bluuebunny/crossref_metadata_2025 huggingface dataset:
Chest wall volume regulation during exercise in COPD patients with GOLD stages II to IV
Authors: Vogiatzis I. , Stratakos G. , Athanasopoulos D. , Georgiadou O. , Golemati S. , Koutsoukou A. , Weisman I. , Roussos C. , Zakynthinos S.
Published: March 2008

The present study investigated how end-expiratory ribcage and abdominal volume regulation during exercise is related to the degree of dynamic chest wall hyperinflation in patients with different spirometric severity of chronic obstructive pulmonary disease (COPD) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification.

In total, 42 COPD patients and 11 age-matched healthy subjects were studied during a ramp-incremental cycling test to the limit of tolerance (Wpeak). Volume variations of the chest wall (at end expiration (EEVcw) and end inspiration) and its compartments (ribcage (Vrc) and abdominal (Vab)) were computed by optoelectronic plethysmography.

At Wpeak, only patients in GOLD stages III and IV exhibited a significant increase in EEVcw(increase of 454±509 and 562±363 mL, respectively). These patients did not significantly reduce end-expiratoryVab, whereas patients in GOLD stage II resembled healthy subjects with significantly reduced end-expiratoryVab(decrease of 287±350 mL). In patients, the greater the increase in EEVcwat Wpeak, the smaller the reductions in end-expiratoryVaband the greater the increase in end-expiratoryVrc.

In chronic obstructive pulmonary disease patients with different spirometric disease severity, greater degrees of exercise-induced dynamic chest wall hyperinflation were accompanied by lower degrees of end-expiratory abdominal volume displacement and larger increases in end-expiratory ribcage volume.
Exogenous surfactant application in a rat lung ischemia reperfusion injury model: effects on edema formation and alveolar type II cells
Authors: Dreyer Niels , Mühlfeld Christian , Fehrenbach Antonia , Pech Thomas , von Berg Sebastian , Nagib Ragi , Richter Joachim , Wittwer Thorsten , Wahlers Thorsten , Ochs Matthias
Published: March 2008

Background

Prophylactic exogenous surfactant therapy is a promising way to attenuate the ischemia and reperfusion (I/R) injury associated with lung transplantation and thereby to decrease the clinical occurrence of acute lung injury and acute respiratory distress syndrome. However, there is little information on the mode by which exogenous surfactant attenuates I/R injury of the lung. We hypothesized that exogenous surfactant may act by limiting pulmonary edema formation and by enhancing alveolar type II cell and lamellar body preservation. Therefore, we investigated the effect of exogenous surfactant therapy on the formation of pulmonary edema in different lung compartments and on the ultrastructure of the surfactant producing alveolar epithelial type II cells.

Methods

Rats were randomly assigned to a control, Celsior (CE) or Celsior + surfactant (CE+S) group (n = 5 each). In both Celsior groups, the lungs were flush-perfused with Celsior and subsequently exposed to 4 h of extracorporeal ischemia at 4°C and 50 min of reperfusion at 37°C. The CE+S group received an intratracheal bolus of a modified natural bovine surfactant at a dosage of 50 mg/kg body weight before flush perfusion. After reperfusion (Celsior groups) or immediately after sacrifice (Control), the lungs were fixed by vascular perfusion and processed for light and electron microscopy. Stereology was used to quantify edematous changes as well as alterations of the alveolar epithelial type II cells.

Results

Surfactant treatment decreased the intraalveolar edema formation (mean (coefficient of variation): CE: 160 mm3 (0.61) vs. CE+S: 4 mm3 (0.75); p < 0.05) and the development of atelectases (CE: 342 mm3 (0.90) vs. CE+S: 0 mm3; p < 0.05) but led to a higher degree of peribronchovascular edema (CE: 89 mm3 (0.39) vs. CE+S: 268 mm3 (0.43); p < 0.05). Alveolar type II cells were similarly swollen in CE (423 μm3(0.10)) and CE+S (481 μm3(0.10)) compared with controls (323 μm3(0.07); p < 0.05 vs. CE and CE+S). The number of lamellar bodies was increased and the mean lamellar body volume was decreased in both CE groups compared with the control group (p < 0.05).

Conclusion

Intratracheal surfactant application before I/R significantly reduces the intraalveolar edema formation and development of atelectases but leads to an increased development of peribronchovascular edema. Morphological changes of alveolar type II cells due to I/R are not affected by surfactant treatment. The beneficial effects of exogenous surfactant therapy are related to the intraalveolar activity of the exogenous surfactant.
Polymorphism Interaction Analysis (PIA): a method for investigating complex gene-gene interactions
Authors: Mechanic Leah E , Luke Brian T , Goodman Julie E , Chanock Stephen J , Harris Curtis C
Published: March 2008

Background

The risk of common diseases is likely determined by the complex interplay between environmental and genetic factors, including single nucleotide polymorphisms (SNPs). Traditional methods of data analysis are poorly suited for detecting complex interactions due to sparseness of data in high dimensions, which often occurs when data are available for a large number of SNPs for a relatively small number of samples. Validation of associations observed using multiple methods should be implemented to minimize likelihood of false-positive associations. Moreover, high-throughput genotyping methods allow investigators to genotype thousands of SNPs at one time. Investigating associations for each individual SNP or interactions between SNPs using traditional approaches is inefficient and prone to false positives.

