Untersuchungen zur Expression und Regulation der Tumorsuppressorgene H-rev107-1 und H-rev107-2 bei malignen hämatopoetischen Zellen

Das Gen H-rev107 wurde mit einer subtraktiven cDNS-Bibliothek zwischen H-ras-transformierten und H-ras-resistenten Fibroblasten isoliert. Es wurde als ein Klasse II Tumorsuppressorgen bezeichnet, dessen Expression die H-ras-induzierte maligne Transformation unterdrückt. Weitere Untersuchungen zeigten die Existenz einer Genfamilie mit dem Gen H-rev107-1 auf Chromosom 11q11-12 und H-rev107-2/TIG3/RARRES3 auf 11q23. Die Induzierbarkeit in epithelialen Zellen durch Interferon-gamma (H-rev107-1) und Retinoide (H-rev107-2) legten eine Beteiligung der Expression beider Gene bei der Regulation der Hämatopoese nahe. In der vorliegenden Arbeit wurde mittels RT-PCR in 8/15 Patientenproben (10 AML, 5 ALL) eine Expression von H-rev107-2 gefunden. H-rev107-2 wurde durch IFN-gamma in 14/14 Proben und durch all-trans Retinsäure (ATRA) in 5/15 Proben induziert. In Zelllinien maligner hämatopoetischer Erkrankungen konnte mit RT-PCR und Northern-Blot-Analysen bei CEM eine deutliche, bei Raji und HL-60 eine schwache Expression und bei NB-4, U937, K562 und Jurkat keine Expression von H-rev107-2 nachgewiesen werden. In allen 7 Zelllinien konnte H-rev107-2 durch IFN-gamma induziert werden. Die Induzierbarkeit durch ATRA und IFN-alpha war Zelllinien abhängig. Die stärkste Induktion durch ATRA erfolgte bei der akuten Promyelozytenleukämie-Zelllinie NB-4. Eine Induktionskinetik erbrachte eine H-rev107-2-Expression frühestens nach 4 h Inkubation mit IFN-gamma oder ATRA. Die Inhibition des MAPK-Signalwegs durch den MEK-Inhibitor PD098059 und des Signaltransduktors JAK2 durch AG490 hatte bei den myeloischen Zelllinien weder Einfluss auf die H-rev107-2-Expression noch auf die H-rev107-2-Induktion durch IFN-gamma oder ATRA. Die Expression von H-rev107-1 konnte bei U937, CEM und K562 gezeigt werden, wogegen die RT-PCR-Analysen bei NB-4, HL-60, Raji und Jurkat sowie bei 8 Patientenproben (6 AML, 2 ALL) keine H-rev107-2-Transkripte nachwiesen. Eine schwache Induktion von H-rev107-1 konnte nur bei den Zelllinien NB-4 durch ATRA und IFN-gamma und bei K562 durch IFN-gamma und IFN-alpha erzielt werden. Zusammenfassend legen die Ergebnisse dieser Arbeit eine Beteiligung von H-rev107-2/TIG3/RARRES3 bei der Regulation der Hämatopoese als ein mögliches Interferon- und ATRA-Target nahe.The H-rev107 gene has been isolated by cDNA subtraction from a cell culture model of H-ras transformed fibroblasts. It was characterized as a class II tumor suppressor gene confering resistance to H-ras induced transformation. Further investigation has demonstrated the presence of a human gene family with H-rev107-1 localized on chromosome 11q11-12 and H-rev107-2/TIG3/RARRES3 on 11q23. Inducibility of the genes in epithelial cells by interferon-gamma (H-rev107-1) and retinoids (H-rev107-2) has suggested that expression of the H-rev107 genes might be relevant in hematopoesis. In the present study RT-PCR analysis revealed an expression of H-rev107-2 in 8/15 samples of leukaemic blasts derived from patients suffering from acute leukaemias (10 AML, 5 ALL). H-rev107-2 was induced upon incubation with IFN-gamma ?in 14/14 samples and with ATRA in 5/15 samples. In cell lines derived from myeloid and lymphoid tumors an expression of H-rev107-2 was found in CEM (strong), Raji and HL-60 (both weak), whereas in NB-4, U937, K562 and Jurkat no H-rev107-2 transcripts were detected by RT-PCR and Northern Blot analysis. In all cell lines H-rev107-2 could be strongly induced by IFN-gamma. Inducibility of H-rev107-2 upon treatment with IFN-alpha or ATRA was dependent on the type of cell line. In contrast to the weak effect seen in the myeloblastic cell line HL-60 a strong induction of H-rev107-2 by ATRA occurred in the acute promyelocytic leukaemia cell line NB-4. Transcripts of H-rev107-2 in NB-4 were detected at the earliest after 4 h incubation with ATRA or IFN-gamma. Inhibition of the MAPK-pathway by the MEK-inhibitor PD089059 or the signal transducer JAK2 by AG490 had neither influence on the H-rev107-2 expression nor on the IFN-gamma- and ATRA-dependent H-rev107-2 induction. H-rev107-1 expression was detectable in U937, CEM and K562, whereas RT-PCR analysis of the other cell lines and of 8 samples of primary leukaemic blasts (6 AML, 2 ALL) revealed no H-rev107-1 expression. An induction of H-rev107-1 occurred exclusively in NB-4 by ATRA and IFN-gamma and in K562 by IFN-gamma and IFN-alpha? to a weak extend. In conclusion, this work revealed a likely involvement of the class II tumor suppressor gene H-rev107-2/TIG3/RARRES3 in the regulation of hematopoesis being a potential IFN and ATRA target

