bluuebunny/crossref_metadata_2025 huggingface dataset:
Water and Inca cosmogony: myths, geology and engineering in the Peruvian Andes
Authors: Mazadiego L. F. , Puche O. , Hervás A. M.
Published: March 2009

Water was a key element in the Inca civilization (
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.
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1438–1534), both for their crops and as part of their vision of the cosmos. According to myths on the origin of the Incas, their civilization arose from the sea through one of its main manifestations, Lake Titicaca. Throughout the period of Inca dominance, as in some of the cultures that preceded them, water was a sacred element. This vision of the cosmos can be regarded as a hydrogeological model with similarities to the beliefs in force in Europe from the classical period until the end of the seventeenth century. Because of their excellent intuitive understanding of water, the Incas developed a complex irrigation system to channel water to their agricultural lands. Coinciding with the distribution of water, they organized periodical thanksgiving festivals, when farming communities gathered to celebrate the beginning of a new agricultural cycle with songs, dances and festivities. However, the centralized control of water resources introduced in the twentieth century led to the disappearance of many of these traditions and to the replacement of an irrigation system that had proved acceptable, by one that was alien to the customs and history of the country people. This led to the first conflicts over water control. As a result, the vision of the cosmos based on water and rooted in agricultural communities has been lost.
Theodicic creationism: its membership and motivations
Authors: Peters Richard A.
Published: March 2009

This paper aims to facilitate understanding of the most radical form of contemporary creationism by describing the principal motivations of its adherents from the perspective of a former insider. Creationism that produces and promotes accounts of natural history that differ radically from conventional accounts—made up of so-called ‘biblical’ or ‘young-Earth’ creationists, ‘anti-evolutionists’ and ‘Flood geologists’—is herein called ‘theodicic creationism’.

Theodicic creationism is primarily concerned with defending God against the charge that he is responsible for natural evil; in other words, it is engaged in the production of a form of theodicy. Rather than accepting modern scientific accounts of natural history and then argue that these are compatible with the goodness of God, however, theodicic creationists conclude that conventional natural histories are not compatible with their view of God. They therefore begin with belief in a benevolent Creator and set out to produce an account of natural history that is compatible with it. Because almost any natural history will do for their purposes if it can shift the burden of responsibility for natural evil from divine to human shoulders, theodicic creationists are a relatively cohesive group, despite deep disagreements about the age of the Earth, the extent and role of Noah's Flood, the extent and role of evolution, and even the nature of the Bible.
An Anglican priest's perspective on the doctrine of creation in the church today
Authors: Roberts Michael B.
Published: March 2009

The Protestant understanding of creation in relation to science has been slightly different from that described for the Catholic churches and more diverse, as Protestants emphasize the authority of the Bible and private judgement. The conflict thesis of science and religion is rejected, but there were four skirmishes: over heliocentricity, the rise of geology, evolution and, today, the impact of creationism. The variety of belief among Protestants, and especially Anglicans, is expounded from non-realism, which denies the existence of God, to critical realism, in its liberal and conservative forms, which totally accept modern science, to ‘naive’ realism, which emphasizes the plain, or literal, reading of the Bible and rejects evolution and, often, geological time, and has given rise to ‘creationism’. Representative examples of each are introduced.
The providence of mineral generation in the sermons of Johann Mathesius (1504–1565)
Authors: Norris John A.
Published: March 2009

Johann Mathesius (1504–1565) was a Protestant minister in the northern Bohemian mining town of Joachimsthal (now Jáchymov in the Czech Republic). His
Sarepta oder Bergpostill
(1562) is a collection of sermons in which he discussed various aspects of metals, minerals and mining. His description of mineral generation emphasized the ‘gur theory’, which arose within the sixteenth-century mining literature and became highly influential in the seventeenth and eighteenth centuries. The sermons contained numerous biblical references to mining and mineral generation. These did not directly correspond to the generative theories he described, and their purpose seems to have been inspirational rather than didactic. In this way, and by presenting the beauty and utility of metallic minerals as an example of God's providence, Mathesius encouraged his congregation of miners to take an interest in the more wondrous aspects of their labours. His work is significant in its consideration of mineral theories, mineral identities and terminology, and as an early example of a providential perspective that characterized many geological ideas of later centuries.
Earthquakes as God's punishment in 17th- and 18th-century Spain
Authors: Udías Agustín
Published: March 2009

It is generally believed that before the Enlightenment earthquakes were considered as signs of the wrath of God as punishment for men's sins, and that Earth tremors were not considered as natural occurrences until modern times. However, this is an oversimplification, as we can see in Spanish writings of the 17th and 18th centuries. In these writings we have to distinguish between popular and religious documents and academic studies. In the 17th century Spanish authors held the Aristotelian doctrine about earthquakes and regarded them as natural occurrences. Some regarded them as God's punishment for sinful people. The occurrence of a destructive earthquake in Malaga in 1680 brought this question into the open. At that time no opinions were presented against the religious interpretation. The Lisbon earthquake of 1 November 1755 and the subsequent tsunami caused considerable damage in many Spanish cities, and the earthquake was felt throughout Spain. After that earthquake an abundant literature of popular, religious, philosophical and scientific character was published. A strong controversy arose as to whether the earthquake was of natural or supernatural character, with theologians and philosophers on both sides. An important group defended the natural character of the occurrence and deplored the exaggerated position of their opponents.
The idiom of a six day creation and global depictions in Theories of the Earth
Authors: Magruder Kerry V.
Published: March 2009

