bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the Role of Networks in Collective Learning Processes: The Experiences of Women
Authors: Cross Christine , Armstrong Claire
Published: June 2008

The problem and the solution. Despite the rapid increase of women in both junior and middle management positions in organizations globally, women comprise a very small percentage of senior executives. One explanation for the scarcity of senior women in organizational life is that women tend to lack access to the relevant networks, which are often biased toward male membership.To reach senior executive positions, women need to either bypass or establish a way into these networks.Within these networks, the learning tends to begin as individualized incidental learning, but develops into collective learning, as women form their own networks and learn from each other in an anticipatory fashion.The authors believe that through efforts to provide more direct access to formal female networks, collective learning can take place in a more structured and efficient fashion. Providing such structured opportunities for knowledge sharing among female managers could form the lynchpin of a successful collective learning strategy.
Informal and Qualitative Assessment of Writing Skills in Students With Disabilities
Authors: Miller Lynda
Published: June 2008

While formal, standardized assessment instruments provide valuable and necessary information about students' various abilities and skills, the use of informal and qualitative assessment approaches has the benefit of leading directly to instruction based squarely on an individual student's needs, strengths, and existing skills. This article describes a series of assessments that teachers can use to evaluate their students' writing abilities, knowledge, and goals. The assessments are described in the context of ongoing instruction and are accompanied by examples from the procedures used with a sixth-grade student.
Back-to-School Health Promotion
Authors: Terre Lisa
Published: June 2008

This review discusses school-based health promotion, including evidence-based perspectives on the school's feasibility as a venue for lifestyle risk reduction and disease prevention efforts. Future directions for inquiry and implications for empirically driven public policy initiatives are addressed.
A Clinical Analysis of Dupuytren’s Disease of the Thumb
Authors: FIGUS A. , BRITTO J. A. , RAGOOWANSI R. H. , ELLIOT D.
Published: June 2008

Although Dupuytren’s disease of the thumb was first described in 1833, the literature on this subject is limited to a few anatomical and clinical studies. This study examined the pattern of cords of Dupuytren’s disease in 260 thumbs in 181 consecutive patients with evidence of disease relating to the thumb attending an out-patient clinic over a period of 36 months. Discrepancies in the literature are discussed in the light of the findings of this more detailed analysis and a simple but practical pictorial system for recording disease severity and detailing progression over time is presented.
The Value of Plain X-Rays in Predicting TFCC Injury after Distal Radial Fractures
Authors: BOMBACI H. , POLAT A. , DENIZ G. , AKINCI O.
Published: June 2008

In this prospective study, the plain X-rays and MRI scans of 60 patients with intraarticular distal radius fractures were examined in random order. MRI evaluation revealed that 27 of the 60 patients (45%) had triangular fibrocartilage lesions. No correlation was found between triangular fibrocartilage injury and the Melone classification system, the presence of an ulnar styloid fracture, comminution of the articular surface of the distal radius, >20° dorsal angulation of the distal radius or subluxation/dislocation of the distal radioulnar joint on the plain X-rays. When Frykman Type VI and VIII fractures were compared with all the other Frykman subtypes, a significant difference in the incidence of triangular fibrocartilage complex tears was observed. We conclude that triangular fibrocartilage injury should be considered with all distal radial fractures, especially the Frykman Types VI and VIII.
Original Research: Local TAT-p27Kip1 Fusion protein inhibits cell proliferation in rat Carotid arteries
Authors: Neukamm Birgit , Miyakawa Ayumi A. , Fukada Sandra Y. , de Andrade Claudia R. , Pacheco Fernando P. , da Silva Thaís G. , Ramalho Leandra N. Z. , de Oliveira Ana Maria , Krieger Jose E.
Published: June 2008

Introduction: p27Kip1 is a cyclin kinase inhibitor that induces cell cycle arrest. In this study, the efficacy of fusion protein TAT- p27Kip1 to inhibit cell proliferation in rat perivascular injured carotid arteries was tested.

Methods: The cDNA of p27Kip1 and GFP (green fluorescein protein) fused to the TAT epitope, which allows cell penetration, yielded TAT-p27 Kip1 and TAT-GFP fusion proteins. In vitro biological activity on cell proliferation was evaluated by [3H] thymidine DNA incorporation in rabbit aortic endothelial cells (REC). An in vivo model used a silicone collar filled with saline positioned around the carotid vessel for 14 days to produce an increased adventitia cross-sectional area.

