genes. These gene remnants produce miRNA-like small RNAs which are predominantly 21- and 22-nt long, dependent of DCL1 but independent of RDR2 and DCL2/3/4, and associated with AGO1. Additionally, we found two classes of transcription start site associated- (TSSa-) RNAs located at sense (+) and antisense (−) approximately 100 ~ 200 bp downstream of TSSs, but are differentially incorporated into AGO1 and AGO4, respectively.
High-throughput sequencing; small RNAs; Principal component analysis; TSS-associated RNAs
We investigated serum total immunoglobulin E (IgE), IgG, and IgG1 levels in patients with and without echinococcosis-induced anaphylactic shock. This was a case-control study of 11 patients with echinococcosis-induced anaphylactic shock and 22 echinococcosis patients with cyst rupture but without anaphylactic shock. Blood was collected before surgery (T0), at the time of cyst rupture (T1), and shock (Tx), 1 h (T2), 1 day (T3), and 1 week (T4) after cyst rupture. Serum IgE, IgG, and IgG1 were determined by enzyme-linked immunosorbent assay. Serum IgE, IgG, and IgG1 levels were significantly higher in patients who developed anaphylactic shock at all time points. Increased pre-surgical IgG and IgG1 levels were identified to be a significant risk factors for developing anaphylactic shock. The results showed that a serum IgG concentration of 312.25 μg/mL could be used as a cut-off point to predict whether an echinococcosis patient would develop anaphylactic shock.
There are controversies on the association between interleukin-13 (IL-13) +1923C/T polymorphism (rs1295686) and the risk of asthma. We performed this study to assess the association by the method of meta-analysis. A systematic search current to October 16, 2012, was conducted using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) and identified ten studies comprising 13698 cases and 38209 controls. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. There was a significant association between IL-13 +1923C/T polymorphism and asthma risk in codominant model. When stratified by ethnicity, IL-13 +1923C/T polymorphism remained significantly associated with higher asthma risk in Asians and Caucasians. In the subgroup analysis by study quality, a significantly increased asthma risk was observed in high quality studies. Sensitivity analysis and cumulative analysis further strengthened the validity of the results. No publication bias was found in this meta-analysis. In conclusion, results from this meta-analysis suggested that IL-13 +1923C/T polymorphism was a risk factor of asthma.
Summary: Transcription and chromatin regulators, and histone modifications play essential roles in gene expression regulation. We have created CistromeMap as a web server to provide a comprehensive knowledgebase of all of the publicly available ChIP-Seq and DNase-Seq data in mouse and human. We have also manually curated metadata to ensure annotation consistency, and developed a user-friendly display matrix for quick navigation and retrieval of data for specific factors, cells and papers. Finally, we provide users with summary statistics of ChIP-Seq and DNase-Seq studies.
Availability: Freely available on the web at http://cistrome.dfci.harvard.edu/pc/
Epigenetic regulators represent a promising new class of therapeutic targets for cancer. Enhancer of zeste homolog 2 (EZH2), a subunit of Polycomb repressive complex 2 (PRC2), silences gene expression via its histone methyltransferase activity. Here we report that the oncogenic function of EZH2 in castration-resistant prostate cancer (CRPC) is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a co-activator for critical transcription factors including the androgen receptor (AR). This functional switch is dependent on phosphorylation of EZH2, and requires an intact methyltransferase domain. Hence, targeting the non-PRC2 function of EZH2 may have significant therapeutic efficacy for treating metastatic, hormone-refractory prostate cancer.
Nuclear receptors (NRs) comprise a superfamily of ligand-activated transcription factors that play important roles in both physiology and diseases including cancer. The technologies of Chromatin ImmunoPrecipitation followed by array hybridization (ChIP-chip) or massively parallel sequencing (ChIP-seq) has been used to map, at an unprecedented rate, the in vivo genome-wide binding (cistrome) of NRs in both normal and cancer cells. We developed a curated database of 88 NR cistrome datasets and other associated high-throughput datasets, including 121 collaborating factor cistromes, 94 epigenomes and 319 transcriptomes. Through integrative analysis of the curated NR ChIP-chip/seq datasets, we discovered novel factor-specific noncanonical motifs that may have important regulatory roles. We also revealed a common feature of NR pioneering factors to recognize relatively short and AT-rich motifs. Most NRs bind predominantly to introns and distal intergenetic regions, and binding sites closer to transcription start sites (TSSs) were found to be neither stronger nor more evolutionarily conserved. Interestingly, while most NRs appear to be predominantly transcriptional activators, our analysis suggests that the binding of ESR1, RARA and RARG has both activating and repressive effects. Through meta-analysis of different omic data of the same cancer cell line model from multiple studies, we generated consensus cistrome and expression profiles. We further made probabilistic predictions of the NR target genes by integrating cistrome and transcriptome data, and validated the predictions using expression data from tumor samples. The final database, with comprehensive cistrome, epigenome, transcriptome datasets, and downstream analysis results, constitutes a valuable resource for the nuclear receptor and cancer community.
