bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigations geomecaniques des emplacements de tunnels en rocher sur l'ile de Montreal
Authors: Gill D. E. , Ballivy G.
Published: October 2008

Due to the extent of projects of the Montreal Urban Community involving rock tunnelling, the possibility of using full face boring machine had to be considered. The usual site investigation techniques had to be revised. The main purpose of this paper is to describe, discuss and illustrate the new investigation techniques.Problems related to geology that might be encountered with full face boring machines are reviewed and the various investigations which lead to a better geomechanical knowledge of tunnel sites are presented. The diamond drilling program and the aspects which need to be stressed in the reports are discussed.The laboratory testing program includes splitting tests, uniaxial and triaxial compression tests, and modified Handewith punching tests. In situ testing program comprises Ménard pressio-permeameter tests, Goodman jack tests, and borehole punching tests performed with an apparatus developed at Ecole Polytechnique de Montréal.
What Limits Trees in C4 Grasslands and Savannas?
Authors: Bond William J.
Published: October 2008

Though the distribution of global vegetation can generally be predicted from climate, grasslands are an exception. C4 grassy biomes cover vast areas that are warm enough and wet enough to support closed forests. The extent of this climate mismatch has been revealed by physiologically based global vegetation simulations and by large empirical data sets. Reasons for the existence of grassy biomes have long been debated, polarized into bottom-up (resources) or top-down (fire, herbivory) arguments. Recent studies indicate that both are important, especially in suppressing woody recruits. Grasses are formidable competitors belowground, create highly flammable fuels, and can support large herbivore densities. The net effect on trees is rare and episodic recruitment of adults in tree-fall gaps. The implication is that ecosystem structure and function depend on demographic transitions. Tree cover is increasing and grass/forest boundaries are changing. These changes can have large feedbacks to the earth-atmosphere system. Though progress has been made, there is still great uncertainty in predicting the future of C4 grassy biomes.
Plague Minnow or Mosquito Fish? A Review of the Biology and Impacts of Introduced Gambusia Species
Authors: Pyke Graham H.
Published: October 2008

Gambusia affinis and G. holbrooki, introduced worldwide from eastern North America, are collectively the most abundant, widespread freshwater fish in the world, which is not surprising because they tolerate, and sometimes thrive under, an exceptional range of environmental conditions and have high reproductive potential. Some know them as mosquitofish because of a legendary ability to control mosquitoes, and diseases they carry, while others doubt this ability or argue that indigenous fish are equally or more effective. However, rigorous evidence to support these views remains scant, so the legend persists. Some know them as plague minnow because of negative impacts on many native animal species, and abundant evidence exists to support this view. Despite such polarized attitudes toward them, their high abundance and wide distribution, and a large scientific literature devoted to them, many important aspects of their biology remain poorly known.
Species Selection: Theory and Data
Authors: Jablonski David
Published: October 2008

Species selection in the broad sense—also termed species sorting—shapes evolutionary patterns through differences in speciation and extinction rates (and their net outcome, often termed the emergent fitness of clades) that arise by interaction of intrinsic biological traits with the environment. Effect-macroevolution occurs when those biotic traits, such as body size or fecundity, reside at the organismic level. Strict-sense species selection occurs when those traits are emergent at the species level, such as geographic range or population size. The fields of paleontology, comparative phylogenetic analysis, macroecology, and conservation biology are rich in examples of species sorting, but relatively few instances have been well documented, so the extent and efficacy of the specific processes remain poorly known. A general formalization of these processes remains challenging, but approaches drawing on hierarchical covariance models appear promising. Analyses integrating paleontological and neontological data for a single set of clades would be especially powerful.
The Ecological Performance of Protected Areas
Authors: Gaston Kevin J. , Jackson Sarah F. , Cantú-Salazar Lisette , Cruz-Piñón Gabriela
Published: October 2008

Protected areas are a cornerstone of local, regional, and global strategies for the conservation of biodiversity. However, the ecological performance of these areas, both in terms of the representation and the maintenance of key biodiversity features, remains poorly understood. A large and rapidly expanding literature bears on these issues, but it is highly fragmented, principally comprises particular case studies, and employs a diverse array of approaches. Here we provide a synthetic review of this work, discriminating between issues of performance of inventory and condition at the scale of individual protected areas, portfolios, and networks of protected areas. We emphasize the insights that follow and the links between the different issues, as well as highlight the major problems that remain unresolved.
Thrombopoietin and Thrombopoietin Mimetics in the Treatment of Thrombocytopenia
Authors: Kuter David J.
Published: October 2008

Although the thrombopoietin receptor was discovered in 1991 and thrombopoietin (TPO) was purified in 1994, the development of a clinically useful TPO was hampered by the appearance of neutralizing antibodies to some forms of recombinant TPO. However, in 2008 two new drugs that mimic the effect of TPO became available to treat thrombocytopenia. Romiplostim is a TPO peptide mimetic given by subcutaneous injection that activates the TPO receptor by binding to the distal hematopoietic receptor domain just like TPO. Eltrombopag is a TPO nonpeptide mimetic administered orally that activates the TPO receptor by binding to the transmembrane domain. Both increase the platelet count in healthy humans as well as in >80% of patients with immune thrombocytopenic purpura (ITP). Although initially restricted to the second-line treatment of ITP, both agents could help treat many thrombocytopenic disorders. Both agents are well tolerated, with mild headache being the most common complaint. Potential long-term complications include thrombosis, increased bone marrow reticulin, rebound worsening of thrombocytopenia upon discontinuation, and increased blast formation. Ongoing studies should establish the incidence of these complications and determine the efficacy of these new agents in a variety of other thrombocytopenic conditions.
IL-23 and Autoimmunity: New Insights into the Pathogenesis of Inflammatory Bowel Disease
Authors: Abraham Clara , Cho Judy H.
Published: October 2008

