bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial Modulation of the Tumor Microenvironment Accounts for Thalidomide Activity in Prostate Cancer
Authors: Efstathiou Eleni , Troncoso Patricia , Wen Sijin , Do Kim-Anh , Pettaway Curtis A. , Pisters Louis L. , McDonnell Timothy J. , Logothetis Christopher J. 
Published: February 2007

Abstract
Purpose: Disruption of stromal-epithelial interactions favoring prostate cancer progression may affect the phenotype of the disease. We did a preoperative study to test the hypothesis that thalidomide, an active agent in metastatic disease, is a modulator of the tumor microenvironment.
Experimental Design: Eighteen men with high-risk prostate cancer were given thalidomide at doses escalated to 600 mg for 12 weeks, followed by radical prostatectomy. We constructed tissue microarrays from prostatectomy specimens from 15 treated patients and 15 matched untreated control subjects to assess effects of thalidomide on the tumor microenvironment. We compared the immunohistochemical expression of three groups of markers linked to angiogenesis, stromal-epithelial interactions, or the epithelial compartment. Levels of circulating basic fibroblast growth factor, interleukin-6, tumor necrosis factor-α, and vascular endothelial growth factor were also assessed.
Results: Thalidomide was well tolerated and induced a median reduction in prostate-specific antigen of 41% without affecting testosterone. Tissue microarray analyses indicated modulation of vascular marker expression accompanied by a reduction in microvessel density in the treated group. Comparison of broader stromal-epithelial interaction markers between treated and control groups suggested a transition to a less aggressive phenotype as a result of thalidomide treatment. Hedgehog signaling was attenuated and the ratio of matrix metalloproteinases to E-cadherin shifted to favor E-cadherin. No differences were noted in proliferation or apoptosis in the epithelial compartment.
Conclusions: These findings are the first clinical evidence to support the hypothesis that the reported thalidomide clinical efficacy is attributable to early modulation of the tumor microenvironment and suggest that stromal-targeting therapies will be effective against prostate cancer.
Toll-like Receptor-4 Is Up-Regulated in Hematopoietic Progenitor Cells and Contributes to Increased Apoptosis in Myelodysplastic Syndromes
Authors: Maratheftis Christos I. , Andreakos Evangelos , Moutsopoulos Haralampos M. , Voulgarelis Michael 
Published: February 2007

Abstract
Purpose: To investigate the function and expression of Toll-like receptors (TLR) in bone marrow cells of myelodysplastic syndrome (MDS) patients and to examine their involvement in the apoptotic phenomenon characterizing MDS hematopoiesis.
Experimental Design: TLR mRNA and protein expression was investigated in bone marrow cell populations of MDS patients and controls. TLR-4 ability to recognize lipopolysaccharide and up-regulate self mRNA and protein expression was examined. Tumor necrosis factor involvement in the constitutive and lipopolysaccharide (LPS)-induced TLR expression was also evaluated. Possible correlation between TLR-4 overexpression and apoptosis was investigated by simultaneous staining with Annexin V and TLR-4.
Results: TLR-2 and TLR-4 are expressed in almost all bone marrow cell lineages including megakaryocytes, erythroid cells, myeloid precursors, monocytes, and B lymphocytes and are up-regulated in MDS patients compared with controls. In hematopoietic CD34+ cells, TLR-4 is also expressed and significantly up-regulated at both the mRNA and protein levels. Treatment with an anti–tumor necrosis factor antibody reduces both constitutive and LPS-induced TLR-4 levels. Increased TLR-4 expression correlates with increased apoptosis as TLR-4 is almost exclusively found in apoptotic bone marrow mononuclear and CD34+ cells. The addition of the TLR-4 ligand LPS further enhances the apoptosis of these cells.
Conclusions: TLR-4 and other TLRs are significantly up-regulated in MDS patients whereas TLR-4 is involved in promoting apoptosis, possibly contributing to MDS cytopenia.
Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma
Authors: Vredenburgh James J. , Desjardins Annick , Herndon James E. , Dowell Jeannette M. , Reardon David A. , Quinn Jennifer A. , Rich Jeremy N. , Sathornsumetee Sith , Gururangan Sridharan , Wagner Melissa , Bigner Darell D. , Friedman Allan H. , Friedman Henry S. 
Published: February 2007

