bluuebunny/crossref_metadata_2025 huggingface dataset:
Smart Options for Functional Finishing of Linen-containing Fabrics
Authors: Ibrahim N.A. , Eid B.M. , Hashem M.M. , Refai R. , El-Hossamy M.
Published: February 2010

This study examined an innovative approach to functional finishes of linen-containing fabrics. Modification of surface properties along with creation on new interactive site onto the fabrics surfaces, i.e., —COOH or —NH2 groups, using oxygen-or nitrogen plasma followed by subsequent treatments with selected ionic dyes, certain metal salts, nano-scale metal or metal oxides, quaternary ammonium salt or nominated antibiotics were carried out to obtain linen-based textiles with upgrade UV-protection and/or antibacterial functions. The results detailed in this paper demonstrate that: (i) post-basic dyeing of oxygen plasma-treated substrates with C.I. Basic Red 24 brings about a significant improvement in the UV-protection and antibacterial activity against the G +ve (Staphylococcus aureus) and G —ve (Escherichia coli) bacteria, (ii) post-reactive dyeing of nitrogen plasma-treated substrates with C.I. Reactive violet 5, results in a remarkable improvement in both UV-blocking and antibacterial properties. (iii) the extent of improvement in the above-mentioned properties of the obtained dyeings is determined by the type of substrate, kind and concentration of the ionic dye, (iv) loading of the metal ions onto the preactivated fabric surfaces upgraded their UV-protection valued as well as their antibacterial efficiency, and the extent of enhancement is governed by the kind and concentration of metal salt as well as type of bacteria, (v) loading of nano-scale Ag, TiO2, or ZrO onto the plasma-treated substrates brings about a remarkable improvement in their functional properties, (vi) loading of the used antibiotics or choline chloride onto the plasma-treated substrates gives rise to better antibacterial ability, (vii) both the UV-protection ability and the antibacterial activity of selected samples were retained even after 10 laundering cycles, and (viii) the options described here for attaining linen-containing fabrics with high functional properties are effective, simple and applicable.
Off-Label Medication Use in Frontotemporal Dementia
Authors: Bei Hu  , Ross Leslie , Neuhaus John , Knopman David , Kramer Joel , Boeve Bradley , Caselli Richard J. , Graff-Radford Neill , Mendez Mario F. , Miller Bruce L. , Boxer Adam L.
Published: February 2010

Objective: There are no Food and Drug Administration (FDA)-approved medications indicated for the treatment of frontotemporal dementia (FTD). We sought to determine the most commonly used drugs used to treat behavioral variant FTD (bvFTD) in specialized dementia clinics. Methods: Medication and demographic data from the Alzheimer’s Disease Research Centers of California (ARCC) and a multicenter FTD natural history study (NHS) data set were compared in bvFTD and Alzheimer’s disease (AD), and effects of demographic variables were assessed using logistic regression. Results: Overall, the percentage of patients taking one or more FDA-approved AD or psychiatric medications was similar in bvFTD and AD; however, after controlling for demographic variables, acetylcholinesterase inhibitor (AChI) use was less common in bvFTD, whereas memantine use remained similar in the 2 groups. Conclusions: Despite lack of evidence for efficacy, the use of AChIs and memantine is common in bvFTD. Clinical trials should be pursued to determine the optimal therapeutic interventions for bvFTD.
Quantification of illite and smectite and their layer charges in sandstones and shales from shallow burial depth
Authors: Środoń J.
Published: February 2010

Precise measurement of the content and the layer charge of illite and smectite is an important aspect of the mineralogical calibration of geophysical well logs and of the evaluation of mechanical and chemical properties of sedimentary rocks. Ate chnique for obtaining such measurements was developed during mineralogical studies of the Miocene clastic rocks from the Carpathian Foredeep. X-ray diffraction (XRD), chemical, cation exchange capacity (CEC), H2O sorption, and ethylene glycol monoethyl ether (EGME) sorption data were obtained for 65 samples of sandstones, shales and carbonates. The illite + smectite sum, involving all detected 2:1 minerals (smectite, illite-smectite, illite, glauconite and muscovite) was measured by XRD. The content of the illitic component was evaluated separately using % K2O and accounting for % K2O in K-feldspar. The content of the smectitic component was estimated from EGME retention using the reference data for a smectite standard, and from CEC assuming the smectitic layer charge of 0.41/O10(OH)2 (Środoń et al., in press). All these measurements produced very consistent results.
Ni-sepiolite-falcondoite in garnierite mineralization from the Falcondo Ni-laterite deposit, Dominican Republic
Authors: Tauler E. , Proenza J. A. , Galí S. , Lewis J. F. , Labrador M. , García-Romero E. , Suarez M. , Longo F. , Bloise G.
Published: February 2010