The intestinal immune system has the challenge of maintaining both a state of tolerance toward intestinal antigens and the ability to combat pathogens. This balance is partially achieved by reciprocal regulation of proinflammatory, effector CD4+T cells and tolerizing, suppressive regulatory T cells. Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have linked CD to a number of IL-23 pathway genes, notably IL23R (interleukin 23 receptor). Similar associations in IL-23 pathway genes have been observed in UC. IL23R is a key differentiation feature of CD4+Th17 cells, effector cells that are critical in mediating antimicrobial defenses. However, IL-23 and Th17 cell dysregulation can lead to end-organ inflammation. The differentiation of inflammatory Th17 cells and suppressive CD4+Treg subsets is reciprocally regulated by relative concentrations of TGFβ, with the concomitant presence of proinflammatory cytokines favoring Th17 differentiation. The identification of IL-23 pathway and Th17 expressed genes in IBD pathogenesis highlights the importance of the proper regulation of the IL-23/Th17 pathway in maintaining intestinal immune homeostasis.
Atomic-Scale Templates Patterned by Ultrahigh Vacuum Scanning Tunneling Microscopy on Silicon
Authors: Walsh Michael A. , Hersam Mark C.
Published: October 2008

The ultrahigh vacuum (UHV) scanning tunneling microscope (STM) enables patterning and characterization of the physical, chemical, and electronic properties of nanostructures on surfaces with atomic precision. On hydrogen-passivated Si(100) surfaces, selective nanopatterning with the STM probe allows the creation of atomic-scale templates of dangling bonds surrounded by a robust hydrogen resist. Feedback-controlled lithography, which can remove a single hydrogen atom from the Si(100):H surface, demonstrates high-resolution nanopatterning. The resulting patterns can be used as templates for a variety of materials to form hybrid silicon nanostructures while maintaining a pristine background resist. The versatility of this UHV-STM nanolithography approach has led to its use on a variety of other substrates, including alternative hydrogen-passivated semiconductor surfaces, molecular resists, and native oxide resists. This review discusses the mechanisms of STM-induced hydrogen desorption, the postpatterning deposition of molecules and materials, and the implications for nanoscale device fabrication.
Cost-Sharing: A Blunt Instrument
Authors: Remler Dahlia K. , Greene Jessica
Published: October 2008

Cost-sharing is a health care cost-containment technique in which health care services are partially paid for by patients out of pocket. Cost-sharing can reduce non-cost-effective care, but it can also undermine the financial protection and access values of health insurance. We review the empirical evidence published since the mid-1980s about cost-sharing's effect on utilization, expenditures, health, and adverse consequences, including how the effects vary by form of care, by health status, and by sociodemographic characteristics. Some cost-sharing, such as emergency department copayments, reduces utilization without any harmful effects, whereas other cost-sharing reduces valuable care such as maintenance drug use among the chronically ill. Cost-sharing should be used judiciously, with attention taken not to reduce highly cost-effective care.
Early rise in inflammation and microcirculatory disorder determine the development of autoimmune pancreatitis in the MRL/Mp-mouse
Authors: Sorg Heiko , Lorch Benjamin , Jaster Robert , Fitzner Brit , Ibrahim Saleh , Holzhueter Stephanie-Anna , Nizze Horst , Vollmar Brigitte
Published: October 2008

Autoimmune pancreatitis (AIP) is a rare cause of chronic pancreatitis and mimics pancreatic cancer. Although there is strong interest in research, etiology and pathophysiology of AIP are still unknown. Therefore, we analyzed a total of 92 MRL/Mp-mice of either sex, which are prone to develop AIP, in four different age groups (8–12, 16–20, 24–28, and 32–40 wk). Using intravital fluorescence microscopy, histology, laboratory analysis, and Western blot, onset, severity, and pathophysiological mechanisms of AIP were evaluated. Female animals showed in vivo an age-dependent increase of intrapancreatic leukocyte accumulation, as well as a loss in functional capillary perfusion. In contrast, intrapancreatic inflammation in male mice was less pronounced and not age dependent. Furthermore, pancreatic tissue specimen of female animals exhibited major organ destruction with significantly higher values of mean pathological scores (1.5 ± 0.3 vs. ≤0.2; P < 0.05), as well as significantly increased CD4-, CD8-, CD11b-, and CD138-positive cells compared with male animals of the same age. Interestingly, there was a significant positive correlation between intravascular leukocyte adherence and the histopathological score of the pancreas, indicating a determining role of the innate immune system for the late onset of AIP. The present study shows that the onset of AIP is characterized by an inflammatory response and microcirculatory failure, most probably constituting initiators and propagators of this autoimmune disease.
Macropinocytosis in Shiga toxin 1 uptake by human intestinal epithelial cells and transcellular transcytosis
Authors: Malyukova Irina , Murray Karen F. , Zhu Chengru , Boedeker Edgar , Kane Anne , Patterson Kathleen , Peterson Jeffrey R. , Donowitz Mark , Kovbasnjuk Olga
Published: October 2008

