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  • American Society of Hematology  (52,917)
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  • 1
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    American Meteorological Society
    In:  EPIC3Journal of Climate, American Meteorological Society, 37(6), pp. 2059-2080, ISSN: 0894-8755
    Publication Date: 2024-04-22
    Description: Heat stress is projected to intensify with global warming, causing significant socioeconomic impacts and threatening human health. Wet-bulb temperature (WBT), which combines temperature and humidity effects, is a useful indicator for assessing regional and global heat stress variability and trends. However, the variations of European WBT and their underlying mechanisms remain unclear. Using observations and reanalysis datasets, we demonstrate a remarkable warming of summer WBT during the period 1958–2021 over Europe. Specifically, the European summer WBT has increased by over 1.08C in the past 64 years. We find that the increase in European summer WBT is driven by both near-surface warming temperatures and increasing atmospheric moisture content. We identify four dominant modes of European summer WBT variability and investigate their linkage with the large-scale atmospheric circulation and sea surface temperature anomalies. The first two leading modes of the European WBT variability exhibit prominent interdecadal to long-term variations, mainly driven by a circumglobal wave train and concurrent sea surface temperature variations. The last two leading modes of European WBT variability mainly show interannual variations, indicating a direct and rapid response to large-scale atmospheric dynamics and nearby sea surface temperature variations. Further analysis shows the role of global warming and changes in midlatitude circulations in the variations of summer WBT. Our findings can enhance the understanding of plausible drivers of heat stress in Europe and provide valuable insights for regional decision-makers and climate adaptation planning.
    Repository Name: EPIC Alfred Wegener Institut
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  • 2
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    American Meteorological Society
    In:  EPIC3Journal of Climate, American Meteorological Society, 37(8), pp. 2505-2518, ISSN: 0894-8755
    Publication Date: 2024-04-29
    Description: A fundamental statistic of climate variability is its spatiotemporal correlation function. Its complex structure can be concisely summarized by a frequency-dependent measure of the effective spatial degrees of freedom (ESDOF). Here we present, for the first time, frequency-dependent ESDOF estimates of global natural surface temperature variability from purely instrumental measurements, using the HadCRUT4 dataset (1850-2014). The approach is based on a newly developed method for estimating the frequency-dependent spatial correlation function from gappy data fields. Results reveal a multicomponent structure of the spatial correlation function, including a large-amplitude short-distance component (with weak time scale dependence) and a small-amplitude long-distance component (with increasing relative amplitude toward the longer time scales). Two frequency-dependent ESDOF measures are applied, each responding mainly to either of the two components. Both measures exhibit a significant ESDOF reduction from monthly to multidecadal time scales, implying an increase of the effective spatial scale of natural surface temperature fluctuations. Moreover, it is found that a good approximation to the global number of equally spaced samples needed to estimate the variance of global mean temperature is given, at any frequency, by the greater one of the two ESDOF measures, decreasing from ;130 at monthly to ;30 at multidecadal time scales. Finally, the multicomponent structure of the correlation function together with the detected ESDOF scaling properties indicate that the ESDOF reduction toward the longer time scales cannot be explained simply by diffusion acting on stochastically driven anomalies, as it might be suggested f rom simple stochastic-diffusive energy balance models.
    Repository Name: EPIC Alfred Wegener Institut
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  • 3
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    American Meteorological Society
    In:  EPIC3Journal of Physical Oceanography, American Meteorological Society, 54(4), pp. 1003-1018, ISSN: 0022-3670
    Publication Date: 2024-04-25
    Description: Coastal upwelling, driven by alongshore winds and characterized by cold sea surface temperatures and high upper-ocean nutrient content, is an important physical process sustaining some of the oceans’ most productive ecosystems. To fully understand the ocean properties in eastern boundary upwelling systems, it is important to consider the depth of the source waters being upwelled, as it affects both the SST and the transport of nutrients toward the surface. Here, we construct an upwelling source depth distribution for parcels at the surface in the upwelling zone. We do so using passive tracers forced at the domain boundary for every model depth level to quantify their contributions to the upwelled waters. We test the dependence of this distribution on the strength of the wind stress and stratification using high-resolution regional ocean simulations of an idealized coastal upwelling system. We also present an efficient method for estimating the mean upwelling source depth. Furthermore, we show that the standard deviation of the upwelling source depth distribution increases with increasing wind stress and decreases with increasing stratification. These results can be applied to better understand and predict how coastal upwelling sites and their surface properties have and will change in past and future climates.
    Repository Name: EPIC Alfred Wegener Institut
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  • 4
    Publication Date: 2023-02-28
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(12),(2022): 3199-3219, https://doi.org/10.1175/jpo-d-22-0009.1.
    Description: The abyssal overturning circulation is thought to be primarily driven by small-scale turbulent mixing. Diagnosed water-mass transformations are dominated by rough topography “hotspots,” where the bottom enhancement of mixing causes the diffusive buoyancy flux to diverge, driving widespread downwelling in the interior—only to be overwhelmed by an even stronger upwelling in a thin bottom boundary layer (BBL). These water-mass transformations are significantly underestimated by one-dimensional (1D) sloping boundary layer solutions, suggesting the importance of three-dimensional physics. Here, we use a hierarchy of models to generalize this 1D boundary layer approach to three-dimensional eddying flows over realistically rough topography. When applied to the Mid-Atlantic Ridge in the Brazil Basin, the idealized simulation results are roughly consistent with available observations. Integral buoyancy budgets isolate the physical processes that contribute to realistically strong BBL upwelling. The downward diffusion of buoyancy is primarily balanced by upwelling along the sloping canyon sidewalls and the surrounding abyssal hills. These flows are strengthened by the restratifying effects of submesoscale baroclinic eddies and by the blocking of along-ridge thermal wind within the canyon. Major topographic sills block along-thalweg flows from restratifying the canyon trough, resulting in the continual erosion of the trough’s stratification. We propose simple modifications to the 1D boundary layer model that approximate each of these three-dimensional effects. These results provide local dynamical insights into mixing-driven abyssal overturning, but a complete theory will also require the nonlocal coupling to the basin-scale circulation.
    Description: We acknowledge funding support from National Science Foundation Awards 1536515, 1736109, and 2149080. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant 174530.
    Description: 2023-05-18
    Keywords: Abyssal circulation ; Diapycnal mixing ; Meridional overturning circulation ; Topographic effects ; Upwelling/downwelling ; Bottom currents/bottom water
    Repository Name: Woods Hole Open Access Server
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  • 5
    Publication Date: 2023-02-28
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(6), (2022): 1091–1110, https://doi.org/10.1175/JPO-D-21-0068.1.
    Description: Hundreds of full-depth temperature and salinity profiles collected by Deepglider autonomous underwater vehicles (AUVs) in the North Atlantic reveal robust signals in eddy isopycnal vertical displacement and horizontal current throughout the entire water column. In separate glider missions southeast of Bermuda, subsurface-intensified cold, fresh coherent vortices were observed with velocities exceeding 20 cm s−1 at depths greater than 1000 m. With vertical resolution on the order of 20 m or less, these full-depth glider slant profiles newly permit estimation of scaled vertical wavenumber spectra from the barotropic through the 40th baroclinic mode. Geostrophic turbulence theory predictions of spectral slopes associated with the forward enstrophy cascade and proportional to inverse wavenumber cubed generally agree with glider-derived quasi-universal spectra of potential and kinetic energy found at a variety of locations distinguished by a wide range of mean surface eddy kinetic energy. Water-column average spectral estimates merge at high vertical mode number to established descriptions of internal wave spectra. Among glider mission sites, geographic and seasonal variability implicate bottom drag as a mechanism for dissipation, but also the need for more persistent sampling of the deep ocean.
    Description: This work was funded by NSF Grant 1736217 and would not have been possible without the help of Kirk O’Donnell, James Bennett, Noel Pelland, and all contributors to Deepglider development. We additionally thank the captain crew of the R/V Atlantic Explorer and the BATS team at the Bermuda Institute of Ocean Sciences, particularly Rod Johnson, as well as Seakeepers International for their professionalism, capability, and generous assistance in deploying and recovering gliders.
    Keywords: North Atlantic Ocean ; Eddies ; Mesoscale processes ; Turbulence ; Energy transport ; In situ oceanic observations ; Oceanic variability
    Repository Name: Woods Hole Open Access Server
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  • 6
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    American Meteorological Society
    In:  EPIC3Journal of Climate, American Meteorological Society, pp. 1-40, ISSN: 0894-8755
    Publication Date: 2023-09-04
    Description: 〈jats:title〉Abstract〈/jats:title〉 〈jats:p〉Tipping points in the Earth system describe critical thresholds beyond which a single component, part of the system, or the system as a whole changes from one stable state to another. In the present-day Southern Ocean, the Weddell Sea constitutes an important dense-water formation site, associated with efficient deep-ocean carbon and oxygen transfer and low ice-shelf basal melt rates. Here, a regime shift will occur when continental shelves are continuously flushed with warm, oxygen-poor offshore waters from intermediate depth, leading to less efficient deep-ocean carbon and oxygen transfer and higher ice-shelf basal melt rates. We use a global ocean–biogeochemistry model including ice-shelf cavities and an eddy-permitting grid in the southern Weddell Sea to address the susceptibility of this region to such a system change for four 21〈jats:sup〉st〈/jats:sup〉-century emission scenarios. Assessing the projected changes in shelf–open ocean density gradients, bottom-water properties, and on-shelf heat transport, our results indicate that the Weddell Sea undergoes a regime shift by 2100 in the highest-emission scenario SSP5-8.5, but not yet in the lower-emission scenarios. The regime shift is imminent by 2100 in the scenarios SSP3-7.0 and SSP2-4.5, but avoidable under the lowest-emission scenario SSP1-2.6. While shelf-bottom waters freshen and acidify everywhere, bottom waters in the Filchner Trough undergo accelerated warming and deoxygenation following the system change, with implications for local ecosystems and ice-shelf basal melt. Additionally, deep-ocean carbon and oxygen transfer decline, implying that the local changes ultimately affect ocean circulation, climate, and ecosystems globally.〈/jats:p〉
    Repository Name: EPIC Alfred Wegener Institut
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  • 7
    Publication Date: 2023-03-02
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(12), (2022): 3221–3240, https://doi.org/10.1175/jpo-d-22-0010.1.
    Description: Small-scale mixing drives the diabatic upwelling that closes the abyssal ocean overturning circulation. Indirect microstructure measurements of in situ turbulence suggest that mixing is bottom enhanced over rough topography, implying downwelling in the interior and stronger upwelling in a sloping bottom boundary layer. Tracer release experiments (TREs), in which inert tracers are purposefully released and their dispersion is surveyed over time, have been used to independently infer turbulent diffusivities—but typically provide estimates in excess of microstructure ones. In an attempt to reconcile these differences, Ruan and Ferrari derived exact tracer-weighted buoyancy moment diagnostics, which we here apply to quasi-realistic simulations. A tracer’s diapycnal displacement rate is exactly twice the tracer-averaged buoyancy velocity, itself a convolution of an asymmetric upwelling/downwelling dipole. The tracer’s diapycnal spreading rate, however, involves both the expected positive contribution from the tracer-averaged in situ diffusion as well as an additional nonlinear diapycnal distortion term, which is caused by correlations between buoyancy and the buoyancy velocity, and can be of either sign. Distortion is generally positive (stretching) due to bottom-enhanced mixing in the stratified interior but negative (contraction) near the bottom. Our simulations suggest that these two effects coincidentally cancel for the Brazil Basin Tracer Release Experiment, resulting in negligible net distortion. By contrast, near-bottom tracers experience leading-order distortion that varies in time. Errors in tracer moments due to realistically sparse sampling are generally small (〈20%), especially compared to the O(1) structural errors due to the omission of distortion effects in inverse models. These results suggest that TREs, although indispensable, should not be treated as “unambiguous” constraints on diapycnal mixing.
    Description: We acknowledge funding support from National Science Foundation Awards 1536515 and 1736109. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant 174530. This research is also supported by the NOAA Climate and Global Change Postdoctoral Fellowship Program, administered by UCAR’s Cooperative Programs for the Advancement of Earth System Science (CPAESS) under Award NA18NWS4620043B.
    Description: 2023-05-18
    Keywords: Diapycnal mixing ; Diffusion ; Upwelling/downwelling ; Bottom currents/bottom water ; Tracers
    Repository Name: Woods Hole Open Access Server
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  • 8
    Publication Date: 2023-02-25
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(11), (2022): 2841–2852, https://doi.org/10.1175/jpo-d-22-0025.1.
    Description: Prediction of rapid intensification in tropical cyclones prior to landfall is a major societal issue. While air–sea interactions are clearly linked to storm intensity, the connections between the underlying thermal conditions over continental shelves and rapid intensification are limited. Here, an exceptional set of in situ and satellite data are used to identify spatial heterogeneity in sea surface temperatures across the inner core of Hurricane Sally (2020), a storm that rapidly intensified over the shelf. A leftward shift in the region of maximum cooling was observed as the hurricane transited from the open gulf to the shelf. This shift was generated, in part, by the surface heat flux in conjunction with the along- and across-shelf transport of heat from storm-generated coastal circulation. The spatial differences in the sea surface temperatures were large enough to potentially influence rapid intensification processes suggesting that coastal thermal features need to be accounted for to improve storm forecasting as well as to better understand how climate change will modify interactions between tropical cyclones and the coastal ocean.
    Description: This research was made possible by the NOAA RESTORE Science Program (NA17NOS4510101 and NA19NOS4510194) and the NASA Physical Oceanography program (80NSSC21K0553 and WBS 281945.02.25.04.67) and NOAA IOOS program via GCOOS (NA16NOS0120018). The authors declare that they have no competing interests.
    Keywords: Seas/gulfs/bays ; Atmosphere–ocean interaction ; Currents ; Tropical cyclones ; Buoy observations ; In situ oceanic observations
    Repository Name: Woods Hole Open Access Server
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  • 9
    Publication Date: 2023-02-25
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(8), (2022): 1797–1815, https://doi.org/10.1175/JPO-D-21-0288.1.
    Description: Intruding slope water is a major source of nutrients to sustain the high biological productivity in the Gulf of Maine (GoM). Slope water intrusion into the GoM is affected by Gulf Stream warm-core rings (WCRs) impinging onto the nearby shelf edge. This study combines long-term mooring measurements, satellite remote sensing data, an idealized numerical ocean model, and a linear coastal-trapped wave (CTW) model to examine the impact of WCRs on slope water intrusion into the GoM through the Northeast Channel. Analysis of satellite sea surface height and temperature data shows that the slope sea region off the GoM is a hotspot of ring activities. A significant linear relationship is found between interannual variations of ring activities in the slope sea region off the GoM and bottom salinity at the Northeast Channel, suggesting the importance of WCRs in modulating variability of intruding slope water. Analysis of the mooring data reveals enhanced slope water intrusion through bottom-intensified along-channel flow following impingements of WCRs on the nearby shelf edge. Numerical simulations qualitatively reproduce the observed WCR impingement processes and associated episodic enhancement of slope water intrusion in the Northeast Channel. Diagnosis of the model result indicates that baroclinic CTWs excited by the ring–topography interaction are responsible for the episodically intensified subsurface along-channel inflow, which carries more slope water into the GoM. A WCR that impinges onto the shelf edge to the northeast of the Northeast Channel tends to generate stronger CTWs and cause stronger enhancement of the slope water intrusion into the GoM.
    Description: This study is supported by the National Science Foundation through Grant OCE-1634965.
    Keywords: Continental shelf/slope ; Channel flows ; Mesoscale processes ; In situ oceanic observations ; Satellite observations ; Numerical analysis/modeling
    Repository Name: Woods Hole Open Access Server
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  • 10
    Publication Date: 2023-02-17
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of the Atmospheric and Oceanic Technology 39(10), (2022): 1525–1539, https://doi.org/10.1175/jtech-d-21-0186.1.
    Description: The static and dynamic performances of the RBRargo3 are investigated using a combination of laboratory-based and in situ datasets from floats deployed as part of an Argo pilot program. Temperature and pressure measurements compare well to co-located reference data acquired from shipboard CTDs. Static accuracy of salinity measurements is significantly improved using 1) a time lag for temperature, 2) a quadratic pressure dependence, and 3) a unit-based calibration for each RBRargo3 over its full pressure range. Long-term deployments show no significant drift in the RBRargo3 accuracy. The dynamic response of the RBRargo3 demonstrates the presence of two different adjustment time scales: a long-term adjustment O(120) s, driven by the temperature difference between the interior of the conductivity cell and the water, and a short-term adjustment O(5–10) s, associated to the initial exchange of heat between the water and the inner ceramic. Corrections for these effects, including dependence on profiling speed, are developed.
    Keywords: Data processing/distribution ; In situ oceanic observations ; Profilers ; Oceanic
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  • 11
    Publication Date: 2023-04-26
    Description: Mechanisms behind the phenomenon of Arctic amplification are widely discussed. To contribute to this debate, the (AC)3 project was established in 2016 (www.ac3-tr.de/). It comprises modeling and data analysis efforts as well as observational elements. The project has assembled a wealth of ground-based, airborne, shipborne, and satellite data of physical, chemical, and meteorological properties of the Arctic atmosphere, cryosphere, and upper ocean that are available for the Arctic climate research community. Short-term changes and indications of long-term trends in Arctic climate parameters have been detected using existing and new data. For example, a distinct atmospheric moistening, an increase of regional storm activities, an amplified winter warming in the Svalbard and North Pole regions, and a decrease of sea ice thickness in the Fram Strait and of snow depth on sea ice have been identified. A positive trend of tropospheric bromine monoxide (BrO) column densities during polar spring was verified. Local marine/biogenic sources for cloud condensation nuclei and ice nucleating particles were found. Atmospheric–ocean and radiative transfer models were advanced by applying new parameterizations of surface albedo, cloud droplet activation, convective plumes and related processes over leads, and turbulent transfer coefficients for stable surface layers. Four modes of the surface radiative energy budget were explored and reproduced by simulations. To advance the future synthesis of the results, cross-cutting activities are being developed aiming to answer key questions in four focus areas: lapse rate feedback, surface processes, Arctic mixed-phase clouds, and airmass transport and transformation.
