bluuebunny/crossref_metadata_2025 huggingface dataset:
Presweetened and Nonpresweetened Ready-to-Eat Cereals at Breakfast Are Associated With Improved Nutrient Intake but Not With Increased Body Weight of Children and Adolescents
Authors: O’Neil Carol E. , Zanovec Michael , Nicklas Theresa A. , Cho Susan S.
Published: May 2011

This study compared nutrient intake and body weight measures in children 4 to 8 (n = 1480) and 9 to 13 (n = 1790), and adolescents 14 to 18 years of age (n = 1826) participating in 1999-2002 NHANES and consuming a presweetened ready-to-eat cereal (PSRTEC), a non-PSRTEC (NPSRTEC), or other breakfast (OB). Sample weights were applied, and logistic regression identified differences among breakfast consumption groups controlling for appropriate covariates. Breakfast type varied by the above-mentioned age groups: 34% (n = 507), 33% (n = 593), and 23% (n = 416) consumed PSRTEC, respectively; 12% (n = 178), 9% (n = 165), and 8% (n = 144), respectively, consumed NPSRTEC; and 54% (n = 795), 58% (n = 1032), and 69% (n = 1266), respectively, consumed OBs. RTEC consumers had significantly higher intakes of thiamin, riboflavin, niacin, vitamin B6 and B12, folate, calcium, magnesium, iron, and zinc than OB consumers. In children 4 to 8 years old and 9 to 13 years old, added sugars (103.3 ± 2.6 and 111.3 ± 3.0 g) were highest in PSRTEC consumers. Fiber intake was highest in NPSRTEC (4-8 and 9-13 years of age) consumers (14.3 ± 0.4 and 14.7 ± 0.7 g) and lowest in 14- to 18-year-old OB consumers (11.9 ± 0.3 g). Weight measures were not higher in either group of RTEC consumers compared with OB consumers. Data suggest that RTEC contribute a high level of nutrients to the diet, and PSRTEC is not associated with higher body weight in children.
Relationship of blood pressure and obesity with inflammatory cytokines among African Americans
Authors: DeLoach Stephanie , Huan Yonghong , Keith Scott W. , Martinez Cantarin Maria P. , Falkner Bonita
Published: May 2011

Objectives: Hypertension and obesity are major public health issues. Both conditions are highly prevalent among African Americans and contribute to the increased burden of cardiovascular disease in this group. Inflammation is considered to be an underlying process in both conditions. The authors sought to determine if there is an interaction between high blood pressure (HBP) and obesity that is associated with markedly elevated plasma levels of proinflammatory cytokines in African American adults.

Methods: This study examined 484 African Americans, aged 18–45 years, including people with and without obesity, and also with and without HBP. People known to have diabetes were not enrolled. Plasma levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), plasminogen activator inhibitor 1, tumor necrosis factor alpha (TNF-α), and adiponectin were measured. Participants also underwent an oral glucose tolerance test and measurement of blood pressure and body mass index (BMI).

Results: There was no statistically significant interaction between obesity and HBP on plasma levels of adiponectin or the inflammatory cytokines. When both conditions were present, HBP and obesity had additive associations with the expected geometric mean ratios for IL-6 (1.44, 95% CI 1.18 to 1.75), TNF-α (1.31, 95% CI 1.11 to 1.53), hsCRP (2.55, 95% CI 1.99 to 3.26) and negative association with adiponectin (0.61, 95% CI 0.52 to 0.71). Compared with HBP, obesity had the predominant association with cytokine levels. An increase in cytokine plasma levels was detectable when BMI exceeded 25 kg/m2.

Conclusions: Biomarkers of inflammation in African Americans are strongly associated with BMI. A modest additive effect is found with HBP. Interventions to reduce obesity-related inflammation may impact cardiovascular disease outcomes.
Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis
Authors: Zimmer Stephanie N. , Zhou Qing , Zhou Ting , Cheng Ziming , Abboud-Werner Sherry L. , Horn Diane , Lecocke Mike , White Ruth , Krivtsov Andrei V. , Armstrong Scott A. , Kung Andrew L. , Livingston David M. , Rebel Vivienne I.
Published: May 2011

CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp+/− mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU-fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp+/− endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation.
Redirecting αβT cells against cancer cells by transfer of a broadly tumor-reactive γδT-cell receptor
Authors: Marcu-Malina Victoria , Heijhuurs Sabine , van Buuren Marit , Hartkamp Linda , Strand Susanne , Sebestyen Zsolt , Scholten Kirsten , Martens Anton , Kuball Jürgen
Published: May 2011

