bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 1 Pharmacokinetic and Pharmacodynamic Study of the Histone Deacetylase Inhibitor Belinostat in Patients with Advanced Solid Tumors
Authors: Steele Nicola L. , Plumb Jane A. , Vidal Laura , Tjørnelund Jette , Knoblauch Poul , Rasmussen Annie , Ooi Chean Eng , Buhl-Jensen Peter , Brown Robert , Evans T.R. Jeffry , DeBono Johann S. 
Published: February 2008

Abstract
Purpose: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors.
Experimental Design: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels.
Results: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m2/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m2; one patient at 1,200 mg/m2), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m2), grade 3 atrial fibrillation (one patient at 1,200 mg/m2; one patient at 1,000 mg/m2), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m2). The maximum tolerated dose was 1,000 mg/m2/d. I.v. belinostat displayed linear pharmacokinetics with respect to Cmax and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for ≥4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m2/d), 50% achieved stable disease.
Conclusions: I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.
T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome
Authors: Baleydier Frederic , Decouvelaere Anne-Valerie , Bergeron Julie , Gaulard Philippe , Canioni Danielle , Bertrand Yves , Lepretre Stephane , Petit Barbara , Dombret Herve , Beldjord Kheira , Molina Thierry , Asnafi Vahid , Macintyre Elizabeth 
Published: February 2008

Abstract
Purpose: T lymphoblastic lymphomas (T-LBL) are rare disorders of immature T cells which predominantly involve the mediastinum. Their oncogenic pathways and prognostic variables are not clear.
Experimental Design: We undertook a retrospective study of 41 cytoplasmic CD3+ T-LBL (nine cases aged &lt;16 years) by assessing stage of maturation arrest based on T cell receptor (TCR) immunogenotyping, immunohistochemistry, and quantification of the oncogenes thought to be important in immature T cell malignancies.
Results: Application of a TCR-based immunogenetic classification allowed the identification of three subcategories: 11 immature IM0/D-LBL showed no TCR or only incomplete TCRD DJ rearrangement and corresponded to cytoplasmic CD3+ precursors of uncertain lineage. Sixteen mature TCRDdel-LBL showed biallelic TCRD deletion and both TCRG and TCRB rearrangement, consistent with TCRαβ lineage restriction. Fourteen intermediate LBL (Int-LBL) showed complete TCRD VDJ and TCRG VJ rearrangement, with TCRB VDJ rearrangement in the majority. All Int-LBL expressed HOX11/TLX1 or HOXA9 transcripts and a proportion of the latter were associated with CALM-AF10 or NUP214-ABL fusion transcripts. IM0/D-LBL were restricted to adults with extrathymic disease and bone marrow involvement, whereas Int-LBL and TCRDdel-LBL were found in children and adults with predominantly thymic disease. In adults, the Int-LBL subgroup was associated with a significantly superior clinical outcome. This subgroup can be identified either by TCR immunogenotyping or HOXA9/TLX1 transcript quantification.
Conclusion: Application of this molecular classification will allow the prospective evaluation of prognostic effects within pediatric and adult protocols.
An Exploratory Study of Systemic Administration of the Toll-like Receptor-7 Agonist 852A in Patients with Refractory Metastatic Melanoma
Authors: Dummer Reinhard , Hauschild Axel , Becker Juergen C. , Grob Jean-Jacques , Schadendorf Dirk , Tebbs Veronica , Skalsky Jeannine , Kaehler Katharina C. , Moosbauer Stephanie , Clark Ruth , Meng Tze-Chiang , Urosevic Mirjana 
Published: February 2008

Abstract
Purpose: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma.
Experimental Design: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m2 and increasing to 0.9 mg/m2 based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood.
Results: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for &gt;100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m2 than after 0.6 mg/m2 (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007).
Conclusion: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy.
Imaging Epidermal Growth Factor Receptor Expression In vivo: Pharmacokinetic and Biodistribution Characterization of a Bioconjugated Quantum Dot Nanoprobe
Authors: Diagaradjane Parmeswaran , Orenstein-Cardona Jacobo M. , E. Colón-Casasnovas Norman , Deorukhkar Amit , Shentu Shujun , Kuno Norihito , Schwartz David L. , Gelovani Juri G. , Krishnan Sunil 
Published: February 2008

