bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of manganese addition on carbon release from forest floor horizons
Authors: Trum Florence , Titeux Hugues , Cornelis Jean-Thomas , Delvaux Bruno
Published: March 2011

Lignin concentration in organic residues largely controls their decomposition. Mn2+ may well play a key role in ligninolysis because it is a cofactor of manganese peroxidase, an enzyme of the lignin-degrading system. This study aims to investigate the effects of Mn2+ addition on forest floor horizon decomposition during laboratory incubation. Therefore, we sampled two distinct forest floors from European beech ( Fagus sylvatica L.) stands: a mor and a moder. Lignin and Mn concentrations in forest floor upper layer were significantly larger in moder than in mor. Three horizons from each forest floor were separately incubated with or without Mn2+ addition (250 mg Mn·kg dry matter–1) and the release of both CO2 and dissolved organic C was measured. The dissolved organic C release was not impacted by the Mn2+ addition, while a clear increase in CO2 release from specific horizons was observed. Our data suggest that the impact of the Mn2+ addition depends on (i) the forest floor type and on (ii) the organic matter decomposition stage.
Optimizing spatial habitat suitability and timber revenue in long-term forest planning
Authors: Öhman Karin , Edenius Lars , Mikusiński Grzegorz
Published: March 2011

Effective tools must be developed that include consideration of biodiversity in the traditional forest planning process. The objective of this study is to present a spatial habitat suitability model that could be included in the optimization of long-term forest planning where the problem can be solved with an exact solution method. This could be an advantage, since, e.g., many forest planning systems available today are designed for problems that could be solved with an exact solution method. The habitat model consists of two parts: suitability assessment of stand-wise conditions and spatial conditions. To investigate whether the model works in a realistic setting, we used a case study and applied the model to the habitat demands for Hazel Grouse ( Bonasa bonasia L.). The results from the case study indicate that the model is effective for including spatial habitat consideration and that the model could be used for creating different degrees of the clustering of habitats. Further, the loss in net present value as a result of the spatial habitat demands was limited in the case study. We suggest that this modeling approach could be extended to other species with large area requirements and add to the existing tools for forest biodiversity assessment in forest management planning.
Factors affecting northern white-cedar (Thuja occidentalis) seedling establishment and early growth in mixedwood stands
Authors: Larouche Catherine , Ruel Jean-Claude , Lussier Jean-Martin
Published: March 2011

Regeneration of northern white-cedar ( Thuja occidentalis L.) is often deficient after harvesting in mixedwood stands growing on mesic sites even where browsing pressure is low. We compared the effectiveness of silviculture treatments on early regeneration of white-cedar after single-tree selection cutting (25% of basal area removed), shelterwood seed cut (50% of basal area removed), and group selection cutting (gaps of 625 m2) in three yellow birch ( Betula alleghaniensis Britt.) – softwood uneven-aged stands in Quebec, Canada. Three years after harvesting, the combination of factors that maximized abundance of white-cedar seedlings was single-tree selection cutting with artificial seeding on exposed mineral seedbeds (68.8% of plots with the presence of white-cedar). Early growth of planted white-cedar seedlings (40 cm tall) and biomass production were proportional to light availability, i.e., best under group selection cutting (mean height increment = 14.8 cm/year, mean root collar diameter increment = 3.0 mm/year). Browsing pressure has regional impacts depending on herbivore occupancy of the area. Our study was conducted near the northern limit of white-tailed deer ( Odocoileus virginianus (Zimmerman, 1780)), and deer were locally absent, while snowshoe hare ( Lepus americanus Erxleben, 1777) did not have a consistent effect on seedling abundance and early survival, limiting height growth only during the first year following planting.
Tree recruitment, growth, and distribution at the circumpolar forest–tundra transition: introduction
Authors: Hofgaard Annika , Harper Karen A.
Published: March 2011

Causes and consequences of changes in the circumpolar forest–tundra transition have received recent interest due to the increasing awareness of human-caused global climate change. The International Polar Year core project PPS Arctic focused these topics through exploring processes, changes, and spatiotemporal variability of biotic and abiotic drivers of change in the forest–tundra transition. The papers in this special feature present constraints and drivers of tree recruitment and tree encroachment of tundra areas, climate – tree growth relations in the ecotone, and changes in tree spatial pattern across the forest–tundra ecotone.
Comment on “Present-day expansion of American beech in northeastern hardwood forests: Does soil base status matter?”Appears in Can. J. For. Res. 39: 2273–2282 (2009).
Authors: Messier Christian , Bélanger Nicolas , Brisson Jacques , Lechowicz Martin J. , Gravel Dominique
Published: March 2011

