bluuebunny/crossref_metadata_2025 huggingface dataset:
Low stress welding technology without post-weld heat treatment
Authors: Xu J. J. , Chen L. G. , Ni C. Z.
Published: December 2008

In order to assure the tightness and the service life of a full welded body ball valve, the temperature of grommet cannot exceed 150°C. Therefore, post-weld heat treatment cannot be used to relieve the welding residual stresses. In this study, a low stress welding technology was studied. The type of welding joint was optimised through the finite element method and vibratory welding was employed to decrease the residual stress. At the same time, the fracture toughness behaviour of weld zone and heat affected zone in terms of crack tip opening displacement was investigated to assess the safety of valve without PWHT in the active service. Finally, the results are discussed and analysed.
Measured residual stress distributions for low and high heat input single weld beads deposited on to SA508 steel
Authors: Francis J. A. , Turski M. , Withers P. J.
Published: December 2008

In steel welds, the development of residual stress is often complicated by the solid state phase transformations that occur upon cooling. Here the authors present bulk residual stress distributions, as measured by neutron diffraction, for the configuration of a single pass gas tungsten arc weld bead deposited on to a 20 mm thick SA508 steel substrate. Two specimens were manufactured, one with a low heat input (1·2 kJ mm−1) and another with a high heat input (2·4 kJ mm−1). The resulting microstructures and residual stress distributions are discussed in terms of the differing thermal excursions across each weld. In regions that are austenitised during welding, the transformation strain on cooling is shown to compensate in part for thermal contraction strains. Accordingly, phase transformations in SA508 steel led to significant reductions in stress within the weld bead and much of the heat affected zone, while the highest tensile stresses were located immediately outside the heat affected zone boundary in the untransformed region.
A functional calcium-binding site in the metalloprotease domain of ADAMTS13
Authors: Gardner Michelle D. , Chion Chan K. N. K. , de Groot Rens , Shah Anuja , Crawley James T. B. , Lane David A.
Published: December 2008

ADAMTS13 regulates the multimeric size of von Willebrand factor (VWF). Its function is highly dependent upon Ca2+ ions. Using the initial rates of substrate (VWF115, VWF residues 1554-1668) proteolysis by ADAMTS13 preincubated with varying Ca2+ concentrations, a high-affinity functional ADAMTS13 Ca2+-binding site was suggested with KD(app) of 80 μM (± 15 μM) corroborating a previously reported study. When Glu83 or Asp173 (residues involved in a predicted Ca2+-binding site in the ADAMTS13 metalloprotease domain) were mutated to alanine, Ca2+ dependence of proteolysis of the substrate was unaffected. Consequently, we sought and identified a candidate Ca2+-binding site in proximity to the ADAMTS13 active site, potentially comprising Glu184, Asp187, and Glu212. Mutagenesis of these residues within this site to alanine dramatically attenuated the KD(app) for Ca2+ of ADAMTS13, and for D187A and E212A also reduced the Vmax to approximately 25% of normal. Kinetic analysis of the Asp187 mutant in the presence of excess Ca2+ revealed an approximately 13-fold reduction in specificity constant, kcat/Km, contributed by changes in both Km and kcat. These results were corroborated using plasma-purified VWF as a substrate. Together, our results demonstrate that a major influence of Ca2+ upon ADAMTS13 function is mediated through binding to a high-affinity site adjacent to its active site cleft.
Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100
Authors: Nervi Bruno , Ramirez Pablo , Rettig Michael P. , Uy Geoffrey L. , Holt Matthew S. , Ritchey Julie K. , Prior Julie L. , Piwnica-Worms David , Bridger Gary , Ley Timothy J. , DiPersio John F.
Published: December 2008

The CXCR4–SDF-1 axis plays a central role in the trafficking and retention of normal and malignant stem cells in the bone marrow (BM) microenvironment. Here, we used a mouse model of acute promyelocytic leukemia (APL) and a small molecule competitive antagonist of CXCR4, AMD3100, to examine the interaction of mouse APL cells with the BM microenvironment. APL cells from a murine cathepsin G-PML-RARα knockin mouse were genetically modified with firefly luciferase (APLluc) to allow tracking by bioluminescence imaging. Coculture of APLluc cells with M2-10B4 stromal cells protected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneic recipients, APLluc cells rapidly migrated to the BM followed by egress to the spleen then to the peripheral blood with death due to leukostasis by day 15. Administration of AMD3100 to leukemic mice induced a 1.6-fold increase in total leukocytes and a 9-fold increase of circulating APL blast counts, which peak at 3 hours and return to baseline by 12 hours. Treatment of leukemic mice with chemotherapy plus AMD3100 resulted in decreased tumor burden and improved overall survival compared with mice treated with chemotherapy alone. These studies provide a proof-of-principle for directing therapy to the critical tethers that promote AML-niche interactions.
Regulation of growth differentiation factor 15 expression by intracellular iron
Authors: Lakhal Samira , Talbot Nick P. , Crosby Alexi , Stoepker Chantal , Townsend Alain R. M. , Robbins Peter A. , Pugh Christopher W. , Ratcliffe Peter J. , Mole David R.
Published: December 2008

