bluuebunny/crossref_metadata_2025 huggingface dataset:
Scheuchzer, von Haller and de Luc: geological world-views and religious backgrounds in opposition or collaboration?
Authors: Schweizer Claudia
Published: March 2009

This paper describes the influence exerted by religious belief on the scientific accomplishments of three distinctive naturalists of three successive generations in the era of Enlightenment: Johann Jacob Scheuchzer (1672–1733), Albert von Haller (1708–1777), and Jean-André de Luc (1727–1817). The religious attitudes and their impact on the geological views of these naturalists are compared, with focus on the belief in the biblical Flood and its geological interpretation. In all three cases, a religious belief proved to benefit scientific knowledge; furthermore, the attempt to prove the account in Genesis by scientific means united two contrasting views of the Enlightenment: rationalism and biblical dogma. The Enlightenment thus became the ground on which a new, rational–religious world-view started growing.
Biblical Flood and geological deluge: the amicable dissociation of geology and Genesis
Authors: Rudwick Martin J. S.
Published: March 2009

This paper summarizes debates, among European geologists in the early nineteenth century, about the possible equivalence (or non-equivalence) between the biblical account of Noah's Flood, and new and cumulative evidence for an exceptional watery catastrophe or ‘geological deluge’ in very recent Earth history. The ‘diluvial theory’ deserves to be taken seriously as an attempted explanation of some extremely puzzling physical features (many of them reinterpreted later as traces of a glacial ‘catastrophe’ or Ice Age). The ‘geological deluge’ was eventually recognized as having been far earlier in Earth history than any event recorded by literate human societies. Among geologists, although not always among the wider public, this gradual dissociation between biblical Flood and geological deluge was generally amicable, not acrimonious. It was facilitated by the concurrent development of biblical scholarship, which showed that earlier literalistic interpretations were no longer tenable (and were also destructive of religious meaning). What was transposed into geology in the course of these debates was the strong Judaeo-Christian sense that the world has had a directional and contingent history, which might have been punctuated by occasional catastrophic events.
‘Our favourite science’: Lord Bute and James Parkinson searching for a Theory of the Earth
Authors: Lewis Cherry L. E.
Published: March 2009

John Stuart, the third earl of Bute and the British Prime Minister from 1762 to 1763, and the apothecary surgeon James Parkinson both amassed large and important geological collections; both believed in the biblical Deluge; both admired the work of Jean André de Luc; and both were fascinated by the study of geology. Each sought a theory that would explain the geological phenomena they observed but which also allowed them to maintain their religious integrity. They were men of their time, struggling to come to terms with a new science that challenged their strongly held religious beliefs. Bute's
Observations on the Natural History of the Earth
, never published, provides us with a snapshot of his thinking about prevailing theories of the Earth. He dismissed all except those that fitted the geological facts as understood at the time, but was nevertheless unable to progress from a rigid belief in the biblical Flood having been a miracle. Parkinson's
Organic Remains of a Former World
reveals a man fully conversant with contemporary geological ideas being propounded elsewhere in Europe. Also highly religious, Parkinson oscillated between his deeply held beliefs and the contradictory evidence provided by the fossils he held in his hand.
Jean-André de Luc (1727–1817): an atheist's comparative view of the historiography
Authors: Oldroyd David R.
Published: March 2009

The paper considers issues arising when historians of different theological persuasions write about geologists whose religious principles influenced their geological work. For illustrative purposes, three accounts of the work of Jean-André de Luc are discussed, written by a freethinker (Charles Gillispie); an Anglican (Martin Rudwick); and two co-authors, one a Calvinist (François Ellenberger) and the other an atheist (Gabriel Gohau). The issue of understanding or empathizing (or otherwise) with one's subject in writing the history of geology is raised. It is suggested that the accounts of de Luc discussed here show the marks of the religious views of the different historians. In discussing this suggestion, the concepts of ‘emic’ and ‘etic’ from cultural anthropology are deployed. (These terms indicate, respectively, an ‘insider's’ or an ‘outsider's’ approach to a subject.) Older geological writings commonly reflected their authors' religious perspectives; but this is much less common in modern work. Therefore the science–religion issue will become of less importance for historians writing about the history of geology for the twentieth century onwards.
Religious convictions as support in dangerous expeditions: Hermann Abich (1806–1886) and Heinrich Barth (1821–1865)
Authors: Seibold Eugen , Seibold Ilse
Published: March 2009

Abich and Barth came from a North German bourgeois background and received a strict religious education. Later, when studying at the University of Berlin, both came under the strong influence of the geographer Carl Ritter and of his Pietist family. Abich became the doyen of Caucasus geology, and engaged in intensive and often perilous fieldwork in the region between 1842 and 1876. The help he received during his first two years in the field convinced him that it was God's will for him to bring this work to completion. His trust in the Bible was so firm that, after setting foot on the summit of Mount Ararat, he asked himself where exactly Noah's ark might have landed. Barth's most outstanding achievement was the exploration of the central Sahara and southern Sudan between 1849 and 1855. Here he worked mostly alone. In relationship to Muslims, he demonstrated an uncompromising and therefore convincing Christian faith. He survived the dangers of the desert and various illnesses with resilience, which he attributed to his unshakable faith.
Franz Unger and Sebastian Brunner on evolution and the visualization of Earth history; a debate between liberal and conservative Catholics
Authors: Klemun Marianne
Published: March 2009

