bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Role for Mek1 but not Mek2 in the Induction of Epidermal Neoplasia
Authors: Scholl Florence A. , Dumesic Phillip A. , Barragan Deborah I. , Harada Kazutoshi , Charron Jean , Khavari Paul A. 
Published: April 2009

Abstract
The Ras/Raf/Mek/Erk mitogen-activated protein kinase pathway regulates fundamental processes in normal and malignant cells, including proliferation, differentiation, and cell survival. Mutations in this pathway have been associated with carcinogenesis and developmental disorders, making Mek1 and Mek2 prime therapeutic targets. In this study, we examined the requirement for Mek1 and Mek2 in skin neoplasia using the two-step 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) skin carcinogenesis model. Mice lacking epidermal Mek1 protein develop fewer papillomas than both wild-type and Mek2-null mice following DMBA/TPA treatment. Mek1 knockout mice had smaller papillomas, delayed tumor onset, and half the tumor burden of wild-type mice. Loss of one Mek1 allele, however, did not affect tumor development, indicating that one Mek1 allele is sufficient for normal papilloma formation. No difference in TPA-induced hyperproliferation, inflammation, or Erk activation was observed between wild-type, conditional Mek1 knockout, and Mek2-null mice, indicating that Mek1 findings were not due to a general failure of these processes. These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting. [Cancer Res 2009;69(9):3772–8]
Administration of Glucocorticoids to Ovarian Cancer Patients Is Associated with Expression of the Anti-apoptotic Genes SGK1 and MKP1/DUSP1 in Ovarian Tissues
Authors: Melhem Amal , Yamada S. Diane , Fleming Gini F. , Delgado Bertha , Brickley Deanna R. , Wu Wei , Kocherginsky Masha , Conzen Suzanne D. 
Published: April 2009

Abstract
Purpose: To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulated kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline.
Experimental Design: Eighteen patients were randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were determined using quantitative real-time PCR.
Results: Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor.
Conclusion: Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patients through increased anti-apoptotic gene expression.
Estrous Cycle Modulates Ovarian Carcinoma Growth
Authors: Armaiz-Pena Guillermo N. , Mangala Lingegowda S. , Spannuth Whitney A. , Lin Yvonne G. , Jennings Nicholas B. , Nick Alpa M. , Langley Robert R. , Schmandt Rosemarie , Lutgendorf Susan K. , Cole Steven W. , Sood Anil K. 
Published: April 2009

Abstract
Purpose: The effects of reproductive hormones on ovarian cancer growth are not well understood. Here, we examined the effects of estrous cycle variation and specific reproductive hormones on ovarian cancer growth.
Experimental Design: We investigated the role of reproductive hormones in ovarian cancer growth using both in vivo and in vitro models of tumor growth.
Results: In vivo experiments using the HeyA8 and SKOV3ip1 ovarian cancer models showed that tumor cell inoculation during proestrus significantly increased tumor burden (251-273%) compared with injection during the estrus phase. Treatment of ovariectomized mice with 17β-estradiol resulted in a 404% to 483% increase in tumor growth compared with controls. Progestins had no significant effect, but did block estrogen-stimulated tumor growth. Tumors collected from mice sacrificed during proestrus showed increased levels of vascular endothelial growth factor (VEGF) and microvessel density compared with mice injected during estrus. HeyA8, SKOV3ip1, and mouse endothelial (MOEC) cells expressed estrogen receptor α and β and progesterone receptor at the protein and mRNA levels, whereas 2774 ovarian cancer cells were estrogen receptor–negative. In vitro assays showed that 17β-estradiol significantly increased ovarian cancer cell adhesion to collagen in estrogen receptor–positive, but not in estrogen receptor–negative cells. Additionally, 17β-estradiol increased the migratory potential of MOEC cells, which was abrogated by the mitogen-activated protein kinase (MAPK) inhibitor, PD 09859. Treatment with 17β-estradiol activated MAPK in MOEC cells, but not in HeyA8 or SKOV3ip1 cells.
Conclusion: Our data suggest that estrogen may promote in vivo ovarian cancer growth, both directly and indirectly, by making the tumor microenvironment more conducive for cancer growth.
Phosphatidylinositol-3-Kinase as a Therapeutic Target in Melanoma
Authors: Aziz Saadia A. , Davies Michael , Pick Elah , Zito Christopher , Jilaveanu Lucia , Camp Robert L. , Rimm David L. , Kluger Yuval , Kluger Harriet M. 
Published: April 2009

