bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts
Authors: Schwock Joerg , Dhani Neesha , Cao Mary Ping-Jiang , Zheng Jinzi , Clarkson Richard , Radulovich Nikolina , Navab Roya , Horn Lars-Christian , Hedley David W. 
Published: May 2009

Abstract
Focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase and key modulator of integrin signaling, is widely expressed in different tissues and cell types. Recent evidence indicates a central function of FAK in neoplasia where the kinase contributes to cell proliferation, resistance to apoptosis and anoikis, invasiveness, and metastasis. FAK, like other signaling kinases, is dependent on the chaperone heat shock protein 90 (Hsp90) for its stability and proper function. Thus, inhibition of Hsp90 might be a way of disrupting FAK signaling and, consequently, tumor progression. FAK is expressed in high-grade squamous intraepithelial lesions and metastatic cervical carcinomas but not in nonneoplastic cervical mucosa. In SiHa, a cervical cancer cell line with characteristics of epithelial-to-mesenchymal transition, the stable expression of dominant-negative FAK-related nonkinase decreases anchorage independence and delays xenograft growth. FAK-related nonkinase as well as the Hsp90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin both negatively interfere with FAK signaling and focal adhesion turnover. Short-term 17-dimethylaminoethylamino-17-demethoxygeldanamycin treatment prolongs survival in a SiHa lung metastasis model and chronic administration suppresses tumor growth as well as metastatic spread in orthotopic xenografts. Taken together, our data suggest that FAK is of importance for tumor progression in cervical cancer and that disruption of FAK signaling by Hsp90 inhibition might be an avenue to restrain tumor growth as well as metastatic spread. [Cancer Res 2009;69(11):4750–9]
Quality of Reporting of Serious Adverse Drug Events to an Institutional Review Board: A Case Study with the Novel Cancer Agent, Imatinib Mesylate
Authors: Dorr David A. , Burdon Rachel , West Dennis P. , Lagman Jennifer , Georgopoulos Christina , Belknap Steven M. , McKoy June M. , Djulbegovic Benjamin , Edwards Beatrice J. , Weitzman Sigmund A. , Boyle Simone , Tallman Martin S. , Talpaz Moshe , Sartor Oliver , Bennett Charles L. 
Published: May 2009

Abstract
Purpose: Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB.
Experimental Design: sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed.
Results: Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P &lt; 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P &lt; 0.05). Some key clinical information was discrepant between the two sources.
Conclusions: The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients.
ERBB1 and ERBB2 Have Distinct Functions in Tumor Cell Invasion and Intravasation
Authors: Kedrin Dmitriy , Wyckoff Jeffrey , Boimel Pamela J. , Coniglio Salvatore J. , Hynes Nancy E. , Arteaga Carlos L. , Segall Jeffrey E. 
Published: May 2009

Abstract
Purpose: The epidermal growth factor receptor (ERBB1) and related family member HER-2/neu (ERBB2) are often overexpressed in aggressive breast cancers and their overexpression is correlated with poor prognosis. Clinical studies using ERBB inhibitors have focused on tumor growth effects, but ERBBs can contribute to malignancy independent of their effects on tumor growth. Our studies were designed to evaluate the effect of ERBB inhibition on tumor cell motility and intravasation in vivo using clinically relevant small-molecule inhibitors.
Experimental Design: Using in vivo mouse models of breast cancer, we test the effects of ERBB1 and ERBB2 inhibitors AC480 and lapatinib, ERBB1 inhibitor gefitinib, and ERBB2 inhibitor AG825 on in vivo tumor cell invasive properties in mammary fat pad tumors.
Results: ERBB1 and ERBB2 inhibition rapidly (within 3 h) inhibits both tumor cell motility and intravasation. Using gefitinib, ERBB1 inhibition rapidly inhibits tumor cell motility and invasion but not intravasation, whereas ERBB2 inhibition by AG825 rapidly blocks intravasation.
Conclusions: ERBB1 and ERBB2 inhibition can rapidly block tumor cell invasive properties. In addition, we differentiate for the first time the contributions of ERBB1 and ERBB2 to the key metastatic properties of in vivo tumor cell invasion and intravasation. These experiments temporally and molecularly separate two key stages in tumor cell entry into blood vessels: invasion and intravasation. These results indicate that ERBB inhibition should be considered for blocking other tumor cell malignant properties besides growth.
Interaction of TFAP2C with the Estrogen Receptor-α Promoter Is Controlled by Chromatin Structure
Authors: Woodfield George W. , Hitchler Michael J. , Chen Yizhen , Domann Frederick E. , Weigel Ronald J. 
Published: May 2009