During the 17th century, in a new contested tradition known as Theories of the Earth, conventions for the visual representation of the Earth as a whole developed alongside the expression of biblical idiom. Global depictions carried embedded biblical idiom that shaped the formulation of questions, the development of theories, and the exchange of discoveries and ideas. In several examples I contrast the varying ways in which biblical idiom was expressed within global depictions, particularly hexameral idiom (i.e. the language of the six day creation in Genesis 1). I discuss the Jesuit mathematician Gabriele Beati and meteorological and cosmic sections; the cosmogonic sections and hexameral idiom of Robert Fludd; the geogonic sections and hexameral idiom of René Descartes; the apocalyptic idiom of Thomas Burnet; and the global depictions and hexameral idiom of William Whiston in the controversy over Burnet. Biblical and particularly hexameral idiom proved durable and versatile for more than a century after Fludd, and facilitated the development of a directionalist sense of Earth history. The continuities of visual conventions, the durability of hexameral idiom, and the contrasts of disciplinary perspectives and local contexts observed in the examples considered here conform well to the characterization of Theories of the Earth as a contested print tradition.
Flood conceptions in Vallisneri's thought
Authors: Luzzini Francesco
Published: March 2009

The scientific studies of the Italian physician and naturalist Antonio Vallisneri (1661–1730) were concerned with the cultural and religious implications of the debate on fossils in the early decades of the eighteenth century. In
De' Corpi Marini
he summarized the main diluvial theories but declined to support them. He explained the presence of fossils in strata in mountainous regions as the result of localized multiple flood and emersion sequences, and restricted the direct action of God to the biblical Deluge. This theory clearly contradicted the biblical interpretation provided by Catholic orthodoxy, which affirmed the existence of a single global Deluge. Vallisneri therefore had to gloss over its real meaning and use a careful self-censorship system, a strategy that he frequently used in his books. The comparison with the work of several Italian and European authors had great relevance to Vallisneri's theories. He continually exchanged correspondence and natural objects with some of the most outstanding of the eighteenth century natural philosophers. This involvement with other scholars deeply influenced his thought, and helped him to reach a pre-eminent status in the Italian scientific community of the time.
The Contribution of Hospitals and Health Care Systems to Community Health
Authors: Shortell Stephen M. , Washington Pamela K. , Baxter Raymond J.
Published: March 2009

This article reviews evidence on hospitals’ and health systems’ impacts on community health improvement. We begin with an overview of the history of community benefit and then discuss the lack of a widely accepted definition and measurement of community benefit activities as well as the expectations and accountability of tax-exempt not-for-profit hospitals and health systems in community initiatives. We highlight the approaches of two systems and identify strategic, cultural, technical, and structural challenges associated with increasing community benefit and health-improvement activities. We conclude by offering recommendations for policy and practice.
Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism
Authors: Yoshikawa Noritada , Nagasaki Masao , Sano Motoaki , Tokudome Satori , Ueno Kazuko , Shimizu Noriaki , Imoto Seiya , Miyano Satoru , Suematsu Makoto , Fukuda Keiichi , Morimoto Chikao , Tanaka Hirotoshi
Published: March 2009

Recent studies have documented various roles of adrenal corticosteroid signaling in cardiac physiology and pathophysiology. It is known that glucocorticoids and aldosterone are able to bind glucocorticoid receptor (GR) and mineralocorticoid receptor, and these ligand-receptor interactions are redundant. It, therefore, has been impossible to delineate how these nuclear receptors couple with corticosteroid ligands and differentially regulate gene expression for operation of their distinct functions in the heart. Here, to particularly define the role of GR in cardiac muscle cells, we applied a ligand-based approach involving the GR-specific agonist cortivazol (CVZ) and the GR antagonist RU-486 and performed microarray analysis using rat neonatal cardiomyocytes. We indicated that glucocorticoids appear to be a major determinant of GR-mediated gene expression when compared with aldosterone. Moreover, expression profiles of these genes highlighted numerous roles of glucocorticoids in various aspects of cardiac physiology. At first, we identified that glucocorticoids, via GR, induce mRNA and protein expression of a transcription factor Kruppel-like factor 15 and its downstream target genes, including branched-chain aminotransferase 2, a key enzyme for amino acid catabolism in the muscle. CVZ treatment or overexpression of KLF15 decreased cellular branched-chain amino acid concentrations and introduction of small-interfering RNA against KLF15 cancelled these CVZ actions in cardiomyocytes. Second, glucocorticoid-GR signaling promoted gene expression of the enzymes involved in the prostaglandin biosynthesis, including cyclooxygenase-2 and phospholipase A2 in cardiomyocytes. Together, we may conclude that GR signaling should have distinct roles for maintenance of cardiac function, for example, in amino acid catabolism and prostaglandin biosynthesis in the heart.
Association of luteinizing hormone receptor gene expression with cell cycle progression in granulosa cells
Authors: Cannon Jennifer D. , Seekallu Srinivas V. , VandeVoort Catherine A. , Chaffin Charles L.
Published: March 2009

