bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence of functional gender polymorphisms in a population of the hermaphroditic lowbush blueberry (Vaccinium angustifolium)1This article is part of a Special Issue entitled “A tribute to Sam Vander Kloet FLS: Pure and applied research from blueberries to heathland ecology”.
Authors: Bell Daniel J. , Drummond Frank A. , Rowland Lisa J.
Published: May 2012

Lowbush blueberry ( Vaccinium angustifolium Aiton) is a wild, but cultivated for profit, agricultural system grown primarily in the northeastern regions of North America. It has been suggested that a functional gender specialization may be occurring in this hermaphroditic species in which some individuals (termed clones) effectively function as bearers (high ovule production but little or nonviable pollen) or as pollen donors (low ovule number with high quantities of viable pollen). The purpose of this study was to investigate if functional gender specialization was occurring in a randomly chosen population of 56 clones from the Blueberry Hill Research Farm in Jonesboro, Maine. For each clone, the mean number of ovules and the mean number of viable microspores per flower were determined. From this, functional gender was calculated. Five out of 56 clones, or approximately 10% of clones, were found to be functioning primarily as females, owing to their low levels of viable pollen. Thus, some evidence was found of a functional gender specialization occurring—the presence of a few plants that were nearly male-sterile. Since the most common evolutionary pathway to gynodioecy involves the invasion of male steriles, it is interesting to speculate that a trend towards gender dimorphism could be occurring in lowbush blueberry.
Dispersion of gold in stream sediments in the Sungai Kuli region, Sabah, Malaysia
Authors: Fletcher W. K. , Muda Joanes
Published: May 2012

The distribution of Au has been investigated under tropical rainforest conditions in an Au-rich tributary of the Sungai Kuamut, Sabah, Malaysia. Paired high- and low-energy sediment samples were collected, before disturbance by logging, from gravel and cobble sites on bars and riffles. Gold content of five size fractions finer than 212 μm was determined by fire-assay atomic absorption spectrometry (FA-AAS). Use of a bulk leach cyanidation (BLC) procedure for Au was also tested. A strong, but extremely erratic, Au anomaly is present in the sand-size fractions. The highest Au values are found in gravel environments and concentrations decrease with decreasing grain size to a minimum in the −53 μm fraction. To maintain anomaly contrast while minimizing the chance of missing the erratic Au anomalies, use of the −105 μm fraction is recommended for stream sediment exploration surveys in the region. Because of the abundance and low Au content of the −53 μm fraction, increased erosion and additional inputs of this fraction into the stream after logging activity could significantly dilute the Au anomaly.
Groundwater flow in playa lake environments: impact on gold and pathfinder element distributions in groundwaters surrounding mesothermal gold deposits, St. Ives area, Eastern Goldfields, Western Australia
Authors: Carey M. L. , McPhail D. C. , Taufen P. M.
Published: May 2012

Geochemical sampling of groundwater may be an effective tool in exploring for Au deposits in areas of transported overburden. However, to use hydrogeochemistry effectively, we need to understand which elements are useful pathfinders and how their distribution patterns are affected by groundwater flow and geochemistry, especially in areas that have hypersaline groundwater. A hydrogeochemical survey was completed over the strongly Au-endowed St. Ives area of the Eastern Goldfields of Western Australia. Extensive geochemical and hydrogeological data were measured from 80 holes drilled on a kilometre-spaced grid. A numerical model was developed to quantify the groundwater flow regime in the study area. Also, hydrogeological data in combination with the geochemistry of the waters were used to identify a complex flow regime adjacent to Lake Lefroy, a playa lake in the area. Regional brine flows towards the salt lake, evaporation occurs and hypersaline (playa) brines are formed that sink and flow away from Lake Lefroy and beneath the regional brines. Density-driven, convective mixing of these two brines is responsible for forming a zone of brines with transitional compositions located near the edge of Lake Lefroy. Knowledge of the groundwater flow regime was used to interpret the distribution of elements around bedrock Au mineralization. An Au-only groundwater anomaly (>10 ppt, maximum 52 ppt) is located downstream of the Junction Au ore body. No anomaly was identified in deep brines associated with the nearby Argo/Apollo Au ore body; however, shallow regional brines sampled in a previous survey showed elevated Au values overlying and downstream of the mineralization. The lack of elevated Au concentrations in deeper groundwater associated with Argo/Apollo is because the samples collected were hypersaline playa brines sourced from Lake Lefroy that had not flowed over the mineralization. Possible pathfinder elements, such as Sb, Bi and Te, were either present in concentrations too low to detect or showed no spatial pattern related to known mineralization; however, a strong correlation was noted between some of their concentrations and salinity. Evaluation of the groundwater anomalies observed in this study suggests that hydrogeochemical exploration is most effective at a resolution of 0.5–4 km spacing, and does not require fully cased and packed wells, at least in cases where no confined aquifers are intersected in drilling. The results of this study illustrate the importance of understanding groundwater flow regimes in planning and interpreting hydrogeochemical surveys.
Performance of commercial laboratories in analysis of geochemical samples for gold and the platinum group elements
Authors: Hall G. E. M. , Oates C. J.
Published: May 2012

