bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrafirm Competition in Multinational Corporations: Towards a Political Framework
Authors: Becker-Ritterspach Florian , Dörrenbächer Christoph
Published: August 2009

Intrafirm competition is one of the most contentious issues in multinational companies (MNCs). It occurs when different subsidiaries of an MNC overlap with regard to products, markets or technologies and headquarters try to make use of this overlap by coercive comparisons. It also occurs when a subsidiary takes an initiative that challenges an existing mandate of another subsidiary. Despite the large potential for conflict in intrafirm competition, neither the literature on intrafirm competition nor the more extensive literature on subsidiary mandate change has paid systematic attention to the political dimension of intrafirm competition. Therefore, a political framework to study intrafirm competition is developed in this paper, drawing on classical organisational politics approaches. The focus of this framework is on core actors in intrafirm competition, i.e. headquarters and subsidiary executives, their interest-based strategies, and their interaction in micro-political games evolving around intrafirm competition.
Issue Selling and Bargaining Power in Intrafirm Competition: The Differentiating Impact of the Subsidiary Management Composition
Authors: Gammelgaard Jens
Published: August 2009

This paper reports the findings from five case studies on Danish-owned subsidiaries in China and India and demonstrates how a subsidiary's issue-selling strategy influences its bargaining power in intrafirm competition within a multinational corporation. Issue-selling strategies of subsidiaries involve various activities aiming at (a) making the parent company understand an issue, (b) attracting parent-company attention to an issue, and (c) lobbying for an issue at the parent company. Next to illustrating these activities, the empirical part of the paper shows that subsidiaries managed by parent-company nationals have more bargaining power than subsidiaries managed by host-country nationals. To begin with, parent-company national subsidiary managers are better at translating the context-specific information deriving from cultural distances between the parent company and the subsidiary. Second, they are better at packaging the issue in order to match parent-company formalised application requirements. Further, they are better at framing the issue to match the parent-company goals and objectives. And last, they often have closer relationships with decision makers within the parent company.
Understanding the effect of aluminium on microstructure in low level nitrogen steels
Authors: Palizdar Y. , Scott A. J. , Cochrane R. C. , Brydson R.
Published: August 2009

The influence of aluminium on steel microstructure has been examined in low nitrogen steels. There is a lack of knowledge in the literature about the effect of aluminium on steel microstructure at levels greater than 0·1 wt-%. This has not been important as aluminium additions are typically low, with the aluminium being added as a deoxidant and grain refining element. However, recently aluminium has been added at significantly higher levels (0·5–2 wt-%) in new types of transformation induced plasticity (TRIP) steels to delay the bainitic transformation and give a dual phase microstructure. Furthermore, recent studies have shown that aluminium can be considered as a solid solution strengthener in low nitrogen steels. To investigate the effect of aluminium on steel microstructure, steels of differing aluminium composition between 0·02 and 0·98 wt-% have been prepared and investigated by metallography and EBSD. The results show that aluminium has a significant effect on ferrite grain size and ferrite grain size distribution.
Thrombin induces the expression of oncostatin M via AP-1 activation in human macrophages: a link between coagulation and inflammation
Authors: Kastl Stefan P. , Speidl Walter S. , Katsaros Katharina M. , Kaun Christoph , Rega Gersina , Assadian Afshin , Hagmueller Georg W. , Hoeth Martina , de Martin Rainer , Ma Yongsheng , Maurer Gerald , Huber Kurt , Wojta Johann
Published: August 2009

Macrophages as inflammatory cells are involved in the pathogenesis of atherosclerosis that today is recognized as an inflammatory disease. Activation of coagulation leads to the late complication of atherosclerosis, namely atherothrombosis with its clinical manifestations stroke, unstable angina, myocardial infarction, and sudden cardiac death. Thus inflammation and coagulation play fundamental roles in the pathogenesis of atherosclerosis. We show that the coagulation enzyme thrombin up-regulates oncostatin M (OSM), a pleiotropic cytokine implicated in the pathophysiology of vascular disease, in human monocyte-derived macrophages (MDMs) up to 16.8-fold. A similar effect was seen in human peripheral blood monocytes and human plaque macrophages. In MDMs, the effect of thrombin on OSM was abolished by PPACK and mimicked by a PAR-1–specific peptide. Thrombin induced phosphorylation of ERK1/2 and p38 in MDMs. The ERK1/2 inhibitor PD98059 blocked the effect of thrombin on OSM production in MDMs, whereas the p38 inhibitor SB202190 had no effect. Thrombin induced translocation of c-fos and c-jun to the nucleus of MDMs. Using OSM promoter–luciferase reporter constructs transfected into MDMs, we show that a functional AP-1 site is required for promoter activation by thrombin. We present another link between coagulation and inflammation, which could impact on the pathogenesis of atherosclerosis.
Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells
Authors: Kaufman Dan S.
Published: August 2009