Abstract
Purpose: Phosphatidylinositol-3 kinases (PI3K) are critical for malignant cellular processes including growth, proliferation, and survival, and are targets of drugs in clinical development. We assessed expression of PI3K in melanomas and nevi, and studied associations between PI3K pathway members and in vitro response to a PI3K inhibitor, LY294002.
Experimental Design: Using Automated Quantitative Analysis, we quantified expression of p85 and p110α subunits in 540 nevi and 523 melanomas. We determined the IC50 for LY294002 for 11 melanoma cell lines and, using reverse phase protein arrays, assessed the association between levels of PI3K pathway members and sensitivity to LY294002.
Results: p85 and p110α tend to be coexpressed (P &lt; 0.0001); expression was higher in melanomas than nevi (P &lt; 0.0001) for both subunits, and higher in metastatic than primary melanomas for p85 (P &lt; 0.0001). Although phospho-Akt (pAkt) levels decreased in all cell lines treated with LY294002, sensitivity was variable. We found no association by t tests between baseline p85, p110α, and pAkt levels and sensitivity to LY294002, whereas pS6 Ser235 and Ser240 were lower in the more resistant cell lines (P = 0.01 and P = 0.004, respectively).
Conclusions: Expression of p85 and p110α subunits is up-regulated in melanoma, indicating that PI3K is a good drug target. Pretreatment pS6 levels correlated with sensitivity to the PI3K inhibitor, LY294002, whereas PI3K and pAkt did not, suggesting that full activation of the PI3K pathway is needed for sensitivity to PI3K inhibition. pS6 should be evaluated as a predictor of response in melanoma patients treated with PI3K inhibitors, as these drugs enter clinical trials.
Epigenetic reversal of acquired resistance to 5-fluorouracil treatment
Authors: Humeniuk Rita , Mishra Prasun J. , Bertino Joseph R. , Banerjee Debabrata 
Published: April 2009

Abstract
Acquired and intrinsic resistance still remains a limitation to the clinical use of 5-fluorouracil (5-FU). The contribution of epigenetic changes to the development of drug resistance remains to be elucidated. Several genes that are hypermethylated and silenced have been identified in colorectal cancer. Based on the findings described in the accompanying article, we hypothesized that acquired resistance to “pulse” 5-FU has an epigenetic origin and might be reversed. Here, we present a novel therapeutic approach to circumvent clinical resistance to bolus 5-FU, that is, treatment of bolus 5-FU-resistant colorectal cancer cells with low-dose 5-azadeoxycytidine (DAC), an inhibitor of DNA hypermethylation, restored sensitivity to 5-FU as well as 5-fluorouridine. Moreover, treatment of nude mice bearing a 5-FU-resistant tumor, characterized by decreased levels of UMP kinase (UMPK), with DAC overcame resistance to bolus 5-FU. DAC-mediated restoration of 5-FU sensitivity was associated with increases in UMPK levels. An increase in UMPK protein and mRNA levels following treatment with low-dose DAC was observed in cultured bolus 5-FU-resistant colorectal cancer cells (HCT-8) and in mice bearing these tumors. We conclude that DAC-mediated restoration of sensitivity to bolus 5-FU is mediated at least in part by increased UMPK levels and clinical resistance to 5-FU due to decreased UMPK in colorectal cancer may be overcome by including methylation inhibitors such as DAC. [Mol Cancer Ther 2009;8(5):1045–54]
Young Men and Islam in the 1990s: Rethinking an Intergenerational Perspective
Authors: Savadogo Mathias , LeBlanc Marie-Nathalie , Gomez-Perez Muriel 
Published: April 2009

