bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing angle gauges in variable plot sampling: Is there a bias under ordinary conditions?
Authors: Iles Kim , Wilson William H.
Published: January 2008

Changing the basal area factor in variable plot or angle count sampling to give tree counts in an acceptable range is biased. The very reasonable sounding assumption that changing basal area factors will cause an inverse and proportional change in tree count will "prove" that there is no bias, but this assumption is not likely to be true in actual forest conditions. Changing prisms should not be done unless the user has shown, by field tests, that the bias is within acceptable limits. Reducing the fieldwork by splitting the plot and measuring a random half is unbiased and practical. Zero-count plots should not be changed. Lower average tree counts are preferred to the bias caused by edge effect or by missing scattered large trees. Methods are suggested for verifying these effects locally with minimal effort to the cruising staff.
Relations among stand structure, dispersal of second-instar western spruce budworm, defoliation, and height growth of young conifers
Authors: Carlson Clinton E. , McCaughey Ward W. , Theroux Leon J.
Published: January 2008

Local stand structure had little influence on dispersal of second-instar western spruce budworm (Choristoneuraoccidentalis Freeman). Numbers of dispersing larvae caught on traps averaged 37 larvae/m2 in the cut stands, as high as were found in adjacent uncut stands, and were not related to basal area of overstory in harvested stands, distance to the adjacent uncut stands, or budworm populations in the uncut stands. Despite high numbers of dispersing larvae, defoliation of host regeneration in cut stands was low (87% of the nonlarch host incurred less than 25% defoliation) and was not predictable (p ≤ 0.05) from dispersing larvae. Defoliation of mature trees in the adjacent uncut stands averaged 20% and ranged to 45%. Three-year height growth of postharvest host conifers in the cut stands increased with smaller overstory basal area, greater initial height, and greater crown ratio, but was not affected by the small amount of budworm defoliation. Regression models of 3-year height growth were similar among host western larch (Larixoccidentalis Nutt.), grouped nonlarch hosts (Douglas-fir, Pseudotsugamenziesii var. glauca (Beissn.) Franco; grand fir, Abiesgrandis (Dougl.) Forbes; and subalpine fir, A. lasiocarpa (Hook.) Nutt.), and grouped nonhosts (ponderosa pine, Pinusponderosa Dougl.; and lodgepole pine, P. contorta var. latifolia). Larval dispersal may be influenced more by forestwide conditions and spring weather than by local stand factors. Larvae reaching target seedlings likely are removed by predators such as birds and ants. Vigorous small host trees appear to be poor habitat for budworms; the insect had little effect on height growth of 5- to 20-year-old seral conifer stands of western Montana.
Bulldozing stumps and nitrogen fertilization affect growth of Douglas-fir seedlings
Authors: Thies W. G. , Nelson E. E.
Published: January 2008

Eight treatments involving stump removal by bulldozing in combination with nitrogen fertilization were applied to 0.04-ha circular plots in a clear-cut on the Olympic Peninsula, Washington. Treatments included stump removal (either all stumps removed or the plot left undisturbed) and broadcast fertilization with ammonium nitrate (0, 336, 672, or 1345 kg N ha−1). Diameter at breast height and height of Douglas-fir (Pseudotsugamenziesii (Mirb.) Franco) seedlings, planted several months after treatment, were recorded five and eight seasons after outplanting. The results showed that either bulldozing stumps from the site or fertilizing with ammonium nitrate increased growth of seedlings through their eighth growing season. After eight growing seasons, bulldozing had increased seedling height by 23% and diameter at breast height by 43%; fertilizing produced increases of 13% in height and 17% in diameter at breast height.
Compatible crown ratio and crown height models: Reply
Authors: Dyer Michael E. , Burkhart Harold E.
Published: January 2008

not available
SPECTRA OF SELF-ADJOINT EXTENSIONS AND APPLICATIONS TO SOLVABLE SCHRÖDINGER OPERATORS
Authors: BRÜNING JOCHEN , GEYLER VLADIMIR , PANKRASHKIN KONSTANTIN
Published: January 2008

We give a self-contained presentation of the theory of self-adjoint extensions using the technique of boundary triples. A description of the spectra of self-adjoint extensions in terms of the corresponding Krein maps (Weyl functions) is given. Applications include quantum graphs, point interactions, hybrid spaces and singular perturbations.
Z12−IOrbifold Compactification toward SUSY Standard Model
Authors: Kim Jihn E.
Published: January 2008

We explain the orbifold compactification in string models and present a Z12−Iorbifold compactification toward supersymmetric standard models. We also point out an effective R-parity from this string construction. The VEVs of gauge singlets are chosen such that phenomenological constraints are satisfied.
ON THE IMPLICATIONS OF A DILATON IN GAUGE THEORY
Authors: CHABAB MOHAMED
Published: January 2008

Some recent work on the implications of a dilaton in 4 d gauge theories are revisited. In part I of this paper we see how an effective dilaton coupling to gauge kinetic term provides a simple attractive mechanism to generate confinement. In particular, we put emphasis on the derivation of confining analytical solutions and look into the problem how dilaton degrees of freedom modify Coulom potential and when a confining phase occurs. In part II, we solve the semi-relativistic wave equation, for Dick interquark potential using the Shifted l-expansion technique (SLET) in the heavy quarkonium sector. The results of this phenomenological analysis proves that these effective theories can be relevant to model quark confinement and may shed some light on confinement mechanism.
Particle Physics in the Sky: the Current Status of Inflation
Authors: Kinney William H.
Published: January 2008