Twenty-six international geological certified reference materials (CRM) and two in-house soil control samples were gathered and submitted ‘blind’ in duplicate to five commercial geochemical laboratories for the determination of Au and the platinum group elements (PGEs). The methods employed comprise: Pb fire assay (PbFA) combined with inductively coupled plasma mass spectrometry (ICP-MS); NiS fire assay combined with ICP-MS or instrumental neutron activation analysis (INAA); and aqua regia ICP-MS, with and without prior roasting of the sample at 600
o
C. The CRMs vary widely in their matrix and PGE concentrations, ranging from a background soil (e.g. GPt-1), sediment (e.g. GPt-2, JSd-2), and rock (e.g. WGB-1, CHR-Bkg) to altered rocks (e.g. WPR-1) and ore material (e.g. GPt-6, SARM-7b, WMS-1). The results of this ‘round-robin’ are provided and discussed in this paper.

Results for Au showed the greatest variation across the laboratories, with one evidently encountering significant and spurious contamination. Comparison of the two fire assay techniques for Au, Pt and Pd was difficult as the number of data points was low and the variance within each technique across laboratories was too high. In general, PbFA-based methods for Au, Pt and Pd produced more accurate and precise results than those by NiS fusion and the data support PbFA detection limits for a 5–10 g sample of 1, 0.1 and 0.5 ppb for Au, Pt and Pd, respectively. A PbFA dataset for Rh demonstrated that this element is not recovered efficiently using an Ag inquart. Measurement of Rh by INAA rather than ICP-MS following NiS fusion facilitates detection below 1 ppb to
c.
0.1–0.2 ppb. NiS/ICP-MS results for Ru, Os and Ir support detection limits of 1–2, 2–3 and 0.1 ppb, respectively; mean precision for these elements is in the range 10–15% RSD. Recovery of Os was very low by one laboratory, probably caused by its volatilization as OsO
4
during final digestion in the NiS procedure. As expected, recovery of the analytes by aqua regia was low and highly variable across the different matrices for Pt, Ru, Os and Ir but that for Au and Pd was often >80%; prior roasting of the samples had mixed effects.
Lithostratigraphic controls on recharge to the Chalk aquifer of Southern England
Authors: Gallagher Alexander J. , Rutter Helen K. , Buckley David K. , Molyneux Ian
Published: May 2012

Newly developed borehole closed circuit television (CCTV) lighting has shown that films of water can develop on open borehole walls at discrete levels within the deep unsaturated zone of the chalk, the levels being associated with marl horizons. The CCTV images, together with jacking tensiometers, have been used to observe unsaturated zone processes in selected boreholes. Work focused on two catchments in southern England, the Pang in Berkshire and the Brighton ‘block’ in Sussex. Deep jacking tensiometers were used to measure the associated pressure head (matric potential). The data suggest that recharge to the water table occurs through the matrix, throughout the year. The data also suggest that marl seams can influence recharge processes significantly, creating horizons with high matric potential. As a result, fracture flow and storage could be more important in chalk sequences where they are abundant and well developed.
Earth fissure formation from groundwater pumping and the influence of a stiff upper cemented layer
Authors: Budhu Muniram , Adiyaman Ibrahim
Published: May 2012

Typical soil profiles in arid and semi-arid regions where groundwater is pumped consist of geological materials that vary from uncemented soils to rock. A finite-element analysis using a 20 m thick stiff cemented top layer over a 400 m thick aquifer is used to study how the cemented layer affects earth fissure initiation. This paper presents the results of this study on the key parameters influencing earth fissure formation in a soil profile with a top cemented layer. Three scenarios, each representing three cementation strength parameters, are investigated. A method based on the gradient of the slope of the subsidence bowl is proposed to determine earth fissure initiation. It is shown that earth fissures will not form for gradients below 8 × 10
−5
. The gradient at which an earth fissure would form depends on the cementation strength and tensile strength of the upper cemented alluvium layer. A highly cemented upper alluvium layer is more prone to earth fissure formation than an uncemented one. However, if the top layer is stiff enough to be classified as a ‘rock’, it will be less prone to earth fissure initiation when the cementation increases.
The accuracy of sand and gravel reserve estimates
Authors: Wardrop D. R.
Published: May 2012

