White blood cell DNA methylation and risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)

Background Several studies have suggested that global DNA methylation in circulating white blood cells (WBC) is associated with breast cancer risk. Methods To address conflicting results and concerns that the findings for WBC DNA methylation in some prior studies may reflect disease effects, we evaluated the relationship between global levels of WBC DNA methylation in white blood cells and breast cancer risk in a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. A total of 428 invasive breast cancer cases and 419 controls, frequency matched on age at entry (55–59, 60–64, 65–69, ≥70 years), year of entry (on/before September 30, 1997, on/after October 1, 1997) and period of DNA extraction (previously extracted, newly extracted) were included. The ratio of 5-methyl-2’ deoxycytidine [5-mdC] to 2’-deoxyguanine [dG], assuming [dG] = [5-mdC] + [2’-deoxycytidine [dC]] (%5-mdC), was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry, an especially accurate method for assessing total genomic DNA methylation. Results Odds ratio (OR) estimates and 95% confidence intervals (CI) for breast cancer risk adjusted for age at entry, year of entry, and period of DNA extraction, were 1.0 (referent), 0.89 (95% CI, 0.6–1.3), 0.88 (95% CI, 0.6–1.3), and 0.84 (95% CI, 0.6–1.2) for women in the highest compared to lowest quartile levels of %5md-C (p for trend = .39). Effects did not meaningfully vary by time elapsed from WBC collection to diagnosis. Discussion These results do not support the hypothesis that global DNA hypomethylation in WBC DNA is associated with increased breast cancer risk prior to the appearance of clinical disease

Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

BACKGROUND Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (±SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8±0.4 percent in the spine, 5.9±0.5 percent in the femoral neck, 7.8±0.6 percent in the trochanter, and 2.5±0.3 percent in the total body (P CONCLUSIONS Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis

Quantitative analysis of a footwall‐scarp degradation complex and syn‐rift stratigraphic architecture, Exmouth Plateau, NW Shelf, offshore Australia

Interactions between footwall‐, hangingwall‐ and axial‐derived depositional systems make syn‐rift stratigraphic architecture difficult to predict, and preservation of net‐erosional source landscapes is limited. Distinguishing between deposits derived from fault‐scarp degradation (consequent systems) and those derived from long‐lived catchments beyond the fault block crest (antecedent systems) is also challenging, but important for hydrocarbon reservoir prospecting. We undertake geometric and volumetric analysis of a fault‐scarp degradation complex and adjacent hangingwall‐fill associated with the Thebe‐2 fault block on the Exmouth Plateau, NW Shelf, offshore Australia, using high resolution 3D seismic data. Vertical and headward erosion of the complex and fault throw are measured. Seismic‐stratigraphic and seismic facies mapping allow us to constrain the spatial and architectural variability of depositional systems in the hangingwall. Footwall‐derived systems interacted with hangingwall‐ and axial‐derived systems, through diversion around topography, interfingering or successive onlap. We calculate the volume of footwall‐sourced hangingwall fans (VHW) for nine quadrants along the fault block, and compare this to the volume of material eroded from the immediately up‐dip fault‐scarp (VFW). This analysis highlights areas of sediment bypass (VFW > VHW) and areas fed by sediment sources beyond the degraded fault scarp (VHW > VFW). Exposure of the border fault footwall and adjacent fault terraces produced small catchments located beyond the fault block crest that fed the hangingwall basin. One source persisted throughout the main syn‐rift episode, and its location coincided with: (a) an intra‐basin topographic high; (b) a local fault throw minimum; (c) increased vertical and headward erosion within the fault‐scarp degradation complex; and (d) sustained clinoform development in the immediate hangingwall. Our novel quantitative volumetric approach to identify through‐going sediment input points could be applied to other rift basin‐fills. We highlight implications for hydrocarbon exploration and emphasize the need to incorporate interaction of multiple sediment sources and their resultant architecture in tectono‐stratigraphic models for rift basins

Unexpected transformations: The Internet\u27s effect on political associations in American politics

What is the internee\u27s principle impact on American politics? This dissertation argues that the major effects of the new information medium can be traced to the new forms of political association enabled by the online information regime. Dramatic reductions in transaction costs, combined with the condition of “information abundance,” enable novel structures for collective action, shifts in nonprofit membership and fundraising regimes, and the development of large-scale, internet-mediated organizations. These organizations mobilize their related issue publics around an expanded issue set, using nimble tactical repertoires and new political engagement tools both online and off. As a result, the avenues for entry into America\u27s elite political system are becoming more porous and we are seeing a redistribution of power within elite political networks. The dissertation draws upon a variety of literatures and research methods to argue that we are experiencing a “generation shift” within America\u27s interest group population. Similar in form to “interest group explosion” of the early 1970s, which also was rooted in the opportunities provided by new information technologies, we are not only seeing an increased number of political associations, but also a difference-in-kind with regards to their structure. The new groups define membership loosely, offer an expansive array of participatory opportunities, and jump from issue to issue, mobilizing around whatever topic is at the top of the public agenda. Their low overhead costs, combined with mastery of new technology, yields substantial competitive advantages over the older generation of advocacy organizations, making the new information environment a “disruptive” type of innovation. The project explores the new generation of political associations through in-depth analysis of the political blogosphere, MoveOn, Democracy for America, and related organizations. It additionally discusses the dearth of online infrastructure among political conservatives, providing original theoretical contributions regarding the partisan adoption of innovative campaign technologies and strategies. Ultimately, the study concludes that the interne is creating new opportunities for political engagement, while rendering the longstanding interest group population vulnerable to the dramatic changes in revenue streams that have upset many other financial sectors. The result is a system that is still elite-dominated, but more porous in nature

The rationale and design of TransCon Growth Hormone for the treatment of growth hormone deficiency

The fundamental challenge of developing a long-acting growth hormone (LAGH) is to create a more convenient growth hormone (GH) dosing profile while retaining the excellent safety, efficacy and tolerability of daily GH. With GH receptors on virtually all cells, replacement therapy should achieve the same tissue distribution and effects of daily (and endogenous) GH while maintaining levels of GH and resulting IGF-1 within the physiologic range. To date, only two LAGHs have gained the approval of either the Food and Drug Administration (FDA) or the European Medicines Agency (EMA); both released unmodified GH, thus presumably replicating distribution and pharmacological actions of daily GH. Other technologies have been applied to create LAGHs, including modifying GH (for example, protein enlargement or albumin binding) such that the resulting analogues possess a longer half-life. Based on these approaches, nearly 20 LAGHs have reached various stages of clinical development. Although most have failed, lessons learned have guided the development of a novel LAGH. TransCon GH is a LAGH prodrug in which GH is transiently bound to an inert methoxy polyethylene glycol (mPEG) carrier. It was designed to achieve the same safety, efficacy and tolerability as daily GH but with more convenient weekly dosing. In phase 2 trials of children and adults with growth hormone deficiency (GHD), similar safety, efficacy and tolerability to daily GH was shown as well as GH and IGF-1 levels within the physiologic range. These promising results support further development of TransCon GH