Major limitations of currently investigated αβT cells redirected against cancer by transfer of tumor-specific αβTCR arise from their low affinity, MHC restriction, and risk to mediate self-reactivity after pairing with endogenous α or βTCR chains. Therefore, the ability of a defined γ9δ2TCR to redirect αβT cells selectively against tumor cells was tested and its molecular interaction with a variety of targets investigated. Functional analysis revealed that a γ9δ2TCR efficiently reprograms both CD4+ and CD8+ αβT cells against a broad panel of cancer cells while ignoring normal cells, and substantially reduces but does not completely abrogate alloreactivity. γ9δ2TCR-transduced αβT cells reduced colony formation of progenitor cells of primary acute myeloid leukemia blasts and inhibited leukemia growth in a humanized mouse model. Thereby, metabolites of a dysregulated mevalonate pathway are targeted and the additional application of widely used biphosphonates is crucial for in vivo efficacy most likely because of its modulating effect on cytokine secretion of γ9δ2TCR-transduced αβT cells. Expression of NKG2D ligands and F1-ATPase contributed to the activity of γ9δ2TCR-transduced αβT cells but were not mandatory. In summary, γ9δ2 TCRs are an attractive alternative to broadly redirect αβT cells against cancer cells with both an improved efficacy and safety profile compared with currently used αβTCRs.
To aggregate or not to aggregate high-dimensional classifiers
Authors: Xu Cheng-Jian , Hoefsloot Huub CJ , Smilde Age K
Published: May 2011

Background

High-throughput functional genomics technologies generate large amount of data with hundreds or thousands of measurements per sample. The number of sample is usually much smaller in the order of ten or hundred. This poses statistical challenges and calls for appropriate solutions for the analysis of this kind of data.

Results

Principal component discriminant analysis (PCDA), an adaptation of classical linear discriminant analysis (LDA) for high-dimensional data, has been selected as an example of a base learner. The multiple versions of PCDA models from repeated double cross-validation were aggregated, and the final classification was performed by majority voting. The performance of this approach was evaluated by simulation, genomics, proteomics and metabolomics data sets.

Conclusions

The aggregating PCDA learner can improve the prediction performance, provide more stable result, and help to know the variability of the models. The disadvantage and limitations of aggregating were also discussed.
A high-density transcript linkage map with 1,845 expressed genes positioned by microarray-based Single Feature Polymorphisms (SFP) in Eucalyptus
Authors: Neves Leandro G , MC Mamani Eva , Alfenas Acelino C , Kirst Matias , Grattapaglia Dario
Published: May 2011

Background

Technological advances are progressively increasing the application of genomics to a wider array of economically and ecologically important species. High-density maps enriched for transcribed genes facilitate the discovery of connections between genes and phenotypes. We report the construction of a high-density linkage map of expressed genes for the heterozygous genome of Eucalyptus using Single Feature Polymorphism (SFP) markers.

Results

SFP discovery and mapping was achieved using pseudo-testcross screening and selective mapping to simultaneously optimize linkage mapping and microarray costs. SFP genotyping was carried out by hybridizing complementary RNA prepared from 4.5 year-old trees xylem to an SFP array containing 103,000 25-mer oligonucleotide probes representing 20,726 unigenes derived from a modest size expressed sequence tags collection. An SFP-mapping microarray with 43,777 selected candidate SFP probes representing 15,698 genes was subsequently designed and used to genotype SFPs in a larger subset of the segregating population drawn by selective mapping. A total of 1,845 genes were mapped, with 884 of them ordered with high likelihood support on a framework map anchored to 180 microsatellites with average density of 1.2 cM. Using more probes per unigene increased by two-fold the likelihood of detecting segregating SFPs eventually resulting in more genes mapped. In silico validation showed that 87% of the SFPs map to the expected location on the 4.5X draft sequence of the Eucalyptus grandis genome.

Conclusions

The Eucalyptus 1,845 gene map is the most highly enriched map for transcriptional information for any forest tree species to date. It represents a major improvement on the number of genes previously positioned on Eucalyptus maps and provides an initial glimpse at the gene space for this global tree genome. A general protocol is proposed to build high-density transcript linkage maps in less characterized plant species by SFP genotyping with a concurrent objective of reducing microarray costs. HIgh-density gene-rich maps represent a powerful resource to assist gene discovery endeavors when used in combination with QTL and association mapping and should be especially valuable to assist the assembly of reference genome sequences soon to come for several plant and animal species.
PHENOPSIS DB: an Information System for Arabidopsis thalianaphenotypic data in an environmental context
Authors: Fabre Juliette , Dauzat Myriam , Nègre Vincent , Wuyts Nathalie , Tireau Anne , Gennari Emilie , Neveu Pascal , Tisné Sébastien , Massonnet Catherine , Hummel Irène , Granier Christine
Published: May 2011

Background

Renewed interest in plant × environment interactions has risen in the post-genomic era. In this context, high-throughput phenotyping platforms have been developed to create reproducible environmental scenarios in which the phenotypic responses of multiple genotypes can be analysed in a reproducible way. These platforms benefit hugely from the development of suitable databases for storage, sharing and analysis of the large amount of data collected. In the model plant Arabidopsis thaliana, most databases available to the scientific community contain data related to genetic and molecular biology and are characterised by an inadequacy in the description of plant developmental stages and experimental metadata such as environmental conditions. Our goal was to develop a comprehensive information system for sharing of the data collected in PHENOPSIS, an automated platform for Arabidopsis thaliana phenotyping, with the scientific community.