Diabetes mellitus (DM) exacerbates coronary artery disease (CAD) morbidity and mortality. Mesenchymal stem cells (MSCs) play an important therapeutic role in myocardial ischemic injury. However, little is known about changes in the cardioprotective characteristics of MSCs from patients with DM.
Sternal bone marrow aspirates were taken at the time of coronary artery bypass graft surgery. The morphology and growth characteristics of hMSCs were observed in passage 3. Differences in gene expression profiling were measured by Affymetrix GeneChipHuman Genome U133 Plus 2.0 Arrays. Forty two adult male rats with experimentally CAD were randomized into three groups. MSCs from patients with CAD+DM or CAD were injected into the infarcted myocardium. Control animals received culture medium. Echocardiography, TUNEL, immunohistochemistry and Western-blot analysis were performed 4 weeks after transplantation.
Growth curves showed that proliferation of hMSCs in the CAD+DM group was significantly lower than in the CAD group. Nine transcripts of genes related to apoptosis containing Bcl-2 were found to differentiate the two groups. Transplantation of hMSCs in the infarcted border zone improved cardiac function, but DM partly impaired this effect. Similar results were observed from TUNEL, immunohistochemistry and Western-blot analysis.
hMSCs from patients with CAD+DM and CAD alone both have proliferative properties. Transplantation of hMSCs ameliorate heart function, but proliferative ability and myocardial protection decrease significantly in MSCs obtained from patients with CAD+DM compared with cultures from patients with CAD alone, possibly as a result of differences in Bcl-2 protein expression and reduced anti-apoptosis.
Mesenchymal stem cells; Coronary artery disease; Diabetes mellitus; Myocardial infarction; Bcl-2
Left supraclavicular lymph node metastasis is a rare presentation of hepatocellular carcinoma (HCC). This phenomenon is easily neglected in the clinic. A 56-year-old man presented with HCC. On examination, a 1cm long left supraclavicular lymph node was palpated. Auxiliary examination indicated a lesion located in the right lobe of the liver. Fine needle aspiration cytology (FNAC) of the enlarged lymph node was performed; however, only necrosis was found. Hepatectomy was performed and HCC was confirmed by Hematoxylin-Eosin staining. However, 14 d after surgery, significantly enlarged left supraclavicular lymph nodes, a new intrahepatic lesion, and pulmonary and mediastinal metastasis appeared. An excisional biopsy of the left supraclavicular lymph node was performed, and its findings confirmed metastatic HCC. The patient’s HCC rapidly progressed and he died one month later. It is possible for HCC to metastasize to the left supraclavicular lymph node. Surgeons should always consider an overall physical examination. When left supraclavicular lymphadenopathy of unknown origin is encountered, FNAC should be performed initially. If the results are negative, an excisional biopsy and subsequent Positron emission tomography - computed tomography scanning should be performed. These are very important for making the correct diagnosis and for selecting reasonable therapies.
Left supraclavicular lymph node; Metastasis; Hepatocellular carcinoma; Fine needle aspiration cytology; Misdiagnosis
We performed a systematic evaluation of how variations in sequencing depth and other parameters influence interpretation of Chromatin immunoprecipitation (ChIP) followed by sequencing (ChIP-seq) experiments. Using Drosophila S2 cells, we generated ChIP-seq datasets for a site-specific transcription factor (Suppressor of Hairy-wing) and a histone modification (H3K36me3). We detected a chromatin state bias, open chromatin regions yielded higher coverage, which led to false positives if not corrected and had a greater effect on detection specificity than any base-composition bias. Paired-end sequencing revealed that single-end data underestimated ChIP library complexity at high coverage. The removal of reads originating at the same base reduced false-positives while having little effect on detection sensitivity. Even at a depth of ~1 read/bp coverage of mappable genome, ~1% of the narrow peaks detected on a tiling array were missed by ChIP-seq. Evaluation of widely-used ChIP-seq analysis tools suggests that adjustments or algorithm improvements are required to handle datasets with deep coverage.