New chemical and structural data on sepiolite-falcondoite in garnierite veins from the Falcondo Ni-laterite deposits, central Dominican Republic, are reported. Samples of Ni-sepiolite-falcondoite vary in colour from whitish green to green depending on the NiO content (wt.%) and the amount of silica present. The texture is normally schistose and friable but samples with considerable quartz and/or amorphous silica are compact and hard. Back-scattered electron images indicate that the samples are composed of at least three generations of Ni-sepiolite-falcondoite. The extreme refined cell parameters for Ni-sepiolite-falcondoite vary from 13.400(2), 27.006(4), 5.273(1) Å to 13.340(3), 27.001(6), 5.267(1) Å (space group Pncn). As the Ni content increases there is a small reduction in the a parameter. Chemical compositions determined by electron probe microanalysis cover a large interval of the Ni-sepiolite-falcondoite solid solution (Fal3 and Fal77). Individual samples show a considerable range in composition with the widest range determined in one sample from 4.63 to 22.40 wt.% NiO.
Adult T-cell leukemia/lymphoma development in HTLV-1–infected humanized SCID mice
Authors: Banerjee Prabal , Tripp Adam , Lairmore Michael D. , Crawford Lindsey , Sieburg Michelle , Ramos Juan Carlos , Harrington William , Beilke Mark A. , Feuer Gerold
Published: February 2010

The molecular and genetic factors induced by human T-lymphotropic virus type-1 (HTLV-1) that initiate adult T-cell leukemia/lymphoma (ATLL) remain unclear, in part from the lack of an animal model that accurately recapitulates leukemogenesis. HTLV-1–infected humanized nonobese diabetic severe combined immunodeficiency (HU-NOD/SCID) mice were generated by inoculation of NOD/SCID mice with CD34+ hematopoietic progenitor and stem cells (CD34+ HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice exclusively developed CD4+ T-cell lymphomas with characteristics similar to ATLL and elevated proliferation of infected human stem cells (CD34+CD38−) in the bone marrow were observed in mice developing malignancies. Purified CD34+ HP/HSCs from HTLV-1–infected patient peripheral blood mononuclear cells revealed proviral integrations suggesting viral infection of human bone marrow–derived stem cells. NOD/SCID mice reconstituted with CD34+ HP/HSCs transduced with a lentivirus vector expressing the HTLV-1 oncoprotein (Tax1) also developed CD4+ lymphomas. The recapitulation of a CD4+ T-cell lymphoma in HU-NOD/SCID mice suggests that HSCs provide a viral reservoir in vivo and act as cellular targets for cell transformation in humans. This animal model of ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development.
The Thiamine diphosphate dependent Enzyme Engineering Database: A tool for the systematic analysis of sequence and structure relations
Authors: Widmann Michael , Radloff Robert , Pleiss Jürgen
Published: February 2010

Background

Thiamine diphosphate (ThDP)-dependent enzymes form a vast and diverse class of proteins, catalyzing a wide variety of enzymatic reactions including the formation or cleavage of carbon-sulfur, carbon-oxygen, carbon-nitrogen, and especially carbon-carbon bonds. Although very diverse in sequence and domain organisation, they share two common protein domains, the pyrophosphate (PP) and the pyrimidine (PYR) domain. For the comprehensive and systematic comparison of protein sequences and structures the Thiamine diphosphate (ThDP)-dependent Enzyme Engineering Database (TEED) was established.

Description

The TEED http://www.teed.uni-stuttgart.de contains 12048 sequence entries which were assigned to 9443 different proteins and 379 structure entries. Proteins were assigned to 8 different superfamilies and 63 homologous protein families. For each family, the TEED offers multisequence alignments, phylogenetic trees, and family-specific HMM profiles. The conserved pyrophosphate (PP) and pyrimidine (PYR) domains have been annotated, which allows the analysis of sequence similarities for a broad variety of proteins. Human ThDP-dependent enzymes are known to be involved in many diseases. 20 different proteins and over 40 single nucleotide polymorphisms (SNPs) of human ThDP-dependent enzymes were identified in the TEED.

Conclusions

The online accessible version of the TEED has been designed to serve as a navigation and analysis tool for the large and diverse family of ThDP-dependent enzymes.
Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison
Authors: Redana Stefania , Donadio Michela , Nolè Franco , Jacomuzzi Maria Elena , Beano Alessandra , Martinello Rossella , Sapino Anna , Viale Giuseppe , Aglietta Massimo , Montemurro Filippo
Published: February 2010

Background

Combinations of trastuzumab with either docetaxel or vinorelbine are considered valuable treatment options for HER2-positive metastatic breast cancer patients. We performed a retrospective comparison of the clinical outcomes associated with either one of these combinations.

Methods

From a multi-institutional database we retrieved 179 patients treated with either docetaxel or vinorelbine plus trastuzumab as first-line therapy for HER2-positive advanced breast cancer.

Results

Docetaxel-trastuzumab was superior to vinorelbine-trastuzumab in terms of response rate (RR: 77 vs 57%, p = 0.01) and median overall survival (OS: 35 vs 23 months, p = 0.04), but not in median time to progression (TTP: 12 vs 10 months, p = 0.53). At multivariate analysis, type of treatment was not associated with TTP but was an independent predictor of OS, with a significant reduction in the risk of death in favor of docetaxel-trastuzumab (HR 0.474, 95% IC 0,303-0.742, p < 0.01).