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor–β superfamily and has been identified in different contexts as a hypoxia-inducible gene product and as a molecule involved in hepcidin regulation. The biology of iron and oxygen is closely related, and known regulatory pathways involving hypoxia-inducible factor (HIF) and iron-regulatory proteins (IRPs) are responsive to both these stimuli. We therefore sought to characterize the regulation of GDF15 by iron and oxygen and to define the involvement or otherwise of HIF and IRP pathways. Here we show that GDF15 is strongly up-regulated by stimuli that deplete cells of iron and that this response is specifically antagonized by the reprovision of iron. GDF15 exhibits greater sensitivity to iron depletion than hypoxia, and responses to hypoxia and iron depletion are independent of HIF and IRP activation, suggesting a novel mechanism of regulation. We also report significant induction of serum GDF15 in iron-deficient subjects and after administration of an iron chelator to normal subjects. These findings indicate that GDF15 can be induced by pathophysiologic changes in iron availability, raising important questions about the mechanism of regulation and its role in iron homeostasis.
Viperin is required for optimal Th2 responses and T-cell receptor–mediated activation of NF-κB and AP-1
Authors: Qiu Lian-Qun , Cresswell Peter , Chin Keh-Chuang
Published: December 2008

Viperin (virus inhibitory protein, endoplasmic reticulum [ER]–associated, interferon-inducible) has been identified as a highly inducible ER protein that has antiviral activity. Here, we characterized the phenotype of mice deficient in viperin and examined the biological function of viperin in peripheral T-cell activation and differentiation. Splenic CD4+ T cells deficient in viperin exhibited normal anti–T-cell receptor (TCR)–induced proliferation and IL-2 production, but produced significantly less T helper 2 (Th2) cytokines, including IL-4, IL-5, and IL-13, in association with impaired GATA3 activation, after stimulation with anti-CD3 antibody, which was not restored upon costimulation with anti-CD28. Th2 differentiation of viperin-deficient naive T cells was also impaired in the presence of strong TCR signaling and minimum IL-4, but not under optimal Th2-skewed conditions. In parallel, viperin-deficient T cells showed decreases in NF-κB1/p50 and AP-1/JunB DNA binding activities after TCR engagement. Thus, viperin facilitates TCR-mediated GATA-3 activation and optimal Th2 cytokine production by modulating NF-κB and AP-1 activities.
Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study
Authors: Nowak-Göttl Ulrike , Fröhlich Birgit , Thedieck Sabine , Huge Andreas , Stoll Monika
Published: December 2008

To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)–based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, χ2 = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.
Relationship between ventilatory constraint and muscle fatigue during exercise in COPD
Authors: Butcher S. J. , Lagerquist O. , Marciniuk D. D. , Petersen S. R. , Collins D. F. , Jones R. L.
Published: December 2008

Dynamic hyperinflation and leg muscle fatigue are independently associated with exercise limitation in patients with chronic obstructive pulmonary disease (COPD). The aims of the present study were to examine 1) the relationship between these limitations and 2) the effect of delaying ventilatory limitation on exercise tolerance and leg muscle fatigue.

In total, 11 patients with COPD (with a forced expiratory volume in one second of 52% predicted) completed two cycling bouts breathing either room air or heliox, and one bout breathing heliox but stopping at room air isotime. End-expiratory lung volume (EELV), leg muscle fatigue and exercise time were measured.

On room air, end-exercise EELV was negatively correlated with leg fatigue. Heliox increased exercise time (from 346 to 530 s) and leg fatigue (by 15%). At isotime, there was no change in leg fatigue, despite a reduction in EELV compared with end-exercise, in both room air and heliox. The change in exercise time with heliox was best correlated with room air leg fatigue and end-inspiratory lung volume.

Patients with chronic obstructive pulmonary disease who had greater levels of dynamic hyperinflation on room air had less muscle fatigue. These patients were more likely to increase exercise tolerance with heliox, which resulted in greater leg muscle fatigue.
Reduced risk of next exacerbation and mortality associated with antibiotic use in COPD
Authors: Roede B. M. , Bresser P. , Prins J. M. , Schellevis F. , Verheij T. J. M. , Bindels P. J. E.
Published: December 2008

The long-term risk of a subsequent exacerbation of chronic obstructive pulmonary disease (COPD) after treatment with oral corticosteroids without (OS) or with antibiotics (OSA) was compared in a historical general practice-based cohort.

Eligible patients were ≥50 yrs of age, had a registered diagnosis of COPD, were on maintenance respiratory drugs, and had experienced at least one exacerbation defined as a prescription OS or OSA. Times to second and third exacerbations were assessed using Kaplan–Meier survival analysis; the risk of a subsequent exacerbation was assessed in a Cox proportional hazards analysis; and all-cause mortality was assessed using Kaplan–Meier survival and Cox proportional hazards analyses.