Staphylococcus aureus is the major cause of hospital-acquired and community-acquired pneumonia. Host defense to S.aureus infection is largely mediated by the innate immune system. γδ T cells play an important role in innate immunity to many infectious diseases. However, less is known about the role of these cells during S.aureus-induced pneumonia. In this study, we examined the response and the role of γδ T cells to pulmonary S.aureus infection.
Mice infected with S. aureus intranasally showed rapid γδ T cells accumulation in the lung. Deficiency of γδ T cells led to attenuated bacterial clearance and less tissue damage in lung compared with WT mice. Moreover, TCR-δ−/− mice exhibited impaired neutrophil recruitment and reduced cytokine production at the site of infection. The γδ T cells in response to pulmonary S. aureus infection mainly secreted IL-17 and γδ T cells deficiency reduced IL-17 production, which might regulate the production of neutrophil-inducing cytokine/chemokine in the S. aureus-infected lungs.
Accumulation of γδ T cells in the lungs to S. aureus infection is beneficial for bacteria clearance and also contributes to the tissue damage. These cells were the primary source of IL-17, which might influence the recruitment of neutrophils at the early stage of infection.
Disruption of the circadian clock exacerbates metabolic diseases including obesity and diabetes. Here we show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.
The complete mitochondrial DNA (mtDNA) of Gracilariopsis lemaneiformis was sequenced (25883 bp) and mapped to a circular model. The A+T composition was 72.5%. Forty six genes and two potentially functional open reading frames were identified. They include 24 protein-coding genes, 2 rRNA genes, 20 tRNA genes and 2 ORFs (orf60, orf142). There is considerable sequence synteny across the five red algal mtDNAs falling into Florideophyceae including Gr. lemaneiformis in this study and previously sequenced species. A long stem-loop and a hairpin structure were identified in intergenic regions of mt genome of Gr. lemaneiformis, which are believed to be involved with transcription and replication. In addition, the mtDNAs of two mutagenic cultivated breeds (“981” and “07-2”) were also sequenced. Compared with the mtDNA of wild Gr. lemaneiformis, the genome size and gene length and order of three strains were completely identical except nine base mutations including eight in the protein-coding genes and one in the tRNA gene. None of the base mutations caused frameshift or a premature stop codon in the mtDNA genes. Phylogenetic analyses based on mitochondrial protein-coding genes and rRNA genes demonstrated Gracilariopsis andersonii had closer phylogenetic relationship with its parasite Gracilariophila oryzoides than Gracilariopsis lemaneiformis which was from the same genus of Gracilariopsis.
We generated extensive transcriptional and proteomic profiles from a Her2-driven mouse model of breast cancer that closely recapitulates human breast cancer. This report makes these data publicly available in raw and processed forms, as a resource to the community. Importantly, we previously made biospecimens from this same mouse model freely available through a sample repository, so researchers can obtain samples to test biological hypotheses without the need of breeding animals and collecting biospecimens.
Twelve datasets are available, encompassing 841 LC-MS/MS experiments (plasma and tissues) and 255 microarray analyses of multiple tissues (thymus, spleen, liver, blood cells, and breast). Cases and controls were rigorously paired to avoid bias.
In total, 18,880 unique peptides were identified (PeptideProphet peptide error rate ≤1%), with 3884 and 1659 non-redundant protein groups identified in plasma and tissue datasets, respectively. Sixty-one of these protein groups overlapped between cancer plasma and cancer tissue.
Conclusions and clinical relevance
These data are of use for advancing our understanding of cancer biology, for software and quality control tool development, investigations of analytical variation in MS/MS data, and selection of proteotypic peptides for MRM-MS. The availability of these datasets will contribute positively to clinical proteomics.