Shiga toxin 1 and 2 production is a cardinal virulence trait of enterohemorrhagic Escherichia coli infection that causes a spectrum of intestinal and systemic pathology. However, intestinal sites of enterohemorrhagic E. coli colonization during the human infection and how the Shiga toxins are taken up and cross the globotriaosylceramide (Gb3) receptor-negative intestinal epithelial cells remain largely uncharacterized. We used samples of human intestinal tissue from patients with E. coli O157:H7 infection to detect the intestinal sites of bacterial colonization and characterize the distribution of Shiga toxins. We further used a model of largely Gb3-negative T84 intestinal epithelial monolayers treated with B-subunit of Shiga toxin 1 to determine the mechanisms of non-receptor-mediated toxin uptake. We now report that E. coli O157:H7 were found at the apical surface of epithelial cells only in the ileocecal valve area and that both toxins were present in large amounts inside surface and crypt epithelial cells in all tested intestinal samples. Our in vitro data suggest that macropinocytosis mediated through Src activation significantly increases toxin endocytosis by intestinal epithelial cells and also stimulates toxin transcellular transcytosis. We conclude that Shiga toxin is taken up by human intestinal epithelial cells during E. coli O157:H7 infection regardless of the presence of bacterial colonies. Macropinocytosis might be responsible for toxin uptake by Gb3-free intestinal epithelial cells and transcytosis. These observations provide new insights into the understanding of Shiga toxin contribution to enterohemorrhagic E. coli-related intestinal and systemic diseases.
Alterations inN-methyl-d-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats
Authors: Banerjee Banani , Medda Bidyut K. , Zheng Yue , Miller Heather , Miranda Adrian , Sengupta Jyoti N. , Shaker Reza
Published: October 2008

The excitatory amino acid glutamate plays an important role in the development of neuronal sensitization and the ionotropic N-methyl-d-aspartate receptor (NMDAR) is one of the major receptors involved. The objective of this study was to use a cat model of gastroesophageal reflux disease (GERD) to investigate the expression of the NR1 and NR2A subunits of NMDAR in the vagal and spinal afferent fibers innervating the esophagus. Two groups of cats (Acid-7D and PBS-7D) received 0.1 N HCl (pH 1.2) or 0.1 M PBS (pH 7.4) infusion in the esophagus (1 ml/min for 30 min/day for 7 days), respectively. NR1 splice variants (both NH2and COOH terminals) and NR2A in the thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophagus were evaluated by RT-PCR, Western blot, and immunohistochemistry. Acid produced marked inflammation and a significant increase in eosinophil peroxidase and myeloperoxidase contents compared with PBS-infused esophagus. The NR1-4 splice variant gene exhibited a significant upregulation in DRGs and esophagus after acid infusion. In DRGs, NGs, and esophagus, acid infusion resulted in significant upregulation of NR1 and downregulation of NR2A subunit gene expression. A significant increase in NR1 polypeptide expression was observed in DRGs and NGs from Acid-7D compared with control. In conclusion, long-term acid infusion in the cat esophagus resulted in ulcerative esophagitis and differential expressions of NR1 and NR2A subunits. It is possible that these changes may in part contribute to esophageal hypersensitivity observed in reflux esophagitis.
H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of KATP channels
Authors: Siebert Nikolai , Cantré Daniel , Eipel Christian , Vollmar Brigitte
Published: October 2008

Hepatic blood supply is uniquely regulated by the hepatic arterial buffer response (HABR), counteracting alterations of portal venous blood flow by flow changes of the hepatic artery. Hydrogen sulfide (H2S) has been recognized as a novel signaling molecule with vasoactive properties. However, the contribution of H2S in mediating the HABR is not yet studied. In pentobarbital-anesthetized and laparotomized rats, flow probes around the portal vein and hepatic artery allowed for assessment of the portal venous (PVBF) and hepatic arterial blood flow (HABF) under baseline conditions and stepwise reduction of PVBF for induction of HABR. Animals received either the H2S donor Na2S, DL-propargylglycine as inhibitor of the H2S synthesizing enzyme cystathionine-γ-lyase (CSE), or saline alone. Additionally, animals were treated with Na2S and the ATP-sensitive potassium channel (KATP) inhibitor glibenclamide or with glibenclamide alone. Na2S markedly increased the buffer capacity to 27.4 ± 3.0% ( P < 0.05 vs. controls: 15.5 ± 1.7%), whereas blockade of H2S formation by DL-propargylglycine significantly reduced the buffer capacity (8.5 ± 1.4%). Glibenclamide completely reversed the H2S-induced increase of buffer capacity to the control level. By means of RT-PCR, Western blot analysis, and immunohistochemistry, we observed the expression of both H2S synthesizing enzymes (CSE and cystathionine-β-synthase) in aorta, vena cava, hepatic artery, and portal vein, as well as in hepatic parenchymal tissue. Terminal branches of the hepatic afferent vessels expressed only CSE. We show for the first time that CSE-derived H2S contributes to HABR and partly mediates vasorelaxation of the hepatic artery via activation of KATP channels.
High glucose-induced Nox1-derived superoxides downregulate PKC-βII, which subsequently decreases ACE2 expression and ANG(1-7) formation in rat VSMCs
Authors: Lavrentyev Eduard N. , Malik Kafait U.
Published: October 2008