Abstract
Purpose: To develop and validate an optical imaging nanoprobe for the discrimination of epidermal growth factor (EGF) receptor (EGFR)–overexpressing tumors from surrounding normal tissues that also expresses EGFR.
Experimental Design: Near-infrared (NIR) quantum dots (QD) were coupled to EGF using thiol-maleimide conjugation to create EGF-QD nanoprobes. In vitro binding affinity of these nanoprobes and unconjugated QDs was evaluated in a panel of cell lines, with and without anti-EGFR antibody pretreatment. Serial optical imaging of HCT116 xenograft tumors was done after systemic injection of QD and EGF-QD.
Results: EGF-QD showed EGFR-specific binding in vitro. In vivo imaging showed three distinct phases, tumor influx (∼3 min), clearance (∼60 min), and accumulation (1-6 h), of EGF-QD nanoprobes. Both QD and EGF-QD showed comparable nonspecific rapid tumor influx and clearance followed by attainment of an apparent dynamic equilibrium at ∼60 min. Subsequently (1-6 h), whereas QD concentration gradually decreased in tumors, EGF-QDs progressively accumulated in tumors. On delayed imaging at 24 h, tumor fluorescence decreased to near-baseline levels for both QD and EGF-QD. Ex vivo whole-organ fluorescence, tissue homogenate fluorescence, and confocal microscopic analyses confirmed tumor-specific accumulation of EGF-QD at 4 h. Immunofluorescence images showed diffuse colocalization of EGF-QD fluorescence within EGFR-expressing tumor parenchyma compared with patchy perivascular sequestration of QD.
Conclusion: These results represent the first pharmacokinetic characterization of a robust EGFR imaging nanoprobe. The measurable contrast enhancement of tumors 4 h after systemic administration of EGF-QD and its subsequent normalization at 24 h imply that this nanoprobe may permit quantifiable and repetitive imaging of EGFR expression.
Inhibition of Plasminogen Activator Inhibitor-1
Authors: Izuhara Yuko , Takahashi Satoru , Nangaku Masaomi , Takizawa Shunya , Ishida Hideyuki , Kurokawa Kiyoshi , van Ypersele de Strihou Charles , Hirayama Noriaki , Miyata Toshio 
Published: February 2008

Objective—Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Inhibition of serpins may prove therapeutic. As yet, however, only very few small molecule serpin inhibitors have been reported. For the first time, we apply a new approach of virtual screening to discover novel, orally active, small molecule serpin inhibitors and report their effectiveness.Methods and Results—We focused on a clinically important serpin, plasminogen activator inhibitor-1 (PAI-1), whose crystal structure has been described. We identify novel, orally active molecules able to enter into the strand 4 position (s4A) of the A β-sheet of PAI-I as a mock compound. In vitro they specifically inhibit the PAI-1 activity and enhance fibrinolysis activity. In vivo the most effective molecule (TM5007) inhibits coagulation in 2 models: a rat arteriovenous (AV) shunt model and a mouse model of ferric chloride–induced testicular artery thrombosis. It also prevents the fibrotic process initiated by bleomycin in mouse lung.Conclusions—The present study demonstrates beneficial in vitro and in vivo effects of novel PAI-1 inhibitors. Our methodology proves to be a useful tool to obtain effective inhibitors of serpin activity.
A Scholar in the Company of Female Entertainers: Changing Notions of Integrity in Song to Ming Dynasty Painting
Authors: Blanchard Lara 
Published: February 2008

AbstractThe Ming dynasty painting Su Dongpo Returning to the Hanlin Academy represents an important departure from earlier images of prominent scholars, demonstrating how the visual tropes associated with integrity change over time. First, it depicts the eleventh-century official following his reinstatement in the capital, quite a change from Song and Yuan images of men of integrity retiring to the wilderness. Second, many female entertainers accompany him, a juxtaposition considered inappropriate for viewing in previous periods but increasingly popular in Ming painting. This paper proposes that by the mid-Ming dynasty, the figure of the female entertainer specifically connotes an urban setting, and, when paired with a scholar, suggests the high-minded and untrammeled qualities of the court or city hermit.
Words of Seduction, Lines of Resistance: Writing and Gender in Zheng Xi's Dream of Spring (1318)
Authors: de Pee Christian 
Published: February 2008

AbstractThis article contains a full, annotated translation of A Dream of Spring (Chunmeng lu), written in 1318 by Zheng Xi (1324 jinshi). In A Dream of Spring, Zheng Xi, despite being married, accepts a matchmaker's request to submit a poem to the family of Miss Wu. In the ensuing correspondence with Miss Wu, Zheng Xi uses his masculine literary prerogative to compromise her chastity, which she struggles to defend by the more stringent conventions of feminine composition. The analysis of this fourteenth-century story supplements studies of gendered subjects in the literature of the late Ming and Qing dynasties.
Reconstructing Religions: Jewish place and space in the Jerusalem YMCA Building, 1919-1933
Authors: Gitler Inbal Ben-Asher 
Published: February 2008