Breast cancer; Her2; mouse; proteome; transcriptome
This study investigated the effect of Icariin (ICA) supplementation on diabetic retinopathy (DR) in a streptozotocin-induced diabetic rat model system. Fifty Sprague Dawley rats were randomly distributed into a control group and a streptozotocin-induced diabetes group. Diabetic rats were randomly divided into two groups; one group received ICA 5 mg/kg/day for 12 weeks by oral gavage; the other group received saline gavage as a placebo. Retinal morphological changes, endothelial markers (RECA), collagen IV (Col-IV), vascular endothelial growth factor (VEGF), and neuropathic changes (Thy-1 and Brn3a expression) of the retinal ganglion cells (RGCs) were investigated. The effects of ICA at various concentrations (0, 101, 102, 103 nmol/mL) on neurite growth were investigated also in retinal ganglion cells (RGC) cultured from both diabetic and normal animals. Numerous pathological changes (deceased expression of RECA, VEGF, Thy-1, and Brn3a as well as decreased Collagen IV and Müller cell content) were noted in the retinal vessels of diabetic rats; these changes were attenuated in diabetic animals that received ICA. ICA enhanced neurite growth in RGC from both normal rats and diabetic rats in a dose dependent fashion. ICA may be useful in the treatment of diabetic retinopathy. Further investigations are indicated.
icariin; streptozotocin; diabetes; retina; diabetic retinopathy
Recent studies have shown that androgen displays an inhibitory effect on breast cancer cell lines that express androgen receptor (AR) but not estrogen receptor (ER) and progesterone receptor (PR). We have previously reported that approximately 1/3 of ER negative high grade invasive ductal carcinomas express AR. Thus, AR can serve as a potential therapeutic target for this group of patients.
Here we investigated AR expression patterns in 980 consecutive breast carcinomas.
We found that (1) AR was expressed more frequently (77%) than ER (61%) and PR (60%) in breast carcinomas; (2) AR expression was associated with ER and PR expression (P < 0.0001), small tumor size (P = 0.0324) and lower Ki-67 expression (P = 0.0013); (3) AR expression was found in 65% of ER negative tumors; (4) AR expression was associated with PR and Ki-67 in ER negative tumors, but not in ER positive tumors; (5) AR expression was higher in ER positive subtypes (Luminal A, Luminal B and Luminal HER2 subtypes, 80%–86%) and lower in ER negative subtypes [HER2, triple negative (TN), and TN EFGR positive subtypes; 52%–66%], with over 50% of TN tumors expressing AR.
More breast carcinomas express AR than ER and PR, including significant numbers of ER negative and TN tumors, for which AR could serve as a potential therapeutic target.
androgen receptor; breast cancer; estrogen receptor; HER2; Ki-67; molecular classification; progesterone receptor
The increasing volume of ChIP-chip and ChIP-seq data being generated creates a challenge for standard, integrative and reproducible bioinformatics data analysis platforms. We developed a web-based application called Cistrome, based on the Galaxy open source framework. In addition to the standard Galaxy functions, Cistrome has 29 ChIP-chip- and ChIP-seq-specific tools in three major categories, from preliminary peak calling and correlation analyses to downstream genome feature association, gene expression analyses, and motif discovery. Cistrome is available at http://cistrome.org/ap/.
We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor–binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor–binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
Prediction of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is of major interest in AD research. A large number of potential predictors have been proposed, with most investigations tending to examine one or a set of related predictors. In this study, we simultaneously examined multiple features from different modalities of data, including structural magnetic resonance imaging (MRI) morphometry, cerebrospinal fluid (CSF) biomarkers and neuropsychological and functional measures (NMs), to explore an optimal set of predictors of conversion from MCI to AD in an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. After FreeSurfer-derived MRI feature extraction, CSF and NM feature collection, feature selection was employed to choose optimal subsets of features from each modality. Support vector machine (SVM) classifiers were then trained on normal control (NC) and AD participants. Testing was conducted on MCIc (MCI individuals who have converted to AD within 24 months) and MCInc (MCI individuals who have not converted to AD within 24 months) groups. Classification results demonstrated that NMs outperformed CSF and MRI features. The combination of selected NM, MRI and CSF features attained an accuracy of 67.13%, a sensitivity of 96.43%, a specificity of 48.28%, and an AUC (area under curve) of 0.796. Analysis of the predictive values of MCIc who converted at different follow-up evaluations showed that the predictive values were significantly different between individuals who converted within 12 months and after 12 months. This study establishes meaningful multivariate predictors composed of selected NM, MRI and CSF measures which may be useful and practical for clinical diagnosis.