In a recent rapid communication, Duchesne and Ouimet (2009. Can. J. For. Res. 39: 2273–2282) reported that the current expansion of American beech ( Fagus grandifolia Ehrh.) in Quebec is mainly caused by soil base cation depletion due to atmospheric acid deposition. They based their conclusions on an examination of the relationships between stem densities in the sapling and tree strata compared against canopy composition and the availability of base cations in 426 sample plots. Here in this comment, we raise some shortcomings with their study and provide a more prudent and complete perspective on the complex dynamics associated with fluctuations in American beech and sugar maple ( Acer saccharum Marsh.).
FOLD–HOPF BIFURCATIONS OF THE ROSE–HINDMARSH MODEL WITH TIME DELAY
Authors: MA SUQI , FENG ZHAOSHENG
Published: March 2011

In neural processing information, when we consider the finite propagation speed of signals in synapses, a time delay signal self-feedback mechanism is introduced into the well-known Rose–Hindmarsh Model. The Fold–Hopf bifurcation of this model is analyzed near equilibria. To discuss the singularity of this Codim-2 bifurcation, we discuss the normal form near the Fold–Hopf points on the center manifold. Bifurcations are studied and the stability is investigated by classifying neighborhood regimes near the Fold–Hopf points. Finally, as one of the most important electrical behaviors in neurons, the complex bursting-spiking firing modes associated with bifurcations are illustrated by numerical simulations.
DYNAMICAL ANALYSIS OF A THREE-DIMENSIONAL PREDATOR-PREY MODEL WITH IMPULSIVE HARVESTING AND DIFFUSION
Authors: JIAO JIANJUN , CAI SHAOHONG , CHEN LANSUN
Published: March 2011

In this work, we consider a three-dimensional predator-prey model with impulsive harvesting and diffusion at different fixed moments. We prove that all solutions of the investigated system are uniformly ultimately bounded. The conditions of the globally asymptotically stable prey-extinction boundary periodic solution of the investigated system are obtained, as well the permanence of the investigated system. Finally, numerical analysis is inserted to illustrate the results which provide reliable tactic basis for the practical biological resource management.
DUAL SKEW PRODUCTS, GENERICITY OF THE EXACTNESS PROPERTY AND FINANCE
Authors: KOWALSKI ZBIGNIEW S.
Published: March 2011

By introducing the concept of dual skew products and dual measures we obtain the class of skew products over Bernoulli shifts for which exactness is generic. We use the above to describe the stationary distributions of random walks determined by skew products as above. Finally, the application to binomial model for asset prices is presented.
COX-2 is not required for the development of murine chronic pancreatitis
Authors: Silva Alberto , Weber Achim , Bain Martha , Reding Theresia , Heikenwalder Mathias , Sonda Sabrina , Graf Rolf
Published: March 2011

Chronic pancreatitis is a severe inflammation of the pancreas associated with destruction of the parenchyma, fibrosis, and persistent abdominal pain. Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins, key mediators of the inflammatory response, are elevated in patients with chronic pancreatitis. Previous studies investigated COX-2 as a therapeutic target. These reports showed a reduced pathology in COX-2-deficient mice with a better outcome. Here we compared the role of COX-2 in acute and chronic pancreatic inflammation using the same COX-2−/− mouse model of cerulein-induced pancreatitis. In a setting of acute pancreatitis, juvenile COX-2−/− mice exhibited a reduced histopathological score compared with wild-type littermates; on the contrary, adult mice did not show any difference in the development of the disease. Similarly, in a setting of chronic pancreatitis induced over a period of 4 wk, adult mice of the two strains showed comparable histological score and collagen deposition. However, the abundance of mRNAs coding for profibrotic genes, such as collagen, α-smooth muscle actin, and transforming growth factor-β was consistently lower in COX-2−/− mice. In addition, comparable histological scores and collagen deposition were observed in wild-type mice treated with a COX-2 inhibitor. We conclude that, in contrast to what was observed in the rat pancreatitis models, COX-2 has a limited and age-dependent effect on inflammatory processes in the mouse pancreas. These results suggest that COX-2 modulates the inflammatory process during the development of pancreatitis in a species-specific manner. Thus the pathophysiological roles of COX-2 and its therapeutic implications in patients with pancreatitis should be reexamined.
Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/− mouse model
Authors: Martin Claire A. , Guzadhur Laila , Grace Andrew A. , Lei Ming , Huang Christopher L.-H.
Published: March 2011

Two major mechanisms have been postulated for the arrhythmogenic tendency observed in Brugada Syndrome (BrS): delays in conduction or increased heterogeneities in repolarization. We use a contact mapping system to directly investigate the interacting roles of these two mechanisms in arrhythmogenesis using a genetic murine model for BrS for the first time. Electrograms were obtained from a multielectrode recording array placed against the left ventricle and right ventricle (RV) of spontaneously beating Langendorff-perfused wild type (WT) and Scn5a+/− mouse hearts. Scn5a+/− hearts showed activation waves arriving at the epicardial surface consistent with slowed conduction, which was exacerbated in the presence of flecainide. Lines of conduction block across the RV resulting from premature ventricular beats led to the formation of reentrant circuits and polymorphic ventricular tachycardia. WT hearts showed an inverse relationship between activation times and activation recovery intervals measured at the epicardial surface, which resulted in synchronicity of repolarization times. In contrast, Scn5a+/− hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT. Isochronal maps showed that their normal activation recovery interval gradients at the epicardial surface were disrupted, leading to heterogeneity in repolarization times. We thus directly demonstrate the initiation of arrhythmia in the RV of Scn5a+/− hearts. This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits. The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.
Akt activation induces hypertrophy without contractile phenotypic maturation in airway smooth muscle
Authors: Ma Lan , Brown Melanie , Kogut Paul , Serban Karina , Li Xiaojing , McConville John , Chen Bohao , Bentley J. Kelley , Hershenson Marc B. , Dulin Nickolai , Solway Julian , Camoretti-Mercado Blanca
Published: March 2011