I discuss the current status of inflationary cosmology in light of the recent WMAP 3-year data release. The basic predictions of inflation are all supported by the data. Inflation also makes predictions which are have not been well tested by current data but can be by future experiments, most notably a deviation from a scale-invariant power spectrum and the production of primordial gravitational waves. A scale-invariant spectrum is disfavored by current data, but not conclusively. Tensor modes are currently poorly constrained, and slow-roll inflation does not make an unambiguous prediction of the expected amplitude of primordial gravitational waves. A tensor/scalar ratio of r ≃ 0.01 is within reach of near-future measurements.
PREDICTIONS FROM NON-TRIVIAL QUARK-LEPTON COMPLEMENTARITY
Authors: PICARIELLO MARCO , CHAUHAN BHAG C. , PULIDO JOÃO , TORRENTE-LUJAN EMILIO
Published: January 2008

The complementarity between the quark and lepton mixing matrices is shown to provide robust predictions. We obtain these predictions by first showing that the matrix VM, product of the quark (CKM) and lepton (PMNS) mixing matrices, may have a zero (1,3) entry which is favored by experimental data.

We obtain that any theoretical model with a vanishing (1,3) entry of VM that is in agreement with quark data, solar, and atmospheric mixing angle leads to [Formula: see text]. This value is consistent with the present 90% CL experimental upper limit. We also investigate the prediction on the lepton phases. We show that the actual evidence, under the only assumption that the correlation matrix VM product of CKM and PMNS has a zero in the entry (1, 3), gives us a prediction for the three CP-violating invariants J, S1, and S2. A better determination of the lepton mixing angles will give stronger prediction for the CP-violating invariants in the lepton sector. These will be tested in the next generation experiments. Finally we compute the effect of non diagonal neutrino mass in li → ljγ in SUSY theories with non trivial Quark-Lepton complementarity and a flavor symmetry. The Quark-Lepton complementarity and the flavor symmetry strongly constrain the theory and we obtain a clear prediction for the contribution to μ → eγ and the τ decays τ → eγ and τ → μγ. If the Dirac neutrino Yukawa couplings are degenerate but the low energy neutrino masses are not degenerate, then the lepton decays are related among them by the VM entries. On the other hand, if the Dirac neutrino Yukawa couplings are hierarchical or the low energy neutrino masses are degenerate, then the prediction for the lepton decays comes from the CKM hierarchy.
RECENT RESULTS FROM B FACTORIES
Authors: HAMEL de MONCHENAULT GAUTIER
Published: January 2008

We review some of the key 2006 measurements constraining the Unitarity Triangle and probing New Physics at B factory experiments BELLE and BABAR.
A NEW EXPERIMENT TO STUDY HYPERON CP VIOLATION AND THE CHARMONIUM SYSTEM
Authors: KAPLAN DANIEL M.
Published: January 2008

Fermilab operates the world's most intense antiproton source, now exclusively dedicated to serving the needs of the Tevatron Collider. The anticipated 2009 shutdown of the Tevatron presents the opportunity for a world-leading low- and medium-energy antiproton program. We summarize the status of the Fermilab antiproton facility and review physics topics for which a future experiment could make the world's best measurements.
Bounds on new physics from Bs mixing
Authors: Nierste Ulrich
Published: January 2008

I summarize the observables constraining the [Formula: see text] mixing complex and present a new calculation of the element [Formula: see text] of the decay matrix. [Formula: see text] enters the prediction of the width difference ΔΓs, for which we obtain [Formula: see text], if no new physics enters [Formula: see text] mixing. Applying our formulae to Tevatron data we find a deviation of the [Formula: see text] mixing phase φs from its Standard Model value by 2 standard deviations. I stress that present data do not give any information on the sign of ΔΓs.
SUPERSYMMETRIC CONTRIBUTIONS TO CP ASYMMETRY IN τ-DECAYS
Authors: Delepine D. , Faisel G. , Khalil S. , Shalaby M.
Published: January 2008

We review the CP violation in the semileptonic |ΔS| = 1 τ-decays in supersymmetric extensions of the standard model (SM). We show that Within SUSY models with conserved R parity, the CP asymmetry of τ → kπν is below the current experimental limits, although it is enhanced by several order of magnitude than the SM results. We also study the impact of the lepton violation terms in SUSY models with R parity violation. We show that the CP asymmetry of τ-decay is enhanced significantly and the current experimental limits obtained by CLEO collaborations can be easily accommodated.
CP violation in Charged Higgs Bosons decays H± → W± (γ, Z) in the Minimal Supersymmetric Standard Model (MSSM)
Authors: ARHRIB ABDESSLAM , BENBRIK RACHID , CHABAB MOHAMED , CHANG WEI TING , YUAN TZU-CHIANG
Published: January 2008

