Replication of gene polymorphisms associated with periodontitis-related traits in an elderly cohort: the Washington Heights/Inwood Community Aging Project Ancillary Study of Oral Health.

AIM: We sought to replicate findings from published genome-wide association studies (GWAS), linking specific candidate gene loci with periodontitis-related clinical/microbial traits. MATERIALS AND METHODS: In the published GWAS, a total of 2196 single nucleotide polymorphisms associated with periodontitis-related traits at a p ≤ 5 × 10-6 and mapped to 136 gene loci. The replication cohort included 1124 individuals, 65-98 years old (67% female, 45% Hispanic, 30% Black, 23% White) with available genome-wide genotypes and full-mouth periodontal status. Microbial profiles using checkerboard DNA-DNA hybridization and 16SrRNA sequencing were available from 912 and 739 participants, respectively. RESULTS: Using gene-specific p-values after linkage disequilibrium pruning, the following gene/phenotype associations replicated successfully: CLEC19A with edentulism and %teeth with pocket depth (PD) ≥4 mm; IL37, HPVC1, TRPS1, ABHD12B, LDLRAD4 (C180rF1), TGM3, and GRK5 with %teeth with PD ≥4 mm; DAB2IP with presence of PD ≥6 mm; KIAA1715(LNPK), ROBO2, RAB28, LINC01017, NELL1, LDLRAD4(C18orF1), and CRYBB2P1 with %teeth with clinical attachment level (CAL) ≥3 mm; RUNX2 and LAMA2 with %teeth with CAL ≥5 mm; and KIAA1715(LNPK) with high colonization by Aggregatibacter actinomycetemcomitans. In addition, CLEC19A, IQSEC1, and EMR1 associated with microbial abundance based on checkerboard data, LBP and NCR2 with abundance based on sequencing data, and NCR2 with microbial diversity based on sequencing data. CONCLUSIONS: Several gene loci identified in published GWAS as associated with periodontitis-related phenotypes replicated successfully in an elderly cohort.

The GDNF Family: A Role in Cancer?

The glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) comprising of GDNF, neurturin, artemin, and persephin plays an important role in the development and maintenance of the central and peripheral nervous system, renal morphogenesis, and spermatogenesis. Here we review our current understanding of GFL biology, and supported by recent progress in the area, we examine their emerging role in endocrine-related and other non-hormone-dependent solid neoplasms. The ability of GFLs to elicit actions that resemble those perturbed in an oncogenic phenotype, alongside mounting evidence of GFL involvement in tumor progression, presents novel opportunities for therapeutic intervention.

Autocrine human growth hormone reduces mammary and endometrial carcinoma cell sensitivity to mitomycin C.

Drug resistance is a major cause of chemotherapy failure in breast cancer patients with metastatic disease. We previously demonstrated that autocrine human growth hormone (hGH) plays a key role in oncogenic transformation and progression of mammary carcinoma. The present study investigated the role of autocrine hGH in the development of resistance to mitomycin C (MMC), an alkylating agent utilised in the treatment of advanced metastatic breast cancer. Stable forced expression of the hGH gene was established in the mammary carcinoma cell lines MDA-MB-231, MCF-7 and T47D. Autocrine hGH reduced the sensitivity of mammary carcinoma cells to MMC in cell viability assays and reduced MMC-induced apoptotic cell death when compared to a control cell line. In addition, autocrine hGH enhanced MDA-MB-231 clonogenic survival, anchorage independent cell growth, growth in 3D Matrigel and protected MDA-MB-231 cells from induction of DNA double-strand breaks following MMC treatment. Functional antagonism of hGH in the endometrial carcinoma cell line RL95-2, which endogenously expresses hGH, significantly increased the sensitivity of these cells to MMC-induced DNA damage and cell death. Thus, autocrine hGH promotes mammary and endometrial carcinoma cell resistance to MMC. These studies indicate a potential role for antagonism of autocrine hGH in chemoresistant breast cancer.