bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma
Authors: DuBois Steven G. , Groshen Susan , Park Julie R. , Haas-Kogan Daphne A. , Yang Xiaodong , Geier Ethan , Chen Eugene , Giacomini Kathy , Weiss Brian , Cohn Susan L. , Granger M. Meaghan , Yanik Gregory A. , Hawkins Randall , Courtier Jesse , Jackson Hollie , Goodarzian Fariba , Shimada Hiroyuki , Czarnecki Scarlett , Tsao-Wei Denice , Villablanca Judith G. , Marachelian Araz , Matthay Katherine K. 
Published: February 2015

Abstract
Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.
Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.
Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.
Conclusions: Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. Clin Cancer Res; 21(12); 2715–21. ©2015 AACR.
Radiosensitization of Primary Human Glioblastoma Stem-like Cells with Low-Dose AKT Inhibition
Authors: Mehta Monal , Khan Atif , Danish Shabbar , Haffty Bruce G. , Sabaawy Hatem E. 
Published: February 2015

Abstract
Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells, and the high levels of recurrence due to chemo- and radioresistance make this cancer an extremely difficult disease to treat. Emerging studies have focused on inhibiting AKT activation; here, we demonstrate that in primary GBM tumor samples, full-dose inhibition of AKT activity leads to differential responses among samples in the context of cell death and self-renewal, reinforcing the notion that GBM is a heterogeneous disease. In contrast, low-dose AKT inhibition when combined with fractionation of radiation doses leads to a significant apoptosis-mediated cell death of primary patient–derived GBM cells. Therefore, low-dose–targeted therapies might be better for radiosensitization of primary GBM cells and further allow for reducing the clinical toxicities often associated with targeting the AKT/PI3K/mTOR pathway. This work emphasizes the discrepancies between cell lines and primary tumors in drug testing, and indicates that there are salient differences between patients, highlighting the need for personalized medicine in treating high-grade glioma. Mol Cancer Ther; 14(5); 1171–80. ©2015 AACR.
A Novel Neutralizing Antibody Targeting Pregnancy-Associated Plasma Protein-A Inhibits Ovarian Cancer Growth and Ascites Accumulation in Patient Mouse Tumorgrafts
Authors: Becker Marc A. , Haluska Paul , Bale Laurie K. , Oxvig Claus , Conover Cheryl A. 
Published: February 2015

Abstract
The majority of ovarian cancer patients acquire resistance to standard platinum chemotherapy and novel therapies to reduce tumor burden and ascites accumulation are needed. Pregnancy-associated plasma protein-A (PAPP-A) plays a key role in promoting insulin-like growth factor (IGF) pathway activity, which directly correlates to ovarian cancer cell transformation, growth, and invasiveness. Herein, we evaluate PAPP-A expression in tumors and ascites of women with ovarian cancer, and determine the antitumor efficacy of a neutralizing monoclonal PAPP-A antibody (mAb-PA) in ovarian cancer using primary patient ovarian tumorgrafts (“Ovatars”). PAPP-A mRNA expression in patient ovarian tumors correlated with poor outcome and was validated as a prognostic surrogate in Ovatar tumors. Following confirmation of mAb-PA bioavailability and target efficacy in vivo, the antitumor efficacy of mAb-PA in multiple Ovatar tumor models was examined and the response was found to depend on PAPP-A expression. Strikingly, the addition of mAb-PA to standard platinum chemotherapy effectively sensitized platinum-resistant Ovatar tumors. PAPP-A protein in ascites was also assessed in a large cohort of patients and very high levels were evident across the entire sample set. Therefore, we evaluated targeted PAPP-A inhibition as a novel approach to managing ovarian ascites, and found that mAb-PA inhibited the development, attenuated the progression, and induced the regression of Ovatar ascites. Together, these data indicate PAPP-A as a potential palliative and adjunct therapeutic target for women with ovarian cancer. Mol Cancer Ther; 14(4); 973–81. ©2015 AACR.
Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus
Authors: Liu Yingmiao , Starr Mark D. , Brady John C. , Rushing Christel , Bulusu Anuradha , Pang Herbert , Honeycutt Wanda , Amara Anthony , Altomare Ivy , Uronis Hope E. , Hurwitz Herbert I. , Nixon Andrew B. 
Published: February 2015

