bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway Improves Response of Long-term Estrogen-Deprived Breast Cancer Xenografts to Antiestrogens
Authors: Sabnis Gauri , Goloubeva Olga , Jelovac Danijela , Schayowitz Adam , Brodie Angela 
Published: May 2007

Abstract
Purpose: Aromatase inhibitors that block the synthesis of estrogen are proving to be superior to antiestrogens and may replace tamoxifen as first-line treatment for postmenopausal estrogen receptor (ER)–positive breast cancer patients. However, acquisition of resistance to all forms of treatments is inevitable and a major clinical concern. In this study, we have investigated the effects of long-term estrogen deprivation in the breast cancer xenograft model and whether sensitivity to antiestrogens can be restored in vivo. We also compared whether combining wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone.
Experimental Design: Long-term estrogen-deprived aromatase-transfected human ER-positive breast cancer cells (UMB-1Ca) were grown as tumors in ovariectomized athymic nude mice. Twelve weeks after inoculation, when tumors reached 300 mm3, animals were grouped and injected with vehicle, Δ4A, letrozole, tamoxifen, fulvestrant, wortmannin, tamoxifen plus wortmannin, and wortmannin plus fulvestrant. Tumor volumes were measured weekly.
Results: Tumors of UMB-1Ca cells grew equally well with and without androstenedione, indicating the ability of the cells to proliferate in the absence of estrogen. The combination of wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone. The combination of wortmannin plus fulvestrant was the most effective treatment that maintained tumor regression for a prolonged time.
Conclusion: These results suggest that blocking both ER and growth factor receptor pathways could provide effective control over tumor growth of long-term estrogen-deprived human breast cancers.
A Cross-sectional Study of a Prototype Carcinogenic Human Papillomavirus E6/E7 Messenger RNA Assay for Detection of Cervical Precancer and Cancer
Authors: Castle Philip E. , Dockter Janel , Giachetti Cristina , Garcia Francisco A.R. , McCormick Mary Kay , Mitchell Amy L. , Holladay E. Blair , Kolk Daniel P. 
Published: May 2007

Abstract
Purpose: To evaluate carcinogenic human papillomavirus (HPV) mRNA for E6 and E7 mRNA detection on clinical specimens to identify women with cervical precancer and cancer.
Experimental Design: We evaluated a prototype assay that collectively detects oncogenes E6/E7 mRNA for 14 carcinogenic HPV genotypes on a sample of liquid cytology specimens (n = 531), masked to clinical data and to the presence of HPV genotypes detected by PGMY09/11 L1 consensus primer PCR assay.
Results: We found an increasing likelihood of testing positive for carcinogenic HPV E6/E7 mRNA with increasing severity of cytology (PTrend &lt; 0.0001) and histology (PTrend &lt; 0.0001), with 94% of cervical intraepithelial neoplasia grade 3 (CIN3) histology cases (46 of 49) and all five cancer cases testing positive for carcinogenic HPV E6/E7 mRNA. Overall, fewer specimens tested positive for carcinogenic HPV E6/E7 mRNA than for carcinogenic HPV DNA (P &lt; 0.0001, McNemar's χ2 test), especially in women with &lt;CIN1 (P &lt; 0.0001). We also found that using a higher positive cutpoint for detection of carcinogenic HPV E6/E7 mRNA improved the association of positive test results with cervical precancer and cancer by reducing the number of test positives in women without precancer without reducing clinical sensitivity for cervical precancer and cancer compared with detection of carcinogenic HPV E6/E7 mRNA using a lower positive cutpoint by the same assay and with detection of carcinogenic HPV DNA.
Conclusions: We found that carcinogenic HPV E6/E7 mRNA is a potentially useful biomarker for detection of cervical precancer and cancer and warrants further evaluation.
Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer
Authors: Adjei Alex A. , Molina Julian R. , Mandrekar Sumithra J. , Marks Randolph , Reid Joel R. , Croghan Gary , Hanson Lorelei J. , Jett James R. , Xia Chenghua , Lathia Chetan , Simantov Ronit 
Published: May 2007

AbstractPurpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced non–small cell lung cancer.Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed.Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib Cmax (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease ≥4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily.Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non–small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.
Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma
Authors: Azuma Yumiko , Ishikawa Yuji , Kawai Shigeto , Tsunenari Toshiaki , Tsunoda Hiroyuki , Igawa Tomoyuki , Iida Shin-ichiro , Nanami Masahiko , Suzuki Masami , Irie Reiko F. , Tsuchiya Masayuki , Yamada-Okabe Hisafumi 
Published: May 2007