One loop mediated charged Higgs bosons decays H± → W±V, V = Z, γ are studied in the Minimal Supersymmetric Standard Model (MSSM) with and without CP violating phases. We evaluate the MSSM contributions to these processes taking into account B → Xsγ constraint as well as experimental constraints on the MSSM parameters. In the MSSM, we found that in the intermediate range of tan β ≲ 10 and for large At and large μ, where the lightest top squark becomes very light and hence non-decoupled, the branching ratio of H± → W±Z can be of the order 10−3 while the branching ratio of H± → W±γ is of the order 10−5. We found also that the CP violating phases of soft SUSY parameters can modify the branching ratio by about one order of magnitude. We also show that MSSM with CP violating phases lead to CP-violating asymmetry in the decays H+ → W+V and H− → W−V. Such CP asymmetry can be rather large and can reach 80% in some region of parameter space.
HIGHLY RELIABLE CAE MODEL, THE KEY TO STRATEGIC DEVELOPMENT OF ADVANCED TDS
Authors: AMASAKA KAKURO
Published: January 2008

In recent years, the advanced manufacturing industry is engaging in a "global production strategy — for simultaneous achievement of QCD". A close look at the development designing and production process stage reveals an excessive repetition of "experiment, prototyping, and evaluation" that prevents the "scale-up effect" generated in the bridging stage between prototyping, experiment, evaluation, and mass production. Consequently, what is urgently needed, is innovation to promote the advance from the conventional evaluation-based development, that uses the prototyping and experiment process which had long supported highly reliable designing, to a CAE prediction-based designing process. To accomplish this, a new development designing technique was established, the "Highly Reliable CAE Model. This is the key to strategic promotion of the "Total Integrated Development Design model — Advanced TDS" which utilizes the core element of the "Total Development System, TDS" of "New JIT". In an effort to realize this, the author has proposed the "high quality assurance model for super short period development designing, a "Highly Reliable CAE Numerical Simulation" and demonstrated its effectiveness. As an application example, a simulation technology was developed for molding urethane foam and it was implemented as the "Production of CAE Software for Molding Automotive Seat Pads — Urethane Foam Molding Simulator".
LEAN REMANUFACTURING: A CELLULAR CASE STUDY
Authors: HUNTER STEVE L. , BLACK J. T.
Published: January 2008

This paper documents the basic manufacturing philosophies and methodologies utilized for the design and implementation of a Lean Manufacturing remanufacture cell. Remanufacture deals with overhauling or reworking products that have been in service and need modification in order to continue to be serviceable. This remanufacturing cell implementation is the first cell of an eighteen-cell manufacturing and remanufacturing system. A systematic detailed case study is utilized as a Lean Production example and proves the flexibility of Lean Manufacturing to be adaptive while being cost effective in the remanufacture arena. This study provides key insights into a concept and strategy for implementing Lean Production thinking — cellular manufacturing. Most factories need significant assistance in understanding how to make Lean Production work; this paper provides many insights into both the theory and application of cellular manufacturing/assembly systems for remanufacture.
The Adventures of Sonic Hedgehog in Development and Repair. II. Sonic hedgehog and liver development, inflammation, and cancer
Authors: Omenetti Alessia , Diehl Anna Mae
Published: January 2008

Hedgehog (Hh) signaling modulates tissue remodeling by controlling the fate of Hh-responsive cells. Healthy adult livers exhibit little Hh activity. However, cells involved in adult liver repair, including myofibroblasts and progenitors, are capable of producing and responding to Hh ligands. During adult liver injury, Hh ligand production increases and populations of Hh-responsive cells expand. This process is accompanied by fibrosis. Ligand production and Hh-responsive cells diminish as fibrosis resolves and normal hepatic architecture is restored, but Hh signaling persists in hepatocellular carcinomas. These findings suggest that the Hh pathway mediates remodeling responses that are triggered by adult liver damage.
Spatially discordant alternans in cardiomyocyte monolayers
Authors: de Diego Carlos , Pai Rakesh K. , Dave Amish S. , Lynch Adam , Thu Mya , Chen Fuhua , Xie Lai-Hua , Weiss James N. , Valderrábano Miguel
Published: January 2008

Repolarization alternans is a harbinger of sudden cardiac death, particularly when it becomes spatially discordant. Alternans, a beat-to-beat alternation in the action potential duration (APD) and intracellular Ca (Cai), can arise from either tissue heterogeneities or dynamic factors. Distinguishing between these mechanisms in normal cardiac tissue is difficult because of inherent complex three-dimensional tissue heterogeneities. To evaluate repolarization alternans in a simpler two-dimensional cardiac substrate, we optically recorded voltage and/or Cai in monolayers of cultured neonatal rat ventricular myocytes during rapid pacing, before and after exposure to BAY K 8644 to enhance dynamic factors promoting alternans. Under control conditions ( n = 37), rapid pacing caused detectable APD alternans in 81% of monolayers, and Cai transient alternans in all monolayers, becoming spatially discordant in 62%. After BAY K 8644 ( n = 28), conduction velocity restitution became more prominent, and APD and Cai alternans developed and became spatially discordant in all monolayers, with an increased number of nodal lines separating out-of-phase alternating regions. Nodal lines moved closer to the pacing site with faster pacing rates and changed orientation when the pacing site was moved, as predicted for the dynamically generated, but not heterogeneity-based, alternans. Spatial APD gradients during spatially discordant alternans were sufficiently steep to induce conduction block and reentry. These findings indicate that spatially discordant alternans severe enough to initiate reentry can be readily induced by pacing in two-dimensional cardiac tissue and behaves according to predictions for a predominantly dynamically generated mechanism.
Effect of carbohydrate ingestion and ambient temperature on muscle fatigue development in endurance-trained male cyclists
Authors: Abbiss Chris R. , Peiffer Jeremiah J. , Peake Jonathan M. , Nosaka Kazunori , Suzuki Katsuhiko , Martin David T. , Laursen Paul B.
Published: January 2008