Abstract
Purpose: Transcriptional regulation of estrogen receptor-α (ERα) involves both epigenetic mechanisms and trans-active factors, such as TFAP2C, which induces ERα transcription through an AP-2 regulatory region in the ERα promoter. Attempts to induce endogenous ERα expression in ERα-negative breast carcinomas by forced overexpression of TFAP2C have not been successful. We hypothesize that epigenetic chromatin structure alters the activity of TFAP2C at the ERα promoter.
Experimental Design: DNA methylation, histone acetylation, and chromatin accessibility were examined at the ERα promoter in a panel of breast carcinoma cell lines. TFAP2C and polymerase II binding were analyzed by chromatin immunoprecipitation. Epigenetic chromatin structure was altered using drug treatment with 5-aza-2′-deoxycytidine (AZA) and trichostatin A (TSA).
Results: The ERα promoter in the ERα-negative lines MDA-MB-231, MCF10A, and MCF7-5C show CpG island methylation, histone 3 lysine 9 deacetylation, and decreased chromatin accessibility compared with ERα-positive cell lines MCF7 and T47-D. Treatment with AZA/TSA increased chromatin accessibility at the ERα promoter and allowed TFAP2C to induce ERα expression in ERα-negative cells. Chromatin immunoprecipitation analysis showed that binding of TFAP2C to the ERα promoter is blocked in ERα-negative cells but that treatment with AZA/TSA enabled TFAP2C and polymerase II binding.
Conclusion: We conclude that the activity of TFAP2C at specific target genes depends upon epigenetic chromatin structure. Furthermore, the combination of increasing chromatin accessibility and inducing TFAP2C provides a more robust activation of the ERα gene in ERα-negative breast cancer cells.
Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study
Authors: Ricart Alejandro D. , Sarantopoulos John , Calvo Emiliano , Chu Quincy S. , Greene Douglas , Nathan Faith E. , Petrone Michael E. , Tolcher Anthony W. , Papadopoulos Kyriakos P. 
Published: May 2009

Abstract
Purpose: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors.
Experimental Design: Satraplatin was administered orally at 80 mg/m2 once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state.
Results: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed.
Conclusions: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.
Proteasome Enzymatic Activities in Plasma as Risk Stratification of Patients with Acute Myeloid Leukemia and Advanced-Stage Myelodysplastic Syndrome
Authors: Ma Wanlong , Kantarjian Hagop , Bekele Benjamin , Donahue Amber C. , Zhang Xi , Zhang Zhong J. , O'Brien Susan , Estey Elihu , Estrov Zeev , Cortes Jorge , Keating Michael , Giles Francis , Albitar Maher 
Published: May 2009

Abstract
Purpose: Cytogenetic abnormalities are currently the most important predictors of response and clinical outcome for patients with acute myeloid leukemia (AML) or advanced-stage myelodysplastic syndrome (MDS). Because clinical outcomes vary markedly within cytogenetic subgroups, additional biological markers are needed for risk stratification.
Experimental Design: We assessed the utility of measuring pretreatment proteasome chymotrypsin-like, caspase-like, and trypsin-like activities in plasma to predict response and survival of patients with AML (n = 174) or advanced-stage MDS (n = 52).
Results: All three enzymatic activities were significantly (P &lt; 0.001) increased in the plasma of patients with AML and MDS compared with normal controls. Both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, correlated with outcome. Chymotrypsin-like and caspase-like activities, but not trypsin-like activity, predicted response in univariate analysis (P = 0.002). However, only chymotrypsin-like activity was independent predictor of response from age grouping (&lt;70 versus ≥70 years), cytogenetics, and blood urea nitrogen in multivariate analysis. Similarly, both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, were predictors of overall survival in univariate analysis (P &lt; 0.0001), but only chymotrypsin-like activity was independent of cytogenetics, age, performance status, blood urea nitrogen, and β2-microglobulin in multivariate Cox regression models. Chymotrypsin-like activity was also a strong independent predictor of survival in patients with intermediate karyotype (n = 124).
Conclusions: Measuring plasma chymotrypsin-like activity may provide a powerful biomarker for risk stratification in patients with AML and advanced-stage MDS, including those with normal karyotype.
A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and IV Melanoma
Authors: Yip Dana , Le Maithao N. , Chan Joseph L.-K. , Lee Jonathan H. , Mehnert Janice A. , Yudd Anthony , Kempf Jeffery , Shih Weichung J. , Chen Suzie , Goydos James S. 
Published: May 2009

