Browsing by Author "Liu, Y."
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Item CpG island shore methylation regulates caveolin-1 expression in breast cancer(Springer Nature, 2013) Rao, X.; Evans, J.; Chae, H.; Pilrose, J.; Kim, S.; Yan, P.; Huang, R-L; Lai, H-C; Lin, H.; Liu, Y.; Miller, D.; Rhee, J-K; Huang, Y-W; Gu, F.; Gray, J. W.; Huang, TH-M; Nephew, K. P.; Medical and Molecular Genetics, School of MedicineCaveolin-1 (Cav1) is an integral membrane, scaffolding protein found in plasma membrane invaginations (caveolae). Cav1 regulates multiple cancer-associated processes. In breast cancer, a tumor suppressive role for Cav1 has been suggested; however, Cav1 is frequently overexpressed in aggressive breast cancer subtypes, suggesting an oncogenic function in advanced-stage disease. To further delineate Cav1 function in breast cancer progression, we evaluated its expression levels among a panel of cell lines representing a spectrum of breast cancer phenotypes. In basal-like (the most aggressive BC subtype) breast cancer cells, Cav1 was consistently upregulated, and positively correlated with increased cell proliferation, anchorage-independent growth, and migration and invasion. To identify mechanisms of Cav1 gene regulation, we compared DNA methylation levels within promoter 'CpG islands' (CGIs) with 'CGI shores', recently described regions that flank CGIs with less CG-density. Integration of genome-wide DNA methylation profiles ('methylomes') with Cav1 expression in 30 breast cancer cell lines showed that differential methylation of CGI shores, but not CGIs, significantly regulated Cav1 expression. In breast cancer cell lines having low Cav1 expression (despite promoter CGI hypomethylation), we found that treatment with a DNA methyltransferase inhibitor induced Cav1 expression via CGI shore demethylation. In addition, further methylome assessments revealed that breast cancer aggressiveness associated with Cav1 CGI shore methylation levels, with shore hypermethylation in minimally aggressive, luminal breast cancer cells and shore hypomethylation in highly aggressive, basal-like cells. Cav1 CGI shore methylation was also observed in human breast tumors, and overall survival rates of breast cancer patients lacking estrogen receptor α (ERα) negatively correlated with Cav1 expression. Based on this first study of Cav1 (a potential oncogene) CGI shore methylation, we suggest this phenomenon may represent a new prognostic marker for ERα-negative, basal-like breast cancer.Item Gene Expression Patterns in Bone Following Mechanical Loading(Office of the Vice Chancellor for Research, 2010-04-09) Mantila Roosa, S.M.; Liu, Y.; Turner, C.H.Mechanical loading is a potent anabolic stimulus that substantially strengthens bones, and the time course of bone formation after initiating mechanical loading is well characterized. However, the time sequence for gene expression in a bone subjected to mechanical loading, over an extended period of time, has not been established. The advent of high-throughput measurements of gene expression and bioinformatics analysis methods offers new ways to study gene expression patterns. The primary goal of this study was to determine the time sequence for gene expression in a bone subjected to mechanical loading, during key periods of the bone formation process, including expression of matrix-related genes, the appearance of active osteoblasts, and bone desensitization. We evaluated loading-induced gene expression over a time course of 4 hours to 32 days. We then used bioinformatics tools to cluster genes into similar expression patterns and created groups of genes with common functions or signaling pathways.Item Genetic variants in the folate metabolic pathway genes predict melanoma-specific survival(Oxford University Press, 2020-10) Dai, W.; Liu, H.; Liu, Y.; Xu, X.; Qian, D.; Luo, S.; Cho, E.; Zhu, D.; Amos, C.I.; Fang, S.; Lee, J.E.; Li, X.; Nan, H.; Li, C.; Wei, Q.; Epidemiology, School of Public