Results

We developed the Polymorphism Interaction Analysis tool (PIA version 2.0) to include different approaches for ranking and scoring SNP combinations, to account for imbalances between case and control ratios, stratify on particular factors, and examine associations of user-defined pathways (based on SNP or gene) with case status. PIA v. 2.0 detected 2-SNP interactions as the highest ranking model 77% of the time, using simulated data sets of genetic models of interaction (minor allele frequency = 0.2; heritability = 0.01; N = 1600) generated previously [Velez DR, White BC, Motsinger AA, Bush WS, Ritchie MD, Williams SM, Moore JH: A balanced accuracy function for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction. Genet Epidemiol 2007, 31:306–315.]. Interacting SNPs were detected in both balanced (20 SNPs) and imbalanced data (case:control 1:2 and 1:4, 10 SNPs) in the context of non-interacting SNPs.

Conclusion

PIA v. 2.0 is a useful tool for exploring gene*gene or gene*environment interactions and identifying a small number of putative associations which may be investigated further using other statistical methods and in replication study populations.
The adaptive evolution of the mammalian mitochondrial genome
Authors: da Fonseca Rute R , Johnson Warren E , O'Brien Stephen J , Ramos Maria João , Antunes Agostinho
Published: March 2008

Background

The mitochondria produce up to 95% of a eukaryotic cell's energy through oxidative phosphorylation. The proteins involved in this vital process are under high functional constraints. However, metabolic requirements vary across species, potentially modifying selective pressures. We evaluate the adaptive evolution of 12 protein-coding mitochondrial genes in 41 placental mammalian species by assessing amino acid sequence variation and exploring the functional implications of observed variation in secondary and tertiary protein structures.

Results

Wide variation in the properties of amino acids were observed at functionally important regions of cytochrome b in species with more-specialized metabolic requirements (such as adaptation to low energy diet or large body size, such as in elephant, dugong, sloth, and pangolin, and adaptation to unusual oxygen requirements, for example diving in cetaceans, flying in bats, and living at high altitudes in alpacas). Signatures of adaptive variation in the NADH dehydrogenase complex were restricted to the loop regions of the transmembrane units which likely function as protons pumps. Evidence of adaptive variation in the cytochrome c oxidase complex was observed mostly at the interface between the mitochondrial and nuclear-encoded subunits, perhaps evidence of co-evolution. The ATP8 subunit, which has an important role in the assembly of F0, exhibited the highest signal of adaptive variation. ATP6, which has an essential role in rotor performance, showed a high adaptive variation in predicted loop areas.

Conclusion

Our study provides insight into the adaptive evolution of the mtDNA genome in mammals and its implications for the molecular mechanism of oxidative phosphorylation. We present a framework for future experimental characterization of the impact of specific mutations in the function, physiology, and interactions of the mtDNA encoded proteins involved in oxidative phosphorylation.
Pleiotropic phenotypes of a Yersinia enterocolitica flhD mutant include reduced lethality in a chicken embryo model
Authors: Townsend Megan K , Carr Nathan J , Iyer Jyoti G , Horne Shelley M , Gibbs Penelope S , Prüß Birgit M
Published: March 2008

Background

The Yersinia enterocolitica flagellar master regulator FlhD/FlhC affects the expression levels of non-flagellar genes, including 21 genes that are involved in central metabolism. The sigma factor of the flagellar system, FliA, has a negative effect on the expression levels of seven plasmid-encoded virulence genes in addition to its positive effect on the expression levels of eight of the flagellar operons. This study investigates the phenotypes of flhD and fliA mutants that result from the complex gene regulation.

Results

Phenotypes relating to central metabolism were investigated with Phenotype MicroArrays. Compared to the wild-type strain, isogenic flhD and fliA mutants exhibited increased growth on purines and reduced growth on N-acetyl-D-glucosamine and D-mannose, when used as a sole carbon source. Both mutants grew more poorly on pyrimidines and L-histidine as sole nitrogen source. Several intermediates of the tricarboxylic acid and the urea cycle, as well as several dipeptides, provided differential growth conditions for the two mutants. Gene expression was determined for selected genes and correlated with the observed phenotypes. Phenotypes relating to virulence were determined with the chicken embryo lethality assay. The assay that was previously established for Escherichia coli strains was modified for Y. enterocolitica. The flhD mutant caused reduced chicken embryo lethality when compared to wild-type bacteria. In contrast, the fliA mutant caused wild-type lethality. This indicates that the virulence phenotype of the flhD mutant might be due to genes that are regulated by FlhD/FlhC but not FliA, such as those that encode the flagellar type III secretion system.

