bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia in Models of Lung Cancer: Implications for Targeted Therapeutics
Authors: Graves Edward E. , Vilalta Marta , Cecic Ivana K. , Erler Janine T. , Tran Phuoc T. , Felsher Dean , Sayles Leanne , Sweet-Cordero Alejandro , Le Quynh-Thu , Giaccia Amato J. 
Published: September 2010

Abstract
Purpose: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response.
Experimental Design: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers.
Results: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types.
Conclusions: These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies. Clin Cancer Res; 16(19); 4843–52. ©2010 AACR.
CD44: A Cancer Stem Cell–Related Biomarker with Predictive Potential for Radiotherapy
Authors: Baumann Michael , Krause Mechthild 
Published: September 2010

Abstract
CD44, a cancer stem cell (CSC)-related surface marker, correlates with local control after radiotherapy of early laryngeal cancer. For the first time, a CSC-related marker has been functionally validated for radiotherapy in patients. CD44 expression bears the potential to predict the outcome of radiotherapy by assessment of CSC density. Clin Cancer Res; 16(21); 5091–3. ©2010 AACR.
Monitoring Molecular-Specific Pharmacodynamics of Rapamycin In vivo with Inducible Gal4→Fluc Transgenic Reporter Mice
Authors: Pan Mei-Hsiu , Lin Jeffrey , Prior Julie L. , Piwnica-Worms David 
Published: September 2010

Abstract
Rapamycin (Rap), a small-molecule inhibitor of mTOR, is an immunosuppressant, and several Rap analogues are cancer chemotherapeutics. Further pharmacologic development will be significantly facilitated if in vivo reporter models are available to enable monitoring of molecular-specific pharmacodynamic actions of Rap and its analogues. Herein we present the use of a Gal4→Fluc reporter mouse for the study of Rap-induced mTOR/FKBP12 protein-protein interactions in vivo with the use of a mouse two-hybrid transactivation strategy, a derivative of the yeast two-hybrid system applied to live mice. Upon treatment with Rap, a bipartite transactivator was reconstituted, and transcription of a genomic firefly luciferase reporter was activated in a concentration-dependent (Kd = 2.3 nmol/L) and FK506-competitive (Ki = 17.1 nmol/L) manner in cellulo, as well as in a temporal and specific manner in vivo. In particular, after a single dose of Rap (4.5 mg/kg, i.p.), peak Rap-induced protein-protein interactions were observed in the liver at 24 hours post treatment, with photon flux signals 600-fold over baseline, which correlated temporally with suppression of p70S6 kinase activity, a downstream effector of mTOR. The Gal4→Fluc reporter mouse provides an intact physiologic system to interrogate protein-protein interactions and molecular-specific pharmacodynamics during drug discovery and lead characterization. Imaging protein interactions and functional proteomics in whole animals in vivo may serve as a basic tool for screening and mechanism-based analysis of small molecules targeting specific protein-protein interactions in human diseases. Mol Cancer Ther; 9(10); 2752–60. ©2010 AACR.
Targeted Delivery of Saporin Toxin by Monoclonal Antibody to the Transcobalamin Receptor, TCblR/CD320
Authors: Quadros Edward V. , Nakayama Yasumi , Sequeira Jeffrey M. 
Published: September 2010

Abstract
Cellular uptake of cobalamin (Cbl) occurs by endocytosis of transcobalamin saturated with Cbl by the transcobalamin receptor (TCblR/CD320). The cell cycle–associated overexpression of this receptor in many cancer cells provides a suitable target for delivering chemotherapeutic drugs and cytotoxic molecules to these cells while minimizing the effect on the normal cell population. We have used monoclonal antibodies to the extracellular domain of TCblR to deliver saporin-conjugated secondary antibody to various cell lines propagating in culture. A molar ratio of 2.5:10 nmol/L of primary:secondary antibody concentration was identified as the lowest concentration needed to produce the optimum cytotoxic effect. The effect was more pronounced when cells were seeded at lower density, suggesting lack of cell division in a fraction of the cells at higher density as the likely explanation. Cells in suspension culture, such as K562 and U266 cells, were more severely affected than adherent cultures, such as SW48 and KB cells. This differential effect of the anti–TCblR-saporin antibody conjugate and the ability of an anti-TCblR antibody to target proliferating cells were further evident by the virtual lack of any effect on primary skin fibroblasts and minimal effect on bone marrow cells. These results indicate that preferential targeting of some cancer cells could be accomplished through the TCblR. Mol Cancer Ther; 9(11); 3033–40. ©2010 AACR.
Hsp27 Protects Adenocarcinoma Cells from UV-Induced Apoptosis by Akt and p21-Dependent Pathways of Survival
Authors: Kanagasabai Ragu , Karthikeyan Krishnamurthy , Vedam Kaushik , Qien Wang , Zhu Qianzheng , Ilangovan Govindasamy 
Published: September 2010