In rat diabetic animal models, ANG(1-7) treatment prevents the development of cardiovascular complications. Angiotensin-converting enzyme (ACE)2 is a major ANG(1-7)-generating enzyme in vascular smooth muscle cells (VSMCs), and its expression is decreased by a prolonged exposure to high glucose (HG), which is reflected by lower ANG(1-7) levels. However, the underlying mechanism of its downregulation is unknown and was the subject of this study. Rat aortic VSMCs were maintained in normal glucose (NG) or HG (∼4.1 and ∼23.1 mmol/l, respectively) for up to 72 h. Several PKC and NADPH oxidase inhibitors and short interfering (si)RNAs were used to determine the mechanism of HG-induced ACE2 downregulation. Cell lysates were subjected to Western blot analysis, real-time quantitative PCR, and ANG(1-7) radioimmunodetection. At 72 h of HG exposure, ACE2 mRNA, protein, and ANG(1-7) levels were decreased (0.17 ± 0.01-, 0.47 ± 0.03-, and 0.16 ± 0.01-fold, respectively), and the expression of NADPH oxidase subunit Nox1 was increased (1.70 ± 0.2-fold). The HG-induced ACE2 decrease was reversed by antioxidants and Nox1 siRNA as well as by inhibitors of glycotoxin formation. ACE2 expression was PKC-βII dependent, and PKC-βII protein levels were reduced in the presence of HG (0.32 ± 0.03-fold); however, the PKC-βII inhibitor CG-53353 prevented the HG-induced ACE2 loss and Nox1 induction, suggesting a nonspecific effect of the inhibitor. Our data suggest that glycotoxin-induced Nox1 expression is regulated by conventional PKCs. ACE2 expression is PKC-βII dependent. Nox1-derived superoxides reduce PKC-βII expression, which lowers ACE2 mRNA and protein levels and consequently decreases ANG(1-7) formation.
Human sinus arrhythmia: inconsistencies of a teleological hypothesis
Authors: Tzeng Y. C. , Sin P. Y. W. , Galletly D. C.
Published: October 2008

Respiratory sinus arrhythmia (RSA) may serve an inherent function in optimizing pulmonary gas exchange efficiency via clustering and scattering of heart beats during the inspiratory and expiratory phases of the respiratory cycle. This study sought to determine whether physiological levels of RSA, enhanced by slow paced breathing, caused more heart beats to cluster in inspiration. In 12 human subjects, we analyzed the histogram distribution of heart beats throughout the respiratory cycle during paced breathing at 12, 9, and 6 breaths/min (br/min). The inspiratory period-to-respiratory period ratio was fixed at ∼0.5. RSA and its relationship with respiration was characterized in the phase domain by average cubic-spline interpolation of electrocardiographic R wave-to-R wave interval fluctuations throughout all respiratory cycles. Although 6 br/min breathing was associated with a significant increase in RSA amplitude ( P < 0.01), we observed no significant increase in the proportion of heart beats in inspiration ( P = 0.34). Contrary to assumptions in the literature, we observed no significant clustering of heart beats even with high levels of RSA enhanced by slow breathing. The results of this study do not support the hypothesis that RSA optimizes pulmonary gas exchange efficiency via clustering of heart beats in inspiration.
Novel human bronchial epithelial cell lines for cystic fibrosis research
Authors: Fulcher M. L. , Gabriel S. E. , Olsen J. C. , Tatreau J. R. , Gentzsch M. , Livanos E. , Saavedra M. T. , Salmon P. , Randell S. H.
Published: October 2008

Immortalization of human bronchial epithelial (hBE) cells often entails loss of differentiation. Bmi-1 is a protooncogene that maintains stem cells, and its expression creates cell lines that recapitulate normal cell structure and function. We introduced Bmi-1 and the catalytic subunit of telomerase (hTERT) into three non-cystic fibrosis (CF) and three ΔF508 homozygous CF primary bronchial cell preparations. This treatment extended cell life span, although not as profoundly as viral oncogenes, and at passages 14 and 15, the new cell lines had a diploid karyotype. Ussing chamber analysis revealed variable transepithelial resistances, ranging from 200 to 1,200 Ω·cm2. In the non-CF cell lines, short-circuit currents were stimulated by forskolin and inhibited by CFTR(inh)-172 at levels mostly comparable to early passage primary cells. CF cell lines exhibited no forskolin-stimulated current and minimal CFTR(inh)-172 response. Amiloride-inhibitable and UTP-stimulated currents were present, but at lower and higher amplitudes than in primary cells, respectively. The cells exhibited a pseudostratified morphology, with prominent apical membrane polarization, few apoptotic bodies, numerous mucous secretory cells, and occasional ciliated cells. CF and non-CF cell lines produced similar levels of IL-8 at baseline and equally increased IL-8 secretion in response to IL-1β, TNF-α, and the Toll-like receptor 2 agonist Pam3Cys. Although they have lower growth potential and more fastidious growth requirements than viral oncogene transformed cells, Bmi-1/hTERT airway epithelial cell lines will be useful for several avenues of investigation and will help fill gaps currently hindering CF research and therapeutic development.
Neural circuits controlling diaphragm function in the cat revealed by transneuronal tracing
Authors: Lois James H. , Rice Cory D. , Yates Bill J.
Published: October 2008