Conclusion

Docetaxel or vinorelbine, when combined with trastuzumab, provide excellent rates of tumor control in patients with previously untreated HER2-positive advanced breast cancer. Docetaxel may offer some advantage in terms of response rate and resulted in a significantly prolonged overall survival, which, because of the retrospective design of our study, deserves further investigation in prospective trials.
Identification of recurring protein structure microenvironments and discovery of novel functional sites around CYS residues
Authors: Wu Shirley , Liu Tianyun , Altman Russ B
Published: February 2010

Background

The emergence of structural genomics presents significant challenges in the annotation of biologically uncharacterized proteins. Unfortunately, our ability to analyze these proteins is restricted by the limited catalog of known molecular functions and their associated 3D motifs.

Results

In order to identify novel 3D motifs that may be associated with molecular functions, we employ an unsupervised, two-phase clustering approach that combines k-means and hierarchical clustering with knowledge-informed cluster selection and annotation methods. We applied the approach to approximately 20,000 cysteine-based protein microenvironments (3D regions 7.5 Å in radius) and identified 70 interesting clusters, some of which represent known motifs (e.g. metal binding and phosphatase activity), and some of which are novel, including several zinc binding sites. Detailed annotation results are available online for all 70 clusters at http://feature.stanford.edu/clustering/cys.

Conclusions

The use of microenvironments instead of backbone geometric criteria enables flexible exploration of protein function space, and detection of recurring motifs that are discontinuous in sequence and diverse in structure. Clustering microenvironments may thus help to functionally characterize novel proteins and better understand the protein structure-function relationship.
Intracellular Ca2+ regulating proteins in vascular smooth muscle cells are altered with type 1 diabetes due to the direct effects of hyperglycemia
Authors: Searls Yvonne M , Loganathan Rajprasad , Smirnova Irina V , Stehno-Bittel Lisa
Published: February 2010

Background

Diminished calcium (Ca2+) transients in response to physiological agonists have been reported in vascular smooth muscle cells (VSMCs) from diabetic animals. However, the mechanism responsible was unclear.

Methodology/Principal Findings

VSMCs from autoimmune type 1 Diabetes Resistant Bio-Breeding (DR-BB) rats and streptozotocin-induced rats were examined for levels and distribution of inositol trisphosphate receptors (IP3R) and the SR Ca2+ pumps (SERCA 2 and 3). Generally, a decrease in IP3R levels and dramatic increase in ryanodine receptor (RyR) levels were noted in the aortic samples from diabetic animals. Redistribution of the specific IP3R subtypes was dependent on the rat model. SERCA 2 was redistributed to a peri-nuclear pattern that was more prominent in the DR-BB diabetic rat aorta than the STZ diabetic rat. The free intracellular Ca2+ in freshly dispersed VSMCs from control and diabetic animals was monitored using ratiometric Ca2+ sensitive fluorophores viewed by confocal microscopy. In control VSMCs, basal fluorescence levels were significantly higher in the nucleus relative to the cytoplasm, while in diabetic VSMCs they were essentially the same. Vasopressin induced a predictable increase in free intracellular Ca2+ in the VSMCs from control rats with a prolonged and significantly blunted response in the diabetic VSMCs. A slow rise in free intracellular Ca2+ in response to thapsigargin, a specific blocker of SERCA was seen in the control VSMCs but was significantly delayed and prolonged in cells from diabetic rats. To determine whether the changes were due to the direct effects of hyperglycemica, experiments were repeated using cultured rat aortic smooth muscle cells (A7r5) grown in hyperglycemic and control conditions. In general, they demonstrated the same changes in protein levels and distribution as well as the blunted Ca2+ responses to vasopressin and thapsigargin as noted in the cells from diabetic animals.

Conclusions/Significance

This work demonstrates that the previously-reported reduced Ca2+ signaling in VSMCs from diabetic animals is related to decreases and/or redistribution in the IP3R Ca2+ channels and SERCA proteins. These changes can be duplicated in culture with high glucose levels.
Axin downregulates TCF-4 transcription via β-catenin, but not p53, and inhibits the proliferation and invasion of lung cancer cells
Authors: Yang Lian-He , Xu Hong-Tao , Han Yang , Li Qing-Chang , Liu Yang , Zhao Yue , Yang Zhi-Qiang , Dong Qian-Ze , Miao Yuan , Dai Shun-Dong , Wang En-Hua
Published: February 2010

Background

We previously reported that overexpression of Axin downregulates T cell factor-4 (TCF-4) transcription. However, the mechanism(s) by which Axin downregulates the transcription and expression of TCF-4 is not clear. It has been reported that β-catenin promotes and p53 inhibits TCF-4 transcription, respectively. The aim of this study was to investigate whether β-catenin and/or p53 is required for Axin-mediated downregulation of TCF-4.

