bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Biodistribution and Pharmacokinetic Trial of Humanized Monoclonal Antibody Hu3s193 in Patients with Advanced Epithelial Cancers that Express the Lewis-Y Antigen
Authors: Scott Andrew M. , Tebbutt Niall , Lee Fook-Thean , Cavicchiolo Tina , Liu Zhanqi , Gill Sanjeev , Poon Aurora M.T. , Hopkins Wendie , Smyth Fiona E. , Murone Carmel , MacGregor Duncan , Papenfuss Anthony T. , Chappell Bridget , Saunder Timothy H. , Brechbiel Martin W. , Davis Ian D. , Murphy Roger , Chong Geoffrey , Hoffman Eric W. , Old Lloyd J. 
Published: June 2007

Abstract
Purpose: We report a first-in-man trial of a humanized antibody (hu3S193) against the Ley antigen.
Experimental Design: Patients with advanced Ley-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m2). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients.
Results: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non–small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40mg/m2 dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of 111In-hu3S193 showed no evidence of any consistent normal tissue uptake, and 111In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T1/2β = 189.63 ± 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed.
Conclusion: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Ley-expressing cancers.
The peroxisome proliferator-activated receptor-γ agonist troglitazone inhibits transforming growth factor-β–mediated glioma cell migration and brain invasion
Authors: Coras Roland , Hölsken Annett , Seufert Sebastian , Hauke Jan , Eyüpoglu Ilker Y. , Reichel Martin , Tränkle Christian , Siebzehnrübl Florian A. , Buslei Rolf , Blümcke Ingmar , Hahnen Eric 
Published: June 2007

AbstractGliomas are the most common primary tumors of the central nervous system, with glioblastomas as the most malignant entity. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Considering its promigratory properties, the transforming growth factor-β (TGF-β) signaling pathway has become a major therapeutic target. Analyses of resected glioma tissues revealed an intriguing correlation between tumor grade and the expression of TGF-β1-3 as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR-γ activator troglitazone blocked glioma progression without neurotoxic damage to the organotypic neuronal environment observed. This intriguing antiglioma property of troglitazone seems to be only partially based on its moderate cytostatic effects. We identified troglitazone as a potent inhibitor of glioma cell migration and brain invasion, which occurred in a PPAR-γ–independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-β1-3 and their receptors I and II and associated with reduced TGF-β release. Due to its capacity to counteract TGF-β release and glioma cell motility and invasiveness already at low micromolar doses, troglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities. [Mol Cancer Ther 2007;6(6):1745–54]
A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia
Authors: Ikezoe Takayuki , Yang Jing , Nishioka Chie , Tasaka Taizo , Taniguchi Ayuko , Kuwayama Yoshio , Komatsu Naoki , Bandobashi Kentaro , Togitani Kazuto , Koeffler H. Phillip , Taguchi Hirokuni 
Published: June 2007

Abstract
The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia. [Mol Cancer Ther 2007;6(6):1851–7]
Detection of myeloma in skeleton of mice by whole-body optical fluorescence imaging
Authors: Oyajobi Babatunde O. , Muñoz Steve , Kakonen Rami , Williams Paul J. , Gupta Anjana , Wideman Christi L. , Story Beryl , Grubbs Barry , Armstrong Allison , Dougall William C. , Garrett I. Ross , Mundy Gregory R. 
Published: June 2007

Abstract
Development of new therapies for myeloma has been hindered by the lack of suitable preclinical animal models of the disease in which widespread tumor foci in the skeleton can be detected reliably. Traditional means of detecting skeletal tumor infiltration such as histopathology are cumbersome and labor-intensive and do not allow temporal monitoring of tumor progression or regression in response to therapy. To resolve this problem, we modified the Radl 5TGM1 model of myeloma bone disease such that fluorescent myeloma tumors can be optically imaged in situ. Here, we show that murine myeloma 5TGM1 tumor cells, engineered to express enhanced green fluorescent protein (eGFP; 5TGM1-eGFP cells), can be imaged in a temporal fashion using a fluorescence illuminator and a charge-coupled device camera in skeletons of live C57BL/KaLwRij mice. High-resolution, whole-body images of tumor-bearing mice revealed that myeloma cells homed almost exclusively to the skeleton, with multiple focal tumor foci in the axial skeleton, consistent with myeloma tumor distribution in humans. Finally, the tested antitumor treatment effect of Velcade (bortezomib), a proteasome inhibitor used clinically in myeloma, was readily detected by GFP imaging, suggesting the power of the technique in combination with the Radl 5TGM1-eGFP model for rapid preclinical assessment and sensitive monitoring of novel and potential therapeutics. Whole-body GFP imaging is practical, convenient, inexpensive, and rapid, and these advantages should enable a high throughput when evaluating in vivo efficacy of new potential antimyeloma therapeutics and assessing response to treatment. [Mol Cancer Ther 2007;6(6):1701–8]
Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non–small cell lung carcinoma
Authors: Frederick Barbara A. , Helfrich Barbara A. , Coldren Christopher D. , Zheng Di , Chan Dan , Bunn Paul A. , Raben David 
Published: June 2007