During hormonally induced ovarian follicle growth, granulosa cell proliferation increases and returns to baseline prior to the administration of an ovulatory stimulus. Several key genes appear to follow a similar pattern, including the luteinizing hormone receptor (LHCGR), suggesting an association between cell cycle progression and gene expression. The expression of LHCGR mRNA in granulosa cells isolated from immature rats and treated in culture with FSH increased in a time-dependent manner, whereas administration of the cell cycle inhibitor mimosine completely suppressed expression. Although forskolin was able to induce luteinization in cells treated with mimosine, human chorionic gonadotropin had no effect, indicating the functional loss of LHCGR. The effects of mimosine on cell cycle progression and LHCGR mRNA expression were reversible within 24 h of mimosine removal. Cell cycle inhibition did not alter the stability of LHCGR mRNA, indicating that the primary effect was at the transcriptional level. To determine whether the relationship between LHCGR expression and cell cycle were relevant in vivo, immature rats were given a bolus of PMSG, followed by a second injection of either saline or PMSG 24 h later to augment levels of proliferation. The expression of LHCGR mRNA was elevated in the ovaries of animals receiving a supplement of PMSG. Mimosine also blocked cell cycle progression and LHCGR mRNA expression in macaque granulosa cells isolated following controlled ovarian stimulation cycles and in two different mouse Leydig tumor lines. These data collectively indicate that LHCGR mRNA is expressed as a function of the passage of cells across the G1-S phase boundary.
Photoperiod and acute energy deficits interact on components of the thyroid hormone system in hypothalamic tanycytes of the Siberian hamster
Authors: Herwig Annika , Wilson Dana , Logie Tracy J. , Boelen Anita , Morgan Peter J. , Mercer Julian G. , Barrett Perry
Published: March 2009

In the Siberian hamster, seasonal weight loss occurs gradually over many weeks during autumn and winter. This is driven by a regulatory mechanism that is able to integrate duration of exposure to short days (SDs) with the size of body energy reserves. After food restriction in SDs, followed by ad libitum refeeding, body weight of the hamster does not return to its former level; rather, it increases to a level defined by the length of time spent in SDs. In this report, we show that components of the thyroid hormone system that are involved in seasonal weight loss change expression in response to 48 h of starvation. Eight weeks in an SD photoperiod induced weight loss in the Siberian hamster. In the hypothalamus of these hamsters, type II deiodinase expression was decreased and type III deiodinase expression was induced, but there was no change in hypothalamic neuropeptide Y or thyrotropin-releasing hormone gene expression. For the first time, we show that the thyroid hormone transporter monocarboxylate transporter 8 is expressed in tanycytes and is increased in response to an SD photoperiod. Food restriction (48 h of starvation) reversed the direction of gene expression change for type II and III deiodinase and monocarboxylate transporter 8 induced by SD photoperiods. Furthermore, fasting increased neuropeptide Y expression and decreased thyrotropin-releasing hormone expression. VGF, a gene upregulated in SDs in the dorsal region of the medial posterior area of the arcuate nucleus, was not changed by starvation. These data point to a mechanism whereby energy deprivation can interact with an SD photoperiod on hypothalamic tanycytes to regulate components of the thyroid hormone system involved in photoperiodic regulation of seasonal physiology.
Drinking-induced thermoregulatory panting in rehydrated sheep: influences of oropharyngeal/esophageal signals, core temperature, and thirst satiety
Authors: McKinley M. J. , Weissenborn F. , Mathai M. L.
Published: March 2009

Dehydrated mammals conserve body water by reducing thermoregulatory evaporative cooling responses e.g., panting and sweating. Increased core temperature (Tc) may result. Following rehydration and correction of fluid deficits, panting and sweating commence. We investigated the role of oropharyngeal/esophageal, postabsorptive and thermal signals in the panting response, and reduced Tc that occurs when unshorn sheep drink water following water deprivation for 2 days (ambient temperature 20°C). Ingestion of water (at body temperature) resulted in increased respiratory rate (panting) and reduced Tc within 4 min that persisted for at least 90 min. Initially, a similar panting response and reduced Tc occurred following rehydration by drinking isotonic saline solution, but panting was not sustained after 20 min, and Tc began to rise again. Rehydration by intraruminal administration of water, without any drinking, resulted in delayed panting and fall in Tc. Intraruminal infusion of saline was ineffective. Rehydration by drinking cool water (20°C) resulted in a rapid fall in Tc without increased panting. Shorn sheep had lower basal Tc that did not increase during 2 days of water deprivation, and they did not pant on rehydration by drinking water. Our results indicate that signals from the oropharyngeal and/or esophageal region associated with the act of drinking play a crucial role in the initial 20–30 min of the panting response to rehydration. Postabsorptive factors most likely reduced plasma tonicity and cause continued panting and further reduction in Tc. Tc also influences rehydration-induced panting. It occurs only if sheep incur a heat load during bodily dehydration.
Polyneuronal Innervation of Single Muscle Fibers in Cat Eye Muscle: Inferior Oblique
Authors: Dimitrova Diana M. , Allman Brian L. , Shall Mary S. , Goldberg Stephen J.
Published: March 2009