Results: TAT-p27Kip1 inhibited REC proliferation in vitro using either 100, 200, and 500 nM compared to control (88.2 ± 4.4, 81.3 ± 7, 71.9 ± 4.2 vs. 100 ± 6.7%, N = 3, respectively, p < 0 .05). This response was stable for purified proteins stored at -20•C for at least 23 days. In vivo , TAT-p27Kip1 solution reduced adventitia cross-sectional area in a dose-dependent manner compared to TAT-GFP (area in mm2 — TAT-p27Kip1: 200 nM, 0.160 ± 0.018; 500 nM, 0.050 ± 0.005 vs. TAT-GFP: 500 nM, 0.595 ± 0.066 vs. the contralateral: 0.047 ± 0.005, N = 7, p < 0 .01).

Conclusion: Taken together, these results provide evidence that TAT-p27Kip1 can inhibit vascular cells proliferation. It is the first successful demonstration that the cell permeable TAT-p27Kip1 has potential as a vascular anti-proliferative agent.
Review: The therapeutic role of RAS blockade in chronic heart failure
Authors: Werner Christian M. , Böhm Michael
Published: June 2008

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, end-organ damage, and ultimately to chronic heart failure (CHF) and premature death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors and/or angiotensin II type 1 receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Several mechanisms govern the progression of structural myocardial damage to end-stage CHF. Chronic neuroendocrine activation fosters left ventricular remodeling and dilatation and leads to clinical symptoms of CHF via forward/backward failure. RAS inhibition is a cornerstone of neuroendocrine blockade in CHF patients, and combined RAS blockade is especially effective in patients presenting with repetitive cardiac decompensations. This review focuses on the therapeutic role of inhibitors of different RAS components in chronic heart failure caused by systolic left ventricular dysfunction.
Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells
Authors: Tam Winnie F. , Gu Ting-Lei , Chen Jing , Lee Benjamin H. , Bullinger Lars , Fröhling Stefan , Wang Andrew , Monti Stefano , Golub Todd R. , Gilliland D. Gary
Published: June 2008

Oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFβR, and FLT3-ITD, play a major role in the development of hematopoietic malignancy. They activate many of the same signal transduction pathways. To identify the critical target genes required for transformation in hematopoietic cells, we used a comparative gene expression strategy in which selective small molecules were applied to 32Dcl3 cells that had been transformed to factor-independent growth by these respective oncogenic alleles. We identified inhibitor of DNA binding 1 (Id1), a gene involved in development, cell cycle, and tumorigenesis, as a common target of these oncogenic kinases. These findings were prospectively confirmed in cell lines and primary bone marrow cells engineered to express the respective tyrosine kinase alleles and were also confirmed in vivo in murine models of disease. Moreover, human AML cell lines Molm-14 and K562, which express the FLT3-ITD and BCR-ABL tyrosine kinases, respectively, showed high levels of Id1 expression. Antisense and siRNA based knockdown of Id1-inhibited growth of these cells associated with increased p27Kip1 expression and increased sensitivity to Trail-induced apoptosis. These findings indicate that Id1 is an important target of constitutively activated tyrosine kinases and may be a therapeutic target for leukemias associated with oncogenic tyrosine kinases.
Adenosine receptors in regulation of dendritic cell differentiation and function
Authors: Novitskiy Sergey V. , Ryzhov Sergey , Zaynagetdinov Rinat , Goldstein Anna E. , Huang Yuhui , Tikhomirov Oleg Y. , Blackburn Michael R. , Biaggioni Italo , Carbone David P. , Feoktistov Igor , Dikov Mikhail M.
Published: June 2008