AbstractThe modest response of patients with head and neck squamous cell carcinoma (HNSCC) and non–small cell lung carcinoma (NSCLC) to epithelial growth factor receptor tyrosine kinase inhibitors such as gefitinib and erlotinib indicates the need for the development of biomarkers to predict response. We determined gefitinib sensitivity in a panel of HNSCC cell lines by a 5-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and confirmed these responses with analysis of downstream signaling by immunoblotting and cell cycle arrest. Basal gene expression profiles were then determined by microarray analysis and correlated with gefitinib response. These data were combined with previously reported NSCLC microarray results to generate a broader predictive index. Common markers of resistance between the two tumor types included genes associated with the epithelial to mesenchymal transition. We confirmed that increased protein expression of vimentin combined with the loss of E-cadherin, claudin 4, and claudin 7 by immunoblotting was associated with gefitinib resistance in both HNSCC and NSCLC cell lines. In addition, the loss of the Ca2+-independent cell-cell adhesion molecules EpCAM and TROP2 in resistant lines was confirmed by immunofluorescence. Tumor xenografts derived from the gefitinib-sensitive UM-SCC-2 were growth-delayed by gefitinib, whereas the gefitinib-resistant 1483 xenografts were unaffected. These data support a role for epithelial to mesenchymal transition in establishing gefitinib resistance for both HNSCC and NSCLC, and indicate that clinical trials should address whether these biomarkers will be useful for patient selection. [Mol Cancer Ther 2007;6(6):1683–91]
Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation
Authors: Langlois Stéphanie , Nyalendo Carine , Di Tomasso Geneviève , Labrecque Lyne , Roghi Christian , Murphy Gillian , Gingras Denis , Béliveau Richard 
Published: June 2007

Abstract
Proteolysis of extracellular matrix proteins by membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in tumor and endothelial cell migration. In addition to its proteolytic activity, several studies indicate that the proinvasive properties of MT1-MMP also involve its short cytoplasmic domain, but the specific mechanisms mediating this function have yet to be fully elucidated. Having previously shown that the serum factor sphingosine 1-phosphate stimulates MT1-MMP promigratory function through a process that involves its cytoplasmic domain, we now extend these findings to show that this cooperative interaction is permissive to cellular migration through MT1-MMP–dependent transactivation of the epidermal growth factor receptor (EGFR). In the presence of sphingosine 1-phosphate, MT1-MMP stimulates EGFR transactivation through a process that is dependent upon the cytoplasmic domain of the enzyme but not its catalytic activity. The MT1-MMP–induced EGFR transactivation also involves Gi protein signaling and Src activities and leads to enhanced cellular migration through downstream extracellular signal-regulated kinase activation. The present study, thus, elucidates a novel role of MT1-MMP in signaling events mediating EGFR transactivation and provides the first evidence of a crucial role of this receptor activity in MT1-MMP promigratory function. Taken together, our results suggest that the inhibition of EGFR may represent a novel target to inhibit MT1-MMP–dependent processes associated with tumor cell invasion and angiogenesis. (Mol Cancer Res 2007;5(6):569–83)
Paleolithic Ornaments: Implications for Cognition, Demography and Identity
Authors: Kuhn Steven L. , Stiner Mary C. 
Published: June 2007

AbstractBeads and other ‘body ornaments’ are very widespread components of the archaeological record of early modern humans (Homo sapiens). They appear first in the Middle Stone Age in Africa, and somewhat later in the Early Upper Paleolithic of Eurasia. The manufacture and use of ornaments is widely considered to be evidence for significant developments in human cognition. In our view, the appearance of these objects represents the interaction of evolved cognitive capacities with changing social and demographic conditions. Body ornamentation is a medium or technology for communication, particularly of socially-relevant information. The widespread adoption of beads and other discrete objects as media for communication implies changes in the complexity and stability of social messages, as well as the scale of social networks. The relatively sudden appearance of beads in the Paleolithic archaeological record coincides with genetic and archaeological evidence for expansion of human populations. We argue that these changes reflect expanding scales of social interaction and more complex social landscapes resulting from unprecedentedly large and internally differentiated human populations.
The Origin of Art
Authors: Lorblanchet Michel 
Published: June 2007