Although a number of studies have considered the neural circuitry that regulates diaphragm activity, these pathways have not been adequately discerned, particularly in animals such as cats that utilize the respiratory muscles during a variety of different behaviors and movements. The present study employed the retrograde transneuronal transport of rabies virus to identify the extended neural pathways that control diaphragm function in felines. In all animals deemed to have successful rabies virus injections into the diaphragm, large, presumed motoneurons were infected in the C4–C6spinal segments. In addition, smaller presumed interneurons were labeled bilaterally throughout the cervical and upper thoracic spinal cord. While in short and intermediate survival cases, infected interneurons were concentrated in the vicinity of phrenic motoneurons, in late survival cases, the distribution of labeling was more expansive. Within the brain stem, the earliest infected neurons included those located in the classically defined pontine and medullary respiratory groups, the medial and lateral medullary reticular formation, the region immediately ventral to the spinal trigeminal nucleus, raphe pallidus and obscurus, and the vestibular nuclei. At longer survival times, infection appeared in the midbrain, which was concentrated in the lateral portion of the periaqueductal gray, the region of the tegmentum that contains the locomotion center, and the red nucleus. Considerable labeling was also present in the fastigial nucleus of the cerebellum, portions of the posterior and lateral hypothalamus and the adjacent fields of Forel known to contain hypocretin-containing neurons and the precruciate gyrus of cerebral cortex. These data raise the possibility that several parallel pathways participate in regulating the activity of the feline diaphragm, which underscores the multifunctional nature of the respiratory muscles in this species.
Cessation of daily wheel running differentially alters fat oxidation capacity in liver, muscle, and adipose tissue
Authors: Laye Matthew J. , Rector R. Scott , Borengasser Sarah J. , Naples Scott P. , Uptergrove Grace M. , Ibdah Jamal A. , Booth Frank W. , Thyfault John P.
Published: October 2008

Physical inactivity is associated with the increased risk of developing chronic metabolic diseases. To understand early alterations caused by physical inactivity, we utilize an animal model in which rats are transitioned from daily voluntary wheel running to a sedentary condition. In the hours and days following this transition, adipose tissue mass rapidly increases, due in part to increased lipogenesis. However, whether a concurrent decrease in fatty acid oxidative capacity (FAO) in skeletal muscle, liver, and adipose tissue occurs during this period is unknown. Following 6 wk of access to voluntary running wheels (average distance of ∼6 km a night), rats were rapidly transitioned to a sedentary state by locking the wheels for 5 h (WL5) or 173 h (WL173). Complete ([14C]palmitate oxidation to14CO2) and incomplete ([14C]palmitate oxidation to14C-labeled acid soluble metabolites) was determined in isolated mitochondrial and whole homogenate preparations from skeletal muscle and liver and in isolated adipocytes. Strikingly, the elevated complete FAO in the red gastrocnemius at WL5 fell to that of rats that never ran (SED) by WL173. In contrast, hepatic FAO was elevated at WL173 above both WL5 and SED groups, while in isolated adipocytes, FAO remained higher in both running groups (WL5 and WL173) compared with the SED group. The alterations in muscle and liver fat oxidation were associated with changes in carnitine palmitoyl transferase-1 activity and inhibition, but not significant changes in other mitochondrial enzyme activities. In addition, peroxisome proliferator-activated receptor coactivator-1α mRNA levels that were higher in both skeletal muscle and liver at WL5 fell to SED levels at WL173. This study is the first to demonstrate that the transition from high to low daily physical activity causes rapid, tissue-specific changes in FAO.
Loss of Histone H4K20 Trimethylation Occurs in Preneoplasia and Influences Prognosis of Non–Small Cell Lung Cancer
Authors: Van Den Broeck Arnaud , Brambilla Elisabeth , Moro-Sibilot Denis , Lantuejoul Sylvie , Brambilla Christian , Eymin Beatrice , Khochbin Saadi , Gazzeri Sylvie
Published: October 2008

Purpose: Epigenetic modifications of histone have crucial roles in the control of gene activity, nuclear architecture, and genomic stability. In this respect, they may contribute to the development and progression of cancer. We investigated whether epigenetic changes of histone H4 are involved in lung carcinogenesis.

Experimental Design: Epigenetic modifications of histone H4 were studied by immunohistochemistry in normal lung and 157 lung carcinoma using antibodies specifically recognizing the acetylated (Ac) lysines 5 (K5), K8, K12, K16, and trimethylated (me3) K20 residues of histone H4. Western blotting was used to validate the immunohistochemistry results. H4K20me3 was also studied in 17 preneoplastic lesions. Expression of the Suv4-20h1/2 trimethyltransferases was analyzed by quantitative reverse transcription-PCR in a subset of tumor samples.