Airway smooth muscle (ASM) hypertrophy is a cardinal feature of severe asthma, but the underlying molecular mechanisms remain uncertain. Forced protein kinase B/Akt 1 activation is known to induce myocyte hypertrophy in other muscle types, and, since a number of mediators present in asthmatic airways can activate Akt signaling, we hypothesized that Akt activation could contribute to ASM hypertrophy in asthma. To test this hypothesis, we evaluated whether Akt activation occurs naturally within airway myocytes in situ, whether Akt1 activation is sufficient to cause hypertrophy of normal airway myocytes, and whether such hypertrophy is accompanied by excessive accumulation of contractile apparatus proteins (contractile phenotype maturation). Immunostains of human airway sections revealed concordant activation of Akt (reflected in Ser473 phosphorylation) and of its downstream effector p70S6Kinase (reflected in Thr389 phosphorylation) within airway muscle bundles, but there was no phosphorylation of the alternative Akt downstream target glycogen synthase kinase (GSK) 3β. Artificial overexpression of constitutively active Akt1 (by plasmid transduction or lentiviral infection) caused a progressive increase in size and protein content of cultured canine tracheal myocytes and increased p70S6Kinase phosphorylation but not GSK3β phosphorylation; however, constitutively active Akt1 did not cause disproportionate overaccumulation of smooth muscle (sm) α-actin and SM22. Furthermore, mRNAs encoding sm-α-actin and SM22 were reduced. These results indicate that forced Akt1 signaling causes hypertrophy of cultured airway myocytes without inducing further contractile phenotypic maturation, possibly because of opposing effects on contractile protein gene transcription and translation, and suggest that natural activation of Akt1 plays a similar role in asthmatic ASM.
Diaphragm long-term facilitation following acute intermittent hypoxia during wakefulness and sleep
Authors: Terada J. , Mitchell G. S.
Published: March 2011

Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Here, we tested four hypotheses in unanesthetized, spontaneously breathing rats using radiotelemetry for EEG and diaphragm electromyography (Dia EMG) activity: 1) AIH induces LTF in Dia EMG activity; 2) diaphragm LTF (Dia LTF) is more robust during sleep vs. wakefulness; 3) AIH (or repetitive AIH) disrupts natural sleep-wake architecture; and 4) preconditioning with daily AIH (dAIH) for 7 days enhances Dia LTF. Sleep-wake states and Dia EMG were monitored before (60 min), during, and after (60 min) AIH (10, 5-min hypoxic episodes, 5-min normoxic intervals; n = 9), time control (continuous normoxia, n = 8), and AIH following dAIH preconditioning for 7 days (n = 7). Dia EMG activities during quiet wakefulness (QW), rapid eye movement (REM), and non-REM (NREM) sleep were analyzed and normalized to pre-AIH values in the same state. During NREM sleep, diaphragm amplitude (25.1 ± 4.6%), frequency (16.4 ± 4.7%), and minute diaphragm activity (amplitude × frequency; 45.2 ± 6.6%) increased above baseline 0–60 min post-AIH (all P < 0.05). This Dia LTF was less robust during QW and insignificant during REM sleep. dAIH preconditioning had no effect on LTF ( P > 0.05). We conclude that 1) AIH induces Dia LTF during NREM sleep and wakefulness; 2) Dia LTF is greater in NREM sleep vs. QW and is abolished during REM sleep; 3) AIH and repetitive AIH disrupt natural sleep patterns; and 4) Dia LTF is unaffected by dAIH. The capacity for plasticity in spinal pump muscles during sleep and wakefulness suggests an important role in the neural control of breathing.
Acute effects of hydrogen peroxide on skeletal muscle microvascular oxygenation from rest to contractions
Authors: Hirai Daniel M. , Copp Steven W. , Schwagerl Peter J. , Musch Timothy I. , Poole David C.
Published: March 2011