Conclusion

Phenotypes of flhD and fliA mutants are related to central metabolism and virulence and correlate with gene regulation.
Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria
Authors: Ruiz-Peña Juan Luís , Duque Pablo , Izquierdo Guillermo
Published: March 2008

Background

A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation.

Methods

Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN β1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years.

Results

We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m – last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m – last visit; CH: 0.29, NCH: 0.13).

Conclusion

Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.
Biomonitoring of complex occupational exposures to carcinogens: The case of sewage workers in Paris
Authors: Al Zabadi Hamzeh , Ferrari Luc , Laurent Anne-Marie , Tiberguent Aziz , Paris Christophe , Zmirou-Navier Denis
Published: March 2008

Background

Sewage workers provide an essential service in the protection of public and environmental health. However, they are exposed to varied mixtures of chemicals; some are known or suspected to be genotoxics or carcinogens. Thus, trying to relate adverse outcomes to single toxicant is inappropriate. We aim to investigate if sewage workers are at increased carcinogenic risk as evaluated by biomarkers of exposure and early biological effects.

Methods/design

This cross sectional study will compare exposed sewage workers to non-exposed office workers. Both are voluntaries from Paris municipality, males, aged (20–60) years, non-smokers since at least six months, with no history of chronic or recent illness, and have similar socioeconomic status. After at least 3 days of consecutive work, blood sample and a 24-hour urine will be collected. A caffeine test will be performed, by administering coffee and collecting urines three hours after. Subjects will fill in self-administered questionnaires; one covering the professional and lifestyle habits while the a second one is alimentary. The blood sample will be used to assess DNA adducts in peripheral lymphocytes. The 24-hour urine to assess urinary 8-oxo-7, 8-dihydro-2'-deoxy-Guanosine (8-oxo-dG), and the in vitro genotoxicity tests (comet and micronucleus) using HeLa S3 or HepG2 cells. In parallel, occupational air sampling will be conducted for some Polycyclic Aromatic Hydrocarbons and Volatile Organic Compounds. A weekly sampling chronology at the offices of occupational medicine in Paris city during the regular medical visits will be followed. This protocol has been accepted by the French Est III Ethical Comitee with the number 2007-A00685-48.

Discussion

Biomarkers of exposure and of early biological effects may help overcome the limitations of environmental exposure assessment in very complex occupational or environmental settings.
Tissue factor/FVIIa activates Bcl-2 and prevents doxorubicin-induced apoptosis in neuroblastoma cells
Authors: Fang Jun , Gu Lubing , Zhu Ningxi , Tang Hao , Alvarado Carlos S , Zhou Muxiang
Published: March 2008

Background

Tissue factor (TF) is a transmembrane protein that acts as a receptor for activated coagulation factor VII (FVIIa), initiating the coagulation cascade. Recent studies demonstrate that expression of tumor-derived TF also mediates intracellular signaling relevant to tumor growth and apoptosis. Our present study investigates the possible mechanism by which the interaction between TF and FVIIa regulates chemotherapy resistance in neuroblastoma cell lines.

Methods

Gene and siRNA transfection was used to enforce TF expression in a TF-negative neuroblastoma cell line and to silence endogenous TF expression in a TF-overexpressing neuroblastoma line, respectively. The expression of TF, Bcl-2, STAT5, and Akt as well as the phosphorylation of STAT5 and Akt in gene transfected cells or cells treated with JAK inhibitor and LY294002 were determined by Western blot assay. Tumor cell growth was determined by a clonogenic assay. Cytotoxic and apoptotic effect of doxorubicin on neuroblastoma cell lines was analyzed by WST assay and annexin-V staining (by flow cytometry) respectively.

Results

Enforced expression of TF in a TF-negative neuroblastoma cell line in the presence of FVIIa induced upregulation of Bcl-2, leading to resistance to doxorubicin. Conversely, inhibition of endogenous TF expression in a TF-overexpressing neuroblastoma cell line using siRNA resulted in down-regulation of Bcl-2 and sensitization to doxorubicin-induced apoptosis. Additionally, neuroblastoma cells expressing high levels of either endogenous or transfected TF treated with FVIIa readily phosphorylated STAT5 and Akt. Using selective pharmacologic inhibitors, we demonstrated that JAK inhibitor I, but not the PI3K inhibitor LY294002, blocked the TF/FVIIa-induced upregulation of Bcl-2.

Conclusion

This study shows that in neuroblastoma cell lines overexpressed TF ligated with FVIIa produced upregulation of Bcl-2 expression through the JAK/STAT5 signaling pathway, resulting in resistance to apoptosis. We surmise that this TF-FVIIa pathway may contribute, at least in part, to chemotherapy resistance in neuroblastoma.
Broad and narrow personality traits as markers of one-time and repeated suicide attempts: A population-based study
Authors: Brezo Jelena , Paris Joel , Hébert Martine , Vitaro Frank , Tremblay Richard , Turecki Gustavo
Published: March 2008

Background

Studying personality traits with the potential to differentiate between individuals engaging in suicide attempts of different degrees of severity could help us to understand the processes underlying the link of personality and nonfatal suicidal behaviours and to identify at-risk groups. One approach may be to examine whether narrow, i.e., lower-order personality traits may be more useful than their underlying, broad personality trait dimensions.