Abstract
Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma.
Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m2, whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m2. Toxicity and response were assessed.
Results: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke.
Conclusions: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.
Lack of Apoptotic Protease Activating Factor-1 Expression and Resistance to Hypoxia-Induced Apoptosis in Cervical Cancer
Authors: Leo Cornelia , Horn Lars-Christian , Rauscher Cora , Hentschel Bettina , Richter Christine E. , Schütz Alexander , Leo Chandra Paul , Höckel Michael 
Published: February 2007

Abstract
Purpose: Clinical observations suggest that intratumoral hypoxia increases the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein apoptotic protease activating factor-1 (Apaf-1) in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Furthermore, the effect of hypoxia and apoptosis on survival was examined.
Experimental Design: In 56 patients, intratumoral oxygenation measurements and subsequent needle biopsies were done. The obtained tissue was analyzed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assays and by immunohistochemistry with an Apaf-1 antibody.
Results: Apaf-1 was expressed in 86% of cancers. The median apoptosis rate was 1.0%. There was no correlation between Apaf-1 expression and intratumoral hypoxia. However, Apaf-1 expression was negative in 37.5% of hypoxic cervical cancers (pO2 ≤ 10 mmHg) with low apoptosis rates (≤1.0%) compared with only 5.0% in nonhypoxic cancers and hypoxic cancers with high apoptosis (P = 0.005; Fisher's exact test). With a median follow-up period of 44 months, there was a nonsignificant trend toward worse prognosis in the hypoxic low-apoptotic group (P = 0.08).
Conclusions: Although Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a lack of Apaf-1 expression. This finding suggests that loss of Apaf-1 expression is a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis. Thus, low Apaf-1 expression in hypoxic tumors may be an unfavorable prognostic factor.
Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab
Authors: Wu Gong , Yang Weilian , Barth Rolf F. , Kawabata Shinji , Swindall Michele , Bandyopadhyaya Achintya K. , Tjarks Werner , Khorsandi Behrooz , Blue Thomas E. , Ferketich Amy K. , Yang Ming , Christoforidis Gregory A. , Sferra Thomas J. , Binns Peter J. , Riley Kent J. , Ciesielski Michael J. , Fenstermaker Robert A. 
Published: February 2007

Abstract
Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98EGFR.
Experimental Design: A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection.
Results: The amount of boron retained by F98EGFR gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 μg/g, respectively, with normal brain and blood boron values &lt;0.05 μg/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of Technology Research Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA.
Conclusions: The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent. This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.
Poor Outcome in Estrogen Receptor–Positive Breast Cancers Predicted by Loss of Plexin B1
Authors: Rody Achim , Holtrich Uwe , Gaetje Regine , Gehrmann Mathias , Engels Knut , von Minckwitz Gunter , Loibl Sibylle , Diallo-Danebrock Raihanatou , Ruckhäberle Eugen , Metzler Dirk , Ahr Andre , Solbach Christine , Karn Thomas , Kaufmann Manfred 
Published: February 2007

Abstract
Purpose: A common characteristic of mammary carcinomas is an inverse relationship between the estrogen receptor (ER) status and the proliferative activity of the tumor. Yet, a subset of ER-positive breast cancers is characterized by a high proliferation, suggesting malfunctions in ER responsiveness that influence the biological and therapeutic behavior of tumor cells. The expression of several ER-dependent genes seems to be dysregulated among those “uncoupled” tumors. One of those genes is plexin B1, a cell-surface receptor for the semaphorin Sema4D (CD 100). However, the biological role of plexin B1 in breast cancer is largely unknown.
Experimental Design: Expression data of plexin B1 were obtained from Affymetrix microarray analysis of n = 119 breast cancer specimens. Validation was done by quantitative real-time PCR and protein expression was evaluated by immunohistochemistry. Expression data were compared with clinical characteristics as well as follow-up data of the disease.
Results: Low plexin B1 expression levels characterize a more aggressive tumor phenotype. The expression of plexin B1 is strongly correlated with the ER status. However, even among ER-positive tumors, loss of plexin B1 is associated with an impaired prognosis of breast cancer patients in both univariate (all patients, P = 0.0062; ER positive, P = 0.0107) and multivariate analyses (all patients, P = 0.032; ER positive, P = 0.022). Immunohistochemistry reveals that the tumor cells themselves and not the endothelial cells are the major source of plexin B1 expression in the tumor.
Conclusion: Plexin B1 acts not only as a new important prognostic but should also represent a predictive marker indicating an endocrine resistance. These data give a new insight in markers that could be involved in endocrine dysregulation of breast cancer.
A Pacific Moisture Conveyor Belt and Its Relationship to a Significant Precipitation Event in the Semiarid Southwestern United States
Authors: Knippertz Peter , Martin Jonathan E. 
Published: February 2007