AbstractInterest in the question of youth and Islam in West Africa stems from the overwhelming demographic weight of youth and their relatively recent incursion into the public domain, as well a wave of Islamic revivalism that has swept across Africa from the late 1970s on. In this paper, we propose to examine the sociopolitical role of young men in Islamic revivalist movements that occurred in urban centers in Côte d'Ivoire, Burkina Faso and Senegal in the 1980-1990s. Such movements were particularly popular among secularly educated young men who attended French-speaking schools. While the role of young men in revivalist movements suggests new configurations of authority and charisma, their religious agency remains closely embedded within relationships that extend across generations. Here, we examine instances of conflicts between generations and pay attention to sites of negotiation, such as mosques and voluntary associations.
Modes of Explanation in the Aristotelian Mechanical Problems
Authors: De Groot Jean 
Published: April 2009

AbstractScholars have been puzzled by the central argument of MP 1 where the author addresses the basic principle behind the balance and lever. It is not clear what is intended to provide the explanation—the dynamic concepts of force and constraint or the geometrical demonstration. Nor is it clear whether the geometrical part of the argument carries any logical force or has value as a proof. This paper makes a case for the cogency of the argument as a kinematic, not dynamic, account. MP 1 proceeds systematically as it extends the explanatory power of the parallelogram of movements from rectilinear motion to circular motion. Euclid's Elements I.43 provides insight on the author's procedure. His general method is demonstrative, as described in Posterior Analytics I.1.
Structures of Argument and Concepts of Force in the Aristotelian Mechanical Problems
Authors: Schiefsky Mark 
Published: April 2009

AbstractI argue that the main goal of the Mechanical Problems, a short treatise transmitted in the Corpus Aristotelicum, is to explain the working of technology in terms of the concepts of Aristotelian natural philosophy. The author's explanatory strategy is to reduce the thirty-five "problems" or questions that he discusses to one or more of three simple models: the circle, balance, and lever. The conceptual foundation of this reduction program is a principle concerning circular motion, viz. that a point on the circumference of a larger circle moves more quickly than one on a smaller circle, assuming that the circles turn about the same center at the same angular speed. I analyze the author's argument for this principle and his application of it throughout the text, especially to the analysis of the lever. The main conclusions are (1) that the author's justification of the circular motion principle is based on an innovative geometrical analysis of motion, not on a highly theoretical conceptualization of force; and (2) while the author is aware of a reciprocal relationship between weights and distances from the fulcrum in the case of the lever, his explanation of this fact makes no reference to the conditions for static equilibrium.
The Simple Ontology of Kalām Atomism: An Outline
Authors: Sabra Abdelhamid I. 
Published: April 2009

AbstractThis paper aims to present concisely the Islamic kalām atomism as an alternative philosophy to Hellenizing falsafa. Kalām is a theological-philosophical discourse which, first (in the third/ninth century) ventured to rival the falsafa represented early by al-Kindī (d.ca. 252/866), then by al-Fārābī and Avicenna in the fourth/tenth and fifth/eleventh centuries, and which eventually (in the sixth/twelfth century and after) appeared to be inclined to propose a mingling of the kalām discourse with falsafa in a series of varied "syntheses".—Focusing on the simple ontology of the basic kalām atomism, and noting the hybrid character of kalām, the aim of this paper is to help to clarify the inevitable problematic consequences of those late ventures of Islamic intellectualism.
Footprints of "Experiment" in Early Arabic Optics
Authors: Kheirandish Elaheh 
Published: April 2009