Methods

We investigated qualitative and quantitative differences in broad and narrow personality traits between one-time and repeated suicide attempters in a longitudinal, population-based sample of young French Canadian adults using two multivariate regression models.

Results

One broad (Compulsivity: OR = 2.0; 95% CI 1.2–3.5) and one narrow personality trait (anxiousness: OR = 1.1; 95% CI 1.01–1.1) differentiated between individuals with histories of repeated and one-time suicide attempts. Affective instability [(OR = 1.1; 95% CI 1.04–1.1)] and anxiousness [(OR = .92; 95% CI .88–.95)], on the other hand, differentiated between nonattempters and one-time suicide attempters.

Conclusion

Emotional and cognitive dysregulation and associated behavioural manifestations may be associated with suicide attempts of different severity. While findings associated with narrow traits may be easier to interpret and link to existing sociobiological theories, larger effect sizes associated with broad traits such as Compulsivity may be better suited to objectives with a more clinical focus.
Hue-shifted monomeric variants of Clavulariacyan fluorescent protein: identification of the molecular determinants of color and applications in fluorescence imaging
Authors: Ai Hui-wang , Olenych Scott G , Wong Peter , Davidson Michael W , Campbell Robert E
Published: March 2008

Background

In the 15 years that have passed since the cloning of Aequorea victoria green fluorescent protein (avGFP), the expanding set of fluorescent protein (FP) variants has become entrenched as an indispensable toolkit for cell biology research. One of the latest additions to the toolkit is monomeric teal FP (mTFP1), a bright and photostable FP derived from Clavularia cyan FP. To gain insight into the molecular basis for the blue-shifted fluorescence emission we undertook a mutagenesis-based study of residues in the immediate environment of the chromophore. We also employed site-directed and random mutagenesis in combination with library screening to create new hues of mTFP1-derived variants with wavelength-shifted excitation and emission spectra.

Results

Our results demonstrate that the protein-chromophore interactions responsible for blue-shifting the absorbance and emission maxima of mTFP1 operate independently of the chromophore structure. This conclusion is supported by the observation that the Tyr67Trp and Tyr67His mutants of mTFP1 retain a blue-shifted fluorescence emission relative to their avGFP counterparts (that is, Tyr66Trp and Tyr66His). Based on previous work with close homologs, His197 and His163 are likely to be the residues with the greatest contribution towards blue-shifting the fluorescence emission. Indeed we have identified the substitutions His163Met and Thr73Ala that abolish or disrupt the interactions of these residues with the chromophore. The mTFP1-Thr73Ala/His163Met double mutant has an emission peak that is 23 nm red-shifted from that of mTFP1 itself. Directed evolution of this double mutant resulted in the development of mWasabi, a new green fluorescing protein that offers certain advantages over enhanced avGFP (EGFP). To assess the usefulness of mTFP1 and mWasabi in live cell imaging applications, we constructed and imaged more than 20 different fusion proteins.

Conclusion

Based on the results of our mutagenesis study, we conclude that the two histidine residues in close proximity to the chromophore are approximately equal determinants of the blue-shifted fluorescence emission of mTFP1. With respect to live cell imaging applications, the mTFP1-derived mWasabi should be particularly useful in two-color imaging in conjunction with a Sapphire-type variant or as a fluorescence resonance energy transfer acceptor with a blue FP donor. In all fusions attempted, both mTFP1 and mWasabi give patterns of fluorescent localization indistinguishable from that of well-established avGFP variants.
Prostaglandin E2metabolism in rat brain: Role of the blood-brain interfaces
Authors: Alix Eudeline , Schmitt Charlotte , Strazielle Nathalie , Ghersi-Egea Jean-François
Published: March 2008

Background

Prostaglandin E2 (PGE2) is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE2 by metabolic inactivation.

Methods

The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE2 metabolites produced ex vivo by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection.

Results

The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE2, mainly into 13,14-dihydro-15-keto-PGE2. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma.

Conclusion

The rat choroidal tissue has a significant ability to metabolize PGE2 during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE2 in the brain, or function as an enzymatic barrier acting to maintain PGE2 homeostasis in CSF during the critical early postnatal period of brain development.
Ability of pleth variability index to detect hemodynamic changes induced by passive leg raising in spontaneously breathing volunteers
Authors: Keller Geoffray , Cassar Emmanuel , Desebbe Olivier , Lehot Jean-Jacques , Cannesson Maxime
Published: March 2008

Introduction

Pleth Variability Index (PVI) is a new algorithm that allows continuous and automatic estimation of respiratory variations in the pulse oximeter waveform amplitude. Our aim was to test its ability to detect changes in preload induced by passive leg raising (PLR) in spontaneously breathing volunteers.

