Elucidating the IGFBP2 signaling pathway in glioma development and progression

Diffuse gliomas are highly lethal central nervous system malignancies which, unfortunately, are the most common primary brain tumor and also the least responsive to the very few therapeutic modalities currently available to treat them. IGFBP2 is a newly recognized oncogene that is operative in multiple cancer types, including glioma, and shows promise for a targeted therapeutic approach. Elevated IGFBP2 expression is present in high-grade glioma and correlates with poor survival. We have previously demonstrated that IGFBP2 induces glioma development and progression in a spontaneous glioma mouse model, which highlighted its significance and potential for future therapy. However, we did not yet know the key physiological pathways associated with this newly characterized oncogene. We first evaluated human glioma genomics data harnessed from the publicly available Rembrandt source to identify major pathways associated with IGFBP2 expression. Integrin and ILK, among other cell migration and invasion-related pathways, were the most prominently associated. We confirmed that these pathways are regulated by IGFBP2 in glioma cells lines, and demonstrated that 1) IGFBP2 activates integrin α5β1, leading to the activation of key pathways important in glioma; 2) IGFBP2 mediates cell migration pathways through ILK; and 3) IGFBP2 activates NF-kB via an integrin α5 interaction. We then sought to determine whether this was a physiologically active signaling pathway in vivo by assessing its ability to induce glioma progression in the RCAS/tv-a spontaneous glioma mouse model. We found that ILK is a key downstream mediator of IGFBP2 that is required for the induction of glioma progression. Most significantly, a genetic therapeutic approach revealed that perturbation of any point in the pathway thwarted tumor progression, providing strong evidence that targeting the key players could potentially produce a significant benefit for human glioma patients. The elucidation of this signaling pathway is a critical step, since efforts to create a small molecule drug targeting IGFBP2 have so far not been successful, but a number of inhibitors of the other pathway constituents, including ILK, integrin and NF-kB, have been developed.

DEVELOPMENT AND IMPLEMENTATION OF A REMOTE AUDIT TOOL FOR HIGH DOSE RATE (HDR) 192IR BRACHYTHERAPY USING OPTICALLY STIMULATED LUMINESCENCE DOSIMETRY

This work aimed to create a mailable and OSLD-based phantom with accuracy suitable for RPC audits of HDR brachytherapy sources at institutions participating in NCI-funded cooperative clinical trials. An 8 × 8 × 10 cm3 prototype with two slots capable of holding nanoDot Al2O3:C OSL dosimeters (Landauer, Glenwood, IL) was designed and built. The phantom has a single channel capable of accepting all 192Ir HDR brachytherapy sources in current clinical use in the United States. Irradiations were performed with an 192Ir HDR source to determine correction factors for linearity with dose, dose rate, and the combined effect of irradiation energy and phantom construction. The uncertainties introduced by source positioning in the phantom and timer resolution limitations were also investigated. It was found that the linearity correction factor was where dose is in cGy, which differed from that determined by the RPC for the same batch of dosimeters under 60Co irradiation. There was no significant dose rate effect. Separate energy+block correction factors were determined for both models of 192Ir sources currently in clinical use and these vendor-specific correction factors differed by almost 2.6%. For Nucletron sources, this correction factor was 1.026±0.004 (99% Confidence Interval) and for Varian sources it was 1.000±0.007 (99% CI). Reasonable deviations in source positioning within the phantom and the limited resolution of the source timer had insignificant effects on the ability to measure dose. Overall measurement uncertainty of the system was estimated to be ±2.5% for both Nucletron and Varian source audits (95% CI). This uncertainty was sufficient to establish a ±5% acceptance criterion for source strength audits under a formal RPC audit program. Trial audits of eight participating institutions resulted in an average RPC-to-institution dose ratio of 1.000 with a standard deviation of 0.011.