AbstractThe very concept of the ‘birth’ or ‘origin’ of art may seem inappropriate, since humans are by nature artists and the history of art begins with that of humanity. In their artistic impulses and achievements humans express their vitality, their ability to establish a beneficial and positive relationship with their environment, to humanize nature; their behaviour as artists is one of the characteristics for selection favourable to the evolution of the human species. Evidence from a huge analysis of rock art and cave paintings and engravings shows that, from their origins, humans have also been Homo aestheticus.
The Origin of Humanity and Modern Cultures: Archaeology's View
Authors: d'Errico Francesco 
Published: June 2007

AbstractIt is hard to define cultural modernity. Nonetheless, apparently there is no match between biological and cultural evolution, between biological and archaeological data. The features of cultural modernity cannot be seen as a direct consequence of the biological origin of our species. A second crucial aspect is that the subsistence strategies, technological and symbolic traditions of Neanderthals are not significantly different from those of modern humans living in Africa and the Near East at the same period. Europe, at the level of human evolution, was a cul-de-sac and not a disseminating centre. Bifaces reached Europe a million years after their invention in Africa. Homo sapiens and Neanderthals thus evolved in parallel, even though speed and cultural forms varied from one population to another. It now seems clear that the features we recognize as ‘modern’ appeared in different regions and in different human groups. It would be the same later with the invention of agriculture, writing, state societies, which appeared separately at several points on the planet.
MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism
Authors: Pei Xin-Yan , Dai Yun , Tenorio Sarah , Lu Jianghua , Harada Hisashi , Dent Paul , Grant Steven 
Published: June 2007

AbstractThe role of Bim in synergistic interactions between UCN-01 and MEK1/2 inhibitors in human multiple myeloma cells was investigated. Exposure of U266 or RPMI8226 cells to UCN-01 resulted in ERK1/2 activation-associated BimEL phosphorylation/down-regulation, events abrogated by MEK1/2 inhibitors. Enforced activation of ERK1/2 by transfection with constitutively active MEK1 diminished the capacity of PD98059 but not PD184352 to block UCN-01–mediated BimEL phosphorylation and to potentiate apoptosis. Cotreatment with MEK1/2 inhibitors increased the association of BimEL with both Bcl-2 and Bcl-xL in UCN-01–treated cells, leading to Bax/Bak conformational change and Bax mitochondrial translocation. Down-regulation of BimEL by shRNA substantially diminished UCN-01/MEK inhibitor-mediated Bax/Bak activation and apoptosis. Furthermore, transfection of cells with S65A Bim, a mutant resistant to UCN-01–mediated phosphorylation, significantly sensitized cells to UCN-01 lethality. Conversely, ectopic expression of either Bcl-2 or Bcl-xL did not alter UCN-01/MEK1/2 inhibitor-mediated modifications in BimEL phosphorylation but largely prevented cell death. Finally, IL-6 or IGF-1 failed to prevent MEK1/2 inhibitors from blocking UCN-01–induced BimEL phosphorylation/degradation or cell death. Collectively, these findings argue that UCN-01–mediated ERK1/2 activation leads to BimEL phosphorylation/inactivation, resulting in cytoprotection, and that interference with these events by MEK1/2 inhibitors plays a critical role in synergistic induction of apoptosis by these agents.
sIR: siRNA Information Resource, a web-based tool for siRNA sequence design and analysis and an open access siRNA database
Authors: Shah Jyoti K , Garner Harold R , White Michael A , Shames David S , Minna John D 
Published: June 2007

Abstract

Background
RNA interference has revolutionized our ability to study the effects of altering the expression of single genes in mammalian (and other) cells through targeted knockdown of gene expression. In this report we describe a web-based computational tool, siRNA Information Resource (sIR), which consists of a new open source database that contains validation information about published siRNA sequences and also provides a user-friendly interface to design and analyze siRNA sequences against a chosen target sequence.

Results
The siRNA design tool described in this paper employs empirically determined rules derived from a meta-analysis of the published data; it uses a weighted scoring system that determines the optimal sequence within a target mRNA and thus aids in the rational selection of siRNA sequences. This scoring system shows a non-linear correlation with the knockdown efficiency of siRNAs. sIR provides a fast, customized BLAST output for all selected siRNA sequences against a variety of databases so that the user can verify the uniqueness of the design. We have pre-designed siRNAs for all the known human genes (24,502) in the Refseq database. These siRNAs were pre-BLASTed against the human Unigene database to estimate the target specificity and all results are available online.