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide remarkable cellular platforms to better understand human hematopoiesis and to develop clinically applicable hematopoietic cell–based therapies. Over the past decade, hESCs have been used to characterize molecular and cellular mechanisms underpinning the differentiation of hematopoietic progenitors and mature, functional hematopoietic cells. These advances are now poised to lead to clinical translation of hESC- and iPSC-derived hematopoietic cells for novel therapies in the next few years. On the basis of areas of recent success, initial clinical use of hematopoietic cells derived from human pluripotent stem cells will probably be in the areas of transfusion therapies (erythrocytes and platelets) and immune therapies (natural killer cells). In contrast, efficient development and isolation of hematopoietic stem cells capable of long-term, multilineage engraftment still remains a significant challenge. Technical, safety, and regulatory concerns related to clinical applications of human PSCs must be appropriately addressed. However, proper consideration of these issues should facilitate and not inhibit clinical translation of new therapies. This review outlines the current status of hematopoietic cell development and what obstacles must be surmounted to bring hematopoietic cell therapies from human PSCs from “bench to bedside.”
Which missing value imputation method to use in expression profiles: a comparative study and two selection schemes
Authors: Brock Guy N , Shaffer John R , Blakesley Richard E , Lotz Meredith J , Tseng George C
Published: August 2009

Background

Gene expression data frequently contain missing values, however, most down-stream analyses for microarray experiments require complete data. In the literature many methods have been proposed to estimate missing values via information of the correlation patterns within the gene expression matrix. Each method has its own advantages, but the specific conditions for which each method is preferred remains largely unclear. In this report we describe an extensive evaluation of eight current imputation methods on multiple types of microarray experiments, including time series, multiple exposures, and multiple exposures × time series data. We then introduce two complementary selection schemes for determining the most appropriate imputation method for any given data set.

Results

We found that the optimal imputation algorithms (LSA, LLS, and BPCA) are all highly competitive with each other, and that no method is uniformly superior in all the data sets we examined. The success of each method can also depend on the underlying "complexity" of the expression data, where we take complexity to indicate the difficulty in mapping the gene expression matrix to a lower-dimensional subspace. We developed an entropy measure to quantify the complexity of expression matrixes and found that, by incorporating this information, the entropy-based selection (EBS) scheme is useful for selecting an appropriate imputation algorithm. We further propose a simulation-based self-training selection (STS) scheme. This technique has been used previously for microarray data imputation, but for different purposes. The scheme selects the optimal or near-optimal method with high accuracy but at an increased computational cost.

Conclusion

Our findings provide insight into the problem of which imputation method is optimal for a given data set. Three top-performing methods (LSA, LLS and BPCA) are competitive with each other. Global-based imputation methods (PLS, SVD, BPCA) performed better on mcroarray data with lower complexity, while neighbour-based methods (KNN, OLS, LSA, LLS) performed better in data with higher complexity. We also found that the EBS and STS schemes serve as complementary and effective tools for selecting the optimal imputation algorithm.
Inferring gene expression dynamics via functional regression analysis
Authors: Müller Hans-Georg , Chiou Jeng-Min , Leng Xiaoyan
Published: August 2009

Background

Temporal gene expression profiles characterize the time-dynamics of expression of specific genes and are increasingly collected in current gene expression experiments. In the analysis of experiments where gene expression is obtained over the life cycle, it is of interest to relate temporal patterns of gene expression associated with different developmental stages to each other to study patterns of long-term developmental gene regulation. We use tools from functional data analysis to study dynamic changes by relating temporal gene expression profiles of different developmental stages to each other.

Results

We demonstrate that functional regression methodology can pinpoint relationships that exist between temporary gene expression profiles for different life cycle phases and incorporates dimension reduction as needed for these high-dimensional data. By applying these tools, gene expression profiles for pupa and adult phases are found to be strongly related to the profiles of the same genes obtained during the embryo phase. Moreover, one can distinguish between gene groups that exhibit relationships with positive and others with negative associations between later life and embryonal expression profiles. Specifically, we find a positive relationship in expression for muscle development related genes, and a negative relationship for strictly maternal genes forDrosophila, using temporal gene expression profiles.

Conclusion

Our findings point to specific reactivation patterns of gene expression during theDrosophilalife cycle which differ in characteristic ways between various gene groups. Functional regression emerges as a useful tool for relating gene expression patterns from different developmental stages, and avoids the problems with large numbers of parameters and multiple testing that affect alternative approaches.
Exposure to light enhances pre-adult fitness in two dark-dwelling sympatric species of ants
Authors: Lone Shahnaz Rahman , Sharma Vijay Kumar
Published: August 2009

Background

In insects, circadian clocks play a key role in enhancing fitness by regulating life history traits such as developmental time and adult lifespan. These clocks use environmental light/dark (LD) cycles to fine-tune a wide range of behavioral and physiological processes. To study the effect of environmental LD conditions on pre-adult fitness components, we used two dark-dwelling sympatric species of ants (the night active Camponotus compressus and the day active Camponotus paria), which normally develop underground and have fairly long pre-adult developmental time.