Description

PHENOPSIS DB is a publicly available (URL: http://bioweb.supagro.inra.fr/phenopsis/) information system developed for storage, browsing and sharing of online data generated by the PHENOPSIS platform and offline data collected by experimenters and experimental metadata. It provides modules coupled to a Web interface for (i) the visualisation of environmental data of an experiment, (ii) the visualisation and statistical analysis of phenotypic data, and (iii) the analysis of Arabidopsis thaliana plant images.

Conclusions

Firstly, data stored in the PHENOPSIS DB are of interest to the Arabidopsis thaliana community, particularly in allowing phenotypic meta-analyses directly linked to environmental conditions on which publications are still scarce. Secondly, data or image analysis modules can be downloaded from the Web interface for direct usage or as the basis for modifications according to new requirements. Finally, the structure of PHENOPSIS DB provides a useful template for the development of other similar databases related to genotype × environment interactions.
Becoming a general practitioner - Which factors have most impact on career choice of medical students?
Authors: Kiolbassa Kathrin , Miksch Antje , Hermann Katja , Loh Andreas , Szecsenyi Joachim , Joos Stefanie , Goetz Katja
Published: May 2011

Background

In Germany, there is a shortage of young physicians in several specialties, the situation of general practitioners (GP) being especially precarious. The factors influencing the career choice of German medical students are poorly understood. This study aims to identify factors influencing medical students' specialty choice laying a special focus on general practice.

Methods

The study was designed as a cross-sectional survey. In 2010, students at the five medical schools in the federal state of Baden-Wuerttemberg (Germany) filled out an online-questionnaire. On 27 items with 5-point Likert scales, the students rated the importance of specified individual and occupational aspects. Furthermore, students were asked to assign their intended medical specialty.

Results

1,299 students participated in the survey. Thereof, 1,114 students stated a current choice for a specialty, with 708 students choosing a career in one of the following 6 specialties: internal medicine, surgery, gynaecology and obstetrics, paediatrics, anaesthetics and general practice. Overall, individual aspects ('Personal ambition', 'Future perspective', 'Work-life balance') were rated as more important than occupational aspects (i.e. 'Variety in job', 'Job-related ambition') for career choice. For students favouring a career as a GP individual aspects and the factor 'Patient orientation' among the occupational aspects were significantly more important and 'Job-related ambition' less important compared to students with other specialty choices.

Conclusions

This study confirms that future GPs differ from students intending to choose other specialties particularly in terms of patient-orientation and individual aspects such as personal ambition, future perspective and work-life balance. Improving job-conditions in terms of family compatibility and work-life balance could help to increase the attractiveness of general practice. Due to the shortage of GPs those factors should be made explicit at an early stage at medical school to increase the number of aspirants for general practice.
The association of HLA-DQB1, -DQA1 and -DPB1 alleles with anti- glomerular basement membrane (GBM) disease in Chinese patients
Authors: Luo Huan , Chen Min , Cui Zhao , Yang Rui , Xu Peng-Cheng , Zhou Xu-Jie , Zhao Ming-Hui
Published: May 2011

Background

Human leukocyte antigen (HLA) alleles are associated with many autoimmune diseases, including anti-glomerular basement membrane (GBM) disease. In our previous study, it was demonstrated that HLA-DRB1*1501 was strongly associated with anti-GBM disease in Chinese. However, the association of anti-GBM disease and other HLA class II genes, including HLA-DQB1, -DQA1,-DPB1 alleles, has rarely been investigated in Asian, especially Chinese patients. The present study further analyzed the association between anti-GBM disease and HLA-DQB1, -DQA1, and -DPB1 genes. Apart from this, we tried to locate the potential risk amino acid residues of anti-GBM disease.

Methods

This study included 44 Chinese patients with anti-GBM disease and 200 healthy controls. The clinical and pathological data of the patients were collected and analyzed. Typing of HLA-DQB1, -DQA1 and -DPB1 alleles were performed by bi-directional sequencing of exon 2 using the SeCoreTM Sequencing Kits.

Results

Compared with normal controls, the prevalence of HLA-DPB1*0401 was significantly lower in patients with anti-GBM disease (3/88 vs. 74/400, p = 4.4 × 10-4, pc = 0.039). Comparing with normal controls, the combination of presence of DRB1*1501 and absence of DPB1*0401 was significantly prominent among anti-GBM patients (p = 2.0 × 10-12, pc = 1.7 × 10-10).