AbstractThis study traces the early developments of the concept of experiment with a view of extending the subject in both content and approach. It extends the content of the subject slightly backward, prior to the methodological breakthroughs of the Optics of Ibn al-Haytham (Alhazen or Alhacen, d. ca. 1040), which are credited as a "significant landmark in the history of experimental science." And it extends the approach to the subject slightly forward, from the premise that early science was "largely carried out in books," to a close examination of the books through which the footprints of 'experiment' may be traced. The point of departure is the Optics of Ahmad ibn 'Ī;sā, a revealing text for the early developments of concepts such as 'demonstration' and 'experiment', and one through which some modern discussions are examined and extended with reference to this and other historical sources.
The "Experience-Based Medicine" of the Thirteenth Century
Authors: McVaugh Michael 
Published: April 2009

AbstractWe should not assume that medieval physicians did not take pains to found their practice upon evidence. Academic physicians at Montpellier ca. 1300 were cautious about accepting textbook claims for the powers of drugs, and tried to verify each drug's physiological effects before using it; yet they were also flexible, ready to believe that powerful new medicines might be discovered empirically that were unknown to their authorities or superficially inconsistent with existing knowledge. Likewise, physicians were careful to observe their patients closely and to try to identify the condition from which each was suffering, and when they were unsure of the nature of an illness, they feared to administer medicines lest their known effects might be harmful to the patient. Anticipating today's "evidence-based medicine," the physician's practice involved the conscientious use of current best evidence.
The Intellect Naturalized: Roger Bacon on the Existence of Corporeal Species within the Intellect
Authors: Raizman-Kedar Yael 
Published: April 2009

AbstractIn this paper I challenge the claim that Bacon considered the operation of species as limited to the physical and sensory levels and demonstrate that in his view, the very same species issued by physical objects operate within the intellect as well. I argue that in Bacon the concept of illumination plays a secondary role in the acquisition of knowledge, and that he regarded innate knowledge as dispositional and confused. What was left as the main channel through which knowledge is gained were species received through the senses. I argue that according to Bacon these species, representing their agents in essence, definition and operation, arrive in the intellect without undergoing a complete abstraction from matter and while still retaining the character of agents acting naturally. In this way Bacon sets the intellect as separate from the natural world not in any essential way, but rather as it were in degree, thus supplying a theoretical justification for the ability to access and know nature.
Magic and the Physical World in Thirteenth-Century Scholasticism
Authors: Marrone Steven 
Published: April 2009

AbstractThe turn to modern science in the Scientific Revolution of the seventeenth century is typically characterized as dependent on the novel adoption of a mechanical hypothesis for operations in nature. In fact, the Middle Ages saw a partial anticipation of this phenomenon in the scholastic physics of the thirteenth century. More precisely, it was just the two factors, denial of action at a distance and an emphasis on the primary materiality of causation, that constituted this early mechanism—or "protomechanism." The latter's emergence can be seen most clearly where scholastic thinkers—here, William of Auvergne, Thomas Aquinas and Giles of Rome—confronted the theoretical limits of natural cause and effect in their efforts to determine the reality of magic and locate its place in the natural world.
The Debate over the Nature of Motion: John Buridan, Nicole Oresme and Albert of Saxony. With an Edition of John Buridan's Quaestiones super libros Physicorum, secundum ultimam lecturam, Book III, q. 7
Authors: Thijssen Johannes 
Published: April 2009

AbstractThe so-called 'Buridan school' at the University of Paris has obtained a considerable fame in the history of science. Pierre Duhem had made some bold claims about the achievements by John Buridan and his 'pupils' Nicole Oresme and Albert of Saxony in the field of medieval dynamics. Although generally, Duhem's views are no longer accepted, the idea of a 'Buridan school' has survived. This idea is, however, misleading. John Buridan, Nicole Oresme and Albert of Saxony should rather be viewed as members of an intellectual network. While interested in similar philosophical themes and understanding each other's conceptual language, they also disagreed about numerous topics. One case in point is the nature of motion, as discussed in their respective Questions on the Physics. Despite the common features of the language in which they discuss motion, the three thinkers defend different positions. This article compares the three sets of Questions on the Physics and presents a critical edition of Buridan's "ultima lectura", Book III, q. 7.
John Buridan and Critical Realism
Authors: Sylla Edith Dudley 
Published: April 2009