A total of 842 patients had one or more exacerbations. The median time from first to second exacerbation was comparable for the OS and OSA groups, but the time from second to third exacerbation differed: 189versus258 days, respectively. The protective effect of OSA was most pronounced during the first 3 months following treatment (hazards ratio 0.72, 95% confidence interval 0.62–0.83). Exposure to antibiotics unrelated to a course of oral corticosteroids almost halved the risk of a new exacerbation. Mortality during follow-up was considerably lower in the OSA group.

Adding antibiotics to oral corticosteroids was associated with: reduced risk of subsequent exacerbation, particularly in patients with recurrent exacerbations; and reduced risk of all-cause mortality.
Sex differences in mortality in patients with COPD
Authors: de Torres J. P. , Cote C. G. , López M. V. , Casanova C. , Díaz O. , Marin J. M. , Pinto-Plata V. , de Oca M. M. , Nekach H. , Dordelly L. J. , Aguirre-Jaime A. , Celli B. R.
Published: December 2008

Little is known about survival and clinical prognostic factors in females with chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine the survival difference between males and females with COPD and to compare the value of the different prognostic factors for the disease.

In total, 265 females and 272 males with COPD matched at baseline by BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) and American Thoracic Society/European Respiratory Society/Global Initiative of Chronic Obstructive Lung Disease criteria were prospectively followed. Demographics, lung function, St George’s Respiratory Questionnaire, BODE index, the components of the BODE index and comorbidity were determined. Survival was documented and sex differences were determined using Kaplan–Meier analysis. The strength of the association of the studied variables with mortality was determined using multivariate and receiver operating curves analysis.

All-cause (40versus18%) and respiratory mortality (24versus10%) were higher in males than females. Multivariate analysis identified the BODE index in females and the BODE index and Charlson comorbidity score in males as the best predictors of mortality. The area under the curve of the BODE index was a better predictor of mortality than the forced expiratory volume in one second for both sexes.

At similar chronic obstructive pulmonary disease severity by BODE index and forced expiratory volume in one second, females have significantly better survival than males. For both sexes the BODE index is a better predictor of survival than the forced expiratory volume in one second.
Circulating cell-derived microparticles in patients with minimally symptomatic obstructive sleep apnoea
Authors: Ayers L. , Ferry B. , Craig S. , Nicoll D. , Stradling J. R. , Kohler M.
Published: December 2008

Moderate–severe obstructive sleep apnoea (OSA) has been associated with several pro-atherogenic mechanisms and increased cardiovascular risk, but it is not known if minimally symptomatic OSA has similar effects. Circulating cell-derived microparticles have been shown to have pro-inflammatory, pro-coagulant and endothelial function-impairing effects, as well as to predict subclinical atherosclerosis and cardiovascular risk.

In 57 patients with minimally symptomatic OSA, and 15 closely matched control subjects without OSA, AnnexinV-positive, platelet-, leukocyte- and endothelial cell-derived microparticles were measured by flow cytometry.

In patients with OSA, median (interquartile range) levels of AnnexinV-positive microparticles were significantly elevated compared with control subjects: 2,586 (1,566–3,964) μL−1versus1,206 (474–2,501) μL−1, respectively. Levels of platelet-derived and leukocyte-derived microparticles were also significantly higher in patients with OSA (2,267 (1,102–3,592) μL−1and 20 (14–31) μL−1, respectively) compared with control subjects (925 (328–2,068) μL−1and 15 (5–23) μL−1, respectively). Endothelial cell-derived microparticle levels were similar in patients with OSA compared with control subjects (13 (8–25) μL−1versus11 (6–17) μL−1).

In patients with minimally symptomatic obstructive sleep apnoea, levels of AnnexinV-positive, platelet- and leukocyte-derived microparticles are elevated when compared with closely matched control subjects without obstructive sleep apnoea. These findings suggest that these patients may be at increased cardiovascular risk, despite being minimally symptomatic.
Inference of haplotypic phase and missing genotypes in polyploid organisms and variable copy number genomic regions
Authors: Su Shu-Yi , White Jonathan , Balding David J , Coin Lachlan JM
Published: December 2008

Background

The power of haplotype-based methods for association studies, identification of regions under selection, and ancestral inference, is well-established for diploid organisms. For polyploids, however, the difficulty of determining phase has limited such approaches. Polyploidy is common in plants and is also observed in animals. Partial polyploidy is sometimes observed in humans (e.g. trisomy 21; Down's syndrome), and it arises more frequently in some human tissues. Local changes in ploidy, known as copy number variations (CNV), arise throughout the genome. Here we present a method, implemented in the software polyHap, for the inference of haplotype phase and missing observations from polyploid genotypes. PolyHap allows each individual to have a different ploidy, but ploidy cannot vary over the genomic region analysed. It employs a hidden Markov model (HMM) and a sampling algorithm to infer haplotypes jointly in multiple individuals and to obtain a measure of uncertainty in its inferences.