The point of departure for this study of the debate on links between sciences and religion is a church newspaper that appeared in Vienna after the revolution of 1848. In it we find the arguments of a particularly conservative journalist and priest (Brunner) who attacked scientific topics, such as evolution and the position of Franz Unger (1800–1871), who was a professor at the University of Vienna and who is a well-known figure in the history of science, because of his numerous contributions to cellular biology, plant physiology, biogeography and palaeobotany, and most of all because of his surveys of pre-Darwinian evolution theory. He was one of the first scientists who tried, in 1852, to suggest the temporal development of the natural world in a visual form. I propose here that the controversy between conservative clergy and liberal academics was invigorated not least because Unger was capable of using Catholic culture to communicate his concepts and representations of evolution and the Earth's development and to make them understandable. In return, Brunner understood how to exploit Unger's work and use Mosaic geology as a counterpoint for his strengthening of Catholic orthodoxy. This debate proves not to be a permanent conflict between religion and science, but to lie within the Viennese Catholic culture within which the protagonists took their stance.
From the beginning: faith and geology at evangelical Wheaton College
Authors: Moshier S. O. , Maas D. E. , Greenberg J. K.
Published: March 2009

Geology has been part of the curriculum at Wheaton College, Illinois, since it was established in 1860 as a non-denominational, Christian liberal arts college. The school continues to maintain a strong identity with evangelical Christian theology and subculture. The first president Jonathan Blanchard recruited George Frederick Barker to teach geology and natural history on the personal recommendations of the renowned geologists Agassiz, Silliman and Hitchcock. Barker taught at Wheaton for only one year, and was followed by a succession of other young scientists who kept geology in the curriculum to the end of the nineteenth century. These teachers respected the geological evidence for an ancient Earth and interpreted the creation days in Genesis 1 as representing extended epochs of God's creative activity. In the early twentieth century, Professors James Bole and L. Allen Higley harmonized mainstream geological history and the Bible through the gap or ruin–restoration interpretation, wherein eons of geological time preceded six days of Edenic re-creation only thousands of years ago. Higley's background in geology, his role in recruiting additional science faculty staff, and his influence among fundamentalists set the stage for the acceptance by subsequent Wheaton geologists of mainstream geology and their rejection of emerging popular fundamentalist ideas about a six day creation and Flood geology. Geology was established as a major subject in 1935 and an independent Geology Department was established in 1958. Geology education at Wheaton College was profoundly influenced by the tension over creation issues in the evangelical subculture, and different models for understanding the relationship between science and Christian theology have been employed by teachers and students.
The history of the doctrine of creation; a Catholic perspective
Authors: Ostermann Martin
Published: March 2009

The history of the emancipation of modern science can be traced in the history of the relationship between creation and evolution, but this is also an example of the growing importance of scholarly–theoretical issues within theology, especially in relation to the interpretation of the Bible. Three phases can be distinguished: (1) the time when teachings about creation were the dominant model; (2) the time when the scientific model of evolution clashed with the theological doctrine of creation; (3) a phase of open dialogue. The third phase began with the recognition of the scientific method by the encyclicals ofPope Pius XII in 1943and1950. However, only in the recent past, initiated by the second Vatican Council, was room made for a fruitful collaboration and the instigation of complementary scientific–theological models. The basic openness to dialogue and the recognition of the working methods of theology and science highlight extreme positions that, from their method of argumentation, must be called fundamentalist. ‘Creationism’ insists upon a literal–naive understanding of the Bible, which cannot be supported by scholarly–theological means, whereas the ‘intelligent design movement’, under the guise of empirical science, tries to present religiously motivated statements as empirical facts. Both groups are characterized by a closed world view and the use of arguments that do not follow from their premises. The present attempts at a scientific–theological synthesis are diverse and show that creation and evolution can be thought of together without inconsistency. For this dialogue to be successful, the open demonstration of one's own methods and the recognition of the theoretically accounted for methods of the dialogue partner are essential. This paper endeavours to demonstrate some of the theological methods relevant to the question of creation and evolution.
Explanations of the Earth's features and origin in pre-Meiji Japan
Authors: Barbaro P.
Published: March 2009

