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- environmental tobacco smoke (6)
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Prieto García, Cristian ; Hartmann, Oliver ; Reissland, Michaela ; Braun, Fabian ; Bozkurt, Süleyman ; Pahor, Nikolett ; Fuß, Carmina Teresa ; Schirbel, Andreas ; Schülein, Christina ; Buchberger, Alexander ; Calzado Canale, Marco A. ; Rosenfeldt, Mathias Tillmann ; Đikić, Ivan ; Münch, Christian ; Diefenbacher, Markus Elmar
Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R-, BRAFV600E- or PI3KH1047R-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.
Koromina, Maria ; Ravi, Ashvin ; Panagiotaropoulou, Georgia ; Schilder, Brian M. ; Humphrey, Jack ; Braun, Alice ; Bidgeli, Tim ; Chatzinakos, Chris ; Coombes, Brandon ; Kim, Jaeyoung ; Liu, Xiaoxi ; Terao, Chikashi ; O'Connell, Kevin S. ; Adams, Mark ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Andlauer, Till ; Andreassen, Ole A. ; Antoniou, Anastasia ; Baune, Bernhard T. ; Bengesser, Susanne ; Biernacka, Joanna ; Boehnke, Michael ; Bosch, Rosa ; Cairns, Murray ; Carr, Vaughan J. ; Casas Brugué, Miquel ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dafnas, Konstantinos ; Dalkner, Nina ; Dannlowski, Udo ; Degenhardt, Franziska ; Di Florio, Arianna ; Dikeos, Dimitris ; Fellendorf, Frederike Tabea ; Ferentinos, Panagiotis ; Forstner, Andreas Josef ; Forty, Liz ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gizer, Ian R. ; Gordon-Smith, Katherine ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Guzman-Parra, José ; Hahn, Tim ; Henskens, Frans ; Hillert, Jan ; Jablensky, Assen V. ; Jones, Lisa ; Jones, Ian ; Jonsson, Lina ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kittel-Schneider, Sarah ; Kogevinas, Manolis ; Landén, Mikael ; Leboyer, Marion ; Lenger, Melanie ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; MacIntyre, Donald ; Martin, Nicholas G. ; Maratou, Eirini ; Mathews, Carol A. ; Mayoral, Fermı́n ; McElroy, Susan L. ; McGregor, Nathaniel W. ; McIntosh, Andrew M. ; McQuillin, Andrew ; Michie, Patricia ; Milanova, Vihra ; Mitchell, Philip B. ; Moutsatsou, Paraskevi ; Mowry, Bryan ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Nenadić, Igor ; Nöthen, Markus Maria ; O'Donovan, Claire ; O'Donovan, Michael ; Ophoff, Roel André ; Owen, Michael J. ; Pantelis, Christos ; Pato, Carlos ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Perlis, Roy H. ; Porichi, Evgenia ; Posthuma, Danielle ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Schall, Ulrich ; Schulze, Thomas Gerd ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Shannon Weickert, Cynthia ; Smoller, Jordan W. ; Soler Artigas, Marı́a ; Stein, Dan J. ; Streit, Fabian ; Toma, Claudio ; Tooney, Paul ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Thomas ; Witt, Stephanie H. ; Hong, Kyung Sue ; Ikeda, Masashi ; Iwata, Nakao ; Świątkowska, Beata ; Won, Hong-Hee ; Edenberg, Howard J. ; Ripke, Stephan ; Raj, Towfique ; Coleman, Jonathan R. I. ; Mullins, Niamh
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Klingelhöfer, Doris ; Müller, Ruth ; Braun, Markus ; Brüggmann, Dörthe ; Groneberg, Jan David Alexander
Background: Climate change is safe to be one of the biggest challenges of mankind. Human activities, especially the combustion of fossil fuels, contribute to the increase of greenhouse gases in the atmosphere and thus to the pace of climate change. The effects of climate change are already being felt, and the resulting damage will most likely be enormous worldwide. Because global impacts vary widely and will lead to very different national vulnerability to climate impacts, each country, depending on its economic background, has different options to ward off negative impacts. Decisions have to be made to mitigate climate consequences according to the preparedness and the vulnerability of countries against the presumed impacts. This requires a profound scientific basis. To provide sound background information, a bibliometric study was conducted to present global research on climate change using established and specific parameters. Bibliometric standard parameters, established socioeconomic values, and climate change specific indices were used for the analyses. This allowed us to provide an overall picture of the global research pattern not only in terms of general aspects, but also in terms of climate change impacts, its effects and regional differences. For this purpose, we choose representative indices, such as the CO2 emissions for the responsibility of countries, the global climate risk index as a combination value for the different types of damage that countries can expect, the increase in sea level as a specific parameter as a measure of the huge global environmental impacts, and the readiness and vulnerability index for the different circumstances of individual countries under which climate change will take place. We hope to have thus made a comprehensive and representative selection of specific parameters that is sufficient to map the global research landscape. We have supplemented the methodology accordingly.