Results: As compared with normal lung, cancer cells displayed an aberrant pattern of histone H4 modifications with hyperacetylation of H4K5/H4K8, hypoacetylation of H4K12/H4K16, and loss of H4K20 trimethylation. Alteration of H4K20 trimethylation was frequent in squamous cell carcinoma (67%) and was observed in early precursors lesions in which the level of H4K20me3 staining strongly decreased with disease progression. In adenocarcinoma, the down-regulation of H4K20me3 was less frequent (28%) but allowed the identification of a subgroup of stage I adenocarcinoma patients with reduced survival (P = 0.007). Loss of H4K20 trimethylation was associated with decreased expression of Suv4-20h2, a specific H4K20 trimethyltransferase involved in telomere length maintenance.

Conclusions: Our findings indicate an important role of histone H4 modifications in bronchial carcinogenesis and highlight H4K20me3 as a candidate biomarker for early detection of and therapeutic approaches to lung cancer.
HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells
Authors: Bachleitner-Hofmann Thomas , Sun Mark Y. , Chen Chin-Tung , Tang Laura , Song Lin , Zeng Zhaoshi , Shah Manish , Christensen James G. , Rosen Neal , Solit David B. , Weiser Martin R.
Published: October 2008

Tumor cells with genomic amplification of MET display constitutive activation of the MET tyrosine kinase, which renders them highly sensitive to MET inhibition. Several MET inhibitors have recently entered clinical trials; however, as with other molecularly targeted agents, resistance is likely to develop. Therefore, elucidating possible mechanisms of resistance is of clinical interest. We hypothesized that collateral growth factor receptor pathway activation can overcome the effects of MET inhibition in MET-amplified cancer cells by reactivating key survival pathways. Treatment of MET-amplified GTL-16 and MKN-45 gastric cancer cells with the highly selective MET inhibitor PHA-665752 abrogated MEK/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling, resulting in cyclin D1 loss and G1 arrest. PHA-665752 also inhibited baseline phosphorylation of epidermal growth factor receptor (EGFR) and HER-3, which are transactivated via MET-driven receptor cross-talk in these cells. However, MET-independent HER kinase activation using EGF (which binds to and activates EGFR) or heregulin-β1 (which binds to and activates HER-3) was able to overcome the growth-inhibitory effects of MET inhibition by restimulating MEK/MAPK and/or PI3K/AKT signaling, suggesting a possible escape mechanism. Importantly, dual inhibition of MET and HER kinase signaling using PHA-665752 in combination with the EGFR inhibitor gefitinib or in combination with inhibitors of MEK and AKT prevented the above rescue effects. Our results illustrate that highly targeted MET tyrosine kinase inhibition leaves MET oncogene-“addicted” cancer cells vulnerable to HER kinase-mediated reactivation of the MEK/MAPK and PI3K/AKT pathways, providing a rationale for combined inhibition of MET and HER kinase signaling in MET-amplified tumors that coexpress EGFR and/or HER-3. [Mol Cancer Ther 2008;7(11):3499–508]
A RNA antagonist of hypoxia-inducible factor-1α, EZN-2968, inhibits tumor cell growth
Authors: Greenberger Lee M. , Horak Ivan D. , Filpula David , Sapra Puja , Westergaard Majken , Frydenlund Henrik F. , Albæk Charlotte , Schrøder Henrik , Ørum Henrik
Published: October 2008

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in angiogenesis, survival, metastasis, drug resistance, and glucose metabolism. Elevated expression of the α-subunit of HIF-1 (HIF-1α), which occurs in response to hypoxia or activation of growth factor pathways, is associated with poor prognosis in many types of cancer. Therefore, down-regulation of HIF-1α protein by RNA antagonists may control cancer growth. EZN-2968 is a RNA antagonist composed of third-generation oligonucleotide, locked nucleic acid, technology that specifically binds and inhibits the expression of HIF-1α mRNA. In vitro, in human prostate (15PC3, PC3, and DU145) and glioblastoma (U373) cells, EZN-2968 induced a potent, selective, and durable antagonism of HIF-1 mRNA and protein expression (IC50, 1-5 nmol/L) under normoxic and hypoxic conditions associated with inhibition of tumor cell growth. Additionally, down-regulation of HIF-1α protein by EZN-2968 led to reduction of its transcriptional targets and of human umbilical vein endothelial cell tube formation. In vivo, administration of EZN-2968 to normal mice led to specific, dose-dependent, and highly potent down-regulation of endogenous HIF-1α and vascular endothelial growth factor in the liver. The effect can last for days after administration of single dose of EZN-2968 and is associated with long residence time of locked nucleic acid in certain tissues. In efficacy studies, tumor reduction was found in nude mice implanted with DU145 cells treated with EZN-2968. Ongoing phase I studies of EZN-2968 in patients with advanced malignancies will determine optimal dose and schedule for the phase II program. [Mol Cancer Ther 2008;7(11):3598–608]
Carprofen induction of p75NTR-dependent apoptosis via the p38 mitogen-activated protein kinase pathway in prostate cancer cells
Authors: Khwaja Fatima S. , Quann Emily J. , Pattabiraman Nagarajan , Wynne Shehla , Djakiew Daniel
Published: October 2008