Conclusions

HLA-DPB1*0401 might be a protective allele to anti-GBM disease in Chinese patients. The combined presence of DRB1*1501 and absence of DPB1*0401 might have an even higher risk to anti-GBM disease than HLA-DRB1*1501 alone.
CD248 facilitates tumor growth via its cytoplasmic domain
Authors: Maia Margarida , DeVriese Astrid , Janssens Tom , Moons Michaël , Lories Rik J , Tavernier Jan , Conway Edward M
Published: May 2011

Background

Stromal fibroblasts participate in the development of a permissive environment for tumor growth, yet molecular pathways to therapeutically target fibroblasts are poorly defined. CD248, also known as endosialin or tumor endothelial marker 1 (TEM1), is a transmembrane glycoprotein expressed on activated fibroblasts. We recently showed that the cytoplasmic domain of CD248 is important in facilitating an inflammatory response in a mouse model of arthritis. Others have reported thatCD248gene inactivation in mice results in dampened tumor growth. We hypothesized that the conserved cytoplasmic domain of CD248 is important in regulating tumor growth.

Methods

Mice lacking the cytoplasmic domain of CD248 (CD248CyD/CyD) were generated and evaluated in tumor models, comparing the findings with wild-type mice (CD248WT/WT).

Results

As compared to the response in CD248WT/WTmice, growth of T241 fibrosarcomas and Lewis lung carcinomas was significantly reduced in CD248CyD/CyDmice. Tumor size was similar to that seen with CD248-deficient mice. Conditioned media from CD248CyD/CyDfibroblasts were less effective at supporting T241 fibrosarcoma cell survival. In addition to our previous observation of reduced release of activated matrix metalloproteinase (MMP)-9, CD248CyD/CyDfibroblasts also had impaired PDGF-BB-induced migration and expressed higher transcripts of tumor suppressor factors, transgelin (SM22α), Hes and Hey1.

Conclusions

The multiple pathways regulated by the cytoplasmic domain of CD248 highlight its potential as a therapeutic target to treat cancer.
Comparison of commercial kits to measure cytokine responses to Plasmodium falciparum by multiplex microsphere suspension array technology
Authors: Berthoud Tamara K , Manaca Maria Nelia , Quelhas Diana , Aguilar Ruth , Guinovart Caterina , Puyol Laura , Barbosa Arnoldo , Alonso Pedro L , Dobaño Carlota
Published: May 2011

Background

Multiplex cytokine profiling systems are useful tools for investigating correlates of protective immunity. Several Luminex and flow cytometry methods are commercially available but there is limited information on the relative performance of different kits. A series of comparison experiments were carried out to determine the most appropriate method for our subsequent studies.

Methods

Two Luminex methods were compared, the Bio-Rad human 17-plex panel and the Invitrogen (formerly BioSource) human cytokine 10-plex kit, and two flow cytometry methods, the Becton Dickinson Human Th1/Th2 Cytokine Kit (CBA) and the Bender MedSystems Human Th1/Th2 11plex FlowCytomix Multiplex Kit. All kits were tested for the measurement of cytokines in supernatants collected from human leukocytes stimulated with viable Plasmodium falciparum infected red blood cells (iRBC) or P. falciparum schizont lysates.

Results

Data indicated that the kits differed in sensitivity and reproducibility depending on the cytokine, and detected different quantities of some cytokines. The Bio-Rad 17-plex kit was able to detect more positive responses than the Invitrogen 10-plex kit. However, only when detecting IL-1, IL-6 or TNF did the two Luminex based methods correlate with one another. In this study, the flow cytometry based techniques were less variable and correlated better with one another. The two flow cytometry based kits showed significant correlation when detecting IFN-γ, IL-2, TNF, IL-10 and IL-6, but overall the BD kit detected more positive responses than the Bender MedSystems kit.

Conclusions

The microsphere suspension array technologies tested differed in reproducibility and the absolute quantity of cytokine detected. Sample volume, the number of cytokines measured, and the time and cost of the assays also differed. These data provide an accurate assessment of the four techniques, which will allow individual researchers to select the tool most suited for their study population.
Evaluation of three high abundance protein depletion kits for umbilical cord serum proteomics
Authors: Liu Bin , Qiu Fang-hua , Voss Courtney , Xu Yun , Zhao Ming-zhe , Wu Yan-xin , Nie Jing , Wang Zi-lian
Published: May 2011

Background

High abundance protein depletion is a major challenge in the study of serum/plasma proteomics. Prior to this study, most commercially available kits for depletion of highly abundant proteins had only been tested and evaluated in adult serum/plasma, while the depletion efficiency on umbilical cord serum/plasma had not been clarified. Structural differences between some adult and fetal proteins (such as albumin) make it likely that depletion approaches for adult and umbilical cord serum/plasma will be variable. Therefore, the primary purposes of the present study are to investigate the efficiencies of several commonly-used commercial kits during high abundance protein depletion from umbilical cord serum and to determine which kit yields the most effective and reproducible results for further proteomics research on umbilical cord serum.

Results

The immunoaffinity based kits (PROTIA-Sigma and 5185-Agilent) displayed higher depletion efficiency than the immobilized dye based kit (PROTBA-Sigma) in umbilical cord serum samples. Both the PROTIA-Sigma and 5185-Agilent kit maintained high depletion efficiency when used three consecutive times. Depletion by the PROTIA-Sigma Kit improved 2DE gel quality by reducing smeared bands produced by the presence of high abundance proteins and increasing the intensity of other protein spots. During image analysis using the identical detection parameters, 411 ± 18 spots were detected in crude serum gels, while 757 ± 43 spots were detected in depleted serum gels. Eight spots unique to depleted serum gels were identified by MALDI- TOF/TOF MS, seven of which were low abundance proteins.