Abstract
Transcriptional activation of p53 target genes, due to DNA damage, causes either apoptosis or survival by cell cycle arrest and DNA repair. However, the regulators of the choice between cell death and survival signaling have not been completely elucidated. Here, we report that human adenocarcinoma cells (MCF-7) survive UV-induced DNA damage by heat shock protein 27 (Hsp27)–assisted Akt/p21 phosphorylation/translocation. Protein levels of the p53 target genes, such as p21, Bcl-2, p38MAPK, and Akt, showed a positive correlation to Hsp27 level during 48 hours postirradiation, whereas p53 expression increased initially but started decreasing after 12 hours. Hsp27 prevented the G1-S phase cell cycle arrest, observed after 8 hours of post–UV irradiation, and PARP-1 cleavage was inhibited. Conversely, silencing Hsp27 enhanced G1-S arrest and cell death. Moreover, use of either Hsp27 or Akt small interference RNA reduced p21 phosphorylation and enhanced its retention in nuclei even after 48 hours postirradiation, resulting in enhanced cell death. Our results showed that Hsp27 expression and its direct chaperoning interaction increases Akt stability, and p21 phosphorylation and nuclear-to-cytoplasm translocation, both essential effects for the survival of UV-induced DNA-damaged cells. We conclude that the role of Hsp27 in cancer is not only for enhanced p53 proteolysis per se, rather it is also a critical determinant in p21 phosphorylation and translocation. Mol Cancer Res; 8(10); 1399–412. ©2010 AACR.
Genome-Wide Linkage and Positional Candidate Gene Study of Blood Pressure Response to Dietary Potassium Intervention
Authors: Kelly Tanika N. , Hixson James E. , Rao Dabeeru C. , Mei Hao , Rice Treva K. , Jaquish Cashell E. , Shimmin Lawrence C. , Schwander Karen , Chen Chung-Shuian , Liu Depei , Chen Jichun , Bormans Concetta , Shukla Pramila , Farhana Naveed , Stuart Colin , Whelton Paul K. , He Jiang , Gu Dongfeng 
Published: September 2010

Background—
Genetic determinants of blood pressure (BP) response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity.

Methods and Results—

A total of 1906 Han Chinese participants took part in a 7-day high-sodium diet followed by a 7-day high-sodium plus potassium dietary intervention. BP measurements were obtained at baseline and after each intervention using a random-zero sphygmomanometer. Significant linkage signals (logarithm of odds [LOD] score, >3) for BP responses to potassium were detected at chromosomal regions 3q24-q26.1, 3q28, and 11q22.3-q24.3. Maximum multipoint LOD scores of 3.09 at 3q25.2 and 3.41 at 11q23.3 were observed for absolute diastolic BP (DBP) and mean arterial pressure (MAP) responses, respectively. Linkage peaks of 3.56 at 3q25.1 and 3.01 at 11q23.3 for percent DBP response and 3.22 at 3q25.2, 3.01 at 3q28, and 4.48 at 11q23.3 for percent MAP response also were identified. Angiotensin II receptor, type 1 (
AGTR1
), single-nucleotide polymorphism rs16860760 in the 3q24-q26.1 region was significantly associated with absolute and percent systolic BP responses to potassium (
P
=0.0008 and
P
=0.0006, respectively). Absolute (95% CI) systolic BP responses for genotypes C/C, C/T, and T/T were −3.71 (−4.02 to −3.40), −2.62 (−3.38 to −1.85), and 1.03 (−3.73 to 5.79) mm Hg, respectively, and percent responses (95% CI) were −3.07 (−3.33 to −2.80), −2.07 (−2.74 to −1.41), and 0.90 (−3.20 to 4.99), respectively. Similar trends were observed for DBP and MAP responses.

Conclusions—

Genetic regions on chromosomes 3 and 11 may harbor important susceptibility loci for potassium sensitivity. Furthermore, the
AGTR1
gene was a significant predictor of BP responses to potassium intake.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00721721.
Regulating Tissue Research: Do We Need Additional Rules to Protect Research Participants?
Authors: Wright Jessica , Gevers Sjef , Ploem Corrette , Śliwka Marcin 
Published: September 2010

AbstractThis article explores whether additional rules are needed for the regulation of tissue research in Europe. A human rights-based approach (referring to international documents and illustrative examples from national legislation) is taken to address the question: what is so special about tissue, in particular when compared to personal data? The existing regimes in Europe on data protection and clinical trials are presented and examined for their suitability to govern tissue research, taking into account the differences between data and tissue. Six recommendations are outlined, highlighting important points future legislation on tissue research must take into account.
Structure and Causes of the Pulsation Mode in the Antarctic Circumpolar Current South of Australia
Authors: Dufour C. O. , Le Sommer J. , Penduff T. , Barnier B. , England M. H. 
Published: September 2010

