Prenatal Exposure to Perfluorooctanoate and Risk of Overweight at 20 Years of Age: A Prospective Cohort Study

Background: Perfluoroalkyl acids are persistent compounds used in various industrial -applications. Of these compounds, perfluorooctanoate (PFOA) is currently detected in humans worldwide. A recent study on low-dose developmental exposure to PFOA in mice reported increased weight and elevated biomarkers of adiposity in postpubertal female offspring

Biochemical markers of ongoing joint damage in rheumatoid arthritis - current and future applications, limitations and opportunities

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond

Abstract 3568: CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides

Abstract: While cytochrome P450 enzymes (CYPs) are implicated in tumor angiogenesis through biosynthesis of epoxyeicosatrienoic acids (EETs), little is known about breast cancer cell-intrinsic CYPs that exhibit epoxygenase activity, such as CYP3A4. In an orthotopic breast cancer model, silencing of epithelial CYP3A4 suppressed angiogenesis-related escape of ER+ breast tumors from dormancy. While the diabetes drug metformin inhibits mitochondrial complex I and inhibits tumor growth, how it does so is unknown. Metformin inhibited CYP epoxygenase activity and co-crystallized in the active site of CYP3A4, hydrogen bonding with arginine 212, allowing the development of hexyl-benzyl-biguanide (HBB) as a CYP3A4 inhibitor using molecular modeling. HBB exhibited more than 10-fold greater potency than metformin for inhibition of ER+ mammary tumor growth and inhibited associated tumor angiogenesis. HBB inhibited EET biosynthesis ∼40-fold more potently than metformin and was ∼40-fold more potent for activation of AMPK phosphorylation. EETs suppressed and CYP silencing promoted AMPK phosphorylation, linking CYPs with AMPK regulation in breast cancer. HBB depolarized mitochondria, reduced oxygen consumption rates and suppressed the Warburg effect, while EETs restored the mitochondrial membrane potential. CYP3A4 silencing and HBB treatment increased reactive oxygen species (ROS) production, suggesting that CYPs suppress cancer cell death, in part, through suppression of ROS. CYP3A4 silencing sensitized breast cancer cells to hormonal therapy and chemotherapy, abrogated by EETs. Because EETs are autocrine, paracrine and endocrine, these results implicate CYPs in tumor growth, in part, through cell-cell mediation of mitochondrial homeostasis and demonstrate the potential of CYP3A4 as a therapeutic target in breast cancer. Citation Format: Zhijun Guo, Irina F. Sevrioukova, Eric Hanse, Ilia Denisov, Xia Zhang, Ting-Lan Chiu, Daniel Swedien, Justin Stamschror, Juan Alvarez, William Marerro Ortiz, Monique Morgan, Michael Maher, Kathryn J. Chavez, Dafydd Thomas, Young Kyung Bae, Jonathan Henriksen, Beverly Norris, Robert J. Schumacher, Henry Wang, Robin Bliss, Haitao Chu, Rebecca Cuellar, Thomas L. Poulos, Stephen G. Sligar, William Atkins, Stephen Schmechel, Jorge Capdevila, John Falck, Ian Blair, Jeffrey P. Jones, Gunda Georg, Kalpna Gupta, Ameeta Kelekar, Elizabeth Amin, David A. Potter. CYP3A4 epoxygenase activity mediates ER+ mammary tumor growth and angiogenesis, in part, through EET biosynthesis and is inhibited by biguanides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2015-356

FELLESSKAPETS SAMMENBRUDD OG KOLLEKTIV SMERTE

Georg Henriksen: The collapse of the community and collective pain This article deals with the the collapse of a community and the pain felt by the individuals living in it. It understands pain as an experience which is at the same time collective and individual, shared and existential. Since 1996 Georg Henriksen has foliowed the Mushuau Innu, an Indian community in the northem part of Canada. With informant’s experience from this community as reference Henriksen points out how the levels of individual, community, and over all social, eco- nomical, and political processes are interwowen. By being integrated in white society the Innu have lost their own social and moral order and at the same time they have stayed marginalized in relation to the surrounding society. The result of this intemal collapse and extemal marginalization is anomie - suicides, drinking, violence and the feeling of loneliness. Henriksen points out the responsibility of the govemment to establish a political and social field for the Innu to exist in and the necessity of understanding and bringing an end to the structural violence inflicted on the Innu

Adsorptive Hydrogen Storage: Experimental investigations on thermal conductivity in porous media

The objective of this work was to install and verify the Hot Disk TPS measurement setup for thermal conductivity measurements, and to carry out experiments on various porous materials. A literature survey on gas/solid porous media, with emphasis on the transport mechanisms and predictive models, was conducted. Special interest was taken in the widely-used Zehner/Bauer/Schlünder (ZBS) model for effective stagnant thermal conductivity of packed beds. Great care was shown in the determination of bed-properties such as porosity, because of the large effect it has on the effective thermal conductivity.The porous materials investigated were the Metal Organic Framework (MOF) hydrogen adsorbents Cu-btc (HKUST-1) and Fe-btc-xerogel. Large (⌀1.395mm) and smaller (⌀0.38mm) glass beads served as a reference material for preliminary tests and setup validations. In a later stage the Cu-btc and Fe-btc was experimentally investigated. Thermal conductivity measurements were conducted on a packed bed with air, nitrogen (N2) or helium (He) as fluid, in temperatures ranging from 243K<T<423K at an absolute pressure of zero to 0.5 bar. The smaller glass beads (⌀0.38mm) were also tested together with an open-cell, high-porosity aluminum foam. The purpose of the metal foam in adsorption hydrogen storage is to increases the effective thermal conductivity of the bed. Experiments showed that applying the aluminum foam increased the magnitude of the effective thermal conductivity of a bed consisting of glass beads and air by a factor of 17 from 0.22 W/m×K to 3.7W/m×K at room temperature.The preliminary experiments revealed a calibration error in the Hot Disk software, creating a discontinuity in the effective thermal conductivity in the range of 273K<T<283K. Outside that range, the Hot Disk measurement setup provides accurate measurements of the effective thermal conductivity of porous materials.Hot Disk gives a measurement uncertainty of 5%. In addition to this comes the uncertainty of the theoretical model, due to the input of measured parameters such as porosity. An uncertainty analysis on the ZBS model gave an uncertainty of approximately ±10% for the glass beads and ±5% for the MOF, respectively. Adding the uncertainty of the ZBS model to the uncertainty of the experiments gives a total uncertainty of 15% for the glass beads experiments and 10% for the MOF.Through a least square procedure, the solid conductivity of the MOF materials were fitted to the values of the ZBS model, determining temperature dependent functions for the solid conductivity yielding for each of the MOF?s. The ZBS model proved to be a reliable estimate for the effective thermal conductivity in a packed bed, differing from the measurements with less than 10%