Results

Axin mutants that lack p53/HIPK2 and/or β-catenin binding domains were expressed in lung cancer cells, BE1 (mutant p53) and A549 (wild type p53). Expression of Axin or AxinΔp53 downregulates β-catenin and TCF-4, and knock-down of β-catenin upregulates TCF-4 in BE1 cells. However, expression of AxinΔβ-ca into BE1 cells did not downregulate TCF-4 expression. These results indicate that Axin downregulates TCF-4 transcription via β-catenin. Although overexpression of wild-type p53 also downregulates TCF-4 in BE1 cells, cotransfection of p53 and AxinΔβ-ca did not downregulate TCF-4 further. These results suggest that Axin does not promote p53-mediated downregulation of TCF-4. Axin, AxinΔp53, and AxinΔβ-ca all downregulated β-catenin and TCF-4 in A549 cells. Knock-down of p53 upregulated β-catenin and TCF-4, but cotransfection of AxinΔβ-ca and p53 siRNA resulted in downregulation of β-catenin and TCF-4. These results indicate that p53 is not required for Axin-mediated downregulation of TCF-4. Knock-down or inhibition of GSK-3β prevented Axin-mediated downregulation of TCF-4. Furthermore, expression of Axin and AxinΔp53, prevented the proliferative and invasive ability of BE1 and A549, expression of AxinΔβ-ca could only prevented the proliferative and invasive ability effectively.

Conclusions

Axin downregulates TCF-4 transcription via β-catenin and independently of p53. Axin may also inhibits the proliferation and invasion of lung cancer cells via β-catenin and p53.
The mutation T477A in HIV-1 reverse transcriptase (RT) restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site
Authors: Abram Michael E , Sarafianos Stefan G , Parniak Michael A
Published: February 2010

Background

The p51 subunit of the HIV-1 reverse transcriptase (RT) p66/p51 heterodimer arises from proteolytic cleavage of the RT p66 subunit C-terminal ribonuclease H (RNH) domain during virus maturation. Our previous work showed that mutations in the RT p51↓RNH cleavage site resulted in virus with defects in proteolytic processing of RT and significantly attenuated infectivity. In some cases, virus fitness was restored after repeated passage of mutant viruses, due to reversion of the mutated sequences to wild-type. However, in one case, the recovered virus retained the mutated p51↓RNH cleavage site but also developed an additional mutation, T477A, distal to the cleavage site. In this study we have characterized in detail the impact of the T477A mutation on intravirion processing of RT.

Results

While the T477A mutation arose during serial passage only with the F440V mutant background, introduction of this substitution into a variety of RT p51↓RNH cleavage site lethal mutant backgrounds was able to restore substantial infectivity and normal RT processing to these mutants. T477A had no phenotypic effect on wild-type HIV-1. We also evaluated the impact of T477A on the kinetics of intravirion Gag-Pol polyprotein processing of p51↓RNH cleavage site mutants using the protease inhibitor ritonavir. Early processing intermediates accumulated in p51↓RNH cleavage site mutant viruses, whereas introduction of T477A promoted the completion of processing and formation of the fully processed RT p66/p51 heterodimer.

Conclusions

This work highlights the extraordinary plasticity of HIV-1 in adapting to seemingly lethal mutations that prevent RT heterodimer formation during virion polyprotein maturation. The ability of T477A to restore RT heterodimer formation and thus intravirion stability of the enzyme may arise from increased conformation flexibility in the RT p51↓RNH cleavage site region, due to loss of a hydrogen bond associated with the normal threonine residue, thereby enabling proteolytic cleavage near the normal RT p51↓RNH cleavage site.
Differential impact of ageing on cellular and humoral immunity to a persistent murine γ-herpesvirus
Authors: Yager Eric J , Kim In-Jeong , Freeman Michael L , Lanzer Kathleen G , Burkum Claire E , Cookenham Tres , Woodland David L , Blackman Marcia A
Published: February 2010

Background

Oncogenic γ-herpesviruses establish life-long infections in their hosts and control of these latent infections is dependent on continual immune surveillance. Immune function declines with age, raising the possibility that immune control of γ-herpesvirus infection becomes compromised with increasing age, allowing viral reactivation and/or increased latent load, both of which are associated with the development of malignancies.

Results

In this study, we use the experimental mouse γ-herpesvirus model, γHV68, to investigate viral immunity in aged mice. We found no evidence of viral recrudescence or increased latent load in aged latently-infected mice, suggesting that effective immune control of γ-herpesvirus infection remains intact with ageing. As both cellular and humoral immunity have been implicated in host control of γHV68 latency, we independently examined the impact of ageing on γHV68-specific CD8 T cell function and antibody responses. Virus-specific CD8 T cell numbers and cytolytic function were not profoundly diminished with age. In contrast, whereas ELISA titers of virus-specific IgG were maintained over time, there was a progressive decline in neutralizing activity. In addition, although aged mice were able to control de novo acute infection with only slightly delayed viral clearance, serum titers of neutralizing antibody were reduced in aged mice as compared to young mice.

Conclusion

Although there is no obvious loss of immune control of latent virus, these data indicate that ageing has differential impacts on anti-viral cellular and humoral immune protection during persistent γHV68 infection. This observation has potential relevance for understanding γ-herpesvirus immune control during disease-associated or therapeutic immunosuppression.
Small interference RNA profiling reveals the essential role of human membrane trafficking genes in mediating the infectious entry of dengue virus
Authors: Ang Firzan , Wong Andrew Phui Yew , Ng Mary Mah-Lee , Chu Justin Jang Hann
Published: February 2010

Background

Dengue virus (DENV) is the causative agent of Dengue fever and the life-threatening Dengue Haemorrhagic fever or Dengue shock syndrome. In the absence of anti-viral agents or vaccine, there is an urgent need to develop an effective anti-viral strategy against this medically important viral pathogen. The initial interplay between DENV and the host cells may represent one of the potential anti-viral targeting sites. Currently the involvements of human membrane trafficking host genes or factors that mediate the infectious cellular entry of dengue virus are not well defined.

