bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of curcumin or dexamethasone on lung ischaemia–reperfusion injury in rats
Authors: Sun J. , Yang D. , Li S. , Xu Z. , Wang X. , Bai C.
Published: September 2008

The present study aimed to investigate potential effects of curcumin (CUR) and dexamethasone (DXM) on ischaemia–reperfusion (I/R) induced lung injury in rats.

Experimental rats were pre-treated with a singlei.p.dose of vehicle, CUR (50 mg·kg−1or 200 mg·kg−1) or DXM (5 mg·kg−1), 2 h before anaesthesia and subjected to left lung hilus clamping with 90-min ischaemia followed by 4 h of reperfusion.

Pre-treatment with CUR (200 mg·kg−1) or DXM markedly attenuated I/R-induced barrier disruption, lung oedema, tissue inflammation, hypoxaemia 4 h after reperfusion, and overactivation of nuclear factor-κB, inflammatory cytokines, myeloperoxidase and malondialdehyde.

It appears that curcumin attenuates acute lung injury, probably through improving oxidative stress and inhibiting nuclear factor-κB-mediated expression of inflammatory cytokines. Thus, curcumin may be an alternative therapy for improving the outcomes of ischaemia–reperfusion-induced lung injury.
MiMiR – an integrated platform for microarray data sharing, mining and analysis
Authors: Tomlinson Chris , Thimma Manjula , Alexandrakis Stelios , Castillo Tito , Dennis Jayne L , Brooks Anthony , Bradley Thomas , Turnbull Carly , Blaveri Ekaterini , Barton Geraint , Chiba Norie , Maratou Klio , Soutter Pat , Aitman Tim , Game Laurence
Published: September 2008

Background

Despite considerable efforts within the microarray community for standardising data format, content and description, microarray technologies present major challenges in managing, sharing, analysing and re-using the large amount of data generated locally or internationally. Additionally, it is recognised that inconsistent and low quality experimental annotation in public data repositories significantly compromises the re-use of microarray data for meta-analysis. MiMiR, the Mi croarray data Mi ning R esource was designed to tackle some of these limitations and challenges. Here we present new software components and enhancements to the original infrastructure that increase accessibility, utility and opportunities for large scale mining of experimental and clinical data.

Results

A user friendly Online Annotation Tool allows researchers to submit detailed experimental information via the web at the time of data generation rather than at the time of publication. This ensures the easy access and high accuracy of meta-data collected. Experiments are programmatically built in the MiMiR database from the submitted information and details are systematically curated and further annotated by a team of trained annotators using a new Curation and Annotation Tool. Clinical information can be annotated and coded with a clinical Data Mapping Tool within an appropriate ethical framework. Users can visualise experimental annotation, assess data quality, download and share data via a web-based experiment browser called MiMiR Online. All requests to access data in MiMiR are routed through a sophisticated middleware security layer thereby allowing secure data access and sharing amongst MiMiR registered users prior to publication. Data in MiMiR can be mined and analysed using the integrated EMAAS open source analysis web portal or via export of data and meta-data into Rosetta Resolver data analysis package.

Conclusion

The new MiMiR suite of software enables systematic and effective capture of extensive experimental and clinical information with the highest MIAME score, and secure data sharing prior to publication. MiMiR currently contains more than 150 experiments corresponding to over 3000 hybridisations and supports the Microarray Centre's large microarray user community and two international consortia. The MiMiR flexible and scalable hardware and software architecture enables secure warehousing of thousands of datasets, including clinical studies, from microarray and potentially other -omics technologies.
The Drosophila IKK-related kinase (Ik2) and Spindle-F proteins are part of a complex that regulates cytoskeleton organization during oogenesis
Authors: Dubin-Bar Dikla , Bitan Amir , Bakhrat Anna , Kaiden-Hasson Rotem , Etzion Sharon , Shaanan Boaz , Abdu Uri
Published: September 2008

Background

IkappaB kinases (IKKs) regulate the activity of Rel/NF-kappaB transcription factors by targeting their inhibitory partner proteins, IkappaBs, for degradation. The Drosophila genome encodes two members of the IKK family. Whereas the first is a kinase essential for activation of the NF-kappaB pathway, the latter does not act as IkappaB kinase. Instead, recent findings indicate that Ik2 regulates F-actin assembly by mediating the function of nonapoptotic caspases via degradation of DIAP1. Also, it has been suggested that ik2 regulates interactions between the minus ends of the microtubules and the actin-rich cortex in the oocyte. Since spn-F mutants display oocyte defects similar to those of ik2 mutant, we decided to investigate whether Spn-F could be a direct regulatory target of Ik2.

Results

We found that Ik2 binds physically to Spn-F, biomolecular interaction analysis of Spn-F and Ik2 demonstrating that both proteins bind directly and form a complex. We showed that Ik2 phosphorylates Spn-F and demonstrated that this phosphorylation does not lead to Spn-F degradation. Ik2 is localized to the anterior ring of the oocyte and to punctate structures in the nurse cells together with Spn-F protein, and both proteins are mutually required for their localization.