Pre-Meiji Japan was a religiously rich and intellectually varied country, where a large number of theories and beliefs about the origin of the Earth and its features coexisted. The history of science, and the history of geology in particular, lacks an account of this fertile and stimulating socio-cultural system and intellectual environment. The present paper aims to contribute to its understanding, by providing an overview of the most influential religious and scholarly approaches to geological topics in Japan from the eighth century to 1868. The comparison of explanations and beliefs on subjects such as fossils, volcanic eruptions, mountains and the origin of the Earth, and the analysis of geological expertise confirm the heterodox and holistic tendency of the Japanese intellectual and religious environment, which has had positive and negative outcomes for scientific thinking. It also reveals the importance of power structures, and of the social division of labour and knowledge, in the shaping of the Japanese intellectual and religious history.
Extreme Makeover: Transformation of the Veterans Health Care System
Authors: Kizer Kenneth W. , Dudley R. Adams
Published: March 2009

The veterans health care system administered by the U.S. Department of Veterans Affairs (VA) was established after World War I to provide health care for veterans who suffered from conditions related to their military service. It has grown to be the nation's largest integrated health care system.

As the system grew, a number of factors contributed to its becoming increasingly dysfunctional. By the mid-1990s, VA health care was widely criticized for providing fragmented and disjointed care of unpredictable and irregular quality, which was expensive, difficult to access, and insensitive to individual needs.

Between 1995 and 1999, the VA health care system was reengineered, focusing especially on management accountability, care coordination, quality improvement, resource allocation, and information management. Numerous systemic changes were implemented, producing dramatically improved quality, service, and operational efficiency. VA health care is now considered among the best in America, and the VA transformation is viewed as a model for health care reform.
Regulated renin release from 3T3-L1 adipocytes
Authors: Fowler Jason D. , Johnson Nathan D. , Haroldson Thomas A. , Brintnall Joy A. , Herrera Julio E. , Katz Stephen A. , Bernlohr David A.
Published: March 2009

Whereas adipose tissue possesses a local renin-angiotensin system, the synthesis and regulated release of renin has not been addressed. To that end, we utilized differentiating 3T3-L1 cells and analyzed renin expression and secretion. Renin mRNA expression and protein enzymatic activity were not detectable in preadipocytes. However, upon differentiation, renin mRNA and both intracellular and extracellular renin activity were upregulated. In differentiated adipocytes, forskolin treatment resulted in a 28-fold increase in renin mRNA, whereas TNFα treatment decreased renin mRNA fourfold. IL-6, insulin, and angiotensin (Ang) II were without effect. In contrast, forskolin and TNFα each increased renin protein secretion 12- and sevenfold, respectively. Although both forskolin and TNFα induce lipolysis in adipocytes, fatty acids, prostaglandin E2, and lipopolysaccharide had no effect on renin mRNA or secretion. To evaluate the mechanism(s) by which forskolin and/or TNFα are able to regulate renin secretion, a general lipase inhibitor (E600) and PKA inhibitor (H89) were used. Both inhibitors attenuated forskolin-induced renin release, whereas they had no effect on TNFα-regulated secretion. In contrast, E600 potentiated forskolin-stimulated renin mRNA levels, whereas H89 had no effect. Neither inhibitor had any influence on TNFα regulation of renin mRNA. Relative to lean controls, renin expression was reduced 78% in the epididymal adipose tissue of obese male C57Bl/6J mice, consistent with TNFα-mediated downregulation of renin mRNA in the culture system. In conclusion, the expression and secretion of renin are regulated under a complex series of hormonal and metabolic determinants in mature 3T3-L1 adipocytes.
Bumetanide, an NKCC1 Antagonist, Does Not Prevent Formation of Epileptogenic Focus but Blocks Epileptic Focus Seizures in Immature Rat Hippocampus
Authors: Nardou Romain , Ben-Ari Yehezkel , Khalilov Ilgam
Published: March 2009

Excitatory GABA action induced by high [Cl−]i is thought to contribute to seizure generation in neonatal neurons although the mechanism of this effect remains unclear. We report that bumetanide, a NKCC1 antagonist, reduces driving force of GABA-mediated currents (DFGABA) in neonatal hippocampal neurons and blocks the giant depolarizing potentials (GDPs), a spontaneous pattern of network activity. In the preparation composed of two intact interconnected hippocampi, bumetanide did not prevent generation of kainate-induced seizures, their propagation to the contralateral hippocampus, and formation of an epileptogenic mirror focus. However, in the isolated mirror focus, bumetanide effectively blocked spontaneous epileptiform activity transforming it to the GDP-like activity pattern. Bumetanide partially reduced DFGABA and therefore the excitatory action of GABA in epileptic neurons. Therefore bumetanide is a potent anticonvulsive agent although it cannot prevent formation of the epileptogenic mirror focus. We suggest that an additional mechanism other than NKCC1-mediated contributes to the persistent increase of DFGABA in epileptic neurons.
Genomic profiling of developing cardiomyocytes from recombinant murine embryonic stem cells reveals regulation of transcription factor clusters
Authors: Seewald Michael J. , Ellinghaus Peter , Kassner Astrid , Stork Ines , Barg Martina , Niebrügge Sylvia , Golz Stefan , Summer Holger , Zweigerdt Robert , Schräder Eva-Maria , Feicht Samantha , Jaquet Kornelia , Reis Stephanie , Körfer Reiner , Milting Hendrik
Published: March 2009