Conclusions

The immunoaffinity based kits exceeded the immobilized dye based kit in high abundance protein depletion of umbilical cord serum samples and dramatically improved 2DE gel quality for detection of trace biomarkers.
Facile solution growth of vertically aligned ZnO nanorods sensitized with aqueous CdS and CdSe quantum dots for photovoltaic applications
Authors: Luan Chunyan , Vaneski Aleksandar , Susha Andrei S , Xu Xueqing , Wang Hong-En , Chen Xue , Xu Jun , Zhang Wenjun , Lee Chun-Sing , Rogach Andrey L , Zapien Juan Antonio
Published: May 2011

Vertically aligned single crystalline ZnO nanorod arrays, approximately 3 μm in length and 50-450 nm in diameter are grown by a simple solution approach on a Zn foil substrate. CdS and CdSe colloidal quantum dots are assembled onto ZnO nanorods array using water-soluble nanocrystals capped as-synthesized with a short-chain bifuncional linker thioglycolic acid. The solar cells co-sensitized with both CdS and CdSe quantum dots demonstrate superior efficiency compared with the cells using only one type of quantum dots. A thin Al2O3 layer deposited prior to quantum dot anchoring successfully acts as a barrier inhibiting electron recombination at the Zn/ZnO/electrolyte interface, resulting in power conversion efficiency of approximately 1% with an improved fill factor of 0.55. The in situ growth of ZnO nanorod arrays in a solution containing CdSe quantum dots provides better contact between two materials resulting in enhanced open circuit voltage.
Numerical evaluation of laminar heat transfer enhancement in nanofluid flow in coiled square tubes
Authors: Sasmito Agus Pulung , Kurnia Jundika Candra , Mujumdar Arun Sadashiv
Published: May 2011

Convective heat transfer can be enhanced by changing flow geometry and/or by enhancing thermal conductivity of the fluid. This study proposes simultaneous passive heat transfer enhancement by combining the geometry effect utilizing nanofluids inflow in coils. The two nanofluid suspensions examined in this study are: water-Al2O3 and water-CuO. The flow behavior and heat transfer performance of these nanofluid suspensions in various configurations of coiled square tubes, e.g., conical spiral, in-plane spiral, and helical spiral, are investigated and compared with those for water flowing in a straight tube. Laminar flow of a Newtonian nanofluid in coils made of square cross section tubes is simulated using computational fluid dynamics (CFD)approach, where the nanofluid properties are treated as functions of particle volumetric concentration and temperature. The results indicate that addition of small amounts of nanoparticles up to 1% improves significantly the heat transfer performance; however, further addition tends to deteriorate heat transfer performance.
Effect of Eu-implantation and annealing on the GaN quantum dots excitonic recombination
Authors: Peres Marco , Magalhães Sérgio , Fellmann Vincent , Daudin Bruno , Neves Armando José , Alves Eduardo , Lorenz Katharina , Monteiro Teresa
Published: May 2011

Undoped self-assembled GaN quantum dots (QD) stacked in superlattices (SL) with AlN spacer layers were submitted to thermal annealing treatments. Changes in the balance between the quantum confinement, strain state of the stacked heterostructures and quantum confined Stark effect lead to the observation of GaN QD excitonic recombination above and below the bulk GaN bandgap. In Eu-implanted SL structures, the GaN QD recombination was found to be dependent on the implantation fluence. For samples implanted with high fluence, a broad emission band at 2.7 eV was tentatively assigned to the emission of large blurred GaN QD present in the damage region of the implanted SL. This emission band is absent in the SL structures implanted with lower fluence and hence lower defect level. In both cases, high energy emission bands at approx. 3.9 eV suggest the presence of smaller dots for which the photoluminescence intensity was seen to be constant with increasing temperatures. Despite the fact that different deexcitation processes occur in undoped and Eu-implanted SL structures, the excitation population mechanisms were seen to be sample-independent. Two main absorption bands with maxima at approx. 4.1 and 4.7 to 4.9 eV are responsible for the population of the optically active centres in the SL samples.
The effects of high dose interferon-β1a on plasma microparticles: Correlation with MRI parameters
Authors: Lowery-Nordberg Mary , Eaton Erin , Gonzalez-Toledo Eduardo , Harris Meghan K , Chalamidas Kathrine , McGee-Brown Jeanie , Ganta Chaitanya V , Minagar Alireza , Cousineau David , Alexander J Steven
Published: May 2011

Objectives

We previously reported a correlation between levels of microparticles carrying CD31 (PMPCD31+) and disease activity in MS. However, the effects of long term (12 month) treatment with high dose, high frequency interferon-β1a (Rebif™) on plasma levels of PMPCD31+, PMPCD146+, and PMPCD54+and MRI measures of disease activity have not yet been assessed.