Results

In this study, we have used a targeted small interfering RNA (siRNA) library to identify and profile key cellular genes involved in processes of endocytosis, cytoskeletal dynamics and endosome trafficking that are important and essential for DENV infection. The infectious entry of DENV into Huh7 cells was shown to be potently inhibited by siRNAs targeting genes associated with clathrin-mediated endocytosis. The important role of clathrin-mediated endocytosis was confirmed by the expression of well-characterized dominant-negative mutants of genes in this pathway and by using the clathrin endocytosis inhibitor chlorpromazine. Furthermore, DENV infection was shown to be sensitive to the disruption of human genes in regulating the early to late endosomal trafficking as well as the endosomal acidic pH. The importance and involvement of both actin and microtubule dynamics in mediating the infectious entry of DENV was also revealed in this study.

Conclusions

Together, the findings from this study have provided a detail profiling of the human membrane trafficking cellular genes and the mechanistic insight into the interplay of these host genes with DENV to initiate an infection, hence broadening our understanding on the entry pathway of this medically important viral pathogen. These data may also provide a new potential avenue for development of anti-viral strategies and treatment of DENV infection.
Remodeling of inhibitory synaptic connections in developing ferret visual cortex
Authors: Dalva Matthew B
Published: February 2010

Background

In the visual cortex, as in many other regions of the developing brain, excitatory synaptic connections undergo substantial remodeling during development. While evidence suggests that local inhibitory synapses may behave similarly, the extent and mechanisms that mediate remodeling of inhibitory connections are not well understood.

Results

Using scanning laser photostimulation in slices of developing ferret visual cortex, we assessed the overall patterns of developing inhibitory and excitatory synaptic connections converging onto individual neurons. Inhibitory synaptic inputs onto pyramidal neurons in cortical layers 2 and 3 were already present as early as postnatal day 20, well before eye opening, and originated from regions close to the recorded neurons. During the ensuing 2 weeks, the numbers of synaptic inputs increased, with the numbers of inhibitory (and excitatory) synaptic inputs peaking near the time of eye opening. The pattern of inhibitory inputs refined rapidly prior to the refinement of excitatory inputs. By uncaging the neurotransmtter GABA in brain slices from animals of different ages, we find that this rapid refinement correlated with a loss of excitatory activity by GABA.

Conclusion

Inhibitory synapses, like excitatory synapses, undergo significant postnatal remodeling. The time course of the remodeling of inhibitory connections correlates with the emergence of orientation tuning in the visual cortex, implicating these rearrangements in the genesis of adult cortical response properties.
Vein of Galen arteriovenous malformation with PAPVR and use of serial B-type natriuretic peptide levels in the management: a case report and review of the literature
Authors: Purdy Isabell B , Halnon Nancy , Singh Namrata , Milisavljevic Vladana
Published: February 2010

Background

Arteriovenous malformation of the vein of Galen with partial anomalous pulmonary venous return can lead to a critically challenging condition associated with a high morbidity and mortality.

Case report

We report a case of a full term infant born with a vein of Gallen arteriovenous malformation complicated by partial anomalous pulmonary venous return and congestive heart failure where B-type natriuretic peptide was used as a vital tool in clinical assessment and treatment management.

Conclusions

Rapid diagnosis and treatment in infants with complex conditions such as this are imperative to expedite appropriate treatments, preventing long term negative outcome.
Immunity of replicating Mu to self-integration: a novel mechanism employing MuB protein
Authors: Ge Jun , Lou Zheng , Harshey Rasika M
Published: February 2010

We describe a new immunity mechanism that protects actively replicating/transposing Mu from self-integration. We show that this mechanism is distinct from the established cis-immunity mechanism, which operates by removal of MuB protein from DNA adjacent to Mu ends. MuB normally promotes integration into DNA to which it is bound, hence its removal prevents use of this DNA as target. Contrary to what might be expected from a cis-immunity mechanism, strong binding of MuB was observed throughout the Mu genome. We also show that the cis-immunity mechanism is apparently functional outside Mu ends, but that the level of protection offered by this mechanism is insufficient to explain the protection seen inside Mu. Thus, both strong binding of MuB inside and poor immunity outside Mu testify to a mechanism of immunity distinct from cis-immunity, which we call 'Mu genome immunity'. MuB has the potential to coat the Mu genome and prevent auto-integration as previously observed in vitro on synthetic A/T-only DNA, where strong MuB binding occluded the entire bound region from Mu insertions. The existence of two rival immunity mechanisms within and outside the Mu genome, both employing MuB, suggests that the replicating Mu genome must be segregated into an independent chromosomal domain. We propose a model for how formation of a 'Mu domain' may be aided by specific Mu sequences and nucleoid-associated proteins, promoting polymerization of MuB on the genome to form a barrier against self-integration.
Serum neutrophil gelatinase-associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury
Authors: Kümpers Philipp , Hafer Carsten , Lukasz Alexander , Lichtinghagen Ralf , Brand Korbinian , Fliser Danilo , Faulhaber-Walter Robert , Kielstein Jan T
Published: February 2010

Introduction

Neutrophil gelatinase-associated lipocalin (NGAL) is a promising novel biomarker that correlates with the severity and outcome of acute kidney injury (AKI). However, its prognostic utility during the late course of AKI, especially in patients that require renal replacement therapy (RRT) remains unknown. The aim of this study was to evaluate the predictive value of serum NGAL in patients with established AKI at inception of RRT in the intensive care unit (ICU).