Reactive oxygen species, such as hydrogen peroxide (H2O2), exert a critical regulatory role on skeletal muscle function. Whether acute increases in H2O2 modulate muscle microvascular O2 delivery-utilization (Q̇o2/V̇o2) matching [i.e., microvascular partial pressure of O2 (PmvO2)] at rest and following the onset of contractions is unknown. The hypothesis was tested that H2O2 treatment (exogenous H2O2) would enhance PmvO2 and slow PmvO2 kinetics during contractions compared with control. Anesthetized, healthy young Sprague-Dawley rats had their spinotrapezius muscles either exposed for measurement of blood flow (and therefore Q̇o2), V̇o2, and PmvO2, or exteriorized for measurement of force production. Electrically stimulated twitch contractions (1 Hz, ∼7 V, 2-ms pulse duration, 3 min) were evoked following acute superfusion with Krebs-Henseleit (control) and H2O2 (100 μM). Relative to control, H2O2 treatment elicited disproportionate increases in Q̇o2 and V̇o2 that elevated PmvO2 at rest and throughout contractions and slowed overall PmvO2 kinetics (i.e., ∼85% slower mean response time; P < 0.05). Accordingly, H2O2 resulted in ∼33% greater overall PmvO2, as assessed by the area under the PmvO2 curve ( P < 0.05). Muscle force production was not altered with H2O2 treatment ( P > 0.05), evidencing reduced economy during contractions (∼40% decrease in the force/V̇o2 relationship; P < 0.05). These findings indicate that, although increasing the driving force for blood-myocyte O2 flux (i.e., PmvO2), transient elevations in H2O2 impair skeletal muscle function (i.e., reduced economy during contractions), which mechanistically may underlie, in part, the reduced exercise tolerance in conditions associated with oxidative stress.
Powder diffraction study of some mixed ligand complexes of Mn(II), Ni(II), Cu(II), Zn(II), and Cd(II)
Authors: Ghose Ranjana , Kumar Rajesh
Published: March 2011

The mixed ligand complexes of manganese(II), nickel(II), copper(II), zinc(II), and cadmium(II) involving aspartic acid and benzoic acid have been synthesized. The complexes were studied by various spectroscopic techniques such as infrared, electronic, X-ray diffraction, and magnetic measurements. The complexes were found to have octahedral geometry. The X-ray powder diffraction results show that the crystal systems of Mn(II)-Asp-Ben complex are hexagonal, and Ni(II)-Asp-Ben, Cu(II)-Asp-Ben, Zn(II)-Asp-Ben, and Cd(II)-Asp-Ben complexes are found to be triclinic. The value of unit-cell parameters and XRD data for the five mixed ligand complexes are reported.
X-ray powder diffraction data for a DACH Pt nitrate, cis-[bis(acetonitrile)]-[(1R,2R)-1,2-diaminocyclohexane-κN, κN′]platinum(II)nitrate (1:2) monohydrate
Authors: Pažout R. , Maixner J. , Kačer P. , Housková J.
Published: March 2011

X-ray powder diffraction data, unit cell parameters, and space group for a new platinum-based anticancer complex cis-[bis(acetonitrile)]-[(1R,2R)-1,2-diaminocyclohexane-κN, κN′]platinum (II)nitrate (1:2) monohydrate, cis-[Pt(C2H3N)2(C6H14N2)](NO3)2·H2O, are presented [a=12.638(3) Å, b=12.153(2) Å, c=11.881(3) Å, β=95.145(4)°, space group P21, cell volume=1817.5 Å3, and Z=4]. All measured lines were indexed and are consistent with the P21 space group. No detectable impurities were observed.
Subsolidus phase relations of the Dy-Fe-Al system
Authors: Chen Y. Q. , Liang J. K. , Luo J. , Li J. B. , Rao G. H.
Published: March 2011

The subsolidus phase relations of the Dy-Fe-Al system have been investigated by means of X-ray powder diffraction. There are 5 ternary compounds, 10 binary compounds, and 21 three-phase regions in this system. The solid-solution regions of Dy(Fe1−xAlx)2, DyFe3−xAlx, Dy2(Fe1−xAlx)17, and DyFe12−xAlx have been determined based on the dependence of their unit-cell parameters on the Al content.
Structure and X-ray powder reference patterns for hexagonal perovskite-related phases, (Sr0.8Ca0.2)5Co4O12 and Sr6Co5O15
Authors: Wong-Ng W. , Kaduk J. A. , Liu G.
Published: March 2011

Two selected members of the homologous series An+2BBn′O3n+3 (A=Sr and Ca; B and B′=Co) have been investigated for their crystal structures because of their potential applications as thermoelectric materials. A combined Rietveld refinement and spin-polarized magnetic geometry optimization technique was employed for the structural studies. Both the n=3 member, (Sr0.8Ca0.2)5Co4O12, and the n=4 member, Sr6Co5O15, have distorted hexagonal perovskite-related structures that possess one-dimensional cobalt oxide chains separated by alkaline-earth cations. The linear chains consist of one unit of CoO6 trigonal prism alternating with n units of CoO6 octahedra. Crystal structures and reference powder X-ray diffraction patterns of (Sr0.8Ca0.2)5Co4O11 [P3c1, a=9.4196(2) Å, c=19.9857(6) Å, V=825.83 Å3, and Dx=5.358 g/cm3] and Sr6Co5O15 [R32, a=9.497 64(12) Å, c=12.3956(2) Å, V=968.34 Å3, and Dx=5.455 g/cm3] are reported.
New Strategies in Metastatic Prostate Cancer: Targeting the Androgen Receptor Signaling Pathway
Authors: Attard Gerhardt , Richards Juliet , de Bono Johann S.
Published: March 2011