Abstract
A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (P &lt; 0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-α, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology. Mol Cancer Ther; 14(4); 1048–56. ©2015 AACR.
PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2
Authors: Kozlova Nina , Jensen Jan K. , Franklin Chi Tabughang , Samoylenko Anatoly , Kietzmann Thomas 
Published: February 2015

SummaryPlasminogen activator inhibitor-1 (PAI-1) is the major and most specific acting urokinase (uPA) and tissue plasminogen activator (tPA) inhibitor. Apart from its function in the fibrinolytic system, PAI-1 was also found to contribute to processes like tissue remodelling, angiogenesis, and tumour progression. However, the role of PAI-1 in those processes remains largely controversial with respect to the influence of PAI-1 on cell signalling pathways. Although PAI-1 does not possess its own cellular receptor, it can be bound to low-density lipoprotein receptor- related protein 1 (LRP1) which was proposed to modulate the β-catenin pathway. Therefore, we used wild-type mouse embryonic fibroblasts (MEFs), and MEFs deficient of LRP1 to study PAI-1 as modulator of the β-catenin pathway. We found that PAI-1 influences MEF proliferation and motility in a LRP1-dependent manner and that β-catenin is important for that response. In addition, expression of β-catenin and β-catenin-dependent transcriptional activity were induced by PAI-1 in wild type MEFs, but not in LRP1-deficient cells. Moreover, PAI-1-induced ERK1/2 activation was more prominent in the LRP1-deficient cells and interestingly knockdown of β-catenin abolished this effect. Together, the data of the current study show that PAI-1 can promote cell migration via LRP1-dependent activation of the β-catenin and ERK1/2 MAPK pathway which may be important in stage-specific treatment of human diseases associated with high PAI-1 levels.
Platelet adhesion to podoplanin under flow is mediated by the receptor CLEC-2 and stabilised by Src/Syk-dependent platelet signalling
Authors: Y. Pollitt Alice , Lowe Kate , Latif Arusa , B. Nash Gerard , P. Watson Steve , Navarro-Núñez Leyre 
Published: February 2015

SummaryPlatelet-specific deletion of CLEC-2, which signals through Src and Syk kinases, or global deletion of its ligand podoplanin results in bloodfilled lymphatics during mouse development. Platelet-specific Syk deficiency phenocopies this defect, indicating that platelet activation is required for lymphatic development. In the present study, we investigated whether CLEC-2-podoplanin interactions could support platelet arrest from blood flow and whether platelet signalling is required for stable platelet adhesion to lymphatic endothelial cells (LECs) and recombinant podoplanin under flow. Perfusion of human or mouse blood over human LEC monolayers led to platelet adhesion and aggregation. Following α∥bβ3 blockade, individual platelets still adhered. Platelet binding occurred at venous but not arterial shear rates. There was no adhesion using CLEC-2-deficient blood or to vascular endothelial cells (which lack podoplanin). Perfusion of human blood over human Fc-podoplanin (hFcPDPN) in the presence of monoclonal antibody IV.3 to block FcγR∥A receptors led to platelet arrest at similar shear rates to those used on LECs. Src and Syk inhibitors significantly reduced global adhesion of human or mouse platelets to LECs and hFcPDPN. A similar result was seen using Syk-deficient mouse platelets. Reduced platelet adhesion was due to a decrease in the stability of binding. In conclusion, our data reveal that CLEC-2 is an adhesive receptor that supports platelet arrest to podoplanin under venous shear. Src/Syk-dependent signalling stabilises platelet adhesion to podoplanin, providing a possible molecular mechanism contributing to the lymphatic defects of Syk-deficient mice.
Sit Verum Obligationes and Counterfactual Reasoning
Authors: Uckelman Sara L. 
Published: February 2015