AbstractThis paper discusses the representation of Jewish religion and culture in the architecture of the YMCA Building in Jerusalem, a prominent edifice built by the New York architect Arthur Loomis Harmon for the American YMCA. Within it, Jewish place and space were reconstructed as part of an architecture planned to promote Jewish, Christian and Moslem co-existence through an American secular cultural curriculum and a Christian vision of peace.
Distribución sociométrica en las aulas de chicos y chicas a lo largo de la escolaridad
Authors: García-Bacete Francisco-Juan , Sureda Inmaculada , Monjas Inés 
Published: February 2008

La muestra está formada por 2173 alumnos escolarizados (45.7% eran chicas y el 54.3% chicos) en 92 aulas de todos los cursos desde el segundo ciclo de infantil al primer ciclo de secundaria, de 24 colegios públicos de Castellón, Valladolid y Palma de Mallorca. Chicos y chicas son sociométricamente diferentes en todos los ciclos. Ellos son más rechazados y controvertidos y ellas más ignoradas y promedio. Sólo la proporción entre chicos-controvertidos y chicas-controvertidas varía en la escolaridad. La distribución sociométrica de los chicos es estable durante toda la escolaridad, la de las chica cambia (menos preferidas al principio y final de la escolaridad y más controvertidas en secundaria). El rechazo está asociado al género masculino. Hay variaciones en la distribución sociométrica de un aula a otra.
The Stationary Frontal Wave Packet Spontaneously Generated in Mesoscale Dipoles
Authors: Viúdez Álvaro 
Published: February 2008

Abstract
Three-dimensional numerical simulations of rotating, statically and inertially stable, mesoscale flows show that wave packets, with vertical velocity comparable to that of the balanced flow, can be spontaneously generated and amplified in the frontal part of translating vortical structures. These frontal wave packets remain stationary relative to the vortical structure (e.g., in the baroclinic dipole, tripole, and quadrupole) and are due to inertia–gravity oscillations, near the inertial frequency, experienced by the fluid particles as they decelerate when leaving the large speed regions. The ratio between the horizontal and vertical wavenumbers depends on the ratio between the horizontal and vertical shears of the background velocity. Theoretical solutions of plane waves with varying wavenumbers in background flow confirm these results. Using the material description of the fields it is shown that, among the particles simultaneously located in the vertical column in the dipole’s center, the first ones to experience the inertia–gravity oscillations are those in the upper layer, in the region of the maximum vertical shear. The wave packet propagates afterward to the fluid particles located below.
Tropical Atlantic Decadal Oscillation and Its Potential Impact on the Equatorial Atmosphere–Ocean Dynamics: A Simple Model Study
Authors: Lee Sang-Ki , Wang Chunzai 
Published: February 2008

Abstract
Simple coupled atmosphere–ocean models are used to study the potential influence of the tropical Atlantic Ocean decadal oscillation on the equatorial Atlantic atmosphere–ocean dynamics. Perturbing the model tropical Atlantic at the extratropics (25°–30°) with a decadal frequency, interhemispheric SST dipole mode emerges due to the wind–evaporation–SST feedback. Near the equator, a cross-equatorial oceanic gyre develops owing to the dipole-induced wind stress curl. Once formed, this oceanic gyre transports surface water across the equator from the cold to the warm hemisphere in the western boundary region and from the warm to the cold hemisphere in the Sverdrup interior. Interestingly, this occurs during both the positive and negative phases of the dipole oscillation, thus producing a persistent positive zonal SST gradient along the equator. Bjerknes-type feedback later kicks in to further strengthen the equatorial SST anomaly. Eventually, this feature grows to a quasi-stationary stage sustaining the equatorial westerly wind anomalies, thus also causing the depression (uplift) of the equatorial thermocline in the east (west), a condition similar to the Atlantic Niño. The dynamic relationship between the dipole SST oscillation and the equatorial thermocline suggests that a strengthening (weakening) of the dipole mode corresponds to a weakening (strengthening) of the equatorial thermocline slope.
Eddy Modulation of Air–Sea Interaction and Convection
Authors: Cerovečki Ivana , Marshall John 
Published: February 2008

Abstract
Eddy modulation of the air–sea interaction and convection that occurs in the process of mode water formation is analyzed in simulations of a baroclinically unstable wind- and buoyancy-driven jet. The watermass transformation analysis of Walin is used to estimate the formation rate of mode water and to characterize the role of eddies in that process. It is found that diabatic eddy heat flux divergences in the mixed layer are comparable in magnitude, but of opposite sign, to the surface air–sea heat flux and largely cancel the direct effect of buoyancy loss to the atmosphere. The calculations suggest that mode water formation estimates based on climatological air–sea heat flux data and outcrops, which do not fully resolve ocean eddies, may neglect a large opposing term in the heat budget and are thus likely to significantly overestimate true formation rates. In Walin’s watermass transformation framework, this manifests itself as a sensitivity of formation rate estimates to the averaging period over which the outcrops and air–sea fluxes are subjected. The key processes are described in terms of a transformed Eulerian-mean formalism in which eddy-induced mean flow tends to cancel the Eulerian-mean flow, resulting in weaker residual mean flow, subduction, and mode water formation rates.
Brine-Driven Eddies under Sea Ice Leads and Their Impact on the Arctic Ocean Mixed Layer
Authors: Matsumura Yoshimasa , Hasumi Hiroyasu 
Published: February 2008