In 1999 the author reported the results of an 18 year study into the accuracy of sand and gravel reserve calculations. Since that time some changes have been made in the company’s resource investigation practices in certain types of deposit, and the data gathering has continued. The paper presents the results of significantly more data than previously, considered on their own and in combination with those from the first exercise. The analysis shows closely similar outcomes in respect of accuracies, the distribution of results, and the magnitude of excursions from the bulk of results. Conclusions and the statistics from the 1999 study are supported by the greater volume of data, and it can be suggested that attempting to improve accuracy by the last few per cent could be disproportionately expensive.
Some observations about man-made features on natural terrain in Hong Kong
Authors: Styles K. A. , Law M. H.
Published: May 2012

Much of Hong Kong is currently undeveloped and consists of vegetated, relatively steep hillsides, which are considered to be natural terrain. However, in many of these areas there is evidence in old aerial photographs of man-made features, which for the last 30–40 years or so have been hidden by dense vegetation. Before the 1970s the vegetation was considerably less dense than today and much of the ground surface was bare and clearly apparent. Preliminary study of old aerial photographs indicates some 10 types of man-made features, including agricultural, military, mining, prospecting, and other activities. Some are fairly recent, but relatively surprising is the widespread evidence of old to ancient land management practices, particularly on the more remote, elevated steep terrain away from existing villages. These features include stone walls, stone structures and a variety of stone terraces and unsupported earthen step-form terraces, some of which may have their origins with pre-Chinese aboriginal hill tribes. Their distribution, nature and occurrence provide an insight into the history of human settlement in Hong Kong, which is generally unknown within the earth science and engineering communities. These man-made features occur over extensive areas, with many on steep slopes and in natural drainage lines, and with some stone walls and agricultural terraces in excess of 3 m in height. These features should be recognized during natural terrain landslide hazard assessments and other engineering geological and geotechnical studies.
Subsidence map of underground mining influence for urban planning: an example from the Czech Republic
Authors: Marschalko Marian , Yilmaz Işık , Bednárik Martin , Kubečka Karel , Bouchal Tomáš , Závada Jaroslav
Published: May 2012

The objective of this study is to produce a subsidence map linked to underground mining influence in a mining region. Ground subsidence represents the most important characteristic of a subsidence basin. However, ground subsidence itself does not carry information on geohazards by means of the impacts on the built-up area. Based on long-term experience and studies carried out, three basic subsidence intervals of varying influence were proposed. The lowest degree of undermining influence is connected with subsidence up to 12 cm; the second category is for subsidence from 12 to 100 cm, where constructions are considered possible under certain conditions but special technological procedures must be adhered to; and the third category of hazard is for subsidence over 100 cm. The study was implemented in the largest mining region (black coal deep mining) of the Czech Republic, in the locality of Orlova, Petrvald and Karvina. The study also involved an overall evaluation of subsidence influence, its variation with time, its relation to the current built-up area and to the future built-up area according to the land use plan, and its relation to engineering-geological zones and landslides.
Animation cartography—intrinsic reconstruction of shape and motion
Authors: Tevs Art , Berner Alexander , Wand Michael , Ihrke Ivo , Bokeloh Martin , Kerber Jens , Seidel Hans-Peter
Published: May 2012

In this article, we consider the problem of animation reconstruction, that is, the reconstruction of shape and motion of a deformable object from dynamic 3D scanner data, without using user-provided template models. Unlike previous work that addressed this problem, we do not rely on locally convergent optimization but present a system that can handle fast motion, temporally disrupted input, and can correctly match objects that disappear for extended time periods in acquisition holes due to occlusion. Our approach is motivated by cartography: We first estimate a few landmark correspondences, which are extended to a dense matching and then used to reconstruct geometry and motion. We propose a number of algorithmic building blocks: a scheme for tracking landmarks in temporally coherent and incoherent data, an algorithm for robust estimation of dense correspondences under topological noise, and the integration of local matching techniques to refine the result. We describe and evaluate the individual components and propose a complete animation reconstruction pipeline based on these ideas. We evaluate our method on a number of standard benchmark datasets and show that we can obtain correct reconstructions in situations where other techniques fail completely or require additional user guidance such as a template model.
MultiFLIP for energetic two-phase fluid simulation
Authors: Boyd Landon , Bridson Robert
Published: May 2012

Physically-based liquid animations often ignore the influence of air, giving up interesting behavior. We present a new method which treats both air and liquid as incompressible, more accurately reproducing the reality observed at scales relevant to computer animation. The Fluid Implicit Particle (FLIP) method, already shown to effectively simulate incompressible fluids with low numerical dissipation, is extended to two-phase flow by associating a phase bit with each particle. The liquid surface is reproduced at each time step from the particle positions, which are adjusted to prevent mixing near the surface and to allow for accurate surface tension. The liquid surface is adjusted around small-scale features so they are represented in the grid-based pressure projection, while separate, loosely coupled velocity fields reduce unwanted influence between the phases. The resulting scheme is easy to implement, requires little parameter tuning, and is shown to reproduce lively two-phase fluid phenomena.
The notion of a rational convex program, and an algorithm for the arrow-debreu Nash bargaining game
Authors: Vazirani Vijay V.
Published: May 2012