The aim of the present study was to determine the effect of carbohydrate (CHO; sucrose) ingestion and environmental heat on the development of fatigue and the distribution of power output during a 16.1-km cycling time trial. Ten male cyclists (V̇o2max = 61.7 ± 5.0 ml·kg−1·min−1, mean ± SD) performed four 90-min constant-pace cycling trials at 80% of second ventilatory threshold (220 ± 12 W). Trials were conducted in temperate (18.1 ± 0.4°C) or hot (32.2 ± 0.7°C) conditions during which subjects ingested either CHO (0.96 g·kg−1·h−1) or placebo (PLA) gels. All trials were followed by a 16.1-km time trial. Before and immediately after exercise, percent muscle activation was determined using superimposed electrical stimulation. Power output, integrated electromyography (iEMG) of vastus lateralis, rectal temperature, and skin temperature were recorded throughout the trial. Percent muscle activation significantly declined during the CHO and PLA trials in hot (6.0 and 6.9%, respectively) but not temperate conditions (1.9 and 2.2%, respectively). The decline in power output during the first 6 km was significantly greater during exercise in the heat. iEMG correlated significantly with power output during the CHO trials in hot and temperate conditions ( r = 0.93 and 0.73; P < 0.05) but not during either PLA trial. In conclusion, cyclists tended to self-select an aggressive pacing strategy (initial high intensity) in the heat.
Effects of jump training on bone are preserved after detraining, regardless of estrogen secretion state in rats
Authors: Umemura Yoshihisa , Nagasawa Seigo , Sogo Naota , Honda Akiko
Published: January 2008

We investigated whether the effects of jump training on bone are preserved after a detraining period in female normal and estrogen-deficient rats. Forty-four 11-wk-old Wistar rats were divided into the following four groups: sham sedentary ( n = 12), sham exercised ( n = 11), ovariectomized sedentary ( n = 10), and ovariectomized exercised ( n = 11). An 8-wk exercise period was introduced in which the rats in the exercised groups were jumped 10 times/day, 5 days/wk. This was followed by 24 wk of detraining. At the end of the exercise period, the jump training significantly increased the bone mineral content of the tibia ( P < 0.001), measured by dual-energy X-ray absorptiometry. After the detraining period, the bone mineral content ( P < 0.01), strength ( P < 0.001), and cross-sectional widths ( P < 0.001) of the tibia in the exercised groups were still greater than in the sedentary groups, without significant surgery-exercise interactions, although bone stiffness in the fracture test ( P < 0.05) and bone area in the center-proximal region, as measured by dual-energy X-ray absorptiometry ( P < 0.05), showed significant surgery-exercise interactions. These findings suggest that the exercise effect on bone strength is preserved, accompanied by cross-sectional morphological changes, even under estrogen deficiency.
Effect of airways constriction on exhaled nitric oxide
Authors: Verbanck Sylvia , Kerckx Yannick , Schuermans Daniel , Vincken Walter , Paiva Manuel , Van Muylem Alain
Published: January 2008

While airway constriction has been shown to affect exhaled nitric oxide (NO), the mechanisms and location of constricted airways most likely to affect exhaled NO remain obscure. We studied the effects of histamine-induced airway constriction and ventilation heterogeneity on exhaled NO at 50 ml/s (FeNO,50) and combined this with model simulations of FeNO,50 changes due to constriction of airways at various depths of the lung model. In 20 normal subjects, histamine induced a 26 ± 15(SD)% FeNO,50 decrease, a 9 ± 6% forced expiratory volume in 1 s (FEV1) decrease, a 19 ± 9% mean forced midexpiratory flow between 25% and 75% forced vital capacity (FEF25–75) decrease, and a 94 ± 119% increase in conductive ventilation heterogeneity. There was a significant correlation of FeNO,50 decrease with FEF25–75 decrease ( P = 0.006) but not with FEV1 decrease or with increased ventilation heterogeneity. Simulations confirmed the negligible effect of ventilation heterogeneity on FeNO,50 and showed that the histamine-induced FeNO,50 decrease was due to constriction, with associated reduction in NO flux, of airways located proximal to generation 15. The model also indicated that the most marked effect of airways constriction on FeNO,50 is situated in generations 10–15 and that airway constriction beyond generation 15 markedly increases FeNO,50 due to interference with the NO backdiffusion effect. These mechanical factors should be considered when interpreting exhaled NO in lung disease.
Neural control of breathing: insights from genetic mouse models
Authors: Gaultier C. , Gallego J
Published: January 2008