Conclusion

We conclude that Ik2 and Spn-F form a complex, which regulates cytoskeleton organization during Drosophila oogenesis and in which Spn-F is the direct regulatory target for Ik2. Interestingly, Ik2 in this complex does not function as a typical IKK in that it does not direct SpnF for degradation following phosphorylation.
Prolonged exposure to bacterial toxins downregulated expression of toll-like receptors in mesenchymal stromal cell-derived osteoprogenitors
Authors: Mo Irene Fung Ying , Yip Kevin Hak Kong , Chan Wing Keung , Law Helen Ka Wai , Lau Yu Lung , Chan Godfrey Chi Fung
Published: September 2008

Background

Human mesenchymal stromal cells (MSCs, also known as mesenchymal stem cells) are multipotent cells with potential therapeutic value. Owing to their osteogenic capability, MSCs may be clinically applied for facilitating osseointegration in dental implants or orthopedic repair of bony defect. However, whether wound infection or oral microflora may interfere with the growth and osteogenic differentiation of human MSCs remains unknown. This study investigated whether proliferation and osteogenic differentiation of MSCs would be affected by potent gram-positive and gram-negative derived bacterial toxins commonly found in human settings.

Results

We selected lipopolysaccharide (LPS) fromEscherichia coliand lipoteichoic acid (LTA) fromStreptococcus pyogenesas our toxins of choice. Our findings showed both LPS and LTA did not affect MSC proliferation, but prolonged LPS challenge upregulated the osteogenic differentiation of MSCs, as assessed by alkaline phosphatase activity and calcium deposition. Because toll-like receptors (TLRs), in particularly TLR4 and TLR2, are important for the cellular responsiveness to LPS and LTA respectively, we evaluated their expression profiles serially from MSCs to osteoblasts by quantitative PCR. We found that during osteogenic differentiation, MSC-derived osteoprogenitors gradually expressed TLR2 and TLR4 by Day 12. But under prolonged incubation with LPS, MSC-derived osteoprogenitors had reduced TLR2 and TLR4 gene expression. This peculiar response to LPS suggests a possible adaptive mechanism when MSCs are subjected to continuous exposure with bacteria.

Conclusion

In conclusion, our findings support the potential of using human MSCs as a biological graft, even under a bacterial toxin-rich environment.
WebScipio: An online tool for the determination of gene structures using protein sequences
Authors: Odronitz Florian , Pillmann Holger , Keller Oliver , Waack Stephan , Kollmar Martin
Published: September 2008

Background

Obtaining the gene structure for a given protein encoding gene is an important step in many analyses. A software suited for this task should be readily accessible, accurate, easy to handle and should provide the user with a coherent representation of the most probable gene structure. It should be rigorous enough to optimise features on the level of single bases and at the same time flexible enough to allow for cross-species searches.

Results

WebScipio, a web interface to the Scipio software, allows a user to obtain the corresponding coding sequence structure of a here given a query protein sequence that belongs to an already assembled eukaryotic genome. The resulting gene structure is presented in various human readable formats like a schematic representation, and a detailed alignment of the query and the target sequence highlighting any discrepancies. WebScipio can also be used to identify and characterise the gene structures of homologs in related organisms. In addition, it offers a web service for integration with other programs.

Conclusion

WebScipio is a tool that allows users to get a high-quality gene structure prediction from a protein query. It offers more than 250 eukaryotic genomes that can be searched and produces predictions that are close to what can be achieved by manual annotation, for in-species and cross-species searches alike. WebScipio is freely accessible at http://www.webscipio.org.
Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice
Authors: Abdul-Majid Khairul-Bariah , Ly Lan H , Converse Paul J , Geiman Deborah E , McMurray David N , Bishai William R
Published: September 2008

Background

Mouse virulence assessments of certainMycobacterium tuberculosismutants have revealed an immunopathology defect in which high tissue CFU counts are observed but the tissue pathology and lethality are reduced.M. tuberculosismutants which grow and persist in the mouse lungs, but have attenuated disease progression, have the immunopathology (imp) phenotype. The antigenic properties of these strains may alter the progression of disease due to a reduction in host immune cell recruitment to the lungs resulting in disease attenuation and prolonged host survival.

Results

In this study we focused on the mouse immune response to one such mutant; theM. tuberculosisΔsigCmutant. Aerosol infection of DBA/2 and SCID mice with theM. tuberculosisΔsigCmutant, complemented mutant and wild type strain showed proliferation of mutant bacilli in mouse lungs, but with decreased inflammation and mortality in DBA/2 mice. SCID mice shared the same phenotype as the DBA/2 mice in response to the ΔsigCmutant, however, they succumbed to the infection faster. Bronchoalveolar lavage (BAL) fluid analysis revealed elevated numbers of infiltrating neutrophils in the lungs of mice infected with wild type and complemented ΔsigCmutant strains but not in mice infected with the ΔsigCmutant. In addition, DBA/2 mice infected with the ΔsigCmutant had reduced levels of TNF-α, IL-1β, IL-6 and IFN-γ in the lungs. Similarly, there was a reduction in proinflammatory cytokines in the lungs of SCID mice. In contrast to the mouse model, the ΔsigCmutant had reduced initial growth in guinea pig lungs. A possible mechanism of attenuation in the ΔsigCmutant may be a reduction in neutrophilic-influx in the alveolar spaces of the lungs, and decreased proinflammatory cytokine secretion. In contrast to mouse data, theM. tuberculosisΔsigCmutant proliferates slowly in guinea pig lungs, a setting characterized by caseating necrosis.