Single muscle fibers with multiple axonal endplates (multiply innervated fibers) are normally present in adult extraocular muscles (EOMs), while most other mammalian skeletal muscles contain fibers with a single myoneural junction. Recent findings by others led us to investigate for the presence of polyneuronal innervation (innervation of a single muscle fiber by >1 motoneuron) in the inferior oblique (IO) muscle of pentobarbital anesthetized cats. The IO muscle nerve branches, as they coursed through the orbit, were further divided for independent or simultaneous electrical stimulation with bipolar electrodes. Four of five established tests for polyneuronal innervation gave positive results. The sum of the twitch (1) and tetanic (2) tensions in response to individual nerve branch stimulation was greater than that for simultaneous (whole) nerve stimulation. The summed electromyographic (EMG) responses (3) gave a similar positive result. The result for crossed tetanic potentiation (4) was negative for polyneuronal innervation while the crossed fatigue (5) test was positive. These results are consistent with recent studies. That the EOMs exhibit polyneuronal innervation further explains the eye-movement system's functional integrity during some neuromuscular disorders as well as its ability to operate with precision after the loss of numerous motoneurons.
Dynamics of Primate Oculomotor Plant Revealed by Effects of Abducens Microstimulation
Authors: Anderson Sean R. , Porrill John , Sklavos Sokratis , Gandhi Neeraj J. , Sparks David L. , Dean Paul
Published: March 2009

Despite their importance for deciphering oculomotor commands, the mechanics of the extraocular muscles and orbital tissues (oculomotor plant) are poorly understood. In particular, the significance of plant nonlinearities is uncertain. Here primate plant dynamics were investigated by measuring the eye movements produced by stimulating the abducens nucleus with brief pulse trains of varying frequency. Statistical analysis of these movements indicated that the effects of stimulation lasted about 40 ms after the final pulse, after which the eye returned passively toward its position before stimulation. Behavior during the passive phase could be approximated by a linear plant model, corresponding to Voigt elements in series, with properties independent of initial eye position. In contrast, behavior during the stimulation phase revealed a sigmoidal relation between stimulation frequency and estimated steady-state tetanic tension, together with a frequency-dependent rate of tension increase, that appeared very similar to the nonlinearities previously found for isometric-force production in primate lateral rectus muscle. These results suggest that the dynamics of the oculomotor plant have an approximately linear component related to steady-state viscoelasticity and a nonlinear component related to changes in muscle activation. The latter may in part account for the nonlinear relations observed between eye-movement parameters and single-unit firing patterns in the abducens nucleus. These findings point to the importance of recruitment as a simplifying factor for motor control with nonlinear plants.
Modulation of Spontaneous and Odorant-Evoked Activity of Rat Olfactory Sensory Neurons by Two Anorectic Peptides, Insulin and Leptin
Authors: Savigner Agnès , Duchamp-Viret Patricia , Grosmaitre Xavier , Chaput Michel , Garcia Samuel , Ma Minghong , Palouzier-Paulignan Brigitte
Published: March 2009

In mammals, the sense of smell is modulated by the status of satiety, which is mainly signaled by blood-circulating peptide hormones. However, the underlying mechanisms linking olfaction and food intake are poorly understood. Here we investigated the effects of two anorectic peptides, insulin and leptin, on the functional properties of olfactory sensory neurons (OSNs). Using patch-clamp recordings, we analyzed the spontaneous activity of rat OSNs in an in vitro intact epithelium preparation. Bath perfusion of insulin and leptin significantly increased the spontaneous firing frequency in 91.7% ( n = 24) and 75.0% ( n = 24) of the cells, respectively. When the activity was electrically evoked, both peptides shortened the latency to the first action potential by ∼25% and decreased the interspike intervals by ∼13%. While insulin and leptin enhanced the electrical excitability of OSNs in the absence of odorants, they surprisingly reduced the odorant-induced activity in the olfactory epithelium. Insulin and leptin decreased the peak amplitudes of isoamyl acetate-induced electroolfactogram (EOG) signals to 46 and 38%, respectively. When measured in individual cells by patch-clamp recordings, insulin and leptin decreased odorant-induced transduction currents and receptor potentials. Therefore by increasing the spontaneous activity but reducing the odorant-induced activity of OSNs, an elevated insulin and leptin level (such as after a meal) may result in a decreased global signal-to-noise ratio in the olfactory epithelium, which matches the smell ability to the satiety status.
The Membrane Mucin Muc4 Inhibits Apoptosis Induced by Multiple Insults via ErbB2-Dependent and ErbB2-Independent Mechanisms
Authors: Workman Heather C. , Sweeney Colleen , Carraway Kermit L.
Published: March 2009