HealthBackground: Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWASs) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway. Objectives: To examine associations between SNPs in folate metabolic pathway genes and CMSS. Methods: We comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11·1%) and 48/409 (11·7%) patients died of cutaneous melanoma, respectively. Results: We identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1·75 (95% confidence interval 1·32-2·32, P = 9·96 × 10-5 ) and 2·05 (1·39-3·01, P = 2·84 × 10-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for the biological plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS. Conclusions: Two possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1 rs1950902 and ALPL rs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.Item Genome-wide meta-analyses of smoking behaviors in African Americans(Springer Nature, 2012-05-22) David, S. P.; Hamidovic, A.; Chen, G. K.; Bergen, A. W.; Wessel, J.; Kasberger, J. L.; Brown, W. M.; Petruzella, S.; Thacker, E. L.; Kim, Y.; Nalls, M. A.; Tranah, G. J.; Sung, Y. J.; Ambrosone, C. B.; Arnett, D.; Bandera, E. V.; Becker, D. M.; Becker, L.; Berndt, S. I.; Bernstein, L.; Blot, W. J.; Broeckel, U.; Buxbaum, S. G.; Caporaso, N.; Casey, G.; Chanock, S. J.; Deming, S. L.; Diver, W. R.; Eaton, C. B.; Evans, D. S.; Evans, M. K.; Fornage, M.; Franceschini, N.; Harris, T. B.; Henderson, B. E.; Hernandez, D. G.; Hitsman, B.; Hu, J. J.; Hunt, S. C.; Ingles, S. A.; John, E. M.; Kittles, R.; Kolb, S.; Kolonel, L. N.; Le Marchand, L.; Liu, Y.; Lohman, K. K.; McKnight, B.; Millikan, R. C.; Murphy, A.; Neslund-Dudas, C.; Nyante, S.; Press, M.; Psaty, B. M.; Rao, D. C.; Redline, S.; Rodriguez-Gil, J. L.; Rybicki, B. A.; Signorello, L. B.; Singleton, A. B.; Smoller, J.; Snively, B.; Spring, B.; Stanford, J. L.; Strom, S. S.; Swan, G. E.; Taylor, K. D.; Thun, M. J.; Wilson, A. F.; Witte, J. S.; Yamamura, Y.; Yanek, L. R.; Yu, K.; Zheng, W.; Ziegler, R. G.; Zonderman, A. B.; Jorgenson, E.; Haiman, C. A.; Furberg, H.; Medicine, School of MedicineThe identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n=32 389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β=0.040, s.e.=0.007, P=1.84 × 10−8). This variant is present in the 5′-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.Item Identification of functional variants from whole-exome sequencing, combined with neuroimaging genetics(Springer Nature, 2013) Nho, K.; Corneveaux, J. J.; Kim, S.; Lin, H.; Risacher, S. L.; Shen, L.; Swaminathan, S.; Ramanan, V. K.; Liu, Y.; Foroud, T.; Inlow, M. H.; Siniard, A. L.; Reiman, R. A.; Aisen, P. S.; Petersen, R. C.; Green, R. C.; Jack, C. R.; Weiner, M. W.; Baldwin, C. T.; Lunetta, K.; Farrer, L. A.; Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study; Furney, S. J.; Lovestone, S.; Simmons, A.; Mecocci, P.; Vellas, B.; Tsolaki, M.; Kloszewska, I.; Soininen, H.; AddNeuroMed Consortium; McDonald, B. C.; Farlow, M. R.; Ghetti, B.; Indiana Memory and Aging Study; Huentelman, M. J.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of MedicineItem Interspecies Comparison of Alveolar Bone Biology, Part I: Morphology and Physiology of Pristine Bone(Sage, 2021) Pilawski, I.; Tulu, U. S.; Ticha, P.; Schüpbach, P.; Traxler, H.; Xu, Q.; Pan, J.; Coyac, B. R.; Yuan, X.; Tian, Y.; Liu, Y.; Chen, J.; Erdogan, Y.; Arioka, M.; Armaro, M.; Wu, M.; Brunski, J. B.; Helms, J. A.; Otolaryngology -- Head and Neck Surgery, School of MedicineIntroduction: Few interspecies comparisons of alveolar bone have been documented, and this knowledge gap raises questions about which animal models most accurately represent human dental conditions or responses to surgical interventions. Objectives: The objective of this study was to employ state-of-the-art quantitative metrics to directly assess and compare the structural and functional characteristics of alveolar bone among humans, mini pigs, rats, and mice. Methods: The same anatomic location (i.e., the posterior maxillae) was analyzed in all species via micro-computed tomographic imaging, followed by quantitative