Methods

We conducted a prospective observational study. Twenty-five spontaneously breathing volunteers were enrolled. PVI, heart rate and noninvasive arterial pressure were recorded. Cardiac output was assessed using transthoracic echocardiography. Volunteers were studied in three successive positions: baseline (semirecumbent position); after PLR of 45° with the trunk lowered in the supine position; and back in the semirecubent position.

Results

We observed significant changes in cardiac output and PVI during changes in body position. In particular, PVI decreased significantly from baseline to PLR (from 21.5 ± 8.0% to 18.3 ± 9.4%; P < 0.05) and increased significantly from PLR to the semirecumbent position (from 18.3 ± 9.4% to 25.4 ± 10.6 %; P < 0.05). A threshold PVI value above 19% was a weak but significant predictor of response to PLR (sensitivity 82%, specificity 57%, area under the receiver operating characteristic curve 0.734 ± 0.101).

Conclusion

PVI can detect haemodynamic changes induced by PLR in spontaneously breathing volunteers. However, we found that PVI was a weak predictor of fluid responsiveness in this setting.
Development of a Cross-Disciplinary Investigative Model for the Introduction of Microarray Techniques at Non-R1 Undergraduate Institutions
Authors: Walker David E. , Lutz Gary P. , Alvarez Consuelo J.
Published: March 2008

Integrating advanced biological techniques into instruction at non-R1 institutions can prove to be a challenge. Here, we report the creation of a model for the introduction of gene expression microarray technology into a research laboratory. A student assessment tool was used to evaluate 1) technical skill development, 2) cross-disciplinary issues, 3) development of trouble-shooting skills, and 4) career evaluation. The exposure of Saccharomyces cerevisiae yeast cells to three plasticizers served as a template for the introduction of this technology. Cells were harvested at mid-log phase, and RNA was extracted. The mRNA was converted to cDNA by using reverse transcriptase primers containing a capture sequence that was later recognized by a fluorescent dendrimer by using cyanine (Cy)3 or Cy5 dyes. cDNA was hybridized onto yeast microarray chips provided by the Genome Consortium for Active Teaching. Exposure to phthalate plasticizers revealed genes with differential gene expression. Trouble-shooting approaches were used as learning opportunities for the evaluation of RNA extraction methods, and data analysis highlighted the use of mathematics in a molecular biology context. This article describes a promising model for the introduction of interdisciplinary, student-based projects involving microarray technology at non-R1 undergraduate institutions.
Bioengineering and Bioinformatics Summer Institutes: Meeting Modern Challenges in Undergraduate Summer Research
Authors: Butler Peter J. , Dong Cheng , Snyder Alan J. , Jones A. Daniel , Sheets Erin D.
Published: March 2008

Summer undergraduate research programs in science and engineering facilitate research progress for faculty and provide a close-ended research experience for students, which can prepare them for careers in industry, medicine, and academia. However, ensuring these outcomes is a challenge when the students arrive ill-prepared for substantive research or if projects are ill-defined or impractical for a typical 10-wk summer. We describe how the new Bioengineering and Bioinformatics Summer Institutes (BBSI), developed in response to a call for proposals by the National Institutes of Health (NIH) and the National Science Foundation (NSF), provide an impetus for the enhancement of traditional undergraduate research experiences with intense didactic training in particular skills and technologies. Such didactic components provide highly focused and qualified students for summer research with the goal of ensuring increased student satisfaction with research and mentor satisfaction with student productivity. As an example, we focus on our experiences with the Penn State Biomaterials and Bionanotechnology Summer Institute (PSU-BBSI), which trains undergraduates in core technologies in surface characterization, computational modeling, cell biology, and fabrication to prepare them for student-centered research projects in the role of materials in guiding cell biology.
An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition
Authors: Nomellini Vanessa , Faunce Douglas E , Gomez Christian R , Kovacs Elizabeth J
Published: March 2008

Burn patients over the age of 60 are at a greater risk for developing pulmonary complications than younger patients. The mechanisms for this, however, have yet to be elucidated. The objective of this study was to determine whether increased chemoattraction plays a role in the age-related differences in pulmonary inflammation after burn injury. At 6 or 24 h after receiving sham or 15% total body surface area scald injury, lungs from young and aged mice were analyzed for leukocyte content by histological examination and immunostaining. Lungs were then homogenized, and levels of neutrophil chemokines, MIP-2 and KC, were measured. At 6 h after burn, the number of neutrophils was four times higher in the lungs of both burn groups compared with aged-matched controls (P<0.05), but no age difference was evident. At 24 h, in contrast, neutrophils returned to sham levels in the lungs of young, burn-injured mice (P<0.05) but did not change in the lungs of aged, burn-injured mice. Pulmonary levels of the neutrophil chemokine KC but not MIP-2 were consistently three times higher in aged, burn-injured mice compared with young, burn-injured mice at both time-points analyzed. Administration with anti-CXCR2 antibody completely abrogated the excessive pulmonary neutrophil content by 24 h (P<0.05), while not affecting the inflammatory response of the wounds. These studies show that CXCR2-mediated chemoattraction is involved in the pulmonary inflammatory response after burn and suggest that aged individuals sustaining a burn injury may benefit from treatment strategies that target neutrophil chemokines.
Risk of New Primary Nonbreast Cancers After Breast Cancer Treatment: A Dutch Population-Based Study
Authors: Schaapveld Michael , Visser Otto , Louwman Marieke J. , de Vries Elisabeth G.E. , Willemse Pax H.B. , Otter Renée , van der Graaf Winette T.A. , Coebergh Jan-Willem W. , van Leeuwen Flora E.
Published: March 2008