Differentiation of functional dendritic cells (DCs) critically depends on the microenvironment. DCs differentiate in hypoxic tumor sites and inflamed or damaged tissue. Because local concentrations of adenosine reach high physiologically relevant levels in these conditions, we assessed the expression of adenosine receptors and the effect of their activation on differentiation of human monocytes and mouse peritoneal macrophages and hematopoietic progenitor cells (HPCs) into myeloid DCs. Stimulation of adenosine receptors skews DC differentiation toward a distinct cell population characterized by expression of both DC and monocyte/macrophage cell surface markers. Pharmacologic analysis and experiments with cells from A2B adenosine receptor knockout mice identified A2B receptor as the mediator of adenosine effects on DCs. Unlike normal myeloid DCs, adenosine-differentiated DCs have impaired allostimulatory activity and express high levels of angiogenic, pro-inflammatory, immune suppressor, and tolerogenic factors, including VEGF, IL-8, IL-6, IL-10, COX-2, TGF-β, and IDO. They promoted tumor growth if injected into tumors implanted in mice. Using adenosine desaminase knockout animals, we showed that DCs with proangiogenic phenotype are highly abundant under conditions associated with elevated levels of extracellular adenosine in vivo. Adenosine signaling through A2B receptor is an important factor of aberrant DC differentiation and generation of tolerogenic, angiogenic, and proinflammatory cells.
Biologic and genetic characterization of the novel amyloidogenic lambda light chain–secreting human cell lines, ALMC-1 and ALMC-2
Authors: Arendt Bonnie K. , Ramirez-Alvarado Marina , Sikkink Laura A. , Keats Jonathan J. , Ahmann Gregory J. , Dispenzieri Angela , Fonseca Rafael , Ketterling Rhett P. , Knudson Ryan A. , Mulvihill Erin M. , Tschumper Renee C. , Wu Xiaosheng , Zeldenrust Steven R. , Jelinek Diane F.
Published: June 2008

Primary systemic amyloidosis (AL) is a rare monoclonal plasma cell (PC) disorder characterized by the deposition of misfolded immunoglobulin (Ig) light chains (LC) in vital organs throughout the body. To our knowledge, no cell lines have ever been established from AL patients. Here we describe the establishment of the ALMC-1 and ALMC-2 cell lines from an AL patient. Both cell lines exhibit a PC phenotype and display cytokine-dependent growth. Using a comprehensive genetic approach, we established the genetic relationship between the cell lines and the primary patient cells, and we were also able to identify new genetic changes accompanying tumor progression that may explain the natural history of this patient's disease. Importantly, we demonstrate that free lambda LC secreted by both cell lines contained a beta structure and formed amyloid fibrils. Despite absolute Ig LC variable gene sequence identity, the proteins show differences in amyloid formation kinetics that are abolished by the presence of Na2SO4. The formation of amyloid fibrils from these naturally secreting human LC cell lines is unprecedented. Moreover, these cell lines will provide an invaluable tool to better understand AL, from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology.
European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas
Authors: Senff Nancy J. , Noordijk Evert M. , Kim Youn H. , Bagot Martine , Berti Emilio , Cerroni Lorenzo , Dummer Reinhard , Duvic Madeleine , Hoppe Richard T. , Pimpinelli Nicola , Rosen Steven T. , Vermeer Maarten H. , Whittaker Sean , Willemze Rein
Published: June 2008

Primary cutaneous B-cell lymphomas (CBCL) represent approximately 20% to 25% of all primary cutaneous lymphomas. With the advent of the World Health Organization-European Organization for Research and Treatment of Cancer (EORTC) Consensus Classification for Cutaneous Lymphomas in 2005, uniform terminology and classification for this rare group of neoplasms were introduced. However, staging procedures and treatment strategies still vary between different cutaneous lymphoma centers, which may be because consensus recommendations for the management of CBCL have never been published. Based on an extensive literature search and discussions within the EORTC Cutaneous Lymphoma Group and the International Society for Cutaneous Lymphomas, the present report aims to provide uniform recommendations for the management of the 3 main groups of CBCL. Because no systematic reviews or (randomized) controlled trials were available, these recommendations are mainly based on retrospective studies and small cohort studies. Despite these limitations, there was consensus among the members of the multidisciplinary expert panel that these recommendations reflect the state-of-the-art management as currently practiced in major cutaneous lymphoma centers. They may therefore contribute to uniform staging and treatment and form the basis for future clinical trials in patients with a CBCL.
Prediction of enzyme function by combining sequence similarity and protein interactions
Authors: Espadaler Jordi , Eswar Narayanan , Querol Enrique , Avilés Francesc X , Sali Andrej , Marti-Renom Marc A , Oliva Baldomero
Published: June 2008

Background

A number of studies have used protein interaction data alone for protein function prediction. Here, we introduce a computational approach for annotation of enzymes, based on the observation that similar protein sequences are more likely to perform the same function if they share similar interacting partners.