CHARACTERIZATION OF THE COUNT RATE PERFORMANCE AND EVALUATION OF THE EFFECTS OF HIGH COUNT RATES ON MODERN GAMMA CAMERAS

CHARACTERIZATION OF THE COUNT RATE PERFORMANCE AND EVALUATION OF THE EFFECTS OF HIGH COUNT RATES ON MODERN GAMMA CAMERAS Michael Stephen Silosky, B.S. Supervisory Professor: S. Cheenu Kappadath, Ph.D. Evaluation of count rate performance (CRP) is an integral component of gamma camera quality assurance and measurement of system dead time (τ) is important for quantitative SPECT. The CRP of three modern gamma cameras was characterized using established methods (Decay and Dual Source) under a variety of experimental conditions. For the Decay method, input count rate was plotted against observed count rate and fit to the paralyzable detector model (PDM) to estimate τ (Rates method). A novel expression for observed counts as a function of measurement time interval was derived and the observed counts were fit to this expression to estimate τ (Counts method). Correlation and Bland-Altman analysis were performed to assess agreement in estimates of τ between methods. The dependencies of τ on energy window definition and incident energy spectrum were characterized. The Dual Source method was also used to estimate τ and its agreement with the Decay method under identical conditions and the effects of total activity and the ratio of source activities were investigated. Additionally, the effects of count rate on several performance metrics were evaluated. The CRP curves for each system agreed with the PDM at low count rates but deviated substantially at high count rates. Estimates of τ for the paralyzable portion of the CRP curves using the Rates and Counts methods were highly correlated (r=0.999) but with a small (~6%) difference. No significant difference was observed between the highly correlated estimates of τ using the Decay or Dual Source methods under identical experimental conditions (r=0.996). Estimates of τ increased as a power-law function with decreasing ratio of counts in the photopeak to the total counts and linearly with decreasing spectral effective energy. Dual Source method estimates of τ varied as a quadratic with the ratio of the single source to combined source activities and linearly with total activity used across a large range. Image uniformity, spatial resolution, and energy resolution degraded linearly with count rate and image distorting effects were observed. Guidelines for CRP testing and a possible method for the correction of count rate losses for clinical images have been proposed.

Abordaje interdisciplinario a Viaje por los estados del Plata de Hermann Burmeister : parte II : abordaje desde la historia

El presente artículo forma parte del proyecto interdisciplinario sobre iterología mendocina que tiene como principal objetivo analizar los relatos de viajeros extranjeros a Mendoza desde una perspectiva histórica, literaria y geográfica. Desde hace tiempo, estos relatos constituyen una fuente indispensable para el estudio de nuestro pasado y el texto de Hermann Burmeister reviste especial importancia para los historiadores debido a que el científico alemán permaneció en la provincia por algo más de un año. Por esta razón sus descripciones son detalladas y minuciosas; además, estuvo en Mendoza antes de que el terremoto de 1861 la destruyera, con lo cual, su relato ayuda a recrear aquella ciudad desaparecida, El objetivo de este trabajo es ejemplificar la metodología de trabajo utilizada por la Historia para analizar el texto de viaje. Para ello, se ha escogido el tema de la presencia de las mujeres en el relato del viajero alemán.

Grain entrainment and transport rates of magnetic minerals of coastal sediment samples from the Bay of Plenty, New Zealand