Conclusion

Our observations suggest that the immunopathology phenotype is associated with the inability to trigger a strong early immune response, resulting in disease attenuation. While macrophages and T cells have been shown to be important in containingM. tuberculosisdisease our study has shown that neutrophils may also play an important role in the containment of this organism.
Factors associated with wife beating in Egypt: Analysis of two surveys (1995 and 2005)
Authors: Akmatov Manas K , Mikolajczyk Rafael T , Labeeb Shokria , Dhaher Enas , Khan Md Mobarak
Published: September 2008

Background

Wife beating is an important public health problem in many developing countries. We assessed the rates of wife beating and examined factors associated with wife beating in 1995 and 2005 in Egypt.

Methods

We used data from two Demographic and Health Surveys (DHS) conducted in Egypt in 1995 and 2005 using multistage household sampling. Data related to wife beating included information from 7122 women in 1995 and 5612 women in 2005. Logistic regression was used to analyze factors independently associated with wife beating. Special weights were used to obtain nationally representative estimates.

Results

In 1995 17.5% of married women in Egypt experienced wife beating in the last 12 months, in 2005 – 18.9% or 16.0%, using different measures. The association between socio-demographic differentials and wife beating was weaker in the newer survey. The 12-month prevalence of wife beating was lower only when both partners were educated, but the differences across education levels were less pronounced in 2005. Based on the information available in the 2005 survey, more educated women experienced less severe forms of wife beating than less educated women.

Conclusion

Different measures used in both surveys make a direct comparison difficult. The observed patterns indicate that the changes in prevalence may be masked by two opposite processes occurring in the society: a decrease in (severe forms of) wife beating and an increase in reporting of wife beating. Improving the access to education for women and raising education levels in the whole society may help reducing wife beating.
Validity of a self-reported measure of familial history of obesity
Authors: Paradis Ann-Marie , Pérusse Louis , Godin Gaston , Vohl Marie-Claude
Published: September 2008

Background

Familial history information could be useful in clinical practice. However, little is known about the accuracy of self-reported familial history, particularly self-reported familial history of obesity (FHO).

Methods

Two cross-sectional studies were conducted. The aims of study 1 was to compare self-reported and objectively measured weight and height whereas the aims of study 2 were to examine the relationship between the weight and height estimations reported by the study participants and the values provided by their family members as well as the validity of a self-reported measure of FHO. Study 1 was conducted between 2004 and 2006 among 617 subjects and study 2 was conducted in 2006 among 78 participants.

Results

In both studies, weight and height reported by the participants were significantly correlated with their measured values (study 1: r = 0.98 and 0.98; study 2: r = 0.99 and 0.97 respectively; p < 0.0001). Estimates of weight and height for family members provided by the study participants were strongly correlated with values reported by each family member (r = 0.96 and 0.95, respectively; p < 0.0001). Substantial agreement between the FHO reported by the participants and the one obtained by calculating the BMI of each family members was observed (kappa = 0.72; p < 0.0001). Sensitivity (90.5%), specificity (82.6%), positive (82.6%) and negative (90.5%) predictive values of FHO were very good.

Conclusion

A self-reported measure of FHO is valid, suggesting that individuals are able to detect the presence or the absence of obesity in their first-degree family members.
FDG-PET/CT imaging for staging and radiotherapy treatment planning of head and neck carcinoma
Authors: Deantonio Letizia , Beldì Debora , Gambaro Giuseppina , Loi Gianfranco , Brambilla Marco , Inglese Eugenio , Krengli Marco
Published: September 2008

Background

Positron emission tomography (PET) has a potential improvement for staging and radiation treatment planning of various tumor sites. We analyzed the use of 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) images for staging and target volume delineation of patients with head and neck carcinoma candidates for radiotherapy.

Methods

Twenty-two patients candidates for primary radiotherapy, who did not receive any curative surgery, underwent both CT and PET/CT simulation. Gross Tumor Volume (GTV) was contoured on CT (CT-GTV), PET (PET-GTV), and PET/CT images (PET/CT-GTV). The resulting volumes were analyzed and compared.

Results

Based on PET/CT, changes in TNM categories and clinical stage occurred in 5/22 cases (22%). The difference between CT-GTV and PET-GTV was not statistically significant (p = 0.2) whereas the difference between the composite volume (PET/CT-GTV) and CT-GTV was statistically significant (p < 0.0001).

Conclusion

PET/CT fusion images could have a potential impact on both tumor staging and treatment planning.
Hope, despair and transformation: Climate change and the promotion of mental health and wellbeing
Authors: Fritze Jessica G , Blashki Grant A , Burke Susie , Wiseman John
Published: September 2008

Background

This article aims to provide an introduction to emerging evidence and debate about the relationship between climate change and mental health.