    Repository Name: EPIC Alfred Wegener Institut
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  • 12
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    American Meteorological Society
    In:  EPIC3Bulletin of the American Meteorological Society, American Meteorological Society, 104(9), pp. s1-s10, ISSN: 0003-0007
    Publication Date: 2024-05-08
    Description: 〈jats:title〉Abstract〈/jats:title〉 〈jats:p〉—J. BLUNDEN, T. BOYER, AND E. BARTOW-GILLIES〈/jats:p〉 〈jats:p〉Earth’s global climate system is vast, complex, and intricately interrelated. Many areas are influenced by global-scale phenomena, including the “triple dip” La Niña conditions that prevailed in the eastern Pacific Ocean nearly continuously from mid-2020 through all of 2022; by regional phenomena such as the positive winter and summer North Atlantic Oscillation that impacted weather in parts the Northern Hemisphere and the negative Indian Ocean dipole that impacted weather in parts of the Southern Hemisphere; and by more localized systems such as high-pressure heat domes that caused extreme heat in different areas of the world. Underlying all these natural short-term variabilities are long-term climate trends due to continuous increases since the beginning of the Industrial Revolution in the atmospheric concentrations of Earth’s major greenhouse gases.〈/jats:p〉 〈jats:p〉In 2022, the annual global average carbon dioxide concentration in the atmosphere rose to 417.1±0.1 ppm, which is 50% greater than the pre-industrial level. Global mean tropospheric methane abundance was 165% higher than its pre-industrial level, and nitrous oxide was 24% higher. All three gases set new record-high atmospheric concentration levels in 2022.〈/jats:p〉 〈jats:p〉Sea-surface temperature patterns in the tropical Pacific characteristic of La Niña and attendant atmospheric patterns tend to mitigate atmospheric heat gain at the global scale, but the annual global surface temperature across land and oceans was still among the six highest in records dating as far back as the mid-1800s. It was the warmest La Niña year on record. Many areas observed record or near-record heat. Europe as a whole observed its second-warmest year on record, with sixteen individual countries observing record warmth at the national scale. Records were shattered across the continent during the summer months as heatwaves plagued the region. On 18 July, 104 stations in France broke their all-time records. One day later, England recorded a temperature of 40°C for the first time ever. China experienced its second-warmest year and warmest summer on record. In the Southern Hemisphere, the average temperature across New Zealand reached a record high for the second year in a row. While Australia’s annual temperature was slightly below the 1991–2020 average, Onslow Airport in Western Australia reached 50.7°C on 13 January, equaling Australia's highest temperature on record.〈/jats:p〉 〈jats:p〉While fewer in number and locations than record-high temperatures, record cold was also observed during the year. Southern Africa had its coldest August on record, with minimum temperatures as much as 5°C below normal over Angola, western Zambia, and northern Namibia. Cold outbreaks in the first half of December led to many record-low daily minimum temperature records in eastern Australia.〈/jats:p〉 〈jats:p〉The effects of rising temperatures and extreme heat were apparent across the Northern Hemisphere, where snow-cover extent by June 2022 was the third smallest in the 56-year record, and the seasonal duration of lake ice cover was the fourth shortest since 1980. More frequent and intense heatwaves contributed to the second-greatest average mass balance loss for Alpine glaciers around the world since the start of the record in 1970. Glaciers in the Swiss Alps lost a record 6% of their volume. In South America, the combination of drought and heat left many central Andean glaciers snow free by mid-summer in early 2022; glacial ice has a much lower albedo than snow, leading to accelerated heating of the glacier. Across the global cryosphere, permafrost temperatures continued to reach record highs at many high-latitude and mountain locations.〈/jats:p〉 〈jats:p〉In the high northern latitudes, the annual surface-air temperature across the Arctic was the fifth highest in the 123-year record. The seasonal Arctic minimum sea-ice extent, typically reached in September, was the 11th-smallest in the 43-year record; however, the amount of multiyear ice—ice that survives at least one summer melt season—remaining in the Arctic continued to decline. Since 2012, the Arctic has been nearly devoid of ice more than four years old.〈/jats:p〉 〈jats:p〉In Antarctica, an unusually large amount of snow and ice fell over the continent in 2022 due to several landfalling atmospheric rivers, which contributed to the highest annual surface mass balance, 15% to 16% above the 1991–2020 normal, since the start of two reanalyses records dating to 1980. It was the second-warmest year on record for all five of the long-term staffed weather stations on the Antarctic Peninsula. In East Antarctica, a heatwave event led to a new all-time record-high temperature of −9.4°C—44°C above the March average—on 18 March at Dome C. This was followed by the collapse of the critically unstable Conger Ice Shelf. More than 100 daily low sea-ice extent and sea-ice area records were set in 2022, including two new all-time annual record lows in net sea-ice extent and area in February.〈/jats:p〉 〈jats:p〉Across the world’s oceans, global mean sea level was record high for the 11th consecutive year, reaching 101.2 mm above the 1993 average when satellite altimetry measurements began, an increase of 3.3±0.7 over 2021. Globally-averaged ocean heat content was also record high in 2022, while the global sea-surface temperature was the sixth highest on record, equal with 2018. Approximately 58% of the ocean surface experienced at least one marine heatwave in 2022. In the Bay of Plenty, New Zealand’s longest continuous marine heatwave was recorded.〈/jats:p〉 〈jats:p〉A total of 85 named tropical storms were observed during the Northern and Southern Hemisphere storm seasons, close to the 1991–2020 average of 87. There were three Category 5 tropical cyclones across the globe—two in the western North Pacific and one in the North Atlantic. This was the fewest Category 5 storms globally since 2017. Globally, the accumulated cyclone energy was the lowest since reliable records began in 1981. Regardless, some storms caused massive damage. In the North Atlantic, Hurricane Fiona became the most intense and most destructive tropical or post-tropical cyclone in Atlantic Canada’s history, while major Hurricane Ian killed more than 100 people and became the third costliest disaster in the United States, causing damage estimated at $113 billion U.S. dollars. In the South Indian Ocean, Tropical Cyclone Batsirai dropped 2044 mm of rain at Commerson Crater in Réunion. The storm also impacted Madagascar, where 121 fatalities were reported.〈/jats:p〉 〈jats:p〉As is typical, some areas around the world were notably dry in 2022 and some were notably wet. In August, record high areas of land across the globe (6.2%) were experiencing extreme drought. Overall, 29% of land experienced moderate or worse categories of drought during the year. The largest drought footprint in the contiguous United States since 2012 (63%) was observed in late October. The record-breaking megadrought of central Chile continued in its 13th consecutive year, and 80-year record-low river levels in northern Argentina and Paraguay disrupted fluvial transport. In China, the Yangtze River reached record-low values. Much of equatorial eastern Africa had five consecutive below-normal rainy seasons by the end of 2022, with some areas receiving record-low precipitation totals for the year. This ongoing 2.5-year drought is the most extensive and persistent drought event in decades, and led to crop failure, millions of livestock deaths, water scarcity, and inflated prices for staple food items.〈/jats:p〉 〈jats:p〉In South Asia, Pakistan received around three times its normal volume of monsoon precipitation in August, with some regions receiving up to eight times their expected monthly totals. Resulting floods affected over 30 million people, caused over 1700 fatalities, led to major crop and property losses, and was recorded as one of the world’s costliest natural disasters of all time. Near Rio de Janeiro, Brazil, Petrópolis received 530 mm in 24 hours on 15 February, about 2.5 times the monthly February average, leading to the worst disaster in the city since 1931 with over 230 fatalities.〈/jats:p〉 〈jats:p〉On 14–15 January, the Hunga Tonga-Hunga Ha'apai submarine volcano in the South Pacific erupted multiple times. The injection of water into the atmosphere was unprecedented in both magnitude—far exceeding any previous values in the 17-year satellite record—and altitude as it penetrated into the mesosphere. The amount of water injected into the stratosphere is estimated to be 146±5 Terragrams, or ∼10% of the total amount in the stratosphere. It may take several years for the water plume to dissipate, and it is currently unknown whether this eruption will have any long-term climate effect.〈/jats:p〉
    Repository Name: EPIC Alfred Wegener Institut
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  • 13
    Publication Date: 2024-05-08
    Description: NORP-SORP Workshop on Polar Fresh Water: Sources, Pathways and Impacts of Freshwater in Northern and Southern Polar Oceans and Seas (SPICE-UP) What: Up to 60 participants at a time and more than twice as many registrants in total from 20 nations and across experience levels met to discuss the current status of research on freshwater in both polar regions, future directions, and synergies between the Arctic and Southern Ocean research communities When: 19–21 September 2022 Where: Online
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  • 14
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    American Meteorological Society
    In:  EPIC3Bulletin of the American Meteorological Society, American Meteorological Society, 104(9), pp. s271-s321, ISSN: 0003-0007
    Publication Date: 2024-05-08
    Repository Name: EPIC Alfred Wegener Institut
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  • 15
    Publication Date: 2023-01-27
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(8), (2022): 1705-1730, https://doi.org/10.1175/jpo-d-21-0243.1.
    Description: Formation and evolution of barrier layers (BLs) and associated temperature inversions (TIs) were investigated using a 1-yr time series of oceanic and air–sea surface observations from three moorings deployed in the eastern Pacific fresh pool. BL thickness and TI amplitude showed a seasonality with maxima in boreal summer and autumn when BLs were persistently present. Mixed layer salinity (MLS) and mixed layer temperature (MLT) budgets were constructed to investigate the formation mechanism of BLs and TIs. The MLS budget showed that BLs were initially formed in response to horizontal advection of freshwater in boreal summer and then primarily maintained by precipitation. The MLT budget revealed that penetration of shortwave radiation through the mixed layer base is the dominant contributor to TI formation through subsurface warming. Geostrophic advection is a secondary contributor to TI formation through surface cooling. When the BL exists, the cooling effect from entrainment and the warming effect from detrainment are both significantly reduced. In addition, when the BL is associated with the presence of a TI, entrainment works to warm the mixed layer. The presence of BLs makes the shallower mixed layer more sensitive to surface heat and freshwater fluxes, acting to enhance the formation of TIs that increase the subsurface warming via shortwave penetration.
    Description: SK is supported by JSPS Overseas Research Fellowships. JS and SK are supported by NASA Grant 80NSSC18K1500. JTF and the mooring deployment were funded by NASA Grants NNX15AG20G and 80NSSC18K1494. DZ is supported by NASA Grant 80NSSC18K1499. This publication is partially funded by the Cooperative Institute for Climate, Ocean, and Ecosystem Studies (CICOES) under NOAA Cooperative Agreement NA20OAR4320271, Contribution 2021-1152. This is PMEL Contribution 5268.
    Description: 2023-01-27
    Keywords: Ocean ; North Pacific Ocean ; Tropics ; Entrainment ; Oceanic mixed layer ; Salinity
    Repository Name: Woods Hole Open Access Server
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  • 16
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    American Meteorological Society
    In:  EPIC3Journal of Climate, American Meteorological Society, 35(23), pp. 7811-7831, ISSN: 0894-8755
    Publication Date: 2023-06-23
    Description: Numerical simulations allow us to gain a comprehensive understanding of the underlying mechanisms of past, present, and future climate changes. The mid-Holocene (MH) and the last interglacial (LIG) were the two most recent warm episodes of Earth’s climate history and are the focus of paleoclimate research. Here, we present results of MH and LIG simulations with two versions of the state-of-the-art Earth system model AWI-ESM. Most of the climate changes in MH and LIG compared to the preindustrial era are agreed upon by the two model versions, including 1) enhanced seasonality in surface temperature that is driven by the redistribution of seasonal insolation; 2) a northward shift of the intertropical convergence zone (ITCZ) and tropical rain belt; 3) a reduction in annual mean Arctic sea ice concentration; 4) weakening and northward displacement of the Northern Hemisphere Hadley circulation, which is related to the decrease and poleward shift of the temperature gradient from the subtropical to the equator in the Northern Hemisphere; 5) a westward shift of the Indo-Pacific Walker circulation due to anomalous warming over the Eurasia and North Africa during boreal summer; and 6) an expansion and intensification of Northern Hemisphere summer monsoon rainfall, with the latter being dominated by the dynamic component of moisture budget (i.e., the strengthening of wind circulation). However, the simulated responses of the Atlantic meridional overturning circulation (AMOC) in the two models yield different results for both the LIG and the MH. AMOC anomalies between the warm interglacial and preindustrial periods are associated with changes in North Atlantic westerly winds and stratification of the water column at the North Atlantic due to changes in ocean temperature, salinity, and density.
    Repository Name: EPIC Alfred Wegener Institut
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  • 17
    Publication Date: 2023-02-01
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(8), (2022): 1927-1943, https://doi.org/10.1175/jpo-d-21-0124.1.
    Description: The Galápagos Archipelago lies on the equator in the path of the eastward flowing Pacific Equatorial Undercurrent (EUC). When the EUC reaches the archipelago, it upwells and bifurcates into a north and south branch around the archipelago at a latitude determined by topography. Since the Coriolis parameter (f) equals zero at the equator, strong velocity gradients associated with the EUC can result in Ertel potential vorticity (Q) having sign opposite that of planetary vorticity near the equator. Observations collected by underwater gliders deployed just west of the Galápagos Archipelago during 2013–16 are used to estimate Q and to diagnose associated instabilities that may impact the Galápagos Cold Pool. Estimates of Q are qualitatively conserved along streamlines, consistent with the 2.5-layer, inertial model of the EUC by Pedlosky. The Q with sign opposite of f is advected south of the Galápagos Archipelago when the EUC core is located south of the bifurcation latitude. The horizontal gradient of Q suggests that the region between 2°S and 2°N above 100 m is barotropically unstable, while limited regions are baroclinically unstable. Conditions conducive to symmetric instability are observed between the EUC core and the equator and within the southern branch of the undercurrent. Using 2-month and 3-yr averages, e-folding time scales are 2–11 days, suggesting that symmetric instability can persist on those time scales.
    Description: This work was supported by the National Science Foundation (Grants OCE-1232971 and OCE-1233282), the NASA Earth and Space Science Fellowship Program (Grant 80NSSC17K0443), and the Global Ocean Monitoring and Observing Program of the National Oceanographic and Atmospheric Administration (NA13OAR4830216). Color maps are from Thyng et al. (2016).
    Description: 2023-02-01
    Keywords: Currents ; In situ oceanic observations ; Instability ; Mixing ; Ocean dynamics ; Pacific Ocean ; Potential vorticity ; Tropics
    Repository Name: Woods Hole Open Access Server
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  • 18
    Publication Date: 2023-02-01
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of the Atmospheric and Oceanic Technology 39(8), (2022): 1183-1198, https://doi.org/10.1175/jtech-d-21-0068.1.
    Description: Horizontal kinematic properties, such as vorticity, divergence, and lateral strain rate, are estimated from drifter clusters using three approaches. At submesoscale horizontal length scales O(1–10)km, kinematic properties become as large as planetary vorticity f, but challenging to observe because they evolve on short time scales O(hourstodays). By simulating surface drifters in a model flow field, we quantify the sources of uncertainty in the kinematic property calculations due to the deformation of cluster shape. Uncertainties arise primarily due to (i) violation of the linear estimation methods and (ii) aliasing of unresolved scales. Systematic uncertainties (iii) due to GPS errors, are secondary but can become as large as (i) and (ii) when aspect ratios are small. Ideal cluster parameters (number of drifters, length scale, and aspect ratio) are determined and error functions estimated empirically and theoretically. The most robust method—a two-dimensional, linear least squares fit—is applied to the first few days of a drifter dataset from the Bay of Bengal. Application of the length scale and aspect-ratio criteria minimizes errors (i) and (ii), and reduces the total number of clusters and so computational cost. The drifter-estimated kinematic properties map out a cyclonic mesoscale eddy with a surface, submesoscale fronts at its perimeter. Our analyses suggest methodological guidance for computing the two-dimensional kinematic properties in submesoscale flows, given the recently increasing quantity and quality of drifter observations, while also highlighting challenges and limitations.
    Description: This research was supported by the Office of Naval Research (ONR) Departmental Research Initiative ASIRI under Grant N00014-13-1-0451 (SE and AM) and Grant N00014-13-1-0477 (VH and LC). The authors thank the captain and crew of the R/V Roger Revelle, and Andrew Lucas with the Multiscale Ocean Dynamics group at the Scripps Institution for Oceanography for providing the FastCTD data collected in 2015, which was supported by ONR Grant N00014-13-1-0489, as well as Eric D’Asaro for helpful discussions and Lance Braasch for assistance with the drifter dataset. AM and SE further thank NSF (Grant OCE-I434788) and ONR (Grant N00014-16-1-2470) for support. VH and LC were additionally supported by ONR Grants N00014-15-1-2286, N00014-14-1-0183, N00014-19-1-26-91 and NOAA Global Drifter Program (GDP) Grant NA15OAR4320071.
    Description: 2023-02-01
    Keywords: Indian Ocean ; Eddies ; Frontogenesis/frontolysis ; Fronts ; Lagrangian circulation/transport ; Ocean circulation ; Ocean dynamics
    Repository Name: Woods Hole Open Access Server
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  • 19
    Publication Date: 2023-02-01
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 35(17), (2022): 5465-5482, https://doi.org/10.1175/jcli-d-21-0671.1.
    Description: Understanding the contribution of ocean circulation to glacial–interglacial climate change is a major focus of paleoceanography. Specifically, many have tried to determine whether the volumes and depths of Antarctic- and North Atlantic–sourced waters in the deep ocean changed at the Last Glacial Maximum (LGM; ∼22–18 kyr BP) when atmospheric pCO2 concentrations were 100 ppm lower than the preindustrial. Measurements of sedimentary geochemical proxies are the primary way that these deep ocean structural changes have been reconstructed. However, the main proxies used to reconstruct LGM Atlantic water mass geometry provide conflicting results as to whether North Atlantic–sourced waters shoaled during the LGM. Despite this, a number of idealized modeling studies have been advanced to describe the physical processes resulting in shoaled North Atlantic waters. This paper aims to critically assess the approaches used to determine LGM Atlantic circulation geometry and lay out best practices for future work. We first compile existing proxy data and paleoclimate model output to deduce the processes responsible for setting the ocean distributions of geochemical proxies in the LGM Atlantic Ocean. We highlight how small-scale mixing processes in the ocean interior can decouple tracer distributions from the large-scale circulation, complicating the straightforward interpretation of geochemical tracers as proxies for water mass structure. Finally, we outline promising paths toward ascertaining the LGM circulation structure more clearly and deeply.
    Description: S.K.H. was supported by the Investment in Science Fund at WHOI and the John E. and Anne W. Sawyer Endowed Fund in Support of Scientific Staff. F.J.P. was supported by a Stanback Postdoctoral Fellowship at Caltech.
    Description: 2023-02-01
    Keywords: Diapycnal mixing ; Meridional overturning circulation ; Ocean circulation
    Repository Name: Woods Hole Open Access Server
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  • 20
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    American Meteorological Society
    In:  EPIC3Journal of Climate, American Meteorological Society, 34(18), pp. 7373-7388, ISSN: 0894-8755
    Publication Date: 2024-04-29
    Description: Climate variability occurs over wide ranges of spatial and temporal scales. It exhibits a complex spatial covariance structure, which depends on geographic location (e.g., tropics vs extratropics) and also consists of a superposition of (i) components with gradually decaying positive correlation functions and (ii) teleconnections that often involve anticorrelations. In addition, there are indications that the spatial covariance structure depends on frequency. Thus, a comprehensive assessment of the spatiotemporal covariance structure of climate variability would require an extensive set of statistical diagnostics. Therefore, it is often desirable to characterize the covariance structure by a simple summarizing metric that is easy to compute from datasets. Such summarizing metrics are useful, for example, in the context of comparisons between climate models or between models and observations. Here we introduce a frequency-dependent version of a simple measure of the effective spatial degrees of freedom. The measure is based on the temporal variance of the global average of some climate variable, and its novel aspect consists in its frequency dependence. We also provide a clear geometric interpretation of the measure. Its easy applicability is demonstrated using near-surface temperature and precipitation fields obtained from a paleoclimate model simulation. This application reveals a distinct scaling behavior of the spatial degrees of freedom as a function of frequency, ranging from monthly to millennial scales.
    Repository Name: EPIC Alfred Wegener Institut
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  • 21
    Publication Date: 2021-08-31
    Description: In this study, we investigate the response of tropical cyclones (TCs) to climate change by using the Princeton environment-dependent probabilistic tropical cyclone (PepC) model and a statistical-deterministic method to downscale TCs using environmental conditions obtained from the Geophysical Fluid Dynamics Laboratory (GFDL) High-resolution Forecast-oriented Low Ocean Resolution (HiFLOR) model, under the Representative Concentration Pathway 4.5 (RCP4.5) emissions scenario for the North Atlantic basin. The downscaled TCs for the historical climate (1986-2005) are compared with those in the mid- (2016-35) and late-twenty-first century (2081-2100). The downscaled TCs are also compared with TCs explicitly simulated in HiFLOR. We show that while significantly more storms are detected in HiFLOR towards the end of the twenty-first century, the statistical-deterministic model projects a moderate increase in TC frequency, and PepC projects almost no increase in TC frequency. The changes in storm frequency in all three datasets are not significant in the mid-twenty-first century. All three project that storms will become more intense and the fraction of major hurricanes and Category 5 storms will significantly increase in the future climates. However, HiFLOR projects the largest increase in intensity while PepC projects the least. The results indicate that HiFLOR’s TC projection is more sensitive to climate change effects and statistical models are less sensitive. Nevertheless, in all three datasets, storm intensification and frequency increase lead to relatively small changes in TC threat as measured by the return level of landfall intensity.
    Print ISSN: 0894-8755
    Electronic ISSN: 1520-0442
    Topics: Geography , Geosciences , Physics
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  • 22
    Publication Date: 2021-08-31
    Description: Tropical convection regimes range from deep organized to shallow convective systems. Mesoscale processes such as cold pools within tropical convective systems can play a significant role in the evolution of convection over land and open ocean. Although cold pools are widely observed, their diurnal properties are not well understood over tropical oceans and land. The oceanic cold pool identification metric applied herein uses the gradient feature (GF) technique and is compared with diurnally-resolved buoy-identified thermal cold pools. This study provides a first-ever diurnal climatology of GF number, area, and attributed TRMM 3B42 precipitation using a space-borne scatterometer (RapidScat). Buoy data over the Pacific, Atlantic, and Indian Ocean have been used to validate and examine the RapidScat-identified diurnal cycle of GF number and precipitation. Buoy-observed cold pool duration, precipitation, temperature, and wind speed is analyzed to understand the in situ cold pool properties over tropical oceans. GF- and buoy-observed cold pool number and precipitation exhibits a similar bimodal diurnal variability with a morning and afternoon maxima, thus establishing confidence in using GF as a proxy to observe cold pools over tropical oceans. The morning peak is attributed to cold pools associated with deep moist convection while the afternoon peak is related to shallower clouds in relatively drier environments resulting in smaller cold pools over global tropical oceans.
    Print ISSN: 0894-8755
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  • 23
    Publication Date: 2021-08-02
    Description: The NOAA National Water Model (NWM), maintained and executed by the NOAA National Weather Service (NWS) Office of Water Prediction, provides operational hydrological guidance throughout the Contiguous United States. Based on the WRF-Hydro model architecture developed by the National Center for Atmospheric Research (NCAR), the NWM was recently modified for semi-arid domains, by permitting it to explicitly resolve infiltration from ephemeral channels into the underlying channel bed as an added model sink term. To analyze the added value of channel infiltration in semi-arid environments, we calibrated NWM v2.1 (with the channel infiltration function) to 56 independent basins in the western CONUS, following identical calibration methods as the pre-operational NWM v2.1 (not including channel infiltration). Calibration of the model consists of two parts, including 1) calibration of channel infiltration only with other parameters set to the calibrated parameters used for pre-operational NWM v2.1 and 2) calibration of all parameters including channel infiltration with settings otherwise equivalent to the calibration of NWM v2.1. The calibrated channel-infiltration enhanced NWM improves predictive skill compared to the control NWM in 85% of evaluated basins, for the calibration period. The current NWM settings for physical processes and the biases of the calibration scheme limit model performance in semi-arid environments. To explore whether channel infiltration paired with an alternative calibration scheme could address these limitations, NWM v2.1 was calibrated with a new objective function in selected basins. We found that this updated objective function could ameliorate model biases in some semi-arid environments.