Abstract
The subsurface variability of potential temperature and salinity south of Australia along 130°E is studied over a 25-yr period (1980–2004). The study is done with fields provided by a global eddy-permitting model of the DRAKKAR project forced by atmospheric reanalysis. The analysis performed by C. Sun and D. R. Watts with in situ hydrographic data is repeated. Sun and Watts have investigated the EOF modes in streamfunction space along the World Ocean Circulation Experiment (WOCE) SR3 section. In particular, they found that an EOF mode, which they called the “pulsation mode,” strongly dominates subsurface thermohaline variations. Here, it is found that, in the model, an EOF mode with spatial structure similar to the Sun and Watts pulsation mode dominates subsurface thermohaline variations in streamfunction space. The mode displays a maximum of variability at the Subantarctic Front (SAF) between Subantarctic Mode Water (SAMW) and Antarctic Intermediate Water (AAIW). The associated time series exhibits an intermittent interseasonal frequency (3–6 months), especially during three periods (1983–84, 1990, and 1994–96). Some energy is also found with a 4-yr period.
Further analyses reveal that the pulsation mode can also be observed in physical space. The pulsation mode is found to be related to movements of the SAF constrained by the bathymetry of the Southeast Indian Ridge. The pulsation mode displays many similarities with cold-core eddy events rather than being related to variations of the westerly wind stress, as previously proposed. The impact of those events on SAMW properties remains unclear.
A New Low-Cost, Stand-Alone Sensor System for Snow Monitoring
Authors: Varhola Andrés , Wawerla Jens , Weiler Markus , Coops Nicholas C. , Bewley Daniel , Alila Younes 
Published: September 2010

Abstract
Monitoring continuous changes in snowpack dynamics and its meteorological drivers is critical for understanding key aspects of water resources, climate variability, and ecology. While manual snow surveys have traditionally been used to evaluate snow processes, their high costs and discrete measurements can lead to biased estimations of accumulation and ablation rates. Ultrasonic range sensors offer an alternative to continuously monitor snow depth but their widespread employment has been limited because of high prices. This paper describes the development of an inexpensive prototype ultrasonic sensor suite characterized by a ready-to-use stand-alone design and flexibility to incorporate additional meteorological instruments. The performance of 48 units was tested during a winter season in central British Columbia, recording snow depth and air temperature data consistent with those from nearby weather stations and manual measurements. Despite a relatively small underestimation of snow depth due to known, repairable reasons, the sensor system demonstrated reliability for research and operations.
Multiple sclerosis and epileptic seizures
Authors: Catenoix H , Marignier R , Ritleng C , Dufour M , Mauguière F , Confavreux C , Vukusic S 
Published: September 2010

Background: The association between epilepsy and multiple sclerosis (MS) is not a coincidence. Objective: Our objective was to compare MS patients with or without history of seizures. Methods: In a population of 5041 MS patients, we identified 102 (2%) patients with epileptic seizures. In 67 patients (1.3%), epileptic seizure could not be explained by any cause other than MS. Results: In these 67 patients, the median age at occurrence of the first epileptic seizure was 33 years. Epilepsy was the initial clinical manifestation of MS in seven patients. In total, 62 patients (92.5%) presented only one or a few seizures, and 18 patients (27%) presented at least one episode of status epilepticus, fatal in two. Compared with MS patients without epilepsy, there was no difference in gender, type of MS course and time from onset of MS to the progressive phase. Conversely, the median age at MS onset was earlier (25.0 years vs. 30, p < 0.0001) and there was a trend for a shorter time from MS onset to non-reversible disability. Conclusions: Our study confirms an increased risk of epileptic seizures in MS patients. It underlines that seizures may be the first observable symptom in MS and the frequency and seriousness of status epilepticus.
From bumps in the road to the edge of chaos: The nature of change in adults
Authors: King Keenan Elizabeth 
Published: September 2010

• Summary: This article explores the question of how human beings change, how change is constrained, and how change emerges out of and subsequently creates new forms of stability with adults. The emergence of Dynamic Systems Theories (DST) from developmental biology and neuroscience provide the tools to engage in such an understanding by attending to the issues of time, balance, influencing parameters (within person and sociocultural and material environments), and multiple adaptive and maladaptive pathways. DST provides the framework to understand the dynamic processes of bio-psychosocial factors that provide human beings with the stability and the flexibility to navigate the challenges and stressors of living. Complexity, the ability to experience inner continuity as one is changing, is a fluid balance that supports effective functioning. • Findings: Key principles and concepts of DST describe multiple pathways of stability and change. A case example illustrates how DST helps social workers understand client experiences and responses to stressors, formulate initial and ongoing assessments, and monitor clients’ participation in change activities. • Application: Social workers seek to help people who experience an imbalance due to an inability to effectively respond to the negative impact of a stressor. By understanding the various pathways of balance and imbalance along the continuum of continuity to change, social workers can better understand how stressors are impacting specific clients, and subsequently the kinds of change that would best assist each client.
Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients
Authors: Leahy Michael F. , Turner J. Harvey 
Published: September 2010