In the early 1980s, Paul V. Spade advanced the thesis that obligational reasoning was counterfactual reasoning, based upon his interpretation of the obligationes of Walter Burley, Richard Kilvington, and Roger Swyneshed. Eleonore Stump in a series of contemporary papers argued against Spade’s thesis with respect to Burley and Swyneshed, provisionally admitting it for Kilvington with the caveat that Kilvington’s theory is by no means clear or non-idiosyncratic. In this paper, we revisit the connection between counterfactual reasoning and obligationes, focusing on one particular treatise, the anonymous early twelfth-century Obligationes Parisienses edited by L.M. de Rijk in the late 70s. We show that while positio in this treatise does not involve counterfactual reasoning, the species sit verum or rei veritas apparently does, and it is precisely this which distinguishes the two species in this treatise.
Description of Sheraphelenchus parabrevigulonis n. sp. (Nematoda: Aphelenchoididae) in pine wood packaging from Italy and redescription of S. sucus in onion bulbs from South Korea, isolated at Ningbo, China
Authors: Fang Yiwu , Gu Jianfeng , Wang Xuan , Wang Jianglin , Li Hongmei 
Published: February 2015

TwoSheraphelenchuspopulations were isolated from pine wood packaging from Italy and onion bulbs from South Korea at Ningbo Port, China, respectively. The former, on the basis of morphology and molecular sequencing, is described asS. parabrevigulonisn. sp., which is characterised by a stylet length of 11 μm, three lines in the lateral field, excretory pore at level with, or slightly posterior to, nerve ring, V = 93.1, and spicules with long condylus and membrane-like rostrum in a shallow triangular shape. The species from onion, also on the basis of morphology and sequence data, was identified asS. sucus, which is characterised by a stylet length of 13 μm (erroneously stated to beca6 μm in the type description), excretory pore at level of, or posterior to, median bulb, and V = 80.9. The phylogeny trees based on rDNA 18S, 28S D2-D3 and ITS1/2 sequences revealed thatS. parabrevigulonisn. sp. andS. sucusclustered into a clear clade and grouped withBursaphelenchusspecies. The study enriched the taxonomic information ofSheraphelenchusand confirmed its status as an independent genus.
Description and molecular characterisation of Xiphinema herakliense n. sp. (Nematoda: Longidoridae) from wild and cultivated olives in Crete
Authors: Tzortzakakis Emmanuel A. , Archidona-Yuste Antonio , Cantalapiedra-Navarrete Carolina , Nasiou Eleni , Palomares-Rius Juan E. , Castillo Pablo 
Published: February 2015

Xiphinema herakliensen. sp. from wild olive and cultivated trees in Vathy Rema and other localities, Heraklion province of Crete, Greece, is described based on morphological and molecular characters. The new species is characterised by having differentiation in the tubular part of the uterus, body length 4.1 (3.3-5.5) mm, odontostyle 149 (135-163) μm long, odontophore 85 (71-98) μm long, female tail dorsally convex-conoid with subdigitate peg, and presence of functional males. The polytomous identification code of the new species is: A4, B2 + 3, C5a, D6(5), E5, F4(5), G3, H2, I3, J5, K5, L2. The new species belongs to morphospeciesXiphinemanon-americanumGroup 5 characterised by having two equally developed female genital branches with uterine differentiation, presence of pseudo-Z-organ with small granular bodies plus small spines (in low number) and crystalloid bodies along uterus, and a short, rounded tail ending in a peg.Xiphinema herakliensen. sp. appears closely related toX. barense,X. horvatovicae,X. lanceolatum,X. loteni,X. sphaerocephalumandX. thorneanum, from which it may be differentiated morphologically and/or molecularly. The results of the phylogenetic analyses based on the sequences of the D2-D3 expansion regions of the 28S rRNA gene and ITS1 rRNA genes are also supportive of its specific status.
Evaluation of a Heuristic Model for Tropical Cyclone Resilience
Authors: Reasor Paul D. , Montgomery Michael T. 
Published: February 2015