Discussion and Conclusion

The authors argue that:

i) the direct impacts of climate change such as extreme weather events will have significant mental health implications;

ii) climate change is already impacting on the social, economic and environmental determinants of mental health with the most severe consequences being felt by disadvantaged communities and populations;

iii) understanding the full extent of the long term social and environmental challenges posed by climate change has the potential to create emotional distress and anxiety; and

iv) understanding the psycho-social implications of climate change is also an important starting point for informed action to prevent dangerous climate change at individual, community and societal levels.
An acutely ischaemic hand in a young adult due to subclavian artery aneurysm (SAA) caused by a cervical rib: A case report
Authors: Tam Karen , Seneviratne Kanchana , Pathak Rajiv , Jayatunga Ajantha
Published: September 2008

Introduction

True subclavian artery aneurysms are relatively rare lesions. Thoracic outlet compression is responsible for 75% of aneurysms. They are formed as a result of compression by, for example a cervical rib.

Case Presentation

We present a case of subclavian artery aneurysm secondary to a cervical rib in a 25-year-old young Asian adult, who presented with an acutely ischaemic upper limb. A Computed Tomography angiogram revealed a right sided cervical rib and sacular aneurysm in the mid-portion of the subclavian artery.

Conclusion

Although it is a rare condition, it is important to be aware especially in the young age group. Surgical management has very favourable outcomes in these patients.
Model-based Analysis of ChIP-Seq (MACS)
Authors: Zhang Yong , Liu Tao , Meyer Clifford A , Eeckhoute Jérôme , Johnson David S , Bernstein Bradley E , Nusbaum Chad , Myers Richard M , Brown Myles , Li Wei , Liu X Shirley
Published: September 2008

We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.
NetGrep: fast network schema searches in interactomes
Authors: Banks Eric , Nabieva Elena , Peterson Ryan , Singh Mona
Published: September 2008

NetGrep (http://genomics.princeton.edu/singhlab/netgrep/) is a system for searching protein interaction networks for matches to user-supplied 'network schemas'. Each schema consists of descriptions of proteins (for example, their molecular functions or putative domains) along with the desired topology and types of interactions among them. Schemas can thus describe domain-domain interactions, signaling and regulatory pathways, or more complex network patterns. NetGrep provides an advanced graphical interface for specifying schemas and fast algorithms for extracting their matches.
Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury
Authors: Davies Jeannette E , Pröschel Christoph , Zhang Ningzhe , Noble Mark , Mayer-Pröschel Margot , Davies Stephen JA
Published: September 2008

Background

Two critical challenges in developing cell-transplantation therapies for injured or diseased tissues are to identify optimal cells and harmful side effects. This is of particular concern in the case of spinal cord injury, where recent studies have shown that transplanted neuroepithelial stem cells can generate pain syndromes.

Results

We have previously shown that astrocytes derived from glial-restricted precursor cells (GRPs) treated with bone morphogenetic protein-4 (BMP-4) can promote robust axon regeneration and functional recovery when transplanted into rat spinal cord injuries. In contrast, we now show that transplantation of GRP-derived astrocytes (GDAs) generated by exposure to the gp130 agonist ciliary neurotrophic factor (GDAsCNTF), the other major signaling pathway involved in astrogenesis, results in failure of axon regeneration and functional recovery. Moreover, transplantation of GDACNTF cells promoted the onset of mechanical allodynia and thermal hyperalgesia at 2 weeks after injury, an effect that persisted through 5 weeks post-injury. Delayed onset of similar neuropathic pain was also caused by transplantation of undifferentiated GRPs. In contrast, rats transplanted with GDAsBMP did not exhibit pain syndromes.

Conclusion

Our results show that not all astrocytes derived from embryonic precursors are equally beneficial for spinal cord repair and they provide the first identification of a differentiated neural cell type that can cause pain syndromes on transplantation into the damaged spinal cord, emphasizing the importance of evaluating the capacity of candidate cells to cause allodynia before initiating clinical trials. They also confirm the particular promise of GDAs treated with bone morphogenetic protein for spinal cord injury repair.
The spatial data-adaptive minimum-variance distortionless-response beamformer on seismic single-sensor data
Authors: Panea Ionelia , Drijkoningen Guy
Published: September 2008

Coherent noise generated by surface waves or ground roll within a heterogeneous near surface is a major problem in land seismic data. Array forming based on single-sensor recordings might reduce such noise more robustly than conventional hardwired arrays. We use the minimum-variance distortionless-response (MVDR) beamformer to remove (aliased) surface-wave energy from single-sensor data. This beamformer is data adaptive and robust when the presumed and actual desired signals are mismatched. We compute the intertrace covariance for the desired signal, and then for the total signal (desired [Formula: see text]) to obtain optimal weights. We use the raw data of only one array for the covariance of the total signal, and the wavenumber-filtered version of a full seismic single-sensor record for the covariance of the desired signal. In the determination of optimal weights, a parameter that controls the robustness of the beamformer against an arbitrary desired signal mismatch has to be chosen so that the results are optimal. This is similar to stabilization in deconvolution problems. This parameter needs to be smaller than the largest eigenvalue provided by the singular value decomposition of the presumed desired signal covariance. We compare results of MVDR beamforming with standard array forming on single-sensor synthetic and field seismic data. We apply 2D and 3D beamforming and show prestack and poststack results. MVDR beamformers are superior to conventional hardwired arrays for all examples.
Generalized effective-medium theory of induced polarization
Authors: Zhdanov Michael
Published: September 2008