Heavy (magnetic & non-magnetic) minerals are found concentrated by natural processes in many fluvial, estuarine, coastal and shelf environments with a potential to form economic placer deposits. Understanding the processes of heavy mineral transport and enrichment is prerequisite to interpret sediment magnetic properties in terms of hydro- and sediment dynamics. In this study, we combine rock magnetic and sedimentological laboratory measurements with numerical 3D discrete element models to investigate differential grain entrainment and transport rates of magnetic minerals in a range of coastal environments (riverbed, mouth, estuary, beach and near-shore). We analyzed grain-size distributions of representative bulk samples and their magnetic mineral fractions to relate grain-size modes to respective transport modes (traction, saltation, suspension). Rock magnetic measurements showed that distribution shapes, population sizes and grain-size offsets of bulk and magnetic mineral fractions hold information on the transport conditions and enrichment process in each depositional environment. A downstream decrease in magnetite grain size and an increase in magnetite concentration was observed from riverine source to marine sink environments. Lower flow velocities permit differential settling of light and heavy mineral grains creating heavy mineral enriched zones in estuary settings, while lighter minerals are washed out further into the sea. Numerical model results showed that higher heavy mineral concentrations in the bed increased the erosion rate and enhancing heavy mineral enrichment. In beach environments where sediments contained light and heavy mineral grains of equivalent grain sizes, the bed was found to be more stable with negligible amount of erosion compared to other bed compositions. Heavy mineral transport rates calculated for four different bed compositions showed that increasing heavy mineral content in the bed decreased the transport rate. There is always a lag in transport between light and heavy minerals which increases with higher heavy mineral concentration in all tested bed compositions. The results of laboratory experiments were validated by numerical models and showed good agreement. We demonstrate that the presented approach bears the potential to investigate heavy mineral enrichment processes in a wide range of sedimentary settings.

Scientific Production on Open Access : A Worldwide Bibliometric Analysis in the Academic and Scientific Context

This research aims to diachronically analyze the worldwide scientific production on open access, in the academic and scientific context, in order to contribute to knowledge and visualization of its main actors. As a method, bibliographical, descriptive and analytical research was used, with the contribution of bibliometric studies, especially the production indicators, scientific collaboration and indicators of thematic co-occurrence. The Scopus database was used as a source to retrieve the articles on the subject, with a resulting corpus of 1179 articles. Using Bibexcel software, frequency tables were constructed for the variables, and Pajek software was used to visualize the collaboration network and VoSViewer for the construction of the keywords' network. As for the results, the most productive researchers come from countries such as the United States, Canada, France and Spain. Journals with higher impact in the academic community have disseminated the new constructed knowledge. A collaborative network with a few subnets where co-authors are from different countries has been observed. As conclusions, this study allows identifying the themes of debates that mark the development of open access at the international level, and it is possible to state that open access is one of the new emerging and frontier fields of library and information science

Scientific Production on Open Access : A Worldwide Bibliometric Analysis in the Academic and Scientific Context

This research aims to diachronically analyze the worldwide scientific production on open access, in the academic and scientific context, in order to contribute to knowledge and visualization of its main actors. As a method, bibliographical, descriptive and analytical research was used, with the contribution of bibliometric studies, especially the production indicators, scientific collaboration and indicators of thematic co-occurrence. The Scopus database was used as a source to retrieve the articles on the subject, with a resulting corpus of 1179 articles. Using Bibexcel software, frequency tables were constructed for the variables, and Pajek software was used to visualize the collaboration network and VoSViewer for the construction of the keywords' network. As for the results, the most productive researchers come from countries such as the United States, Canada, France and Spain. Journals with higher impact in the academic community have disseminated the new constructed knowledge. A collaborative network with a few subnets where co-authors are from different countries has been observed. As conclusions, this study allows identifying the themes of debates that mark the development of open access at the international level, and it is possible to state that open access is one of the new emerging and frontier fields of library and information science