Results

Our results suggest that ants develop fastest as pre-adults when maintained under constant light (LL), followed closely by 12:12 hr light/dark (LD), and then constant darkness (DD). While light exposure alters developmental rates of almost all stages of development, the overall pre-adult development in LL is speeded-up (relative to DD) by ~37% (34 days) in C. compressus and by ~35% (31 days) in C. paria. In LD too, development is faster (relative to DD) by ~29% (26 days) in C. compressus and by ~28% (25 days) in C. paria. Pre-adult viability of both species is also higher under LL and LD compared to DD. While pre-adult development time and viability is enhanced in LL and LD, clutch-size undergoes reduction, at least in C. compressus.

Conclusion

Exposure to light enhances pre-adult fitness in two dark-dwelling species of Camponotus by speeding-up development and by enhancing viability. This suggests that social ants use environmental light/dark cycles to modulate key life history traits such as pre-adult development time and viability.
Comparative metagenomics of Daphnia symbionts
Authors: Qi Weihong , Nong Guang , Preston James F , Ben-Ami Frida , Ebert Dieter
Published: August 2009

Background

Shotgun sequences of DNA extracts from whole organisms allow a comprehensive assessment of possible symbionts. The current project makes use of four shotgun datasets from three species of the planktonic freshwater crustaceans Daphnia: one dataset from clones of D. pulex and D. pulicaria and two datasets from one clone of D. magna. We analyzed these datasets with three aims: First, we search for bacterial symbionts, which are present in all three species. Second, we search for evidence for Cyanobacteria and plastids, which had been suggested to occur as symbionts in a related Daphnia species. Third, we compare the metacommunities revealed by two different 454 pyrosequencing methods (GS 20 and GS FLX).

Results

In all datasets we found evidence for a large number of bacteria belonging to diverse taxa. The vast majority of these were Proteobacteria. Of those, most sequences were assigned to different genera of the Betaproteobacteria family Comamonadaceae. Other taxa represented in all datasets included the genera Flavobacterium, Rhodobacter, Chromobacterium, Methylibium, Bordetella, Burkholderia and Cupriavidus. A few taxa matched sequences only from the D. pulex and the D. pulicaria datasets: Aeromonas, Pseudomonas and Delftia. Taxa with many hits specific to a single dataset were rare. For most of the identified taxa earlier studies reported the finding of related taxa in aquatic environmental samples. We found no clear evidence for the presence of symbiotic Cyanobacteria or plastids. The apparent similarity of the symbiont communities of the three Daphnia species breaks down on a species and strain level. Communities have a similar composition at a higher taxonomic level, but the actual sequences found are divergent. The two Daphnia magna datasets obtained from two different pyrosequencing platforms revealed rather similar results.

Conclusion

Three clones from three species of the genus Daphnia were found to harbor a rich community of symbionts. These communities are similar at the genus and higher taxonomic level, but are composed of different species. The similarity of these three symbiont communities hints that some of these associations may be stable in the long-term.
Impact of Transcription Units rearrangement on the evolution of the regulatory network of gamma-proteobacteria
Authors: González Pérez Abel D , González González Evelyn , Espinosa Angarica Vladimir , Vasconcelos Ana Tereza R , Collado-Vides Julio
Published: August 2009

Background

In the past years, several studies begun to unravel the structure, dynamical properties, and evolution of transcriptional regulatory networks. However, even those comparative studies that focus on a group of closely related organisms are limited by the rather scarce knowledge on regulatory interactions outside a few model organisms, such as E. coli among the prokaryotes.

Results

In this paper we used the information annotated in Tractor_DB (a database of regulatory networks in gamma-proteobacteria) to calculate a normalized Site Orthology Score (SOS) that quantifies the conservation of a regulatory link across thirty genomes of this subclass. Then we used this SOS to assess how regulatory connections have evolved in this group, and how the variation of basic regulatory connection is reflected on the structure of the chromosome. We found that individual regulatory interactions shift between different organisms, a process that may be described as rewiring the network. At this evolutionary scale (the gamma-proteobacteria subclass) this rewiring process may be an important source of variation of regulatory incoming interactions for individual networks. We also noticed that the regulatory links that form feed forward motifs are conserved in a better correlated manner than triads of random regulatory interactions or pairs of co-regulated genes. Furthermore, the rewiring process that takes place at the most basic level of the regulatory network may be linked to rearrangements of genetic material within bacterial chromosomes, which change the structure of Transcription Units and therefore the regulatory connections between Transcription Factors and structural genes.