AbstractPurpose: Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal–regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma.Experimental Design: Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and post-treatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning.Results: We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease.Conclusions: Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy.
Sensitivity of Simulated Climate to Conservation of Momentum in Gravity Wave Drag Parameterization
Authors: Shaw Tiffany A. , Sigmond Michael , Shepherd Theodore G. , Scinocca John F. 
Published: May 2009

Abstract
The Canadian Middle Atmosphere Model is used to examine the sensitivity of simulated climate to conservation of momentum in gravity wave drag parameterization. Momentum conservation requires that the parameterized gravity wave momentum flux at the top of the model be zero and corresponds to the physical boundary condition of no momentum flux at the top of the atmosphere. Allowing momentum flux to escape the model domain violates momentum conservation. Here the impact of momentum conservation in two sets of model simulations is investigated.
In the first set, the simulation of present-day climate for two model-lid height configurations, 0.001 and 10 hPa, which are identical below 10 hPa, is considered. The impact of momentum conservation on the climate with the model lid at 0.001 hPa is minimal, which is expected because of the small amount of gravity wave momentum flux reaching 0.001 hPa. When the lid is lowered to 10 hPa and momentum is conserved, there is only a modest impact on the climate in the Northern Hemisphere; however, the Southern Hemisphere climate is more adversely affected by the deflection of resolved waves near the model lid. When momentum is not conserved in the 10-hPa model the climate is further degraded in both hemispheres, particularly in winter at high latitudes, and the impact of momentum conservation extends all the way to the surface.
In the second set of simulations, the impact of momentum conservation and model-lid height on the modeled response to ozone depletion in the Southern Hemisphere is considered, and it is found that the response can display significant sensitivity to both factors. In particular, both the lower-stratospheric polar temperature and surface responses are significantly altered when the lid is lowered, with the effect being most severe when momentum is not conserved. The implications with regard to the current round of Intergovernmental Panel on Climate Change model projections are discussed.
Insertable Surgical Imaging Device with Pan, Tilt, Zoom, and Lighting
Authors: Hu Tie , Allen Peter K. , Hogle Nancy J. , Fowler Dennis L. 
Published: May 2009

In this paper we describe work we have done in developing an insertable surgical imaging device with multiple degrees of freedom for minimally invasive surgery. The device is fully insertable into the abdomen using standard 12 mm trocars. It consists of a modular camera and lens system which has pan and tilt capability provided by two small DC servo motors. It also has its own integrated lighting system that is part of the camera assembly. Once the camera is inserted into the abdomen, the insertion port is available for additional tooling, motivating the idea of single-port surgery. A third zoom axis has been designed for the camera as well, allowing close-up and far-away imaging of surgical sites with a single camera unit. In animal tests with the device we have performed surgical procedures including cholecystectomy, appendectomy, running (measuring) the bowel, suturing, and nephrectomy. Preliminary tests suggest that the new device may have advantages over a standard laparoscope including the following. • Low-cost and simple design. • Easier and more intuitive to use than a standard laparoscope. • Joystick operation requires no specialized operator training. • Pan/tilt functions provide a large imaging volume not restricted by the fulcrum point of standard laparoscope. • Time to perform procedures was better than or equivalent to a standard laparoscope. We believe these insertable platforms will be an integral part of future surgical systems. The platforms can be used with tooling as well as imaging devices, allowing many surgical procedures to be performed using such a system.
Factoring the Mapping Problem: Mobile Robot Map-building in the Hybrid Spatial Semantic Hierarchy
Authors: Beeson Patrick , Modayil Joseph , Kuipers Benjamin 
Published: May 2009