Recent studies described the in vivo ventilatory phenotype of mutant newborn mice with targeted deletions of genes involved in the organization and development of the respiratory-neuron network. Whole body flow barometric plethysmography is the noninvasive method of choice for studying unrestrained newborn mice. Breathing-pattern abnormalities with apneas occur in mutant newborn mice that lack genes involved in the development and modulation of rhythmogenesis. Studies of deficits in ventilatory responses to hypercapnia and/or hypoxia helped to identify genes involved in chemosensitivity to oxygen and carbon dioxide. Combined studies in mutant newborn mice and in humans have shed light on the pathogenesis of genetically determined respiratory-control abnormalities such as congenital central hypoventilation syndrome, Rett syndrome, and Prader-Willi syndrome. The development of mouse models has opened up the field of research into new treatments for respiratory-control disorders in humans.
Neurovascular responses to mental stress in the supine and upright postures
Authors: Kuipers Nathan T. , Sauder Charity L. , Carter Jason R. , Ray Chester A.
Published: January 2008

The purpose of this study was to determine neurovascular responses to mental stress (MS) in the supine and upright postures. MS was elicited in 23 subjects (26 ± 1 yr) by 5 min of mental arithmetic. In study 1 ( n = 9), Doppler ultrasound was used to measure mean blood flow velocity in the renal (RBFV) and superior mesenteric arteries (SMBFV), and venous occlusion plethysmography was used to measure forearm blood flow (FBF). In study 2 ( n = 14), leg blood flow (LBF; n = 9) was measured by Doppler ultrasound, and muscle sympathetic nerve activity (MSNA; n = 5) was measured by microneurography. At rest, upright posture increased heart rate and MSNA and decreased LBF, FBF, RBFV, and SMBFV and their respective conductances. MS elicited similar increases in mean arterial blood pressure (∼12 mmHg) and heart rate (∼17 beats/min), regardless of posture. MS in both postures elicited a decrease in RBFV, SMBFV, and their conductances and an increase in LBF, FBF, and their conductances. Changes in blood flow were blunted in the upright posture in all vascular beds examined, but the pattern of the vascular response was the same as the supine posture. MS did not change MSNA in either posture (change: ∼1 ± 3 and ∼3 ± 3 bursts/min, respectively). In conclusion, the augmented sympathetic activity of the upright posture does not alter heart rate, mean arterial blood pressure, or MSNA responses to MS. MS elicits divergent vascular responses in the visceral and peripheral vasculature. These results indicate that, although the upright posture attenuates vascular responses to MS, the pattern of neurovascular responses does not differ between postures.
Sodium Thiosulfate Administered Six Hours after Cisplatin Does Not Compromise Antineuroblastoma Activity
Authors: Harned Theresa M. , Kalous Ondrej , Neuwelt Alexander , Loera Jason , Ji Lingyun , Iovine Peter , Sposto Richard , Neuwelt Edward A. , Reynolds C. Patrick
Published: January 2008

Purpose: We determined if the potentially otoprotective agent sodium thiosulfate (STS) could be given 6 h after cisplatin without diminishing the antineuroblastoma activity of cisplatin in human neuroblastoma cell lines in vitro (including cisplatin-resistant cell lines) and in neuroblastoma xenografts in vivo.

Experimental Design: We determined the antineuroblastoma activity of cisplatin with or without the addition of STS at 0 or 6 h after cisplatin in six neuroblastoma cell lines, both in standard cell culture conditions (20% O2) and in physiologic hypoxia (2% O2). Drug cytotoxicity was measured using the DIMSCAN fluorescence/digital imaging microscopy assay. In vivo studies of cisplatin combined with STS used a human neuroblastoma subcutaneous xenograft model (SMS-SAN) in athymic nu/nu mice.

Results: A significant protection against cisplatin cytotoxicity was seen when the neuroblastoma cells were exposed to cisplatin directly combined with STS. However, when cisplatin was given first and STS exposure occurred 6 h later, no effect on cisplatin cytotoxicity was observed. In a subcutaneous neuroblastoma xenograft model in nu/nu mice, mice receiving cisplatin alone or cisplatin + STS at 6 h had significantly better progression-free survival rates (P < 0.03) compared with controls or mice treated with cisplatin + STS concurrently. There was no statistically significant difference in outcomes between mice treated with cisplatin alone and the group treated with cisplatin followed by STS 6 h later (P = 0.9).

Conclusion: These preclinical data suggest that the use of STS 6 h after cisplatin for otoprotection is unlikely to compromise the antineuroblastoma activity of cisplatin.
Role of IG20 Splice Variants in TRAIL Resistance
Authors: Prabhakar Bellur S. , Mulherkar Nirupama , Prasad Kanteti V.
Published: January 2008

Tumor necrosis factor receptor–related apoptosis-inducing ligand (TRAIL) can induce apoptosis primarily in cancer cells with little or no effect on normal cells; therefore, it has the potential for use in cancer therapy. TRAIL binding to death receptors DR4 and DR5 triggers the death-inducing signal complex formation and activation of procaspase-8, which in turn activates caspase-3, leading to cell death. Like FasL, TRAIL can trigger type 1 (caspase-8 → caspase-3) or type 2 (caspase-8 → Bid cleavage → capsase-9 → caspase-3) apoptotic pathways depending on the cell type. Some cancers are resistant to TRAIL treatment because most molecules in the TRAIL signaling pathway, including FLIPs and IAPs, can contribute to resistance. In addition, we have identified an essential role for splice variants of the IG20 gene in TRAIL resistance.
MicroRNAs as Prognostic Indicators and Therapeutic Targets: Potential Effect on Breast Cancer Management
Authors: Lowery Aoife J. , Miller Nicola , McNeill Roisin E. , Kerin Michael J.
Published: January 2008

