Lipogenic effects of androgen signaling in normal and malignant prostate

Prostate cancer is an androgen-dependent cancer with unique metabolic features compared to many other solid tumors, and typically does not exhibit the “Warburg effect”. During malignant transformation, an early metabolic switch diverts the dependence of normal prostate cells on aerobic glycolysis for the synthesis of and secretion of citrate towards a more energetically favorable metabolic phenotype, whereby citrate is actively oxidised for energy and biosynthetic processes (i.e. de novo lipogenesis). It is now clear that lipid metabolism is one of the key androgen-regulated processes in prostate cells and alterations in lipid metabolism are a hallmark of prostate cancer, whereby increased de novo lipogenesis accompanied by over expression of lipid metabolic genes are characteristic of primary and advanced disease. Despite recent advances in our understanding of altered lipid metabolism in prostate tumorigenesis and cancer progression, the intermediary metabolism of the normal prostate and its relationship to androgen signaling remains poorly understood. In this review, we discuss the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues, and the role of androgens in the regulation of lipid metabolism at different stages of prostate tumorigenesis.Chui YanMah, Zeyad D.Nassar, Johannes V.Swinnen, Lisa M.Butle

Enhancing the Social Capital of Learning Communities by Using an Ad Hoc Transient Communities Service

Fetter, S., Berlanga, A. J., & Sloep, P. B. (2009). Enhancing the Social Capital of Learning Communities by Using an Ad Hoc Transient Communities Service. In M. Spaniol, Q. Li, R. Klamma & R. W. H. Lau (Eds.), Proceedings of the 8th International Conference Advances in Web-based Learning - ICWL 2009 (pp. 150-157). August, 19-21, 2009, Aachen, Germany. Lecture Notes in Computer Science 5686; Berlin, Heidelberg: Springer-Verlag.In online learning, communities can help to enhance learning. However, because of the dynamic nature of communities, attaining and sustaining these communities can be difficult. One aspect that has an influence on, and is influenced by these dynamics is the social capital of a community. Features of social capital are the social network structure, the sense of belonging and, the support received and provided. It is hypothesized that these features can be improved by using Ad Hoc Transient Communities (AHTCs). Through an AHTC learners are brought together for a specific, learning-related goal (‘ad hoc’) and for only a limited amount of time (‘transience’). To test whether the use of AHTCs has a positive influence on the social capital, a learner support service which enables the use of AHTCs is proposed. Furthermore, requirements, pre-requisites, and future research are discussed.The work on this publication has been sponsored by the TENCompetence Integrated Project that is funded by the European Commission's 6th Framework Programme, priority IST/Technology Enhanced Learning. Contract 027087 [http://www.tencompetence.org

Dosing of losartan in men vs. women with HFrEF: the HEAAL trial

Background: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit. Methods: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and Machine Learning algorithms. Results: The mean age was 66 years and 30% of the patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses: HR (95%CI) comparing high- vs- low-dose losartan for the composite outcome of all-cause death or all-cause hospitalisation was 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women, interaction P=0.018. Female sex clustered along with older age, ischemic HF, NYHA III/IV, and eGFR<60 ml/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe HF symptoms. Conclusions: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g., kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.Zeyad D Nassar, Chui Yan Mah, Jonas Dehairs, Ingrid JG Burvenich ... Lisa M Butler ... Luke Selth ... et al

Optimal background pharmacological therapy for heart failure patients in clinical trials: JACC review topic of the week

With the current landscape of approved therapies for heart failure (HF), there is a need to determine the role of a standard background therapy against which novel therapies are studied. The Heart Failure Collaboratory convened a multistakeholder group of clinical investigators, clinicians, patients, government representatives including U.S. Food and Drug Administration and National Institutes of Health participants, payers, and industry in March 2021 to discuss whether standardization of background drug therapy is necessary in clinical trials in patients with HF. The current paper summarizes the discussion and provides potential conceptual approaches, with a focus on therapies indicated for HF with reduced ejection fraction

The Theory of Brown Dwarfs and Extrasolar Giant Planets

Straddling the traditional realms of the planets and the stars, objects below the edge of the main sequence have such unique properties, and are being discovered in such quantities, that one can rightly claim that a new field at the interface of planetary science and and astronomy is being born. In this review, we explore the essential elements of the theory of brown dwarfs and giant planets, as well as of the new spectroscopic classes L and T. To this end, we describe their evolution, spectra, atmospheric compositions, chemistry, physics, and nuclear phases and explain the basic systematics of substellar-mass objects across three orders of magnitude in both mass and age and a factor of 30 in effective temperature. Moreover, we discuss the distinctive features of those extrasolar giant planets that are irradiated by a central primary, in particular their reflection spectra, albedos, and transits. Aspects of the latest theory of Jupiter and Saturn are also presented. Throughout, we highlight the effects of condensates, clouds, molecular abundances, and molecular/atomic opacities in brown dwarf and giant planet atmospheres and summarize the resulting spectral diagnostics. Where possible, the theory is put in its current observational context.Comment: 67 pages (including 36 figures), RMP RevTeX LaTeX, accepted for publication in the Reviews of Modern Physics. 30 figures are color. Most of the figures are in GIF format to reduce the overall size. The full version with figures can also be found at: http://jupiter.as.arizona.edu/~burrows/papers/rm