The p75 neurotrophin receptor (p75NTR) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75NTR expression in several prostate cancer cell lines leading to p75NTR-mediated decreased survival. Using the 2-phenyl propionic acid moiety of these profens as a pharmacophore, we screened an in silico database of 30 million compounds and identified carprofen as having an order of magnitude greater activity for induction of p75NTR levels and inhibition of cell survival. Prostate (PC-3 and DU-145) and bladder (T24) cancer cells were more sensitive to carprofen induction of p75NTR-associated loss of survival than breast (MCF-7) and fibroblast (3T3) cells. Transfection of prostate cell lines with a dominant-negative form of p75NTR before carprofen treatment partially rescued cell survival, showing a cause-and-effect relationship between carprofen induction of p75NTR levels and inhibition of survival. Carprofen induced apoptotic nuclear fragmentation in prostate but not in MCF-7 and 3T3 cells. Furthermore, small interfering RNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75NTR by carprofen in both prostate cell lines. Carprofen treatment induced phosphorylation of p38 MAPK as early as within 1 min. Expression of a dominant-negative form of MK2, the kinase downstream of p38 MAPK frequently associated with signaling cascades leading to apoptosis, prevented carprofen induction of the p75NTR protein. Collectively, we identify carprofen as a highly potent profen capable of inducing p75NTR-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells. [Mol Cancer Ther 2008;7(11):3539–45]
Substance P-Immunoreactive Cells in the Ovine Pars Tuberalis
Authors: Skinner Donal C. , Lang A. Lee , Pahl Lindsay , Wang Qi
Published: October 2008

The pars tuberalis (PT) is a distinct subdivision of the anterior pituitary gland that plays a central role in regulating seasonal prolactin release. In sheep, there is compelling evidence that seasonal changes in light, transformed into a melatonin signal, are interpreted by the PT to modulate the release of a factor which affects prolactin release. The identity of this factor(s) is unknown but has been preemptively called ‘tuberalin’. In the present study, we report on an initial immunocytochemical investigation where we have identified that many ovine PT cells are immunoreactive for the tachykinin substance P (SP). Few cells in the pars distalis immunoreact for SP. The SP-immunoreactive cells did not colocalize with β-luteinizing hormone. RT-PCR confirmed the presence of preprotachykinin A mRNA in the PT. We hypothesize that SP, and possibly other preprotachykinin A-derived tachykinins, may play a role in the seasonal regulation of prolactin secretion in sheep.
Vibration Response Imaging in the Detection of Pleural Effusions: A Feasibility Study
Authors: Anantham Devanand , Herth Felix J.F. , Majid Adnan , Michaud Gaëtane , Ernst Armin
Published: October 2008

Background: Computerized analysis of the regional distribution of breath sound intensity during respiration has generated interest as a possible diagnostic modality. Objectives: We hypothesized that pleural effusions would create a dependent region of absent breath sounds and thus vibration response imaging (VRI) could be used in the detection of such pleural effusions. Methods: A prospective, single-blinded and open-labeled trial was carried out, and VRI recordings were compared to upright chest X-rays, bedside ultrasound examinations and volume of fluid drained via thoracentesis. VRI images were interpreted by a physician who was blinded to the patients’ clinical history, physical examination and diagnostic tests. Quantitative assessment of pleural effusion size in the VRI images was performed by ImageJ software and an automatic pixel count analysis. Results: VRI recordings were performed on 57 consecutive patients and correctly predicted the diagnosis in 45 cases (45/56, 80%) as compared to chest X-rays. The calculated sensitivity, specificity, positive predictive value and negative predictive value for diagnosis of pleural effusion were 86% (62/72), 93% (37/40), 95% (62/65) and 79% (37/47), respectively, in a per-hemithorax analysis. In the quantification of effusion size, there were high correlations between VRI images and chest X-ray area as assessed by ImageJ (r = 0.67) and pixel count (r = –0.77). The level of agreement between VRI readings and ultrasonography was 75% (41/55), and correlation with the volume of fluid drained in therapeutic thoracentesis was moderate (r = –0.49). No side effects from the VRI recordings were documented. Conclusions: VRI can be used to detect and quantify pleural effusions.
S-Endoglin Expression Is Induced in Senescent Endothelial Cells and Contributes to Vascular Pathology
Authors: Blanco Francisco J. , Grande María T. , Langa Carmen , Oujo Barbara , Velasco Soraya , Rodriguez-Barbero Alicia , Perez-Gomez Eduardo , Quintanilla Miguel , López-Novoa Jose M. , Bernabeu Carmelo
Published: October 2008

Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-β receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-β receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-β type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-β–responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-β
1
administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Symptomatic and Silent Ischemia Associated With Microsurgical Clipping of Intracranial Aneurysms
Authors: Krayenbühl Niklaus , Erdem Eren , Oinas Minna , Krisht Ali F.
Published: October 2008

Background and Purpose—

Silent ischemic events are known to occur during diagnostic and interventional endovascular procedures between 10% and 69% of the time. The occurrence of silent and symptomatic ischemic events in the surgically treated population is not known, although atherosclerotic changes of intracranial vessels or within the aneurysms wall or neck area are seen often during surgery.