A rigorous physical-mathematical model of heterogeneous conductive media is based on the effective-medium approach. A generalization of the classical effective-medium theory (EMT) consists of two major parts: (1) introduction of effective-conductivity models of heterogeneous, multiphase rock formations with inclusions of arbitrary shape and conductivity using the principles of the quasi-linear (QL) approximation within the framework of the EMT formalism and (2) development of the generalized effective-medium theory of induced polarization (GEMTIP), which takes into account electromagnetic-induction (EMI) and induced polarization (IP) effects related to the relaxation of polarized charges in rock formations. The new generalized EMT provides a unified mathematical model of heterogeneity, multiphase structure, and the polarizability of rocks. The geoelectric parameters of this model are determined by the intrinsic petrophysical and geometric characteristics of composite media: the mineralization and/or fluid content of rocks and the matrix composition, porosity, anisotropy, and polarizability of formations. The GEMTIP model allows one to find the effective conductivity of a medium with inclusions that have arbitrary shape and electrical properties. One fundamental IP model of an isotropic, multiphase, heterogeneous medium is filled with spherical inclusions. This model, because of its relative simplicity, makes it possible to explain the close relationships between the new GEMTIP conductivity-relaxation model and an empirical Cole-Cole model or classical Wait’s model of the IP effect.
Molecular Profiling of Carcinoma of Unknown Primary and Correlation With Clinical Evaluation
Authors: Varadhachary Gauri R. , Talantov Dmitri , Raber Martin N. , Meng Christina , Hess Kenneth R. , Jatkoe Tim , Lenzi Renato , Spigel David R. , Wang Yixin , Greco F. Anthony , Abbruzzese James L. , Hainsworth John D.
Published: September 2008

Purpose

To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site.

Patients and Methods

Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy.

Results

The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer–specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement.

Conclusion

This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.
Gene Expression Signatures Predictive of Early Response and Outcome in High-Risk Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study
Authors: Bhojwani Deepa , Kang Huining , Menezes Renee X. , Yang Wenjian , Sather Harland , Moskowitz Naomi P. , Min Dong-Joon , Potter Jeffrey W. , Harvey Richard , Hunger Stephen P. , Seibel Nita , Raetz Elizabeth A. , Pieters Rob , Horstmann Martin A. , Relling Mary V. , den Boer Monique L. , Willman Cheryl L. , Carroll William L.
Published: September 2008

Purpose

To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures.

Patients and Methods

Gene expression profiles were generated from bone marrow blasts at initial diagnosis from a cohort of 99 children with National Cancer Institute–defined high-risk ALL who were treated uniformly on the Children's Oncology Group (COG) 1961 study. For prediction of early response, genes that correlated to marrow status on day 7 were identified on a training set and were validated on a test set. An additional signature was correlated with long-term outcome, and the predictive models were validated on three large, independent patient cohorts.

Results

We identified a 24–probe set signature that was highly predictive of day 7 marrow status on the test set (P = .0061). Pathways were identified that may play a role in early blast regression. We have also identified a 47–probe set signature (which represents 41 unique genes) that was predictive of long-term outcome in our data set as well as three large independent data sets of patients with childhood ALL who were treated on different protocols. However, we did not find sufficient evidence for the added significance of these genes and the derived predictive models when other known prognostic features, such as age, WBC, and karyotype, were included in a multivariate analysis.

Conclusion

Genes and pathways that play a role in early blast regression may identify patients who may be at risk for inferior responses to treatment. A fully validated predictive gene expression signature was defined for high-risk ALL that provided insight into the biologic mechanisms of treatment failure.
Gene Expression Profiling to Identify the Histogenetic Origin of Metastatic Adenocarcinomas of Unknown Primary
Authors: Horlings Hugo M. , van Laar Ryan K. , Kerst Jan-Martijn , Helgason Helgi H. , Wesseling Jelle , van der Hoeven Jacobus J.M. , Warmoes Marc O. , Floore Arno , Witteveen Anke , Lahti-Domenici Jaana , Glas Annuska M. , Van't Veer Laura J. , de Jong Daphne
Published: September 2008

Purpose

Patients with adenocarcinoma of unknown primary origin (ACUP) constitute approximately 4% of all malignancies. For effective treatment of these patients, it is considered optimal to identify the primary tumor origins. Currently, the success rate of the diagnostic work-up is only 20% to 30%. Our goal was to evaluate the contribution of gene expression profiling for routine clinical practice in patients with ACUP.

