| 1. |
- Birney, Ewan, et al.
(author)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Journal article (peer-reviewed)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Antonarakis, Gregory, et al.
(author)
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Bite force and its association with stability following Class II/1 functional appliance treatment
- 2013
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In: European Journal of Orthodontics. - : Oxford University Press (OUP). - 0141-5387 .- 1460-2210. ; 35:4, s. 434-441
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Journal article (peer-reviewed)abstract
- The aims of this study were to investigate the value of pre-treatment maximal molar bite force as a predictive variable in determining post-treatment changes and stability following functional appliance treatment in Class II malocclusion children. Twenty-eight Class II malocclusion children having undergone functional appliance treatment were followed for at least 1 year post-treatment. Maximal molar bite force measurements, lateral cephalograms, and study casts were taken before treatment, after treatment, and after post-treatment follow-up. Relationships between pre-treatment maximal molar bite force and dental or cephalometric changes post-treatment were examined. Patients were divided into stable and unstable groups, based on dental sagittal changes (overjet and molar relationship), and differences between the two groups of patients determined. Post-treatment changes varied widely. Thirteen children showed dentoalveolar sagittal relapse, namely a shift in molars towards a Class II relationship and an increase in overjet, while 15 did not. The unstable group demonstrated a lower pre-treatment maximal molar bite force, as well as a more obtuse gonial angle, than the stable group. The gonial angle was found to be negatively correlated to maximal molar bite force and may thus be a cephalometric indicator partly reflecting the functional condition of the masticatory muscles. Children with a lower pre-treatment maximal molar bite force were more prone to dentoalveolar sagittal relapse following functional appliance treatment.
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| 3. |
- Antonarakis, Gregory
(author)
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Functional appliance treatment and stability in Class II/1 malocclusion, and masticatory muscle characteristics
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Aims: To evaluate the short-term antero-posterior effects on Class II division 1 malocclusion in growing children using functional appliances, and investigate whether the functional capacity of the masticatory musculature can be used as a predictive variable in determining the treatment and post-treatment effects following functional appliance treatment. Material and Methods: Firstly, a literature search was carried out identifying prospective clinical trials on the treatment of Class II malocclusion using functional appliances or/and headgear in growing children. The data provided in the publications underwent meta-analysis using the random effects model with regard to SNA, SNB, ANB, and overjet. Then, two samples of Class II malocclusion growing children, 22 treated with twin-block appliances and 25 with activators, were examined and associations between treatment outcomes and masseter muscle thickness measured by ultrasound or maximal molar bite force, respectively, were determined. Finally, 28 Class II malocclusion growing children having undergone activator treatment were followed-up post-treatment and relationships between maximal molar bite force and post-treatment outcomes and stability were determined. Results: Functional appliances used in the treatment of Class II division 1 malocclusion growing children may bring about an improvement in sagittal intermaxillary relationships mainly by acting on mandibular position. Twin-block appliances also seem to act on the maxilla. During and following this treatment, an adaptation of the masticatory muscles is observed, namely a decrease in masseter muscle thickness and in maximal molar bite force during treatment, and an increase in maximal molar bite force once appliances are discontinued. Children with thinner pre-treatment masseter muscles show a greater proclination of mandibular incisors, distalisation of maxillary molars and posterior displacement of the cephalometric A point during treatment, as well as a less pronounced increase in posterior facial height, condyle-ramus height, and mandibular unit length. Likewise, children with weaker maximal molar bite force pre-treatment show greater improvement in dentoalveolar sagittal relationships, as well as greater changes in SNB and ANB angles. Following activator treatment, children who show dentoalveolar sagittal relapse are more likely to have a lower maximal molar bite force pre-treatment. Moreover, children with an obtuse gonial angle are more likely to show greater incisor compensation during treatment, as well as a greater risk of relapse post-treatment. Conclusions: Mild atrophy of the masticatory muscles may occur due to their decreased functional activity during functional appliance treatment. The functional capacity of the masticatory muscles, and their impact on mandibular morphology and gonial angle shape, may play a role in contributing to the variation seen as regards treatment outcomes and stability.
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| 4. |
- Antonarakis, Gregory, et al.
(author)
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Predictive value of molar bite force on Class II functional appliance treatment outcomes
- 2012
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In: European Journal of Orthodontics. - : Oxford University Press (OUP). - 0141-5387 .- 1460-2210. ; 34, s. 244-249
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Journal article (peer-reviewed)abstract
- Sagittal intermaxillary changes brought about by functional appliances show large inter-individual variation. One factor that may in part explain these differences is the masticatory musculature and its functional capacity. The aims of this study were to investigate changes in maximal molar bite force during functional appliance treatment and to assess the influence of pre-treatment maximal molar bite force on treatment outcomes with functional appliances used in Class II malocclusion children. Twenty-five children (17 males and 8 females), aged 9-13 years, with a Class II malocclusion and increased overjet were treated with functional appliances for 1-2 years. Dental casts, lateral cephalograms, maximal molar bite force, and finger force measurements were performed before (T1) and after (T2) treatment. These same measurements were also performed 1-2 years before treatment (T0); the intermediate period before starting treatment served as the control. Multiple regression analyses were used to determine possible correlations between initial maximal molar bite force and dental or cephalometric changes during treatment. Maximal molar bite force, which increased pre-treatment (T0-T1), decreased during functional appliance treatment (T1-T2). Children with a weaker T1 maximal molar bite force showed a larger overjet reduction, greater improvement in molar relationship, greater reduction in ANB angle, and greater augmentation in SNB angle from T1 to T2. Treatment of children with Class II malocclusions with functional appliances seems to lead to more favourable treatment outcomes in those with a weaker maximal molar bite force. This was observed both as regards improvements in dental sagittal relationships, namely overjet and molar Class, as well as skeletal changes due to a decrease in ANB and an increase in SNB angles. © The Author 2011. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved.
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| 5. |
- Bettegowda, Chetan, et al.
(author)
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Detection of circulating tumor DNA in early- and late-stage human malignancies
- 2014
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:224, s. 224ra24-
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Journal article (peer-reviewed)abstract
- The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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| 6. |
- Elsik, Christine G., et al.
(author)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Journal article (peer-reviewed)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 7. |
- Margulies, Elliott H, et al.
(author)
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Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
- 2007
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In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 760-774
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Journal article (peer-reviewed)abstract
- A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.
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