Abstract
Eddy generation induced by a line-shaped salt flux under a sea ice lead and associated salt transport are investigated using a three-dimensional numerical model. The model is designed to represent a typical condition for the wintertime Arctic Ocean mixed layer, where new ice formation within leads is known to be one of the primary sources of dense water. The result shows that along-lead baroclinic jets generate anticyclonic eddies at the base of the mixed layer, and almost all the lead-originated salt is contained inside these eddies. These eddies survive for over a month after closing of the lead and transport the lead-originated salt laterally. Consequently, the lead-origin salt settles only on the top of the halocline and is not used for increasing salinity of the mixed layer. Sensitivity experiments suggest that the horizontal scale of generated eddies depends only on the surface forcing and is proportional to the cube root of the total amount of salt input. This scaling of eddy size is consistent with a theoretical argument based on a linear instability theory. Parameterizing these processes would improve representation of the Arctic Ocean mixed layer in ocean general circulation models.
On Quadratic Bottom Drag, Geostrophic Turbulence, and Oceanic Mesoscale Eddies
Authors: Arbic Brian K. , Scott Robert B. 
Published: February 2008

Abstract
Many investigators have idealized the oceanic mesoscale eddy field with numerical simulations of geostrophic turbulence forced by a horizontally homogeneous, baroclinically unstable mean flow. To date such studies have employed linear bottom Ekman friction (hereinafter, linear drag). This paper presents simulations of two-layer baroclinically unstable geostrophic turbulence damped by quadratic bottom drag, which is generally thought to be more realistic. The goals of the paper are 1) to describe the behavior of quadratically damped turbulence as drag strength changes, using previously reported behaviors of linearly damped turbulence as a point of comparison, and 2) to compare the eddy energies, baroclinicities, and horizontal scales in both quadratic and linear drag simulations with observations and to discuss the constraints these comparisons place on the form and strength of bottom drag in the ocean. In both quadratic and linear drag simulations, large barotropic eddies develop with weak damping, large equivalent barotropic eddies develop with strong damping, and the comparison in goal 2 above is closest when the nondimensional friction strength parameter is of order 1. Typical values of the quadratic drag coefficient (cd ∼ 0.0025) and of boundary layer depths (Hb ∼ 50 m) imply that the quadratic friction strength parameter cdLd/Hb, where Ld is the deformation radius, may indeed be of order 1 in the ocean. Model eddies are realistic over a wider range of friction strengths when drag is quadratic, because of a reduced sensitivity to friction strength in that case. The quadratic parameter is independent of the mean shear, in contrast to the linear parameter. Plots of eddy length scales, computed from satellite altimeter data, versus mean shear and versus rough estimates of the friction strength parameters suggest that both linear and quadratic bottom drag may be active in the ocean. Topographic wave drag contains terms that are linear in the bottom flow, thus providing some justification for the use of linear bottom drag in models.
Mesoscale to Submesoscale Transition in the California Current System. Part II: Frontal Processes
Authors: Capet X. , McWilliams J. C. , Molemaker M. J. , Shchepetkin A. F. 
Published: February 2008

Abstract
This is the second of three papers investigating the regime transition that occurs in numerical simulations for an idealized, equilibrium, subtropical, eastern boundary, upwelling current system similar to the California Current. The emergent upper-ocean submesoscale fronts are analyzed from phenomenological and dynamical perspectives, using a combination of composite averaging and separation of distinctive subregions of the flow. The initiating dynamical process for the transition is near-surface frontogenesis. The frontal behavior is similar to both observed meteorological surface fronts and solutions of the approximate dynamical model called surface dynamics (i.e., uniform interior potential vorticity q and diagnostic force balance) in the intensification of surface density gradients and secondary circulations in response to a mesoscale strain field. However, there are significant behavioral differences compared to the surface-dynamics model. Wind stress acts on fronts through nonlinear Ekman transport and creation and destruction of potential vorticity. The strain-induced frontogenesis is disrupted by vigorous submesoscale frontal instabilities that in turn lead to secondary frontogenesis events, submesoscale vortices, and excitation of even smaller-scale flows. Intermittent, submesoscale breakdown of geostrophic and gradient-wind force balance occurs during the intense frontogenesis and frontal-instability events.