Results

The method has been tested against the PSI-BLAST program using a set of 3,890 protein sequences from which interaction data was available. For protein sequences that align with at least 40% sequence identity to a known enzyme, the specificity of our method in predicting the first three EC digits increased from 80% to 90% at 80% coverage when compared to PSI-BLAST.

Conclusion

Our method can also be used in proteins for which homologous sequences with known interacting partners can be detected. Thus, our method could increase 10% the specificity of genome-wide enzyme predictions based on sequence matching by PSI-BLAST alone.
Phagocytosis of Aspergillus fumigatus conidia by primary nasal epithelial cells in vitro
Authors: Botterel Françoise , Gross Karine , Ibrahim-Granet Oumaïma , Khoufache Khaled , Escabasse Virginie , Coste André , Cordonnier Catherine , Escudier Estelle , Bretagne Stéphane
Published: June 2008

Background

Invasive aspergillosis, which is mainly caused by the fungus Aspergillus fumigatus, is an increasing problem in immunocompromised patients. Infection occurs by inhalation of airborne conidia, which are first encountered by airway epithelial cells. Internalization of these conidia into the epithelial cells could serve as a portal of entry for this pathogenic fungus.

Results

We used an in vitro model of primary cultures of human nasal epithelial cells (HNEC) at an air-liquid interface. A. fumigatus conidia were compared to Penicillium chrysogenum conidia, a mould that is rarely responsible for invasive disease. Confocal microscopy, transmission electron microscopy, and anti-LAMP1 antibody labeling studies showed that conidia of both species were phagocytosed and trafficked into a late endosomal-lysosomal compartment as early as 4 h post-infection. In double immunolabeling experiments, the mean percentage of A. fumigatus conidia undergoing phagocytosis 4 h post-infection was 21.8 ± 4.5%. Using combined staining with a fluorescence brightener and propidium iodide, the mean rate of phagocytosis was 18.7 ± 9.3% and the killing rate 16.7 ± 7.5% for A. fumigatus after 8 h. The phagocytosis rate did not differ between the two fungal species for a given primary culture. No germination of the conidia was observed until 20 h of observation.

Conclusion

HNEC can phagocytose fungal conidia but killing of phagocytosed conidia is low, although the spores do not germinate. This phagocytosis does not seem to be specific to A. fumigatus. Other immune cells or mechanisms are required to kill A. fumigatus conidia and to avoid further invasion.
LuxS-independent formation of AI-2 from ribulose-5-phosphate
Authors: Tavender Timothy J , Halliday Nigel M , Hardie Kim R , Winzer Klaus
Published: June 2008

Background

In many bacteria, the signal molecule AI-2 is generated from its precursor S-ribosyl-L-homocysteine in a reaction catalysed by the enzyme LuxS. However, generation of AI-2-like activity has also been reported for organisms lacking the luxS gene and the existence of alternative pathways for AI-2 formation in Escherichia coli has recently been predicted by stochastic modelling. Here, we investigate the possibility that spontaneous conversion of ribulose-5-phosphate could be responsible for AI-2 generation in the absence of luxS.

Results

Buffered solutions of ribulose-5-phosphate, but not ribose-5-phosphate, were found to contain high levels of AI-2 activity following incubation at concentrations similar to those reported in vivo. To test whether this process contributes to AI-2 formation by bacterial cells in vivo, an improved Vibrio harveyi bioassay was used. In agreement with previous studies, culture supernatants of E. coli and Staphylococcus aureus luxS mutants were found not to contain detectable levels of AI-2 activity. However, low activities were detected in an E. coli pgi-eda-edd-luxS mutant, a strain which degrades glucose entirely via the oxidative pentose phosphate pathway, with ribulose-5-phosphate as an obligatory intermediate.