    Print ISSN: 1525-755X
    Electronic ISSN: 1525-7541
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  • 24
    Publication Date: 2021-08-27
    Description: Teleconnections from the Tropics energize variations of the North Pacific climate, but detailed diagnosis of this relationship has proven difficult. Simple univariate methods, such as regression on El Niño-Southern Oscillation (ENSO) indices, may be inadequate since the key dynamical processes involved -- including ENSO diversity in the Tropics, re-emergence of mixed layer thermal anomalies, and oceanic Rossby wave propagation in the North Pacific -- have a variety of overlapping spatial and temporal scales. Here we use a multivariate Linear Inverse Model to quantify tropical and extra-tropical multi-scale dynamical contributions to North Pacific variability, in both observations and CMIP6 models. In observations, we find that the Tropics are responsible for almost half of the seasonal variance, and almost three quarters of the decadal variance, along the North American coast and within the subtropical front region northwest of Hawaii. SST anomalies that are generated by local dynamics within the Northeast Pacific have much shorter time scales, consistent with transient weather forcing by Aleutian low anomalies. Variability within the Kuroshio-Oyashio Extension (KOE) region is considerably less impacted by the Tropics, on all time scales. Consequently, without tropical forcing the dominant pattern of North Pacific variability would be a KOE pattern, rather than the Pacific Decadal Oscillation (PDO). In contrast to observations, most CMIP6 historical simulations produce North Pacific variability that maximizes in the KOE region, with amplitude significantly higher than observed. Correspondingly, the simulated North Pacific in all CMIP6 models is shown to be relatively insensitive to the Tropics, with a dominant spatial pattern generally resembling the KOE pattern, not the PDO.
    Print ISSN: 0894-8755
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  • 25
    Publication Date: 2021-08-13
    Description: The extratropical effect of the quasi-biennial oscillation (QBO), known as the Holton-Tan effect, is manifest as aweaker, warmer winter Arctic polar vortex during the east QBO phase. While previous studies have shown that the extratropical QBO signal is caused by the modified propagation of planetary waves in the stratosphere, the mechanism dominating the onset and seasonal development of the Holton-Tan effects remains unclear. Here, the governing wave-mean flow dynamics of the early winter extratropical QBO signal onset and its reversibility is investigated on a synoptic timescale with a finite-amplitude diagnostic using reanalysis and a chemistry-climate model. The extratropical QBO signal onset in October is found to primarily result from modulated stratospheric life-cycles of wave pulses entering the stratosphere from the troposphere, rather than from a modulation of their tropospheric wave source. A comprehensive analysis of the wave activity budget during fall, when the stratospheric winter polar vortex starts forming and waves start propagating up into the stratosphere, shows significant differences. During the east QBO phase, the deceleration of the mid-high latitude stratospheric zonal mean jet by the upward propagating wave pulses is less reversible, due to stronger dissipation processes, while during the west phase, a more reversible deceleration of the main polar vortex is found owing to the waves being dissipated at lower latitudes, accompanied by a weak but different response of the tropospheric subtropical jet. From this synoptic wave-event viewpoint, the early season onset of the Holton-Tan effect results from the cumulative effect of the QBO dependent wave-induced deceleration during the life cycle of individual upward wave pulses.
    Print ISSN: 0022-4928
    Electronic ISSN: 1520-0469
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  • 26
    Publication Date: 2021-08-27
    Description: A model diagnosis for the energy flux of off-equatorial Rossby waves in the atmosphere has previously been done using quasi-geostrophic equations and is singular at the equator. The energy flux of equatorial waves has been separately investigated in previous studies using a space-time spectral analysis or a ray theory. A recent analytical study has derived an exact universal expression for the energy flux which can indicate the direction of the group velocity for linear shallow water waves at all latitudes. This analytical result is extended in the present study to a height-dependent framework for three-dimensional waves in the atmosphere. This is achieved by investigating the classical analytical solution of both equatorial and off-equatorial waves in a Boussinesq fluid. For the horizontal component of the energy flux, the same expression has been obtained between equatorial waves and off-equatorial waves in the height-dependent framework, which is linked to a scalar quantity inverted from the isentropic perturbation of Ertel’s potential vorticity. The expression of the vertical component of the energy flux requires computation of another scalar quantity that may be obtained from the meridional integral of geopotential anomaly in a wavenumber-frequency space. The exact version of the universal expression is explored and illustrated for three-dimensional waves induced by an idealized Madden-Julian Oscillation forcing in a basic model experiment. The zonal and vertical fluxes manifest the energy transfer of both equatorial Kelvin waves and off-equatorial Rossby waves with a smooth transition at around 10°S and around 10°N. The meridional flux of wave energy represents connection between off-equatorial divergence regions and equatorial convergence regions.
    Print ISSN: 0022-4928
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  • 27
    Publication Date: 2021-08-19
    Description: In the hydrological sciences, the outstanding challenge of regional modeling requires to capture common and event-specific hydrologic behaviors driven by rainfall spatial variability and catchment physiography during floods. The overall objective of this study is to develop robust understanding and predictive capability of how rainfall spatial variability influences flood peak discharge relative to basin physiography. A machine learning approach is used on a high-resolution dataset of rainfall and flooding events spanning 10 years, with rainfall events and basins of widely varying characteristics selected across the continental United States. It overcomes major limitations in prior studies that were based on limited observations or hydrological model simulations. This study explores first-order dependencies in the relationships between peak discharge, rainfall variability, and basin physiography, and it sheds light on these complex interactions using a multi-dimensional statistical modeling approach. Amongst different machine learning techniques, XGBoost is used to determine the significant physiographical and rainfall characteristics that influence peak discharge through variable importance analysis. A parsimonious model with low bias and variance is created which can be deployed in the future for flash flood forecasting. The results confirm that although the spatial organization of rainfall within a basin has a major influence on basin response, basin physiography is the primary driver of peak discharge. These findings have unprecedented spatial and temporal representativeness in terms of flood characterization across basins. An improved understanding of sub-basin scale rainfall spatial variability will aid in robust flash flood characterization as well as with identifying basins which could most benefit from distributed hydrologic modeling.
    Print ISSN: 1525-755X
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  • 28
    Publication Date: 2021-10-08
    Description: This paper investigates the value of weather and climate information at different timescales for decision making in the Tanzanian disaster risk reduction sector using non-monetary approaches. Interviews and surveys were conducted with institutions responsible for disaster management at national, regional and district level. A range of values were identified including: 1) making informed decisions for disaster preparedness, response, recovery and restoration related activities; 2) tailoring of directives and actions based on sectoral impacts; 3) identification of hotspot areas for diseases outbreaks and surplus food production. However, while, a number of guidelines, policies, acts and regulations for disaster risk reduction exist it is not clear how well they promote the use of weather and climate information across climate sensitive sectors. Nonetheless, we find that well-structured disaster risk reduction coordination across sectors and institutions from the national to district level exists, although there is a need for further development of integrated Early Warning Systems, and a common platform to evaluate effectiveness and usefulness of weather warnings and advisories. Key challenges to address in increasing the uptake of weather warnings and advisories include language barriers, limited dissemination to rural areas, and limited awareness of forecasts. Based on the findings of this study, we recommend further quantitative evaluation of the skill of the severe weather warnings issued by the Tanzania Meteorological Authority, and an assessment of how decisions and actions are made by recipients of the warnings in the disaster risk reduction sector at different stages in the warning, response and recovery process.
    Print ISSN: 1948-8327
    Electronic ISSN: 1948-8335
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  • 29
    Publication Date: 2021-09-27
    Description: This paper reports the assimilation of cloud optical depth datasets into a variational data assimilation system to improve cloud ice, cloud water, rain, snow, and graupel analysis in extreme weather events for improving forecasts. A cloud optical depth forward operator was developed and implemented in the Space and Time Multiscale Analysis System (STMAS), a multiscale three-dimensional variational analysis system. Using this improved analysis system, the NOAA GOES-15 DCOMP (Daytime Cloud Optical and Microphysical Properties) cloud optical depth products were assimilated to improve the microphysical states. For an eight-day period of extreme weather events in September 2013 in Colorado, the United States, the impact of the cloud optical depth assimilation on the analysis results and forecasts was evaluated. The DCOMP products improved the cloud ice and cloud water predictions significantly in convective and lower levels. The DCOMP products also reduced errors in temperature and relative humidity data at the top (250–150 hPa) and bottom (850–700 hPa) layers. With the cloud ice improvement at higher layers, the DCOMP products provided better forecasts of cloud liquid at low layers (900–700 hPa), temperature and wind at all layers, and relative humidity at middle and bottom layers. Furthermore, for this extreme weather event, both equitable threat score (ETS) and bias were improved throughout the 12 h period, with the most significant improvement observed in the first 3 h. This study will raise the expectation of cloud optical depth product assimilation in operational applications.
    Print ISSN: 0882-8156
    Electronic ISSN: 1520-0434
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  • 30
    Publication Date: 2021-09-02
    Description: The provision of climate services has the potential to generate adaptive capacity and help coffee farmers become or remain profitable by integrating climate information in a risk-management framework. Yet, in order to achieve this goal, it is necessary to identify the local demand for climate information, the relationships between coffee yield and climate variables, farmers’ perceptions, and to examine the potential actions that can be realistically put in place by farmers at the local level. In this study, we assessed the climate information demands from coffee farmers and their perception on the climate impacts to coffee yield in the Samalá watershed in Guatemala. After co-identifying the related candidate climate predictors, we propose an objective, flexible forecast system for coffee yield based on precipitation. The system, known as NextGen, analyzes multiple historical climate drivers to identify candidate predictors, and provides both deterministic and probabilistic forecasts for the target season. To illustrate the approach, a NextGen implementation is conducted in the Samalá watershed in southwestern Guatemala. The results suggest that accumulated June-July-August precipitation provides the highest predictive skill associated with coffee yield for this region. In addition to a formal cross-validated skill assessment, retrospective forecasts for the period 1989-2009 were compared to agriculturalists’ perception on the climate impacts to coffee yield at the farm level. We conclude with examples of how demand-based climate service provision in this location can inform adaptation strategies like optimum shade, pest control, and fertilization schemes months in advance. These potential adaptation strategies were validated by local agricultural technicians at the study site.
    Print ISSN: 0882-8156
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  • 31
  • 32
    Publication Date: 2021-10-29
    Description: Droughts are widespread disasters worldwide and are concurrently influenced by multiple large-scale climate signals. This is particularly true over Japan, where drought has strong heterogeneity due to multiple factors such as monsoon, topography, and ocean circulations. Regional heterogeneity poses challenges for drought prediction and management. To overcome this difficulty, this study provides a comprehensive analysis of teleconnection between climate signals and homogeneous drought zones over Japan. First, droughts are characterized by simulated soil moisture from land surface model during 1958-2012. The Mclust toolkit, distinct empirical orthogonal function, and wavelet coherence analysis are used, respectively, to investigate the homogeneous drought zone, principal component of each homogeneous zone, and teleconnection between climate signals and drought. Results indicate that nine homogeneous drought zones with different characteristics are defined and quantified. Among these nine zones, zone-1 is dominated by extreme drought events. Zone-2 and zone-6 are typical representatives of spring droughts, while zone-7 is wet for most of the period. The Hokkaido region is divided into wetter zone-4 and drier zone-9. Zone-3, zone-5 and zone-8 are distinguished by the topography. The analyses also reveal almost nine zones have a high level of homogeneity, with more than 60% explained variance. Also, these nine zones are dominated by different large-scale climate signals: the Arctic Oscillation has the strongest impact on zone-1, zone-7, and zone-8; the influence of the North Atlantic Oscillation on zone-3, zone-4, and zone-6 is significant; zone-2 and zone-9 are both dominated by the Pacific Decadal Oscillation; El Niño-Southern Oscillation dominates zone-5. The results will be valuable for drought management and drought prevention.
    Print ISSN: 1558-8424
    Electronic ISSN: 1558-8432
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  • 33
    Publication Date: 2021-09-22
    Description: Complex-terrain locations often have repeatable near-surface wind patterns, such as synoptic gap flows and local thermally forced flows. An example is the Columbia River Valley in east-central Oregon-Washington, a significant wind-energy-generation region and the site of the Second Wind-Forecast Improvement Project (WFIP2). Data from three Doppler lidars deployed during WFIP2 define and characterize summertime wind regimes and their large-scale contexts, and provide insight into NWP model errors by examining differences in the ability of a model [NOAA’s High-Resolution Rapid-Refresh (HRRR-version1)] to forecast wind-speed profiles for different regimes. Seven regimes were identified based on daily time series of the lidar-measured rotor-layer winds, which then suggested two broad categories. First, in three regimes the primary dynamic forcing was the large-scale pressure gradient. Second, in two regimes the dominant forcing was the diurnal heating-cooling cycle (regional sea-breeze-type dynamics), including the marine intrusion previously described, which generates strong nocturnal winds over the region. The other two included a hybrid regime and a non-conforming regime. For the large-scale pressure-gradient regimes, HRRR had wind-speed biases of ~1 m s−1 and RMSEs of 2-3 m s−1. Errors were much larger for the thermally forced regimes, owing to the premature demise of the strong nocturnal flow in HRRR. Thus, the more dominant the role of surface heating in generating the flow, the larger the errors. Major errors could result from surface heating of the atmosphere, boundary-layer responses to that heating, and associated terrain interactions. Measurement/modeling research programs should be aimed at determining which modeled processes produce the largest errors, so those processes can be improved and errors reduced.
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  • 34
    Publication Date: 2021-09-14
    Description: Forecasts of marine cold air outbreaks critically rely on the interplay of multiple parameterisation schemes to represent sub-grid scale processes, including shallow convection, turbulence, and microphysics. Even though such an interplay has been recognised to contribute to forecast uncertainty, a quantification of this interplay is still missing. Here, we investigate the tendencies of temperature and specific humidity contributed by individual parameterisation schemes in the operational weather prediction model AROME-Arctic. From a case study of an extensive marine cold air outbreak over the Nordic Seas, we find that the type of planetary boundary layer assigned by the model algorithm modulates the contribution of individual schemes and affects the interactions between different schemes. In addition, we demonstrate the sensitivity of these interactions to an increase or decrease in the strength of the parameterised shallow convection. The individual tendencies from several parameterisations can thereby compensate each other, sometimes resulting in a small residual. In some instances this residual remains nearly unchanged between the sensitivity experiments, even though some individual tendencies differ by up to an order of magnitude. Using the individual tendency output, we can characterise the subgrid-scale as well as grid-scale responses of the model and trace them back to their underlying causes. We thereby highlight the utility of individual tendency output for understanding process-related differences between model runs with varying physical configurations and for the continued development of numerical weather prediction models.
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  • 35
    Publication Date: 2021-09-13
    Description: This study investigates the stratosphere-troposphere coupling associated with the Scandinavian (SCA) pattern in boreal winter. The results indicate that the SCA impacts stratospheric circulation but that its positive and negative phases have different effects. The positive phase of the SCA (SCA+) pattern is restricted to the troposphere, but the negative phase (SCA−) extends to the upper stratosphere. The asymmetry between phases is also visible in the lead-lag evolution of the stratosphere and troposphere. Prominent stratospheric anomalies are found to be intensified following SCA+ events, but prior to SCA− events. Further analysis reveals that the responses are associated with upward propagation of planetary waves, especially wavenumber 1 which is asymmetric between SCA phases. The wave amplitudes in the stratosphere, originating from the troposphere, are enhanced after the SCA+ events and before the SCA− events. Furthermore, the anomalous planetary wave activity can be understood through its interference with climatological stationary waves. Constructive wave interference is accompanied by clear upward propagation in the SCA+ events, while destructive interference suppresses stratospheric waves in the SCA− events. Our results also reveal that the SCA+ events are more likely to be followed by sudden stratospheric warming (SSW) events, because of the deceleration of stratospheric westerlies following the SCA+ events.
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  • 36
    Publication Date: 2021-09-09
    Description: The reproducibility of precipitation in the early stages of forecasts, often called a spin-down or spin-up problem, has been a significant issue in numerical weather prediction. This problem is caused by moisture imbalance in the analysis data, and in the case of the Japan Meteorological Agency’s (JMA’s) mesoscale data assimilation system JNoVA, we found that the imbalance stems from the existence of unrealistic supersaturated states in the minimal solution of the cost function in JNoVA. Based on the theory of constrained optimization problems, we implemented an exterior penalty function method for the mixing ratio within JNoVA to suppress unrealistic supersaturated states. The advantage of this method is the simplicity of its theory and implementation. The results of twin data assimilation cycle experiments conducted for the Heavy Rain Event of July 2018 over Japan show that—with the new method—unrealistic supersaturated states are reduced successfully, negative temperature bias to the observations is alleviated, and a sharper distribution of the mixing ratio is obtained. These changes help to initiate the development of convection at the proper location and improve the fractions skill score (FSS) of precipitation in the early stages of the forecast. From these results, we conclude that the initial shock caused by moisture imbalance is mitigated by implementing the penalty function method, and the new moisture balance has a positive impact on the reproducibility of precipitation in the early stages of forecasts.
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  • 37
    Publication Date: 2021-09-09
    Description: Based on observational data analyses and idealized modeling experiments, we investigated the distinctive impacts of central Pacific (CP-) El Niño and eastern Pacific (EP-) El Niño on the Antarctic sea ice concentration (SIC) in austral spring (September to November). The tropical heat sources associated with EP-El Niño and the co-occurred positive phase of Indian Ocean Dipole (IOD) excite two branches of Rossby wave trains that propagate southeastward, causing an anomalous anticyclone over the eastern Ross-Amundsen-Bellingshausen Seas. Anomalous northerly (southerly) wind west (east) of the anomalous anticyclone favor poleward (offshore) movements of sea ice, resulting in a sea ice loss (growth) in the eastern Ross-Amundsen Seas (the Bellingshausen-Weddell Seas). Meanwhile, the anomalous northerly (southerly) wind also advected warmer and wetter (colder and drier) air into the eastern Ross-Amundsen Seas (the Bellingshausen-Weddell Seas), causing surface warming (cooling) through the enhanced (reduced) surface heat fluxes and thus contributing to the sea ice melting (growth). CP-El Niño, however, forces a Rossby wave train that generates an anomalous anticyclone in the eastern Ross-Amundsen Seas, 20° west of that caused by EP-El Niño. Consequently, a positive SIC anomaly occurs in the Bellingshausen Sea. A dry version of the Princeton atmospheric general circulation model was applied to verify the roles of anomalous heating in the tropics. The result showed that EP-El Niño can remotely induce an anomalous anticyclone and associated dipole temperature pattern in the Antarctic region, whereas CP-El Niño generates a similar anticyclone pattern with its location shift westward by 20° in longitudes.
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  • 38
    Publication Date: 2021-09-14
    Description: Despite an increased understanding of environments favorable for tornadic supercells, it is still sometimes unknown why one favorable environment produces many long-tracked tornadic supercells and another seemingly equally-favorable environment produces only short-lived supercells. One relatively unexplored environmental parameter that may differ between such environments is the degree of backing or veering of the midlevel shear vector, especially considering that such variations may not be captured by traditional supercell or tornado forecast parameters. We investigate the impact of the 3-6 km shear vector orientation on simulated supercell evolution by systematically varying it across a suite of idealized simulations. We found that the orientation of the 3-6 km shear vector dictates where precipitation loading is maximized in the storms, and thus alters the storm-relative location of downdrafts and outflow surges. When the shear vector is backed, outflow surges generally occur northwest of an updraft, produce greater convergence beneath the updraft, and do not disrupt inflow, meaning that the storm is more likely to persist and produce more tornado-like vortices (TLVs). When the shear vector is veered, outflow surges generally occur north of an updraft, produce less convergence beneath the updraft, and sometimes undercut it with outflow, causing it to tilt at low levels, sometimes leading to storm dissipation. These storms are shorter lived and thus also produce fewer TLVs. Our simulations indicate that the relative orientation of the 3-6 km shear vector may impact supercell longevity and hence the time period over which tornadoes may form.
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  • 39
    Publication Date: 2021-09-09
    Description: As a key to modulate the negative feedback to tropical cyclone (TC) intensity, the TC-induced inner-core sea surface cooling (SSCIC) is poorly understood. Using a linear two-layer theory and OGCM experiments, this study illustrates that the pattern of the inner-core mixing can be well interpreted by the wind-driven currents in the mixed layer (ML). This interpretation is based on: 1) the mixing is triggered by the ML bulk shear instability; 2) the lag of upwelling makes the inner-core bulk shear equivalent to the inner-core wind-driven currents. Overall, the patterns of the inner-core bulk shear and mixing resemble the crescent body of a sickle. As an accumulative result of mixing, the SSCIC is clearly weaker than the maximum cold wake because of the weaker mixing ahead of the inner core and nearly zero mixing in a part of the inner core. The SSCIC induced by a rectilinear-track TC is mainly dominated by the inner-core mixing. Only for a slow-moving case, upwelling and horizontal advection can make minor contributions to the SSCIC by incorporating them with mixing. The SSCIC strength is inversely proportional to the moving speed, suggesting the mixing time rather than the mixing strength dominates the SSCIC. Despite inability in treating the mixing strength, this study elucidates the fundamental dynamical mechanisms of SSCIC, especially emphasizes the different roles of mixing, upwelling and horizontal advection for fast- and slow-moving TCs, and thus provides a good start point to understand SSCIC.