Abstract
In this study the term moisture conveyor belt (MCB) is defined as an elongated band of enhanced poleward water vapor fluxes (WVFs) above the PBL that is rooted in the Tropics. This new terminology is illustrated through an exemplary detailed case study of an MCB over the northeastern Pacific during 9–13 November 2003 that provides the moisture for a significant precipitation event in the dry southwestern United States. The analysis of the involved moisture transports and dynamics comprises both Eulerian and Lagrangian approaches, and is based upon output from a simulation with the University of Wisconsin-Nonhydrostatic Modeling System, as well as analysis data, surface observations, and satellite images.
The formation of the MCB is related to a quasi-stationary upper-level cutoff low (COL) resulting from a wave-breaking event over the North Pacific. A pronounced upper-tropospheric baroclinic zone and a strong, inertially unstable subtropical jet (STJ) are found to the east of the COL, where at later stages an elongated tropical cloud plume developed in association with a marked flare-up of ITCZ convection. Part of the extratropical air that subsides to the west of the COL becomes involved in this convection; another part feeds the so-called dry slot at the base of the COL. The actual MCB consists of midlevel trajectories that curve anticyclonically away from the moist tropical easterlies and cause a northeastward-directed WVF maximum at around 700 hPa over the subtropical northeast Pacific and a marked humidity gradient toward the subsided extratropical air. At late stages, frontogenetic circulations lead to WVF convergence involving air from the midlevel subtropical troposphere. At the surface, cyclogenesis and thermal contrasts are weak, and northeasterly trade winds prevail, which clearly distinguishes this MCB from a classical extratropical warm conveyor belt. Other important differences are the high elevation of the WVF maximum, as well as the quasi-horizontal track and origin above the PBL of most moist trajectories. Three precipitation regions with different influence factors can be distinguished. 1) Close to the COL center, moist tropical air is overrun by the dry slot, resulting in convective instability and extreme hail in the Los Angeles, California, area. 2) To the north and east, quasigeostrophic forcing and midlevel warm frontogenesis generate ascent, where the northern branch of the MCB circulates around the COL. 3) Along the anticyclonic shear side of the STJ, convection forms within potentially unstable MCB air benefiting from the inertial instability at the outflow level. It is suggested that this set of circumstances is quite similar to those that conspire to produce heavy precipitation events in subtropical West Africa.
Reexamination of Tropical Cyclone Wind–Pressure Relationships
Authors: Knaff John A. , Zehr Raymond M. 
Published: February 2007

Abstract
Tropical cyclone wind–pressure relationships are reexamined using 15 yr of minimum sea level pressure estimates, numerical analysis fields, and best-track intensities. Minimum sea level pressure is estimated from aircraft reconnaissance or measured from dropwindsondes, and maximum wind speeds are interpolated from best-track maximum 1-min wind speed estimates. The aircraft data were collected primarily in the Atlantic but also include eastern and central North Pacific cases. Global numerical analyses were used to estimate tropical cyclone size and environmental pressure associated with each observation. Using this dataset (3801 points), the influences of latitude, tropical cyclone size, environmental pressure, and intensification trend on the tropical cyclone wind–pressure relationships were examined. Findings suggest that latitude, size, and environmental pressure, which all can be quantified in an operational and postanalysis setting, are related to predictable changes in the wind–pressure relationships. These factors can be combined into equations that estimate winds given pressure and estimate pressure given winds with greater accuracy than current methodologies. In independent testing during the 2005 hurricane season (524 cases), these new wind–pressure relationships resulted in mean absolute errors of 5.3 hPa and 6.2 kt compared with the 7.7 hPa and 9.0 kt that resulted from using the standard Atlantic Dvorak wind–pressure relationship. These new wind–pressure relationships are then used to evaluate several operational wind–pressure relationships. These intercomparisons have led to several recommendations for operational tropical cyclone centers and those interested in reanalyzing past tropical cyclone events.
Facing the Challenges of the International Airways Volcano Watch: The 2004/05 Eruptions of Manam, Papua New Guinea
Authors: Tupper Andrew , Itikarai Ima , Richards Michael , Prata Fred , Carn Simon , Rosenfeld Daniel 
Published: February 2007