Recent data report that abiraterone acetate, a specific inhibitor of CYP17 that is key to androgen and estrogen synthesis, improves survival in metastatic castration-resistant prostate cancer (CRPC), confirming the continued dependency of CRPC on the androgen receptor (AR) signaling pathway. MDV3100 is a novel antagonist of AR that is also in phase III clinical trials. In addition, several other agents targeting the AR axis are undergoing evaluation in early clinical studies. CRPC patients progress on these therapies with an increasing prostate specific antigen (PSA), suggesting that repeated therapeutic interventions targeting the AR signaling axis could induce secondary responses and achieve prolonged clinical benefit for a subgroup of patients. These exciting results are good news for patients but introduce a number of treatment paradigm dilemmas for physicians. Clinical studies evaluating the ideal sequence of administration of these new agents, best timing for initiation, combination strategies, discontinuation beyond progression and after commencement of subsequent therapies, and coordination with other treatments have not been done. Predictive biomarkers could allow patient selection for a specific treatment, but in their absence, most physicians will rely on a trial of treatment with a preferred agent and substitute for an alternative therapy on objective progression. Current data suggest that the response rate to drugs targeting the AR ligand-binding domain decreases with each treatment, but we hypothesize that a significant proportion of CRPC remains dependent on the AR axis and, therefore, novel strategies for disrupting AR signaling merit evaluation. Clin Cancer Res; 17(7); 1649–57. ©2011 AACR.
Direct Effects of Type I Interferons on Cells of the Immune System
Authors: Hervas-Stubbs Sandra , Perez-Gracia Jose Luis , Rouzaut Ana , Sanmamed Miguel F. , Le Bon Agnes , Melero Ignacio
Published: March 2011

Type I interferons (IFN-I) are well-known inducers of tumor cell apoptosis and antiangiogenesis via signaling through a common receptor interferon alpha receptor (IFNAR). IFNAR induces the Janus activated kinase–signal transducer and activation of transcription (JAK-STAT) pathway in most cells, along with other biochemical pathways that may differentially operate, depending on the responding cell subset, and jointly control a large collection of genes. IFNs-I were found to systemically activate natural killer (NK) cell activity. Recently, mouse experiments have shown that IFNs-I directly activate other cells of the immune system, such as antigen-presenting dendritic cells (DC) and CD4 and CD8 T cells. Signaling through the IFNAR in T cells is critical for the acquisition of effector functions. Cross-talk between IFNAR and the pathways turned on by other surface lymphocyte receptors has been described. Importantly, IFNs-I also increase antigen presentation of the tumor cells to be recognized by T lymphocytes. These IFN-driven immunostimulatory pathways offer opportunities to devise combinatorial immunotherapy strategies. Clin Cancer Res; 17(9); 2619–27. ©2011 AACR.
Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents
Authors: Buddingh Emilie P. , Kuijjer Marieke L. , Duim Ronald A.J. , Bürger Horst , Agelopoulos Konstantin , Myklebost Ola , Serra Massimo , Mertens Fredrik , Hogendoorn Pancras C.W. , Lankester Arjan C. , Cleton-Jansen Anne-Marie
Published: March 2011

Purpose: High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis by studying tumor cells and their stromal context.

Experimental Design: To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases.

Results: A total of 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1- (CD14/HLA-DRα positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis).

Conclusions: In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage activating agents, such as muramyl tripeptide. Clin Cancer Res; 17(8); 2110–9. ©2011 AACR.
CDDO-Imidazolide Induces DNA Damage, G2/M Arrest and Apoptosis in BRCA1-Mutated Breast Cancer Cells
Authors: Kim Eun-Hee , Deng Chu-Xia , Sporn Michael B. , Liby Karen T.
Published: March 2011