analyses, coupled with histology and immunohistochemistry. Bone remodeling was evaluated with alkaline phosphatase activity and tartrate-resistant acid phosphatase staining to identify osteoblast and osteoclast activities. In vivo fluorochrome labeling was used as a means to assess mineral apposition rates. Results: Collectively, these analyses demonstrated that bone volume differed among the species, while bone mineral density was equal. All species showed a similar density of alveolar osteocytes, with a highly conserved pattern of collagen organization. Collagen maturation was equal among mouse, rat, and mini pig. Bone remodeling was a shared feature among the species, with morphologically indistinguishable hemiosteonal appearances, osteocytic perilacunar remodeling, and similar mineral apposition rates in alveolar bone. Conclusions: Our analyses demonstrated equivalencies among the 4 species in a plurality of the biological features of alveolar bone. Despite contradictory results from older studies, we found no evidence for the superiority of pig models over rodent models in representing human bone biology. Knowledge transfer statement: Animal models are extensively used to evaluate bone tissue engineering strategies, yet there are few state-of-the-art studies that rigorously compare and quantify the factors influencing selection of a given animal model. Consequently, there is an urgent need to assess preclinical animal models for their predictive value to dental research. Our article addresses this knowledge gap and, in doing so, provides a foundation for more effective standardization among animal models commonly used in dentistry.Item Predicting Hazardous Driving Events Using Multi-Modal Deep Learning Based on Video Motion Profile and Kinematics Data(IEEE, 2018-11) Gao, Z.; Liu, Y.; Zheng, J. Y.; Yu, R.; Wang, X.; Sun, P.; Computer and Information Science, School of ScienceAs the raising of traffic accidents caused by commercial vehicle drivers, more regulations have been issued for improving their safety status. Driving record instruments are required to be installed on such vehicles in China. The obtained naturalistic driving data offer insight into the causal factors of hazardous events with the requirements to identify where hazardous events happen within large volumes of data. In this study, we develop a model based on a low-definition driving record instrument and the vehicle kinematic data for post-accident analysis by multi-modal deep learning method. With a higher camera position on commercial vehicles than cars that can observe further distance, motion profiles are extracted from driving video to capture the trajectory features of front vehicles at different depths. Then random forest is used to select significant kinematic variables which can reflect the potential crash. Finally, a multi-modal deep convolutional neural network (DCNN) combined both video and kinematic data is developed to identify potential collision risk in each 12-second vehicle trip. The analysis results indicate that the proposed multi-modal deep learning model can identify hazardous events within a large volumes of data at an AUC of 0.81, which outperforms the state-of-the-art random forest model and kinematic threshold method.Item Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment(Springer Nature, 2013) Nho, K.; Corneveaux, J. J.; Kim, S.; Lin, H.; Risacher, S. L.; Shen, L.; Swaminathan, S.; Ramanan, V. K.; Liu, Y.; Foroud, T.; Inlow, M. H.; Siniard, A. L.; Reiman, R. A.; Aisen, P. S.; Petersen, R. C.; Green, R. C.; Jack, C. R.; Weiner, M. W.; Baldwin, C. T.; Lunetta, K.; Farrer, L. A.; Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study; Furney, S. J.; Lovestone, S.; Simmons, A.; Mecocci, P.; Vellas, B.; Tsolaki, M.; Kloszewska, I.; Soininen, H.; AddNeuroMed Consortium; McDonald, B. C.; Farlow, M. R.; Ghetti, B.; Indiana Memory and Aging Study; Huentelman, M. J.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of MedicineWhole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.