Conclusion
Although most of the rules for this scoring system were influenced by previously published rules, the weighted scoring system provides better flexibility in designing an appropriate siRNA when compared to the un-weighted scoring system. sIR is not only a comprehensive tool used to design siRNA sequences and lookup pre-designed siRNAs, but it is also a platform where researchers can share information on siRNA design and use.
A set of stage-specific gene transcripts identified in EK stage X and HH stage 3 chick embryos
Authors: Lee Bo Ram , Kim Heebal , Park Tae Sub , Moon Sunjin , Cho Seoae , Park Taesung , Lim Jeong Mook , Han Jae Yong 
Published: June 2007

Abstract

Background
The embryonic developmental process in avian species is quite different from that in mammals. The first cleavage begins 4 h after fertilization, but the first differentiation does not occur until laying of the egg (Eyal-Giladi and Kochav (EK) stage X). After 12 to 13 h of incubation (Hamburger and Hamilton (HH) stage 3), the three germ layers form and germ cell segregation in the early chick embryo are completed. Thus, to identify genes associated with early embryonic development, we compared transcript expression patterns between undifferentiated (stage X) and differentiated (HH stage 3) embryos.

Results
Microarray analysis primarily showed 40 genes indicating the significant changes in expression levels between stage X and HH stage 3, and 80% of the genes (32/40) were differentially expressed with more than a twofold change. Among those, 72% (23/32) were relatively up-regulated at stage X compared to HH stage 3, while 28% (9/32) were relatively up-regulated at HH stage 3 compared to stage X. Verification and gene expression profiling of these GeneChip expression data were performed using quantitative RT-PCR for 32 genes at developmental four points; stage X (0 h), HH stage 3 (12 h), HH stage 6 (24 h), and HH stage 9 (30 h). Additionally, we further analyzed four genes with less than twofold expression increase at HH stage 3. As a result, we identified a set of stage-specific genes during the early chick embryo development; 21 genes were relatively up-regulated in the stage X embryo and 12 genes were relatively up-regulated in the HH stage 3 embryo based on both results of microarray and quantitative RT-PCR.

Conclusion
We identified a set of genes with stage-specific expression from microarray Genechip and quantitative RT-PCR. Discovering stage-specific genes will aid in uncovering the molecular mechanisms involved the formation of the three germ layers and germ cell segregation in the early chick embryos.
Nasal carriage of a single clone of community-acquired methicillin-resistant Staphylococcus aureus among kindergarten attendees in northern Taiwan
Authors: Lo Wen-Tsung , Lin Wei-Jen , Tseng Min-Hua , Lu Jang-Jih , Lee Shih-Yi , Chu Mong-Ling , Wang Chih-Chien 
Published: June 2007

Abstract

Background:
To evaluate the prevalence and microbiological characterization of community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage in a kindergarten.

Methods:
Point prevalence study. Nasal swabs were collected from healthy children younger than 7 years of age who were attending a kindergarten in Taipei, Taiwan. A parent questionnaire regarding MRSA risk factors was administered simultaneously. All CA-MRSA colonization isolates were archived for subsequent antimicrobial susceptibility and molecular typing.

Results:
Of the 68 children who participated in the study, 17 (25%) had S. aureus isolated from nasal swabs. Nine (13.2%) of the 68 children had CA-MRSA carriage, and none of them had any identified risk factors. Antimicrobial susceptibility testing revealed all of the 9 CA-MRSA colonization isolates had uniformly high resistance (100%) to both clindamycin and erythromycin, the macrolide-lincosamide-streptogramin-constitutive phenotype and the ermB gene. Pulsed-field gel electrophoresis revealed 8 (88.9%) of 9 CA-MRSA colonization isolates were genetically related and multilocus sequence typing revealed all isolates had sequence type 59. All of the colonization isolates carried the staphylococcal cassette chromosome mec type IV, but none were positive for the Panton-Valentine leukocidin genes.

Conclusion:
The results of this study suggest that a single predominant CA-MRSA colonization strain featuring high clindamycin resistance circulated in this kindergarten. Additionally, due to the established transmissibility of colonization isolates, the high prevalence of nasal carriage of CA-MRSA among healthy attendees in kindergartens may indicate the accelerated spread of CA-MRSA in the community.
Protein kinase C and human uterine contractility
Authors: Eude-Le Parco Isabelle , Dallot Emmanuelle , Breuiller-Fouché Michelle 
Published: June 2007

Abstract
Abnormalities in uterine contractility are thought to contribute to several clinical problems, including preterm labor. A better understanding of the mechanisms controlling uterine activity would make it possible to propose more appropriate and effective management practices than those currently in use. Recent advances point to a role of the protein kinase C (PRKC) family in the regulation of uterine smooth muscle contraction at the end of pregnancy. In this review, we highlight recent work that explores the involvement of individual PRKC isoforms in cellular process, with an emphasis on the properties of PRKCZ isoform.