The discovery of microRNAs (miRNA) as novel modulators of gene expression has resulted in a rapidly expanding repertoire of molecules in this family, as reflected in the concomitant expansion of scientific literature. MiRNAs are a category of naturally occurring RNA molecules that play important regulatory roles in plants and animals by targeting mRNAs for cleavage or translational repression. Characteristically, miRNAs are noncoding, single-stranded short (18-22 nucleotides) RNAs, features which possibly explain why they had not been intensively investigated until recently. Accumulating experimental evidence indicates that miRNAs play a pivotal role in many cellular functions via the regulation of gene expression. Furthermore, their dysregulation and/or mutation has been shown in carcinogenesis. We provide a brief review of miRNA biogenesis and discuss the technical challenges of modifying experimental techniques to facilitate the identification and characterization of these small RNAs. MiRNA function and their involvement in malignancy, particularly their putative role as oncogenes or tumor suppressors is also discussed, with a specific emphasis on breast cancer. Finally, we comment on the potential role of miRNAs in breast cancer management, particularly in improving current prognostic tools and achieving the goal of individualized cancer treatment.
Clinical Validation of a Customized Multiple Signature Microarray for Breast Cancer
Authors: Tan Benita K.T. , Tan Lay Keng , Yu Kun , Tan Puay Hoon , Lee Ming , Sii Lang Hiong , Wong Chow Yin , Ho Gay Hui , Yeo Allen W.Y. , Chow Pierce K.H. , Koong Heng Nung , Yong Wei Sean , Lim Dennis T.H. , Ooi London L.P.J. , Soo Khee Chee , Tan Patrick
Published: January 2008

Purpose: Current histopathologic systems for classifying breast tumors require evaluation of multiple variables and are often associated with significant interobserver variability. Recent studies suggest that gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we investigated the use of a customized microarray as a potential tool for clinical practice.

Experimental Design: We fabricated custom 188-gene microarrays containing expression signatures for three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2), and “basaloid”], the Nottingham prognostic index (NPI-ES), and low histologic grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort of 165 patients with primary breast cancer.

Results: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry reported on diagnosis (P < 0.001). This remained unchanged at 89% (P < 0.001) when the immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio ≥2.2; P < 0.001), which further improved to 89% when the ratio cutoff was raised to ≥5. A proportion of low-level FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2 signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry. Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002) and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019).

Conclusion: The consistency of the MSA platform in an independent patient population suggests that custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH in clinical practice.
Ductal Carcinoma In situ and the Emergence of Diversity during Breast Cancer Evolution
Authors: Allred D. Craig , Wu Yun , Mao Sufeng , Nagtegaal Iris D. , Lee Sangjun , Perou Charles M. , Mohsin Syed K. , O'Connell Peter , Tsimelzon Anna , Medina Dan
Published: January 2008

Purpose: Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs.

Experimental Design: The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes.

Results: DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007).

Conclusions: These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.
Large Deletions of the PRKAR1A Gene in Carney Complex
Authors: Horvath Anelia , Bossis Ioannis , Giatzakis Christoforos , Levine Elizabeth , Weinberg Frank , Meoli Elise , Robinson-White Audrey , Siegel Jennifer , Soni Payal , Groussin Lionel , Matyakhina Ludmila , Verma Somya , Remmers Elaine , Nesterova Maria , Carney J. Aidan , Bertherat Jérôme , Stratakis Constantine A.
Published: January 2008

Purpose: Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found in ∼70% of the patients. To date, no germ-line PRKAR1A deletion and/or insertion exceeded a few base pairs (up to 15). Although a few families map to chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes in PRKAR1A–mutation-negative individuals with Carney complex.

Experimental Design: To screen for gross alterations of the PRKAR1A gene, we applied Southern hybridization analysis on 36 unrelated Carney complex patients who did not have small intragenic mutations or large aberrations in PRKAR1A, including the probands from two kindreds mapping to chromosome 2.

Results: We found large PRKAR1A deletions in the germ-line of two patients with Carney complex, both sporadic cases; no changes were identified in the remaining patients, including the two chromosome-2-mapping families. In the first patient, the deletion is expected to lead to decreased PRKAR1A mRNA levels but no other effects on the protein; the molecular phenotype is predicted to be PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing Carney complex. In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic protein kinase A subunit. In vitro transfection studies of the mutant PRKAR1A showed impaired ability to bind cyclic AMP and activation of the protein kinase A enzyme. The patient bearing this mutation had a more-severe-than-average Carney complex phenotype that included the relatively rare psammomatous melanotic schwannoma.