Methods

Serum NGAL (ELISA methodology) was measured in 109 critically ill patients with AKI at inception of RRT in 7 ICUs of a tertiary care university hospital. The primary outcome studied was 28-day mortality. Secondary outcome measures were ICU length of stay, ventilator-free days, and renal recovery at day 28.

Results

There was a significant difference in serum NGAL between healthy subjects (median [interquartile range] 39.0 [37.5-42.75] ng/mL), critically ill patients with systemic inflammatory response syndrome (SIRS) (297 [184-490] ng/mL), and critically ill patients with sepsis (708 [365-1301] ng/mL; P < 0.0001), respectively. Multiple linear regression showed that NGAL levels were independently related to the severity of AKI and the extent of systemic inflammation. NGAL levels were higher in non-survivors (430 [303-942] ng/mL) compared to survivors (298 [159-506] ng/mL; P = 0.004). Consistently, Cox proportional hazards regression analysis identified NGAL as a strong independent predictor for 28-day survival (hazard ratio 1.6 (95% confidence interval [CI] 1.15 - 2.23), P = 0.005).

Conclusions

This is the first prospective evaluation of serum NGAL as an outcome-specific biomarker in critically ill patients at initiation of RRT. The results from this study indicate that serum NGAL is as an independent predictor of 28-day mortality in ICU patients with dialysis-dependent AKI.
Gene Expression Profiling for Survival Prediction in Pediatric Rhabdomyosarcomas: A Report From the Children's Oncology Group
Authors: Davicioni Elai , Anderson James R. , Buckley Jonathan D. , Meyer William H. , Triche Timothy J.
Published: February 2010

Purpose

We investigated whether tumors from diagnostic biopsies of primary rhabdomyosarcoma (RMS) contain relevant prognostic information in the form of gene expression signatures that can be used to model and predict outcome of patients.

Patients and Methods

A 22,000-probe set microarray was used to evaluate 120 RMS specimens and correlate gene expression patterns to survival. Multivariate gene expression models or metagenes were developed using cross-validated Cox regression proportional hazards modeling and were evaluated using Kaplan-Meier analysis.

Results

A 34-metagene, based on expression patterns of 34 genes, was highly predictive of outcome. It was not highly correlated with individual clinical risk factors such as patient age, stage, tumor size, or histology. However, it was correlated with a risk classification used by the Children's Oncology Group and the biologic subsets of alveolar histology tumors.

Conclusion

These data support further evaluation of RMS metagenes to discriminate patients with good prognosis from those with poor prognosis, with the potential to direct risk-adapted therapy.
Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women
Authors: Dunbier Anita K. , Anderson Helen , Ghazoui Zara , Folkerd Elizabeth J. , A'Hern Roger , Crowder Robert J. , Hoog Jeremy , Smith Ian E. , Osin Peter , Nerurkar Ashutosh , Parker Joel S. , Perou Charles M. , Ellis Matthew J. , Dowsett Mitch
Published: February 2010

Purpose

To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women.

Materials and Methods

Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers.

Results

The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively).

Conclusion

Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.
Comparison of Two Doses of Imatinib for the Treatment of Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Meta-Analysis of 1,640 Patients
Authors:   Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)
Published: February 2010

Purpose

The Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) project aims to additionally explore the data of the two large, randomized, cooperative-group studies comparing two doses of imatinib (400 mg daily v twice daily) in 1,640 patients with advanced GIST.

Methods

End points were progression-free survival (PFS) and overall survival (OS). Investigated cofactors included age, sex, performance status (PS), primary tumor site, time from diagnosis, prior therapies, baseline biology, and KIT/PDGFRα mutations for a subset of 772 patients. Univariate and multivariate models were used for the analysis.

Results

At a median follow-up of 45 months, a small but significant PFS advantage was documented for the high-dose arm. OS was identical in the two arms. The multivariate prognostic models included the following adverse factors: male sex, poor PS, and high baseline neutrophils counts (PFS and OS); low hemoglobin and GIST from small bowel origin (PFS); and advanced age, large tumor size, low albumin level, and prior chemotherapy (OS). In patients analyzed for mutations, patients with wild type, patients with KIT exon 9 mutations, and patients with other mutations had worse prognoses than patients with KIT exon 11 mutations for both end points. The mutation status was the only predictive factor for the PFS benefit attributed to high-dose treatment that resulted in significantly longer PFS (and higher objective response rate) for patients with KIT exon 9 mutations.