Purpose

To assess the risk of secondary nonbreast cancers (SNBCs) in a recently treated population-based cohort of breast cancer patients focused on the association with treatment and prognostic implications.

Patients and Methods

In 58,068 Dutch patients diagnosed with invasive breast cancer between 1989 and 2003, SNBC risk was quantified using standardized incidence ratios (SIRs), cumulative incidence, and Cox regression analysis, adjusted for competing risks.

Results

After a median follow-up of 5.4 years, 2,578 SNBCs had occurred. Compared with the Dutch female population at large, in this cohort, the SIR of SNBCs was increased (SIR, 1.22; 95% CI, 1.17 to 1.27). The absolute excess risk was 13.6 (95% CI, 9.7 to 17.6) per 10,000 person-years. SIRs were elevated for cancers of the esophagus, stomach, colon, rectum, lung, uterus, ovary, kidney, and bladder cancers, and for soft tissue sarcomas (STS), melanoma, non-Hodgkin's lymphoma, and acute myeloid leukemia (AML). The 10-year cumulative incidence of SNBCs was 5.4% (95% CI, 5.1% to 5.7%). Among patients younger than 50 years, radiotherapy was associated with an increased lung cancer risk (hazard ratio [HR] = 2.31; 95% CI, 1.15 to 4.60) and chemotherapy with decreased risk for all SNBCs (HR = 0.78; 95% CI, 0.63 to 0.98) and for colon and lung cancer. Among patients age 50 years and older, radiotherapy was associated with raised STS risk (HR = 3.43; 95% CI, 1.46 to 8.04); chemotherapy with increased risks of melanoma, uterine cancer, and AML; and hormonal therapy with all SNBCs combined (HR = 1.10; 95% CI, 1.01 to 1.21) and uterine cancer (HR = 1.78; 95% CI, 1.40 to 2.27). An SNBC worsened survival (HR = 3.98; 95%CI 3.77 to 4.20).

Conclusion

Breast cancer patients diagnosed in the 1990s experienced a small but significant excess risk of developing an SNBC.
The Safety of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Trastuzumab in HER-2/neu Overexpressed/Amplified Breast Cancer
Authors: Dang Chau , Fornier Monica , Sugarman Steven , Troso-Sandoval Tiffany , Lake Diana , D'Andrea Gabriella , Seidman Andrew , Sklarin Nancy , Dickler Maura , Currie Violante , Gilewski Theresa , Moynahan Mary Ellen , Drullinsky Pamela , Robson Mark , Wasserheit-Leiblich Carolyn , Mills Nancy , Steingart Richard , Panageas Katherine , Norton Larry , Hudis Clifford
Published: March 2008

Purpose

Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzuamb (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival.

Methods

Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of ≥ 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m2) × 4 followed by P (175 mg/m2) × 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T ×1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18.

Results

From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced conestive heart failure (CHF). There were no cardiac deaths.

Conclusion

Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.
Monitoring the Response of Circulating Epithelial Tumor Cells to Adjuvant Chemotherapy in Breast Cancer Allows Detection of Patients at Risk of Early Relapse
Authors: Pachmann Katharina , Camara Oumar , Kavallaris Andreas , Krauspe Sabine , Malarski Nele , Gajda Mieczyslaw , Kroll Torsten , Jörke Cornelia , Hammer Ulrike , Altendorf-Hofmann Annelore , Rabenstein Carola , Pachmann Ulrich , Runnebaum Ingo , Höffken Klaus
Published: March 2008

Purpose

To demonstrate that it is possible to monitor the response to adjuvant therapy by repeated analysis of circulating epithelial tumor cells (CETCs) and to detect patients early who are at risk of relapse.

Patients and Methods

In 91 nonmetastatic primary breast cancer patients, CETCs were quantified using laser scanning cytometry of anti–epithelial cell adhesion molecule–stained epithelial cells from whole unseparated blood before and during adjuvant chemotherapy.