Conclusions: Large PRKAR1A deletions may be responsible for Carney complex in patients that do not have PRKAR1A gene defects identifiable by sequencing. Preliminary data indicate that these patients may have a different phenotype especially if their defect results in an expressed, abnormal version of the PRKAR1A protein.
Plasma Stromal Cell–Derived Factor-1: Host Derived Marker Predictive of Distant Metastasis in Breast Cancer
Authors: Hassan Saima , Baccarelli Andrea , Salvucci Ombretta , Basik Mark
Published: January 2008

Purpose: Homing of breast cancer cells to metastatic sites may be regulated by the production of stromal cell–derived factor (SDF)-1 by specific target organs, which attracts CXCR4-expressing breast cancer cells. We investigated the value of SDF-1 as a predictive blood marker of distant metastasis in breast cancer, together with a common polymorphism of SDF-1, SDF-1-3′A.

Experimental Design: Plasma samples were collected prospectively for 270 consecutive primary breast cancer patients with a median follow-up of 3.3 years. Plasma SDF-1 levels were measured using an ELISA, and the polymorphism was identified via PCR-RFLP analysis.

Results: Plasma SDF-1 levels were divided into two groups, low and high, based on the median SDF-1 value of 2,661 pg/mL. Patients with low SDF-1 showed an increased risk of developing distant metastasis (relative risk, 1.94; P = 0.02) and poorer breast cancer–specific survival [adjusted hazard ratio (AHR), 3.92; P = 0.007]. Patients with both low plasma SDF-1 levels and the SDF-1-3′A polymorphism showed a poorer breast cancer–specific survival (AHR, 3.98; P = 0.001) and distant disease-free survival (AHR, 2.88; P = 0.003). In a separate cohort of 22 breast cancer patients, we found no significant difference in SDF-1 levels before and posttumor resection.

Conclusion: We found that low plasma SDF-1 is an independent host-derived predictive marker of distant metastasis in breast cancer. The prognostic value of the combination of a low plasma SDF-1 level and the SDF-1-3′A polymorphism identifies a cohort of patients with an intrinsic susceptibility for poorer survival.
Identification of Novel Nasopharyngeal Carcinoma Biomarkers by Laser Capture Microdissection and Proteomic Analysis
Authors: Cheng Ai-Lan , Huang Wei-Guo , Chen Zhu-Chu , Peng Fang , Zhang Peng-Fei , Li Mao-Yu , Li Feng , Li Jian-Ling , Li Cui , Yi Hong , Yi Bin , Xiao Zhi-Qiang
Published: January 2008

Purpose: To identify novel nasopharyngeal carcinoma (NPC) biomarkers by laser capture microdissection and a proteomic approach.

Experimental Design: Proteins from pooled microdissected NPC and normal nasopharyngeal epithelial tissues (NNET) were separated by two-dimensional gel electrophoresis, and differential proteins were identified by mass spectrometry. Expression of three differential proteins (stathmin, 14-3-3σ, and annexin I) in the above two tissues as well as four NPC cell lines was determined by Western blotting. Immunohistochemistry was also done to detect the expression of three differential proteins in 98 cases of primary NPC, 30 cases of NNET, and 20 cases of cervical lymph node metastases, and the correlation of their expression levels with clinicopathologic features and clinical outcomes were evaluated.

Results: Thirty-six differential proteins between the NPC and NNET were identified. The expression levels of stathmin, 14-3-3σ, and annexin I in the two types of tissues were confirmed and related to differentiation degree and/or metastatic potential of the NPC cell lines. Significant stathmin up-regulation and down-regulation of 14-3-3σ and annexin I were observed in NPC versus NNET, and significant down-regulation of 14-3-3σ and annexin I was also observed in lymph node metastasis versus primary NPC. In addition, stathmin up-regulation and down-regulation of 14-3-3σ and annexin I were significantly correlated with poor histologic differentiation, advanced clinical stage, and recurrence, whereas down-regulation of 14-3-3σ and annexin I was also significantly correlated with lymph node and distant metastasis. Furthermore, survival curves showed that patients with stathmin up-regulation and down-regulation of 14-3-3σ and annexin I had a poor prognosis. Multivariate analysis revealed that the expression status of stathmin, 14-3-3σ, and annexin I was an independent prognostic indicator.

Conclusion: The data suggest that stathmin, 14-3-3σ, and annexin I are potential biomarkers for the differentiation and prognosis of NPC, and their dysregulation might play an important role in the pathogenesis of NPC.
Carcinoembryonic Antigen Cell Adhesion Molecule 6 Predicts Breast Cancer Recurrence following Adjuvant Tamoxifen
Authors: Maraqa Loaie , Cummings Michele , Peter Mark B. , Shaaban Abeer M. , Horgan Kieran , Hanby Andrew M. , Speirs Valerie
Published: January 2008

Purpose: Tamoxifen remains therapy of choice for premenopausal estrogen receptor α–positive breast cancer. However, resistance and recurrence are serious problems. Our previous work indicated that carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) was significantly up-regulated in tamoxifen-resistant (TAMr) MCF-7 derivatives. The aim of this study was to determine the functional role of CEACAM6 in endocrine-resistant breast cancer and to retrospectively test whether it was predictive of resistance in a large cohort of breast cancers with long-term follow-up.

Experimental Design: siRNA silencing of CEACAM6 was done in TAMr cells and effects on clonogenicity and endocrine sensitivity were determined. CEACAM6 immunohistochemistry was done on a tissue microarray comprising 108 relapsed primary human breast cancers and 243 tamoxifen-sensitive controls.