The aberrant expression of membrane mucins such as Muc1 and Muc4 by tumor cells has been shown to engage signaling pathways that promote cellular properties associated with tumor progression. Our previous studies have shown that Muc4 interacts with and potentiates signaling by the ErbB2 (HER2) receptor tyrosine kinase through an epidermal growth factor–like domain in its extracellular region. Here, we show that expression of Muc4 in human A375 melanoma cells and MCF7 breast cancer cells confers resistance to apoptosis induced by a variety of stimuli, including chemotherapeutic agents, the absence of serum factors, and the loss of cellular adhesion. Mapping experiments revealed that the O-glycosylation and cytosolic domains of Muc4 are dispensable for its antiapoptotic activity, and are also dispensable for the potentiation of signaling by ErbB2. Knockdown of endogenous Muc4 in JIMT-1 breast cancer cells sensitizes cells to apoptotic stimuli, and this can be rescued by Muc4 forms lacking the O-glycosylation or cytosolic domains. Surprisingly, however, the molecular mechanisms underlying Muc4 antiapoptotic activity vary among cell lines. Although Muc4 in JIMT-1 cells engages ErbB2 to promote cell survival, its antiapoptotic mechanism in MCF7 and A375 cells seems to be independent of ErbB2. However, Muc4 expression in all cell lines culminates in the phosphorylation and inactivation of the proapoptotic protein Bad and the elevation of the prosurvival protein Bcl-xL. Our observations suggest that tumor cells can exploit the versatile antiapoptotic activities of Muc4 to acquire resistance to therapeutic agents, and augment cell survival after the loss of adhesion and microenvironment-derived survival factors. [Cancer Res 2009;69(7):2845–52]
Spleen Tyrosine Kinase Functions as a Tumor Suppressor in Melanoma Cells by Inducing Senescence-like Growth Arrest
Authors: Bailet Olivier , Fenouille Nina , Abbe Patricia , Robert Guillaume , Rocchi Stéphane , Gonthier Nadège , Denoyelle Christophe , Ticchioni Michel , Ortonne Jean-Paul , Ballotti Robert , Deckert Marcel , Tartare-Deckert Sophie
Published: March 2009

Loss of tumor-suppressive pathways that control cellular senescence is a crucial step in malignant transformation. Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase that has been recently implicated in tumor suppression of melanoma, a deadly skin cancer derived from pigment-producing melanocytes. However, the mechanism by which Syk suppresses melanoma growth remains unclear. Here, we report that reexpression of Syk in melanoma cells induces a p53-dependent expression of the cyclin-dependent kinase (cdk) inhibitor p21 and a senescence program. We first observed that Syk expression is lost in a subset of melanoma cell lines, primarily by DNA methylation–mediated gene silencing and restored after treatment with the demethylating agent 5-aza-2-deoxycytidine. We analyzed the significance of epigenetic inactivation of Syk and found that reintroduction of Syk in melanoma cells dramatically reduces clonogenic survival and three-dimensional tumor spheroid growth and invasion. Remarkably, melanoma cells reexpressing Syk display hallmarks of senescent cells, including reduction of proliferative activity and DNA synthesis, large and flattened morphology, senescence-associated β-galactosidase activity, and heterochromatic foci. This phenotype is accompanied by hypophosphorylated retinoblastoma protein (Rb) and accumulation of p21, which depends on functional p53. Our results highlight a new role for Syk tyrosine kinase in regulating cellular senescence and identify Syk-mediated senescence as a novel tumor suppressor pathway the inactivation of which may contribute to melanoma tumorigenicity. [Cancer Res 2009;69(7):2748–56]
The EGF/CSF-1 Paracrine Invasion Loop Can Be Triggered by Heregulin β1 and CXCL12
Authors: Hernandez Lorena , Smirnova Tatiana , Kedrin Dmitriy , Wyckoff Jeffrey , Zhu Liyin , Stanley E. Richard , Cox Dianne , Muller William J. , Pollard Jeffrey W. , Van Rooijen Nico , Segall Jeffrey E.
Published: March 2009

An important step in the process of metastasis from the primary tumor is invasive spread into the surrounding stroma. Using an in vivo invasion assay, we have previously shown that imposed gradients of epidermal growth factor (EGF) or colony-stimulating factor-1 (CSF-1) can induce invasion through an EGF/CSF-1 paracrine loop between cancer cells and macrophages. We now report that invasion induced by other ligands also relies on this EGF/CSF-1 paracrine invasive loop. Using an in vivo invasion assay, we show that MTLn3 breast cancer cells overexpressing ErbB3 exhibit enhanced invasion compared with control MTLn3 cells in response to the ErbB3 ligand HRG-β1. The invasive response of both MTLn3-ErbB3 and transgenic MMTV-Neu tumors to HRG-β1 is inhibited by blocking EGF receptor, CSF-1 receptor, or macrophage function, indicating that invasiveness to HRG-β1 is dependent on the EGF/CSF-1 paracrine loop. Furthermore, we show that CXCL12 also triggers in vivo invasion of transgenic MMTV-PyMT tumors in an EGF/CSF-1–dependent manner. Although the invasion induced by HRG-β1 or CXCL12 is dependent on the EGF/CSF-1 paracrine loop, invasion induced by EGF is not dependent on HRG-β1 or CXCL12 signaling, showing an asymmetrical relationship between different ligand/receptor systems in driving invasion. Our results identify a stromal/tumor interaction that acts as an engine underlying invasion induced by multiple ligands. [Cancer Res 2009;69(7):3221–7]
Quantitative Optical Spectroscopy: A Robust Tool for Direct Measurement of Breast Cancer Vascular Oxygenation and Total Hemoglobin Content In vivo
Authors: Brown J. Quincy , Wilke Lee G. , Geradts Joseph , Kennedy Stephanie A. , Palmer Gregory M. , Ramanujam Nirmala
Published: March 2009