Conclusion

This analysis confirms a small PFS advantage of high-dose imatinib, essentially among patients with KIT exon 9 mutations, but no OS advantage.
Comparison of the Prognostic Value of Assessing Tumor Diameter Versus Tumor Volume at Diagnosis or in Response to Initial Chemotherapy in Rhabdomyosarcoma
Authors: Ferrari Andrea , Miceli Rosalba , Meazza Cristina , Casanova Michela , Favini Francesca , Morosi Carlo , Trecate Giovanna , Marchianò Alfonso , Luksch Roberto , Cefalo Graziella , Terenziani Monica , Spreafico Filippo , Polastri Daniela , Podda Marta , Catania Serena , Schiavello Elisabetta , Giannatempo Patrizia , Gandola Lorenza , Massimino Maura , Mariani Luigi
Published: February 2010

Purpose

In this study on a series of 205 patients with rhabdomyosarcoma, we investigated whether the prognostic effect of tumor size, at diagnosis or in terms of tumor response after induction chemotherapy, differed when tumor diameter or tumor volume were considered.

Patients and Methods

Tumor size was assessed radiologically at diagnosis and, for the 108 patients with measurable disease, after three courses of chemotherapy. The analysis was based on multivariable models (linear for association between size and patient/tumor characteristics, Cox for association with survival). The predictive performance of the Cox model (estimated by V measure) was compared for the tumor's diameter and volume.

Results

Initial tumor size was significantly larger in male or older patients and in T2 or alveolar tumors, but was not associated with the achievement of complete surgical resection. Initial tumor size significantly influenced overall survival. The risk of death was comparable for tumors 10 cm in maximum diameter and 194.0 cm3 in volume. The predictive performance of the Cox model was much the same when the tumor's diameter or volume was considered. Tumor response was a significant predictor of survival, again irrespective of the type of tumor measurement considered.

Conclusion

In our analysis, initial tumor size and tumor response were significant prognostic factors in rhabdomyosarcoma, regardless of whether tumor diameter or volume was considered. Three-dimensional tumor assessment was of no greater prognostic value than one-dimensional assessment, neither initially nor after induction treatment.
End-of-Life Discussions, Goal Attainment, and Distress at the End of Life: Predictors and Outcomes of Receipt of Care Consistent With Preferences
Authors: Mack Jennifer W. , Weeks Jane C. , Wright Alexi A. , Block Susan D. , Prigerson Holly G.
Published: February 2010

Purpose

Physicians have an ethical obligation to honor patients' values for care, including at the end of life (EOL). We sought to evaluate factors that help patients to receive care consistent with their preferences.

Methods

This was a longitudinal multi-institutional cohort study. We measured baseline preferences for life-extending versus symptom-directed care and actual EOL care received in 325 patients with advanced cancer. We also measured associated sociodemographic, health, and communication characteristics, including EOL discussions between patients and physicians.

Results

Preferences were assessed a median of 125 days before death. Overall, 68% of patients (220 of 325 patients) received EOL care consistent with baseline preferences. The proportion was slightly higher among patients who recognized they were terminally ill (74%, 90 of 121 patients; P = .05). Patients who recognized their terminal illness were more likely to prefer symptom-directed care (83%, 100 of 121 patients; v 66%, 127 of 191 patients; P = .003). However, some patients who were aware they were terminally ill wished to receive life-extending care (17%, 21 of 121 patients). Patients who reported having discussed their wishes for EOL care with a physician (39%, 125 of 322 patients) were more likely to receive care that was consistent with their preferences, both in the full sample (odds ratio [OR] = 2.26; P < .0001) and among patients who were aware they were terminally ill (OR = 3.94; P = .0005). Among patients who received no life-extending measures, physical distress was lower (mean score, 3.1 v 4.1; P = .03) among patients for whom such care was consistent with preferences.

Conclusion

Patients with cancer are more likely to receive EOL care that is consistent with their preferences when they have had the opportunity to discuss their wishes for EOL care with a physician.
Constraints as Opposed to What?: A Philosophical Approach to the Values of Constrained Writing
Authors: Deming Richard
Published: February 2010

This article investigates the philosophical implications intrinsic to writing that expressly uses constraints and that thereby intentionally limits an author's freedom. Constrained writing imposes formal conditions and strictures as a response to the existential angst—aesthetic as well as ethical—generated by the now maximally open field of contemporary writing. Looking specifically at the work of such writers as Jacques Roubaud and Jacques Jouet, this article shows how dialectical thinking underwrites the poetics of constrained writing and reads such poetics as enacting philosophical, and more specifically Hegelian, values.
Constraint on the Move
Authors: Motte Warren
Published: February 2010

Constraint is often conceived of as a restrictive process, one that severely limits the field of possibilities available to a writer. While it is undoubtedly true that the use of systematic artifice and writing rules in a literary text does narrow an author's choices (one cannot use author, for instance, in a text that is limited to monosyllabic words), it may also provide for fresh and largely unsuspected choices and for new sorts of mobility as well. This essay tests this hypothesis, examining three contemporary works: a collection of sonnets by Raymond Queneau, a novel by Georges Perec, and a travel narrative by Julio Cortázar and Carol Dunlop. Each of the works deploys a different kind of constraint, and each seeks thereby to create an innovative literary dynamic, to renew literature itself, to broaden its horizon of possibility.
Optimal Sales Schemes against Interdependent Buyers
Authors: Aoyagi Masaki
Published: February 2010