Results

In the simulation study, we combine real haplotype data to create artificial diploid, triploid, and tetraploid genotypes, and use these to demonstrate that polyHap performs well, in terms of both switch error rate in recovering phase and imputation error rate for missing genotypes. To our knowledge, there is no comparable software for phasing a large, densely genotyped region of chromosome from triploids and tetraploids, while for diploids we found polyHap to be more accurate than fastPhase. We also compare the results of polyHap to SATlotyper on an experimentally haplotyped tetraploid dataset of 12 SNPs, and show that polyHap is more accurate.

Conclusion

With the availability of large SNP data in polyploids and CNV regions, we believe that polyHap, our proposed method for inferring haplotypic phase from genotype data, will be useful in enabling researchers analysing such data to exploit the power of haplotype-based analyses.
Systematic review of the relation between smokeless tobacco and cancer of the pancreas in Europe and North America
Authors: Sponsiello-Wang Zheng , Weitkunat Rolf , Lee Peter N
Published: December 2008

Background

Recent reviews claiming smokeless tobacco increases pancreatic cancer risk appear not to have considered all available epidemiological evidence; nor were meta-analyses included. We present a systematic review of studies from North America and Europe, since data are lacking from other continents. Risk is also difficult to quantify elsewhere due to the various products, compositions and usage practices involved.

Methods

Epidemiological studies were identified that related pancreatic cancer to use of snuff, chewing tobacco or unspecified smokeless tobacco. Study details and effect estimates (relative risks or odds ratios) were extracted, and combined by meta-analyses.

Results

Nine North American and two Scandinavian studies were identified. Reporting was limited in four studies, so only seven were included in meta-analyses, some providing results for never smokers, some for the overall population of smokers and non-smokers, and some for both.

Giving preference to study-specific estimates for the overall population, if available, and for never smokers otherwise, the random-effects estimate for ever smokeless tobacco use was 1.03 (95% confidence interval 0.71–1.49) based on heterogeneous estimates from seven studies. The estimate varied little by continent, study type, or type of smokeless tobacco.

Giving preference to estimates for never smokers, if available, and overall population estimates otherwise, the estimate was 1.14 (0.67–1.93), again based on heterogeneous estimates. Estimates varied (p = 0.014) between cohort studies (1.75, 1.20–2.54) and case-control studies (0.84, 0.36–1.97). The value for cohort studies derived mainly from one study, which reported an increase for never smokers (2.0, 1.2–3.3), but not overall (0.9, 0.7–1.2). This study also contributed to increases seen for snuff use and for European studies, significant only in fixed-effect analyses.

The studies have various weaknesses, including few exposed cases, reliance in cohort studies on exposure recorded at baseline, poor control groups in some case-control studies, and lack of a dose-response. Publication bias, with some negative studies not being presented, is also possible.

Conclusion

At most, the data suggest a possible effect of smokeless tobacco on pancreatic cancer risk. More evidence is needed. If any risk exists, it is highly likely to be less than that from smoking.
Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition
Authors: Pachikian BD , Neyrinck AM , Cani PD , Portois L , Deldicque L , De Backer FC , Bindels LB , Sohet FM , Malaisse WJ , Francaux M , Carpentier YA , Delzenne NM
Published: December 2008

Background

There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic metabolism.

Results

n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol) as well as an increase in hepatic cholesteryl ester and triglycerides content. Fatty acid pattern is profoundly modified in hepatic phospholipids and triglycerides. The decrease in tissue n-3/n-6 PUFA ratio correlates with steatosis. Hepatic mRNA content of key factors involved in lipid metabolism suggest a decreased lipogenesis (SREBP-1c, FAS, PPARγ), and an increased β-oxidation (CPT1, PPARα and PGC1α) without modification of fatty acid esterification (DGAT2, GPAT1), secretion (MTTP) or intracellular transport (L-FABP). Histological analysis reveals alterations of liver morphology, which can not be explained by inflammatory or oxidative stress. However, several proteins involved in the unfolded protein response are decreased in depleted mice.

Conclusion

n-3 PUFA depletion leads to important metabolic alterations in murine liver. Steatosis occurs through a mechanism independent of the shift between β-oxidation and lipogenesis. Moreover, long term n-3 PUFA depletion decreases the expression of factors involved in the unfolded protein response, suggesting a lower protection against endoplasmic reticulum stress in hepatocytes upon n-3 PUFA deficiency.
Pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide: role of particle surface area
Authors: Sager Tina M , Kommineni C , Castranova Vincent
Published: December 2008

Background

The production and use of nanoparticles is growing rapidly due to the unique physical and chemical properties associated with their nano size and large surface area. Since nanoparticles have unique physicochemical properties, their bioactivity upon exposure to workers or consumers is of interest. In this study, the issue of what dose metric (mass dose versus surface area dose) is appropriate for toxicological studies has been addressed. Rats were exposed by intratracheal instillation to various doses of ultrafine or fine TiO2. At 1, 7, or 42 days post-exposure, inflammatory and cytotoxic potential of each particle type was compared on both a mass dosage (mg/rat) as well as an equal surface area dosage (cm2 of particles per cm2 of alveolar epithelium) basis.