Conclusion

The rearrangements that occur in bacterial chromosomes-mostly inversion or horizontal gene transfer events – are important sources of variation of gene regulation at this evolutionary scale.
Bioluminescence-based visualization of CD4 T cell dynamics using a T lineage-specific luciferase transgenic model1
Authors: Chewning Joseph H , Dugger Kari J , Chaudhuri Tandra R , Zinn Kurt R , Weaver Casey T
Published: August 2009

Background

Rapid clonal expansion of T cells occurs in response to antigenic challenges. The kinetics of the T cell response has previously been described using tissue-based studies performed at defined time points. Luciferase bioluminescence has recently been utilized for non-invasive analysis ofin vivobiologic processes in real-time.

Results

We have created a novel transgenic mouse model (T-Lux) using a human CD2 mini-gene to direct luciferase expression specifically to the T cell compartment. T-Lux T cells demonstrated normal homing patterns within the intact mouse and following adoptive transfer. Bioluminescent signal correlated with T cell numbers in the whole body images as well as within specific organ regions of interest. Following transfer into lymphopenic (RAG2-/-) recipients, homeostatic proliferation of T-Lux T cells was visualized using bioluminescent imaging. Real-time bioluminescent analysis of CD4+T cell antigen-specific responses enabled real-time comparison of the kinetics and magnitude of clonal expansion and contraction in the inductive lymph node and tissue site of antigen injection. T cell expansion was dose-dependent despite the presence of supraphysiologic numbers of OVA-specific OT-II transgenic TCR T-Lux T cells. CD4+T cells subsequently underwent a rapid (3–4 day) contraction phase in the draining lymph node, with a delayed contraction in the antigen delivery site, with bioluminescent signal diminished below initial levels, representing TCR clonal frequency control.

Conclusion

The T-Lux mouse provides a novel, efficient model for trackingin vivoaspects of the CD4+T cell response to antigen, providing an attractive approach for studies directed at immunotherapy or vaccine design.
Confocal Microscopy of Unfixed Breast Needle Core Biopsies: A Comparison to Fixed and Stained Sections
Authors: Schiffhauer Linda M , Boger J Neil , Bonfiglio Thomas A , Zavislan James M , Zuley Margarita , Fox Christi Alessi
Published: August 2009

Background

Needle core biopsy, often in conjunction with ultrasonic or stereotactic guided techniques, is frequently used to diagnose breast carcinoma in women. Confocal scanning laser microscopy (CSLM) is a technology that provides real-time digital images of tissues with cellular resolution. This paper reports the progress in developing techniques to rapidly screen needle core breast biopsy and surgical specimens at the point of care. CSLM requires minimal tissue processing and has the potential to reduce the time from excision to diagnosis. Following imaging, specimens can still be submitted for standard histopathological preparation.

Methods

Needle core breast specimens from 49 patients were imaged at the time of biopsy. These lesions had been characterized under the Breast Imaging Reporting And Data System (BI-RADS) as category 3, 4 or 5. The core biopsies were imaged with the CSLM before fixation. Samples were treated with 5% citric acid and glycerin USP to enhance nuclear visibility in the reflectance confocal images. Immediately following imaging, the specimens were fixed in buffered formalin and submitted for histological processing and pathological diagnosis. CSLM images were then compared to the standard histology.

Results

The pathologic diagnoses by standard histology were 7 invasive ductal carcinomas, 2 invasive lobular carcinomas, 3 ductal carcinomas in-situ (CIS), 21 fibrocystic changes/proliferative conditions, 9 fibroadenomas, and 5 other/benign; two were excluded due to imaging difficulties. Morphologic and cellular features of benign and cancerous lesions were identified in the confocal images and were comparable to standard histologic sections of the same tissue.

Conclusion

CSLM is a technique with the potential to screen needle core biopsy specimens in real-time. The confocal images contained sufficient information to identify stromal reactions such as fibrosis and cellular proliferations such as intra-ductal and infiltrating carcinoma, and were comparable to standard histologic sections of the same tissue. Morphologic and cellular features of benign and cancerous lesions were identified in the confocal images. Additional studies are needed to 1.) establish correlation of the confocal and traditional histologic images for the various diseases of the breast; 2.) validate diagnostic use of CSLM and; 3.) further define features of borderline lesions such as well-differentiated ductal CIS vs. atypical hyperplasia.
Sequence variation of PfEMP1-DBLα in association with rosette formation in Plasmodium falciparum isolates causing severe and uncomplicated malaria
Authors: Horata Natharinee , Kalambaheti Thareerat , Craig Alister , Khusmith Srisin
Published: August 2009

Background

Rosetting and cytoadherence ofPlasmodium falciparum-infected red blood cells have been associated with severity of malaria. ICAM-1 and CD36 are the main host cell receptors, while PfEMP1-DBLα is a major parasite ligand, which can contribute to rosette formation. This study is aimed at demonstrating whether the highly polymorphic PfEMP1-DBLα sequences occurring among Thai isolates causing severe and uncomplicated malaria are associated with their ability to form rosettes and reflected the clinical outcome of the patients.