AbstractPurpose: L612, a human IgM monoclonal antibody produced by an EBV-transformed human B-cell line, binds to ganglioside GM3 and kills GM3-positive human melanoma cells in the presence of complement. It has been shown to be effective in some patients with late-stage melanoma. L612 consists of hexameric IgM (about 20%), pentameric IgM (about 74%), and other minor IgM molecules. Because hexameric IgM activates complement more effectively than pentameric IgM, we developed and evaluated a hexamer-dominant recombinant IgM for clinical applications.Experimental Design: Chinese hamster ovary (CHO) cells were transfected with heavy- and light-chain genes of L612, with or without the joining-chain gene. Antitumor effects of the recombinant IgM secreted from CHO cells were evaluated in vitro and in vivo.Results: Recombinant IgM secreted from CHO cells without the joining chain (designated CA19) was ∼80% hexameric, whereas recombinant IgM from CHO cells transfected with heavy-, light-, and joining-chain genes (designated CJ45) was about 90% pentameric. Both CA19 and CJ45 recombinant IgMs caused complement-dependent cytotoxicity against human and mouse melanoma cell lines, but the amount of CA19 required for 50% specific cytotoxicity was 5 to 10 times smaller. I.v. injection of CA19 compared with CJ45 or native L612 elicited more profound antitumor activity in nude rats bearing a GM3-positive mouse melanoma xenograft.Conclusions: A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.
Phase I Evaluation of J591 as a Vascular Targeting Agent in Progressive Solid Tumors
Authors: Morris Michael J. , Pandit-Taskar Neeta , Divgi Chaitanya R. , Bender Samantha , O'Donoghue Joseph A. , Nacca Angelo , Smith-Jones Peter , Schwartz Lawrence , Slovin Susan , Finn Ronald , Larson Steven , Scher Howard I. 
Published: May 2007

Abstract
Purpose: The antibody J591 targets the external domain of prostate-specific membrane antigen, which is expressed in the neovasculature of nonprostate solid tumors. This phase I trial tested the hypothesis that J591 could be used as a vascular targeting platform for patients with nonprostate solid tumors.
Experimental Design: Patients with progressive solid tumors were eligible. Twenty patients, divided into six dosage cohorts of 3 to 6 patients each, were treated every 3 weeks to a maximum of four doses using either 5, 10, 20, 40, 60, or 100 mg of J591 antibody. Two milligrams of antibody were labeled with 10 mCi of indium-111.
Results: Patients with a wide variety of solid tumors were tested; all had good tumor localization. No dose-limiting toxicities were observed. The serum clearance rate decreased with increasing antibody mass, likely a result of early hepatic uptake of antibody. Half-life for each successive cohort was 0.71, 0.84, 1.86, 1.83, 3.32, and 3.56 days. Hepatic saturation seemed to occur by 60 mg. Seventeen of 18 (94%) patients with soft tissue disease on standard scans showed uptake in the soft tissues on antibody scans as did 6 of 6 patients with bone disease.
Conclusions: The tumoral neovasculature of a variety of solid tumors can be selectively and safely targeted using J591. In planning for future studies using J591 as a radiation delivery platform, an antibody mass of 60 mg should be considered, as it would seem to minimize the radiation delivered to the liver while minimizing the radiation dose to bone.
ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models
Authors: Donawho Cherrie K. , Luo Yan , Luo Yanping , Penning Thomas D. , Bauch Joy L. , Bouska Jennifer J. , Bontcheva-Diaz Velitchka D. , Cox Bryan F. , DeWeese Theodore L. , Dillehay Larry E. , Ferguson Debra C. , Ghoreishi-Haack Nayereh S. , Grimm David R. , Guan Ran , Han Edward K. , Holley-Shanks Rhonda R. , Hristov Boris , Idler Kenneth B. , Jarvis Ken , Johnson Eric F. , Kleinberg Lawrence R. , Klinghofer Vered , Lasko Loren M. , Liu Xuesong , Marsh Kennan C. , McGonigal Thomas P. , Meulbroek Jonathan A. , Olson Amanda M. , Palma Joann P. , Rodriguez Luis E. , Shi Yan , Stavropoulos Jason A. , Tsurutani Alan C. , Zhu Gui-Dong , Rosenberg Saul H. , Giranda Vincent L. , Frost David J. 
Published: May 2007

Abstract
Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888.
Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.
Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with Kis of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d × 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity.
Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
A Correction for Land Contamination of Atmospheric Variables near Land–Sea Boundaries*
Authors: Kara A. Birol , Wallcraft Alan J. , Hurlburt Harley E. 
Published: May 2007