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  • 40
    Publication Date: 2021-12-01
    Description: The reported decreasing trend of the annual tropical cyclone (TC) landfalls in southern China and increasing trend in southeastern China in recent decades are confirmed to be an abrupt shift occurring at the end of the twentieth century, based on a statistical analysis. The opposite trends in the two adjacent regions are often considered to be a result of tropical cyclone landfalls in southern China being deflected northward. However, it is demonstrated in this study that they are phenomenally independent. In fact, the abrupt decrease of TC landfalls in southern China occurs as a result of an abrupt decrease of the westward events in the postpeak season (October–December), which in turn is a consequence of a significant decrease of the TC genesis frequency in the southeastern part of the western North Pacific (WNP) Ocean basin. On the other hand, the abrupt increase of TC landfalls in southeastern China occurs because of an abrupt increase of the northwest events in the peak season (July–September), as the consequence of a statistically westward shift of TC genesis. The relevant variations of TC genesis are shown to be mainly caused by decreased relative vorticity and increased vertical wind shear, which, however, are intrinsically related to the accelerated zonal atmospheric circulation driven by a La Niña–like sea surface warming pattern over the WNP that developed after the end of twentieth century.
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  • 41
    Publication Date: 2021-09-15
    Description: This study explores the possibilities of employing machine learning algorithms to predict foehn occurrence in Switzerland at a north-Alpine (Altdorf) and south-Alpine (Lugano) station from its synoptic fingerprint in reanalysis data and climate simulations. This allows for an investigation on a potential future shift in monthly foehn frequencies. First, inputs from various atmospheric fields from the European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis-Interim (ERAI) were used to train an XGBoost model. Here, similar predictive performance to previous work was achieved, showing that foehn can accurately be diagnosed from the coarse synoptic situation. In the next step, the algorithm was generalized to predict foehn based on Community Earth System Model (CESM) ensemble simulations of a present-day and warming future climate. The best generalization between ERAI and CESM was obtained by including the present-day data in the training procedure and simultaneously optimizing two objective functions, namely the negative log loss and squared mean loss, on both datasets, respectively. It is demonstrated that the same synoptic fingerprint can be identified in CESM climate simulation data. Finally, predictions for present-day and future simulations were verified and compared for statistical significance. Our model is shown to produce valid output for most months, revealing that south foehn in Altdorf is expected to become more common during spring, while north foehn in Lugano is expected to become more common during summer.
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  • 42
    Publication Date: 2021-09-13
    Description: Tropical cyclones are associated with a variety of significant social hazards, including wind, rain, and storm surge. Despite this, most of the model validation effort has been directed toward track and intensity forecasts. In contrast, few studies have investigated the skill of state-of-the-art, high-resolution ensemble prediction systems in predicting associated TC hazards, which is crucial since TC position and intensity do not always correlate with the TC-related hazards, and can result in impacts far from the actual TC center. Furthermore, dynamic models can provide flow-dependent uncertainty estimates, which in turn can provide more specific guidance to forecasters than statistical uncertainty estimates based on past errors. This study validates probabilistic forecasts of wind speed and precipitation hazards derived from the HWRF ensemble prediction system and compares its skill to forecasts by the stochastically-based operational Monte Carlo Model (NHC), the IFS (ECMWF), and the GEFS (NOAA) in use 2017-2019. Wind and Precipitation forecasts are validated against NHC best track wind radii information and the National Stage IV QPE Product. The HWRF 34 kn wind forecasts have comparable skill to the global models up to 60 h lead time before HWRF skill decreases, possibly due to detrimental impacts of large track errors. In contrast, HWRF has comparable quality to its competitors for higher thresholds of 50 kn and 64 kn throughout 120 h lead time. In terms of precipitation hazards, HWRF performs similar or better than global models, but depicts higher, although not perfect, reliability, especially for events over 5 in120h−1. Post-processing, like Quantile Mapping, improves forecast skill for all models significantly and can alleviate reliability issues of the global models.
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  • 43
    Publication Date: 2021-09-09
    Description: Diurnal variation in surface latent heat flux (LHF) and the effects of diurnal variations in LHF-related variables on the climatological LHF are examined using observations from the Global Tropical Moored Buoy Array. The estimated amplitude of the climatological diurnal LHF over the Indo-Pacific warm pool and the equatorial Pacific and Atlantic cold tongues is remarkable, with maximum values exceeding 20.0 W m−2. Diurnal variability of sea surface skin temperature (SSTskin) is the primary contributor to the diurnal LHF amplitude. Because the diurnal SSTskin amplitude has an inverse relationship with surface wind speed over the tropical oceans, an inverse spatial pattern between the diurnal LHF amplitude and surface wind speed results. Resolving diurnal variations in the SSTskin and wind improves the estimate of the climatological LHF by properly capturing the daytime SSTskin and daily mean wind speed, respectively. The diurnal SSTskin-associated contribution is large over the warm pool and equatorial cold tongues where low wind speeds tend to cause strong diurnal SSTskin warming, while the magnitude associated with the diurnal winds is large over the highly dynamic environment of the Inter-Tropical Convergence Zone. The total diurnal contribution is about 9.0 W m−2 on average over the buoy sites. There appears to be a power function (linear) relationship between the diurnal SSTskin-associated (wind-associated) contribution and surface mean wind speed (wind speed enhancement from diurnal variability). The total contribution from diurnal variability can be estimated accurately from high-frequency surface wind measurements using these relationships.
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  • 44
    Publication Date: 2021-09-09
    Description: Modeling studies have shown that surface air temperature (SAT) increase in response to an increase in the atmospheric CO2 concentration is larger over land than over ocean. This so-called land–ocean warming contrast, φ, defined as the land–mean SAT change divided by the ocean-mean SAT change, is a striking feature of global warming. Small heat capacity over land is unlikely the sole cause because the land-ocean warming contrast is found in the equilibrium state of CO2 doubling experiments.Several different mechanisms have been proposed to explain the land–ocean warming contrast, but the comprehensive understanding has not yet been obtained. In Part I of this study, we propose a framework to diagnose φ based on energy budgets at the top of atmosphere and for the atmosphere, which enables the decomposition of contributions from effective radiative forcing (ERF), climate feedback, heat capacity, and atmospheric energy transport anomaly to φ. Using this framework, we analyzed the SAT response to an abrupt CO2 quadrupling using 15 Coupled Model Intercomparison Project Phase 6 (CMIP6) Earth system models. In the near-equilibrium state (years 121-150), φ is 1.49 ± 0.11, which is primarily induced by the land–ocean difference in ERF and heat capacity. We found that contributions from ERF, feedback, and energy transport anomaly tend to cancel each other, leading to a small inter-model spread of φ compared to the large spread of individual components. In the equilibrium state without heat capacity contribution, ERF and energy transport anomaly are the major contributors to φ, which shows a weak negative correlation with the equilibrium climate sensitivity.
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  • 45
    Publication Date: 2021-09-09
    Description: The all-sky assimilation of radiances from microwave instruments is developed in the 4D-EnVar analysis system at Environment and Climate Change Canada (ECCC). Assimilation of cloud-affected radiances from Advanced Microwave Sounding Unit A (AMSUA) temperature sounding channels 4 and 5 for non-precipitating scenes over the ocean surface is the focus of this study. Cloud-affected radiances are discarded in the ECCC operational data assimilation system due to the limitations of forecast model physics, radiative transfer models, and the strong non-linearity of the observation operator. In addition to using symmetric estimate of innovation standard deviation for quality control, a state-dependent observation error inflation is employed at the analysis stage. The background state clouds are scaled by a factor of 0.5 to compensate for a systematic overestimation by the forecast model, before being used in the observation operator. The changes in the fit of the background state to observations show mixed results. The number of AMSUA channels 4 and 5 assimilated observations in the all-sky experiment is 5-12% higher than in the operational system. The all-sky approach improves temperature analysis when verified against ECMWF operational analysis in the areas where the extra cloud-affected observations were assimilated. Statistically significant reductions in error standard deviation by 1-4% for the analysis and forecasts of temperature, specific humidity, and horizontal wind speed up to maximum 4 days were achieved in the all-sky experiment in the lower troposphere. These improvements result mainly from the use of cloud information for computing the observation-minus-background departures. The operational implementation of all-sky assimilation is planned for Fall 2021.
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  • 46
    Publication Date: 2021-09-07
    Description: Accurate representation of stratospheric trace gas transport is important for ozone modeling and climate projection. Intermodel spread can arise from differences in the representation of transport by the diabatic (overturning) circulation vs. comparatively faster adiabatic mixing by breaking waves, or through numerical errors, primarily diffusion. This study investigates the impact of these processes on transport using an idealised tracer, the age-of-air. Transport is assessed in two state-of-the-art dynamical cores based on fundamentally different numerical formulations: finite volume and spectral element. Integrating the models in free-running and nudged tropical wind configurations reveals the crucial impact of tropical dynamics on stratospheric transport. Using age-budget theory, vertical and horizontal gradients of age allow comparison of the roles of the diabatic circulation, adiabatic mixing, and the numerical diffusive flux. Their respective contribution is quantified by connecting the full 3-d model to the tropical leaky pipe framework of Neu and Plumb (1999). Transport by the two cores varies significantly in the free-running integrations, with the age in the middle stratosphere differing by about 2 years primarily due to differences in adiabatic mixing. When winds in the tropics are constrained, the difference in age drops to about 0.5 years; in this configuration, more than half the difference is due to the representation of the diabatic circulation. Numerical diffusion is very sensitive to the resolution of the core, but does not play a significant role in differences between the cores when they are run at comparable resolution. It is concluded that fundamental differences rooted in dynamical core formulation can account for a substantial fraction of transport bias between climate models.
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  • 47
    Publication Date: 2021-12-01
    Description: Future projections of precipitation change over tropical land are often enhanced by vegetation responses to CO2 forcing in Earth system models. Projected decreases in rainfall over the Amazon basin and increases over the Maritime Continent are both stronger when plant physiological changes are modeled than if these changes are neglected, but the reasons for this amplification remain unclear. The responses of vegetation to increasing CO2 levels are complex and uncertain, including possible decreases in stomatal conductance and increases in leaf area index due to CO2 fertilization. Our results from an idealized atmospheric general circulation model show that the amplification of rainfall changes occurs even when we use a simplified vegetation parameterization based solely on CO2-driven decreases in stomatal conductance, indicating that this mechanism plays a key role in complex model projections. Based on simulations with rectangular continents we find that reducing terrestrial evaporation to zero with increasing CO2 notably leads to enhanced rainfall over a narrow island. Strong heating and ascent over the island trigger moisture advection from the surrounding ocean. In contrast, over larger continents rainfall depends on continental evaporation. Simulations with two rectangular continents representing South America and Africa reveal that the stronger decrease in rainfall over the Amazon basin seen in Earth system models is due to a combination of local and remote effects, which are fundamentally connected to South America’s size and its location with respect to Africa. The response of tropical rainfall to changes in evapotranspiration is thus connected to size and configuration of the continents.
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  • 48
    Publication Date: 2021-09-13
    Description: The Subantarctic Mode Water (SAMW) is a major water mass in the South Indian and Pacific oceans and plays an important role in the ocean uptake and anthropogenic heat and carbon. The characteristics, formation, and long-term evolution of the SAMW are investigated in the “historical” and “SSP245” scenario simulations of the sixth Coupled Models Intercomparison Project (CMIP6). Defined by the low potential vorticity, the simulated SAMW is consistently thinner, shallower, lighter, and warmer than in observations, due to biases in the winter mixed layer properties and spatial distribution. The biases are especially large in the South Pacific Ocean. The winter mixed layer bias can be attributed to unrealistic heat loss and stratification in the models. Nevertheless, the SAMW is presented better in the CMIP6 than CMIP5, regarding its volume, location, and physical characteristics. In warmer climate, the simulated SAMW in the South Indian Ocean consistently becomes lighter in density, with a reduced volume and a southward shift in the subduction region. The reduced heat loss, instead of the increased Ekman pumping induced by the poleward intensified westerly wind, dominates in the SAMW change. The winter mixed layer shoals in the northern outcrop region and the SAMW subduction shifts southward where the mixed layer remains deep. The projected reduction of the SAMW volume is likely to impact the heat and freshwater redistribution in the Southern Ocean.
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  • 49
    Publication Date: 2021-09-08
    Description: This study examines historical simulations of ENSO in the E3SM-1-0, CESM2, and GFDL-CM4 climate models, provided by three leading U.S. modeling centers as part of the Coupled Model Intercomparison Project phase 6 (CMIP6). These new models have made substantial progress in simulating ENSO’s key features, including: amplitude; timescale; spatial patterns; phase-locking; spring persistence barrier; and recharge oscillator dynamics. However, some important features of ENSO are still a challenge to simulate. In the central and eastern equatorial Pacific, the models’ weaker-than-observed subsurface zonal current anomalies and zonal temperature gradient anomalies serve to weaken the nonlinear zonal advection of subsurface temperatures, leading to insufficient warm/cold asymmetry of ENSO’s sea surface temperature anomalies (SSTA). In the western equatorial Pacific, the models’ excessive simulated zonal SST gradients amplify their zonal temperature advection, causing their SSTA to extend farther west than observed. The models underestimate both ENSO’s positive dynamic feedbacks (due to insufficient zonal wind stress responses to SSTA) and its thermodynamic damping (due to insufficient convective cloud shading of eastern Pacific SSTA during warm events); compensation between these biases leads to realistic linear growth rates for ENSO, but for somewhat unrealistic reasons. The models also exhibit stronger-than-observed feedbacks onto eastern equatorial Pacific SSTAs from thermocline depth anomalies, which accelerates the transitions between events and shortens the simulated ENSO period relative to observations. Implications for diagnosing and simulating ENSO in climate models are discussed.
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  • 50
    Publication Date: 2009-01-08
    Description: The past decade has shown a marked increase in the use of high-throughput assays in clinical research into human cancer, including acute myeloid leukemia (AML). In particular, genome-wide gene expression profiling (GEP) using DNA microarrays has been extensively used for improved understanding of the diagnosis, prognosis, and pathobiology of this heterogeneous disease. This review discusses the progress that has been made, places the technologic limitations in perspective, and highlights promising future avenues
    Print ISSN: 0006-4971
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  • 51
    Publication Date: 2009-11-20
    Description: Abstract 1689 Poster Board I-715 Introduction The use of the proteasome inhibitor bortezomib has demonstrated activity in multiple myeloma and lymphomas. The HDAC inhibitor romidepsin is being evaluated in CTCL and PTCL, though its activity in B-cell lymphomas is less clear. We hypothesized that the combination of bortezomib and romidepsin would result in synergistic apoptosis in different B-cell NHL cell lines based upon the observed activity of this combination in more mature B-cell malignancies such as myeloma. Experimental Design Daudi, HT, Ramos and SUDHL-4 cell lines were exposed to different concentrations of bortezomib and romidepsin, separately, concurrently, and sequentially. Cell viability was assessed using MTT-assay, induced apoptosis was evaluated using Annexin V and PI staining from 24-48 hours. Apoptosis was also evaluated using western blot analysis of caspases and PARP cleavage. LC3 and HDAC6 level expressions were performed to determine if the effect of the combination was a result of the aggresome or autophagy pathway. Cell cycle studies were also performed to study if there were any changes after treating cells with the combination. Results The combination of bortezomib and romidepsin resulted in synergistic B-cell apoptosis as measured by MTT-assay with combination indices of 〈 0.5. This was associated with increased caspases and PARP cleavage as early as 24 hours after exposure. Order of addition experiments demonstrated definite sequence specificity. When romidepsin was added first, and 6 hours later followed by bortezomib, apoptosis was enhanced, compared to both agents being given concurrently or when bortezomib was administered first. Cell cycle analysis studies demonstrated that pretreatment of cells with romidepsin for 6 hours followed by the addition of bortezomib arrested the cells in G2M phase. HDAC6 expression was significantly reduced following combination therapy, and LC3-I was cleaved to LC3-II in treated cells suggesting that the combination affected aggresome formation and autophagy. Conclusion The combination of romidepsin and bortezomib at low nanomolar concentrations suggests that this may be an important clinical combination to test in patients with relapsed or refractory B-cell malignancies. Sequence of administration data is currently being tested to determine if the effect is a result of autophagy inhibition as is seen in myeloma cell lines. Additional mechanistic studies will be presented with the goals of identifying predictors of response that can then be validated in prospective clinical trials. Disclosures Lechowicz: Gloucester: Consultancy. Kaufman:Millennium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy; Merck: Research Funding; Celgene: Research Funding. Lonial:Gloucester: Research Funding; Novartis: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy. Flowers:Millennium: Research Funding.
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  • 52
    Publication Date: 2009-11-20
    Description: Abstract 3701 Poster Board III-637 Background Romidepsin is an anti-neoplastic agent that has been identified as a novel pan-HDAC inhibitor with single-agent activity in T-cell lymphoma. In a combined analysis of 167 patients (pts) with cutaneous T-cell lymphoma (CTCL) from 2 clinical studies (GPI and NCI studies), the overall response rate was 35%, including 10 pts with a complete clinical response (CCR). Median duration of response was 13.8 months and 42% of pts with advanced disease (stage ≥IIB) responded [Demierre et al. J Clin Oncol 27:15s, 2009 (suppl; abstr 8546)]. The most common hematologic abnormalities in these pts included anemia (41%), thrombocytopenia (34%), neutropenia (27%), and lymphopenia (26%). Most hematologic toxicities were Grade 1 or 2, although 'Grade 3 events were observed. These events were reversible and a small portion of the patients discontinued the study drug because of these events (2%). This report details an analysis of platelet counts in pts receiving romidepsin and an investigation into the mechanism of thrombocytopenia in nonclinical studies. Methods Pts with CTCL who received ≥1 prior systemic therapy failure and had an ECOG PS of 0-2 were enrolled in 2 single-arm, open-label, multicenter and international clinical studies. Treatment with QTc prolonging therapies or CYP34A inhibitors was prohibited and pts with significant cardiovascular abnormalities were excluded. Romidepsin at 14 mg/m2 was administered as a 4-hr IV infusion on days 1, 8, and 15 of a 28 day cycle. Nonclinical studies were conducted in mice to investigate the mechanism of romidepsin effects on platelets. Romidepsin was administered to female BALB/c mice at doses of 1 or 4 mg/kg by tail-vein injection on days 1, 5 and 9. Blood samples were collected every 2 days from alternating groups of mice to minimize effects of bleeding on platelet counts. Results In clinical studies, there is a mean decrease in platelet counts during the treatment period of each cycle, and a return to baseline levels or above between cycles observed in both clinical studies as described in the table below. No clinically meaningful change has been observed in the central tendency over 4 cycles of treatment in both studies. In the mouse studies, dose-dependent effects were seen on both WBC and platelet counts. Day 2 WBC counts dropped to 45% and 10% of normal at the 1 and 4 mg/kg doses, respectively. WBC counts remained low until after the dosing period in the 1 mg/kg romidepsin group, but recovered more quickly in the 4 mg/kg group. Day 2 platelet counts were 70% of normal at the 1 mg/kg dose and remained near this level until day 10, followed by recovery to normal at day 15. At the 4 mg/kg dose, profound thrombycytopenia was induced, with platelet counts only 20% of normal on days 4-6. Platelet counts slowly recovered to 70% of normal by day 15. Plasma thrombopoietin levels were normal throughout the experiment for the 1 mg/kg group, and showed a large increase to 275% of normal on day 6 in the 4 mg/kg group, which is the expected response to thrombocytopenia as a signal to increase platelet production and indicates that platelet reduction is not attributable to defective TPO production. Bone marrow megakaryocyte populations are being examined to determine the effects of romidepsin on these platelet-producing cells. Conclusions Following romidepsin administration, a saw tooth pattern is observed in the reduction and recovery of platelets. Recovery of platelets appears to occur more rapidly in humans than in mice; however, the effects are reversible after dosing in clinical studies and in murine models. In the clinical data the recovery pattern suggests that the transient effects are direct and are not effects on bone marrow. Disclosures: Whittaker: Gloucester Pharmaceuticals: Research Funding. Prince:Gloucester Pharmaceuticals: Consultancy. Demierre:Gloucester Pharmaceuticals: Consultancy, Honoraria. Lonial:Gloucester Pharmaceuticals: Honoraria. Kim:Gloucester Pharmaceuticals: Consultancy, Honoraria. Nichols:Gloucester Pharmaceuticals: Employment, Equity Ownership. Nix:Gloucester Pharmaceuticals: Employment.
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  • 53
    Publication Date: 2009-07-30
    Description: Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents a clinical challenge, because relapses are usually fatal. It is thus necessary to identify high-risk patients as early as possible to effectively individualize treatment. We aimed to define novel molecular risk markers in T-ALL and performed array-based comparative genomic hybridization (array-CGH) and expression analyses in 73 patients. We show that DNA copy-number changes are common in T-ALL and affect 70 of 73 (96%) patients. Notably, genomic imbalances predicted to down-regulate the TGF-β or up-regulate the PI3K-AKT pathways are identified in 25 of 73 (34%) and 21 of 73 (29%) patients, suggesting that these pathways play key roles in T-ALL leukemogenesis. Furthermore, we identified a deletion at 6q15-16.1 in 9 of 73 (12%) of the patients, which predicts poor early treatment response. This deletion includes the CASP8AP2 gene, whose expression is shown to be down-regulated. The interaction of CASP8AP2 with CASP8 plays a crucial role in apoptotic regulation, suggesting a functional link between the clinical effect of the deletion and the molecular mode of action. The data presented here implicate the TGF-β and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of patients with CASP8AP2 deletions and poor early treatment response.