We introduce the notion of a
rational convex program (RCP)
and we classify the known RCPs into two classes: quadratic and logarithmic. The importance of rationality is that it opens up the possibility of computing an optimal solution to the program via an algorithm that is either combinatorial or uses an LP-oracle. Next, we define a new Nash bargaining game, called ADNB, which is derived from the linear case of the Arrow-Debreu market model. We show that the convex program for ADNB is a logarithmic RCP, but unlike other known members of this class, it is nontotal.

Our main result is a combinatorial, polynomial-time algorithm for ADNB. It turns out that the reason for infeasibility of logarithmic RCPs is quite different from that for LPs and quadratic RCPs. We believe that our ideas for surmounting the new difficulties will be useful for dealing with other nontotal RCPs as well. We give an application of our combinatorial algorithm for ADNB to an important “fair” throughput allocation problem on a wireless channel. Finally, we present a number of interesting questions that the new notion of RCP raises.
A theory of goal-oriented communication
Authors: Goldreich Oded , Juba Brendan , Sudan Madhu
Published: May 2012

We put forward a general theory of
goal-oriented communication
, where communication is not an end in itself, but rather a means to achieving some
goals
of the communicating parties. Focusing on goals provides a framework for addressing the problem of potential “misunderstanding” during communication, where the misunderstanding arises from lack of initial agreement on what protocol and/or language is being used in communication. In this context, “reliable communication” means overcoming any initial misunderstanding between parties towards achieving a given goal. Despite the enormous diversity among the goals of communication, we propose a simple model that captures all goals.

In the simplest form of communication we consider, two parties, a
user
and a
server
, attempt to communicate with each other in order to achieve some goal of the user. We show that
any goal
of communication can be modeled mathematically by introducing a third party, which we call the
referee
, who hypothetically monitors the conversation between the user and the server and determines whether or not the goal has been achieved. Potential misunderstanding between the players is captured by allowing each player (the user/server) to come from a (potentially infinite) class of players such that each player is unaware which instantiation of the other it is talking to. We identify a main concept, which we call
sensing
, that allows goals to be achieved even under misunderstanding. Informally,
sensing
captures the user's ability (potentially using help from the server) to simulate the referee's assessment on whether the communication is achieving the goal. We show that when the user can sense progress, the goal of communication can be achieved despite initial misunderstanding. We also show that in certain settings sensing is necessary for overcoming such initial misunderstanding.

Our results significantly extend the scope of the investigation started by Juba and Sudan (STOC 2008) who studied the foregoing phenomenon in the case of a single specific goal. Our study shows that their main suggestion, that misunderstanding can be detected and possibly corrected by focusing on the goal, can be proved in full generality.
Implicit dynamic frames
Authors: Smans Jan , Jacobs Bart , Piessens Frank
Published: May 2012

An important, challenging problem in the verification of imperative programs with shared, mutable state is the frame problem in the presence of data abstraction. That is, one must be able to specify and verify upper bounds on the set of memory locations a method can read and write without exposing that method's implementation.

Separation logic is now widely considered the most promising solution to this problem. However, unlike conventional verification approaches, separation logic assertions cannot mention heap-dependent expressions from the host programming language, such as method calls familiar to many developers. Moreover, separation logic-based verifiers are often based on symbolic execution. These symbolic execution-based verifiers typically do not support non-separating conjunction, and some of them rely on the developer to explicitly fold and unfold predicate definitions. Furthermore, several researchers have wondered whether it is possible to use verification condition generation and standard first-order provers instead of symbolic execution to automatically verify conformance with a separation logic specification.

In this article, we propose a variant of separation logic called
implicit dynamic frames
that supports heap-dependent expressions inside assertions. Conformance with an implicit dynamic frames specification can be checked by proving the validity of a number of first-order verification conditions. To show that these verification conditions can be discharged automatically by standard first-order provers, we have implemented our approach in a verifier prototype and have used this prototype to verify several challenging examples from related work. Our prototype automatically folds and unfolds predicate definitions, as required, during the proof and can reason about non-separating conjunction which is used in the specifications of some of these examples. Finally, we prove the soundness of the approach.
Techniques for knowledge acquisition in dynamically changing environments
Authors: Fisch Dominik , Fisch Dominik , Jänicke Martin , Kalkowski Edgar , Sick Bernhard
Published: May 2012