Results: In terms of absolute publication numbers, the USA was the leading country, followed by the UK, and China in 3rd place. The steep rise in Chinese publication numbers over time came into view, while their citation numbers are relatively low. Scandinavian countries were leading regarding their publication numbers related to CO2 emission and socioeconomic indices. Only three developing countries stand out in all analyses: Costa Rica, the Fiji Atoll, and Zimbabwe, although it is here that the climate impact will be greatest. A positive correlation between countries’ preparedness for the impacts of climate change and their publication numbers could be shown, while the correlation between countries’ vulnerability and their publication numbers was negative.
Conclusions: We could show that there exists an inequity between national research efforts according to the publication output and the demands and necessities of countries related to their socioeconomic status. This inequity calls for a rethink, a different approach, and a different policy to improve countries' preparedness and mitigation capacity, which requires the inclusion of the most affected regions of the world in a strengthened international cooperation network.
Private-label cigarettes are cigarettes that belong to the retailer itself. Private-label cigarettes from discounters or supermarkets are cheaper than brand-name cigarettes, and their lower price has allowed them to garner an ever-increasing share of the tobacco product market, especially among lower socioeconomic groups. Particulate matter (PM), a considerable component of air pollution, is a substantial health-damaging factor. Smoking is the primary source of PM in smokers’ homes. In a 2.88 m3 measuring chamber, the PM emission fractions PM10, PM2.5, and PM1 from three private-label cigarette brands and three brand-name cigarette brands with identical nicotine, tar, and carbon monoxide content were measured and compared to those of a reference cigarette by laser aerosol spectroscopy. All cigarette brands emitted PM in health-threatening quantities. The measurement results ranged from 1394 µg/m3 to 1686 µg/m3 PM10, 1392 µg/m3 to 1682 µg/m3 PM2.5, and 1355 µg/m3 to 1634 µg/m3 PM1, respectively. Only one private-label brand differed significantly (p < 0.001) from the other cigarette brands, which were tested with slightly lower PM levels. All other brands differed only marginally (not significant, p > 0.05) from one another. Significant (p < 0.05) negative correlations between private-label and brand-name cigarettes were found for PM10, PM2.5, and PM1 when accounting for tobacco filling densities, and for PM1 when accounting for filter lengths. The especially health-hazardous fraction PM1 accounted for the largest proportion of PM emissions from the cigarettes tested. The results of this study suggest that- cheaper tobacco products are as harmful as more expensive ones, at least regarding PM emissions. This highlights the importance of anti-smoking campaigns, especially for lower socioeconomic groups, where smoking is more widespread. Governments should reduce the price gap between cheap and more expensive tobacco products by implementing specific tobacco taxes. In such a case, at increasing prices of tobacco products, a downward shift to private-label cigarettes would probably decrease.
Hou, Yunlong ; Adrian-Segarra, Juan M. ; Richter, Manfred ; Kubin, Natalia ; Shin, Jaeyoung ; Werner, Isabella ; Walther, Thomas ; Schönburg, Markus ; Pöling, Jochen ; Warnecke, Henning ; Braun, Thomas ; Kostin, Sawa ; Kubin, Thomas
It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an “omics” toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.
Cycling as a form of active transportation provides many health benefits through increased physical activity. These benefits can be compromised in urban environments due to the intensified respiration while cycling and the proximity to vehicular traffic with associated exposure to traffic-related air pollution from particulate matter. This review provides an overview of the current literature with data on mobile measurements of particulate matter exposure of cyclists in urban areas. Also, the factors influencing particulate matter concentrations from meteorology, traffic, architecture, and the temporal conditions presented in the literature are described. In this respect, cycling represents an efficient method for characterizing individual particulate matter exposure with a high spatiotemporal resolution. Taking the background concentrations into consideration, statements on the relative exposure to pollutants and the associated health risk can be made with knowledge in favor of environmentally compatible inner city traffic planning.