Breast cancer-associated gene 1 (BRCA1) protein plays important roles in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide, CDDO-Im) is a promising anticancer and chemopreventive agent with potent antiproliferative and apoptotic activities against a wide variety of cancer types. However, the mechanisms responsible for the selective apoptotic effects of CDDO-Im in cancer cells remain elusive. In the present work, CDDO-Im induced G2/M arrest and apoptosis in BRCA1-mutated mammary tumor cell lines. Prior to the induction of apoptosis, CDDO-Im induced DNA damage and the phosphorylation of H2AX followed by activation of the DNA damage response. Moreover, CDDO-Im also induced the generation of reactive oxygen species (ROS), which is associated with the induction of DNA damage, in both mouse and human tumor cells containing a BRCA1 mutation. The inhibition of ROS generation by uric acid prevented the induction of DNA damage by CDDO-Im. Furthermore, treatment with CDDO-Im did not induce ROS in nonmalignant MCF-10A breast epithelial cells or in E18–14C-27 breast cancer cells with wild-type BRCA1 genes and was not cytotoxic to normal mouse 3T3 fibroblasts, highlighting a selective therapeutic potential of CDDO-Im for BRCA1-associated breast cancer cells. Altogether, our results show that CDDO-Im induces ROS and subsequent DNA damage, thereby facilitating the activation of the DNA damage checkpoint, G2/M arrest, and finally apoptosis in BRCA1-mutated cancer cells. The particular relevance of these findings to the chemoprevention of cancer is discussed. Cancer Prev Res; 4(3); 425–34. ©2011 AACR.
Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens
Authors: Cramer Daniel W. , Bast Robert C. , Berg Christine D. , Diamandis Eleftherios P. , Godwin Andrew K. , Hartge Patricia , Lokshin Anna E. , Lu Karen H. , McIntosh Martin W. , Mor Gil , Patriotis Christos , Pinsky Paul F. , Thornquist Mark D. , Scholler Nathalie , Skates Steven J. , Sluss Patrick M. , Srivastava Sudhir , Ward David C. , Zhang Zhen , Zhu Claire S. , Urban Nicole
Published: March 2011

Establishing a cancer screening biomarker's intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network or Ovarian Cancer Specialized Program of Research Excellence sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within 6 months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study. Cancer Prev Res; 4(3); 365–74. ©2011 AACR.
Phase 0 Clinical Chemoprevention Trial of the Akt Inhibitor SR13668
Authors: Reid Joel M. , Walden Chad A. , Qin Rui , Ziegler Katie L. Allen , Haslam John L. , Rajewski Roger A. , Warndahl Roger , Fitting Cindy L. , Boring Daniel , Szabo Eva , Crowell James , Perloff Marjorie , Jong Ling , Bauer Brent A. , Mandrekar Sumithra J. , Ames Matthew M. , Limburg Paul J.
Published: March 2011

SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration–time curve (AUC0–∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC0–∞ values were highest in the fed state (range = 122–439 ng/mL × hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2–6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development. Cancer Prev Res; 4(3); 347–53. ©2011 AACR.
Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice
Authors: Shimizu Masahito , Sakai Hiroyasu , Shirakami Yohei , Yasuda Yoichi , Kubota Masaya , Terakura Daishi , Baba Atsushi , Ohno Tomohiko , Hara Yukihiko , Tanaka Takuji , Moriwaki Hisataka
Published: March 2011

Obesity and related metabolic abnormalities, including insulin resistance and a state of chronic inflammation, increase the risk of hepatocellular carcinoma. Abnormal activation of the insulin-like growth factor (IGF)/ IGF-1 receptor (IGF-1R) axis is also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of (−)-epigallocatechin gallate (EGCG), a major biologically active component of green tea, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks and then they received drinking water containing 0.1% EGCG for 34 weeks. At sacrifice, drinking water with EGCG significantly inhibited the development of liver cell adenomas in comparison with the control EGCG-untreated group. EGCG inhibited the phosphorylation of the IGF-1R, ERK (extracellular signal-regulated kinase), Akt, GSK-3β (glycogen synthase kinase-3β), Stat3, and JNK (c-Jun NH2-terminal kinase) proteins in the livers of experimental mice. The serum levels of insulin, IGF-1, IGF-2, free fatty acid, and TNF-α were all decreased by drinking EGCG, which also decreased the expression of TNF-α, interleukin (IL)-6, IL-1β, and IL-18 mRNAs in the livers. In addition, EGCG improved liver steatosis and activated the AMP-activated kinase protein in the liver. These findings suggest that EGCG prevents obesity-related liver tumorigenesis by inhibiting the IGF/IGF-1R axis, improving hyperinsulinemia, and attenuating chronic inflammation. EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals. Cancer Prev Res; 4(3); 396–403. ©2011 AACR.
Phase 0 Trials: Expediting the Development of Chemoprevention Agents
Authors: Kummar Shivaani , Doroshow James H.
Published: March 2011

Phase 0 trials are first-in-human clinical trials performed under the Exploratory IND [investigational new drug] Guidance of the U.S. Food and Drug Administration. Unlike traditional phase I trials, these studies have no therapeutic or diagnostic intent but instead aim to provide only pharmacokinetic and/or pharmacodynamic data to inform the next step in developing an agent. We discuss the role that such trials, including one reported by Reid and colleagues (beginning on page 347 in this issue of the journal), can play in expanding the number of drugs that are evaluated for chemoprevention while compressing the drug-development timeline. Cancer Prev Res; 4(3); 288–92. ©2011 AACR.
Inflammatory Talk: Linking Obesity, NF-κB, and Aromatase
Authors: Hursting Stephen D.
Published: March 2011