Results

Numbers of CETCs were analyzed before therapy, before each new cycle, and at the end of chemotherapy. The following three typical patterns of response were observed: (1) decrease in cell numbers (> 10-fold); (2) marginal changes in cell numbers (< 10-fold); and (3) an (sometimes saw-toothed) increase or an initial decrease with subsequent reincrease (> 10-fold) in numbers of CETCs. Twenty relapses (22%) were observed within the accrual time of 40 months, including one of 28 patients from response group 1, five of 30 patients from response group 2, and 14 of 33 patients from response group 3. The difference in relapse-free survival was highly significant for CETC (hazard ratio = 4.407; 95% CI, 1.739 to 9.418; P < .001) between patients with decreasing cell numbers and those with marginal changes and between patients with marginal changes and those with an increase of more than 10-fold (linear Cox regression model).

Conclusion

These results show that peripherally circulating tumor cells are influenced by systemic chemotherapy and that an increase (even after initial response to therapy) of 10-fold or more at the end of therapy is a strong predictor of relapse and a surrogate marker for the aggressiveness of the tumor cells.
Nomograms to Predict Serious Adverse Events in Phase II Clinical Trials of Molecularly Targeted Agents
Authors: Pond Gregory R. , Siu Lillian L. , Moore Malcolm , Oza Amit , Hirte Hal W. , Winquist Eric , Goss Glenwood , Hudes Gary , Townsley Carol A.
Published: March 2008

Purpose

A tool that quantifies the risk of treatment-related toxicity based on individual patient characteristics can augment the informed consent process and safety monitoring in the setting of phase II cancer treatment trials of molecularly targeted agents (MTAs).

Methods

A regression model was constructed to predict the risk of a serious adverse event (SAE) with an MTA and presented as a nomogram. Estimation of risk can be performed by integrating risk estimates from the nomogram and from a reference or average patient. Internal validation was performed using bootstrapping techniques.

Results

A total of 578 patients were treated with one of 14 MTAs given alone or in combination on one of 27 clinical trials performed by the Princess Margaret Hospital Drug Development Program between 2001 and 2006. Approximately 50% and 24% of patients experienced an SAE and an attributable SAE (SAEatt) during cycle 1, respectively. Albumin, lactate dehydrogenase (LDH), number of target lesions, prior radiotherapy, Charlson score, age, and performance status were included in the optimal model as predictors of a cycle 1 SAE, whereas the number of prior chemotherapy regimens, baseline creatinine, LDH, prior radiotherapy, Charlson score, body-surface area, and performance status were included as predictors of an SAEatt. Moderate-good internal validity was demonstrated, with area under the curve estimates ranging from 56.7% to 86.1% for all SAEs and 63.0% to 89.7% for SAEatts.

Conclusion

A regression model was constructed that predicts the SAE and SAEatt risk for an individual patient during cycle 1 of phase II trial treatment with moderate to good internal validity. External validation is still required.
Governance and Community Benefit: Are Nonprofit Hospitals Good Candidates for Sarbanes-Oxley Type Reforms?
Authors: Alexander Jeffrey A. , Young Gary J. , Weiner Bryan J. , Hearld Larry R.
Published: March 2008

Recent investigations into the activities of nonprofit hospitals have pointed to weak or lax governance on the part of some of these organizations. As a result of these events, various federal and state initiatives are now either under way or under discussion to strengthen the governance of hospitals and other nonprofit corporations through mandatory board structures and practices. However, despite policy makers' growing interest in these types of governance reforms, there is in fact little empirical evidence to support their contribution to the effectiveness of hospital boards. The purpose of this article is to report the results of a study examining the relationship between the structure and practices of nonprofit hospital boards relative to the hospital's provision of community benefits. Our results point to modest relationships between these sets of variables, suggesting considerable limitations to what federal and state policy makers can accomplish through legislative initiatives to improve the governance of nonprofit hospitals.
Balancing Regulatory Controls and Incentives: Toward Smarter and More Transparent Oversight in Long-Term Care
Authors: Miller Edward Alan , Mor Vincent
Published: March 2008

Government oversight of long-term care involves inspections of patients' records, limited observations of patients and care practices, reviews of policies and procedures, and distribution of publicly available information. Although many providers bemoan the stifling consequences of excessive regulation, oversight in this area remains a highly legitimate endeavor for the public, though the public has limited trust in the existing regulatory regime. This distrust stems from many sources, not least of which includes considerable variation, both within and across states, in the way government oversight occurs. Reforming the current regulatory structure requires that we regulate “smarter” and more consistently. This means improving and maximizing use of the data already being collected, but it also means explicitly rationalizing the regulator's responsibility to review performance and apply sanctions when necessary. Oversight should more closely resemble consultancy, with regulators sharing information with providers about how to improve quality. Ideally, there needs to be an iterative process in which state inspectors identify performance problems and the nation's quality improvement organizations then help providers design quality improvement interventions to ameliorate the problems identified. The benefits of a revised regulatory approach are especially apparent in the aftermath of Hurricane Katrina, where more effective oversight would have identified nursing home residents at risk for low-quality care before the disaster occurred while better identifying those in need of evacuation or assistance afterward.
Sdmg1 is a conserved transmembrane protein associated with germ cell sex determination and germline-soma interactions in mice
Authors: Best Diana , Sahlender Daniela A. , Walther Norbert , Peden Andrew A. , Adams Ian R.
Published: March 2008