Results

The findings of the study show that on a mass basis the ultrafine particles caused significantly more inflammation and were significantly more cytotoxic than the fine sized particles. However, when doses were equalized based on surface area of particles delivered, the ultrafine particles were only slightly more inflammogenic and cytotoxic when compared to the fine sized particles. Lung burden data indicate that ultrafine TiO2 appears to migrate to the interstitium to a much greater extent than fine TiO2.

Conclusion

This study suggests that surface area of particles may be a more appropriate dose metric for pulmonary toxicity studies than mass of particles.
Transfection of the mutant MYH9 cDNA reproduces the most typical cellular phenotype of MYH9-related disease in different cell lines
Authors: Panza Emanuele , Marini Monica , Pecci Alessandro , Giacopelli Francesca , Bozzi Valeria , Seri Marco , Balduini Carlo , Ravazzolo Roberto
Published: December 2008

Background

Heterozygous mutations of MYH9, encoding the Non-Muscular Myosin Heavy Chain-IIA (NMMHC-IIA), cause a complex disorder named MYH9-related disease, characterized by a combination of different phenotypic features. At birth, patients present platelet macrocytosis, thrombocytopenia and leukocyte inclusions containing NMMHC-IIA. Moreover, later in life some of them develop the additional features of sensorineural hearing loss, cataracts and/or glomerulonephritis that sometimes leads to end stage renal failure.

Results

To clarify the mechanism by which the mutant NMMHC-IIA could cause phenotypic anomalies at the cellular level, we examined the effect of transfection of the full-length mutated D1424H MYH9 cDNAs. We have observed, by confocal microscopy, abnormal distribution of the protein and formation of rod-like aggregates reminiscent of the leukocyte inclusions found in patients. Co-transfection of differently labeled wild-type and mutant full-length cDNAs showed the simultaneous presence of both forms of the protein in the intracellular aggregates.

Conclusion

These findings suggest that the NMMHC-IIA mutated in position 1424 is able to interact with the WT form in living cells, despite part of the mutant protein precipitates in non-functional aggregates. Transfection of the entire WT or mutant MYH9 in cell lines represents a powerful experimental model to investigate consequences of MYH9 mutations.
Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts
Authors: Cardone Monica , Porto Caterina , Tarallo Antonietta , Vicinanza Mariella , Rossi Barbara , Polishchuk Elena , Donaudy Francesca , Andria Generoso , De Matteis Maria Antonietta , Parenti Giancarlo
Published: December 2008

Background

Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself.

Results

We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced.

Conclusion

These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols.
HIV is a virus, not a crime: ten reasons against criminal statutes and criminal prosecutions
Authors: Cameron Edwin , Burris Scott , Clayton Michaela
Published: December 2008

The widespread phenomenon of enacting HIV‐specific laws to criminally punish transmission of, exposure to, or non‐disclosure of HIV, is counter‐active to good public health conceptions and repugnant to elementary human rights principles. The authors provide ten reasons why criminal laws and criminal prosecutions are bad strategy in the epidemic.
Retinoid X receptor and peroxisome proliferator-activated receptor-gamma agonists cooperate to inhibit matrix metalloproteinase gene expression
Authors: Burrage Peter S , Schmucker Adam C , Ren Yanqing , Sporn Michael B , Brinckerhoff Constance E
Published: December 2008

Introduction

We recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit interleukin-1-beta (IL-1-β)-driven matrix metalloproteinase-1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPARγ), for which RXR is an obligate dimerization partner. The goals of this study were to evaluate the inhibition of IL-1-β-induced expression of MMP-1 and MMP-13 by combinatorial treatment with RXR and PPARγ ligands and to investigate the molecular mechanisms of this inhibition.

Methods

We used real-time reverse transcription-polymerase chain reaction to measure LG268- and rosiglitazone-mediated inhibition of MMP gene transcription in IL-1-β-treated SW-1353 chondrosarcoma cells. An in vitro collagen destruction assay was a functional readout of MMP collagenolytic activity. Luciferase reporter assays tested the function of a putative regulatory element in the promoters of MMP-1 and MMP-13, and chromatin immunoprecipitation (ChIP) assays detected PPARγ and changes in histone acetylation at this site. Post-translational modification of RXR and PPARγ by small ubiquitin-like modifier (SUMO) was assayed with immunoprecipitation and Western blot.

Results

Rosiglitazone inhibited MMP-1 and MMP-13 expression in IL-1-β-treated SW-1353 cells at the mRNA and heterogeneous nuclear RNA levels and blunted IL-1-β-induced collagen destruction in vitro. Combining LG268 and rosiglitazone had an additive inhibitory effect on MMP-1 and MMP-13 transcription and collagenolysis. IL-1-β inhibited luciferase expression in the MMP reporter assay, but rosiglitazone and LG268 had no effect. ChIP indicated that treatment with IL-1-β, but not LG268 and rosiglitazone, increased PPARγ at the proximal promoters of both MMPs. Finally, rosiglitazone or LG268 induced 'cross-SUMOylation' of both the target receptor and its binding partner, and IL-1-β-alone had no effect on SUMOylation of RXR and PPARγ but antagonized the ligand-induced SUMOylation of both receptors.