Abstract
This work examines the applicability of a previously postulated heuristic model for the temporal evolution of the small-amplitude tilt of a tropical cyclone–like vortex under vertical shear forcing for both a dry and cloudy atmosphere. The heuristic model hinges on the existence of a quasi-discrete vortex Rossby wave and its ability to represent the coherent precession and tilt decay of a stable vortex in the free-alignment problem. Linearized numerical solutions for a dry and cloudy vortex confirm the model predictions that an increase in the magnitude of the radial potential vorticity (PV) gradient within the vortex skirt surrounding the core yields a more rapid evolution of a sheared vortex toward the equilibrium, left-of-shear tilt configuration. However, in the moist-neutral limit, in which the effective static stability vanishes in rising and sinking regions, the heuristic model yields a poor approximation to the simulated vortex core evolution, but a left-of-shear tilt of the near-core vortex, radially beyond the heating region, remains the preferred long-time solution. Within the near-core skirt, the PV perturbation generated by vertical shearing exhibits continuous-spectrum-type vortex Rossby waves, features that are not captured by the heuristic model. Nevertheless, the heuristic model continues to predict the rapid vertical alignment and equilibrium, left-of-shear tilt configuration of the simulated near-core vortex in the moist-neutral limit.
Interannual Variability in the Large-Scale Dynamics of the South Asian Summer Monsoon
Authors: Walker Jennifer M. , Bordoni Simona , Schneider Tapio 
Published: February 2015

Abstract
This study identifies coherent and robust large-scale atmospheric patterns of interannual variability of the South Asian summer monsoon (SASM) in observational data. A decomposition of the water vapor budget into dynamic and thermodynamic components shows that interannual variability of SASM net precipitation (P − E) is primarily caused by variations in winds rather than in moisture. Linear regression analyses reveal that strong monsoons are distinguished from weak monsoons by a northward expansion of the cross-equatorial monsoonal circulation, with increased precipitation in the ascending branch. Interestingly, and in disagreement with the view of monsoons as large-scale sea-breeze circulations, strong monsoons are associated with a decreased meridional gradient in the near-surface atmospheric temperature in the SASM region. Teleconnections exist from the SASM region to the Southern Hemisphere, whose midlatitude poleward eddy energy flux correlates with monsoon strength. Possible implications of these teleconnection patterns for understanding SASM interannual variability are discussed.
Estimating the Mean Diapycnal Mixing Using a Finescale Strain Parameterization
Authors: Whalen Caitlin B. , MacKinnon Jennifer A. , Talley Lynne D. , Waterhouse Amy F. 
Published: February 2015

AbstractFinescale methods are currently being applied to estimate the mean turbulent dissipation rate and diffusivity on regional and global scales. This study evaluates finescale estimates derived from isopycnal strain by comparing them with average microstructure profiles from six diverse environments including the equator, above ridges, near seamounts, and in strong currents. The finescale strain estimates are derived from at least 10 nearby Argo profiles (generally <60 km distant) with no temporal restrictions, including measurements separated by seasons or decades. The absence of temporal limits is reasonable in these cases, since the authors find the dissipation rate is steady over seasonal time scales at the latitudes being considered (0°–30° and 40°–50°). In contrast, a seasonal cycle of a factor of 2–5 in the upper 1000 m is found under storm tracks (30°–40°) in both hemispheres. Agreement between the mean dissipation rate calculated using Argo profiles and mean from microstructure profiles is within a factor of 2–3 for 96% of the comparisons. This is both congruous with the physical scaling underlying the finescale parameterization and indicates that the method is effective for estimating the regional mean dissipation rates in the open ocean.
Vertical Wind Disturbances during a Strong Wind Event Observed by the PANSY Radar at Syowa Station, Antarctica
Authors: Tomikawa Yoshihiro , Nomoto Masahiro , Miura Hiroaki , Tsutsumi Masaki , Nishimura Koji , Nakamura Takuji , Yamagishi Hisao , Yamanouchi Takashi , Sato Toru , Sato Kaoru 
Published: February 2015