We propose the use of a robust, biopsy needle–based, fiber-optic tool for routine clinical quantification of tumor oxygenation at the time of diagnostic biopsy for breast cancer. The purpose of this study was to show diffuse reflectance spectroscopy as a quantitative tool to measure oxygenation levels in the vascular compartment of breast cancers in vivo via an optical biopsy technique. Thirty-five patients undergoing surgical treatment for breast cancer were recruited for the study at Duke University Medical Center. Diffuse reflectance spectroscopy was performed on the tumors in situ before surgical resection, followed by needle-core biopsy of the optically measured tissue. Hemoglobin saturation and total hemoglobin content were quantified from 76 optical spectra-tissue biopsy pairs, consisting of 20 malignant, 23 benign, and 33 adipose tissues. Hemoglobin saturation in malignant tissues was significantly lower than nonmalignant tissues (P < 0.002) and was negatively correlated with tumor size and pathologic tumor category (P < 0.05). Hemoglobin saturation was positively correlated with total hemoglobin content in malignant tissues (P < 0.02). HER2/neu-amplified tumors exhibited significantly higher total hemoglobin content (P < 0.05) and significantly higher hemoglobin saturation (P < 0.02), which is consistent with a model of increased angiogenesis and tumor perfusion promoted by HER2/neu amplification. Diffuse reflectance spectroscopy could aid in prognosis and prediction in breast cancer via quantitative assessment of tumor physiology at the time of diagnostic biopsy. [Cancer Res 2009;69(7):2919–26]
Thyroid Transcription Factor-1 Inhibits Transforming Growth Factor-β–Mediated Epithelial-to-Mesenchymal Transition in Lung Adenocarcinoma Cells
Authors: Saito Roy-Akira , Watabe Tetsuro , Horiguchi Kana , Kohyama Tadashi , Saitoh Masao , Nagase Takahide , Miyazono Kohei
Published: March 2009

Thyroid transcription factor-1 (TTF-1) is expressed in lung cancer, but its functional roles remain unexplored. TTF-1 gene amplification has been discovered in a part of lung adenocarcinomas, and its action as a lineage-specific oncogene is highlighted. Epithelial-to-mesenchymal transition (EMT) is a crucial event for cancer cells to acquire invasive and metastatic phenotypes and can be elicited by transforming growth factor-β (TGF-β). Mesenchymal-to-epithelial transition (MET) is the inverse process of EMT; however, signals that induce MET are largely unknown. Here, we report a novel functional aspect of TTF-1 that inhibits TGF-β–mediated EMT and restores epithelial phenotype in lung adenocarcinoma cells. This effect was accompanied by down-regulation of TGF-β target genes, including presumed regulators of EMT, such as Snail and Slug. Moreover, silencing of TTF-1 enhanced TGF-β–mediated EMT. Thus, TTF-1 can exert a tumor-suppressive effect with abrogation of cellular response to TGF-β and attenuated invasive capacity. We further revealed that TTF-1 down-regulates TGF-β2 production in A549 cells and that TGF-β conversely decreases endogenous TTF-1 expression, suggesting that enhancement of autocrine TGF-β signaling accelerates the decrease of TTF-1 expression and vice versa. These findings delineate potential links between TTF-1 and TGF-β signaling in lung cancer progression through regulation of EMT and MET and suggest that modulation of TTF-1 expression can be a novel therapeutic strategy for treatment of lung adenocarcinoma. [Cancer Res 2009;69(7):2783–91]
Heterozygosity for Hypoxia Inducible Factor 1α Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model
Authors: Bertout Jessica A. , Patel Shetal A. , Fryer Benjamin H. , Durham Amy C. , Covello Kelly L. , Olive Kenneth P. , Goldschmidt Michael H. , Simon M. Celeste
Published: March 2009

Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and are overexpressed in a number of tumors. Although HIF1α and HIF2α share a high degree of sequence homology, recent work has shown that the two α subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFα subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2α expression and Hif1α+/− mice to homozygotes for the R270H mutation in p53. Here, we report that p53R270H/R270H mice, which have not been previously described, develop a unique tumor spectrum relative to p53R270H/− mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1α significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1α levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. These observations uncover a novel role for HIF1α in Notch pathway activation during T-cell lymphomagenesis. [Cancer Res 2009;69(7):3213–20]
SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer
Authors: Rickman David S. , Pflueger Dorothee , Moss Benjamin , VanDoren Vanessa E. , Chen Chen X. , de la Taille Alexandre , Kuefer Rainer , Tewari Ashutosh K. , Setlur Sunita R. , Demichelis Francesca , Rubin Mark A.
Published: March 2009