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  • 54
    Publication Date: 2009-11-20
    Description: Abstract 1955 Poster Board I-978 The detection of chromosome abnormalities in mature B-cell neoplasms by conventional cytogenetics remains difficult, mainly due to the low proliferative rate of mature lymphoid cells. The current FISH panel for chronic lymphocytic leukemia (CLL) is designed to detect some of the more common abnormalities of prognostic significance in CLL [i.e., del(6q), del(11q), +12, del(13q), del(17p)]. This CLL FISH panel has improved the detection rate of these markers by making it possible to obtain cytogenetic information from interphase cells; however, as it is limited to only these 5 markers, it cannot detect all abnormalities associated with CLL. More importantly, the impact of other chromosome abnormalities on prognosis and disease progression, with and without the presence of these 5 prognostic markers, is not known. CpG-oligodeoxynucleotides (ODNs) such as DSP30 activate cells of the immune system in a sequence-dependent manner and promote proliferation of CLL cells in vitro [Decker et al. Blood 2000;95:999-1006]. They also upregulate costimulatory molecules and potential target antigens during immunotherapy. The use of DSP30 in combination with interleukin 2 (IL2) has proven effective in increasing the detection of chromosome abnormalities in CLL [Dicker et al. Blood 2006;108:3152-60] and other mature B-cell lymphoid malignancies by conventional cytogenetics [Struski et al. Leukemia 2009;23:617-9], when compared to the well-established B-cell mitogens. In our extensive clinical experience of incorporating DSP30/IL2 into our culture media, this cocktail has significantly increased the detection of chromosome abnormalities in CLL by conventional cytogenetics, from 55% to greater than 80%. We thus decided to investigate if various other lymphoid malignancies would respond to the mitogen activity of DSP30/IL2 as well as or better than CLL. Specifically, we evaluated 812 cases of mature B-cell lymphoid malignancies that were abnormal by flow cytometry, morphology, or cytogenetic analysis. All samples (bone marrow or blood) were cultured for approximately 72 hours using the DSP30/IL2 mitogen cocktail. Of these 812 cases, 746 (91%) provided sufficient mitotic index and quality for a complete cytogenetic analysis and interpretation. Of the CLL cases (n=509), 79 were initially interpreted as normal by conventional cytogenetic analysis, but were later interpreted as abnormal by FISH for deletion 13q only. In view of the known cryptic nature of this deletion in CLL, these cases were not included in the study, leaving a total of 430 CLL cases, and thus bringing the total number of cytogenetically successful study cases to 667. In addition to the 430 CLL cases, there were 14 variant CLLs; 36 diffuse large B-cell lymphomas (DLBCLs); 35 follicular lymphomas; 34 non-Hodgkin lymphomas (not further specified); 29 marginal zone B-cell lymphomas of splenic type (sMZBCL); 27 mantle cell lymphomas (MCLs), of which 8 were blastoid; 16 MZBCL of MALT type; 13 hairy cell leukemias (HCLs); 12 lymphoproliferative disorders (not further specified); 10 lymphoplasmacytic lymphomas (LPLs); 6 Burkitt lymphomas; 3 Hodgkin lymphomas; and 2 B-cell prolymphocytic leukemias (PLLs). Of particular interest is the fact that we detected clonal abnormalities in 100% of HCLs, blastoid MCLs, variant CLLs, and B-cell PLL, as well as in 97% of sMZBCLs, 89% of DLBCLs, and 80% of LPLs This is of great importance since HCLs and LPLs are rarely abnormal by conventional cytogenetics using the more traditional combinations of mitogens making it difficult to identify markers of prognostic significance. In conclusion, our findings demonstrate that the DSP30/IL2 cocktail induces proliferation of various B-cell mature lymphoid disorders and that its mitogenic action is not limited to CLL. We are continuing to develop our understanding of the considerable response of specific lymphoid malignancies to the DSP30/IL2 cocktail by correlating additional clinical data, and hope that the end result will open new avenues in regards to prognostic outcome and therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.
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  • 55
    Publication Date: 2009-10-01
    Description: Higher levels of procoagulant factors and factor XII deficiency may be risk factors for first venous thromboembolism (VTE). We studied associations of coagulation factors IX through XIII with risk of future VTE in 2 general population samples. Using a nested case-control study combining the 21 860 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study, we determined antigenic levels of these coagulation factors in primarily pre-event blood samples from 462 participants who subsequently developed VTE and 1047 participants who remained free of VTE. Only elevated levels of factors IX and XI were associated with increased risk of VTE after adjustment for age, sex, race, and study. For factor IX, the odds ratio (OR) was 1.4 (95% confidence interval [CI], 1.0-2.0) comparing the top to bottom quintile. The OR for factor XI was higher: 2.0 (95% CI, 1.4-2.9). With further adjustment for body mass index and diabetes, only elevated factor XI remained associated with VTE risk: OR 1.8 (95% CI, 1.3-2.7). Associations were similar by study and whether the thrombosis was idiopathic or secondary. Factor XII deficiency was not related to VTE risk. Among these procoagulant factors, only elevated factor XI was a risk factor for VTE.
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  • 56
    Publication Date: 2009-07-16
    Description: The concept of endothelial progenitor cells (EPCs) has attracted considerable interest in cardiovascular research, but despite a decade of research there are still no specific markers for EPCs and results from clinical trials remain controversial. Using liquid chromatography–tandem mass spectrometry, we analyzed the protein composition of microparticles (MPs) originating from the cell surface of EPC cultures. Our data revealed that the conventional methods for isolating mononuclear cells lead to a contamination with platelet proteins. Notably, platelets readily disintegrate into platelet MPs. These platelet MPs are taken up by the mononuclear cell population, which acquires “endothelial” characteristics (CD31, von Willebrand factor [VWF], lectin-binding), and angiogenic properties. In a large population-based study (n = 526), platelets emerged as a positive predictor for the number of colony-forming units and early outgrowth EPCs. Our study provides the first evidence that the cell type consistent with current definitions of an EPC phenotype may arise from an uptake of platelet MPs by mononuclear cells resulting in a gross misinterpretation of their cellular progeny. These findings demonstrate the advantage of using an unbiased proteomic approach to assess cellular phenotypes and advise caution in attributing the benefits in clinical trials using unselected bone marrow mononuclear cells (BMCs) to stem cell-mediated repair.
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  • 57
    Publication Date: 2009-11-20
    Description: Abstract 18 Introduction: Long-term survival in pediatric relapsed AML is only 20-30%. Optimal reinduction therapy is unknown, and there is a concern about cardiotoxicity with repeated anthracycline use at relapse. Preclinical in vitro and animal studies, and limited clinical data suggest that liposomal daunorubicin (DaunoXome®, DNX) is less cardiotoxic. These considerations lead to a phase III study, in the setting of the International BFM Study Group. Materials and methods: FLAG was randomised against FLAG/DNX in the 1st reinduction course. The conventional 5-days FLAG only was recommended as the 2nd course. DNX was dosed at 60 mg/m2/day on days 1, 3 and 5. After induction, allogeneic stem cell transplantation was generally recommended, but time-to-transplant could be bridged by high- or low-intensive consolidation therapy. Primary endpoint of the study was early treatment response, based on bone marrow examination shortly before reinduction course 2, and defined as either good (≤20% leukemic blasts) or poor (〉20% leukemic blasts). This endpoint was chosen because of its prognostic value in earlier relapsed AML BFM-trials, and because compliance with an extended protocol guideline was likely to be suboptimal within the context of a highly multinational and multicenter AML Relapse protocol. However, secondary endpoints were defined, including the CR2 rate determined after 2 courses, long-term survival, and toxicity. Patients with AML M3 and those 〉18 years of age at initial diagnosis were ineligible. The study opened in most countries in 2002/2003. The study closed for accrual on April 1, 2009 when the required 360 fully eligible and evaluable patients had been randomized. Early and late relapsed AML was defined as a relapse within or after 1 year from initial diagnosis, but this only influenced treatment in that early relapsed AML patients were eligible for haploidentical SCT, while late relapsed AML patients were eligible for autologous SCT, if a matched or partly mismatched transplant was not possible. Thirteen groups from 20 countries and 〉100 centers have enrolled patients, with informed consent and after approval of the study by regulatory authorities. Data are presented according to intention-to-treat, with a median follow-up of 2.7 years for patients at risk. Results: Overall 4-year probability of survival (pOS) was 35% SE 2%, the overall CR2 rate 62%. The good early responders had a 4-year pOS of 45% SE 3% versus 10% SE 3% for poor responders (p
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  • 58
    Publication Date: 2009-11-20
    Description: Abstract 634 FLT3, a transmembrane receptor tyrosine kinase constitutively activated via mutation in blasts of patients (pts) with AML, is an important therapeutic target. Blasts from approximately 25% of pts have a length or internal tandem duplication (ITD) mutation in the juxtamembrane region or tyrosine kinase domain (TKD1) of FLT3, which is associated with reduced disease-free survival and overall survival (OS), particularly in pts with normal cytogenetics. Blasts from 5–10% of pts have a point mutation (typically D835Y) in the tyrosine kinase domain (TKD); the effect of this mutation on prognosis is uncertain. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with demonstrated clinical activity in FLT3-mutant (FLT3–mut) and FLT3-wild-type (FLT3–wt) AML (peripheral blood blast reduction in 70% and 30% of pts, respectively) but rarely produces complete remissions). Preclinical studies demonstrated synergy between FLT3 inhibitors and chemotherapy. We conducted a Phase 1b trial to investigate the feasibility of administering daunorubicin (60 mg/m2 IV, days 1–3) and cytarabine (100 mg/m2 IVCI, days 1–7) induction and high-dose cytarabine post-remission therapy (3 gm/m2 over 3h every 12h, days 1, 3, and 5 for 3 cycles) plus oral midostaurin at 100 mg or 50 mg each twice daily on days 8–21 (sequentially) or days 1–7, 15–21 (concomitantly) with all chemo cycles in newly diagnosed pts under age 61 with de novo AML. Whereas 100 mg of midostaurin plus induction chemotherapy was poorly tolerated due to nausea and vomiting, the 40 pts who received 50 mg of midostaurin orally twice daily ( 20 each on the sequential and concomitant schedules; 27 FLT3–wt; 13 FLT3–mut [9 with an ITD]), tolerated the combination well. Median midostaurin exposure was 133 days (range 21–975) for the FLT3–mut pts and 90 days (range 7–1016) for FLT3–wt pts. Maintenance therapy with midostaurin was allowed with investigator discretion and was received by 5 pts (3 FLT3–mut, 2 FLT–wt). The median ages for the FLT3–wt and FLT3–mut pts were 50 years (range 25–60) and 46 years (range 20–65), respectively. 77% of the FLT3–mut pts displayed normal, 15% adverse and 8% other intermediate cytogenetics compared with 18.5%, 26%, and 26%, respectively, for FLT3-wt (also 18.5% favorable; 11% unknown). Complete response occurred in 32/40 (80%) of all pts (20/27 [74%] of FLT3–wt patients, 12/13 [92%] of FLT3–mut pts). Patients were censored at the last date they were known to be alive with a median post treatment follow-up for FLT3-mut pts of 1059 days and 1086 days for FLT3-wt. Even accounting for their differing cytogenetics and ages, the OS of the FLT3–mut subgroup was expected to be inferior to that of the FLT3–wt subgroup. However, we report that the 1 and 2 year OS for the pts with FLT3–mut AML was 85% and 62%, respectively, and was comparable to that of the FLT3–wt subgroup (81% and 59%, respectively). Although based on small numbers and not stratified for type of FLT3 mutation (TKD, ITD, ITD length, location, or allelic ratio), these long-term results suggest that combination therapy with a FLT3 inhibitor and chemotherapy might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3–mut AML pts in first complete remission. Moreover, these data support the rationale for the ongoing international phase 3 study of induction, post-remission intensification, and maintenance with midostaurin (50 mg po bid) or placebo. Disclosures: Stone: Novartis: Research Funding, ad hoc consultancy; Cephalon: ad hoc consultancy. Off Label Use: midostaurin with chemothereapy for AML. Paquette:Novartis: Honoraria, Research Funding, Speakers Bureau. Schiller:Novartis: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Genzyme: Research Funding; Vion: Research Funding; Centocor: Research Funding; Eli Lilly: Research Funding; Celgene: Research Funding. Schiffer:Novartis: Consultancy, Research Funding; Genzyme: Consultancy. Ehninger:Novartis: Honoraria, Research Funding. Cortes:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Wyeth: Research Funding. Kantarjian:Novartis: Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon: Speakers Bureau; Novartis: Speakers Bureau. Huntsman-Labed:Novartis: Employment, Equity Ownership. Dutreix:Novartis: Employment, Equity Ownership. Rai:Novartis: Employment, Equity Ownership. Giles:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Vion: Research Funding.
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  • 59
    Publication Date: 2009-11-20
    Description: Abstract 2168 Poster Board II-145 The deregulated tyrosine kinase associated with t(9;22) fusion protein BCR-ABL is efficiently targeted by tyrosine kinase inhibitors (Imatinib, Nilotinib and Dasatinib). It is generally believed that most patients have residual disease. The inability to eliminate the refractory leukemia stem cell in chronic myeloid leukemia (CML) is not well understood. The refractory stem cell is present despite effective inhibition of the BCR-ABL kinase in these cells, and dissociation between kinase inhibition and cell death implies lack of dependency on BCR-ABL aberrant kinase activity, unlike the one seen in more mature CML cells. Thus the oncogene addictive dependency of these leukemia stem cells may be overcome by intrinsic and/or extrinsic factors/pathways. One such pathway involved in hematopoeitic stem cell maintenance is the Wnt/β-catenin signaling pathway. BCR-ABL signaling is known to directly activate the Wnt/β-catenin pathway. The loss of function of a negative regulator of the Wnt/β-catenin pathway, known as GSK3β is associated with CML progression from chronic phase to the blast phase. Lastly, the loss of β-catenin in murine models impairs the self renewal capacity of both the normal and the BCR-ABL+ leukemia stem cell. Thus this pathway is important during various stages of the disease. We explored the effect of Wnt inhibition using a novel Wnt pathway inhibitor (AG-214, University of Michigan). AG-214 is structurally related to a previously reported Wnt-inhibitor. AG-214 is able to antagonize β-catenin/TCF in luciferase reporter assays, and expression of Wnt targets in colon cancer cell lines. We utilized a serum free culture system with 5 added cytokines and treated both CML blast crisis CD34+ as well as chronic phase CD34+ cells with AG-214. Our in vitro experiments show that primary blast crisis CD34+ cells are induced to undergo apoptosis at an IC-50 of approximately 2 μM. Furthermore, combination of 1.25 μM of AG-214 with 2 μM Imatinib achieved greater than 50% apoptosis. Analysis of chronic phase CML CD34+ cells showed that targeting of Wnt/β-catenin pathway requires higher concentration of the Wnt-inhibitor (〉2.5 μM), and that the addition of Imatinib can cooperate to enhance the apoptotic response. Furthermore, chronic phase progenitors (Lin-CD38+/CD34+) are more sensitive to lower concentrations of AG-214 whereas 5 μM is required to induce significant apoptosis of ∼70% in the primitive leukemia stem cell (Lin-/CD38-/CD34+) population, and addition of 2 μM Imatinib increased their apoptotic response to ∼84%. Normal CD34+ cells do not undergo significant apoptosis with 5 μM of AG-214 (∼10%) even when combined with 2 μM Imatinib (∼20%). Targeting of the Wnt/β-catenin pathway enhances apoptosis in both blast crisis and chronic phase CML progenitors and leukemia stem cells. Disclosures: No relevant conflicts of interest to declare.
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  • 60
    Publication Date: 2009-03-26
    Description: Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor αβ (TCR-αβ) versus TCR-γδ lineage decision is still unclear. Although it is clear in the mouse that TCR-γδ development is less Notch dependent compared with TCR-αβ differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and γδ T cells but inhibits differentiation toward the αβ lineage. Reducing the amount of Notch activation rescues αβ-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during αβ-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-γδ development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.
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  • 61
    Publication Date: 2009-07-09
    Description: During surface-initiated blood coagulation in vitro, activated factor XII (fXIIa) converts factor XI (fXI) to fXIa. Whereas fXI deficiency is associated with a hemorrhagic disorder, factor XII deficiency is not, suggesting that fXI can be activated by other mechanisms in vivo. Thrombin activates fXI, and several studies suggest that fXI promotes coagulation independent of fXII. However, a recent study failed to find evidence for fXII-independent activation of fXI in plasma. Using plasma in which fXII is either inhibited or absent, we show that fXI contributes to plasma thrombin generation when coagulation is initiated with low concentrations of tissue factor, factor Xa, or α-thrombin. The results could not be accounted for by fXIa contamination of the plasma systems. Replacing fXI with recombinant fXI that activates factor IX poorly, or fXI that is activated poorly by thrombin, reduced thrombin generation. An antibody that blocks fXIa activation of factor IX reduced thrombin generation; however, an antibody that specifically interferes with fXI activation by fXIIa did not. The results support a model in which fXI is activated by thrombin or another protease generated early in coagulation, with the resulting fXIa contributing to sustained thrombin generation through activation of factor IX.
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  • 62
    Publication Date: 2009-09-10
    Description: The ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.
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  • 63
    Publication Date: 2009-05-28
    Description: Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic events (VTE). However, whether screening for the JAK2V617F mutation in VTE patients is justified remains unclear. Therefore, we performed a systematic review to assess the frequency of JAK2 mutation in VTE patients and the role of JAK2V617F mutation in the diagnosis of myeloproliferative neoplasms. MEDLINE and EMBASE databases were searched. Two reviewers independently performed study selection and extracted study characteristics. Pooled odds ratios of case-control studies and weighted mean proportion of the prevalence of JAK2V617F mutation of uncontrolled series were calculated. Twenty-four studies involving 3123 patients were included. Mean prevalence of JAK2 mutation was 32.7% (95% confidence interval, 25.5%-35.9%) in SVT patients. JAK2 mutation was associated with increased risk of SVT (odds ratio, 53.98; 95% confidence interval, 13.10-222.45). Mean prevalence of JAK2 mutation in other VTE patients was low (range, 0.88%-2.57%). Presence of JAK2V617F mutation in SVT patients was associated with a subsequent diagnosis of myeloproliferative neoplasm in many patients. JAK2 mutation is strongly associated with SVT, and routine screening of JAK2 mutation appears to be indicated in these patients.
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  • 64
    Publication Date: 2009-11-20
    Description: Abstract 3441 Poster Board III-329 Background CLL is characterized by the progressive accumulation of monoclonal B lymphocytes. One theory to explain how CLL cells avoid elimination through immune surveillance mechanisms is through a defect in the ability of T-cells to form immunological synapses with antigen-presenting tumor B-cells (Ramsay et al JCI 2008). Lenalidomide is an immunomodulatory agent with clinical activity in the treatment of B-cell malignancies. Recent laboratory studies showed that lenalidomide not only stimulates T- and natural killer (NK)-cell-mediated ADCC, it also restores the T-cell-mediated ability to form immunological synapses with CLL tumor cells. Since NK cells also exert cytotoxicity through immune synapse formation, here we explore how lenalidomide affects NK-cell-mediated cytotoxicity mechanisms and whether this activity is altered in the presence of rituximab since published studies showed that lenalidomide-pretreated B-cells have a down-regulated surface CD20 expression. Further, we investigated the molecular events associated with immune synapse formation and the effect of lenalidomide. Methods Immune synapse formation was assessed in NK cells (from healthy donors PBMCs) co-cultured with either B-CLL cells derived from pts or with K562 cells (positive control). Cells were fixed and the ability to form synapses was assessed via immunohistochemisty co-staining for either F-actin and CD2, or F-actin and perforin (a cytolytic protein found in NK cells). Synapse formation was visualized by microscopy and measured via relative mean fluorescent intensity. Activity of RhoA, Rac1, Cdc42 were measured using Rho GTPases assay kits. Inhibition of lenalidomide-mediated immune synapse activity was assayed using the cell permeable Rho inhibitor C3 (0.5 mM). Flow cytometry was used to measure changes in surface CD20 and CD54 (ICAM-1) expression in B-CLL samples from 3 pts after treatment with lenalidomide. Results Lenalidomide induced the formation of immunological synapses between NK cells and primary B-CLL cells (p
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  • 65
    Publication Date: 2009-01-29
    Description: The antiphospholipid syndrome (APS) is an acquired thrombophilia, characterized by the occurrence of venous and arterial events. This article examines the laboratory and key clinical aspects of APS. Particular focus is given to anti–beta 2-glycoprotein I (β2GPI) antibodies in view of their recent inclusion in the APS classification criteria. The clinical utility of using the β2GPI enzyme-linked immunosorbent assay, in conjunction with the established lupus anticoagulant assays and cardiolipin enzyme-linked immunosorbent assay, for diagnosing and risk stratifying patients suspected of having APS is discussed. The relative importance of the various assays in diagnosing obstetric APS (early and late gestation miscarriages) is explored. The implications of recent epidemiologic findings for possibly understanding the underlying pathophysiologic mechanisms of obstetric APS are highlighted. Insights into which patients with obstetric APS may be at most risk of thrombotic complications are presented.
