Immunology and Medical Genetics

Columbus, OH, United States

Immunology and Medical Genetics

Columbus, OH, United States
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Sweet K.,Clinical Cancer Genetics Program | Sweet K.,Comprehensive Cancer Center | Sweet K.,Ohio State University | Senter L.,Clinical Cancer Genetics Program | And 8 more authors.
Breast Cancer Research and Treatment | Year: 2010

The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S, and C61G were confirmed as deleterious. © 2009 Springer Science+Business Media, LLC.

Zhang L.,Ohio State University | Xu J.S.,Ohio State University | Sanders V.M.,Immunology and Medical Genetics | Roberts C.J.,Ohio State University | Xu R.X.,Ohio State University
Journal of Biomedical Optics | Year: 2010

We synthesize multifunctional microbubbles (MBs) for targeted delivery of antivascular endothelial growth factor (antiVEGF) therapy with multimodal imaging guidance. Poly-lactic-co-glycolic acid (PLGA) MBs encapsulating Texas Red dye are fabricated by a modified double-emulsion process. Simultaneous ultrasound and fluorescence imaging are achieved using Texas Red encapsulated MBs. The MBs are conjugated with Avastin, an antiVEGF antibody for treating neovascular age-related macular degeneration (AMD). The conjugation efficiency is characterized by enzyme-linked immunosorbent assay (ELISA). The efficiency for targeted binding of Avastinconjugated MBs is characterized by microscopic imaging. Our work demonstrates the technical potential of using multifunctional MBs for targeted delivery of antiVEGF therapy in the treatment of exudative AMD. © 2010 Society of Photo-Optical Instrumentation Engineers.

Zeng X.,Emory University | Shaikh F.Y.,Immunology and Medical Genetics | Harrison M.K.,Emory University | Adon A.M.,Emory University | And 6 more authors.
Oncogene | Year: 2010

Centrosome amplification (CA) contributes to carcinogenesis by generating aneuploidy. Elevated frequencies of CA in most benign breast lesions and primary tumors suggest a causative role for CA in breast cancers. Clearly, identifying which and how altered signal transduction pathways contribute to CA is crucial to breast cancer control. Although a causative and cooperative role for c-Myc and Ras in mammary tumorigenesis is well documented, their ability to generate CA during mammary tumor initiation remains unexplored. To answer that question, K-Ras G12D and c-Myc were induced in mouse mammary glands. Although CA was observed in mammary tumors initiated by c-Myc or K-Ras G12D, it was detected only in premalignant mammary lesions expressing K-Ras G12D. CA, both in vivo and in vitro, was associated with increased expression of the centrosome-regulatory proteins, cyclin D1 and Nek2. Abolishing the expression of cyclin D1, Cdk4 or Nek2 in MCF10A human mammary epithelial cells expressing H-Ras G12V abrogated Ras-induced CA, whereas silencing cyclin E1 or B2 had no effect. Thus, we conclude that CA precedes mammary tumorigenesis, and interfering with centrosome-regulatory targets suppresses CA.

North J.A.,Stanford University | Javaid S.,Immunology and Medical Genetics | Ferdinand M.B.,Ohio State University | Chatterjee N.,Southern Illinois University Carbondale | And 8 more authors.
Nucleic Acids Research | Year: 2011

Nucleosomes, the fundamental units of chromatin structure, are regulators and barriers to transcription, replication and repair. Post-translational modifications (PTMs) of the histone proteins within nucleosomes regulate these DNA processes. Histone H3(T118) is a site of phosphorylation [H3(T118ph)] and is implicated in regulation of transcription and DNA repair. We prepared H3(T118ph) by expressed protein ligation and determined its influence on nucleosome dynamics. We find H3(T118ph) reduces DNA-histone binding by 2 kcal/mol, increases nucleosome mobility by 28-fold and increases DNA accessibility near the dyad region by 6-fold. Moreover, H3(T118ph) increases the rate of hMSH2-hMSH6 nucleosome disassembly and enables nucleosome disassembly by the SWI/SNF chromatin remodeler. These studies suggest that H3(T118ph) directly enhances and may reprogram chromatin remodeling reactions. © 2011 The Author(s).

Urdinguio R.G.,LHospitalet | Fernandez A.F.,LHospitalet | Lopez-Nieva P.,LHospitalet | Rossi S.,University of Texas M. D. Anderson Cancer Center | And 7 more authors.
Epigenetics | Year: 2010