Conclusions

The PPARγ and RXR ligands rosiglitazone and LG268 may act through similar mechanisms, inhibiting MMP-1 and MMP-13 transcription. Combinatorial treatment activates each partner of the RXR:PPARγ heterodimer and inhibits IL-1-β-induced expression of MMP-1 and MMP-13 more effectively than either compound alone. We conclude that the efficacy of combined treatment with lower doses of each drug may minimize potential side effects of treatment with these compounds.
Nitrogen washout/washin, helium dilution and computed tomography in the assessment of end expiratory lung volume
Authors: Chiumello Davide , Cressoni Massimo , Chierichetti Monica , Tallarini Federica , Botticelli Marco , Berto Virna , Mietto Cristina , Gattinoni Luciano
Published: December 2008

Introduction

End expiratory lung volume (EELV) measurement in the clinical setting is routinely performed using the helium dilution technique. A ventilator that implements a simplified version of the nitrogen washout/washin technique is now available. We compared the EELV measured by spiral computed tomography (CT) taken as gold standard with the lung volume measured with the modified nitrogen washout/washin and with the helium dilution technique.

Methods

Patients admitted to the general intensive care unit of Ospedale Maggiore Policlinico Mangiagalli Regina Elena requiring ventilatory support and, for clinical reasons, thoracic CT scanning were enrolled in this study. We performed two EELV measurements with the modified nitrogen washout/washin technique (increasing and decreasing inspired oxygen fraction (FiO2) by 10%), one EELV measurement with the helium dilution technique and a CT scan. All measurements were taken at 5 cmH2O airway pressure. Each CT scan slice was manually delineated and gas volume was computed with custom-made software.

Results

Thirty patients were enrolled (age = 66 +/- 10 years, body mass index = 26 +/- 18 Kg/m2, male/female ratio = 21/9, partial arterial pressure of carbon dioxide (PaO2)/FiO2 = 190 +/- 71). The EELV measured with the modified nitrogen washout/washin technique showed a very good correlation (r2 = 0.89) with the data computed from the CT with a bias of 94 +/- 143 ml (15 +/- 18%, p = 0.001), within the limits of accuracy declared by the manufacturer (20%). The bias was shown to be highly reproducible, either decreasing or increasing the FiO2 being 117+/-170 and 70+/-160 ml (p = 0.27), respectively. The EELV measured with the helium dilution method showed a good correlation with the CT scan data (r2 = 0.91) with a negative bias of 136 +/- 133 ml, and appeared to be more correct at low lung volumes.

Conclusions

The EELV measurement with the helium dilution technique (at low volumes) and modified nitrogen washout/washin technique (at all lung volumes) correlates well with CT scanning and may be easily used in clinical practice.

Trial Registration

Current Controlled Trials NCT00405002.
Phase I Study of ch14.18 With Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 in Children With Neuroblastoma After Autologous Bone Marrow Transplantation or Stem-Cell Rescue: A Report From the Children's Oncology Group
Authors: Gilman Andrew L. , Ozkaynak M. Fevzi , Matthay Katherine K. , Krailo Mark , Yu Alice L. , Gan Jacek , Sternberg Adam , Hank Jacquelyn A. , Seeger Robert , Reaman Gregory H. , Sondel Paul M.
Published: December 2008

Purpose

Recurrence of high-risk neuroblastoma is common despite multimodality therapy. ch14.18, a chimeric human/murine anti-GD2 antibody, lyses neuroblastoma cells. This study determined the maximum tolerable dose (MTD) and toxicity of ch14.18 given in combination with interleukin-2 (IL-2) after high-dose chemotherapy (HDC)/stem-cell rescue (SCR). Biologic correlates including ch14.18 levels, soluble IL-2 receptor levels, and human antichimeric antibody (HACA) activity were evaluated.

Patients and Methods

Patients were given ch14.18 for 4 days at 28-day intervals. Patients received IL-2 during the second and fourth courses of ch14.18 and granulocyte-macrophage colony-stimulating factor (GM-CSF) during the first, third, and fifth courses. The MTD was determined based on toxicities occurring with the second course. After the determination of the MTD, additional patients were treated to confirm the MTD and to clarify appropriate supportive care.

Results

Twenty-five patients were enrolled. The MTD of ch14.18 was determined to be 25 mg/m2/d for 4 days given concurrently with 4.5 × 106 U/m2/d of IL-2 for 4 days. IL-2 was also given at a dose of 3 × 106 U/m2/d for 4 days starting 1 week before ch14.18. Two patients experienced dose-limiting toxicity due to ch14.18 and IL-2. Common toxicities included pain, fever, nausea, emesis, diarrhea, urticaria, mild elevation of hepatic transaminases, capillary leak syndrome, and hypotension. No death attributable to toxicity of therapy occurred. No additional toxicity was seen when cis-retinoic acid (cis-RA) was given between courses of ch14.18. No patient treated at the MTD developed HACA.