Methods

Two hundred and ninety five PfEMP1-DBLα sequences from Thai clinical isolates causing severe and uncomplicated malaria were evaluated by sequencing and direct comparison using the specific text string analysis functions in Microsoft Excel and Perl. The relationships between the PfEMP1-DBLα sequences were also analysed by network analysis. The binding abilities of parasitized red blood cells (PRBCs) to CD36, wild type ICAM-1, ICAM-1Kilifiand ICAM-1S22/Aunder static condition were included.

Results

Two hundred and eighty one non-identical amino acid sequences were identified (< 95% sequence identity). When the distributions of semi-conserved features (PoLV1–4 and sequence group) within the rosetting domain PfEMP1-DBLα were observed, close similarity was found between isolates from the two disease groups. The sequence group 1 representing uncomplicated malaria was significantly different from the sequence group 3 representing the majority of severe malaria (p= 0.027). By using a simple non-phylogenetic approach to visualize the sharing of polymorphic blocks (position specific polymorphic block, PSPB) and cys/PoLV among DBLα sequences, the sequence group 1 was split from the other five sequence groups. The isolates belonging to sequence group 5 gave the highest mean rosetting rate (21.31%). However, within sequence group 2 and group 6, the isolates causing severe malaria had significantly higher rosetting rate than those causing uncomplicated malaria (p= 0.014,p= 0.007, respectively).

Conclusion

This is the first report of PfEMP1-DBLα analysis in clinical Thai isolates using semi-conserved features (cys/PoLV and PSPBs). The cys/PoLV group 5 gave the highest rosetting rate. PfEMP1-DBLα domains in Thai isolates are highly diverse, however, clinical isolates from severe and uncomplicated malaria shared common sequences.
The complete genomic sequence of an in vivo low replicating BLV strain
Authors: Dube Syamalima , Abbott Lynn , Dube Dipak K , Dolcini Guillermina , Gutierrez Silvina , Ceriani Carolina , Juliarena Marcela , Ferrer Jorge , Perzova Raisa , Poiesz Bernard J
Published: August 2009

DNA was extracted from lamb lymphocytes that were infected in vivo with a BLV strain after inoculation with the peripheral blood mononuclear cells from a persistently sero-indeterminate, low viral load, BLV-infected Holstein cow (No. 41) from Argentina. The DNA was PCR amplified with a series of overlapping primers encompassing the entire BLV proviral DNA. The amplified BLV ARG 41 DNA was cloned, sequenced, and compared phylogenetically to other BLV sequences including an in vivo high replicating strain (BLV ARG 38) from the same herd in Argentina. Characterization of BLV ARG 41's deduced proteins and its relationship to other members of the PTLV/BLV genus of retroviruses are discussed.
Municipal policies and plans of action aiming to promote physical activity and healthy eating habits among schoolchildren in Stockholm, Sweden: a cross-sectional study
Authors: Guldbrandsson Karin , Wennerstad Karin Modig , Rasmussen Finn
Published: August 2009

Background

Promoting physical activity and healthy eating habits by structural measures that reach most children in a society is presumably the most sustainable way of preventing development of overweight and obesity in childhood. The main purpose of the present study was to analyse whether policies and plans of action at the central level in municipalities increased the number of measures that aim to promote physical activity and healthy eating habits among schoolchildren aged six to 16. Another purpose was to analyse whether demographic and socio-economic characteristics were associated with the level of such measures.

Methods

Questionnaires were used to collect data from 25 municipalities and 18 town districts in Stockholm County, Sweden. The questions were developed to capture municipal structural work and factors facilitating physical activity and the development of healthy eating habits for children. Local policy documents and plans of action were gathered. Information regarding municipal demographic and socio-economic characteristics was collected from public statistics.

Results

Policy documents and plans of action in municipalities and town districts did not seem to influence the number of measures aiming to promote physical activity and healthy eating habits among schoolchildren in Stockholm County. Municipal demographic and socio-economic characteristics were, however, shown to influence the number of measures. In town districts with a high total population size, and in municipalities and town districts with a high proportion of adults with more than 12 years of education, a higher level of health-promoting measures was found. In municipalities with a high annual population growth, the number of measures was lower than in municipalities with a lower annual population growth. Another key finding was the lack of agreement between what was reported in the questionnaires regarding existence and contents of local policies and plans of action and what was actually found when these documents were scrutinized.