Chromosomal rearrangements account for all erythroblast transformation–specific (ETS) family member gene fusions that have been reported in prostate cancer and have clinical, diagnostic, and prognostic implications. Androgen-regulated genes account for the majority of the 5′ genomic regulatory promoter elements fused with ETS genes. TMPRSS2-ERG, TMPRSS2-ETV1, and SLC45A3-ERG rearrangements account for roughly 90% of ETS fusion prostate cancer. ELK4, another ETS family member, is androgen regulated, involved in promoting cell growth, and highly expressed in a subset of prostate cancer, yet the mechanism of ELK4 overexpression is unknown. In this study, we identified a novel ETS family fusion transcript, SLC45A3-ELK4, and found it to be expressed in both benign prostate tissue and prostate cancer. We found high levels of SLC45A3-ELK4 mRNA restricted to a subset of prostate cancer samples. SLC45A3-ELK4 transcript can be detected at high levels in urine samples from men at risk for prostate cancer. Characterization of the fusion mRNA revealed a major variant in which SLC45A3 exon 1 is fused to ELK4 exon 2. Based on quantitative PCR analyses of DNA, unlike other ETS fusions described in prostate cancer, the expression of SLC45A3-ELK4 mRNA is not exclusive to cases harboring a chromosomal rearrangement. Treatment of LNCaP cancer cells with a synthetic androgen (R1881) revealed that SLC45A3-ELK4, and not endogenous ELK4, mRNA expression is androgen regulated. Altogether, our findings show that SLC45A3-ELK4 mRNA expression is heterogeneous, highly induced in a subset of prostate cancers, androgen regulated, and most commonly occurs through a mechanism other than chromosomal rearrangement (e.g., trans-splicing). [Cancer Res 2009;69(7):2734–8]
EBV-Related Lymphoproliferative Disease Complicating Therapy with the Anti-CD2 Monoclonal Antibody, Siplizumab, in Patients with T-Cell Malignancies
Authors: O'Mahony Deirdre , Morris John C. , Stetler-Stevenson Maryalice , Matthews Helen , Brown Margaret R. , Fleisher Thomas , Pittaluga Stefania , Raffeld Mark , Albert Paul S. , Reitsma Dirk , Kaucic Karen , Hammershaimb Luz , Waldmann Thomas A. , Janik John E.
Published: March 2009

Purpose: We report an increased incidence of EBV-induced B-cell lymphoproliferative disease (LPD) in patients treated with siplizumab, an anti-CD2 antibody. The development of EBV-LPD has been associated with the use of immunosuppressive agents used in solid organ, bone marrow, and stem cell transplantation and in certain congenital immunodeficiencies.

Experimental Design: We conducted a single-institution phase I dose-escalation trial of siplizumab, a humanized monoclonal antibody to CD2, in 29 patients with T-cell malignancies.

Results: Although initial responses were encouraging, 4 (13.7%) patients developed EBV-LPD and the trial was stopped. Reductions in CD4+ and CD8+ cell count numbers in response to therapy were seen in all patients, but in those patients developing EBV-LPD a significantly greater reduction in natural killer (NK) cell number and CD2 expression on T cells was seen. These findings highlight the importance of NK-cell depletion and CD2 expression in addition to T-cell depletion in the etiology of EBV-LPD.

Conclusions: The emergence of EBV-LPD may be associated with the ability of siplizumab to deplete both T and NK cells without affecting B cells. Agents that deplete T- and NK-cell populations without affecting B cell number should be screened for this potentially serious adverse event.
Combined PTEN and p27kip1 Protein Expression Patterns Are Associated with Obesity and Prognosis in Endometrial Carcinomas
Authors: Dellas Athanassios , Jundt Gernot , Sartorius Gideon , Schneider Mischa , Moch Holger
Published: March 2009

Purpose: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) and p27kip1 proteins are key players of the Akt pathway, which is nutritionally regulated by insulin receptor signaling and influenced by estrogens. In this study, the prognostic relevance of the PTEN/p27kip1 protein expression in endometrial carcinoma in relationship to the body mass index (BMI) was determined.

Experimental Design: BMI and prognosis of 452 surgically treated patients with endometrial carcinoma were correlated with histologic subtype, International Federation of Gynecology and Obstetrics (FIGO) stage, and differentiation grade. The expression of PTEN and p27kip1 was examined in 257 tumors by immunohistochemistry using a tissue microarray approach.

Results: Lack of PTEN was observed in 136 of 257 (53%) tumors and absence of p27kip1 expression was observed in 106 of 225 (47%) tumors. Absence of both proteins was significantly associated with well-differentiated tumors [PTEN (P < 0.02) and p27kip1 (P < 0.009)]. Differentiation grade, tumor stage, and histologic type were independent of an increased BMI. Importantly, tumors of obese women expressed significantly less PTEN (P < 0.008) and less p27kip1 (P < 0.01) than tumors from nonobese patients. Combined absence of both PTEN and p27kip1 expression characterized a group of 75 (32%) tumors with favorable clinical outcome, particularly in the FIGO stages I and II (P = 0.003) of obese patients. Cox regression analysis revealed that PTEN/p27kip1 phenotype, FIGO stage, and histologic grade were independent predictors of prognosis in endometrioid endometrial carcinoma.

Conclusions: Inactivation of PTEN/p27kip1 proteins is a specific feature in the progression of endometrial carcinoma in obese patients. The phenotype of the combined loss of PTEN/p27kip1 protein expression in obese patients is associated with a significantly better prognosis in endometrioid endometrial carcinoma.
Stem Cells and the Natural History of Lung Cancer: Implications for Lung Cancer Screening
Authors: van Klaveren Rob J. , van't Westeinde Susan C. , de Hoop Bart-Jan , Hoogsteden Henk C.
Published: March 2009