Conclusion

Our results suggest that LuxS-independent formation of AI-2, via spontaneous conversion of ribulose-5-phosphate, may indeed occur in vivo. It does not contribute to AI-2 formation in wildtype E. coli and S. aureus under the conditions tested, but may be responsible for the AI-2-like activities reported for other organisms lacking the luxS gene.
Expression of Brugmansia candida Hyoscyamine 6beta-Hydroxylase gene in Saccharomyces cerevisiae and its potential use as biocatalyst
Authors: Cardillo Alejandra B , Talou Julián Rodríguez , Giulietti Ana M
Published: June 2008

Background

Tropane alkaloids, mainly hyoscyamine and scopolamine, are widely used in medicine due to their anticholinergic activity. Scopolamine has a higher demand being the more valuable alkaloid due to its fewer side effects and higher physiological activity. Anisodamine (6β-hydroxyhyoscyamine) is the intermediate in the conversion of hyoscyamine into scopolamine. Current studies report that this alkaloid is potentially applicable in medicine. The gene that codifies for Hyoscyamine 6-β hydroxylase, the enzyme responsible for hyoscyamine hydroxylation and epoxidation, leading to scopolamine was isolated from Brugmansia candida.

Results

The h6h cDNA was cloned into pYES2.1 and pYES2.1/V5-His-TOPO vectors to produce an untagged and a tagged protein, respectively. The H6H enzyme was produced in Saccharomyces cerevisiae in order to obtain a biological catalyst for potential industrial applications. Protein extracts of the induced yeast were analyzed by Western blot. The expression was detected 4 h after induction and no degradation was observed during the period assayed. The tagged and the untagged proteins were able to transform hyoscyamine, showing a functional expression of the h6h cDNA.

Conclusion

The strains obtained in this work are promising and potentially applicable in biocatalytic processes.
In silico regulatory analysis for exploring human disease progression
Authors: Holloway Dustin T , Kon Mark , DeLisi Charles
Published: June 2008

Background

An important goal in bioinformatics is to unravel the network of transcription factors (TFs) and their targets. This is important in the human genome, where many TFs are involved in disease progression. Here, classification methods are applied to identify new targets for 152 transcriptional regulators using publicly-available targets as training examples. Three types of sequence information are used: composition, conservation, and overrepresentation.

Results

Starting with 8817 TF-target interactions we predict an additional 9333 targets for 152 TFs. Randomized classifiers make few predictions (~2/18660) indicating that our predictions for many TFs are significantly enriched for true targets. An enrichment score is calculated and used to filter new predictions.

Two case-studies for the TFs OCT4 and WT1 illustrate the usefulness of our predictions:

• Many predicted OCT4 targets fall into the Wnt-pathway. This is consistent with known biology as OCT4 is developmentally related and Wnt pathway plays a role in early development.

• Beginning with 15 known targets, 354 predictions are made for WT1. WT1 has a role in formation of Wilms' tumor. Chromosomal regions previously implicated in Wilms' tumor by cytological evidence are statistically enriched in predicted WT1 targets. These findings may shed light on Wilms' tumor progression, suggesting that the tumor progresses either by loss of WT1 or by loss of regions harbouring its targets.

• Targets of WT1 are statistically enriched for cancer related functions including metastasis and apoptosis. Among new targets are BAX and PDE4B, which may help mediate the established anti-apoptotic effects of WT1.

• Of the thirteen TFs found which co-regulate genes with WT1 (p ≤ 0.02), 8 have been previously implicated in cancer. The regulatory-network for WT1 targets in genomic regions relevant to Wilms' tumor is provided.

Conclusion

We have assembled a set of features for the targets of human TFs and used them to develop classifiers for the determination of new regulatory targets. Many predicted targets are consistent with the known biology of their regulators, and new targets for the Wilms' tumor regulator, WT1, are proposed. We speculate that Wilms' tumor development is mediated by chromosomal rearrangements in the location of WT1 targets.