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  • 66
    Publication Date: 2009-12-03
    Description: To study B-cell development from bone marrow (BM), we generated recombination-activating gene 1 (Rag1)–targeted mice lacking mature lymphocytes. B-cell development can be induced in such mice by B cell–specific restoration of a functional Rag1 transcription unit. Follicular and marginal zone B cells populated the spleen when Rag1 expression was permitted. Notably, the peritoneal cavity was dominated by bona fide B-1a cells, as judged by surface markers and functional properties. These BM-derived B-1a cells exhibited a polyclonal VDJ repertoire with substantial N nucleotide insertions. Nevertheless, physiologic frequencies of phosphatidylcholine-specific B cells were detected. Importantly, the BM of young and 5-month-old mice was indistinguishable with regard to the potential to generate B-1a cells.
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  • 67
    Publication Date: 2009-07-16
    Description: Historically, graft-versus-host disease (GVHD) beyond 100 days after hematopoietic cell transplantation (HCT) was called chronic GVHD, even if the clinical manifestations were indistinguishable from acute GVHD. In 2005, the National Institutes of Health (NIH) sponsored a consensus conference that proposed new criteria for diagnosis and classification of chronic GVHD for clinical trials. According to the consensus criteria, clinical manifestations rather than time after transplantation should be used in clinical trials to distinguish chronic GVHD from late acute GVHD, which includes persistent, recurrent, or late-onset acute GVHD. We evaluated major outcomes according to the presence or absence of NIH criteria for chronic GVHD in a retrospective study of 740 patients diagnosed with historically defined chronic GVHD after allogeneic HCT between 1994 and 2000. The presence or absence of NIH criteria for chronic GVHD showed no statistically significant association with survival, risks of nonrelapse mortality or recurrent malignancy, or duration of systemic treatment. Antecedent late acute GVHD was associated with an increased risk of nonrelapse mortality and prolonged treatment among patients with NIH chronic GVHD. Our results support the consensus recommendation that, with appropriate stratification, clinical trials can include patients with late acute GVHD as well as those with NIH chronic GVHD.
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  • 68
    Publication Date: 2009-01-08
    Description: Chronic immune activation is a major cause for progressive immunodeficiency in human immunodeficiency virus type-1 (HIV) infection. The underlying trigger, however, remains largely unknown. HIV single-stranded RNA is a potent immune activator by triggering Toll-like receptor (TLR) 7/8. Thus, we hypothesized that sustained TLR7 triggering induces chronic immune activation and thereby contributes to progressive immunodeficiency. We used the synthetic compound R848 or a mixture of uridine-rich HIV single-stranded (ss) RNA oligonucleotides—both are potent TLR7/8 agonists—to explore the effects of sustained TLR7 triggering on the murine lymphoid system. Sustained TLR7 triggering induced an immunopathology reminiscent of progressive lymphoid destruction in HIV disease; we observed lymphopenia, elevated proinflammatory cytokines, splenomegaly, contracted lymphoid subsets, and lymphoid microarchitecture alteration with reduced marginal zone B-lymphocytes. Upon exposure to inactivated vesiculo-stomatitis virus, antibody production was abolished, although splenic lymphocytes were activated and total IgG was elevated. Our data imply that HIV itself may directly contribute to immune activation and dysfunction by stimulating TLR7. Thus, manipulation of TLR7 signaling may be a potential strategy to reduce chronic hyper-immune activation and, thereby, disease progression in HIV infection.
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  • 69
    Publication Date: 2009-03-05
    Description: Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C〉T, 1298A〉C), methionine synthase (MTR 2756A〉G), methionine synthase reductase (MTRR 66A〉G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G〉A), nicotinamide N-methyltransferase (NNMT IVS −151C〉T), serine hydroxymethyl transferase (SHMT1 1420C〉T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G〉A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS −151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P 〈 .05). Furthermore, interactions between NNMT and MTHFR 677C〉T and RFC1 were observed. NNMT IVS −151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS −151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G〉A and NNMT IVS −151C〉T variants to an increased ALL susceptibility.
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  • 70
    Publication Date: 2009-11-20
    Description: Abstract 4311 Objectives Oral mucositis is a common complication of high-dose chemotherapy and radiotherapy followed by hematopoietic stem-cell support (HSCT). We evaluated the efficacy and safety of calcium phosphate mouth rinse (Caphosol) for prevention and reduction of severity and duration of oral mucositis in patients treated with HSCT. Methods In 2009 23 patients were treated. Three received allogeneic stem cells (ALLO): 2- Hodgkin disease (HD), 1-myeloma multiplex (MM) and twenty autologous transplantation (AUTO): 8-non-Hodgkin lymphomas (NHL); 7- HD; 3-MM. For ALLO conditioning regimens were composed of: fludarabine 150mg/m 2 and melphalan 140mg/m 2. AUTO were treated with: BEAM: carmustine, etoposide, cytarabine and melphalan (HD and NHL) and melphalan 200mg/m 2 (MM). The source of hematopoietic stem cells was peripheral blood. Caphosol was prepared according to the manufacturer‘s instructions and administered 4 times daily, starting from the day before the beginning of chemotherapy till the end of hospitalization. Control group was composed of patients, who had been treated with HSCT previously, before “palifermin and caphosol era”. The groups were comparable according to number of patients, their age, type of disease, transplant and conditioning regimen. Oral mucositis was assessed with the use of the five-grade World Health Organization (WHO) oral-toxicity scale. Oral mucositis was evaluated daily after the beginning of transplantation procedure until discharge from the BMT Unit. The number of days with painkillers or antibiotics were estimated. Total parenteral nutrition was given according to the standards [Martin-Salces M, De Paz R, Canales MA et al (2008) Nutritional recommendations in hematopoietic stem cell transplantation. Nutrition 24: 769-775]. Treatment with antibiotics was started when neutropenic fever occurred. Safety was assessed on the basis of the incidence of adverse events. Statistical analysis was performed using Wilcoxon‘ test for analysis of differences between groups. Results Oral mucositis grade 2-4 was not observed. In patients treated with calcium phosphate mouth rinse oral mucositis grade 2-4 was not observed. Nobody had to receive opioid analgesics or total parenteral nutrition. 30% patients developed the first degree of oral mucositis 4-5 days' duration. In the control group OM was observed in all cases, 50% patients had III- IV degree. Median duration of OM was 10 and 12 days (range 5- 20) for auto- and allogeneic patients, respectively. As compared with control group, treatment with calcium phosphate mouth rinse was associated with significant reduction of the incidence of oral mucositis in II- IV degrees (0 percent versus 50 percent, p 〈 0.001), duration of oral mucositis (4/ 5 days vs. 10/12 days, p 〈 0.001), duration of pain-killers‘ treatment (0- 22 days vs. 0- 3 days, p 〈 0.001) and number of days with antibiotics‘ treatment (0- 7 days vs. 7- 20 days, p= 0.002). These differences were observed in both types of transplantation. No side effects of calcium/phosphate oral rinse were observed. Conclusion In comparison with control group, treatment with Caphosol was associated with the significant reduction of the incidence of oral mucositis in II- IV degrees, duration of oral mucositis, pain-killers‘ treatment and number of days with antibiotics‘ treatment. Calcium phosphate mouth rinse is a very promising medicine for prevention of oral mucositis for patients treated with high dose chemotherapy supported with hematopoietic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.
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  • 71
    Publication Date: 2009-10-29
    Description: Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P 〈 .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487.
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  • 72
    Publication Date: 2009-09-03
    Description: The role of hematopoietic cytokines in lineage commitment remains uncertain. To gain insight into the contribution of cytokine signaling to myeloid lineage specification, we compared granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) signaling in Ba/F3 cells expressing both the G-CSF and M-CSF receptors and in lineage-negative murine marrow cells. G-CSF and M-CSF serve as prototypes for additional cytokines that also influence immature myeloid cells. G-CSF specifically activated signal transducer and activator of transcription 3 and induced Src homology region 2 domain-containing phosphatase 2 (SHP2) phosphorylation, whereas M-CSF preferentially activated phospholipase Cγ2, and thereby extracellular signal-regulated kinase (ERK), to stabilize c-Fos and stimulate CCAAT/enhancer-binding protein (C/EBP)α(S21) phosphorylation. In contrast, activation of Jun kinase or c-Jun was similar in response to either cytokine. Inhibition of ERK prevented induction of c-Fos by M-CSF and reduced C/EBPα phosphorylation and formation of colony-forming unit–monocytes. SHP2 inhibition reduced ERK activation in G-CSF, but not M-CSF, and reduced colony-forming unit–granulocytes, underscoring divergent pathways to ERK activation. Phorbol ester mimicked the effect of M-CSF, activating ERK independent of SHP2. In summary, M-CSF activates ERK more potently than G-CSF, and thereby induces higher levels of c-Fos and phospho-C/EBPα(S21), which may directly interact to favor monopoiesis, whereas G-CSF activates signal transducer and activator of transcription 3 and SHP2, potentially shifting the balance to granulopoiesis via gene induction by C/EBPα homodimers and via effects of SHP2 on regulators besides ERK.
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  • 73
    Publication Date: 2009-04-09
    Description: To investigate the cell of origin linking follicular (FL) and transformed (t-FL) lymphomas, we analyzed the somatic hypermutation (SHM) pattern of the variable region of the immunoglobulin heavy gene (IgH-VH) in 18 sequential FL/t-FL samples and a father (donor) and son (recipient), who developed FL and t-FL, after transplantation. Genealogic trees showed a pattern compatible with a common progenitor cell (CPC) origin in 13 cases. The identification of the t-FL clonotype in the previous FL sample and of the putative CPC sequence in both the FL/t-FL biopsies showed that the intraclonal diversity of FL and t-FL germinal centers (GCs) is more intricate than previously described, and all 3 clonotypes (CPC, FL, t-FL) may occur simultaneously within the same lymph node. On the basis of the father/son model, this CPC must be long-lived, providing a possible explanation for the incurable nature of this disease.
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  • 74
    Publication Date: 2009-11-12
    Description: Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory-like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selectin-mediated interactions of tumor cells with platelets and leukocytes activated endothelial cells and induced production of C-C chemokine ligand 5 (CCL5). Inhibition of CCL5-dependent monocyte recruitment during the early phase of metastasis by a CCL5 receptor antagonist strongly reduced tumor cell survival and attenuated metastasis. Collectively, these findings demonstrate that the endothelial expression of CCL5 contributes to the formation of a permissive metastatic microenvironment.
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  • 75
    Publication Date: 2009-08-13
    Description: Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P 〈 .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3′ untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca2+ levels after activation with ADP (P 〈 .004). These data provide novel insights into key hubs within platelet signaling networks.
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  • 76
    Publication Date: 2009-11-20
    Description: Abstract 3453 Poster Board III-341 Introduction Increasing insight into the biology of CLL suggests a relevant interplay between tumor cells and the microenvironment. Preclinical data point to the potency of Lenalidomide to favourably modulate such interactions and remarkable clinical activity has been demonstrated in monotherapy trials in pretreated and also in previously untreated CLL patients. However, tumor flare and tumor lysis have been observed as problems and the optimal dose and schedule is still under investigation. In addition, the potential for interaction with effective standard treatment for CLL is unknown. We used a combination of Fludarabine and Rituximab as a backbone to establish a tolerable Lenalidomide dose in a dose escalation design. Study design The study treatment follows two phases: In the induction phase the maximal tolerated dose (MTD) of Lenalidomide in combination with FR should be determined. The protocol combines 6 cycles of Fludarabine (40mg/m2 po d1-3) and Rituximab (375mg/m2 iv day 4 on cycle 1 and 500mg/m2 iv day 1 on cycles 2-6), both in a 28 day cycle. Lenalidomide is given at a starting dose of 2,5 mg daily (day 7-21 of cycle 1) and with dose escalation steps to 5, 10, 15, 20 and 25mg of Lenalidomide from day 1-21 of the following cycles, if toxicity of the combination permits. In a second phase, Rituximab (375mg/m2 iv) at 2, 4 and 6 months after the last cycle is combined with Lenalidomide (day 1-28 of 28 day cycles) at the last tolerated dose for 6 months of maintenance. 40 patients are planned for this study. We herewith present the planned interim analysis for dose finding and safety endpoints for the induction phase of the first 10 patients recruited into the study. Results Mean age of patients was 70 years (range 59-76). Six of 10 patients had stage Rai III/IV and mean WBC count was 159 G/L. Seven of 10 patients had at least one high risk feature from CD38 and FISH analysis or by mutation status. Of the 60 planned cycles 46 (77%) are currently evaluable for this analysis. No systematic toxicity determining MTD was found. 50% of patients proceeded through dose escalation steps as planned. Two patients have already tolerated 25mg of Lenalidomide with their FR cycles. Regarding toxicities, grade 3 and 4 neutropenia was expected in this combination and observed in 7/10 patients. However it was not used as a dose limiting toxicity per se. Still, one 75 year old patient was dose reduced because of febrile neutropenia in the previous cycle. Overall three infectious episodes were observed on treatment. Two patients experienced thrombotic events one of which was then taken off study because of Richter transformation, which might in hindsight have been present from study onset. Surprisingly, 5/10 patients experienced significant skin toxicity, mostly in the form of skin rashes, which was deemed dose limiting in two patients. It was, however, clearly associated with Pneumocystis prophylaxis in one patient, who then went on to receive the full Lenalidomide dose without further rashes. No tumor lysis or flare reaction was observed in the 10 patients reported. Preliminary efficacy data show that all patients achieved at least a PR after 3 cycles of therapy (except for the patient with the Richter transformation). Of the 3 patients currently evaluable after 6 cycles of treatment one CR and two very good PRs were observed before starting the maintenance phase of the study. Conclusions The combination of Lenalidomide with Fludarabine and Rituximab seems clinically feasible and no tumor lysis or flare reaction have been observed, possibly due to the Lenalidomide step up design, as well as the initial tumor load reduction by the chemo-immunotherapy backbone. No clear dose dependent toxicity has emerged as dose limiting for Lenalidomide escalation in this combination. However, 50% of patients had to be dose-limited due to not clearly dose-dependent skin and vascular toxicities. A regime of thromboprophylaxis as well as a delayed start of prophylaxis against pneumocystis have since been amended to improve the management of the patients. In addition, and remarkably, the regimen shows clinical efficacy despite controversial in vitro reports, suggesting a potential negative interaction between Lenalidomide and Rituximab. This might be due to the Lenalidomide pause before each Rituximab cycle or may reflect a difference between in vitro and in vivo. Disclosures Egle: Roche: Research Funding, Speakers Bureau. Off Label Use: Lenalidomide treatment in CLL, Rituximab maintenance in CLL. Greil:Roche: Honoraria, Research Funding; Celgene: Research Funding.
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  • 77
    Publication Date: 2009-11-01
    Description: Abstract LBA-2 Background: In a large proportion of patients that have completed 6 to 12 months of treatment with a vitamin K antagonist (VKA) for their acute episode of venous thromboembolism (VTE) the question arises whether to stop or continue this treatment. Continuation implies the need for regular laboratory control and subsequent dose adjustments. Furthermore, the risk of bleeding persists. New oral anticoagulants hold the promise of simple fixed-dose regimens without the need for monitoring and could make continuation of therapy more attractive. The Einstein-Extension study was therefore designed to assess the relative efficacy and safety of rivaroxaban, a direct oral factor Xa inhibitor, versus placebo in patients who had completed 6 to 12 months of anticoagulant treatment for their acute episode of VTE. Patients in whom there was a clear indication for continued anticoagulant treatment were not eligible. Study Design: This randomized, double-blind, placebo-controlled, superiority study evaluated therapy with rivaroxaban 20 mg once-daily for an additional 6 or 12 months. The primary efficacy outcome was symptomatic recurrent VTE (i.e., the composite of recurrent DVT, non-fatal PE, and fatal PE). The principal safety outcome was major bleeding. Also the occurrence of clinically relevant non-major bleeding (e.g. nose bleeds, large skin hematomas, and macroscopic hematuria) was recorded. The study was event-driven requiring a minimum of 30 confirmed recurrent events. All outcomes were adjudicated by an independent blinded committee. Results: A total of 1197 patients were randomized between February 2007 and May 2009 by 280 study sites in 28 countries. The intention-to-treat population consisted of 602 rivaroxaban and 594 placebo patients. Baseline characteristics and risk factors for VTE were comparable between the two groups. The mean duration of study treatment was 190 days in both groups. During the treatment period, symptomatic recurrent VTE events occurred in 42 (7.1%) of the placebo treated patients and in 8 (1.3%) of the rivaroxaban recipients (hazard ratio, 0.18; 95 % CI, 0.09 – 0.39; p〈 0.0001). After the stop of study medication, 6 symptomatic recurrent VTE events occurred in each group during the one month observational period. Major bleeding did not occur in placebo patients and was observed in 4 (0.7%) rivaroxaban recipients (p=0.106). None of these bleeding events were fatal or in a critical site. Clinically relevant non-major bleeding was noted in 7 (1.2%) and 32 (5.4%) of the placebo and rivaroxaban recipients, respectively. Two (0.3%) patients in the placebo group died versus 1 (0.2%) in the rivaroxaban group. No patients were observed to have an alanine aminotransferase (ALT) rise above 3 times the upper limit of normal (xULN) combined with a total bilirubin above 2 xULN. Conclusion: A fixed dose of 20 mg of rivaroxaban once-daily is associated with an 82% relative risk reduction in the recurrence of VTE in patients who had completed a 6 to 12 month course of anticoagulant therapy for their index event. Based on the estimated cumulative incidence rates, approximately, 15 patients need to be treated to prevent one recurrent VTE event. This clinically relevant reduction in recurrence was associated with a low incidence of major bleeding (0.7%). This oral once-daily regimen provides the clinician with a simple option for patients in whom continued anticoagulant treatment is indicated. Disclosures: Buller: Bayer Healthcare: Research Funding.
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  • 78
    Publication Date: 2009-05-07
    Description: BLyS and its major receptor BAFF-R have been shown to be critical for development and homeostasis of normal B lymphocytes, and for cell growth and survival of neoplastic B lymphocytes, but the biologic mechanisms of this ligand/receptor-derived intracellular signaling pathway(s) have not been completely defined. We have discovered that the BAFF-R protein was present in the cell nucleus, in addition to its integral presence in the plasma membrane and cytoplasm, in both normal and neoplastic B cells. BAFF-R interacted with histone H3 and IKKβ in the cell nucleus, enhancing histone H3 phosphorylation through IKKβ. Nuclear BAFF-R was also associated with NF-κB/c-Rel and bound to NF-κB targeted promoters including BLyS, CD154, Bcl-xL, IL-8, and Bfl-1/A1, promoting the transcription of these genes. These observations suggested that in addition to activating NF-κB pathways in the plasma membrane, BAFF-R also promotes normal B-cell and B-cell non-Hodgkin lymphoma (NHL-B) survival and proliferation by functioning as a transcriptional regulator through a chromatin remodeling mechanism(s) and NF-κB association. Our studies provide an expanded conceptual view of the BAFF-R signaling, which should contribute a better understanding of the physiologic mechanisms involved in normal B-cell survival and growth, as well as in the pathophysiology of aggressive B-cell malignancies and autoimmune diseases.
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  • 79
    Publication Date: 2009-11-20
    Description: Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.
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  • 80
    Publication Date: 2009-09-17
    Description: This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels 〈 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.
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  • 81
    Publication Date: 2009-04-09
    Description: AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein–associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO–mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO.
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  • 82
    Publication Date: 2009-07-16
    Description: Endothelial sialomucin CD34 functions as an L-selectin ligand mediating lymphocyte extravasation only when properly glycosylated to express a sulfated carbohydrate epitope, 6-sulfo sialyl Lewis x (6-sulfo SLex). It is thought that multivalent 6-sulfo SLex expression promotes high-affinity binding to L-selectin by enhancing avidity. However, the reported low amount of 6-sulfo SLex in total human CD34 is inconsistent with this model and prompted us to re-evaluate CD34 glycosylation. We separated CD34 into 2 glycoforms, the L-selectin–binding and nonbinding glycoforms, L-B-CD34 and L-NB-CD34, respectively, and analyzed released O- and N-glycans from both forms. L-B-CD34 is relatively minor compared with L-NB-CD34 and represented less than 10% of total tonsillar CD34. MECA-79, a mAb to sulfated core-1 O-glycans, bound exclusively to L-B-CD34 and this form contained all sulfated and fucosylated O-glycans. 6-Sulfo SLex epitopes occur on core-2 and extended core-1 O-glycans with approximately 20% of total L-B-CD34 O-glycans expressing 6-sulfo SLex. N-glycans containing potential 6-sulfo SLex epitopes were also present in L-B-CD34, but their removal did not abolish binding to L-selectin. Thus, a minor glycoform of CD34 carries relatively abundant 6-sulfo SLex epitopes on O-glycans that are important for its recognition by L-selectin.