Patients and Methods

Formalin-fixed, paraffin-embedded (FFPE) samples were obtained from 84 patients with a known primary adenocarcinoma and from 38 patients with ACUP. An extensive immunohistochemical panel classified 16 of the patients with ACUP, whereas 22 patients remained unclassified for their histogenetic origin. Information about staging procedures and clinical follow-up were available in all patient cases. The expression data were analyzed in relation to clinicopathologic variables and immunohistochemical results.

Results

The gene expression–based assay classified the primary site correctly in 70 (83%) of 84 patient cases of primary and metastatic tumors of known origin, with good sensitivity for the majority of the tumor classes and relatively poor sensitivity for primary lung adenocarcinoma. Gene expression profiling identified 15 (94%) of 16 patients with initial ACUP who were classified by immunohistochemistry, and it made a valuable contribution to a potential site of origin in 14 of the 22 patients with ACUP.

Conclusion

The gene expression platform can classify correctly from FFPE samples the majority of tumors classes both in patients with known primary and in patients with ACUP. Therefore, gene expression profiling represents an additional analytic approach to assist with the histogenetic diagnosis of patients with ACUP.
Identification of Cancer Care and Protocol Characteristics Associated With Recruitment in Breast Cancer Clinical Trials
Authors: Lemieux Julie , Goodwin Pamela J. , Pritchard Kathleen I. , Gelmon Karen A. , Bordeleau Louise J. , Duchesne Thierry , Camden Stéphanie , Speers Caroline H.
Published: September 2008

Purpose

It is estimated that only 5% of patients with cancer participate in a clinical trial. Barriers to participation may relate to available protocols, physicians, and patients, but few data exist on barriers related to cancer care environments and protocol characteristics.

Methods

The primary objective was to identify characteristics of cancer care environments and clinical trial protocols associated with a low recruitment into breast cancer clinical trials. Secondary objectives were to determine yearly recruitment fraction onto clinical trials from 1997 to 2002 in Ontario, Canada, and to compare recruitment fraction among years. Questionnaires were sent to hospitals requesting characteristics of cancer care environments and to cooperative groups/pharmaceutical companies for information on protocols and the number of patients recruited per hospital/year. Poisson regression was used to estimate the recruitment fraction.

Results

Questionnaire completion rate varied between 69% and 100%. Recruitment fraction varied between 5.4% and 8.5% according to year. More than 30% of patients were diagnosed in hospitals with no available trials. In multivariate analysis, the following characteristics were associated with recruitment: use of placebo versus not (relative risk [RR] = 0.80; P = .05), nonmetastatic versus metastatic trial (RR = 2.80; P < .01), and for nonmetastatic trials, protocol allowing an interval of 12 weeks or longer versus less than 12 weeks (from diagnosis, surgery, or end of therapy) before enrollment (RR = 1.36; P < .01).

Conclusion

Allowable interval of 12 weeks or longer to randomly assign patients in clinical trials could help recruitment. In our study, absence of an available clinical trial represented the largest barrier to recruitment.
Randomized Controlled Trial of Collaborative Care Management of Depression Among Low-Income Patients With Cancer
Authors: Ell Kathleen , Xie Bin , Quon Brenda , Quinn David I. , Dwight-Johnson Megan , Lee Pey-Jiuan
Published: September 2008

Purpose

To determine the effectiveness of the Alleviating Depression Among Patients With Cancer (ADAPt-C) collaborative care management for major depression or dysthymia.

Patients and Methods

Study patients included 472 low-income, predominantly female Hispanic patients with cancer age ≥ 18 years with major depression (49%), dysthymia (5%), or both (46%). Patients were randomly assigned to intervention (n = 242) or enhanced usual care (EUC; n = 230). Intervention patients had access for up to 12 months to a depression clinical specialist (supervised by a psychiatrist) who offered education, structured psychotherapy, and maintenance/relapse prevention support. The psychiatrist prescribed antidepressant medications for patients preferring or assessed to require medication.

Results

At 12 months, 63% of intervention patients had a 50% or greater reduction in depressive symptoms from baseline as assessed by the Patient Health Questionnaire-9 (PHQ-9) depression scale compared with 50% of EUC patients (odds ratio [OR] = 1.98; 95% CI, 1.16 to 3.38; P = .01). Improvement was also found for 5-point decrease in PHQ-9 score among 72.2% of intervention patients compared with 59.7% of EUC patients (OR = 1.99; 95% CI, 1.14 to 3.50; P = .02). Intervention patients also experienced greater rates of depression treatment (72.3% v 10.4% of EUC patients; P < .0001) and significantly better quality-of-life outcomes, including social/family (adjusted mean difference between groups, 2.7; 95% CI, 1.22 to 4.17; P < .001), emotional (adjusted mean difference, 1.29; 95% CI, 0.26 to 2.22; P = .01), functional (adjusted mean difference, 1.34; 95% CI, 0.08 to 2.59; P = .04), and physical well-being (adjusted mean difference, 2.79; 95% CI, 0.49 to 5.1; P = .02).