Results: siRNA-mediated silencing of CEACAM6 reduced both clonogenicity and anchorage-dependent and anchorage-independent growth of TAMr cells. Importantly, CEACAM6 silencing restored sensitivity of TAMr cells to 4-hydroxytamoxifen and proliferative response to 17β-estradiol. Immunohistochemistry showed significantly more CEACAM expression in the relapsed group compared with nonrelapsed controls [35 of 108 (33.3%) and 32 of 243 (13.2%), respectively; odds ratio, 3.16 (95% confidence interval, 1.83-5.47); P < 0.0001]. Additionally, we derived an outcome predictor model based on CEACAM expression that restratified patients in the Nottingham prognostic index intermediate-risk group into either higher-risk or lower-risk group.

Conclusions: Our data support an important role for CEACAM6 in endocrine resistance, which can serve as a powerful predictor of future recurrence.
Inverse Relationship between Human Papillomavirus-16 Infection and Disruptivep53Gene Mutations in Squamous Cell Carcinoma of the Head and Neck
Authors: Westra William H. , Taube Janis M. , Poeta M.L. , Begum Shanaz , Sidransky David , Koch Wayne M.
Published: January 2008

Purpose: Squamous cell carcinomas of the head and neck (HNSCC) often harbor p53 mutations, but p53 protein degradation by the viral oncoprotein E6 may supercede p53 mutations in human papillomavirus 16 (HPV16)–positive tumors. The prevalence of p53 mutations in HPV-positive HNSCCs is indeed lower, but in some tumors these alterations coexist. The purpose of this study was to discern whether HNSCCs differ in the type of p53 mutations as a function of HPV16 status.

Experimental Design: The study was nested within a prospective multicenter study (ECOGE 4393/RTOG R9614) of patients with HNSCC treated surgically with curative intent. Tumors from one study center were used to construct a tissue microarray. The tumors were well characterized with respect to p53 mutational status. The tissue microarray was evaluated by HPV16 in situ hybridization. HPV16 analysis was also done on a select group of tonsillar carcinomas known to harbor disruptive p53 mutations defined as stop mutations or nonconservative mutations within the DNA binding domain.

Results: HPV16 was detected in 12 of 89 (13%) HNSCCs. By tumor site, HPV16 was detected in 12 of 21 (57%) tumors from the palatine/lingual tonsils, but in none of 68 tumors from nontonsillar sites (P < 0.00001). Both HPV16-positive and HPV16-negative HNSCCs harbored p53 mutations (25% versus 52%), but disruptive mutations were only encountered in HPV16-negative carcinomas. Of seven tonsillar carcinomas with disruptive p53 mutations, none were HPV16 positive, in contrast to HPV16-positive tonsillar carcinomas without disruptive p53 mutations (0% versus 57%; P = 0.008).

Conclusions: Although HPV16 and mutated p53 may coexist in a subset of HNSCCs, HPV16 and disruptive p53 mutations seem to be nonoverlapping events. A less calamitous genetic profile, including the absence of disruptive p53 mutations, may underlie the emerging clinical profile of HPV16-positive HNSCC such as improved patient outcome.
STX140 Is Efficacious In vitro and In vivo in Taxane-Resistant Breast Carcinoma Cells
Authors: Newman Simon P. , Foster Paul A. , Stengel Chloe , Day Joanna M. , Ho Yaik T. , Judde Jean-Gabriel , Lassalle Myriam , Prevost Gregoire , Leese Mathew P. , Potter Barry V.L. , Reed Michael J. , Purohit Atul
Published: January 2008

Purpose: The aim of these studies was to characterize the action of STX140 in a P-glycoprotein–overexpressing tumor cell line both in vitro and in vivo. In addition, its efficacy was determined against xenografts derived from patients who failed docetaxel therapy.

Experimental Design: The effects of STX140, Taxol, and 2-methoxyestradiol (2-MeOE2) on cell proliferation, cell cycle, and apoptosis were assessed in vitro in drug-resistant cells (MCF-7DOX) and the parental cell line (MCF-7WT). Mice bearing an MCF-7DOX tumor on one flank and an MCF-7WT tumor on the other flank were used to assess the in vivo efficacy. Furthermore, the responses to STX140 of three xenografts, derived from drug-resistant patients, were assessed.

Results: In this study, STX140 caused cell cycle arrest, cyclin B1 induction, and subsequent apoptosis of both MCF-7DOX and MCF-7WT cells. Taxol and 2-MeOE2 were only active in the MCF-7WT parental cell line. Although both STX140 and Taxol inhibited the growth of xenografts derived from MCF-7WT cells, only STX140 inhibited the growth of tumors derived from MCF-7DOX cells. 2-MeOE2 was ineffective at the dose tested against both tumor types. Two out of the three newly derived docetaxel-resistant xenografts, including a metastatic triple-negative tumor, responded to STX140 but not to docetaxel treatment.

Conclusions: STX140 shows excellent efficacy in both MCF-7WT and MCF-7DOX breast cancer xenograft models, in contrast to Taxol and 2-MeOE2. The clinical potential of STX140 was further highlighted by the efficacy seen in xenografts recently derived from patients who had failed on taxane therapy.