In mammals, the supporting cell lineage in an embryonic gonad communicates the sex-determining decision to various sexually dimorphic cell types in the developing embryo, including the germ cells. However, the molecular nature of the sex-determining signals that pass from the supporting cells to the germ cells is not well understood. We have identified a conserved transmembrane protein, Sdmg1, owing to its male-specific expression in mouse embryonic gonads. Sdmg1 is expressed in the Sertoli cells of embryonic testes from 12.5 dpc, and in granulosa cells of growing follicles in adult ovaries. In Sertoli cells, Sdmg1 is localised to endosomes, and knock-down of Sdmg1 in Sertoli cell lines causes mis-localisation of the secretory SNARE Stx2 and defects in membrane trafficking. Upregulation of Sdmg1appears to be part of a larger programme of changes to membrane trafficking pathways in embryonic Sertoli cells, and perturbing secretion in male embryonic gonads in organ culture causes male-to-female germ cell sex reversal. These data suggest that changes that occur in the cell biology of embryonic Sertoli cells may facilitate the communication of male sex-determining decisions to the germ cells during embryonic development.
Nitrate removal by calcined hydrotalcite-type compounds
Authors: Socías-Viciana María M. , Ureña-Amate María D. , González-Pradas Emilio , García-Cortés María J. , López-Teruel Cristina
Published: March 2008

The sorption of nitrate ions on calcined hydrotalcite-type compounds at 550°C (HT550), 650°C (HT650), and 850°C (HT850) from pure water solution at 25°C has been studied. The influence of the temperature was also investigated for the sample calcined at 850°C by studying the sorption process at 10 and 40°C. The experimental sorption data points were fitted to the Langmuir equation in order to calculate the sorption capacities (Xm) of the samples; Xm values range from 61.7 g kg−1 (HT550 at 25°C) to 147.0 g kg−1 (HT850 at 40°C). The values for the removal efficiency (R) obtained ranged from 70.5% for HT550 at 25°C to 99.5% for HT850 at 40°C. The sorption experiments showed that the greater the calcination temperature (850°C), the more effective the removal of nitrate. The increase in the temperature from 10 to 40°C for sample HT850 also tends to increase the sorption of nitrate from 63.3 g kg−1 to 147 g kg−1 and the corresponding removal efficiency from 71.5 to 99.5%.
Hydrothermal synthesis of beidellites: Characterization and study of the cis- and trans-vacant character
Authors: Lantenois Sébastien , Muller Fabrice , Bény Jean-Michel , Mahiaoui Jamel , Champallier Rémi
Published: March 2008

Low-charge beidellites were synthesized by a hydrothermal treatment applied to an amorphous gel phase in basic solution. The hydrothermal conditions for the syntheses were chosen from the stability field of beidellite previously investigated in the literature. The synthetic samples were characterized chemically and structurally using X-ray diffraction, infrared spectroscopy, cation exchange capacity measurement, and chemical and thermal analyses. We compared the synthetic sample with a natural beidellite sample (SbId) from Idaho, USA, looking at chemical composition and particle size. The main difference is the octahedral site occupancy (cis- or trans-vacant layer structure). The natural SbId sample has trans-vacant layers and the synthetic sample has a preferentially cis-vacant character. This character can be modulated, using specific synthesis conditions. The cis- or trans-vacant layer structure of various synthetic beidellites was investigated at low temperature (<350°C) and pressure (<25 MPa). Depending on the pressure and/or synthesis temperature, the proportion of cis-vacant layers ranges from 20 to 100% and increases with the layer-charge deficit.
Lexical and semantic fluency discrepancy scores in aMCI and early Alzheimer's disease
Authors: Lonie Jane A. , Herrmann Lucie L. , Tierney Kevin M. , Donaghey Claire , O'Carroll Ronan , Lee Andrew , Ebmeier Klaus P.
Published: March 2008

Episodic memory is compromised in amnestic mild cognitive impairment (aMCI), but lesser deficits in other cognitive domains are also commonly observed and may be helpful in identifying this group. The relative difference in performance on lexical and semantic fluency tasks may be a sensitive and specific measure in aMCI and early Alzheimer's disease (AD). We compared four groups of participants, 35 early AD, 47 aMCI, 24 healthy controls, and 18 depressive out‐patient controls, on semantic and lexical fluency as well as other neuropsychological tests. Early AD and aMCI patients showed a distinct pattern of semantic impairment in the two fluency measures compared with the healthy and depressive controls. The findings implicate early failure of the semantic memory system in aMCI and AD and suggest that consideration of the discrepancy in performance on semantic and lexical fluency measures may help in the early identification of AD.