Current and future water balance for coupled human-natural systems – Insights from a glacierized catchment in Peru

Study region Santa River basin, Peru. Study focus In the Andes of Peru, climate change and socio-economic development are expected to jeopardize future water availability. However, little is known about the interplay of multiple climatic and non-climatic stressors and related processes driving water resource changes. We developed an integrated model that analyzes different trajectories of water availability including hydro-climatic (water supply) and socio-economic (water demand) variables with consistent multi-descriptor future scenarios until 2050. New hydrological insights for the region At the lower-basin outflow of Condorcerro, mean annual water availability is projected to increase by 10% ± 12% by 2050. This gain is mainly driven by an increase in annual precipitation amounts of about 14% (RCP2.6) and 18% (RCP8.5), respectively, which was computed using a global climate multi-model ensemble. In contrast, mean dry-season water availability is projected to substantially decrease by 33% and 36% ( ± 24%) by 2050, for RCP2.6 and RCP8.5, respectively. This decline is driven by a combination of diminishing glacier discharge and increasing water demand both of which adopt a major role in the absence of considerable precipitation inputs. These seasonal differences highlight the need to adequately consider spatiotemporal scales within multi-scenario water balance models to support local decision-making. Our results elucidate the need for improvements in water management and infrastructure to counteract diminishing dry-season water availability and to reduce future risks of water scarcity

Worker assistance and quality inspection – application of optical 3D metrology and augmented reality technologies

Numerous industrial mount processes are characterized by a high variance due to the individuality of the final products. Manual assembly work subjectively influences the quality of an end product and errors thereby cannot be excluded. Errors that occur in production increase costs as it is likely to happen in the assembly of clamping which is used in CNC machining centers. As they are usually assembled manually, errors might occur

Iron isotope systematics in estuaries : the case of North River, Massachusetts (USA)

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 73 (2009): 4045-4059, doi:10.1016/j.gca.2009.04.026.Recent studies have suggested that rivers may present an isotopically light Fe source to the oceans. Since the input of dissolved iron from river water is generally controlled by flocculation processes that occur during estuarine mixing, it is important to investigate potential fractionation of Fe-isotopes during this process. In this study, we investigate the influence of the flocculation of Fe-rich colloids on the iron isotope composition of pristine estuarine waters and suspended particles. The samples were collected along a salinity gradient from the fresh water to the ocean in the North River estuary (MA, USA). Estuarine samples were filtered at 0.22 μm and the iron isotope composition of the two fractions (dissolved and particles) were analyzed using high resolution MC-ICP-MS after chemical purification. Dissolved iron results show positive δ56Fe values (with an average of 0.43 ± 0.04 ‰) relative to the IRMM-14 standard and do not display any relationships with salinity or with percentage of colloid flocculation. The iron isotopic composition of the particles suspended in fresh water is characterized by more negative δ56Fe values than for dissolved Fe and correlate with the percentage of Fe flocculation. Particulate δ56Fe values vary from -0.09‰ at no flocculation to ~ 0.1‰ at the flocculation maximum, which reflect mixing effects between river-borne particles, lithogenic particles derived from coastal seawaters and newly precipitated colloids. Since the process of flocculation produces minimal Fe-isotope fractionation in the dissolved Fe pool, we suggest that the pristine iron isotope composition of fresh water is preserved during estuarine mixing and that the value of the global riverine source into the ocean can be identified from the fresh water values. However, this study also suggests that δ56Fe composition of rivers can also be characterized by more positive δ56Fe values (up to 0.3 per mil) relative to the crust than previously reported. In order to improve our current understanding of the oceanic iron isotope cycling, further work is now required to determine the processes controlling the fractionation of Fe isotopes during continental run-off.This study was supported by the National Science Foundation (OCE 0550066) to O. Rouxel and Edward Sholkovitz

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Earth Virtualization Engines (EVE)

To manage Earth in the Anthropocene, new tools, new institutions, and new forms of international cooperation will be required. Earth Virtualization Engines is proposed as an international federation of centers of excellence to empower all people to respond to the immense and urgent challenges posed by climate change