Intelligent agents often have the same or similar tasks and sometimes they cooperate to solve a given problem. These agents typically know how to observe their local environment and how to react on certain observations, for instance, and this knowledge may be represented in form of rules. However, many environments are dynamic in the sense that from time to time novel rules are required or old rules become obsolete. In this article we propose and investigate new techniques for knowledge acquisition by novelty detection and reaction as well as obsoleteness detection and reaction that an agent may use for self-adaptation to new situations. For that purpose we consider classifiers based on probabilistic rules. Premises of new rules are learned autonomously while conclusions are either obtained from human experts or from other agents which have learned appropriate rules in the past. By means of knowledge exchange, agents will efficiently be enabled to cope with situations they were not confronted with before. This kind of collaborative intelligence follows the human archetype: Humans are able to learn from each other by communicating learned rules. We demonstrate some properties of the knowledge acquisition techniques using artificial data as well as data from the field of intrusion detection.
A survey of view selection methods
Authors: Mami Imene , Bellahsene Zohra
Published: May 2012

Materialized view selection is a critical problem in many applications such as query processing, data warehousing, distributed and semantic web databases, etc. We refer to the problem of selecting an appropriate set of materialized views as the view selection problem. Many different view selection methods have been proposed in the literature to address this issue. The present paper provides a survey of view selection methods. It defines a framework for highlighting the view selection problem by identifying the main dimensions that are the basis in the classification of view selection methods. Based on this classification, this study reviews most of the view selection methods by identifying respective potentials and limits.
T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis
Authors: Facciabene Andrea , Motz Gregory T. , Coukos George
Published: May 2012

T-regulatory cells (Tregs) are found infiltrating tumors in a vast array of tumor types, and tumor-infiltrating Tregs are often associated with a poor clinical outcome. Tregs are potent immunosuppressive cells of the immune system that promote progression of cancer through their ability to limit antitumor immunity and promote angiogenesis. Here, we discuss the ways in which Tregs suppress the antitumor immune response and elaborate on our recent discovery that Tregs make significant direct contributions to tumor angiogenesis. Further, we highlight several current therapies aimed at eliminating Tregs in cancer patients. Given the multifaceted role of Tregs in cancer, a greater understanding of their functions will ultimately strengthen future therapies. Cancer Res; 72(9); 2162–71. ©2012 AACR.
Epigenetic Resensitization to Platinum in Ovarian Cancer
Authors: Matei Daniela , Fang Fang , Shen Changyu , Schilder Jeanne , Arnold Alesha , Zeng Yan , Berry William A. , Huang Tim , Nephew Kenneth P.
Published: May 2012

Preclinical studies have shown that hypomethylating agents reverse platinum resistance in ovarian cancer. In this phase II clinical trial, based upon the results of our phase I dose defining study, we tested the clinical and biologic activity of low-dose decitabine administered before carboplatin in platinum-resistant ovarian cancer patients. Among 17 patients with heavily pretreated and platinum-resistant ovarian cancer, the regimen induced a 35% objective response rate (RR) and progression-free survival (PFS) of 10.2 months, with nine patients (53%) free of progression at 6 months. Global and gene-specific DNA demethylation was achieved in peripheral blood mononuclear cells and tumors. The number of demethylated genes was greater (P < 0.05) in tumor biopsies from patients with PFS more than 6 versus less than 6 months (311 vs. 244 genes). Pathways enriched at baseline in tumors from patients with PFS more than 6 months included cytokine–cytokine receptor interactions, drug transporters, and mitogen-activated protein kinase, toll-like receptor and Jak-STAT signaling pathways, whereas those enriched in demethylated genes after decitabine treatment included pathways involved in cancer, Wnt signaling, and apoptosis (P < 0.01). Demethylation of MLH1, RASSF1A, HOXA10, and HOXA11 in tumors positively correlated with PFS (P < 0.05). Together, the results of this study suggest that low-dose decitabine altered DNA methylation of genes and cancer pathways, restoring sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resulting in a high RR and prolonged PFS. Cancer Res; 72(9); 2197–205. ©2012 AACR.
Crizotinib for ALK-Rearranged Non–Small Cell Lung Cancer: A New Targeted Therapy for a New Target
Authors: Gandhi Leena , Jänne Pasi A.
Published: May 2012