Cardiomyocytes derived from pluripotent embryonic stem cells (ESC) have the advantage of providing a source for standardized cell cultures. However, little is known on the regulation of the genome during differentiation of ESC to cardiomyocytes. Here, we characterize the transcriptome of the mouse ESC line CM7/1 during differentiation into beating cardiomyocytes and compare the gene expression profiles with those from primary adult murine cardiomyocytes and left ventricular myocardium. We observe that the cardiac gene expression pattern of fully differentiated CM7/1-ESC is highly similar to adult primary cardiomyocytes and murine myocardium, respectively. This finding is underlined by demonstrating pharmacological effects of catecholamines and endothelin-1 on ESC-derived cardiomyocytes. Furthermore, we monitor the temporal changes in gene expression pattern during ESC differentiation with a special focus on transcription factors involved in cardiomyocyte differentiation. Thus, CM7/1-ESC-derived cardiomyocytes are a promising new tool for functional studies of cardiomyocytes in vitro and for the analysis of the transcription factor network regulating pluripotency and differentiation to cardiomyocytes.
New Zealand Ginger mouse: novel model that associates thetyrp1bpigmentation gene locus with regulation of lean body mass
Authors: Duchesnes Cécile E. , Naggert Jürgen K. , Tatnell Michele A. , Beckman Nikki , Marnane Rebecca N. , Rodrigues Jessica A. , Halim Angela , Pontré Beau , Stewart Alistair W. , Wolff George L. , Elliott Robert , Mountjoy Kathleen G.
Published: March 2009

The study of spontaneous mutations in mice over the last century has been fundamental to our understanding of normal physiology and mechanisms of disease. Here we studied the phenotype and genotype of a novel mouse model we have called the New Zealand Ginger (NZG/Kgm) mouse. NZG/Kgm mice are very large, rapidly growing, ginger-colored mice with pink eyes. Breeding NZG/Kgm mice with CAST/Ei or C57BL/6J mice showed that the ginger coat colour is a recessive trait, while the excessive body weight and large body size exhibit a semidominant pattern of inheritance. Backcrossing F1 (NZG/Kgm × CAST/Ei) to NZG/Kgm mice to produce the N2 generation determined that the NZG/Kgm mouse has two recessive pigmentation variant genes ( oca2pand tyrp-1b) and that the tyrp-1bgene locus associates with large body size. Three coat colors appeared in the N2 generation; ginger, brown, and dark. Strikingly, N2 male coat colour associated with body weight; the brown-colored mice weighed the most followed by ginger and then dark. The male brown coat-colored offspring reached adult body weights indistinguishable from NZG/Kgm males. The large NZG/Kgm mouse body size is a result of excessive lean body mass since these mice are not obese or diabetic. NZG/Kgm mice exhibit an unusual pattern of fat distribution; compared with other mouse strains they have disproportionately higher amounts of subcutaneous and gonadal fat. These mice are susceptible to high-fat diet-induced obesity but are resistant to high-fat diet-induced diabetes. We propose NZG/Kgm mice as a novel model to delineate gene(s) that regulate 1) growth and metabolism, 2) resistance to Type 2 diabetes, and 3) preferential fat deposition in the subcutaneous and gonadal areas.
Scaling Properties of a Hybrid Fermi‐Ulam‐Bouncer Model
Authors: Oliveira Diego F. M. , Bizão Rafael A. , Leonel Edson D.
Published: March 2009

Some dynamical properties for a one‐dimensional hybrid Fermi‐Ulam‐bouncer model are studied
under the framework of scaling description. The model is described by using a two‐dimensional nonlinear area preserving mapping. Our results show that the chaotic regime below the lowest energy invariant spanning curve is scaling invariant and the obtained critical exponents are used to find a universal plot for the second momenta of the average velocity.
Evaluation of Fructooligosaccharides and Inulins as Potentially Health Benefiting Food Ingredients by HPAEC‐PED and MALDI‐TOF MS
Authors: Borromei Chiara , Careri Maria , Cavazza Antonella , Corradini Claudio , Elviri Lisa , Mangia Alessandro , Merusi Cristiana
Published: March 2009