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  • 83
    Publication Date: 2009-11-20
    Description: Abstract 3619 Poster Board III-555 Granulocyte colony-stimulating factor (G-CSF) controls neutrophil production in the bone marrow under steady state conditions and during demand-driven hematopoiesis occurring in response to infection. STAT3 is a principal signaling molecule activated by the G-CSF receptor (G-CSFR). We previously reported that STAT3 has an important role in demand-driven granulopoiesis, although its cellular and molecular mechanisms have been unclear. To address this, we investigated STAT3 function in emergency granulopoiesis stimulated by G-CSF administration or infection with Listeria monocytogenes, which is restrained by the G-CSF response pathway in vivo. Our results show that STAT3-deficiency renders hematopoietic stem cells and myeloid progenitors refractory to the proliferation-inducing effects of G-CSF or Listeria monocytogenes infection. STAT3-deficient myeloid progenitors have a cell autonomous defect in G-CSF-responsive cell cycle progression and undergo delayed granulocyte maturation relative to wild type cells. To define STAT3 target pathways in granulocytic progenitors, we investigated the expression of CCAAT enhancer binding protein (C/EBP) beta, a transcription factor that is necessary for G-CSF-driven emergency granulopoiesis. We found that STAT3 directly regulates G-CSF-responsive C/EBPbeta expression by binding to Cebpb promoter. Moreover, we show that STAT3 and C/EBPbeta co-regulate c-Myc during emergency granulopoiesis. These results place STAT3 as a crucial G-CSF-responsive signal transducer during demand-driven granulopoiesis, through its regulation of critical transcription factors in developing granulocytes. Disclosures: Zhang: Amgen: Research Funding. Nguyen-Jackson:Amgen: Research Funding. Watowich:Amgen, Inc: Research Funding.
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  • 84
    Publication Date: 2009-12-24
    Description: Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) is thought to promote tumor angiogenesis mostly through its protease-inducing function and more recently by its ability to increase tumor cell expression of vascular endothelial growth factor (VEGF). In this study, we present evidence that EMMPRIN can promote angiogenesis by a direct effect on endothelial cells through a paracrine regulation of the VEGF/VEGF-receptor (VEGFR) system. Using human microvascular endothelial cell line–1 endothelial cells, we show that EMMPRIN selectively increased the soluble VEGF isoforms (121 and 165), but not the matrix-bound VEGF 189 form. In addition, EMMPRIN up-regulated the expression of VEGFR-2 without an effect on VEGFR-1. This increase in VEGFR-2 was responsible for the observed EMMPRIN stimulation of the migratory and tube formation capacity of endothelial cells. EMMPRIN′s effects, which were matrix metalloproteinase and urokinase-type plasminogen activator independent, were mediated primarily through hypoxia-inducible factor-2α expression, also up-regulated by EMMPRIN. VEGFR-2 increase was also observed in vivo in a mouse model of xenograph tumors overexpressing EMMPRIN. These results suggest that in addition to increasing protease production, EMMPRIN may contribute to the formation of a reactive stroma also through the up-regulation of hypoxia-inducible factor-2α, VEGFR-2, and the soluble forms of VEGF in endothelial cells, thus directly regulating the angiogenic process.
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  • 85
    Publication Date: 2009-11-20
    Description: Abstract 286 It is well established that deregulation of the PI3K signaling pathway plays an important role in the etiology of human malignancies including those of hematologic origin. In 30–50% of solid tumors, oncogenic activation of the PI3K pathway is the result of gain-of-function mutations in the PI3K p110α isoform or due to the loss-of-function of the PTEN phosphatase that is responsible for PI3K downregulation. In B cell malignancies these mutations are rarely observed in spite of the fact that PI3K pathway activation is commonly observed and often essential for tumor cell growth and survival. In this case, PI3K pathway activation has been shown to result from constitutive B cell receptor (BCR) activation and/or from exposure to survival factors present in the microenvironment. The activation of the PI3K pathway by cell surface receptors is directly mediated by the Class I isoforms (α, β, δ, and γ), however, their relative contribution in B cell tumors is unknown. Interestingly, genetic and pharmacological approaches that specifically inactivate the p110δ isoform have demonstrated its important role in normal B cell signaling in response to multiple factors including antigen, CD40L, BAFF, SDF-1 and CXCR13 making it an attractive target for therapeutic intervention in B cell malignancies. CAL-101 is an oral p110δ specific inhibitor which is currently being evaluated in a phase I clinical trial for the treatment of patients with select hematologic malignancies. This compound is a novel potent p110δ inhibitor with an IC50 of 2.5 nM against purified p110δ and EC50 of 65 nM in p110δ-mediated basophil activation in whole blood. CAL-101 demonstrates 300-, 200-, and 40-fold selectivity over the other class I family members (α, β, and, γ respectively) and no activity against class II and III PI3K family members or other PI3K-related proteins including mTOR and DNA-PK. Furthermore, a kinome-wide screen failed to detect activity against any additional kinases. To investigate the potential role of p110δ in B cell hematologic tumors we screened a wide range of leukemia and lymphoma cell lines for constitutive PI3K pathway activation. The expression of p110δ was observed in 〉90% of these cell lines and in many cases was accompanied by constitutive Akt phosphorylation. In this context, CAL-101 was able to reduce p-Akt levels and block additional downstream effectors such as p-S6, and GSK-3β in cells that represent a range of tumor types including follicular lymphoma, acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL). Furthermore, treatment with CAL-101 resulted in growth suppression and induction of apoptosis which was accompanied by PARP and caspase-3 cleavage. Growing evidence suggests that signals from the microenviroment are essential for the expansion, homing, and survival of malignant B cells, in addition to promoting resistance to conventional drug therapy. To investigate the potential role p110δ plays during B cell signaling via interactions with the microenvironment, we examined invoked stimulation of leukemia and lymphoma cell lines with CXCL12, CXCL13, BAFF, or BCR crosslinking in the presence or absence of CAL-101. Stimulation with either chemokines or growth factors resulted in the phosphorylation of Akt which was inhibited by CAL-101 in a dose dependent manner. Moreover, p110δ inhibition with CAL-101 inhibits the chemotaxis of ALL and MCL cell lines to CXCL12. These studies have now been extended to the analysis of primary patient B-ALL and MCL cells to further establish preclinical proof of concept for therapeutic application of CAL-101. In summary, CAL-101 is a potent and selective p110δ kinase inhibitor with broad anti-tumor activity against cancer cells of hematologic origin. Our results demonstrate that selective inhibition of p110δ with CAL-101 inhibits malignant B cell growth, survival, and migration. Furthermore, p110δ inhibition may enhance the effect of cytotoxic drugs or overcome cell mediated drug resistance by inhibiting the protective signals of the microenviroment, providing a rational for combination therapy. These data suggest that p110δ may play an important role in regulating signals between malignant B cells and their microenvironment thereby providing the preclinical rationale for clinical evaluation of CAL-101 alone or in combination with cytotoxics or biologics in patients with hematologic malignancies. Disclosures: Lannutti: Calistoga Pharmaceuticals: Employment. Meadows:Calistoga Pharmaceuticals: Employment. Kashishian:Calistoga Pharmaceuticals: Employment. Steiner:Calistoga Pharmaceuticals: Employment. Johnson:Calistoga Pharmaceuticals: Research Funding. Giese:Calistoga Pharmaceuticals: Employment.
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  • 86
    Publication Date: 2009-06-04
    Description: Radioimmunotherapy (RIT) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited. We evaluated anti-CD45-RIT in human (h) and murine (m) T-NHL. CD45 was highly expressed on hT-NHL patient samples (median, 2.3 × 105 antigen-binding capacity units/cell) and hT-NHL cell lines (3.4 × 105 CD45 antigen-binding capacity units/cell). Biodistribution studies in hTNHL xenografts showed that 131I-labeled BC8 (anti-hCD45) delivered 154% (P = .01) and 237% (P = .002) more radioiodine to tumor sites over control antibodies at 24 hours and 48 hours, respectively. Importantly, tumor sites targeted with 131I-BC8 exhibited 2.5-fold (P = .05), 3.0-fold (P = .007), and 3.6-fold (P = .07) higher 131I retention over the nontarget organs of lungs, liver, and kidneys, respectively (24 hours). Because the clinical use of anti-hCD45 would target both T-NHL and other hematolymphoid tissues, we evaluated the ability of anti-mCD45 to target mT-NHL. mT-NHL grafts targeted with anti-mCD45 correspondingly retained 5.3 (P 〈 .001), 5.4 (P 〈 .001), and 8.7 (P 〈 .001) times the radioactivity in tumor sites compared with nontarget organs of lung, liver, and kidney. 131I-labeled BC8 therapy yielded improved complete remission rates (75% vs 0%, P 〈 .001) and progression-free survivals (median, 23 days vs 4.5 days, P 〈 .001) compared with controls. These data indicate that the high CD45 expression of T-NHL allows reliable tumor targeting and disease control supporting anti-CD45 RIT for T-NHL patients.
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  • 87
    Publication Date: 2009-08-13
    Description: The importance of donor-recipient human leukocyte antigen (HLA)-DPB1 matching for the clinical outcome of unrelated hematopoietic stem cell transplantation (HSCT) is controversial. We have previously described an algorithm for nonpermissive HLA-DPB1 disparities involving HLA-DPB1*0901,*1001,*1701,*0301,*1401,*4501, based on T-cell alloreactivity patterns. By revisiting the immunogenicity of HLA-DPB1*02, a modified algorithm was developed and retrospectively tested in 621 unrelated HSCTs facilitated through the Italian Registry for oncohematologic adult patients. The modified algorithm proved to be markedly more predictive of outcome than the original one, with significantly higher Kaplan-Meier probabilities of 2-year survival in permissive compared with nonpermissive transplantations (55% vs 39%, P = .005). This was the result of increased adjusted hazards of nonrelapse mortality (hazard ratio [HR] = 1.74; confidence interval [CI], 1.19-2.53; P = .004) but not of relapse (HR = 1.02; CI, 0.73-1.42; P = .92). The increase in the hazards of overall mortality by nonpermissive HLA-DPB1 disparity was similar in 10 of 10 (HR = 2.12; CI, 1.23-3.64; P = .006) and 9 of 10 allele-matched transplantations (HR = 2.21; CI, 1.28-3.80; P = .004), both in early-stage and in advanced-stage disease. These data call for revisiting current HLA matching strategies for unrelated HSCT, suggesting that searches should be directed up-front toward identification of HLA-DPB1 permissive, 10 of 10 or 9 of 10 matched donors.
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  • 88
    Publication Date: 2009-11-20
    Description: Abstract 3727 Poster Board III-663 Deacetylases (DACs) are enzymes that remove the acetyl groups from target proteins, leading to regulation of gene transcription and other cellular processes. Entinostat (SNDX-275) is a novel and potent DAC inhibitor that is selective for class I DACs and is currently undergoing pre-clinical and clinical testing in Hodgkin lymphoma (HL). Potent synergistic anti-tumor activity has been observed by combining less potent DAC inhibitors with bortezomib in pre-clinical models. In our efforts to develop more therapeutic options for refractory/resistant B-cell lymphoma, we evaluated the effects of Eentinostat as a single agent and in combination with bortezomib against B-cell non-Hodgkin's lymphoma (NHL) cell lines and primary NHL cells. Studies were conducted in a panel of 12 NHL cell lines representing various subtypes of B-cell lymphoma (i.e. DLBCL/ABC, DLBCL/GCB, Burkitt's, transformed and MCL), which included: rituximab-[chemotherapy]-sensitive cell lines (RSCL, Raji, RL and DHL-4), rituximab-[chemotherapy]-resistant cell lines (RRCL, Raji-4RH, Raji-2R, RL-4RH, and DHL-4 4RH), and primary lymphoma cells isolated from patients with various subtypes of NHL and HL. Patient-derived tumor cells were isolated from fresh specimens by negative selection using magnetic beads. NHL cells and patient-derived primary cells were exposed to entinostat at different doses (0.01 to 100uM) either alone or in combination with CDDP (1 to 100μM), doxorubicin (4 to 16μM), vincristine (1 to 5μM), or bortezomib (1 to 10nM). Anti-tumor activity was measured after a 24 or 48 hr incubation. In cell lines, changes in mitochondrial potential and cell proliferation were determined by alamar blue reduction using a kinetic assay measuring activity at 4 hr intervals for 24 and 48 hrs. For patient-derived primary NHL cells, changes in ATP content (apoptosis) was determined using the cell titer glow assay. Entinostat was highly active in all the cell lines tested including rituximab-[chemotherapy]-resistant cell lines. The IC50 of Entinostat in the majority of the cells tested was 0.5 to 5uM at 48 hrs. Similar findings were observed in primary tumor cells derived from lymphoma patients. In addition, synergistic activity was observed by combining entinostat and bortezomib in both NHL cell lines, as well as in primary NHL/HL tumor specimens. A lesser degree of augmented anti-tumor activity was also observed when entinostat was combined with cisplatin or doxorubicin (but not vincristine). In summary, our data suggests that entinostat is a novel and potent DAC inhibitor with a wide therapeutic spectrum. Entinostat is capable of inducing cell death against various subtypes of B-cell lymphoma cell lines including RSCL, RRCL, as well as patient-derived primary tumor cells and augments the anti-tumor effects of bortezomib and other chemotherapeutic agents. Given the isoform selectivity of entinostat, the results indicate that HDAC1 and 2 may be the key targets of DAC inhibitors in HL and NHL cells. Ongoing studies are evaluating the mechanisms responsible for the synergistic effects of entinostat plus chemotherapy and will be updated at the annual meeting. Current findings strongly suggest that entinostat added to bortezomib and/or other chemo agents may become a novel and potent strategy in the treatment of aggressive and indolent NHL and HL in the future. Disclosures: No relevant conflicts of interest to declare.
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  • 89
    Publication Date: 2009-11-20
    Description: Abstract 4919 Waldenstrom's macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow and the secretion of IgM monoclonal antibody in the serum. Several conventional therapies are available but the disease remains incurable. Recently, bortezomib (a proteasomal inhibitor) has shown promising anti-WM activity with enhanced responses when combined with traditional therapies. Resistance to bortezomib therapy is an important event that is associated with continued treatment. In order to understand the mechanism of bortezomib resistance in WM we exposed BCWM.1 (a known WM cell line) in vitro to increasing concentrations of bortezomib over prolonged periods of time and isolated the bortezomib resistant clone (BCWM.1/BR). This clone was compared with its parent wild type cell line (BCWM.1/WT). Investigation to understand the susceptibility of BCWM.1/Br cells to various therapeutic agents showed that these cells are resistant to many of the agents such as melaphalan, fludarabine or doxorubicin. Interestingly, verapamil, a broad spectrum inhibitor of multidrug resistance, failed to reverse the resistance induced by bortezomib indicating that bortezomib resistance is not because of an activation of multidrug resistance in these cells. While BCWM.1/WT cells showed an IC50 of 7.8nM when treated for 72h with bortezomib, the BCWM.1/BR cells were not inhibited at any concentration of the compound up to 100nM. Furthermore, the cells with the acquired resistance showed a 4 fold increase in the proteasomal activity as measured by the release of a fluorescent product (7-Amino-4-methylcoumarin (AMC)) from its peptide substrate, suc-LLVY-AMC. Biochemical analysis further revealed that many of the proteasomal components are altered in BCWM.1/BR cells as compared to their parental control cells. Interestingly, protein levels of two of the proteasomal catalytic subunits, PSMB5 and PSMB9 are upregulated in resistant cells suggesting a reason for the enhanced proteasomal activity of these cells. The resistant cells showed an altered gene expression profile that indicates a transformation of the parental wild type cell line to acquire resistance. A comparative analysis of the signal transduction pathways operated in these cells showed that many of the activation and cell survival pathways that are present in BCWM.1 cells are inhibited in the resistant cells. For example, BCWM.1 cells show a constitutive activation of AKT and ERK1/2 which are inhibited in the resistant cells thus making them insensitive to the inhibitors of these pathways. Similarly, HSP27 which was earlier shown to contribute to bortezomib induced resistance was completely inhibited in BCWM.1 resistant cells. Interestingly, there is an increase in Bcl-2 protein in BCWM.1/BR cells as compared to WT cells indicating that the resistant cells might be dependent on Bcl-2 family for their survival. Inhibition of Bcl-2 induced potent apoptosis in BCWM.1/BR cells. Thus the results presented here indicate that acquired bortezomib resistance in BCWM.1 cells alters their proteasomal activity, cellular signaling pathways to make them resistant to many of the known therapies but these cells retain the Bcl-2 mediated pathway for targeting thus inhibitors of Bcl-2 may be used in therapy against bortezomib-resistant WM. Disclosures Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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  • 90
    Publication Date: 2009-11-20
    Description: Abstract 4848 Background Myelodysplastic syndrome(MDS) belong to the most common hematological diseases however epidemiological data on MDS are sparse. Until 2008 there were no data about epidemiology of MDS in Poland. Methods From 03.2008-05.2009 we have registered 966 patients in Polish MDS Registry. We have included only alive patients of various time of diagnosis. Patients from 22 centers were diagnosed according to WHO 2001 criteria. Results There were 508(53%)males and 458(47%) females. Median age at diagnosis was 70(range 19-99). Under 50 were 83(9%) cases with preponderance of females- 51 cases( males 32cases), between 50-70 there were 353(41%) cases, half of the patients-432(50%) were above 70( 247 males and 185 females).Prior chemotherapy and/or radiotherapy had 37((3,8%) patients. Distribution of MDS subtypes was as follows: RA-170(20%) cases, RARS-58(7%), RCMD-244(28%), RCMD-RS-18(2%), RAEB-1-120(14%), RAEB-2-169(19,5%), 5q- -40(4,6%), MDS-U-44(5%).In 103(10%) subtype was not done. Karyotype was available in 276(28%) cases. Cytogenetic risk groups were: low risk-182(68%), intermediate-52(20%) and high risk-33(12%). The most frequent cytogenetic results were: normal karyotype 44%, isolated 5q deletion 19%, complex karyotype 6%, 5q deletion + another one change 3% and 5q deletion with at least 2 changes 3%. According to IPSS risk groups low risk was found in 61( 22%) of cases, intermediate-1 -130(48%), intermediate-2-47(17%) and high risk in 31(11,5%). Median values of Hb was 9,1 g/dL, plts 129 G/L, ANC 1,7 G/L. RBC transfusion dependent were 429(44%) patients and platelet transfusion dependent were 100( 11%) pts. At least 2 U/month RBC transfusion requirement was 140(14%) patients. Serum ferritin level was assessed in 530 cases-171 of them( 32%) had higher than 1000μg/L level. Conclusions We have observed predominance of females among MDS patients under 50. Half of the patients had RA or RCMD subtype. Isolated 5 q deletion was the most frequent cytogenetic abnormality. Forty four percentage of patients was RBC transfusion dependant. Serum ferritin level was significantly elevated in 32% of assessed patients at the moment of MDS diagnosis. Disclosures No relevant conflicts of interest to declare.
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  • 91
    Publication Date: 2009-11-20
    Description: Abstract 4915 Multiple studies have highlighted the critical role of mutation and loss of p53 function in multiple myeloma (MM) when acquiring a more aggressive phenotype and refractoriness to treatment. Therefore, agents capable of overcoming p53 mutational status are important in the context of MM therapeutics. We have previously reported the in vitro and in vivo anti-MM activity of the multi-targeted small molecule inhibitor RGB-286638. Using a human MM cell xenograft model in SCID mice we demonstrated that RGB-286638 inhibited tumor growth and prolonged survival. Our data confirmed suppression of CDK1/cyclin B, CDK4, 6/Cyclin D1, D3, and CDK2/Cyclin E complexes in MM.1S MM cells containing wt-p53, which was correlated with rapid downregulation of Rb phosphorylation, resulting in effective G2/M cell cycle blockage and increased sub-G1phase. RGB-286638 induced dose and time-dependent inhibition of RNA pol II phosphorylation as an early event promptly followed by p53 induction. Moreover, RGB-286638 treatment was associated with p53 phosphorylation at ser 15, indicative of DNA damage followed by apoptosis, evidenced by caspases 8, 9 and 3 cleavage and confirmed by Annexin V/PI staining. All together these data suggested that RGB-286638-induced RNA pol II inhibition triggers cytotoxicity in MM cells via p53-dependent apoptosis. Interestingly, RGB-286638 demonstrated cytotoxic activity even in p53-deficient conventional drug-resistant RPMI 8226/Dox 40 MM cells. RGB-286638 treatment of RPMI 8226/Dox40 MM cells showed increased PARP response associated with enhanced NAD depletion followed by increased ATP consumption. Furthermore, concomitant assessment of RGB-286638-induced ATP depletion versus cytotoxicity demonstrated more than 60% ATP loss preceded cell death in RPMI 8226/Dox40 but not in MM.1S. This data suggests the role of either p53-mediated apoptosis (when active) or PARP-induced NAD/ATP depletion and bioenergetic crisis (when absent). Interestingly, the knockdown of p53 did not rescue MM.1S cells from RGB 286638-induced death, suggesting the existence of alternative p53-independent pathways through which RGB-286638 exerts its cytotoxic activity. Ongoing studies are addressing the molecular effects of p53 silencing in MM cells. In addition, dissecting the mechanism of RGB-286638 p53-independent cytotoxicity in MM cells will provide insights for future therapeutic strategies in patients with aggressive MM and associated mutated/deleted-p53. Disclosures Loferer: GPC Biotech AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding.