AbstractIn this paper I examine what John Buridan has to say in his Quaestiones in Analytica Posteriora relevant to the subalternate mathematical sciences, particularly astronomy. Much previous work on the scholastic background to the Scientific Revolution relies on texts that were written in the late sixteenth or seventeenth centuries. Here I am interested in texts that might reflect the context of Copernicus, and, in particular those before 1500. John Buridan and Albert of Saxony were fourteenth century authors influential in Cracow in the fifteenth century, whose conception of science may be characterized as "critical realism." Their view would support the autonomy of astronomy, as well as the idea that sciences may progress over time.
The Significance of "Chymical Atomism"
Authors: Newman William 
Published: April 2009

AbstractThe historical treatment of atomism and the mechanical philosophy largely neglects what I call "chymical atomism," namely a type of pre-Daltonian corpuscular matter theory that postulated particles of matter which were operationally indivisible. From the Middle Ages onwards, alchemists influenced by Aristotle's Meteorology, De caelo, and De generatione et corruptione argued for the existence of robust corpuscles of matter that resisted analysis by laboratory means. As I argue in the present paper, this alchemical tradition entered the works of Daniel Sennert and Robert Boyle, and became the common property of seventeenth-century chymists. Through Boyle, G.E. Stahl, and other chymists, the operational atomism of the alchemists was even transmitted to Antoine Laurent Lavoisier, where it became the basis of his claim that elements are simply "the final limit that analysis reaches."
Conjecture, Probabilism, and Provisional Knowledge in Renaissance Meteorology
Authors: Martin Craig 
Published: April 2009

AbstractFor Renaissance Aristotelian natural philosophers, ideally knowledge was certain and based on syllogistic demonstration. Many Italian scholars, such as Agostino Nifo, Pietro Pomponazzi, and Niccolò Cabeo, considered this ideal as inapplicable to the field of meteorology. Rather, because of the accidental nature of meteorological phenomena and the inherent irregularity of the weather, they believed that causal explanations of meteorology were largely conjectural, provisional, and probabilistic. Several of these natural philosophers applied the standard of "saving the appearances" to the field of meteorology because of the difficulties involved in making accurate observations. This lower epistemological standard contributed to the willingness of Aristotelians to revise meteorological theories and deviate from Aristotle's own positions.
Setting up Copernicus? Astronomy and Natural Philosophy in Giambattista Capuano da Manfredonia's Expositio on the Sphere
Authors: Shank Michael 
Published: April 2009

AbstractIn 1499, while Copernicus studies in Bologna, the commentary on Sacrobosco's Sphere by the Padua master Francesco Capuano da Manfredonia first appears in print. It will be revised and reprinted several times thereafter. Like Copernicus, Capuano has a high view of astronomy and mingles astronomical and physical considerations (flies moving on wheels, men on ships, impetus, comets, raptus). Also, Capuano offers a flawed argument against a two-fold (diurnal and zodiacal) motion of the Earth. Multiple thematic resonances between Capuano's commentary and De revolutionibus, I, 5-11, suggest the hypothesis that Copernicus is answering Capuano, whose work was owned by Joachim Rheticus, if not Copernicus himself.
Copernicus's Mereological Vision of the Universe
Authors: Goddu André 
Published: April 2009

AbstractMereology is the philosophical study of part/whole relations. Copernicus, Mästlin, and Kepler addressed explicitly some of the logical issues in their support of heliocentrism. Their emphasis on harmony and commensurability to evaluate theories as more or less likely fits with their use of part/whole relations to argue for the greater reasonability or probability of heliocentrism. The essay summarizes the logical and metaphysical issues that earlier traditions discussed, and it uses those discussions to illuminate features of heliocentric theories that remain otherwise obscure even in Newton.