Chemistry of upper Eocene microtektites

Late Eocene microtektites and crystal-bearing microkrystites extracted from DSDP and ODP cores from the Atlantic, Pacific, and Indian oceans have been analyzed to address their provenance. A new analysis of Nd and Sr isotopic compositions confirms previous work and the assignment of the uppermost microtektite layer to the North American tektites, which are associated with the 35.5 Ma, 85 km diameter Chesapeake impact structure of Virginia, USA. Extensive major element and Nd and Sr isotopic analyses of the microkrystites from the lowermost layer were obtained. The melanocratic microkrystites from Sites 216 and 462 in the Indian and Pacific oceans possess major element chemistries, Sr and Nd isotopic signatures and Sm-Nd, T CHUR, model ages similar to those of tagamite melt rocks in the Popigai impact structure. They also possess Rb-Sr, T UR, model ages that are younger than the tagamite TCHUR ages by up to ~1 Ga, which require a process, as yet undefined, of Rb/Sr enrichment. These melanocratic microkrystites are consistent with a provenance from the 35.7 Ma, 100 km diameter Popigai impact structure of Siberia, Russia, while ruling out other contemporaneous structures as a source. Melanocratic microkrystites from other sites and leucocratic microkrystites from all sites possess a wide range of isotopic compositions (epsilon (143Nd) values of -16 to -27.7 and epsilon (87Sr) values of 4.1-354.0), making the association with Popigai tagamites less clear. These microkrystites may have been derived by the melting of target rocks of mixed composition, which were ejected without homogenization. Dark glass and felsic inclusions extracted from Popigai tagamites possess epsilon (143Nd) and epsilon (87Sr) values of -26.7 to -27.8 and 374.7 and 432.4, respectively, and T CHUR and T UR model ages of 1640-1870 Ma and 240-1830 Ma, respectively, which require the preservation of initially present heterogeneity in the source materials. The leucocratic microkrystites possess diverse isotopic compositions that may reflect the melting of supra-basement sedimentary rocks from Popigai, or early basement melts that were ejected prior to homogenization of the Popigai tagamites. The ejection of melt rocks with chemistries consistent with a basement provenance, rather than the surface ~1 km of sedimentary cover rocks, atypically indicates a non-surficial source to some of the ejecta. Microkrystites from two adjacent biozones possess statistically indistinguishable major element compositions, suggesting they have a single source. The occurrence of microkrystites derived from a single impact event, but in different biozones, can be explained by: (1) diachronous biozone boundaries; (2) post-accumulation sedimentary reworking; or (3) erroneous biozonation.

Scientific Production on Open Access : A Worldwide Bibliometric Analysis in the Academic and Scientific Context

This research aims to diachronically analyze the worldwide scientific production on open access, in the academic and scientific context, in order to contribute to knowledge and visualization of its main actors. As a method, bibliographical, descriptive and analytical research was used, with the contribution of bibliometric studies, especially the production indicators, scientific collaboration and indicators of thematic co-occurrence. The Scopus database was used as a source to retrieve the articles on the subject, with a resulting corpus of 1179 articles. Using Bibexcel software, frequency tables were constructed for the variables, and Pajek software was used to visualize the collaboration network and VoSViewer for the construction of the keywords' network. As for the results, the most productive researchers come from countries such as the United States, Canada, France and Spain. Journals with higher impact in the academic community have disseminated the new constructed knowledge. A collaborative network with a few subnets where co-authors are from different countries has been observed. As conclusions, this study allows identifying the themes of debates that mark the development of open access at the international level, and it is possible to state that open access is one of the new emerging and frontier fields of library and information science

Results of bulk sediment X-ray diffraction analysis and quantification of mineral phases based on the RockJock and on the QUAX quantitative analysis

We have performed quantitative X-ray diffraction (qXRD) analysis of 157 grab or core-top samples from the western Nordic Seas between (WNS) ~57°-75°N and 5° to 45° W. The RockJock Vs6 analysis includes non-clay (20) and clay (10) mineral species in the <2 mm size fraction that sum to 100 weight %. The data matrix was reduced to 9 and 6 variables respectively by excluding minerals with low weight% and by grouping into larger groups, such as the alkali and plagioclase feldspars. Because of its potential dual origins calcite was placed outside of the sum. We initially hypothesized that a combination of regional bedrock outcrops and transport associated with drift-ice, meltwater plumes, and bottom currents would result in 6 clusters defined by "similar" mineral compositions. The hypothesis was tested by use of a fuzzy k-mean clustering algorithm and key minerals were identified by step-wise Discriminant Function Analysis. Key minerals in defining the clusters include quartz, pyroxene, muscovite, and amphibole. With 5 clusters, 87.5% of the observations are correctly classified. The geographic distributions of the five k-mean clusters compares reasonably well with the original hypothesis. The close spatial relationship between bedrock geology and discrete cluster membership stresses the importance of this variable at both the WNS-scale and at a more local scale in NE Greenland.