Obesity is associated with increased risk and worsened prognosis for postmenopausal breast cancer, but the underlying mechanisms remain unclear. Elegant work reported by Subbaramaiah and colleagues in this issue of the journal (beginning on page 329) adds important insights, particularly into the connections between obesity, inflammation, and aromatase via cross-talk among adipocytes, macrophages, and epithelial cells. This work provides several new molecular targets and strategies to test in model systems for preventing or controlling obesity-related breast cancer and provides a framework for studying the linkages among the complex mechanistic pathways underlying the obesity-cancer relationship. Cancer Prev Res; 4(3); 285–7. ©2011 AACR.
Timing and Dose of Statin Therapy Define Its Impact on Inflammatory and Endothelial Responses During Myocardial Infarction
Authors: Sposito Andrei C. , Santos Simone N. , de Faria Eliana Cotta , Abdalla Dulcineia S.P. , da Silva Luiza P. , Soares Alexandre A. Sousa , Japiassú André V.T. , Quinaglia e Silva Jose C. , Ramires Jose A.F. , Coelho Otavio Rizzi
Published: March 2011

Objective—

Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI.

Methods and Results—

ST-elevation MI patients (n=125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non–statin users (12.0±4.1 mg/L) and patients treated with 20 (8.5±4.0 mg/L), 40 (3.8±2.5 mg/L), and 80 mg/day (1.4±1.5 mg/L), and the daily differences remained significant until the seventh day (
P
<0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-α, the greater the reduction of 8-isoprostane and low-density lipoprotein(−), and the greater the increase in nitrate/nitrite levels during the first 5 days (
P
<0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-α, 8-isoprostane, and low-density lipoprotein(−), as well as in increase in nitrate/nitrite levels (
P
<0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (
P
=0.001).

Conclusion—

This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00906451.
Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21
Cip1
/Ets-1/p300 System
Authors: Katsume Asako , Okigaki Mitsuhiko , Matsui Akihiro , Che Jishan , Adachi Yasushi , Kishita Eigo , Yamaguchi Shinichiro , Ikeda Koji , Ueyama Tomomi , Matoba Satoaki , Yamada Hiroyuki , Matsubara Hiroaki
Published: March 2011

Objective—

Reactive oxygen species (ROS) are involved in the initial process of atherosclerosis, whereas it remains to be determined how atherogenic stimulus causes ROS-mediated proinflammatory reactions. Here, we focused on proline-rich tyrosine kinase (PYK2)–mediated ROS generation and examined how atherogenic stimulus causes early proinflammatory reactions.

Methods and Results—

PYK2-deficient (knockout [KO]) (PYK2-KO) mice were crossbred with apolipoprotein E (ApoE)–deficient (PYK2-KO/ApoE-KO) mice. PYK2-KO/ApoE-KO mice and endothelial cells (EC) were used for the study. Aortic atherogenic lesions in PYK2-KO/ApoE-KO mice were markedly decreased (55% versus ApoE-KO) after 8 weeks of a Western diet. Aortic PYK2 was activated as early as 7 days after the Western diet, when inflammatory cells were not yet activated. Addition of the proatherogenic oxidized phospholipid lysophosphatidylcholine caused activation of endothelial PYK2. Lysophosphatidylcholine-activated PYK2 induced NADPH oxidase–mediated ROS generation and ROS-mediated synthesis of tumor necrosis factor-α (TNFα), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and p21
Cip1
/Ets-1. Neutralizing anti-TNFα antibody or knockdown of p21
Cip1
/Ets-1 system blocked the induction of VCAM-1 and MCP-1. PYK2 deficiency abolished these ROS-mediated proinflammatory reactions. Further analysis revealed that PYK2/ROS-mediated p21
Cip1
/Ets-1 activation upregulated the transcription of the MCP-1 gene in collaboration with p300 transcription coactivator.

Conclusion—

PYK2 is a key tyrosine kinase activated by high cholesterol exposure, which causes ROS-mediated TNFα release and induces TNFα-dependent expression of proinflammatory molecules via the p21
Cip1
/Ets-1/p300 transcription system.
High-Mobility Group Box-1 Mediates Toll-Like Receptor 4–Dependent Angiogenesis
Authors: Lin Qing , Yang Xiao Ping , Fang Dan , Ren Xiangrong , Zhou Hongyan , Fang Jiazhu , Liu Xialin , Zhou Shiyou , Wen Feng , Yao Xiaohong , Wang Ji Ming , Su Shao Bo
Published: March 2011

Objective—

Inflammation is closely linked to angiogenesis, and Toll-like receptors (TLRs) are the key mediators of inflammatory responses. However, the impact of TLRs on angiogenesis is incompletely understood. In this study, we determined the involvement of TLRs in angiogenesis.

Methods and Results—

In a mouse model of alkali-induced corneal neovascularization (CNV), we found that CNV was attenuated in TLR4
−/−
but not TLR2
−/−
mice. Further study revealed that the absence of TLR4 led to decreased production of proangiogenic factors in association with reduced accumulation of macrophages at the site of wounds, which was associated with reduced expression of high-mobility group box-1 (HMGB1) protein, an endogenous ligand for TLR4. Topical application of HMGB1 to the injured cornea promoted CNV with increased macrophage accumulation in wild-type mice but not in TLR4
−/−
mice. HMGB1 treatment in vitro also promoted the production of proangiogenic factors by mouse macrophages in a TLR4-dependent manner. Furthermore, antagonists of HMGB1 and TLR4 reduced CNV and macrophage recruitment in the injured cornea of wild-type mice.