Conclusion

ADAPt-C collaborative care is feasible and results in significant reduction in depressive symptoms, improvement in quality of life, and lower pain levels compared with EUC for patients with depressive disorders in a low-income, predominantly Hispanic population in public sector oncology clinics.
Induction of Immune Responses and Clinical Efficacy in a Phase II Trial of IDM-2101, a 10-Epitope Cytotoxic T-Lymphocyte Vaccine, in Metastatic Non–Small-Cell Lung Cancer
Authors: Barve Minal , Bender James , Senzer Neil , Cunningham Casey , Greco F. Anthony , McCune David , Steis Ronald , Khong Hung , Richards Donald , Stephenson Joe , Ganesa Prasanthi , Nemunaitis Jackie , Ishioka Glenn , Pappen Beena , Nemunaitis Michael , Morse Michael , Mills Bonnie , Maples Phillip B. , Sherman Jeffrey , Nemunaitis John J.
Published: September 2008

Purpose

Generation of broad cytotoxic T-lymphocyte responses against multiple epitopes and tumor-associated antigens (TAAs) may provide effective immunotherapy in patients with cancer. We evaluated a single-vial peptide vaccine consisting of nine HLA-A2 supertype-binding epitopes (two native and seven analog epitopes modified for optimal HLA binding or T-cell receptor stimulation) covering five TAAs and the universal helper pan-DR epitope, formulated as a stable emulsion with incomplete Freund's adjuvant (Montanide ISA 51; Seppic SA, Paris, France). The clinical efficacy, safety, and multiepitope immunogenicity of IDM-2101 was evaluated in patients with stage IIIB or IV non–small-cell lung cancer (NSCLC).

Patients and Methods

A total of 63 patients were enrolled who were positive for HLA-A2. End points included survival, safety, and immune response. IDM-2101 (previously EP-2101) was administered every 3 weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses. Epitope-specific cytotoxic and helper T-lymphocyte immunogenic responses were measured by the interferon gamma enzyme-linked immunosorbent spot assay.

Results

No significant adverse events were noted. Low-grade erythema and pain at the injection site were the most common adverse effects. One-year survival in the treated patients was 60%, and median survival was 17.3 months. One complete and one partial response were identified. Survival was longer in patients demonstrating an immune response to epitope peptides (P < .001).

Conclusion

IDM-2101 was well tolerated, and evidence of efficacy was suggested.
Causes of Fecal and Urinary Incontinence After Total Mesorectal Excision for Rectal Cancer Based on Cadaveric Surgery: A Study From the Cooperative Clinical Investigators of the Dutch Total Mesorectal Excision Trial
Authors: Wallner Christian , Lange Marilyne M. , Bonsing Bert A. , Maas Cornelis P. , Wallace Charles N. , Dabhoiwala Noshir F. , Rutten Harm J. , Lamers Wouter H. , DeRuiter Marco C. , van de Velde Cornelis J.H.
Published: September 2008

Purpose

Total mesorectal excision (TME) for rectal cancer may result in anorectal and urogenital dysfunction. We aimed to study possible nerve disruption during TME and its consequences for functional outcome. Because the levator ani muscle plays an important role in both urinary and fecal continence, an explanation could be peroperative damage of the nerve supply to the levator ani muscle.

Methods

TME was performed on cadaver pelves. Subsequently, the anatomy of the pelvic floor innervation and its relation to the pelvic autonomic innervation and the mesorectum were studied. Additionally, data from the Dutch TME trial were analyzed to relate anorectal and urinary dysfunction to possible nerve damage during TME procedure.

Results

Cadaver TME surgery demonstrated that, especially in low tumors, the pelvic floor innervation can be damaged. Furthermore, the origin of the levator ani nerve was located in close proximity of the origin of the pelvic splanchnic nerves. Analysis of the TME trial data showed that newly developed urinary and fecal incontinence was present in 33.7% and 38.8% of patients, respectively. Both types of incontinence were significantly associated with each other (P = .027). Low anastomosis was significantly associated with urinary incontinence (P = .049). One third of the patients with newly developed urinary and fecal incontinence also reported difficulty in bladder emptying, for which excessive perioperative blood loss was a significant risk factor.

Conclusion

Perioperative damage to the pelvic floor innervation could contribute to fecal and urinary incontinence after TME, especially in case of a low anastomosis or damage to the pelvic splanchnic nerves.
A functional role for semaphorin 4D/plexin B1 interactions in epithelial branching morphogenesis during organogenesis
Authors: Korostylev Alexander , Worzfeld Thomas , Deng Suhua , Friedel Roland H. , Swiercz Jakub M. , Vodrazka Peter , Maier Viola , Hirschberg Alexandra , Ohoka Yoshiharu , Inagaki Shinobu , Offermanns Stefan , Kuner Rohini
Published: September 2008