Conclusion

Policy documents and plans of action aiming to promote physical activity and healthy eating habits among schoolchildren aged six to 16 in municipalities and town districts in Stockholm County did not seem to have an impact on the local level of measures. Demographic and socio-economic characteristics of the municipalities and town districts were on the other hand associated with local health-promoting measures.
Establishment of an animal model of a pasteurized bone graft, with a preliminary analysis of muscle coverage or FGF-2 administration to the graft
Authors: Yoshida Tatsuya , Sakamoto Akio , Tsukamoto Nobuaki , Nakayama Koichi , Iwamoto Yukihide
Published: August 2009

Background

Pasteurized bone grafting is used following the excision of a bone tumor for the purpose of eliminating neoplastic cells while preserving bone-inducing ability. In the hopes of guaranteeing the most favourable results, the establishment of an animal model has been urgently awaited. In the course of establishing such a model, we made a preliminary examination of the effect of muscle coverage or fibroblast growth factor 2 (FGF-2) administration radiographically.

Methods

Forty pasteurized intercalary bone grafts of the Wistar rat femur treated at 60°C for 30 min were reimplanted and stabilized with an intramedullary nail (1.1 mm in diameter). Some grafts were not covered by muscle after the implantation, so that they could act as a clinical model for wide resection, and/or these were soaked with FGF-2 solution prior to implantation. The grafts were then divided into 3 groups, comprising 12 grafts with muscle-covering but without FGF-2 (MC+; FGF2-), 12 grafts without muscle-covering and without FGF-2 (MC-; FGF2-) and 16 grafts without muscle covering but with FGF-2 (MC-; FGF2+).

Results

At 2 weeks after grafting, the pasteurized bone model seemed to be successful in terms of eliminating living cells, including osteocytes. At 4 weeks after grafting, partial bone incorporation was observed in half the (MC+; FGF2-) cases and in half the (MC-; FGF2+) cases, but not in any of the (MC-; FGF2-) cases. At 12 weeks after grafting, bone incorporation was seen in 3 out of 4 in the (MC+; FGF2-) group (3/4: 75%) and in 3 out of 8 in the (MC-; FGF2+) group (3/8: 38%). However, most of the grafted bones without FGF-2 were absorbed in all the cases, massively, regardless of whether there had been muscle-covering (MC+; FGF2-; 4/4: 100%) or no muscle-covering (MC-; FGF2-; 4/4: 100%), while bone absorption was noted at a lower frequency (2/8: 25%) and to a lower degree in the (MC-; FGF2+) group.

Conclusion

In conclusion, we have established an animal pasteurized bone graft model in rats. Pasteurized bone was able to maintain bone induction ability. Despite the low number of cases in each group, the results of each group suggest that muscle-covering has an effect on bone incorporation, but that it is not able to prevent bone absorption to the pasteurized bone. However, an application of FGF-2 may have a positive effect on bone incorporation and may be able to prevent bone absorption of the graft in cases of pasteurized bone graft.
Unconventional antigen-presenting cells in the induction of peripheral CD8+ T cell tolerance
Authors: Reynoso Erika D , Turley Shannon J
Published: August 2009

This review highlights the role of nonhematopoietic cells in the induction and maintenance of peripheral CD8+ T cell tolerance.

Bone marrow-derived APCs are considered the predominant cell type involved in the induction and maintenance of T cell tolerance in vivo. In the periphery, cross-presentation of self-antigens by DCs, in particular, CD8α+ DCs, has been the most discussed mechanism underlying the induction of CD8+ T cell tolerance against self. However, nonhematopoietic APCs in the liver, skin, parenchymal tissues, and lymph nodes can also present self- and exogenous antigens to CD8+ T cells under steady-state conditions. Although far surpassed by their DC counterparts in their ability to stimulate T cell responses, these unconventional APCs have been shown to play a role in the induction, maintenance, and regulation of peripheral CD8+ T cell tolerance by a multitude of mechanisms. In this review, we will discuss the different nonhematopoietic cells that have been shown to present tissue-specific or exogenous antigens to naïve CD8+ T cells, thereby contributing to the regulation of T cell responses in the periphery.
Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia
Authors: Jeha Sima , Razzouk Bassem , Rytting Michael , Rheingold Susan , Albano Edythe , Kadota Richard , Luchtman-Jones Lori , Bomgaars Lisa , Gaynon Paul , Goldman Stewart , Ritchey Kim , Arceci Robert , Altman Arnold , Stine Kimo , Steinherz Laurel , Steinherz Peter
Published: August 2009

Purpose

To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML).

Patients and Methods

A phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m2 daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel.

Results

The 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to ≥ 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to ≥ 160 weeks. Five patients (12%) remain alive post-transplantation at ≥ 63, ≥ 71, ≥ 86, ≥ 114, and ≥ 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event.