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  • 92
    Publication Date: 2009-11-20
    Description: Abstract 4886 Detection of high molecular weight light chain oligomers in urinary exosomes of patients with AL amyloidosis. Background Exosomes are microvesicles that are part of the multivesicular body (MVB) pathway. They are created by the inward budding of the cell surface membrane and contain both surface bound membrane proteins and cytosolic proteins which can be used to identify the cell of origin. Immunoglobulin light chain amyloidosis (AL) occurs as the result of amyloid formation by the misfolding of monoclonal light chains (LC) and deposition of these amyloid fibrils in various soft tissues. This reaction requires the organization of the monoclonal LC's into protofibrils which are then weave into amyloid fibrils. This study was undertaken to determine whether urinary exosomes of glomerular origin contain intermediate species of amyloid formation. Method Urine samples from patients with AL, light chain deposition disease (LCDD), multiple myeloma (MM) and monoclonal clonal gammopathy of undetermined significance (MGUS) were collected. Urinary exosomes were isolated and separated into fractions by gradient centrifugation. Western blots were performed on the urinary exosome fractions using anti-kappa or anti-lambda antibodies. Glomerular fractions were identified using antibodies directed toward podocin. Results Urine samples were collected from 5 patients with AL, 2 from LCDD, 1 from MM and 1 MGUS. On the Western blot, immunoglobulin LC were seen in all exosomal fractions in patients with AL amyloidosis, LCDD, MM but not MGUS which is similar to normal controls (not shown). In patients with AL, oligomeric species were found in the highest concentrations in fraction 4 and 5 (Figure 1). Fraction 4 and 5 were also stained for podocin, a glomerular protein (not shown). The highest molecular weight species was ∼250 kd which corresponds to a LC decamer. High molecular weight species were also identified in 1 of 2 LCDD patients corresponding to a tetramer. The band was identified in fraction 10 which had polycystin-1 expression suggesting a tubular origin. No high molecular weight LC species was found in patients with MM or MGUS. Conclusion Our study found high molecular weight LC species corresponding to the intermediates involved in protofibril formation in urinary exosomes of patients with AL. Smaller (tetramer) high molecular weight LC species were also found in a patient with LCDD but not in patients with MM and MGUS. Not only were the high molecular weight LC species found exclusively in the diseases characterized by deposition of LC aggregates, they were also found in the segments of the nephron where the deposits were expected: glomerulus for AL and tubular epithelium for LCDD. This is consistent with our current understanding of the pathogenic mechanisms of these diseases. We believe urinary exosomes are a powerful tool in the study of diseases involving self-aggregation of monoclonal proteins. It has tremendous potential in both diagnostic and scientific research in this area. Disclosures Gertz: celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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  • 93
    Publication Date: 2009-11-20
    Description: Abstract 4902 Introduction Cytogenetics and fluorescent-in situ hybridization (FISH) are important outcome predictors in multiple myeloma (MM). There were only few small studies that investigated prognostic implication of FISH and/or conventional karyotyping in Korean MM patients. We investigated the incidences and prognostic significances of chromosomal abnormalities detected by FISH and/or conventional karyotyping among Korean MM patients. Patients and Methods We collected data of patients from Korean Myeloma Registry and performed retrospective analysis. We compared the survival of patients with chromosomal abnormalities and other clinical findings. Results From 2000 to 2009, total of 801 newly diagnosed myeloma patients were enrolled in this study. Median age of patients was 62 years. Median overall survival was 82 months, and median follow up of time was 92 months. Among the patients who had conventional karyotype analysis, 17.1% were complex karyotype, followed by del13q (7.4%), hyperdiploidy (7.6%), hypodiploidy (3.0%), and t(11;14) (3.9%). Among the patients who had FISH analysis, 22.8% were del 13q, followed by t(11;14) (18.2%), t(4;14) (13.7%), del17p (11.8%) and t(14;16) (5.9%). Univariate analyses revealed that complex karyotype (p
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  • 94
    Publication Date: 2009-11-20
    Description: Abstract 4873 Angiogenesis plays a significant role in the biology of multiple myeloma (MM). Erythropoiesis stimulating agents (ESAs) have been recently associated with reduced survival in a subset of cancer patients who receive ESAs, including MM but the etiology for this correlation has not been sufficiently explored. It is known that the endothelial cells produce angiogenic factors, promote the growth and survival of MM cells and carry erythropoietin receptors which in hypoxic conditions they transport the signal for their own proliferation and expansion under the influence of the endogenous erythropoietin. The aim of this study was to investigate the possible impact of ESAs administration on post-therapy angiogenesis. We studied 84 newly diagnosed MM patients (47M/37F; median age: 65 years, range: 39-82 years) who underwent conventional anti-myeloma therapy: 62 patients received VAD (53 of whom within the context of the randomized study VAD vs. TVAD, conducted by the Greek Myeloma Study Group) and 22 patients received MP. Fifty-two patients received ESAs for at least 8 weeks (ESA group), while 32 did not receive ESA (non-ESA group). MVD was assessed in bone marrow biopsies at baseline and at the time of best response by using monoclonal antibodies targeting CD34. The number of microvessels expressing the CD34 antibody was counted by two experienced pathologists through a grid at a magnification of 400x and was finally divided to the number of the high power fields used for screening the whole marrow surface. The counts were finally expressed as number of vessels per mm2 area of the involved marrow. Fifteen individuals with normal findings in the bone marrow were used as controls. Furthermore, the following cytokines that are involved in the angiogenesis process in MM were measured in the serum of both patients and controls on the day of the trephine biopsy performance: VEGF, bFGF, TGF-b, IL-6, soluble IL-6R (sIL-6R), IL-1b and TNF-α, using an ELISA methodology (R&D, Minneapolis, MN, USA). Patients characteristics between the ESA and non-ESA groups at baseline were well balanced except of Hb which was, as expected, significantly lower in the ESA-group (p
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  • 95
    Publication Date: 2009-11-20
    Description: Abstract 4815 Algae preparations are commonly used in complementary and alternative medicine for presumed anti-oxidant, anti-inflammatory, and anti-cancer properties. In this study, we have examined the effects of extracts from algae and algae components on the proliferation of normal hematopoietic and leukemia cells. To prepare extracts, 1 gram of Dunaliella salina (Dun), Astaxanthin (Ast), Spirulina (C-phycocyanin) (Spir), or Aphanizomenon flos-aquae (AFA) were added to 10 ml of 70% ethanol and incubated at 4°C on a shaker for 24 hours. The slurry was centrifuged at 400 g for 10 minutes at 4°C, and the supernatant was filtered through 413-grade filter paper. Leukemia cell lines were purchased from ATCC and blood or marrow aspirates from normal subjects or patients with leukemia were subjected to Ficoll-Hypaque density gradient centrifugation. CD34+ cells were isolated using Miltenyi Biotec MiniMACS magnetic bead cell separation columns. To determine effects on cell proliferation, increasing concentrations of algae extracts were added in fresh medium to plated cells, and MTT reagent was added followed by detergent and absorbance readings were recorded at 570 nm. Leukemic cell lines such as HL60 and MV4-11 were significantly inhibited by Ast and AFA at concentration of 0.8 mg/mL of extract (p
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  • 96
    Publication Date: 2009-11-20
    Description: Abstract 4877 Introduction The CD138negCD20+ cell population has been suggested as the putative multiple myeloma (MM) cancer stem cells, both in MM cell lines and in patient specimens. CD200 is an immunosuppressive membrane glycoprotein reported to be co-expressed with other stem-cell markers in prostate, breast, brain, and colon cancers. Also, CD200 is a negative prognostic factor for MM. It remains unknown whether CD200 is expressed in the CD138negCD20+ MM cell population, the putative MM cancer stem cells. Here we addressed this question by assessing CD200 expression in different subpopulations of MM cells according to their CD138 expression levels. Methods Two MM cell lines (RPMI8226 and NCI-H929) were co-stained with FITC-labeled anti-CD200, PE-labeled anti-CD20, and APC-labeled anti-CD138 antibodies for multicolor flow cytometry analysis. The cells were gated into 4 subpopulations (h1〉h2〉h3〉h4 corresponding to CD138 expression levels: high〉dim〉low〉negative). In each gated cell population, CD200 expression was assessed, and the CD200+ and CD200neg cell subpopulations were further gated for analysis of their CD20 expression levels. Results In the RPMI 8226 cell line, the distribution of gated h1, h2, h3, and h4 populations was 87.51%, 5.86%, 5.26%, and 1.29%, respectively. In the h2 (CD138dim) population, 22.88% of the cells were CD200+. In contrast, CD200 was expressed at much lower levels in the other three populations, ranging from 7.28% (h1), 6.65% (h3), to 0.48% (h4). In CD200+ cells from the gated h1, h2, h3, and h4 population, CD20+ cells were 19.50%, 23.03%, 27.67%, and 18.75%, respectively, while in the CD200neg cells, CD20+ cells were 20.79%, 22.50%, 25.08%, and 28.02%, respectively. In the NCI-H929 cell line, 18.59% of the cells in the h2 population were CD200+, whereas only 1.61%, 1.69%, and 0.47% of the cells in the h1, h3, and h4 populations were CD200+. In each population, there were more CD20+ cells in CD200+ cells than in CD200neg cells, which were 24.52% vs 0.04% (h1), 41.94% vs 11.34% (h2), 11.11% vs 3.06% (h3), and 50.00% vs 2.25% (h4), respectively. Conclusions These results demonstrate that the immunosuppressive molecule CD200 is preferentially expressed in a CD138dim subpopulation of multiple myeloma cells. Depending on cell line, the putative myeloma stem cell marker CD20 is either preferentially, or not preferentially, expressed in the CD200+ cells, suggesting that an immune-resistant subpopulation of MM stem cells might exist, which may have important implications for designing immunotherapeutic approaches to treat this disease. Disclosures Goldenberg: Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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  • 97
    Publication Date: 2009-11-20
    Description: Abstract 4841 Myelodysplastic syndromes (MDS) are a group of acquired clonal stem cell disorders that mainly affect the elderly population, characterized by ineffective hematopoiesis and high risk of leukemic transformation. MDS are heterogeneous in terms of morphology, clinical features and survival. An increasing body of work reveals that there might be differences in clinical features between Asian and Western cases. Japanese patients seem to be younger, have a lower frequency of refractory anemia (RA) with ringed sideroblast (RARS) and a higher frequency of RA, according to FAB classification, as well as different prognostic factors such as the frequency of cytogenetic abnormalities. Incidence rates for MDS in Brazil are unavailable. The purpose of the study was to obtain epidemiological data of MDS adult patients who presented from January 2003 to December 2007 in 10 Brazilian tertiary-care hematology centers from different regions of the country. Patient data collected by participating physicians were entered and stored with the use of an internet-based, data collection tool. Blood counts, bone marrow aspiration, trephine biopsy and chromosomal study were recorded. Survival was estimated through Kaplan-Meier method and the difference between survival curves was assessed by means of Log-Rank Test. Death incidence rates were estimated and compared. Statistical analyses of relevant variables were performed. Three hundred and forty three patients with diagnosis of MDS according to FAB/WHO classification were included in this retrospective analysis. The mean age at presentation was 68 years (range 17 to 98). Fifty percent of cases were male. Cigarette smoking, alcohol abuse and pesticide/herbicide exposure were reported in 33.5%, 13.4% and 14.3% respectively. Median hemoglobin was 8.7 g/dL, median neutrophils count was 1,575/mm3 and median platelets count was 97,000/mm3. There was no excess of blasts in 68.4% of cases. Bone marrow biopsy was performed in 78.5% of patients. Lymphoid nodules were seen in 11.3% and any degree of fibrosis in 28.6%. Cytogenetic analysis was performed in 67.8% of cases and showed chromosomal abnormalities in 50.5%. The del(5q) isolated or combined with other alterations were observed in 6.0%. Flow cytometry analysis for CD55 and CD59 was performed in 11,3% and was normal in 97,4%. Near 8% of cases were classified as secondary MDS. The distribution of disease subtypes according to FAB classification was: RA 42,3%, RARS 9,0%, RA with excess of blasts (RAEB) 20,7%, RAEB-t 4,2% and chronic myelomonocytic leukemia (CMML) 3,9%. According to IPSS patients were stratified as low-risk (low risk plus intermediate I) 55,9% and high risk (intermediate II and high risk) 13,1%. In 30,1% no stratification was possible. In 26,5% of cases iron overload was diagnosed although only 28,3% of cases had performed serum ferritin. The follow-up time ranged from 1 to 78 months (mean: 28 months). Thirty-six percent of patients died and the death was MDS-related in 68.3% of cases. The high and low risk survival curves were significantly different (p
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  • 98
    Publication Date: 2009-11-20
    Description: Abstract 2496 Poster Board II-473 Background: HMG-CoA reductase inhibitors (statins) have been used to treat hypercholesterolemia and hyperlipidemia for over 20 years. Statins competitively inhibit HMG-CoA reductase thereby blocking the synthesis of mevalonate. They directly inhibit synthesis of steroid hormones and cholesterol but also indirectly inhibit prenylation and ubiqitination. As all currently marketed statins are lipophillic, with the exception of Pravachol (pravastatin), several therapeutic trials have attempted to exploit these indirect actions to treat both neoplastic (glioblastoma, anaplastic astrocytoma) and degenerative (Alzheimer's, Parkinson's) neurologic disease. We studied the impact of incidentally prescribed statins on high-risk patients with primary central nervous system diffuse large B cell lymphoma (PCNSL). Methods: We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, to identify all patients diagnosed with primary central nervous system lymphoma (PCNSL) between 1991 and 2007 (n=118). We excluded pediatric patients, patients who did not receive curative treatment and patients who failed to achieve a CR with initial therapy. Automated analysis of billing and medication administration records was used to identify the administration of statins to these patients. We compared the outcome of patients who were receiving statins to controls with PCNSL who did not receive statins. We excluded patients who did not receive statins within the time interval from 6 months prior to 2 years after their PCNSL diagnosis. As only a single statin pt was less than 50 we excluded all pts below this age from the cases and controls. All patients received high dose MTX based therapy. Overall survival (OS) was calculated from the date of first methotrexate. Results: Median age of statin patients was 66 yrs (range 52 – 76); median age of controls was 66 years (range 50 - 86). Nine patients were on atorvastatin, 9 were on simvastatin, 1 each were on pravastatin, rosuvastatin and fluvastatin. At a median follow-up of 47.5 months, concurrent statin therapy was associated with improved OS (62% vs. 37%)(p=0.04 Log-rank test). The median OS for all statin patients 〉 50 years old (n=21) was 60 months versus 37 months for all other patients 〉 50 years old (n=67) (p=
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  • 99
    Publication Date: 2009-11-20
    Description: Abstract 2475 Poster Board II-452 Introduction: Non-Hodgkin Lymphoma (NHL) is the fifth most common type of malignancy in Canada. The most common subtype of NHL is diffuse large B-cell lymphoma (DLBCL). Initial standard treatment for DLBCL includes combination immuno-chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This regimen is typically administered every 21 days for a total of 6 cycles. Febrile neutropenia (FN) is a serious toxicity of lymphoma chemotherapy and patients with this condition must be treated aggressively as it could lead to complications such as prolonged hospitalization and death. Granulocyte-colony stimulating factors such as filgrastim and pegfilgrastim are efficacious in preventing FN, yet their cost-effectiveness has not been evaluated in the publicly funded Canadian healthcare system. Methods: A Markov model was constructed to evaluate the cost-effectiveness (cost-utility) of filgrastim and pegfilgrastim as primary prophylaxis versus no primary prophylaxis against FN in DLBCL patients receiving induction chemotherapy. Health states included in the model were hospitalization for FN, and receiving chemotherapy with no FN. It was assumed that patients in the no primary prophylaxis arm of the model who experienced a FN episode would receive secondary prophylaxis with filgrastim for all subsequent chemotherapy cycles. The time horizon of the model was 18 weeks, the time period over which the six cycles of chemotherapy are administered. The analysis was conducted from the hospital perspective. Costs are reported in 2009 Canadian dollars and outcomes in quality-adjusted life years (QALY). One-way sensitivity analyses were done on model parameters. A probabilistic sensitivity analysis was done to evaluate overall uncertainty in the model. Results: In the base case analysis costs associated with the no primary prophylaxis, filgrastim and pegfilgrastim interventions were $6044, $9450 and $15899, respectively. Quality-adjusted life years associated with the three interventions were 0.198, 0.200, and 0.202 respectively (over the 18-week model time horizon). The incremental cost-effectiveness ratio (ICER) of filgrastim compared to no primary prophylaxis was estimated to be $1.7 million (M)/QALY [95% confidence interval: -14M/QALY (dominated) to $15M/QALY]; for pegfilgrastim compared to filgrastim the ICER was estimated to be $4.4M/QALY [95% confidence interval: -25M/QALY (dominated) to $22.7M/QALY]. All one-way sensitivity analyses yielded ICERs of greater than $1M/QALY. Conclusions: The ICERs for filgrastim and pegfilgrastim when used as primary prophylaxis against FN in DLBCL patients receiving induction chemotherapy are well above the usually accepted cost-effectiveness threshold of $50,000/QALY. Disclosures: Mittmann: Amgen Canada: Unrestriced educational grant.
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  • 100
    Publication Date: 2009-11-20
    Description: Abstract 2484 Poster Board II-461 Background: Hematologic (HM) and solid tumor malignancy (STM) patients may be immunocompromised (IC) due to their underlying diseases and the immunosuppressive therapies they received. Availability of a practical and robust algorithm to classify HM and STM patients into IC levels using data from healthcare databases could be valuable for a variety of epidemiologic, health service or outcome research in the field of oncology. Classification of the IC status of patients also permits accurate prediction of the types of supportive care that such patients may need to prevent infectious complications that often accompany treatments for the underlying malignancy. Methods: An expert panel mainly comprised of hematologists and oncologists developed an algorithm to classify HM and STM patients' level of IC into either none/low, medium, or high, using data available in electronic databases. The algorithm was based on the following factors: (1) the type of chemotherapy agents and/or corticosteroids, (2) time since last chemotherapy/corticosteroid treatment, and (3) specific type of HM (for HM patients). Chemotherapy agents were classified into levels of IC, irrespective of dose used. Corticosteroid therapy was classified into levels of IC based on dose and duration of treatment. IC levels were allowed to change monthly to reflect what chemotherapy agents were used, dose and duration of corticosteroid if any, and time since the last IC treatment. In the base case scenario, the patient's IC level (based on treatment) stayed at an assigned level for 6 months after the last treatment and then moved to the next lower level for an additional 6 months. In alternative scenarios, sensitivity analyses were also performed using the 1, 3, 9, and 12 month cutoffs. If the patient received multiple chemotherapy agents/corticosteroid regimens, the most immunocompromising agent determined the IC level during that time period. We applied and tested this algorithm in a study of HM and STM patients diagnosed in 2001-2005 at Kaiser Permanente Northern California (KPNC). Herpes zoster (HZ), a viral disease caused by the reactivation of varicella zoster virus, is associated with impairment of cell-mediated immunity. Therefore, we used incidence of HZ as a proxy for true IC status. The KPNC cancer registry was used to identify cancer diagnoses and the type, stage and grade of the underlying HM. Data on specific chemotherapy agents and/or dose and duration of corticosteroids as well as time since last IC treatment were obtained from KPNC pharmacy databases. Potential episodes of HZ in 2001-2006 were identified from HZ diagnosis codes and antiviral use in various KPNC databases. HZ diagnosis was confirmed by clinical review of patient's medical records. We measured HZ incidence rates in HM and STM patients and examined whether they were correlated with IC level based on our algorithm. Results: In the base case scenario, among the 4,465 patient-years (py) of follow-up in HM patients, 25.3%, 34.4%, and 40.3% of follow-up time was categorized as none/low, medium, or high IC, respectively. The corresponding rates of HZ were 13, 25, and 48/1000 py. Among the 23,072 py of follow-up in STM patients, 74.9%, 8.0%, and 17.1% of follow-up time was categorized as none/low, medium, or high IC, respectively. The corresponding rates of HZ were 10, 20, and 19/1000 py, respectively. The algorithm was not sensitive to changes from 3 to 12 months, but was sensitive to the 1 month cutoff, in the assumption of duration of IC since the last IC treatment. Conclusions: It is feasible and practical to categorize cancer patients into IC levels using electronic pharmacy and cancer registry databases. The correlation between incidence of HZ and levels of IC in both HM and STM patients suggested that the proposed algorithm may appropriately assign IC levels in these patients. Additional testing in other cancer populations may be needed to further validate this algorithm. Disclosures: Tran: Merck & Co., Inc.: Employment. Ray:Merck & Co., Inc.: Investigative. Saddier:Merck & Co., Inc.: Employment. Trigg:Merck & Co., Inc.: Employment. Hayes:Merck & Co., Inc.: Consultancy. Li:Merck & Co., Inc.: Investigative. Rizzieri:Merck & Co., Inc.: Consultancy. Stein:Merck & Co., Inc.: Consultancy. Weber:Merck & Co., Inc.: Consultancy. Serody:Merck & Co., Inc.: Consultancy. Raasch:Merck & Co., Inc.: Consultancy. Habel:Merck & Co., Inc.: Investigative.
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