Conclusion

ch14.18 in combination with IL-2 was tolerable in the early post-HDC/SCR period. cis-RA can be administered safely between courses of ch14.18 and cytokines.
Cardiovascular Mortality After Androgen Deprivation Therapy for Locally Advanced Prostate Cancer: RTOG 85-31
Authors: Efstathiou Jason A. , Bae Kyounghwa , Shipley William U. , Hanks Gerald E. , Pilepich Miljenko V. , Sandler Howard M. , Smith Matthew R.
Published: December 2008

Purpose

Gonadotropin-releasing hormone (GnRH) agonists are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about potential impact on cardiovascular mortality. We assessed the relationship between GnRH agonists and cardiovascular mortality in a large randomized phase III trial of men treated with or without adjuvant goserelin after radiation therapy (RT) for locally advanced prostate cancer.

Patients and Methods

Between 1987 and 1992, 945 men with locally advanced prostate cancer were randomly assigned to RT and adjuvant goserelin or RT alone. Fine and Gray's regression was used to evaluate treatment effect on cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus (DM), body mass index, race, Gleason score, stage, acid phosphatase level, prostatectomy history, and nodal involvement.

Results

After a median follow-up of 8.1 years, there were 117 cardiovascular-related deaths but no treatment-related increase in cardiovascular mortality. At 9 years, cardiovascular mortality for men receiving adjuvant goserelin was 8.4% v 11.4% for men treated without adjuvant goserelin (Gray's P = .17). In multiple regression analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR] = 0.73; 95% CI, 0.47 to 1.15; P = .16; when censoring at time of salvage goserelin therapy, HR = 0.99; 95% CI, 0.58 to 1.69; P = .97). Traditional cardiac risk factors, including prevalent CVD and DM, were significantly associated with greater cardiovascular mortality.

Conclusion

GnRH agonists do not seem to increase cardiovascular mortality in men with locally advanced prostate cancer. Further studies are warranted to evaluate adverse effects of GnRH agonists in men with lower cancer-specific mortality.
Age-Related Risk Profile and Chemotherapy Dose Response in Acute Myeloid Leukemia: A Study by the German Acute Myeloid Leukemia Cooperative Group
Authors: Büchner Thomas , Berdel Wolfgang E. , Haferlach Claudia , Haferlach Torsten , Schnittger Susanne , Müller-Tidow Carsten , Braess Jan , Spiekermann Karsten , Kienast Joachim , Staib Peter , Grüneisen Andreas , Kern Wolfgang , Reichle Albrecht , Maschmeyer Georg , Aul Carlo , Lengfelder Eva , Sauerland Maria-Cristina , Heinecke Achim , Wörmann Bernhard , Hiddemann Wolfgang
Published: December 2008

Purpose

The purpose of the study was to assess the contribution of age and disease variables to the outcome of untreated patients with acute myeloid leukemia (AML) receiving varying intensive induction chemotherapy.

Patients and Methods

Patients 16 to 85 years of age with primary AML, known karyotype, and uniform postremission chemotherapy enrolled onto two consecutive trials were eligible and were randomly assigned to induction either with a standard-dose (cytarabine, daunorubicin, and 6-thioguanine) and a high-dose (cytarabine and mitoxantrone) combination, or with two courses of the high-dose combination. Subgroups were defined by karyotype, nucleophosmin and FLT3 mutation, WBC count, serum lactate dehydrogenase, and residual blasts.

Results

In 1,284 patients, the overall survival at 4 years in those younger and older than 60 years was 37% versus 16% (P < .001) and the ongoing remission duration was 46% versus 22% (P < .001). Similar age-related differences in outcome were found for all defined subgroups. No difference in outcome according to randomly assigned treatment regimen was observed in any age group or prognostic subset. Regarding prognostic subgroups, molecular factors were also considered.

Conclusion

Under harmonized conditions, older and younger patients with AML show modest differences in their risk profiles and equally no dose response to intensified chemotherapy. Their observed fundamental difference in outcome across all subgroups remains unexplained. Further molecular investigation may elucidate the age effect in AML and identify new targets.
Phase II Trial of Sorafenib in Patients With Metastatic Breast Cancer Previously Exposed to Anthracyclines or Taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336
Authors: Moreno-Aspitia Alvaro , Morton Roscoe F. , Hillman David W. , Lingle Wilma L. , Rowland Kendrith M. , Wiesenfeld Martin , Flynn Patrick J. , Fitch Tom R. , Perez Edith A.
Published: December 2008

Purpose

We conducted a cooperative group phase II study to assess antitumor activity and toxicity of sorafenib in patients with metastatic breast cancer (MBC) who had received prior treatment for their disease.

Patient and Methods

Patients were eligible if they had measurable disease and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. The primary end point of the study was tumor response per Response Evaluation Criteria in Solid Tumors (RECIST). The study was designed in two stages. Sorafenib was administered as 400 mg twice daily on days 1 through 28 of each 4-week cycle.