Lung cancer is not simply a single disease, but a collection of several phenotypically very diverse and regionally distinct neoplasias. Its natural history is complex and not yet fully understood. Stem cells and the complex interaction with the microenvironment of the tumor and the immune system play an important role in tumor progression and metastasizing capacity. This finding explains why lung cancer does not always follow the multistep carcinogenetic and exponential growth model and why small lesions do not always equate to early-stage disease. Despite the fact that volume doubling times are increasingly used as surrogate markers for the natural history of lung cancer and as estimates for the proportion of overdiagnosed cases, it is only a momentary impression. At baseline screening especially, screen-detected lung cancer cases are preferably detected when they are in the indolent phase of their growth curve (length-biased sampling), from which it can by no means be concluded that they may not progress or metastasize at a later stage. Because the natural history of lung cancer is only partly elucidated, conclusions on the impact of overdiagnosis in lung cancer screening are premature.
Radioimmunotherapy of Experimental Human Metastatic Melanoma with Melanin-Binding Antibodies and in Combination with Dacarbazine
Authors: Revskaya Ekaterina , Jongco Artemio M. , Sellers Rani S. , Howell Robertha C. , Koba Wade , Guimaraes Allan J. , Nosanchuk Joshua D. , Casadevall Arturo , Dadachova Ekaterina
Published: March 2009

Purpose: Melanin has emerged as an attractive target for radioimmunotherapy (RIT) of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin is currently in clinical evaluation. We investigated two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: (a) the use of an additional mAb to melanin could provide information on whether using antibodies to melanin can serve as a general approach to development of therapeutics for melanoma, and (b) as melanin targeting involves the antibody binding to extracellular melanin released from necrotic melanoma cells, we hypothesized that the administration of a chemotherapeutic agent followed by RIT would facilitate the delivery of radiation to the tumors due to the increased presence of free melanin.

Experimental Design: We evaluated the therapeutic efficacy of two melanin-binding IgM mAbs labeled with 188Re (6D2 and 11B11). We compared the efficacy of RIT with 188Re-6D2 to chemotherapy with dacarbazine (DTIC) and to combined chemotherapy and RIT in human metastatic melanoma-bearing nude mice.

Results: Therapeutic efficacy of 188Re-labeled 6D2 and 11B11 was comparable despite differences in their affinity and binding site numbers. Comparison of chemotherapy with DTIC and RIT revealed that RIT was more effective in slowing tumor growth in mice. Administration of DTIC followed by RIT was more effective than either modality alone.

Conclusions: These results provide encouragement for the development of RIT for melanoma with melanin-binding mAbs and suggest that combining chemotherapy and RIT may be a promising approach for the treatment of metastatic melanoma.
Small-Molecule Antagonists for CXCR2 and CXCR1 Inhibit Human Melanoma Growth by Decreasing Tumor Cell Proliferation, Survival, and Angiogenesis
Authors: Singh Seema , Sadanandam Anguraj , Nannuru Kalyan C. , Varney Michelle L. , Mayer-Ezell Rosemary , Bond Richard , Singh Rakesh K.
Published: March 2009

Purpose: Melanoma, the most aggressive form of skin cancer, accounts for 75% of all skin cancer-related deaths and current therapeutic strategies are not effective in advanced disease. In the current study, we have investigated the efficacy of orally active small-molecule antagonist targeting CXCR2/CXCR1.

Experimental Design: Human A375SM melanoma cells were treated with SCH-479833 or SCH-527123, and their effect on proliferation, motility, and invasion was evaluated in vitro. We examined the downstream signaling events in the cells following treatment with antagonists. For in vivo studies, A375SM cells were implanted subcutaneously into athymic nude mice followed by administration of SCH-479833, SCH-527123, or hydroxypropyl-β-cyclodextrin (20%) orally for 21 days and their effect on tumor growth and angiogenesis was evaluated.

Results: Our data show that SCH-479833 or SCH-527123 inhibited the melanoma cell proliferation, chemotaxis, and invasive potential in vitro. Treatment of melanoma cells with SCH-479833 or SCH-527123 also inhibited tumor growth. Histologic and histochemical analyses showed significant (P < 0.05) decreases in tumor cell proliferation and microvessel density in tumors. Moreover, we observed a significant increase in melanoma cell apoptosis in SCH-479833- or SCH-527123-treated animals compared with controls.

Conclusion: Together, these studies show that selectively targeting CXCR2/CXCR1 with orally active small-molecule inhibitors is a promising therapeutic approach for inhibiting melanoma growth and angiogenesis.
Development of an Adjuvant-Free Cashew Nut Allergy Mouse Model
Authors: Parvataneni Sitaram , Gonipeta Babu , Tempelman Robert J. , Gangur Venu
Published: March 2009

Background: Cashew nut allergy is an emerging food allergy with a high risk of systemic anaphylaxis. Currently, an adjuvant-free animal model to study cashew nut allergy is not available. Methods: BALB/c mice were exposed to cashew nut protein using a transdermal sensitization protocol that does not use adjuvant. Systemic IgE antibody response, systemic anaphylaxis to oral challenge and allergen-driven, spleen-cell, type-2 cytokine responses were studied. Results: Transdermal exposure to cashew nut resulted in a significant dose-dependent allergic response. Oral challenge of sensitized mice with cashew resulted in severe signs of systemic anaphylaxis and a significant hypothermia. Spleen cell culture with cashew nut protein resulted in allergen-driven IL-4, IL-5 and IL-13 responses only in sensitized but not in saline control mice. Conclusions: These data demonstrate that (i) transdermal exposure to cashew nut protein elicits a robust IgE response leading to clinical sensitization of mice for systemic anaphylaxis to oral cashew nut challenge; (ii) cashew nut is a potent activator of type-2 cytokines, thus explaining the mechanism of cashew allergy, and (iii) this mouse model may be useful for further basic and preclinical studies on cashew nut allergy.