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate post-transcriptional gene expression. They influence a wide range of physiological functions, including neuronal processes, and are regulated by various mechanisms, such as DNA methylation. This epigenetic mark is recognized by transcriptional regulators such as the methyl CpG binding protein Mecp2. Rett syndrome is a complex neurological disorder that has been associated with mutations in the gene coding for Mecp2. Thus, we examined the possible miRNA misregulation caused by Mecp2 absence in a mouse model of Rett syndrome. Using miRNA expression microarrays, we observed that the brain of Rett syndrome mice undergoes a disruption of the expression profiles of miRNAs. Among the significantly altered miRNAs (26%, 65 of 245), overall downregulation of these transcripts was the most common feature (71%), while the remaining 30% were upregulated. Further validation by quantitative RT-PCR demonstrated that the most commonly disrupted miRNAs were miR-146a, miR-146b, miR-130, miR-122a, miR-342 and miR-409 (downregulated) and miR-29b, miR329, miR-199b, miR-382, miR-296, miR-221 and miR-92 (upregulated). Most importantly, transfection of miR-146a in a neuroblastoma cell line caused the downregulation of IL-1 receptor-associated kinase 1 (Irak1) levels, suggesting that the identified defect of miR-146a in Rett syndrome mice brains might be responsible for the observed upregulation of Irak1 in this model of the human disease. Overall, we provide another level of molecular deregulation occurring in Rett syndrome that might be useful for understanding the disease and for designing targeted therapies. © 2010 Landes Bioscience.

Kiecolt-Glaser J.K.,Ohio State University | Christian L.,Ohio State University | Malarkey W.B.,Ohio State University | Emery C.F.,Ohio State University | And 2 more authors.
Psychosomatic Medicine | Year: 2010

Objective: To address the mechanisms underlying hatha yoga's potential stress-reduction benefits, we compared inflammatory and endocrine responses of novice and expert yoga practitioners before, during, and after a restorative hatha yoga session, as well as in two control conditions. Stressors before each of the three conditions provided data on the extent to which yoga speeded an individual's physiological recovery. Methods: A total of 50 healthy women (mean age, 41.32 years; range, 30-65 years), 25 novices and 25 experts, were exposed to each of the conditions (yoga, movement control, and passive-video control) during three separate visits. Results: The yoga session boosted participants' positive affect compared with the control conditions, but no overall differences in inflammatory or endocrine responses were unique to the yoga session. Importantly, even though novices and experts did not differ on key dimensions, including age, abdominal adiposity, and cardiorespiratory fitness, novices' serum interleukin (IL)-6 levels were 41% higher than those of experts across sessions, and the odds of a novice having detectable C-reactive protein (CRP) were 4.75 times as high as that of an expert. Differences in stress responses between experts and novices provided one plausible mechanism for their divergent serum IL-6 data; experts produced less lipopolysaccharide-stimulated IL-6 in response to the stressor than novices, and IL-6 promotes CRP production. Conclusion: The ability to minimize inflammatory responses to stressful encounters influences the burden that stressors place on an individual. If yoga dampens or limits stress-related changes, then regular practice could have substantial health benefits. Copyright © 2010 by the American Psychosomatic Society.

Taslim C.,Immunology and Medical Genetics | Taslim C.,Ohio State University | Huang T.,Immunology and Medical Genetics | Lin S.,Immunology and Medical Genetics | Lin S.,Ohio State University
Bioinformatics | Year: 2011

Differential Identification using Mixtures Ensemble (DIME) is a package for identification of biologically significant differential binding sites between two conditions using ChIP-seq data. It considers a collection of finite mixture models combined with a false discovery rate (FDR) criterion to find statistically significant regions. This leads to a more reliable assessment of differential binding sites based on a statistical approach. In addition to ChIP-seq, DIME is also applicable to data from other high-throughput platforms. © The Author 2011. Published by Oxford University Press. All rights reserved.

Amunugama R.,Immunology and Medical Genetics | Groden J.,Immunology and Medical Genetics | Fishel R.,Immunology and Medical Genetics
DNA Repair | Year: 2013

There are six human RAD51 related proteins (HsRAD51 paralogs), HsRAD51B, HsRAD51C, HsRAD51D, HsXRCC2, HsXRCC3 and HsDMC1, that appear to enhance HsRAD51 mediated homologous recombinational (HR) repair of DNA double strand breaks (DSBs). Here we model the structures of HsRAD51, HsRAD51B and HsRAD51C and show similar domain orientations within a hypothetical nucleoprotein filament (NPF). We then demonstrate that HsRAD51B-HsRAD51C heterodimer forms stable complex on ssDNA and partially stabilizes the HsRAD51 NPF against the anti-recombinogenic activity of BLM. Moreover, HsRAD51B-HsRAD51C stimulates HsRAD51 mediated D-loop formation in the presence of RPA. However, HsRAD51B-HsRAD51C does not facilitate HsRAD51 nucleation on a RPA coated ssDNA. These results suggest that the HsRAD51B-HsRAD51C complex plays a role in stabilizing the HsRAD51 NPF during the presynaptic phase of HR, which appears downstream of BRCA2-mediated HsRAD51 NPF formation. © 2013 Elsevier B.V.

PubMed | University of Texas Health Science Center at San Antonio, Ohio State University, Immunology and Medical Genetics. and Immunology and Medical Genetics
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of 1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an 33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.

PubMed | Ohio State University, Comprehensive Cancer Center, Center for Biostatistics and and Immunology and Medical Genetics.
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase (Pol ) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol -mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol -mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol , probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

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