Results

Twenty-three patients were enrolled with a median age of 54 years (range, 37 to 70 years). Twenty-two (96%) had prior anthracycline treatment and 16 (70%) had prior taxane treatment. Patients received sorafenib for a median of two cycles (range, one to 15 cycles) with a median follow-up of 2.4 years (range, 2.2 to 2.6 years). There were no grade 4 toxicities and few grade 3 toxicities. Among the 20 patients eligible for efficacy analysis, no patients experienced a partial response or complete response per RECIST criteria. Thus, the trial stopped at the end of the first stage per study design. Two patients (10%; 90% CI, 1.8% to 28.3%) achieved stable disease lasting longer than 6 months.

Conclusion

Sorafenib as a single agent, although well tolerated, did not exhibit activity when measured by tumor shrinkage in patients with MBC who had received prior treatment. Further research should focus on combinations with standard therapy and end points more sensitive to effects of targeted agents, such as disease stabilization.
Natural History of CNS Relapse in Patients With Aggressive Non-Hodgkin's Lymphoma: A 20-Year Follow-Up Analysis of SWOG 8516—The Southwest Oncology Group
Authors: Bernstein Steven H. , Unger Joseph M. , LeBlanc Michael , Friedberg Jonathan , Miller Thomas P. , Fisher Richard I.
Published: December 2008

Purpose

To investigate the incidence, natural history, and risk factors predictive of CNS relapse in patients with de novo aggressive lymphomas and to evaluate the efficacy of CNS prophylaxis in patients with initial bone marrow (BM) involvement.

Patients and Methods

We conducted an analysis of CNS events from 20-year follow-up data on 899 eligible patients with aggressive lymphoma treated on Southwest Oncology Group protocol 8516, a randomized trial of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), ProMACE (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide)-CytaBOM (cytarabine, bleomycin, vincristine, methotrexate), and m-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide). Patients with BM involvement randomly assigned to receive ProMACE-CytaBOM (63 patients) or m-BACOD (58 patients) were to receive CNS prophylaxis, whereas those randomly assigned to receive CHOP or MACOP-B did not.

Results

CNS relapse is uncommon (25 of 899 patients), with a cumulative incidence of 2.8%. CNS relapse occurs early (median time to relapse, 5.4 months from diagnosis). Indeed, 20 of 25 patients with CNS relapse relapsed during chemotherapy, or within 6 months of completion. The number of extranodal sites and the International Prognostic Index were predictive of CNS relapse. There was no significant benefit of CNS prophylaxis in patients with BM involvement at diagnosis; however, given the small number of events, the power of this analysis is limited.

Conclusion

The early occurrence of CNS events suggests that these patients had subclinical disease at initial diagnosis. As such, strategies to better detect and treat patients with subclinical CNS disease at diagnosis would be anticipated to result in a decrease in the incidence of CNS relapse, without subjecting those patients not destined for CNS relapse to unnecessary and potentially toxic prophylaxis strategies.
Randomized Phase II Study of Pulse Erlotinib Before or After Carboplatin and Paclitaxel in Current or Former Smokers With Advanced Non–Small-Cell Lung Cancer
Authors: Riely Gregory J. , Rizvi Naiyer A. , Kris Mark G. , Milton Daniel T. , Solit David B. , Rosen Neal , Senturk Emir , Azzoli Christopher G. , Brahmer Julie R. , Sirotnak Francis M. , Seshan Venkatraman E. , Fogle Margaret , Ginsberg Michelle , Miller Vincent A. , Rudin Charles M.
Published: December 2008

Purpose

A prior study demonstrated that addition of continuous daily erlotinib fails to improve response rate or survival in non–small-cell lung cancer (NSCLC) patients treated with carboplatin and paclitaxel. However, preclinical data support the hypothesis that intermittent administration of erlotinib before or after chemotherapy may improve efficacy. We tested this hypothesis in patients with advanced NSCLC.

Patients and Methods

Eligible patients were former or current smokers with chemotherapy-naive stage IIIB or IV NSCLC. All patients received up to six cycles of carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2), with random assignment to one of the following three erlotinib treatments: erlotinib 150 mg on days 1 and 2 with chemotherapy on day 3 (150 PRE); erlotinib 1,500 mg on days 1 and 2 with chemotherapy on day 3 (1,500 PRE); or chemotherapy on day 1 with erlotinib 1,500 mg on days 2 and 3 (1,500 POST). The primary end point was response rate.

Results

Eighty-six patients received treatment. The response rates for the 150 PRE, 1,500 PRE, and 1,500 POST arms were 18% (five of 28 patients), 34% (10 of 29 patients), and 28% (eight of 29 patients), respectively. The median overall survival times were 10, 15, and 10 months for the 150 PRE, 1,500 PRE, and 1,500 POST arms, respectively. The most common grade 3 and 4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3 and 4 rash and diarrhea were uncommon.

Conclusion

Patients treated on the 1,500 PRE arm had the highest response rate and longest survival, with ranges similar to those reported for carboplatin, paclitaxel, and bevacizumab in a more restricted population. Further evaluation of this strategy in a phase III trial is proposed.