Abstract
Devastating eruptions occurred at Manam, Papua New Guinea, from October 2004 to January 2005. An unprecedented set of pilot reports were obtained; ground-, air-, and satellite-observed eruption heights differed greatly. Satellite postanalysis and satellite CO2 slicing techniques give consistent heights. The climactic eruption, on 27 January 2005, reached 21–24 km MSL; four other eruptions reached 16.5–19 km. Tracking of these ice-rich clouds was done by monitoring strong “ice” signatures on 11–12-μm infrared imagery (for two eruptions), by using reflectance-based techniques (during the daytime), and by using SO2 detection (available only in postanalysis). A remote lightning detection network could not detect the eruption clouds, despite detecting lightning from thunderstorms in the area. The eruptions appeared to enhance the nocturnal cycle of (ash contaminated) deep convection above the island, consistent with previous work on diurnal volcanic cumulonimbus at Mount Pinatubo. The communications and infrastructure challenges of the region strongly affected the performance of the volcanic ash warning system, but can be partially addressed with the development of appropriate strategies. A strategy of gradual advisory cessation at the end of each event generally worked well but failed where numerical modeling and satellite observation were insufficient. An aircraft apparently encountered SO2 from the cloud over Dili, Timor-Leste; no engine damage was reported, but no close inspection was made at the time. It is suggested that maintenance guidelines be developed to help clarify the risk of volcanic ash damage from encounters with clouds where only SO2 odor is observed.
Evaluation of Probabilistic Precipitation Forecasts Determined from Eta and AVN Forecasted Amounts
Authors: Gallus William A. , Baldwin Michael E. , Elmore Kimberly L. 
Published: February 2007

Abstract
This note examines the connection between the probability of precipitation and forecasted amounts from the NCEP Eta (now known as the North American Mesoscale model) and Aviation (AVN; now known as the Global Forecast System) models run over a 2-yr period on a contiguous U.S. domain. Specifically, the quantitative precipitation forecast (QPF)–probability relationship found recently by Gallus and Segal in 10-km grid spacing model runs for 20 warm season mesoscale convective systems is tested over this much larger temporal and spatial dataset. A 1-yr period was used to investigate the QPF–probability relationship, and the predictive capability of this relationship was then tested on an independent 1-yr sample of data. The same relationship of a substantial increase in the likelihood of observed rainfall exceeding a specified threshold in areas where model runs forecasted higher rainfall amounts is found to hold over all seasons. Rainfall is less likely to occur in those areas where the models indicate none than it is elsewhere in the domain; it is more likely to occur in those regions where rainfall is predicted, especially where the predicted rainfall amounts are largest. The probability of rainfall forecasts based on this relationship are found to possess skill as measured by relative operating characteristic curves, reliability diagrams, and Brier skill scores. Skillful forecasts from the technique exist throughout the 48-h periods for which Eta and AVN output were available. The results suggest that this forecasting tool might assist forecasters throughout the year in a wide variety of weather events and not only in areas of difficult-to-forecast convective systems.
Application of the NCEP Ensemble Prediction System to Medium-Range Forecasting in South Africa: New Products, Benefits, and Challenges
Authors: Tennant Warren J. , Toth Zoltan , Rae Kevin J. 
Published: February 2007

Abstract
The National Centers for Environmental Prediction (NCEP) Ensemble Forecasting System (EFS) is used operationally in South Africa for medium-range forecasts up to 14 days ahead. The use of model-generated probability forecasts has a clear benefit in the skill of the 1–7-day forecasts. This is seen in the forecast probability distribution being more successful in spanning the observed space than a single deterministic forecast and, thus, substantially reducing the instances of missed events in the forecast. In addition, the probability forecasts generated using the EFS are particularly useful in estimating confidence in forecasts. During the second week of the forecast the EFS is used as a heads-up for possible synoptic-scale events and also for predicting average weather conditions and probability density distributions of some elements such as maximum temperature and wind. This paper assesses the medium-range forecast process and the application of the NCEP EFS at the South African Weather Service. It includes a description of the various medium-range products, adaptive bias-correction methods applied to the forecasts, verification of the forecast products, and a discussion on the various challenges that face researchers and forecasters alike.