We propose a factored approach to mobile robot map-building that handles qualitatively different types of uncertainty by combining the strengths of topological and metrical approaches. Our framework is based on a computational model of the human cognitive map; thus it allows robust navigation and communication within several different spatial ontologies. This paper focuses exclusively on the issue of map-building using the framework. Our approach factors the mapping problem into natural sub-goals: building a metrical representation for local small-scale spaces; finding a topological map that represents the qualitative structure of large-scale space; and (when necessary) constructing a metrical representation for large-scale space using the skeleton provided by the topological map. We describe how to abstract a symbolic description of the robot’s immediate surround from local metrical models, how to combine these local symbolic models in order to build global symbolic models, and how to create a globally consistent metrical map from a topological skeleton by connecting local frames of reference.
Patients' Views of Therapeutic Action in Psychoanalytic Group Psychotherapy
Authors: Johansson Lena , Werbart Andrzej 
Published: May 2009

Patients' views of curative and hindering factors in psychoanalytic group psychotherapy are explored, starting with semi-structured interviews with 28 young adult patients at therapy termination. Using grounded theory methodology, a theoretical model of therapeutic action is constructed, elucidating the interactions between positive and negative experiences in the group. The focal point appears to be the patient's experience of their own activity within the context of the group as whole, leading to increased self-knowledge and improved handling of emotions. The positively experienced change is also affected by people outside of therapy and real life events. The patients ascribed most frequent hindering factors to the absence of their own action to other group members and to the therapeutic frames. In contrast to therapist-based theoretical models, positive experience in the group leads patients to minimize the therapist's role, while negative experiences lead patients to want a more active therapist.
The effect of PM10 on human lung fibroblasts
Authors: Alley DF , Langley-Turnbaugh S , Gordon NR , Wise JP , Van Epps G , Jalbert A 
Published: May 2009

Asthma diagnoses are increasing nationally with the highest rates in the New England states. Epidemiological studies have suggested a relationship between airborne particulate matter (PM) and severity of an asthma attack. However, because particulate matter, PM, is such a complex mixture, it is difficult to isolate the exacerbating factors. In this paper we investigate the effect of NIST (National Institute of Standards and Technology) and Maine PM and the soluble metals released from the PM on the growth of human lung fibroblasts. While the NIST PM itself had the most pronounced effect on cell survival rates, solutions of metals extracted from the PM also affected cell survival. Treatment of cells with 10, 50, 100 and 200 ug/cm2 resulted in 84 ± 13%, 69 ± 15%, 58 ± 14% and 58 ± 16% survival, respectively. Appropriate concentrations of eight acid soluble metals from NIST PM were determined and tested on cells giving 91 ± 11%, 87 ± 10%, 72 ± 18% and 66 ± 20% survival, respectively. Soluble metals from Maine PM were extracted and mixtures of appropriate concentrations of these metals were used to treat cells, resulting in 88 ± 5%, 81 ± 5%, 79 ± 3% and 57 ± 9% survival rate. To determine which, if any, of the metals individually affected the cells, Mn, Cu, V and As were used to treat the cells. At the metal concentrations tested, only As and V affected cell survival.
The antioxidant effects of vitamin A, C, and E on aflatoxin B1-induced oxidative stress in human lymphocytes
Authors: Alpsoy L , Yildirim A , Agar G 
Published: May 2009

The aim of this study was to investigate the possible protective role of vitamin A, C, and E on aflatoxin B1-induced in human lymphocytes using biochemical approaches. The control group received dimethyl sulfoxide, the second group of cultures were administered aflatoxin B1 (AFB1) at a dose of 5 μM. The other group of cultures were treated with AFB1+vitamin A (0.5 and 1.0 and 1.5 μM) and AFB1+vitamin C (25, 50, and 100 μM) and AFB1+vitamin E (40, 100, and 200 μM). The results of this experiment show that AFB1 significantly decreased the level of GSH and the activities of superoxide dismutase and GPx and increased level of malondialdehyde. Simultaneous supplementation with vitamin A, C, and E restored these parameters to that of normal range. In conclusion, vitamin A, C, and E exhibited protective effects in human lymphocytes by inhibiting AFB1-induced ROS generation.