This paper describes the complementarity of high‐performance anion exchange chromatography coupled with pulsed electrochemical detection (HPAEC‐PED) and matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐TOF‐MS) to evaluate commercial available fructans (fructooligosaccharides (FOS) and inulins), having different degrees of polymerization (DP) which are usually employed by food industry as functional ingredients either for their prebiotic properties or as a fat replacer, giving a fat‐like mouth feel and texture. The developed HPAEC‐PED methods are able to analyze FOS (fructans with DP 3–10) and inulins (DP ranging from 3 to 80) with a good resolution and relatively short retention times to evaluate structural differences between fructooligosaccharide and inulins and the possible presence of inulooligosaccharides as well as of branching. To characterize FOS and inulin at different degrees of polymerization and to assure correct molecular assignment, MALDI‐TOF MS analysis was also investigated. The 2,5‐dihydroxy benzoic acid (2,5‐DHB) was found to be the best matrix for FOS analysis as Actilight and Raftilose P95 products, while 3‐aminoquinoline (3‐AQ) seems to be the best matrix for inulin with higher DP. The applicability of the optimized methods to the identification and determination of FOS contained in a symbiotic milk as well as a type of inulin added as functional ingredient to a cooked ham is demonstrated.
Experiments and Modelling Techniques for Heat and Mass Transfer in Light Water Reactors
Authors: Ambrosini W. , Bucci M. , Forgione N. , Manfredini A. , Oriolo F.
Published: March 2009

The paper summarizes the lesson learned from theoretical and experimental activities performed at the University of Pisa, Pisa, Italy, in past decades in order to develop a general methodology of analysis of heat and mass transfer phenomena of interest for nuclear reactor applications. An overview of previously published results is proposed, highlighting the rationale at the basis of the performed work and its relevant conclusions. Experimental data from different sources provided information for model development and assessment. They include condensation experiments performed at SIET (Piacenza, Italy) on the PANTHERS prototypical PCCS module, falling film evaporation tests for simulating AP600‐like outer shell spraying conditions, performed at the University of Pisa, experimental data concerning condensation on finned tubes, collected by CISE (Piacenza, Italy) in the frame of the INCON EU Project, and experimental tests performed in the CONAN experimental facility installed at the University of Pisa. The experience gained in these activities is critically reviewed and discussed to highlight the relevant obtained conclusions and the perspectives for future work.
Cathepsin G Recruits Osteoclast Precursors via Proteolytic Activation of Protease-Activated Receptor-1
Authors: Wilson Thomas J. , Nannuru Kalyan C. , Singh Rakesh K.
Published: March 2009

Metastatic breast cancer shows extreme tropism for the bone microenvironment, leading to the establishment of osteolytic metastases. Perpetuation of tumor-induced osteolysis requires a continuous supply of osteoclast precursors migrating into the bone microenvironment that can subsequently differentiate into mature osteoclasts and resorb bone. Thus, identification and subsequent targeting of chemoattractants of osteoclast precursors that are up-regulated at the tumor-bone interface represents a potential avenue to interrupt osteolysis. We report that cathepsin G, a serine protease, plays a vital role in the bone microenvironment by modulating tumor-stromal interaction in a manner that favors tumor establishment and regulates chemotaxis of monocytes, a subset of which has the potential to differentiate into osteoclasts. Our data show that cathepsin G–induced chemotaxis of monocytes is mediated by proteolytic activation of protease-activated receptor-1 (PAR-1). Attenuation of PAR-1 activation abrogates cathepsin G–mediated induction of monocyte chemotaxis. We also show that in vivo inhibition of cathepsin G reduces the number of CD11b+ osteoclast precursors and mature osteoclasts at the tumor-bone interface. Together, these data suggest that therapeutic targeting of both PAR-1 signaling in osteoclast precursors as well as cathepsin G at the tumor-bone interface has the potential to reduce osteolysis by inhibiting the recruitment, differentiation, and activation of osteoclast precursors. [Cancer Res 2009;69(7):3188–95]
Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation
Authors: Simpson Craig D. , Mawji Imtiaz A. , Anyiwe Kika , Williams Moyo A. , Wang Xiaoming , Venugopal Amudha L. , Gronda Marcela , Hurren Rose , Cheng Sonia , Serra Stefano , Zavareh Reza Beheshti , Datti Alessandro , Wrana Jeffrey L. , Ezzat Shereen , Schimmer Aaron D.
Published: March 2009

Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed “anoikis.” However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to anoikis will be useful chemical probes to understand this pathway. To identify novel anoikis sensitizers in anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced anoikis sensitization. Ouabain initiated anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to anoikis by inhibiting its known target, the Na+/K+ ATPase pump, and inducing hypoosmotic stress. Resistance to anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na+/K+ ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides. [Cancer Res 2009;69(7):2739–47]
PME-1 Protects Extracellular Signal-Regulated Kinase Pathway Activity from Protein Phosphatase 2A–Mediated Inactivation in Human Malignant Glioma
Authors: Puustinen Pietri , Junttila Melissa R. , Vanhatupa Sari , Sablina Anna A. , Hector Melissa E. , Teittinen Kaisa , Raheem Olayinka , Ketola Kirsi , Lin Shujun , Kast Juergen , Haapasalo Hannu , Hahn William C. , Westermarck Jukka
Published: March 2009

Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies; however, the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here, we show that methylesterase PME-1–mediated inhibition of the protein phosphatase 2A promotes basal ERK pathway activity and is required for efficient growth factor response. Mechanistically, PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and protein kinase C. In malignant gliomas, PME-1 expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (n = 222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells and suggest an important functional role for PME-1 in the disease progression of human astrocytic gliomas. [Cancer Res 2009;69(7):2870–7]
Tumor-Infiltrating Regulatory Dendritic Cells Inhibit CD8+ T Cell Function via l-Arginine Metabolism
Authors: Norian Lyse A. , Rodriguez Paulo C. , O'Mara Leigh A. , Zabaleta Jovanny , Ochoa Augusto C. , Cella Marina , Allen Paul M.
Published: March 2009

Dendritic cells (DC) have a critical effect on the outcome of adaptive immune responses against growing tumors. Whereas it is generally assumed that the presence of phenotypically mature DCs should promote protective antitumor immunity, evidence to the contrary does exist. We describe here a novel mechanism by which tumor-infiltrating dendritic cells (TIDC) actively contribute to the suppression of protective CD8+ T-cell–based antitumor immunity. Using the BALB/NeuT model of spontaneously arising mammary carcinoma, we found that canonical MHC II+/CD11b+/CD11chigh TIDCs act as regulatory DCs to suppress CD8+ T-cell function, resulting in diminished T-cell–based antitumor immunity in vivo. Stimulation of naive T cells with regulatory TIDCs resulted in an altered cell fate program characterized by minimal T-cell expansion, impaired IFNγ production, and anergy. Suppression by regulatory TIDCs overcame stimulatory signals provided by standard DCs, occurred in the absence of cognate interactions with T cells, and was mediated primarily by arginase metabolism of l-arginine. Immunosuppressive TIDCs were found in every murine tumor type examined and were phenotypically distinct from tumor-infiltrating CD11cint-low/CD11b+/Gr-1+ myeloid-derived suppressor cells. Thus, within the tumor microenvironment, MHC II+ TIDCs can function as potent suppressors of CD8+ T-cell immunity. [Cancer Res 2009;69(7):3086–94]
A Novel Human AlkB Homologue, ALKBH8, Contributes to Human Bladder Cancer Progression
Authors: Shimada Keiji , Nakamura Mitsutoshi , Anai Satoshi , De Velasco Marco , Tanaka Motoyoshi , Tsujikawa Kazutake , Ouji Yukiteru , Konishi Noboru
Published: March 2009

We recently identified a novel human AlkB homologue, ALKBH8, which is expressed in various types of human cancers including human urothelial carcinomas. In examining the role and function of ALKBH8 in human bladder cancer development in vitro, we found that silencing of ALKBH8 through small interfering RNA transfection reduced reactive oxygen species (ROS) production via down-regulation of NAD(P)H oxidase-1 (NOX-1) and induced apoptosis through subsequent activation of c-jun NH2-terminal kinase (JNK) and p38. However, we also found that JNK and p38 activation resulted in phosphorylation of H2AX (γH2AX), a variant of mammalian histone H2A, which contributes to the apoptosis induced by silencing ALKBH8 and NOX-1. Silencing of ALKBH8 significantly suppressed invasion, angiogenesis, and growth of bladder cancers in vivo as assessed both in the chorioallantoic membrane assay and in an orthotopic mouse model using green fluorescent protein–labeled KU7 human urothelial carcinoma cells. Immunohistochemical examination showed high expression of ALKBH8 and NOX-1 proteins in high-grade, superficially and deeply invasive carcinomas (pT1 and >pT2) as well as in carcinoma in situ, but not in low-grade and noninvasive phenotypes (pTa). These findings indicate an essential role for ALKBH8 in urothelial carcinoma cell survival mediated by NOX-1–dependent ROS signals, further suggesting new therapeutic strategies in human bladder cancer by inducing JNK/p38/γH2AX–mediated cell death by silencing of ALKBH8. [Cancer Res 2009;69(7):3157–64]
PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas
Authors: Tan David S.P. , Lambros Maryou B.K. , Rayter Sydonia , Natrajan Rachael , Vatcheva Radost , Gao Qiong , Marchiò Caterina , Geyer Felipe C. , Savage Kay , Parry Suzanne , Fenwick Kerry , Tamber Narinder , Mackay Alan , Dexter Tim , Jameson Charles , McCluggage W. Glenn , Williams Alistair , Graham Ashley , Faratian Dana , El-Bahrawy Mona , Paige Adam J. , Gabra Hani , Gore Martin E. , Zvelebil Marketa , Lord Christopher J. , Kaye Stanley B. , Ashworth Alan , Reis-Filho Jorge S.
Published: March 2009

Purpose: To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer.

Experimental Design: Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers.

Results: Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas.