Conclusion—

Our results suggest that the release of HMGB1 in the wounds initiates TLR4-dependent responses that contribute to neovascularization. Thus, targeting HMGB1-TLR4 signaling cascade may constitute a novel therapeutic approach to angiogenesis-related diseases.
Bridging Intravenous–Intra-Arterial Rescue Strategy Increases Recanalization and the Likelihood of a Good Outcome in Nonresponder Intravenous Tissue Plasminogen Activator-Treated Patients
Authors: Rubiera Marta , Ribo Marc , Pagola Jorge , Coscojuela Pilar , Rodriguez-Luna David , Maisterra Olga , Ibarra Bernardo , Piñeiro Socorro , Meler Pilar , Romero Francisco J. , Alvarez-Sabin Jose , Molina Carlos A.
Published: March 2011

Background and Purpose—

Safety and efficacy of the “bridging therapy” (intra-arterial [IA] reperfusion rescue for nonresponder intravenous [IV] tissue plasminogen activator [tPA]-treated patients) is a matter of debate. Our aim was to compare IV and IV–IA thrombolysis using a case–control approach.

Methods—

Consecutive patients with proximal intracranial occlusion who received IA reperfusion procedures after unsuccessful IV tPA (lack of clinical improvement and arterial recanalization 1 hour after tPA bolus) were studied (IV–IA group). They were compared with occluded vessel, clot location, stroke severity, and time to treatment-matched 1 to 2 historical patients from our prospective IV tPA database with persistent occlusion 1 hour after IV tPA (IV-NR group). Arterial occlusion and recanalization were assessed with transcranial Doppler. Clinical evaluation was assessed by National Institutes of Health Stroke Scale at baseline, 24 hours, and at discharge. Symptomatic intracranial hemorrhage was defined according to the National Institute of Neurological Disorders and Stroke trial. Functional evaluation was determined by modified Rankin Scale, being functional independency defined by modified Rankin Scale score ≤2.

Results—

Forty-two IV–IA patients were compared with 84 matched IV-NR. Mean age was 71.5±2.9 years, 58 (46%) were women, and baseline median National Institutes of Health Stroke Scale score was 20 (interquartile range, 5). Mean time from symptoms to IV tPA was 176.9±113 minutes. On transcranial Doppler, complete recanalization was significantly higher in IV–IA than control subjects (12 hours: 45.2% versus 18.1%,
P
=0.002; 24 hours: 46.3% versus 25.3%,
P
=0.016) with nonsignificant better clinical evolution at 24 hours (40.5% versus 30.1%,
P
=0.169) and discharge (52.5% versus 39.5%,
P
=0.123). Symptomatic intracranial hemorrhage was similar (IV–IA 11.9% versus IV-NR 6%,
P
=0.205). Mortality at 3 months was 50% in the IV–IA group and 35.8% in the IV-NR (
P
=0.154). Forty percent of IV–IA patients were functionally independent at 3 months and only 14.9% IV-NR (
P
=0.012).

Conclusions—

Bridging IV–IA treatment may improve recanalization and clinical outcome in nonresponder IV tPA-treated patients.
Barthel Index for Stroke Trials
Authors: Quinn Terence J. , Langhorne Peter , Stott David J.
Published: March 2011

Background and Purpose—

Robust measures of functional outcome are required to determine treatment effects in stroke trials. Of the various measures available, the Barthel index (BI) is one of the more prevalent. We aimed to describe validity, reliability, and responsiveness (clinimetric properties) of the BI in stroke trials.

Methods—

Narrative review of published articles describing clinimetric properties or use of the BI as a stroke trial end point.

Results—

Definitive statements on properties of BI are limited by heterogeneity in methodology of assessment and in the content of “BI” scales. Accepting these caveats, evidence suggests that BI is a valid measure of activities of daily living; sensitivity to change is limited at extremes of disability (floor and ceiling effects), and reliability of standard BI assessment is acceptable. However, these data may not be applicable to contemporary multicenter stroke trials.

Conclusions—

Substantial literature describing BI clinimetrics in stroke is available; however, questions remain regarding certain properties. The “BI” label is used for a number of instruments and we urge greater consistency in methods, content, and scoring. A 10-item scale, scoring 0 to 100 with 5-point increments, has been used in several multicenter stroke trials and it seems reasonable that this should become the uniform stroke trial BI.
Values and culture in the social shaping of the future
Authors: Bachika Reimon , Schulz Markus S
Published: March 2011

This article introduces the Current Sociology monograph issue on Values and Culture. It discusses sociology’s renewed interest in values and the general approach on which the contributors converge despite diverse theoretical backgrounds, areas of focus and social settings. It explains how the studies in this publication contribute to the understanding of the formation and operation of values on micro, meso and macro levels in an increasingly globalized world.