State of the climate in 2013

In 2013, the vast majority of the monitored climate variables reported here maintained trends established in recent decades. ENSO was in a neutral state during the entire year, remaining mostly on the cool side of neutral with modest impacts on regional weather patterns around the world. This follows several years dominated by the effects of either La Niña or El Niño events. According to several independent analyses, 2013 was again among the 10 warmest years on record at the global scale, both at the Earths surface and through the troposphere. Some regions in the Southern Hemisphere had record or near-record high temperatures for the year. Australia observed its hottest year on record, while Argentina and New Zealand reported their second and third hottest years, respectively. In Antarctica, Amundsen-Scott South Pole Station reported its highest annual temperature since records began in 1957. At the opposite pole, the Arctic observed its seventh warmest year since records began in the early 20th century. At 20-m depth, record high temperatures were measured at some permafrost stations on the North Slope of Alaska and in the Brooks Range. In the Northern Hemisphere extratropics, anomalous meridional atmospheric circulation occurred throughout much of the year, leading to marked regional extremes of both temperature and precipitation. Cold temperature anomalies during winter across Eurasia were followed by warm spring temperature anomalies, which were linked to a new record low Eurasian snow cover extent in May. Minimum sea ice extent in the Arctic was the sixth lowest since satellite observations began in 1979. Including 2013, all seven lowest extents on record have occurred in the past seven years. Antarctica, on the other hand, had above-average sea ice extent throughout 2013, with 116 days of new daily high extent records, including a new daily maximum sea ice area of 19.57 million km2 reached on 1 October. ENSO-neutral conditions in the eastern central Pacific Ocean and a negative Pacific decadal oscillation pattern in the North Pacific had the largest impacts on the global sea surface temperature in 2013. The North Pacific reached a historic high temperature in 2013 and on balance the globally-averaged sea surface temperature was among the 10 highest on record. Overall, the salt content in nearsurface ocean waters increased while in intermediate waters it decreased. Global mean sea level continued to rise during 2013, on pace with a trend of 3.2 mm yr-1 over the past two decades. A portion of this trend (0.5 mm yr-1) has been attributed to natural variability associated with the Pacific decadal oscillation as well as to ongoing contributions from the melting of glaciers and ice sheets and ocean warming. Global tropical cyclone frequency during 2013 was slightly above average with a total of 94 storms, although the North Atlantic Basin had its quietest hurricane season since 1994. In the Western North Pacific Basin, Super Typhoon Haiyan, the deadliest tropical cyclone of 2013, had 1-minute sustained winds estimated to be 170 kt (87.5 m s-1) on 7 November, the highest wind speed ever assigned to a tropical cyclone. High storm surge was also associated with Haiyan as it made landfall over the central Philippines, an area where sea level is currently at historic highs, increasing by 200 mm since 1970. In the atmosphere, carbon dioxide, methane, and nitrous oxide all continued to increase in 2013. As in previous years, each of these major greenhouse gases once again reached historic high concentrations. In the Arctic, carbon dioxide and methane increased at the same rate as the global increase. These increases are likely due to export from lower latitudes rather than a consequence of increases in Arctic sources, such as thawing permafrost. At Mauna Loa, Hawaii, for the first time since measurements began in 1958, the daily average mixing ratio of carbon dioxide exceeded 400 ppm on 9 May. The state of these variables, along with dozens of others, and the 2013 climate conditions of regions around the world are discussed in further detail in this 24th edition of the State of the Climate series. © 2014, American Meteorological Society. All rights reserved

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

TESS Reveals a Short-period Sub-Neptune Sibling (HD 86226c) to a Known Long-period Giant Planet

The Transiting Exoplanet Survey Satellite mission was designed to find transiting planets around bright, nearby stars. Here, we present the detection and mass measurement of a small, short-period (≈4 days) transiting planet around the bright (V = 7.9), solar-type star HD 86226 (TOI-652, TIC 22221375), previously known to host a long-period (∼1600 days) giant planet. HD 86226c (TOI-652.01) has a radius of 2.16 0.08 R ⊕ and a mass of M ⊕, based on archival and new radial velocity data. We also update the parameters of the longer-period, not-known-to-transit planet, and find it to be less eccentric and less massive than previously reported. The density of the transiting planet is 3.97 g cm-3, which is low enough to suggest that the planet has at least a small volatile envelope, but the mass fractions of rock, iron, and water are not well-constrained. Given the host star brightness, planet period, and location of the planet near both the "radius gap"and the "hot Neptune desert,"HD 86226c is an interesting candidate for transmission spectroscopy to further refine its composition