Differential Methylation of Syncytin-1 and 2 Distinguishes Fetal Growth Restriction from Physiologic Small for Gestational Age.

Objective The retroviral genes encoding Syncytin-1 ( SYN1 ) and Syncytin-2 ( SYN2 ) are epigenetically regulated, uniquely expressed in the placenta and critical to placental function. We sought to determine if placental expression and methylation patterns of SYN1 and SYN2 from pregnancies complicated by fetal growth restriction (FGR) differed from physiologic small for gestational age (SGA) and appropriate for gestational age (AGA) controls. Study Design Placental biopsies were obtained from AGA, SGA and FGR neonates delivered at >36 weeks gestation. SGA and FGR were defined as birth weight <10% with FGR additionally requiring abnormal fetal testing. We quantified DNA methylation of SYN1 and SYN2 by EpiTyper and gene expression by RT-qPCR. Results We identified 10 AGA, 9 SGA and 7 FGR placentas. There was decreased methylation in SYN1 and SYN2 in FGR relative to AGA and SGA. When the sum of SYN1 and SYN2 methylation was used for prediction of FGR from SGA, the area under the receiver operator characteristic curve was 0.9048 (0.7602, 1). Conclusion SYN1 and SYN2 methylation marks differ in FGR and SGA. We plan future studies to examine these markers in cell free DNA to determine if these methylation changes could be used as a biomarker for FGR.

Cesium 131 versus iodine 125 implants for prostate cancer: evaluation of early PSA response.

INTRODUCTION: Given the shorter half-life of cesium-131 (Cs-131) compared to iodine-125 (I-125), we hypothesized that initial PSA outcomes may differ. We compare initial PSA outcomes in men undergoing Cs-131 prostate brachytherapy to men treated with I-125. PATIENTS AND METHODS: The first post-treatment PSA (obtained 3-6 months after the procedure) was compared in patients undergoing I-125 prostate brachytherapy to that of patients undergoing Cs-131 prostate brachytherapy at the same institution. Comparisons included the total cohort as well as low and intermediate risk patients. RESULTS: Mean pre-treatment PSA was 6.9 ng/mL in the I-125 cohort, and 6.9 ng/mL in the Cs-131 cohort. Mean initial post-treatment PSA was 0.9 ng/mL (range < 0.1-4.6) in the I-125 cohort and 1.2 ng/mL (range < 0.1-23.5) in the Cs-131 patients. For low risk patients, mean pre-treatment PSA was 5.8 ng/mL in the I-125 cohort, and 5.1 ng/mL in the Cs-131 cohort. Initial mean post-treatment PSA for low risk patients was 1.2 ng/mL (range < 0.1-4.6) in the I-125 group and 1.0 ng/mL (range < 0.1-2.9) in the Cs-131 patients (p = 0.37). For intermediate risk patients, mean pre-treatment PSA was 7.3 ng/mL in the I-125 cohort, and 7.3 ng/mL in the Cs-131 cohort. Mean initial post-treatment PSA in intermediate risk patients was 1.5 ng/mL (range < 0.1-2.9) in the I-125 group and 1.2 ng/mL (range < 0.1-4.6) in the Cs-131 patients (p = 0.52). CONCLUSIONS: Given the shorter half-life of Cs-131 compared to I-125, we hypothesized that initial post-brachytherapy PSA levels were similar between men receiving treatment with Cs-131 and I-125. The aim of the present study is not to predict long term outcome after Cs-131 prostate brachytherapy, but rather to simply compare initial PSA outcomes in men undergoing prostate brachytherapy with I-125 to Cs-131. Long term data are needed to document cancer control achieved with Cs-131.

An extensive genetic program occurring during postnatal growth in multiple tissues.

Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified more than 1600 genes that were regulated with age (1 vs. 4 wk) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly down-regulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and suggested that the decreasing expression with age was due primarily to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0-5 wk of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues, but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size.

Interleukin-7 is a survival factor for CD4+ CD25+ T-cells and is expressed by diabetes-suppressive dendritic cells.

Dendritic cells can facilitate allograft survival and prevent autoimmunity via direct and indirect cell-mediated mechanisms. Recent studies demonstrate that immunoregulatory dendritic cells (iDCs) confer immune hyporesponsiveness in part through CD4(+) CD25(+) T regulatory cells (Tregs). Herein, we provide evidence to support the hypothesis that dendritic cells derived from NOD mice and engineered ex vivo to exhibit suppressed expression of the CD40, CD80, and CD86 costimulatory molecules motivate an increase in the prevalence of regulatory CD4(+) CD25(+) T-cells via interleukin (IL)-7. Unlike control dendritic cells, these dendritic cells expressed significant levels of IL-7. Exogenous addition of IL-7 to NOD T-cells did not promote expansion or proliferation, but instead selectively maintained the number of CD4(+) CD25(+) T-cells by inhibiting activation of apoptosis in these cells. In vitro, IL-7 receptor alpha-chain (IL-7Ralpha) was expressed at significantly higher levels on CD4(+) CD25(+) T-cells compared with CD4(+) CD25(-) T-cells irrespective of resting or stimulated state. In vivo, CD4(+) CD25(+) T-cells obtained from NOD-scid mice reconstituted with ex vivo engineered iDCs and NOD splenocytes expressed significantly higher levels of IL-7Ralpha compared with levels in the CD4(+) CD25(-) subset, especially in diabetes-suppressive dendritic cell-administered NOD-scid recipients. Taken together, our data suggest a novel mechanism by which iDCs delay autoimmunity through the CD4(+) CD25(+) Treg pathway and suggest IL-7 as a survival factor for these putative Tregs, which express the alpha-chain of its receptor at considerably higher levels than CD4(+) CD25(-) T-cells.