Conclusion: Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.
Identification of Major Allergens in Watermelon
Authors: Pastor Carlos , Cuesta-Herranz Javier , Cases Barbara , Pérez-Gordo Marina , Figueredo Elena , de las Heras Manuel , Vivanco Fernando
Published: March 2009

Background: Watermelon is a worldwide consumed Cucurbitaceae fruit that can elicit allergic reactions. However, the major allergens of watermelon are not known. The aim of this study is to identify and characterize major allergens in watermelon. Methods: Twenty-three patients allergic to watermelon took part in the study. The diagnosis was based on a history of symptoms and positive skin prick-prick tests to watermelon, confirmed by positive open oral challenge testing to watermelon pulp. Allergenic components were detected by SDS-PAGE and immunoblotting. Molecular characterization of IgE-binding bands was performed by N-terminal amino acid sequencing and mass spectrometry. Allergens were purified combining several chromatographic steps. Results: Several IgE binding bands (8–120 kDa) were detected in watermelon extract. Three major allergens were identified as malate dehydrogenase (36 kDa), triose phosphate isomerase (28 kDa) and profilin (13 kDa). Purified allergens individually inhibited IgE binding to the whole watermelon extract. Conclusions: All in all these results indicate that malate dehydrogenase, triose phosphate isomerase and profilin are major allergens involved in watermelon allergy.
IL-16 Variability and Modulation by Antiallergic Drugs in a Murine Experimental Allergic Rhinitis Model
Authors: Akiyama Kosuke , Karaki Masayuki , Kobayshi Ryuichi , Dobashi Hiroaki , Ishida Toshihiko , Mori Nozomu
Published: March 2009

Background: Interleukin-16 (IL-16) is a cytokine that induces selective migration of CD4+ cells and participates in inflammatory diseases including allergic rhinitis. Histamine and prostaglandin D2 are important chemical mediators of allergic inflammation, and antiallergic drugs are commonly used for the treatment of allergic rhinitis. It remains unknown whether treatment with the drugs affects IL-16. Objective: We evaluated the variability of IL-16 and the effects of the antiallergic drugs fexofenadine (40 mg/kg/day) and ramatroban (30 mg/kg/day) on IL-16 in an OVA-sensitized BALB/c murine experimental allergic rhinitis model. Methods: We measured the expression level of IL-16 protein in the mouse nasal septal mucosa by immunohistochemistry, and the serum level of IL-16 by ELISA. Several other parameters associated with allergic rhinitis (nasal symptoms, OVA-specific IgE, eosinophil and T cell infiltration) were also measured. Results: Local and systemic expressions of IL-16 were significantly increased in OVA-sensitized mice when compared to the nonsensitized group. Fexofenadine and ramatroban significantly inhibited the following OVA-induced allergic features when compared to the nontreated sensitized group: sneezing, nasal rubbing, eosinophil infiltration, IL-16 expressions in nasal tissue, and serum IL-16 level. Serum OVA-specific IgE and local T cell infiltration were reduced, but they did not reach significant values. Conclusions: These results suggest that IL-16 was both systemically and locally upregulated in the murine allergic rhinitis model and that IL-16 changed in parallel to allergic state by treatment with the drugs.
Cedar and Cypress Pollinosis and Allergic Rhinitis: Quality of Life Effects of Early Intervention with Leukotriene Receptor Antagonists
Authors: Sasaki Keita , Okamoto Yoshitaka , Yonekura Syuji , Okawa Toru , Horiguchi Shigetoshi , Chazono Hideaki , Hisamitsu Minako , Sakurai Daiju , Hanazawa Toyoyuki , Okubo Kimihiro
Published: March 2009

Background: Allergic rhinitis involves inflammation of the nasal passages. The use of nasal steroids is generally very effective in providing significant symptom relief. However, compliance for their use is sometimes poor. Methods: To examine the efficacy of early intervention (before pollen dispersal) with oral cysteinyl leukotriene receptor antagonists (LTRA) on pollinosis in patients with allergy to cedar and Japanese cypress pollens, groups of subjects were treated with LTRA or a placebo for 4 weeks at the beginning of the cedar pollen dispersal season. Subsequently, all patients received nasal steroid therapy concomitantly with LTRA throughout the remaining period of the pollen dispersal season. The effects of such early treatment with LTRA on pollinosis were investigated using symptom scores from an allergy diary and quality of life (QOL) scores. Results: Sneezing and nasal congestion scores were significantly lower in the LTRA-pretreated subjects than observed in the placebo-pretreated patients between weeks 4 and 6 and weeks 3 and 5, respectively. QOL scores improved significantly in all domains after concomitant therapy with nasal steroids. The percent improvement in the nasal congestion score after the concomitant therapy was significantly higher in the LTRA group (69%) than in the placebo group (41%). Conclusion: Significant differences observed in symptoms and in QOL effects between LTRA- and placebo-pretreated patients and the absence of major adverse effects noted in these studies suggest that early intervention with LTRA is beneficial and safe and should be considered in the management of pollinosis-associated allergic rhinitis.
Role of Mammalian Chitinases in Asthma
Authors: Shuhui Lim , Mok Yu-Keung , Wong W.S. Fred
Published: March 2009