Semaphorins and their receptors, plexins, carry out important functions during development and disease. In contrast to the well-characterized plexin A family, however, very little is known about the functional relevance of B-type plexins in organogenesis, particularly outside the nervous system. Here, we demonstrate that plexin B1 and its ligand Sema4d are selectively expressed in epithelial and mesenchymal compartments during key steps in the genesis of some organs. This selective expression suggests a role in epithelial-mesenchymal interactions. Importantly, using the developing metanephros as a model system, we have observed that endogenously expressed and exogenously supplemented Sema4d inhibits branching morphogenesis during early stages of development of the ureteric collecting duct system. Our results further suggest that the RhoA-ROCK pathway, which is activated downstream of plexin B1, mediates these inhibitory morphogenetic effects of Sema4d and suppresses branch-promoting signalling effectors of the plexin B1 signalling complex. Finally, mice that lack plexin B1 show early anomalies in kidney development in vivo. These results identify a novel function for plexin B1 as a negative regulator of branching morphogenesis during kidney development, and suggest that the Sema4d-plexin B1 ligand-receptor pair contributes to epithelial-mesenchymal interactions during organogenesis via modulation of RhoA signalling.
Dopaminergic neuronal cluster size is determined during early forebrain patterning
Authors: Russek-Blum Niva , Gutnick Amos , Nabel-Rosen Helit , Blechman Janna , Staudt Nicole , Dorsky Richard I. , Houart Corinne , Levkowitz Gil
Published: September 2008

We have explored the effects of robust neural plate patterning signals,such as canonical Wnt, on the differentiation and configuration of neuronal subtypes in the zebrafish diencephalon at single-cell resolution. Surprisingly, perturbation of Wnt signaling did not have an overall effect on the specification of diencephalic fates, but selectively affected the number of dopaminergic (DA) neurons. We identified the DA progenitor zone in the diencephalic anlage of the neural plate using a two-photon-based uncaging method and showed that the number of non-DA neurons derived from this progenitor zone is not altered by Wnt attenuation. Using birthdating analysis,we determined the timing of the last cell division of DA progenitors and revealed that the change in DA cell number following Wnt inhibition is not due to changes in cell cycle exit kinetics. Conditional inhibition of Wnt and of cell proliferation demonstrated that Wnt restricts the number of DA progenitors during a window of plasticity, which occurs at primary neurogenesis. Finally, we demonstrated that Wnt8b is a modulator of DA cell number that acts through the Fz8a (Fzd8a) receptor and its downstream effector Lef1, and which requires the activity of the Fezl (Fezf2) transcription factor for this process. Our data show that the differential response of distinct neuronal populations to the Wnt signal is not a simple interpretation of their relative anteroposterior position. This study also shows, for the first time,that diencephalic DA population size is modulated inside the neural plate much earlier than expected, concomitant with Wnt-mediated regional patterning events.
Two CRM protein subfamilies cooperate in the splicing of group IIB introns in chloroplasts
Authors: Asakura Yukari , Bayraktar Omer Ali , Barkan Alice
Published: September 2008

Chloroplast genomes in angiosperms encode ∼20 group II introns, approximately half of which are classified as subgroup IIB. The splicing of all but one of the subgroup IIB introns requires a heterodimer containing the peptidyl-tRNA hydrolase homolog CRS2 and one of two closely related proteins, CAF1 or CAF2, that harbor a recently recognized RNA binding domain called the CRM domain. Two CRS2/CAF-dependent introns require, in addition, a CRM domain protein called CFM2 that is only distantly related to CAF1 and CAF2. Here, we show that CFM3, a close relative of CFM2, associates in vivo with those CRS2/CAF-dependent introns that are not CFM2 ligands. Mutant phenotypes in rice and Arabidopsis support a role for CFM3 in the splicing of most of the introns with which it associates. These results show that either CAF1 or CAF2 and either CFM2 or CFM3 simultaneously bind most chloroplast subgroup IIB introns in vivo, and that the CAF and CFM subunits play nonredundant roles in splicing. These results suggest that the expansion of the CRM protein family in plants resulted in two subfamilies that play different roles in group II intron splicing, with further diversification within a subfamily to accommodate multiple intron ligands.
StAMPL: A Filtration-Oriented Modeling Tool for Multistage Stochastic Recourse Problems
Authors: Fourer Robert , Lopes Leo
Published: September 2008

Every multistage stochastic programming problem with recourse (MSPR) contains a filtration process. In this research, we have created a notation that makes the filtration process the central syntactic construction of the MSPR. As a result, we achieve lower redundancy and higher modularity than is possible using the mathematical notation commonly associated with stochastic programming. To experiment with our ideas, we have created StAMPL, a specialized modeling tool for the MSPR that is based on the AMPL modeling language. StAMPL implements our notation and converts models written in our notation to instances that can be solved using standard methods. Using this approach, we are able to represent models in a very clean, simple, and scalable format while maintaining almost all the power of the AMPL language.
A Complementarity Constraint Formulation of Convex Multiobjective Optimization Problems
Authors: Leyffer Sven
Published: September 2008

We propose a new approach to convex nonlinear multiobjective optimization that captures the geometry of the Pareto set by generating a discrete set of Pareto points optimally. We show that the problem of finding a maximally uniform representation of the Pareto surface can be formulated as a mathematical program with complementarity constraints. The complementarity constraints arise from modeling the set of Pareto points, and the objective maximizes some quality measure of this discrete set. We present encouraging numerical experience on a range of test problems collected from the literature.