Methods

During this prospective 1-year study, we used flow cytometry to measure changes in plasma microparticles (PMP) bearing CD31 (PMPCD31+), CD146 (PMPCD146+), and CD54/ICAM-1 (PMPCD54+) in 16 consecutive patients with relapsing-remitting MS (RRMS) before and after 3, 6, and 12 months of subcutaneous therapy with interferon-beta1a (44 micrograms, 3X weekly). At each visit, clinical exams and expanded disability status scale (EDSS) scores were recorded.

Results

Plasma levels of PMPCD31+, and PMPCD54+were significantly reduced by treatment with IFN-β1a. PMPCD146+appeared to decrease only at 3 months and did not persist at 6 and 12 months (p = 0.0511). In addition, the decrease in plasma levels of PMPCD31+and PMPCD54+levels at 12 months were associated with a significant decrease in the number and volume of contrast enhancing T1-weigthed lesions.

Conclusion

Our data suggest that serial measurement of plasma microparticles (PMP), particularly in the initial stages of MS (when neuro-inflammatory cascades are more intense), may serve as reliable and reproducible surrogate markers of response to IFN-β1a therapy for MS. In addition, the progressive decline in plasma levels of PMPCD31+and PMPCD54+further supports the concept that IFN-β1a exerts stabilizing effect on the cerebral endothelial cells during pathogenesis of MS.
Tat RNA silencing suppressor activity contributes to perturbation of lymphocyte miRNA by HIV-1
Authors: Hayes Amy M , Qian Shuiming , Yu Lianbo , Boris-Lawrie Kathleen
Published: May 2011

Background

MicroRNA (miRNA)-mediated RNA silencing is integral to virtually every cellular process including cell cycle progression and response to virus infection. The interplay between RNA silencing and HIV-1 is multifaceted, and accumulating evidence posits a strike-counterstrike interface that alters the cellular environment to favor virus replication. For instance, miRNA-mediated RNA silencing of HIV-1 translation is antagonized by HIV-1 Tat RNA silencing suppressor activity. The activity of HIV-1 accessory proteins Vpr/Vif delays cell cycle progression, which is a process prominently modulated by miRNA. The expression profile of cellular miRNA is altered by HIV-1 infection in both cultured cells and clinical samples. The open question stands of what, if any, is the contribution of Tat RNA silencing suppressor activity or Vpr/Vif activity to the perturbation of cellular miRNA by HIV-1.

Results

Herein, we compared the perturbation of miRNA expression profiles of lymphocytes infected with HIV-1NL4-3 or derivative strains that are deficient in Tat RNA silencing suppressor activity (Tat K51A substitution) or ablated of the vpr/vif open reading frames. Microarrays recapitulated the perturbation of the cellular miRNA profile by HIV-1 infection. The miRNA expression trends overlapped ~50% with published microarray results on clinical samples from HIV-1 infected patients. Moreover, the number of miRNA perturbed by HIV-1 was largely similar despite ablation of Tat RSS activity and Vpr/Vif; however, the Tat RSS mutation lessened HIV-1 downregulation of twenty-two miRNAs.

Conclusions

Our study identified miRNA expression changes attributable to Tat RSS activity in HIV-1NL4-3. The results accomplish a necessary step in the process to understand the interface of HIV-1 with host RNA silencing activity. The overlap in miRNA expression trends observed between HIV-1 infected CEMx174 lymphocytes and primary cells supports the utility of cultured lymphocytes as a tractable model to investigate interplay between HIV-1 and host RNA silencing. The subset of miRNA determined to be perturbed by Tat RSS in HIV-1 infection provides a focal point to define the gene networks that shape the cellular environment for HIV-1 replication.
Serine 204 phosphorylation and O-β-GlcNAC interplay of IGFBP-6 as therapeutic indicator to regulate IGF-II functions in viral mediated hepatocellular carcinoma
Authors: Ahmad Waqar , Shabbiri Khadija , Ijaz Bushra , Asad Sultan , Nazar Noreen , Nazar Shazia , Fouzia Kiran , Kausar Humera , Gull Sana , Sarwar Muhammad T , Shahid Imran , Hassan Sajida
Published: May 2011

Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-β-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-β-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma.
Frozen Elephant Trunk: A technique which can be offered in complex pathology to fix the whole aorta in one setting
Authors: Kokotsakis John , Anagnostakou Vania , Kratimenos Theodoros , Ashrafian Hutan , Athanasiou Thanos
Published: May 2011

We report a case of treating complex aortic pathology with the use of the Frozen Elephant Trunk technique in a patient with chronic type B aortic dissecting aneurysm associated with arch and ascending aorta dilatation, proximal aortic disease and coronary disease. The case was further complicated due to the involvement of the abdominal vessels and preexisting femoral to femoral crossover bypass. In addition the patient had a tracheostomy for laryngeal cancer.