Abstract
Ocean models need over-ocean atmospheric forcing. However, such forcing is not necessarily provided near the land–sea boundary because 1) the atmospheric model grid used for forcing is frequently much coarser than the ocean model grid, and 2) some of the atmospheric model grid over the ocean includes land values near coastal regions. This paper presents a creeping sea-fill methodology to reduce the improper representation of scalar atmospheric forcing variables near coastal regions, a problem that compromises the usefulness of the fields for ocean model simulations and other offshore applications. For demonstration, atmospheric forcing variables from archived coarse-resolution gridded products—the 1.125° × 1.125° 15-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-15) and 1.0° × 1.0° Navy Operational Global Atmospheric Prediction System (NOGAPS)—are used here. A fine-resolution [1/25° × 1/25° cos(lat)], (longitude × latitude) (∼3.2 km) eddy-resolving Black Sea Hybrid Coordinate Ocean Model (HYCOM) is then forced with/without sea-filled atmospheric variables from these gridded products to simulate monthly mean climatological sea surface temperature (SST). Using only over-ocean values from atmospheric forcing fields in the ocean model simulations significantly reduces the climatological mean SST bias (by ∼1°–3°C) and rms SST difference over the seasonal cycle (by ∼2°–3°C) in coastal regions. Performance of the creeping sea-fill methodology is also directly evaluated using measurements of wind speed at 10 m above the surface from the SeaWinds scatterometer on the NASA Quick Scatterometer (QuikSCAT) satellite. Comparisons of original monthly mean wind speeds from operational ECMWF and NOGAPS products with those from QuikSCAT give basin-averaged rms differences of 1.6 and 1.4 m s−1, respectively, during 2000–03. Similar comparisons performed with sea-filled monthly mean wind speeds result in a much lower rms difference (0.7 m s−1 for both products) during the same time period, clearly confirming the accuracy of the methodology even on interannual time scales. Most of the unrealistically low wind speeds from ECMWF and NOGAPS near coastal boundaries are appropriately corrected with the use of the creeping sea fill. Wind speed errors for ECWMF and NOGAPS (mean bias of ≥ 2.5 m s−1 with respect to QuikSCAT during 2000–03) are substantially eliminated (e.g., almost no bias) near most of the land–sea boundaries. Finally, ocean, atmosphere, and coupled atmospheric–oceanic modelers need to be aware that the creeping sea fill is a promising methodology in significantly reducing the land contamination resulting from an improper land–sea mask existing in gridded coarse-resolution atmospheric products (e.g., ECMWF).
Scale Evolution of Finite-Amplitude Instabilities on a Coastal Upwelling Front
Authors: Durski Scott M. , Allen J. S. , Egbert G. D. , Samelson R. M. 
Published: May 2007

Abstract
Nonlinear model simulations of a coastal upwelling system show frontal instabilities that initiate at short alongshore scales but rapidly evolve to longer wavelengths. Several factors associated with the nonstationarity of this basic state contribute to the progression in scale. A portion of the system evolution is associated with the external forcing. Another portion is associated with the alteration of the alongshore mean flow resulting from wave growth. Direct interactions between the finite-amplitude disturbances also promote emergence of new scales. The relative role of each of these mechanisms is isolated through tangent linear simulations about basic states that approximate the nonlinear system to differing degrees. The basic states include an alongshore uniform time-evolving upwelling solution, the alongshore average of a three-dimensionally evolving upwelling solution, and the full three-dimensional nonlinear solution. Disturbance growth about a frozen-field upwelling state is also examined. Perturbation experiments are performed for persistent and relaxed wind forcing. Although the frontal disturbances in the nonlinear model exhibit a progression to larger scale over the full range of forcing scenarios considered, the mechanisms most responsible for the process differ between wind-forced and unforced cases. Under relaxed wind conditions, the perturbation growth experiments indicate that the scale evolution over the first four days is reflected in the way linear disturbances respond to the adjustment of an alongshore uniform upwelling front to wind cessation. The continued increase in scale between days 4 and 7 is related to the linear disturbance evolution on the alongshore average of a flow state that has been altered by wave–mean flow interaction. Past day 7, the observed scale change is not captured in the linear growth experiments and evidently results largely from nonlinear wave–wave interaction processes. Under sustained upwelling winds, the linear growth experiments fail to describe even the earliest scale change in the nonlinear solutions, indicating that nonlinear wave–wave effects are significant from very near the start of the simulations.
Eddy Amplitudes in Baroclinic Turbulence Driven by Nonzonal Mean Flow: Shear Dispersion of Potential Vorticity
Authors: Smith K. Shafer 
Published: May 2007