Conclusion

Clofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.
Quality of Surveillance for Stage I Testis Cancer in the Community
Authors: Yu Hua-yin , Madison Rodger A. , Setodji Claude M. , Saigal Christopher S.
Published: August 2009

Purpose

Patients with clinical stage I testicular germ cell tumors have been managed with adjuvant radiotherapy, chemotherapy, or retroperitoneal lymph node dissection (RPLND). The use of surveillance-only strategies at referral centers has yielded survival outcomes comparable to those achieved with adjuvant therapy. We evaluated compliance with follow-up protocols developed at referral centers within the community.

Methods

We identified patients with stage I testis cancer within a large private insurance claims database and calculated compliance of follow-up test use with guidelines from the National Comprehensive Cancer Network.

Results

Surveillance was widely used in the community. Compliance with surveillance and postadjuvant therapy follow-up testing was poor and degraded with increasing time from diagnosis. Nearly 30% of all surveillance patients received no abdominal imaging, chest imaging, or tumor marker tests within the first year of diagnosis. Patients who elected RPLND were most compliant with recommended follow-up testing within the first year. Recurrence rates were consistent with previously reported literature, despite poor compliance.

Conclusion

Surveillance is a widely accepted strategy in clinical stage I testicular cancer treatment in the community. However, follow-up care recommendations developed at referral centers are not being adhered to in the community. Although recurrence rates are similar to those of reported literature, the clinical impact of noncompliance on recurrence severity and mortality are not known. Further prospective work needs to be done to evaluate this apparent quality of care problem in the community.
Prospective Study of [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Staging of Muscle-Invasive Bladder Carcinoma
Authors: Kibel Adam S. , Dehdashti Farrokh , Katz Matthew D. , Klim Aleksandra P. , Grubb Robert L. , Humphrey Peter A. , Siegel Cary , Cao Dengfeng , Gao Feng , Siegel Barry A.
Published: August 2009

Purpose

Novel imaging modalities are needed to detect occult metastatic disease in bladder carcinoma. Patients with regional lymphatic spread could be targeted for neoadjuvant chemotherapy, and patients with distant metastatic disease could be spared the unnecessary morbidity of radical cystectomy. Herein, we report a prospective study of positron emission tomography/computed tomography (PET/CT) with [18F]fluorodeoxyglucose (FDG) in patients undergoing radical cystectomy for cT2-3N0M0 urothelial carcinoma of the bladder.

Methods

Forty-three chemotherapy-naïve patients underwent FDG-PET/CT before planned cystectomy. All had negative conventional CT and bone scintigraphy before enrollment. Positive FDG-PET/CT was confirmed by percutaneous biopsy or open surgical exploration, whereas negative FDG-PET/CT was confirmed by complete lymphadenectomy. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were described using the Kaplan-Meier method and compared using log-rank test.

Results

Median follow-up was 14.9 months (range, 0.4 to 46.1 months). One patient who did not undergo lymphadenectomy was excluded from the pathology data analysis (n = 42), whereas another patient who failed to return for follow-up was excluded from survival analysis (n = 42). FDG-PET/CT demonstrated a positive predictive value of 78% (seven of nine), a negative predictive value of 91% (30 of 33), sensitivity of 70% (seven of 10), and specificity of 94% (30 of 32). RFS, DSS, and OS were all significantly poorer in the patients with positive FDG-PET/CT than in those with negative FDG-PET/CT.

Conclusion

FDG-PET/CT detected occult metastatic disease in seven of 42 patients with negative conventional preoperative evaluations. PET findings were strongly correlated with survival. As such, FDG-PET/CT may help in making treatment decisions before radical cystectomy.
Treatment of Fluorouracil-Refractory Patients With Liver Metastases From Colorectal Cancer by Using Yttrium-90 Resin Microspheres Plus Concomitant Systemic Irinotecan Chemotherapy
Authors: van Hazel Guy A. , Pavlakis Nick , Goldstein David , Olver Ian N. , Tapner Michael J. , Price David , Bower Geoffrey D. , Briggs Gregory M. , Rossleigh Monica A. , Taylor D. James , George Jacob
Published: August 2009

Purpose

Liver metastases are the principal cause of death in patients with advanced colorectal cancer (CRC). Irinotecan is a chemotherapeutic agent used in the treatment of CRC and has demonstrated synergistic potential when used with radiation. Radioembolization with yttrium-90 microspheres has demonstrated increased response and survival rates when given with fluorouracil chemotherapy. This study's goal was to evaluate the maximum-tolerated dose of concomitant irinotecan and radioembolization in fluorouracil-refractory patients with CRC hepatic metastases.

Patients and Methods

Twenty-five irinotecan-naïve patients who had experienced relapse after previous chemotherapy were enrolled onto three dose-escalating groups. Irinotecan was administered at 50, 75, or 100 mg/m2 on days 1 and 8 of a 3-week cycle for the first two cycles, and full irinotecan doses (ie, 100 mg/m2) were administered during cycles 3 to 9. Radioembolization was administered during the first chemotherapy cycle.