Abstract
Characteristically strong vertical wind disturbances (VWDs) with magnitudes larger than 1 m s−1 were observed in the Antarctic troposphere using a new mesosphere–stratosphere–troposphere (MST) radar called the Program of the Antarctic Syowa MST/incoherent scatter (IS) Radar (PANSY) during 15–19 June 2012 at Syowa Station (69.0°S, 39.6°E). In the same period, two synoptic-scale cyclones approached Syowa Station and caused a strong wind event (SWE) at the surface. The VWDs observed during the SWE at Syowa Station had a nearly standing (i.e., no phase tilt with height) phase structure up to the tropopause and a power spectrum proportional to the − power of frequency. On the other hand, the observed VWDs were not associated with systematic horizontal momentum fluxes. Meteorological fields around Syowa Station during the SWE were successfully simulated using the Nonhydrostatic Icosahedral Atmospheric Model (NICAM). A strong VWD was also simulated at the model grid of 70.0°S, 40.0°E in NICAM, which had a standing phase structure similar to the observed ones. An analysis based on the Froude number showed that the simulated VWD was likely due to a hydraulic jump leeward of the coastal mountain ridge. The Scorer parameter analysis indicated that the observed VWDs at Syowa Station during 16–17 June 2012 were likely due to the hydraulic jump similar to that in NICAM. On the other hand, a possibility of lee waves was also suggested for the VWD observed on 18 June 2012.
Genesis, Uses, and Significations of the Nunca Más Report in Argentina
Authors: Crenzel Emilio 
Published: February 2015

The Nunca Más (Never Again) report was prepared by Argentina’s Comisión Nacional sobre la Desapareción de Personas (National Commission on the Disappearance of Persons), created in 1983 to investigate the fate of thousands of persons who were disappeared during the dictatorship. It was used in the prosecution of the military juntas, to convey the past to the new generations, and as a model for the reports of truth commissions established in other Latin American countries. Because of its canonical nature, it illustrates the politics of memory regarding forced disappearances in Argentina following the return to democracy. La Comisión Nacional sobre la Desaparición de Personas fue creada en 1983 para investigar el paradero de las miles de personas que fueron desaparecidas durante la dictadura en Argentina. Su informe Nunca Más sirvió para procesar a las juntas militares y dar a conocer el pasado a las nuevas generaciones y como modelo para los informes de las comisiones de la verdad que se establecieron en otros países latinoamericanos. Debido a su carácter canónico, sirve para ilustrar las políticas de la memoria sobre las desapariciones forzadas en la Argentina después del regreso de la democracia.
Anemia and Transfusion in Critical Care
Authors: Spinelli Elena , Bartlett Robert H. 
Published: February 2015

Objective: The objective of this report is to review the physiology and management of anemia in critical care. Selected publications on physiology and transfusion related to anemia and critical care, including the modern randomized trials of conservative versus liberal transfusion policy, were used. Anemia is compensated and tolerated in most critically ill patients as long as oxygen delivery is at least twice oxygen consumption. There are risks to blood transfusion which can be minimized by blood banking practice. The availability of cultured red cells may allow correction of anemia without significant risk. The benefit of transfusion in anemia must be weighted against the risk in any specific patient. Conclusion and Recommendation: In a criticially ill patient, anemia should be managed to avoid oxygen supply dependency (oxygen delivery less than twice comsumption) and to maintain moderate oxygen delivery reserve (DO2/VO2 > 3).