Reviewers

This article was reviewed by Trey Ideker, Vladimir A. Kuznetsov(nominated by Frank Eisenhaber), and Tzachi Pilpel.
Neutrophil-dependent tumor rejection and priming of tumoricidal CD8+ T cell response induced by dendritic cells overexpressing CD95L
Authors: Buonocore Sofia , Haddou Najate Ouled , Moore Fabrice , Florquin Sandrine , Paulart Frédéric , Heirman Carlo , Thielemans Kris , Goldman Michel , Flamand Véronique
Published: June 2008

Overexpression of CD95 (Fas/Apo-1) ligand (CD95L) has been shown to induce T cell tolerance but also, neutrophilic inflammation and rejection of allogeneic tissue. We explored the capacity of dendritic cells (DCs) genetically engineered to overexpress CD95L to induce an antitumor response. We first found that DCs overexpressing CD95L, in addition to MHC class I-restricted OVA peptides (CD95L-OVA-DCs), induced increased antigen-specific CD8+ T cell responses as compared with DCs overexpressing OVA peptides alone. The enhanced T cell responses were associated with improved regression of a tumor expressing OVA, allowing survival of all animals. When DCs overexpressing CD95L (CD95L-DCs) were injected with the tumor expressing OVA, in vivo tumor proliferation was strikingly inhibited. A strong cellular apoptosis and a massive neutrophilic infiltrate developed in this setting. Neutrophil depletion prevented tumor regression as well as enhanced IFN-γ production induced by CD95L-OVA-DCs. Furthermore, the CD8+ T cell response induced by the coadministration of tumor cells and CD95L-DCs led to rejection of a tumor implanted at a distance from the DC injection site. In summary, DCs expressing CD95L promote tumor rejection involving neutrophil-mediated innate immunity and CD8+ T cell-dependent adaptative immune responses.
Phase I/II Study of Biweekly Paclitaxel and Radiation in Androgen-Ablated Locally Advanced Prostate Cancer
Authors: Sanfilippo Nicholas J. , Taneja Samir S. , Chachoua Abraham , Lepor Herbert , Formenti Silvia C.
Published: June 2008

Purpose

To determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and radiation therapy (RT) in patients with locally advanced prostate cancer.

Materials and Methods

Eligible patients had T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10 ng/mL and/or had tumors with pathologic stage TxN1. Hormonal ablation was initiated 3 months before RT and was given for 9 months. RT was delivered daily (1.8 Gy) with concurrent twice-weekly paclitaxel (30 mg/m2). The whole pelvis was irradiated to 39.6 Gy. The radiation dose was escalated as follows: 63 Gy, 66.6 Gy, 70.2 Gy, and 73.8 Gy. The last RT dose level was fixed at 73.8 Gy.

Results

Between January 2000 and October 2006, 22 patients were enrolled. The median age was 59 years (range, 48 to 72 years); the median PSA level was 22.4 ng/mL (range, 2.8 to 113 ng/mL). The number of patients per stage was as follows: three with T1, eight with T2, 11 with T3, and five with pN1 = 5. No grade 3 toxicities occurred at 63 Gy. Grade 3 diarrhea occurred in three patients at 66.6 Gy. The protocol then was amended to treat the prostate volume first followed by the whole pelvis. No grade 3 toxicities were observed at 70.2 Gy. One patient experienced grade 3 diarrhea at 73.8 Gy. Five additional patients were treated to 73.8 Gy without grade 3 toxicity, which established the MTD for combined paclitaxel and RT at 73.8 Gy. At 38 months median follow-up (range, 9 to 87 months), 21 (95%) of 22 patients are alive. Six (27%) of 22 experienced recurrence.

Conclusion

Concurrent biweekly paclitaxel with RT is feasible, with an MTD of 73.8 Gy. Recovery of gonadal function occurs in the majority of patients. These results encourage testing in a phase III setting.
CRHR1 Polymorphisms Predict Bone Density in Survivors of Acute Lymphoblastic Leukemia
Authors: Jones Terreia S. , Kaste Sue C. , Liu Wei , Cheng Cheng , Yang Wenjian , Tantisira Kelan G. , Pui Ching-Hon , Relling Mary V.
Published: June 2008

Purpose

Corticosteroids are a critical component of therapy for acute lymphoblastic leukemia (ALL) but are associated with late effects, such as osteoporosis. Risk factors remain poorly defined. Because CRHR1 polymorphisms have been associated with other corticosteroid effects, our goal was to define whether CRHR1 polymorphisms predict which patients with ALL are likely to develop bone mineral deficits.