Crizotinib (PF02341066, Xalkori; Pfizer) was recently approved by the U.S. Food and Drug Administration for treatment of ALK-positive non–small cell lung cancer (NSCLC) as defined by a jointly approved diagnostic test using a break-apart fluorescence in situ hybridization assay. The approval was based on dramatic response rates in ALK-positive NSCLC patients of 54% to 61% in phase I and II trials. To date, the overall disease control rates in these trials are close to 90%. Progression-free survival approaches 10 months. This review focuses on the ALK-inhibitory activity of crizotinib in preclinical and clinical trials that led to approval, as well as the diagnostic methods to classify patients with ALK-positive NSCLC. Although these patients represent a small subset of all patients with NSCLC, the rapid time course from identification of this unique target to an approved targeted therapy with striking benefit serves as a paradigm for the development of targeted therapeutics in an era of personalized medicine. Clin Cancer Res; 18(14); 3737–42. ©2012 AACR.
Ribonucleotide Reductase Large Subunit (RRM1) Gene Expression May Predict Efficacy of Adjuvant Mitotane in Adrenocortical Cancer
Authors: Volante Marco , Terzolo Massimo , Fassnacht Martin , Rapa Ida , Germano Antonina , Sbiera Silviu , Daffara Fulvia , Sperone Paola , Scagliotti Giorgio , Allolio Bruno , Papotti Mauro , Berruti Alfredo
Published: May 2012

Purpose: Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane.

Experimental Design: Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests.

Results: ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane.

Conclusion: Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC. Clin Cancer Res; 18(12); 3452–61. ©2012 AACR.
LY2109761 Attenuates Radiation-Induced Pulmonary Murine Fibrosis via Reversal of TGF-β and BMP-Associated Proinflammatory and Proangiogenic Signals
Authors: Flechsig Paul , Dadrich Monika , Bickelhaupt Sebastian , Jenne Jürgen , Hauser Kai , Timke Carmen , Peschke Peter , Hahn Eric W. , Gröne Hermann-Josef , Yingling Jonathan , Lahn Michael , Wirkner Ute , Huber Peter E.
Published: May 2012

Purpose: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-β signaling is considered to play an important role.

Experimental Design: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-β receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Noninvasive lung imaging including volume computed tomography (VCT) and MRI was conducted 6, 16, and 20 weeks after irradiation and was correlated to histologic findings. Expression profiling analysis and protein analysis was conducted in human primary fibroblasts.

Results: Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced life span. VCT, MRI, and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically, we found that LY2109761 reduced p-SMAD2 and p-SMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and noncanonical TGF-β signaling and downstream signaling of bone morphogenetic proteins (BMP). LY2109761 also suppressed radiation-induced inflammatory [e.g., interleukin (IL)-6, IL-7R, IL-8] and proangiogenic genes (e.g., ID1) indicating that LY2109761 achieves its antifibrotic effect by suppressing radiation-induced proinflammatory, proangiogenic, and profibrotic signals.

Conclusion: Small-molecule inhibitors of the TGF-β receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis. Clin Cancer Res; 18(13); 3616–27. ©2012 AACR.
A Phase I Pharmacokinetic and Pharmacodynamic Study of CHR-3996, an Oral Class I Selective Histone Deacetylase Inhibitor in Refractory Solid Tumors
Authors: Banerji Udai , van Doorn Leni , Papadatos-Pastos Dionysis , Kristeleit Rebecca , Debnam Phillip , Tall Matthew , Stewart Adam , Raynaud Florence , Garrett Michelle Dawn , Toal Martin , Hooftman Leon , De Bono Johann Sebastian , Verweij Jaap , Eskens Ferry ALM
Published: May 2012

Purpose: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.

Patients and Methods: CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography–tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.

Results: Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.

Conclusions: Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials. Clin Cancer Res; 18(9); 2687–94. ©2012 AACR.
Acquisition of Resistance of Pancreatic Cancer Cells to 2-Methoxyestradiol Is Associated with the Upregulation of Manganese Superoxide Dismutase
Authors: Zhou Jianhong , Du Yuchun
Published: May 2012

Acquired resistance of cancer cells to anticancer drugs or ionizing radiation (IR) is one of the major obstacles in cancer treatment. Pancreatic cancer is an exceptional aggressive cancer, and acquired drug resistance in this cancer is common. Reactive oxygen species (ROS) play an essential role in cell apoptosis, which is a key mechanism by which radio- or chemotherapy induce cell killing. Mitochondria are the major source of ROS in cells. Thus, alterations in the expression of mitochondrial proteins, involved in ROS production or scavenging, may be closely linked to the resistance of cancer cells to radio- or chemotherapy. In the present study, we generated a stable cell line by exposing pancreatic cancer cells to increasing concentrations of ROS-inducing, anticancer compound 2-methoxyestradiol (2-ME) over a 3-month period. The resulting cell line showed strong resistance to 2-ME and contained an elevated level of ROS. We then used a comparative proteomics method to profile the differential expression of mitochondrial proteins between the parental and the resistant cells. One protein identified to be upregulated in the resistant cells was manganese superoxide dismutase (SOD2), a mitochondrial protein that converts superoxide radicals to hydrogen peroxides. Silencing of SOD2 resensitized the resistant cells to 2-ME, and overexpression of SOD2 led the parental cells to 2-ME resistance. In addition, the 2-ME–resistant cells also showed resistance to IR. Our results suggest that upregulation of SOD2 expression is an important mechanism by which pancreatic cancer cells acquire resistance to ROS-inducing, anticancer drugs, and potentially also to IR. Mol Cancer Res; 10(6); 768–77. ©2012 AACR.
Age-Related Decline in Reendothelialization Capacity of Human Endothelial Progenitor Cells Is Restored by Shear Stress
Authors: Xia Wen Hao , Yang Zhen , Xu Shi Yue , Chen Long , Zhang Xiao Yu , Li Jing , Liu Xing , Qiu Yan Xia , Shuai Xin Tao , Tao Jun
Published: May 2012