Abstract
Radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of 131I-rituximab radioimmunotherapy and compares favorably with those reported for 131I-tositumomab or 90Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with 131I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse.
High-definition mapping of retroviral integration sites identifies active regulatory elements in human multipotent hematopoietic progenitors
Authors: Cattoglio Claudia , Pellin Danilo , Rizzi Ermanno , Maruggi Giulietta , Corti Giorgio , Miselli Francesca , Sartori Daniela , Guffanti Alessandro , Di Serio Clelia , Ambrosi Alessandro , De Bellis Gianluca , Mavilio Fulvio 
Published: September 2010

Abstract
Integration of retroviral vectors in the human genome follows nonrandom patterns that favor insertional deregulation of gene expression and increase the risk of their use in clinical gene therapy. The molecular basis of retroviral target site selection is still poorly understood. We used deep sequencing technology to build genomewide, high-definition maps of > 60 000 integration sites of Moloney murine leukemia virus (MLV)– and HIV-based retroviral vectors in the genome of human CD34+ multipotent hematopoietic progenitor cells (HPCs) and used gene expression profiling, chromatin immunoprecipitation, and bioinformatics to associate integration to genetic and epigenetic features of the HPC genome. Clusters of recurrent MLV integrations identify regulatory elements (alternative promoters, enhancers, evolutionarily conserved noncoding regions) within or around protein-coding genes and microRNAs with crucial functions in HPC growth and differentiation, bearing epigenetic marks of active or poised transcription (H3K4me1, H3K4me2, H3K4me3, H3K9Ac, Pol II) and specialized chromatin configurations (H2A.Z). Overall, we mapped 3500 high-frequency integration clusters, which represent a new resource for the identification of transcriptionally active regulatory elements. High-definition MLV integration maps provide a rational basis for predicting genotoxic risks in gene therapy and a new tool for genomewide identification of promoters and regulatory elements controlling hematopoietic stem and progenitor cell functions.
Lyn- and PLC-β3–dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease
Authors: Xiao Wenbin , Ando Tomoaki , Wang Huan-You , Kawakami Yuko , Kawakami Toshiaki 
Published: September 2010

AbstractHyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)–β3-dependent manner. Thus, PLC-β3–deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)– deficient mice. Here we show that Lyn/PLC-β3 doubly deficient lyn−/−;PLC-β3−/− mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn−/−;PLC-β3−/− mice that cause the CMML-like disease, phosphorylation of SHP-1 at Tyr536 and Tyr564 is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr564 by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr536 in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-β3–mediated regulatory mechanism of SHP-1 and Stat5 activities.
Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development
Authors: Schaffner Florence , Versteeg Henri H. , Schillert Anja , Yokota Naho , Petersen Lars C. , Mueller Barbara M. , Ruf Wolfram 
Published: September 2010

AbstractConstitutive expression of tissue factor (TF) by cancer cells triggers local activation of the coagulation cascade and promotes breast cancer progression through cell signaling involving protease activated receptor (PAR)2. In human breast cancer, TF and PAR2 are up-regulated and TF cytoplasmic domain phosphorylation is correlated with relapse. Here we show that cancer cell PAR2 signaling promotes angiogenesis independent of PAR2 phosphorylation at the recognized β-arrestin recruitment site. Similar to PAR2−/− mice, TF cytoplasmic domain–deleted (TFΔCT) mice have delayed spontaneous breast cancer development in the polyoma middle T model. Simultaneous deletion of PAR2 in TFΔCT mice did not further delay tumor appearance, consistent with overlapping roles of TF and PAR2 in promoting the angiogenic switch in early stages of breast cancer. In advanced carcinomas, tumor-associated macrophages were reduced in TFΔCT and TFΔCT/PAR2−/− mice, and increased tumor vessel diameters of TFΔCT mice were partially reversed by PAR2-deficiency, indicating that the TF cytoplasmic domain has additional roles that are interdependent with PAR2 signaling in regulating host angiogenic responses. These experiments demonstrate a crosstalk of tumor cell TF cytoplasmic domain and PAR2 signaling and provide a possible mechanism for the close correlation between TF phosphorylation and cancer recurrence of TF and PAR2-positive clinical breast cancer.