We emphasize the role of the Frozen Elephant Trunk to fix the whole aorta in one setting with special attention given to the changes taking place in vascular perfusion following correction and reconstitution of the true lumen.
'Prechronous' metastasis in clear cell renal cell carcinoma: a case report
Authors: Poon Eileen , Ong Sin Jen , Chuang Xue En , Lim Wan Teck , Mohd Zam Nor Azhari , Chong Tsung Wen , Al Jajeh Issam , Mancer Kent , Tan Min-Han
Published: May 2011

Introduction

Although metastatic carcinoma in the presence of an occult primary tumor is well recognized, underlying reasons for the failure of the primary tumor to manifest are uncertain. Explanations for this phenomenon have ranged from spontaneous regression of the primary tumor to early metastasis of the primary tumor before manifestation of a less aggressive primary tumor. We report a case of 'prechronous' metastasis arising from clear cell renal cell carcinoma, where metastatic disease initially manifested in the absence of a primary renal tumor, followed by aggressive growth of the primary renal lesion.

Case presentation

A 43-year-old Malay man initially presented to our facility with fever and cough. He subsequently underwent surgical resection of a 9 cm right-sided lung mass found on radiological examination. Histology showed a high-grade clear cell tumor with sarcomatoid differentiation, suggestive of a metastasis from clear cell renal cell carcinoma. However, no concurrent renal lesions were noted on computed tomographic evaluation at that time. Then, four months after lung resection, he presented with a subcutaneous mass in the left loin, as well as right loin discomfort. Computed tomography scanning revealed a 10 cm right renal mass, with renal vein and inferior vena cava invasion, as well as recurrent disease in the right thorax. Histological examination of the excised subcutaneous mass revealed a high-grade carcinoma consistent with clear cell renal cell carcinoma.

Conclusions

This is the first reported case of prechronous metastasis of renal cell carcinoma, with metastatic disease manifesting prior to the development of the primary lesion. The underlying mechanism is uncertain, but our patient's case provides anecdotal support for the early dissemination model of metastasis.
Circulating osteopontin: a dual marker of bone destruction and angiogenesis in patients with multiple myeloma
Authors: Sfiridaki Aikaterini , Miyakis Spiros , Pappa Constantina , Tsirakis George , Alegakis Athanasios , Kotsis Vasileios , Stathopoulos Efstathios , Alexandrakis Michael
Published: May 2011

The matrix protein osteopontin has been shown to be a marker of osteoclastic activity in multiple myeloma patients, as well as a regulator of angiogenesis. We measured serum levels of osteopontin in 50 untreated multiple myeloma patients (in 25, also after treatment) and examined the relation to markers of osteolytic and angiogenic activity. The median (range) of serum osteopontin was 85 (5-232) in the patient group vs. 36 (2-190) ng/ml in the control group. Serum osteopontin levels were significantly higher in patients with advanced stage or grade of myeloma disease. All patients with serum osteopontin levels >100 ng/ml had advanced stage (II or III) or high grade bone disease, whereas stage I or low grade patients had serum osteopontin levels <100ng/ml. Serum osteopontin levels significantly decreased after treatment. There was a positive correlation of osteopontin with the bone turnover marker N-terminal propeptide of procollagen type I (NTx) and the angiogenic markers vascular endothelial growth factor (VEGF) and bone marrow microvessel density (r: 0.35, 0.47 and 0.30 respectively, p < 0.05). These results support osteopontin as a dual marker of bone destruction and angiogenic activity in myeloma patients. Osteopontin represents a useful biomarker for monitoring myeloma disease activity.
Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-α-induced protein 6
Authors: Danchuk Svitlana , Ylostalo Joni H , Hossain Fokhrul , Sorge Randy , Ramsey Austin , Bonvillain Ryan W , Lasky Joseph A , Bunnell Bruce A , Welsh David A , Prockop Darwin J , Sullivan Deborah E
Published: May 2011

Introduction

Multipotent stromal cells (MSCs) are currently in clinical trials for a number of inflammatory diseases. Recent studies have demonstrated the ability of MSCs to attenuate inflammation in rodent models of acute lung injury (ALI) suggesting that MSCs may also be beneficial in treating ALI.

Methods

To better understand how human MSCs (hMSCs) may act in ALI, the lungs of immunocompetent mice were exposed to lipopolysaccharide (LPS) and four hours later bone marrow derived hMSCs were delivered by oropharyngeal aspiration (OA). The effect of hMSCs on lung injury was assessed by measuring the lung wet/dry weight ratio and total protein in bronchoalveolar lavage (BAL) fluid 24 or 48 h after LPS. BAL fluid was also analyzed for the presence of inflammatory cells and cytokine expression by multiplex immunoassay. Microarray analysis of total RNA isolated from treated and untreated lungs was performed to elucidate the mechanism(s) involved in hMSC modulation of lung inflammation.