Aging is associated with dysfunction of endothelial progenitor cells (EPCs), and shear stress has a beneficial impact on EPC function; however, the effects of aging and shear stress on the endothelial repair capacity of EPCs after arterial injury have not been reported. Here we investigated the influence of aging and shear stress on the reendothelialization capacity of human EPCs and the related molecular mechanism. Compared with EPCs isolated from young subjects, EPCs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced reendothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury. Shear stress pretreatment enhances the migration, adhesion, and reendothelialization capacity in both young and elderly EPCs; however, it was to a greater extent in EPCs from the elderly. Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1-induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs. Shear stress treatment upregulated CXCR4 expression and phosphorylation and, importantly, restored the stromal cell-derived factor 1/CXCR4-dependent Janus kinase 2 phosphorylation in the elderly EPCs. Furthermore, short hairpin RNA-mediated knockdown of CXCR4 expression or pretreatment with Janus kinase 2 inhibitor diminished the enhancement in the migration, adhesion, and reendothelialization capacity of the elderly EPCs from shear stress treatments. Thus, our study demonstrates that upregulation of the CXCR4/Janus kinase 2 pathway by shear stress contributes to the enhanced reendothelialization capacity of EPCs from elderly men.
Meta-Analysis of Dose-Response Relationships for Hydrochlorothiazide, Chlorthalidone, and Bendroflumethiazide on Blood Pressure, Serum Potassium, and Urate
Authors: Peterzan Mark A. , Hardy Rebecca , Chaturvedi Nish , Hughes Alun D.
Published: May 2012

Thiazide and thiazide-like diuretics are widely used in the management of hypertension, but recently the equivalence of hydrochlorothiazide and chlorthalidone for blood pressure (BP) lowering and prevention of cardiovascular disease has been questioned. We performed a meta-analysis to characterize the dose-response relationships for 3 commonly prescribed thiazide diuretics, hydrochlorothiazide, chlorthalidone, and bendroflumethiazide, on BP, serum potassium, and urate. Randomized, double-blind, parallel placebo-controlled trials meeting the following criteria, ≥2 different monotherapy dose arms, follow-up duration ≥4 weeks, and baseline washout of medication ≥2 weeks, were identified using Embase (1980–2010 week 50), Medline (1950–2010 November week 3), metaRegister of Controlled Trials, and Cochrane Central. A total of 26 trials examined hydrochlorothiazide, 3 examined chlorthalidone, and 1 examined bendroflumethiazide. Studies included a total of 4683 subjects in >53 comparison arms. Meta-regression of the effect of thiazides on systolic BP showed a log-linear relationship with a potency series: bendroflumethiazide>chlorthalidone>hydrochlorothiazide. The estimated dose of each drug predicted to reduce systolic BP by 10 mm Hg was 1.4, 8.6, and 26.4 mg, respectively, and there was no evidence of a difference in maximum reduction of systolic BP by high doses of different thiazides. Potency series for diastolic BP, serum potassium, and urate were similar to those seen for systolic BP. Hydrochlorothiazide, chlorthalidone, and bendroflumethiazide have markedly different potency. This may account for differences in the antihypertensive effect between hydrochlorothiazide and chlorthalidone using standard dose ranges.
A Detailed Normal-Mode Energetics of the General Circulation of the Atmosphere
Authors: Marques C. A. F. , Castanheira J. M.
Published: May 2012