Results

Most patients experienced acute, self-limiting abdominal pain and nausea. Mild lethargy and anorexia were common. Grades 3 to 4 events were seen in three of six patients at 50 mg/m2 (obstructive jaundice, thrombocytopenia, diarrhea), in five of 13 patients at 75 mg/m2 (neutropenia, leukopenia, thrombocytopenia, elevated alkaline phosphatase, abdominal pain, ascites, fatigue) and in four of six patients at 100 mg/m2 (diarrhea, deep vein thrombosis, constipation, leukopenia). Eleven (48%) of 23 patients had a partial response, and nine patients (39%) had stable disease. The median progression-free survival was 6.0 months; the median survival was 12.2 months.

Conclusion

Concomitant use of radioembolization plus irinotecan did not reach a maximum-tolerated dose. The recommended dose of irinotecan in this setting is 100 mg/m2 on days 1 and 8 of a 3-week cycle.
Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia
Authors: Knauf Wolfgang U. , Lissichkov Toshko , Aldaoud Ali , Liberati Anna , Loscertales Javier , Herbrecht Raoul , Juliusson Gunnar , Postner Gerhard , Gercheva Liana , Goranov Stefan , Becker Martin , Fricke Hans-Joerg , Huguet Francoise , Del Giudice Ilaria , Klein Peter , Tremmel Lothar , Merkle Karlheinz , Montillo Marco
Published: August 2009

Purpose

This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL).

Patients and Methods

Patients (≤ 75 years of age) were randomly assigned to receive bendamustine 100 mg/m2/d intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca's normal weight) orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response to treatment was assessed according to National Cancer Institute Working Group criteria, and the final determination of response was made by a blinded independent review committee.

Results

A total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157 chlorambucil-treated patients (P < .0001). More patients showed complete responses with bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6 months with bendamustine and 8.3 months with chlorambucil (P < .0001). Bendamustine was also associated with an improvement in duration of remission, compared with chlorambucil (median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil (occurring in 40% v 19% of patients). Severe infections (grade 3 to 4) occurred in 8% of bendamustine-treated patients and 3% of chlorambucil-treated patients.

Conclusion

Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.
Efficacy and Safety of Trabectedin in Patients With Advanced or Metastatic Liposarcoma or Leiomyosarcoma After Failure of Prior Anthracyclines and Ifosfamide: Results of a Randomized Phase II Study of Two Different Schedules
Authors: Demetri George D. , Chawla Sant P. , von Mehren Margaret , Ritch Paul , Baker Laurence H. , Blay Jean Y. , Hande Kenneth R. , Keohan Mary L. , Samuels Brian L. , Schuetze Scott , Lebedinsky Claudia , Elsayed Yusri A. , Izquierdo Miguel A. , Gómez Javier , Park Youn C. , Le Cesne Axel
Published: August 2009

Purpose

To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide.

Patients and Methods

Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m2 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m2 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images.

Results

Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted.

Conclusion

Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.
Project Zero Delay: A Process for Accelerating the Activation of Cancer Clinical Trials
Authors: Kurzrock Razelle , Pilat Susan , Bartolazzi Marcel , Sanders Dwana , Van Wart Hood Jill , Tucker Stanley D. , Webster Kevin , Mallamaci Michael A. , Strand Steven , Babcock Eileen , Bast Robert C.
Published: August 2009

Drug development in cancer research is lengthy and expensive. One of the rate-limiting steps is the initiation of first-in-human (phase I) trials. Three to 6 months can elapse between investigational new drug (IND) approval by the US Food and Drug Administration and the entry of a first patient. Issues related to patient participation have been well analyzed, but the administrative processes relevant to implementing clinical trials have received less attention. While industry and academia often partner for the performance of phase I studies, their administrative processes are generally performed independently, and their timelines driven by different priorities: safety reviews, clinical operations, regulatory submissions, and contracting of clinical delivery vendors for industry; contracts, budgets, and institutional review board approval for academia. Both processes converge on US Food and Drug Administration approval of an IND. In the context of a strategic alliance between M. D. Anderson Cancer Center and AstraZeneca Pharmaceuticals LP, a concerted effort has been made to eliminate delays in implementing clinical trials. These efforts focused on close communications, identifying and matching key timelines, alignment of priorities, and tackling administrative processes in parallel, rather than sequentially. In a recent, first-in-human trial, the study was activated and the first patient identified in 46 days from completion of the final study protocol and about 48 hours after final US Food and Drug Administration IND approval, reducing the overall timeline by about 3 months, while meeting all clinical good practice guidelines. Eliminating administrative delays can accelerate the evaluation of new drugs without compromising patient safety or the quality of clinical research.