Methods—

Patients with unruptured and ruptured intracranial aneurysms treated by microsurgical clipping were prospectively evaluated with MRI using diffusion-weighted imaging sequences before and within 24 hours after surgery. Patients were evaluated clinically before and after surgery. During surgery, the overall and maximal time of temporary occlusion as well as the total number of temporary and finally applied clips was noted. Diffusion-weighted images were analyzed with determination and characterization of diffusion-weighted imaging abnormalities.

Results—

Thirty-six patients with 51 aneurysms were included. One symptomatic and 5 silent ischemic lesions were found in 5 patients. This represents a risk of silent ischemia of 9.8% per treated aneurysm and a risk of symptomatic stroke of 2%. The most significant risk factor in increasing order was: age (
P
<0.05), presence of thrombus (
P
<0.05), number of final clips applied (
P
<0.05), number of temporary clips used (
P
<0.01), total time of temporary clip occlusion (
P
<0.001), and maximal time of temporary occlusion (
P
<0.001).

Conclusions—

The risk of silent and symptomatic ischemic events during microsurgical clipping of intracranial aneurysms seems to be low. Microsurgical clipping is safe and should continue to be strongly considered as a treatment option.
Extreme Sports
Authors: Brymer E. , Oades L.G.
Published: October 2008

Extreme sports and extreme sports participants have been most commonly explored from a negative perspective, for example, the “need to take unnecessary risks.” This study explored what can be learned from extreme sports about courage and humility—two positive psychology constructs. A phenomenological method was used via unstructured interviews with 15 extreme sports participants and other firsthand accounts. The extreme sports included BASE (building, antenna, span, earth) jumping, big wave surfing, extreme skiing, waterfall kayaking, extreme mountaineering, and solo rope-free climbing. Results indicate that humility and courage can be deliberately sought out by participating in activities that involve a real chance of death, fear, and the realization that nature in its extreme is far greater and more powerful than humanity.
Nonviolent Aspects of Interparental Conflict and Dating Violence Among Adolescents
Authors: Tschann Jeanne M. , Pasch Lauri A. , Flores Elena , VanOss Marin Barbara , Marco Baisch E. , Wibbelsman Charles J.
Published: October 2008

This longitudinal study examined whether nonviolent aspects of interparental conflict, in addition to interparental violence, predicted dating violence perpetration and victimization among 150 Mexican American and European American male and female adolescents, ages 16 to 20. When parents had more frequent conflict, were more verbally aggressive during conflict, had poor conflict resolution, or were physically violent during conflict at baseline, adolescents were more involved in dating violence, both perpetration and victimization, at 1-year follow-up. Adolescents' appraisals of parental conflict and their emotional distress mediated the relationships between nonviolent parental conflict and dating violence. In contrast, interparental violence directly predicted involvement in dating violence. Results provide support for the importance of nonviolent parental conflict as an influence on adolescents' involvement in dating violence, over and above the influence of interparental violence. Cognitive and emotional processes may help explain the way in which nonviolent aspects of parental conflict influence adolescents' behavior in romantic relationships.
Threats to Parental and Romantic Attachment Figures' Availability and Adult Attachment Insecurity
Authors: Holman Thomas B. , Galbraith Richard C. , Mead Timmons Nicole , Steed April , Tobler Samuel B.
Published: October 2008

This study tested hypotheses based on the theoretical idea that threats to parental availability would have a direct effect on later adult attachment insecurity and that this relationship would be partially, but not fully, mediated by threats to the availability of a romantic partner. Participants were 1,063 individuals in a married or unmarried romantic relationship. Individuals completed a questionnaire on threats to attachment figures' availability and completed another questionnaire about attachment insecurity (avoidance and anxiety) approximately 1 year later. In both models, the greater the threats to attachment figures' (parents' or current partners') availability, the greater the attachment avoidance and attachment anxiety. Consistent with theorizing in the literature, the impact of remembered threats to parental availability on adult attachment avoidance and anxiety, although not eliminated, was greatly reduced by the inclusion of current partner's availability in the model.
An Archival Exploration of Homicide—Suicide and Mass Murder in the Context of 19th-Century American Parricides
Authors: Shon Phillip Chong Ho , Roberts Michael A.
Published: October 2008

There has been little attempt to integrate contemporary studies of suicide and mass murder to homicide—suicides. The current research attempts to do so in the context of 19th-century parricides in America. This project uses archival records from The New York Times and the Chicago Tribune, 1851-1899, resulting in a total of 231 incidents. Our results indicate that parricides, mass murders, and suicides tended to originate as spontaneous acts, usually during the course of an argument, gathering momentum as the interaction unfolded. We contend that suicide is one way of alleviating threats to offender’s loss of self-identity.
Introduction
Authors: Rivière Françoise
Published: October 2008

The principle of democracy is one of equal dignity for all cultures. But today the relationship between culture and politics, though close, often appears tense and occasionally contradictory. The introduction to this issue of Diogenes sketches the work done by UNESCO in the frame of the ‘Pathways of Thought' Programme, particularly relating to the way in which a pluralist identity is created in multicultural nations, and to the relationship between non-material heritage, democracy and the quest for new forms of governance.