Citations

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Abstract Background: We previously identified 5 SNPs at 4 susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (Cerhan et al, Nat Gen 2014;46:1233-8); however, much of the heritability remains unexplained. To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original report. Methods: We selected two SNPs rs9831894 (3q13.33) and rs6773363 (3p24.1) for de novo replication from studies at the Mayo Clinic, MD Anderson, and Memorial Sloan Kettering. Logistic regression was used to estimate odds ratios (ORs), using a log-additive model, and adjusting for age, gender and significant eigenvectors for each genotyping center separately. For both SNPs, we then conducted a meta-analysis of all replication studies (n=3) and our original GWAS studies (n=4), encompassing in total 5662 cases and 9237 controls for rs9831894, and 5510 cases and 12,817 controls for rs6773363. Meta-analysis was conducted using the fixed-effects inverse variance method based on the β estimates and standard errors from each study. Results: In a meta-analysis of the 4 original GWAS scans (3856 cases and 7666 controls), rs9831894 (MAF=0.40) was associated with DLBCL risk (OR=0.84, P=4.52 x 10-9) and this replicated in a meta-analysis of the 3 studies with de novo genotyping (OR=0.80, P=4.17 x 10-5); the overall meta-analysis showed a strong association with DLBCL risk (OR=0.83, P=3.62 x 10-13). This locus maps near a plausible candidate gene, CD86, a protein coding gene and a member of the immunoglobulin superfamily that encodes a type I membrane protein. Binding of CD86 with cytotoxic T-lymphocyte-associated protein 4 negatively regulates T-cell activation and diminishes the immune response, while binding of CD86 with CD28 antigen is a costimulatory signal for activation of the T-cell. In a meta-analysis of the same 4 GWAS scans, rs6773363 (MAF=0.45) was tentatively associated with DLBCL risk (OR=1.17, P= 3.68 x 10-7) and this replicated in a meta-analysis of the studies with de novo genotyping (OR=1.27, P=3.78 x 10-7); the overall meta-analysis showed a strong association with DLBCL risk (OR=1.20, P=2.31 x 10-12). This locus also maps near a plausible candidate gene, eomesodermin (EOMES), a transcription factor crucial for embryonic development of the central nervous system and also putatively involved in T-cell differentiation in viral infection defense. Conclusion: In this follow-up analysis of our initial GWAS, we have identified two additional loci associated with risk of DLBCL, the most common lymphoma subtype. These loci provide additional evidence for the role of immune function in the etiology of DLBCL. Citation Format: Geffen Kleinstern, Michelle Hildebrand, Vijai Joseph, Sonja I. Berndt, Hervé Ghesquières, James McKay, Sophia S. Wang, Alexandra Nieters, David Cox, Alain Monnereau, Angela R. Brooks-Wilson, Qing Lan, Mads Melbye, Rebecca D. Jackson, Lauren R. Teras, Mark P. Purdue, Claire M. Vajdic, Demetrius Albanes, Anne Zeleniuch-Jacquotte, Simon Crouch, Yawei Zhang, Susan L. Slager, Xifeng Wu, Karin E. Smedby, Gilles Salles, Christine F. Skibola, Nathaniel Rothman, Stephen J. Chanock, James R. Cerhan. Inherited variants at 3q13.33 and 3p24.1 influences risk of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 221.

A wide range of materials have been used for the development of intervertebral cages. Poly(propylene fumarate) (PPF) has been shown to be an excellent biomaterial with characteristics similar to trabecular bone. Hydroxyapatite (HA) has been shown to enhance biocompatibility and mechanical properties of PPF. The purpose of this study was to characterize the effect of PPF augmented with HA (PPF:HA) and evaluate the feasibility of this material for the development of cervical cages. PPF was synthesized and combined with HA at PPF:HA wt:wt ratios of 100:0, 80:20, 70:30, and 60:40. Molds were fabricated for testing PPF:HA bulk materials in compression, bending, tension, and hardness according to ASTM standards, and also for cage preparation. The cages were fabricated with and without holes and with porosity created by salt leaching. The samples as well as the cages were mechanically tested using a materials testing frame. All elastic moduli as well as the hardness increased significantly by adding HA to PPF (p < 0.0001). The 20 wt % HA increased the moduli significantly compared to pure PPF (p < 0.0001). Compressive stiffness of all cages also increased with the addition of HA. HA increased the failure load of the porous cages significantly (p = 0.0018) compared with nonporous cages. PPF:HA wt:wt ratio of 80:20 proved to be significantly stiffer and stronger than pure PPF. The current results suggest that this polymeric composite can be a suitable candidate material for intervertebral body cages.

Biomimetic biomaterials require good biocompatibility and bioactivity to serve as appropriate scaffolds for tissue engineering applications.

AbstractThree‐dimensional structural scaffolds have played an important role in tissue engineering, especially broad applications in areas such as regenerative medicine. We have developed novel biodegradable porous poly(propylene fumarate)‐co‐poly(lactic‐co‐glycolic acid) (PPF‐co‐PLGA) scaffolds using thermally induced phase separation, and determined the effects of critical parameters such as copolymer concentration (6, 8, and 10 wt %) and the binary solvent ratio of dioxane:water (78/22, 80/20, 82/18 wt/wt %) on the fabrication process. The cloud‐point temperatures of PPF‐co‐PLGA changed in parallel with increasing copolymer concentration, but inversely with increasing dioxane content. The compressive moduli of the scaffolds increased with greater weight composition and dioxane:water ratio. Scaffolds formed using high copolymer concentrations and solvent ratios exhibited preferable biomineralization. All samples showed biodegradation capability in both accelerated solution and phosphate‐buffered saline (PBS). Cell toxicity testing indicated that the scaffolds had good biocompatibility with bone and nerve cells, which adhered well to the scaffolds. Variations in the copolymer concentration and solvent ratio exercised a remarkable influence on morphology, mechanical properties, biomineralization, and biodegradation, but not on the cell viability and adhesion of the cross‐linked scaffolds. An 8 to 10 wt % solute concentration and 80/20 to 82/18 wt/wt dioxane:water ratio were the optimum parameters for scaffold fabrication. PPF‐co‐PLGA scaffolds thus possess several promising prospects for tissue engineering applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2507–2517, 2018.

AbstractGraphene oxide (GO) is an attractive material that can be utilized to enhance the modulus and conductivities of substrates and hydrogels. To covalently cross‐link graphene oxide sheets into hydrogels, abundant cross‐linkable double bonds were introduced to synthesize the graphene‐oxide‐tris‐acrylate sheet (GO‐TrisA). Polyacrylamide (PAM) nanocomposite hydrogels were then fabricated with inherent covalently and permanently cross‐linked GO‐TrisA sheets. Results showed that the covalently cross‐linked GO‐TrisA/PAM nanocomposite hydrogel had enhanced mechanical strength, thermo stability compared with GO/PAM hydrogel maintained mainly by hydrogen bonding between PAM chains and GO sheets. In vitro cell study showed that the covalently cross‐linked rGO‐TrisA/PAM nanocomposite hydrogel had excellent cytocompatibility after in situ reduction. These results suggest that rGO‐TrisA/PAM nanocomposite hydrogel holds great potential for tissue engineering applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1247–1257, 2018.