A database of multi-year (2004-2010) quality-assured surface solar hourly irradiation measurements for the Egyptian territory

A database containing the global and diffuse components of the surface solar hourly irradiation measured from 1 January 2004 to 31 December 2010 at eight stations of the Egyptian Meteorological Authority is presented. For three of these sites (Cairo, Aswan, and El-Farafra), the direct component is also available. In addition, a series of meteorological variables including surface pressure, relative humidity, temperature, wind speed and direction is provided at the same hourly resolution at all stations. The details of the experimental sites and instruments used for the acquisition are given. Special attention is paid to the quality of the data and the procedure applied to flag suspicious or erroneous measurements is described in details. Between 88 and 99% of the daytime measurements are validated by this quality control. Except at Barrani where the number is lower (13500), between 20000 and 29000 measurements of global and diffuse hourly irradiation are available at all sites for the 7-year period. Similarly, from 9000 to 13000 measurements of direct hourly irradiation values are provided for the three sites where this component is measured. With its high temporal resolution this consistent irradiation and meteorological database constitutes a reliable source to estimate the potential of solar energy in Egypt. It is also adapted to the study of high-frequency atmospheric processes such as the impact of aerosols on atmospheric radiative transfer. In the next future, it is planned to complete regularly the present 2004-2010 database.

Tab. 1+7: Hydrochemical analyses of firn and meltwater from different "cold" snow patches

In wide areas of Northern Siberia, glaciers have been absent since the Late Pleistocene. Therefore, ground ice and especially ice wedges are used as archives for paleoclimatic studies. In the present study, carried out on the Bykovsky Peninsula, eastern Lena Delta, we were able to distinguish ice wedges of different genetic units by means of oxygen and hydrogen isotopes. The results obtained by this study on the Ice Complex, a peculiar periglacial phenomenon, allowed the reconstruction of the climate history with a subdivision of a period of very cold winters (60-55 ka), followed by a long stable period of cold winter temperatures (50-24 ka), Between 20 ka and 11 ka, climate warming is indicated in stable isotope compositions, most probably after the Late Glacial Maximum. At that time, a change of the marine source of the precipitation from a more humid source to the present North AtIantic source region was assumed. For the Ice Complex, a continuous age-height relationship was established, indicating syngenetic vertical ice wedge growth and sediment accumulation rates of 0.7 m/ky. During the Holocene optimum, ice wedge growth was probably limited due to the extensive formation of lacustrine environments. Holocene ice wedges in thermokarst depressions (alases) and thermoerosional valleys (logs) were formed after climate deterioration from about 4.5 ka until the present. Winter temperatures were warmer at this time as compared to the cooler Pleistocene. Migration of bound water between ice wedges and segregated ice may have altered the isotopic composition of old ice wedges. The presence of ice wedges as diagnostic features for permafrost conditions since 60 ka, implies that a large glacier extending over the Laptev Sea shelf did not exist. For the remote non-glaciated areas of Northern Siberia, ice wedges were established as a powerful climate archive.

Isotopic composition of ground ice, ebullition gases and thermokarst lake water, North America

Thermokarst lakes are thought to have been an important source of methane (CH4) during the last deglaciation when atmospheric CH4 concentrations increased rapidly. Here we demonstrate that meltwater from permafrost ice serves as an H source to CH4 production in thermokarst lakes, allowing for region-specific reconstructions of dD-CH4 emissions from Siberian and North American lakes. dD CH4 reflects regionally varying dD values of precipitation incorporated into ground ice at the time of its formation. Late Pleistocene-aged permafrost ground ice was the dominant H source to CH4 production in primary thermokarst lakes, whereas Holocene-aged permafrost ground ice contributed H to CH4 production in later generation lakes. We found that Alaskan thermokarst lake dD-CH4 was higher (-334 ± 17 per mil) than Siberian lake dD-CH4 (-381 ± 18 per mil). Weighted mean dD CH4 values for Beringian lakes ranged from -385 per mil to -382 per mil over the deglacial period. Bottom-up estimates suggest that Beringian thermokarst lakes contributed 15 ± 4 Tg CH4 /yr to the atmosphere during the Younger Dryas and 25 ± 5 Tg CH4 /yr during the Preboreal period. These estimates are supported by independent, top-down isotope mass balance calculations based on ice core dD-CH4 and d13C-CH4 records. Both approaches suggest that thermokarst lakes and boreal wetlands together were important sources of deglacial CH4.