An energetics formulation is here introduced that enables an explicit evaluation for the conversion rates between available potential energy and kinetic energy, the nonlinear interactions of both energy forms, and their generation and dissipation rates, in both the zonal wavenumber and vertical mode domains. The conversion rates between available potential energy and kinetic energy are further decomposed into the contributions by the rotational (Rossby) and divergent (gravity) components of the circulation field. The computed energy terms allow one to formulate a detailed energy cycle describing the flow of energy among the zonal mean and eddy components, and also among the barotropic and baroclinic components. This new energetics formulation is a development of the 3D normal-mode energetics scheme. The new formulation is applied on an assessment of the energetics of winter (December–February) circulation in the 40-yr ECMWF Re-Analysis (ERA-40), the 25-yr Japan Meteorological Agency Reanalysis (JRA-25), and the NCEP–Department of Energy Reanalysis 2 (NCEP-R2) datasets.
Propensity Score Analysis With Fallible Covariates
Authors: Raykov Tenko
Published: May 2012

A latent variable modeling approach that permits estimation of propensity scores in observational studies containing fallible independent variables is outlined, with subsequent examination of treatment effect. When at least one covariate is measured with error, it is indicated that the conventional propensity score need not possess the desirable property of bias adjustment with respect to possible prior group differences. For this setting, a modified propensity score is discussed that is based on true scores on fallible covariates and perfectly measured covariates, if available. This modified score can be recommended to use for average treatment effect evaluation in circumstances where selection into groups occurs on corresponding underlying latent dimensions measured with error. The proposed propensity score procedure is illustrated with an example.
Measurement Invariance for Latent Constructs in Multiple Populations
Authors: Raykov Tenko , Marcoulides George A. , Li Cheng-Hsien
Published: May 2012

Popular measurement invariance testing procedures for latent constructs evaluated by multiple indicators in distinct populations are revisited and discussed. A frequently used test of factor loading invariance is shown to possess serious limitations that in general preclude it from accomplishing its goal of ascertaining this invariance. A process of mean intercept invariance evaluation is subsequently examined, and it is indicated that within this framework there is no statistical test available for group identity in them. Rather than pursuing these popular and widely used invariance testing procedures, it is recommended that empirical studies on constructs in multiple populations be concerned in general with alternative measurement invariance examination and ensuring the inclusion of their invariance conditions in models aimed at investigating group differences and similarities in latent means, variances, and interrelationships. The discussion is illustrated using data from a cognitive intervention study.
How to win friendship and trust by influencing people’s feelings: An investigation of interpersonal affect regulation and the quality of relationships
Authors: Niven Karen , Holman David , Totterdell Peter
Published: May 2012

Research suggests that people deliberately try to improve others’ feelings in a variety of social contexts. However, little is known about whether and how interpersonal affect regulation influences the quality of people’s relationships. Two applied social network studies investigated the relational effects of interpersonal affect regulation. In Study 1 attempts to improve others’ affect among grocery store employees were associated with both regulatory targets’ and agents’ perceptions of friendship and trust. In Study 2 we replicated this finding among staff and prisoners in a high-security prison. Additionally, we showed that these associations were mediated by positive changes to regulatory targets’ and agents’ affect. The results provide insights into the social consequences of interpersonal affect regulation and help to elucidate the factors influencing the formation and maintenance of high-quality relationships.
Disaggregating Noncompliance
Authors: Fuhrmann Matthew , Berejikian Jeffrey D.
Published: May 2012

Why do states make disingenuous treaty commitments? Under what conditions will countries refrain from entering cooperative agreements with which they do not expect to comply? This article addresses these questions by analyzing how states that are pursuing nuclear weapons treat the nuclear Nonproliferation Treaty (NPT). The authors develop a distinction between two types of noncooperative behavior. The first is cheating while part of the NPT (predation) and the second is pursuing nuclear weapons outside of the treaty (abstention). The authors’ argument is that democratic proliferators are more likely to abstain because executives in democracies are domestically constrained to a greater degree than authoritarian leaders. Statistical tests in a sample of all countries with active nuclear weapons programs from 1968 to 2004 provide evidence in favor of our argument. Controlling for confounding variables and the factors that motivate states to pursue nuclear weapons, the results show that states with greater constraints on executive authority are less likely to choose predation. Yet, electoral mandates do not appear to dissuade governments from making disingenuous treaty commitments. These findings have important implications for nuclear proliferation, the credibility of international commitments, and efforts to link domestic political institutions with international outcomes.
Locating Praxis for Equity in Mathematics
Authors: Wager Anita A. , Foote Mary Q.
Published: May 2012

In this article, the authors report on a study that contributes to a growing body of literature that considers professional development (PD) focused on mathematics and equity. The authors examined how lived experiences provide a foundation for the ways teachers take up equity in their mathematics teaching practice. The constructs of praxis and figured worlds are used to frame the study. In particular, teachers’ identities in the figured worlds of standards-based mathematics, multicultural education, and equitable mathematics pedagogy were explored with a focus on how they contributed to where the teachers located praxis for equity in mathematics. The teachers’ lived experiences and their participation in the PD were analyzed with an eye toward teachers’ evolving identities and how they contribute to where teachers located praxis.