This paper studies a monopoly pricing problem when the seller can choose the timing of a trade with each buyer, and a buyer's valuation of the seller's good is the weighted sum of his and other buyers' private signals. We show that it is optimal for the seller to employ a sequential scheme that trades with one buyer at a time and allows each buyer to observe the outcomes of all preceding transactions. We also identify conditions under which the seller optimally trades with the buyers in the increasing order of the weights they place on other buyers' signals. (JEL D42, D82, L12)
The Strategic Value of Quantity Forcing Contracts
Authors: Martimort David , Piccolo Salvatore
Published: February 2010

We explore the strategic value of quantity forcing contracts in a manufacturer-retailer environment under both adverse selection and moral hazard. Manufacturers dealing with (exclusive) competing retailers may prefer to leave contracts silent on retail prices, whenever other aspects of the retailers' activity remain nonverifiable. Two effects are at play when moving from retail price maintenance to quantity forcing. First, restricting screening possibilities may increase retailers' rent. Second, such a restriction affects downstream competition. This latter effect may justify using quantity forcing contracts and, more generally, shed light on a novel source of contractual incompleteness. (JEL D82, D86, L14)
An Experimental Test of Flexible Combinatorial Spectrum Auction Formats
Authors: Brunner Christoph , Goeree Jacob K , Holt Charles A , Ledyard John O
Published: February 2010

This paper reports laboratory experiments that evaluate the performance of a flexible package bidding format developed by the FCC, in comparison with other combinatorial formats. In general, the interest of policy makers in combinatorial auctions is justified by the laboratory data. When value complementarities are present, package bidding yields improved performance. We find clear differences among the combinatorial auction formats both in terms of efficiency and seller revenue, however. Notably, the combinatorial clock provides the highest revenue. The FCC's flexible package bidding format performed worse than the alternatives, which is one of the main reasons why it was not implemented. (JEL D44, H82)
Is the EITC as Good as an NIT? Conditional Cash Transfers and Tax Incidence
Authors: Rothstein Jesse
Published: February 2010

The EITC is intended to encourage work. But EITC-induced increases in labor supply may drive wages down. I simulate the economic incidence of the EITC. In each scenario that I consider, a large portion of low-income single mothers' EITC payments is captured by employers through reduced wages. Workers who are EITC ineligible also see wage declines. By contrast, a traditional Negative Income Tax (NIT) discourages work, and so induces large transfers from employers to their workers. With my preferred parameters, $1 in EITC spending increases after-tax incomes by $0.73, while $1 spent on the NIT yields $1.39. (JEL H22, H23, H24, H31, J22)
Tagging and Income Taxation: Theory and an Application
Authors: Cremer Helmuth , Gahvari Firouz , Lozachmeur Jean-Marie
Published: February 2010

We derive a set of analytical results for optimal income taxation with tags using quasilinear preferences and a Rawlsian social welfare function. Secondly, assuming a constant elasticity of labor supply and log-normality of the skills distribution, we analytically identify the winners and losers of tagging. Third, we prove that if the skills distribution in one group first-order stochastically dominates the other, tagging calls for redistribution from the former to the latter group. Finally, we calibrate our model to the US workers using gender as tag. Welfare implications are dramatic. Only male high-wage earners lose. Everyone else gains, some substantially. (JEL H21, H23, H24)
Input Constraints and the Efficiency of Entry: Lessons from Cardiac Surgery
Authors: Cutler David M , Huckman Robert S , Kolstad Jonathan T
Published: February 2010

Prior studies suggest that with elastically supplied inputs free entry may lead to an inefficiently high number of firms in equilibrium. Under input scarcity, however, the welfare loss from free entry is reduced. Further, free entry may increase use of high-quality inputs, as oligopolistic firms underuse these inputs when entry is constrained. We assess these predictions by examining how the 1996 repeal of certificate-of-need (CON ) legislation in Pennsylvania affected the market for cardiac surgery in the state. We show that entry led to a redistribution of surgeries to higher quality surgeons, and that this entry was approximately welfare neutral. (JEL I11, L13)
Zara Uses Operations Research to Reengineer Its Global Distribution Process
Authors: Caro Felipe , Gallien Jérémie , Díaz Miguel , García Javier , Corredoira José Manuel , Montes Marcos , Ramos José Antonio , Correa Juan
Published: February 2010

Overcoming significant technical and human difficulties, Zara recently deployed a new process that relies extensively on sophisticated operations research models to determine each inventory shipment it sends from its two central warehouses to its 1,500 stores worldwide. By taking a retail size-assortment view of a store's inventory, the model incorporates the link between stock levels and demand to select store replenishment quantities. Through a rigorous, controlled field experiment, we estimate that this new process has increased sales by 3–4 percent; this corresponds to estimated profits of approximately $233 million and $353 million in additional revenues for 2007 and 2008, respectively.