Hydrogen and oxygen isotopes in ground lce of Bykovsky Peninsula, North Siberia

In wide areas of Northern Siberia, glaciers have been absent since the Late Pleistocene. Therefore, ground ice and especially ice wedges are used as archives for paleoclimatic studies. In the present study, carried out on the Bykovsky Peninsula, eastern Lena Delta, we were able to distinguish ice wedges of different genetic units by means of oxygen and hydrogen isotopes. The results obtained by this study on the Ice Complex, a peculiar periglacial phenomenon, allowed the reconstruction of the climate history with a subdivision of a period of very cold winters (60-55 ka), followed by a long stable period of cold winter temperatures (50-24 ka), Between 20 ka and I I ka, climate warming is indicated in stable isotope compositions, most probably after the Late Glacial Maximum. At that time, a change of the marine source of the precipitation from a more humid source to the present North Atlantic source region was assumed. For the Ice Complex, a continuous age-height relationship was established, indicating syngenetic vertical ice wedge growth and sediment accumulation rates of 0.7 m/ky. During the Holocene optimum, ice wedge growth was probably limited due to the extensive formation of lacustrine environments. Holocene ice wedges in thermokarst depressions (alases) and thermoerosional valleys (logs) were formed after climate deterioration from about 4.5 ka until the present. Winter temperatures were warmer at this time as compared to the cooler Pleistocene. Migration of bound water between ice wedges and segregated ice may have altered the isotopic composition of old ice wedges. The presence of ice wedges as diagnostic features for permafrost conditions since 60 ka, implies that a large glacier extending over the Laptev Sea shelf did not exist. For the remote non-glaciated areas of Northern Siberia, ice wedges were established as a powerful climate archive.

Chemical concentrations and fluxes from EPICA ice cores EDML and EDC

Continuous sea salt and mineral dust aerosol records have been studied on the two EPICA (European Project for Ice Coring in Antarctica) deep ice cores. The joint use of these records from opposite sides of the East Antarctic plateau allows for an estimate of changes in dust transport and emission intensity as well as for the identification of regional differences in the sea salt aerosol source. The mineral dust flux records at both sites show a strong coherency over the last 150 kyr related to dust emission changes in the glacial Patagonian dust source with three times higher dust fluxes in the Atlantic compared to the Indian Ocean sector of the Southern Ocean (SO). Using a simple conceptual transport model this indicates that transport can explain only 40% of the atmospheric dust concentration changes in Antarctica, while factor 5-10 changes occurred. Accordingly, the main cause for the strong glacial dust flux changes in Antarctica must lie in environmental changes in Patagonia. Dust emissions, hence environmental conditions in Patagonia, were very similar during the last two glacials and interglacials, respectively, despite 2-4 °C warmer temperatures recorded in Antarctica during the penultimate interglacial than today. 2-3 times higher sea salt fluxes found in both ice cores in the glacial compared to the Holocene are difficult to reconcile with a largely unchanged transport intensity and the distant open ocean source. The substantial glacial enhancements in sea salt aerosol fluxes can be readily explained assuming sea ice formation as the main sea salt aerosol source with a significantly larger expansion of (summer) sea ice in the Weddell Sea than in the Indian Ocean sector. During the penultimate interglacial, our sea salt records point to a 50% reduction of winter sea ice coverage compared to the Holocene both in the Indian and Atlantic Ocean sector of the SO. However, from 20 to 80 ka before present sea salt fluxes show only very subdued millennial changes despite pronounced temperature fluctuations, likely due to the large distance of the sea ice salt source to our drill sites.