Abstract
As in the midlatitude atmosphere, midocean eddies are primarily generated by baroclinically unstable mean currents. In contrast to the atmosphere, however, oceanic currents are significantly nonzonal. Even weak nonzonal currents are linearly unstable since β does not suppress growing meridional waves. Theories for the nonlinear equilibration of baroclinic instability, and hence theories for the amplitudes of midocean eddies, must therefore take into account the different dynamics of nonzonal flow. It is shown here that the amplitude of fully developed baroclinic turbulence due to nonzonal shears differs from that due to zonal shears primarily in the nature of the eddy generation. Since β will act to create large-scale zonal jet structures regardless of the generation source, the nature of eddy fluxes of potential vorticity (the source of eddy energy) in the zonal and meridional directions are fundamentally different. The cross-jet mixing has been shown previously to obey a mixing-length scaling, and this corresponds to the generation due to unstable zonal flow. The along-jet mixing, which corresponds to the generation due to the meridional shear, is shown here to be best described by a shear dispersion model. The resulting flux is orders of magnitude higher than in the cross-jet direction, and thus eddy energies driven by baroclinically unstable mean flows with a nonzero meridional component are much larger. This provides an explanation for recently reported results. Moreover, given recent observational and modeling studies showing the ubiquitous presence of zonal jets in the oceans, the results presented here indicate a powerful source of eddy energy.
Storm-Induced Circulation in Lunenburg Bay of Nova Scotia: Observations and Numerical Simulations
Authors: Wang Liang , Sheng Jinyu , Hay Alex E. , Schillinger Douglas J. 
Published: May 2007

Abstract
An extreme weather event (Hurricane Juan) made landfall in Nova Scotia, Canada, in September 2003. The storm produced an ∼70-cm storm surge and ∼40 cm s−1 coastal currents in Lunenburg Bay, registered by a coastal observing system. A fine-resolution (60 m) coastal circulation model is used to examine the response of Lunenburg Bay to Hurricane Juan. The model is forced by local wind stress at the sea surface, and tides and remotely generated waves specified at model open boundaries. The model performance is assessed in terms of γ2, the variance of the model errors normalized by the observed variance. The model reproduces very well the observed surface elevations with γ2 values of less than 0.05, and reasonably well the observed currents with γ2 values between 0.2 and 1.1 in the bay during Hurricane Juan. The model–data comparisons demonstrate that the coastal circulation in the bay is significantly affected by local wind associated with the storm. The model results are also used to demonstrate the importance of nonlinear dynamics in the barotropic response of the bay to the storm.
Dynamics in the Deep Canada Basin, Arctic Ocean, Inferred by Thermistor Chain Time Series
Authors: Timmermans M-L. , Melling H. , Rainville L. 
Published: May 2007

Abstract
A 50-day time series of high-resolution temperature in the deepest layers of the Canada Basin in the Arctic Ocean indicates that the deep Canada Basin is a dynamically active environment, not the quiet, stable basin often assumed. Vertical motions at the near-inertial (tidal) frequency have amplitudes of 10– 20 m. These vertical displacements are surprisingly large considering the downward near-inertial internal wave energy flux typically observed in the Canada Basin. In addition to motion in the internal-wave frequency band, the measurements indicate distinctive subinertial temperature fluctuations, possibly due to intrusions of new water masses.
The Freshening of Surface Waters in High Latitudes: Effects on the Thermohaline and Wind-Driven Circulations
Authors: Fedorov Alexey , Barreiro Marcelo , Boccaletti Giulio , Pacanowski Ronald , Philander S. George 
Published: May 2007

Abstract
The impacts of a freshening of surface waters in high latitudes on the deep, slow, thermohaline circulation have received enormous attention, especially the possibility of a shutdown in the meridional overturning that involves sinking of surface waters in the northern Atlantic Ocean. A recent study by Fedorov et al. has drawn attention to the effects of a freshening on the other main component of the oceanic circulation—the swift, shallow, wind-driven circulation that varies on decadal time scales and is closely associated with the ventilated thermocline. That circulation too involves meridional overturning, but its variations and critical transitions affect mainly the Tropics. A surface freshening in mid- to high latitudes can deepen the equatorial thermocline to such a degree that temperatures along the equator become as warm in the eastern part of the basin as they are in the west, the tropical zonal sea surface temperature gradient virtually disappears, and permanently warm conditions prevail in the Tropics. In a model that has both the wind-driven and thermohaline components of the circulation, which factors determine the relative effects of a freshening on the two components and its impact on climate? Studies with an idealized ocean general circulation model find that vertical diffusivity is one of the critical parameters that affect the relative strength of the two circulation components and hence their response to a freshening. The spatial structure of the freshening and imposed meridional temperature gradients are other important factors.