Results

Administration of hMSCs significantly reduced the expression of pro-inflammatory cytokines, neutrophil counts and total protein in bronchoalveolar lavage. There was a concomitant reduction in pulmonary edema. The anti-inflammatory effects of hMSCs were not dependent on localization to the lung, as intraperitoneal administration of hMSCs also attenuated LPS-induced inflammation in the lung. Microarray analysis revealed significant induction of tumor necrosis factor (TNF)-α-induced protein 6 (TNFAIP6/ TSG-6) expression by hMSCs 12 h after OA delivery to LPS-exposed lungs. Knockdown of TSG-6 expression in hMSCs by RNA interference abrogated most of their anti-inflammatory effects. In addition, intra-pulmonary delivery of recombinant human TSG-6 reduced LPS-induced inflammation in the lung.

Conclusions

These results show that hMSCs recapitulate the observed beneficial effects of rodent MSCs in animal models of ALI and suggest that the anti-inflammatory properties of hMSCs in the lung are explained, at least in part, by activation of hMSCs to secrete TSG-6.
Longitudinal Perceptions of Prognosis and Goals of Therapy in Patients With Metastatic Non–Small-Cell Lung Cancer: Results of a Randomized Study of Early Palliative Care
Authors: Temel Jennifer S. , Greer Joseph A. , Admane Sonal , Gallagher Emily R. , Jackson Vicki A. , Lynch Thomas J. , Lennes Inga T. , Dahlin Connie M. , Pirl William F.
Published: May 2011

Purpose

Understanding of prognosis among terminally ill patients impacts medical decision making. The aims of this study were to explore perceptions of prognosis and goals of therapy in patients with metastatic non–small-cell lung cancer (NSCLC) and to examine the effect of early palliative care on these views over time.

Patients and Methods

Patients with newly diagnosed metastatic NSCLC were randomly assigned to receive either early palliative care integrated with standard oncology care or standard oncology care alone. Participants completed baseline and longitudinal assessments of their perceptions of prognosis and the goals of cancer therapy over a 6-month period.

Results

We enrolled 151 participants on the study. Despite having terminal cancer, one third of patients (46 of 145 patients) reported that their cancer was curable at baseline, and a majority (86 of 124 patients) endorsed getting rid of all of the cancer as a goal of therapy. Baseline perceptions of prognosis (ie, curability) and goals of therapy did not differ significantly between study arms. A greater percentage of patients assigned to early palliative care retained or developed an accurate assessment of their prognosis over time (82.5% v 59.6%; P = .02) compared with those receiving standard care. Patients receiving early palliative care who reported an accurate perception of their prognosis were less likely to receive intravenous chemotherapy near the end of life (9.4% v 50%; P = .02).

Conclusion

Many patients with newly diagnosed metastatic NSCLC hold inaccurate perceptions of their prognoses. Early palliative care significantly improves patient understanding of prognosis over time, which may impact decision making about care near the end of life.
Response, Survival, and Long-Term Toxicity After Therapy With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine Cancers
Authors: Imhof Anna , Brunner Philippe , Marincek Nicolas , Briel Matthias , Schindler Christian , Rasch Helmut , Mäcke Helmut R. , Rochlitz Christoph , Müller-Brand Jan , Walter Martin A.
Published: May 2011

Purpose

To investigate response, survival, and safety profile of the somatostatin-based radiopeptide 90yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ([90Y-DOTA]-TOC) in neuroendocrine cancers.

Patients and Methods

In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [90Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m2 body-surface [90Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity.

Results

Overall, 1,109 patients received 2,472 cycles of [90Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003).

Conclusion

This study documents the long-term outcome of [90Y-DOTA]-TOC treatment in a large cohort. Response to [90Y-DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [90Y-DOTA]-TOC treatment and occurrence of renal toxicity.
Overall Survival As the Outcome for Randomized Clinical Trials With Effective Subsequent Therapies
Authors: Korn Edward L. , Freidlin Boris , Abrams Jeffrey S.
Published: May 2011

We review how overall survival (OS) comparisons should be interpreted with increasing availability of effective therapies that can be given subsequently to the treatment assigned in a randomized clinical trial (RCT). We examine in detail how effective subsequent therapies influence OS comparisons under varying conditions in RCTs. A subsequent therapy given after tumor progression (or relapse) in an RCT that works better in the standard arm than the experimental arm will lead to a smaller OS difference (possibly no difference) than one would see if the subsequent therapy was not available. Subsequent treatments that are equally effective in the treatment arms would not be expected to affect the absolute OS benefit of the experimental treatment but will make the relative improvement in OS smaller. In trials in which control arm patients cross over to the experimental treatment after their condition worsens, a smaller OS difference could be observed than one would see without cross-overs. In particular, use of cross-over designs in the first definitive evaluation of a new agent in a given disease compromises the ability to assess clinical benefit. In disease settings in which there is not an intermediate end point that directly measures clinical benefit, OS should be the primary end point of an RCT. The observed difference in OS should be considered the measure of clinical benefit to the patients, regardless of subsequent therapies, provided that the subsequent therapies used in both treatment arms follow the current standard of care.