Asthma is a chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway hyperresponsiveness. Mechanisms underlying the pathogenesis of asthma are not fully understood. In recent years, there are mounting evidences demonstrating that mammalian chitinases may play a key role in mediating the T-helper 2 cell-driven inflammatory response that is commonly associated with asthma. Chitinases (e.g., chitotriosidase and acidic mammalian chitinase) are enzymes that degrade chitin, the second most abundant biopolymer that can be found in the cell walls of fungi, microfilarial sheaths of helminths, and exoskeletons of insects and crustaceans. There are also chitinase-like proteins (e.g., YKL-40, Ym1 and Ym2) that lack chitinolytic activity but retain chitin-binding ability. Therefore, chitinases were originally believed to function in host defense against parasitic infections, but the first discovery of their role in inflammatory airway diseases came as a surprise. There is ample evidence to support an association of acidic mammalian chitinase and YKL-40 with allergic bronchial asthma in patients. Our recent studies in a mouse asthma model revealed that anti-inflammatory drugs like corticosteroid and cysteinyl leukotriene receptor antagonist were able to suppress elevated pulmonary levels of mammalian chitinases. Taken together, mammalian chitinases may be useful as biomarkers for asthma. Notwithstanding, large-scale multi-center association studies are required to confirm this hypothesis. Besides, substantially more works using knockout mice, recombinant chitinases and siRNA technology are required to investigate a potential role of chitinases in the pathogenesis of asthma.
Patients’ Stratification and Correlation of Brain Magnetic Resonance Imaging Parameters with Disability Progression in Multiple Sclerosis
Authors: Vaneckova Manuela , Seidl Zdenek , Krasensky Jan , Havrdova Eva , Horakova Dana , Dolezal Ondrej , Burgetova Andrea , Masek Martin
Published: March 2009

Aims: The objective was to correlate the change in the lesion load (LL) and brain atrophy in patients with multiple sclerosis (MS) with progression of clinical disability, represented by the Expanded Disability Status Scale (EDSS), and to test if stratification of patients according to magnetic resonance imaging (MRI) criteria can increase the predictive ability of MRI for MS clinical development. Methods: 181 patients with clinically definite relapsing-remitting MS underwent MRI for a period of up to 5 years. Grouping of patients according to the LL value at the study entry revealed a substantial increase in the Spearman rank correlation coefficient R. Results: For the low LL cohort of patients, we found a statistically significant correlation (R up to –0.71 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with increased brain atrophy in the first 2 years. For the high LL group, we found a statistically significant correlation (R up to 0.72 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with an increase in the LL value in the first year. Conclusions: We conclude that stratification of patients according to the MRI criterion (LL) can increase the predictive ability of MRI.
Frequent Premature Atrial Contractions in Stroke of Undetermined Etiology
Authors: Todo Kenichi , Moriwaki Hiroshi , Saito Kozue , Naritomi Hiroaki
Published: March 2009

Background: The cause of ischemic stroke is undetermined in 15–40% of patients. We studied the association between frequent premature atrial contractions (PAC) and stroke of undetermined etiology. Methods: We retrospectively studied ischemic stroke patients who were consecutively admitted to our department and underwent 24-hour Holter ECG recording including 163 noncardioembolic stroke patients (group A), 24 stroke patients of undetermined etiology (group B), and 37 cardioembolic stroke patients with prior-diagnosed paroxysmal atrial fibrillation (group C). The number of PAC per 24 h and the prevalence of patients with frequent PAC (200 or more per 24 h) were compared between the groups. Results: The number of PAC was significantly larger in groups B and C than in group A. The proportion of patients with frequent PAC was larger in group B (13/24, 54%) and in group C (18/37, 48%) than in group A (32/163, 20%). Conclusion: Our data suggest that frequent PAC should be regarded as a masked type of paroxysmal atrial fibrillation and should be included in one of the causes of cardioembolic stroke.
Marie-Jean-Pierre Flourens (1794–1867) and Cortical Localization
Authors: Pearce J.M.S.
Published: March 2009

The child prodigy Marie-Jean-Pierre Flourens received his medical degree at Montpellier when aged 19. As a young promising physician Flourens was asked to investigate Gall’s controversial views on cerebral localization. To test Gall’s assertions, Flourens developed ablation as a procedure to explore the workings of the brain. By removing anatomically defined areas of the brain of an animal and watching its behaviour, he thought he might localize certain functions. Flourens did not favour the idea of cerebral localization and concluded that the brain functioned as a whole and thus arose the concept of ‘cerebral equipotentiality’. This culminated in his 1824 Recherches expérimentales sur les propriétés et les fonctions du système nerveux. His techniques were, however, crude and imperfect, and his experiments were mainly on birds. Much criticism and debate ensued. A gifted man, Flourens also advanced the physiology of the vestibular apparatus and described the anaesthetic properties of ether.