Patients and Methods

The mean bone mineral density z scores of 309 long-term survivors of ALL were determined by quantitative computed tomography of the trabecular lumbar spine. We analyzed whether CRHR1 genotypes, adjusted for sex, ALL treatment regimen, and weight, could predict bone density.

Results

We found that three single nucleotide polymorphisms (SNPs), all in linkage disequilibrium, were associated with bone density in a sex-specific manner. Bone density was lower in males (P = .001), in nonblack patients (P < .08), in those who were not overweight (P < .001), and in those who received intensive antimetabolites and glucocorticoids (P < .001). After adjustment for these features, the G allele at the rs1876828 SNP was associated with lower z scores (P = .02) in males but tended to have the opposite association in females (P = .09).

Conclusion

CRHR1 polymorphisms may impact the risk of bone density deficits in patients treated with corticosteroids and antimetabolites in a sex-specific manner.
Phase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer
Authors: LoRusso Patricia M. , Jones Suzanne F. , Koch Kevin M. , Arya Nikita , Fleming Ronald A. , Loftiss Jill , Pandite Lini , Gadgeel Shirish , Weber Barbara L. , Burris Howard A.
Published: June 2008

Purpose

This phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors.

Patients and Methods

Doses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level.

Results

Fifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m2 (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients (≥ 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately.

Conclusion

The combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.
Longitudinal Changes in Insulin Sensitivity and Body Composition of Small-For-Gestational-Age Adolescents after Cessation of Growth Hormone Treatment
Authors: Willemsen Ruben H. , Willemsen Sten P. , Hokken-Koelega Anita C. S.
Published: June 2008

Context: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stopping GH treatment.

Objective: Our objective was to investigate longitudinal changes in Si, β-cell function, and body composition after cessation of long-term GH treatment.

Design and Patients: We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points.

Outcome Measure: We took paired measurements of Si and β-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry.

Results: After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and β-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher.

Conclusions: The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.
E-cadherin controls β-catenin and NF-κB transcriptional activity in mesenchymal gene expression
Authors: Solanas Guiomar , Porta-de-la-Riva Montserrat , Agustí Cristina , Casagolda David , Sánchez-Aguilera Francisco , Larriba María Jesús , Pons Ferran , Peiró Sandra , Escrivà Maria , Muñoz Alberto , Duñach Mireia , de Herreros Antonio García , Baulida Josep
Published: June 2008

E-cadherin and its transcriptional repressor Snail1 (Snai1) are two factors that control epithelial phenotype. Expression of Snail1 promotes the conversion of epithelial cells to mesenchymal cells, and occurs concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as those encoding fibronectin and LEF1. We studied the molecular mechanism controlling the expression of these genes in mesenchymal cells. Forced expression of E-cadherin strongly downregulated fibronectin and LEF1 RNA levels, indicating that E-cadherin-sensitive factors are involved in the transcription of these genes. E-cadherin overexpression decreased the transcriptional activity of the fibronectin promoter and reduced the interaction of β-catenin and NF-κB with this promoter. Similar to β-catenin, NF-κB was found, by co-immunoprecipitation and pull-down assays, to be associated with E-cadherin and other cell-adhesion components. Interaction of the NF-κB p65 subunit with E-cadherin or β-catenin was reduced when adherens junctions were disrupted by K-ras overexpression or by E-cadherin depletion using siRNA. These conditions did not affect the association of p65 with the NF-κB inhibitor IκBα. The functional significance of these results was stressed by the stimulation of NF-κB transcriptional activity, both basal and TNF-α-stimulated, induced by an E-cadherin siRNA. Therefore, these results demonstrate that E-cadherin not only controls the transcriptional activity of β-catenin but also that of NF-κB. They indicate too that binding of this latter factor to the adherens junctional complex prevents the transcription of mesenchymal genes.
UbcH10 has a rate-limiting role in G1 phase but might not act in the spindle checkpoint or as part of an autonomous oscillator
Authors: Walker Adam , Acquaviva Claire , Matsusaka Takahiro , Koop Lars , Pines Jonathon
Published: June 2008

Ubiquitin-dependent proteolysis mediated by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase lies at the heart of the cell cycle. The APC/C targets mitotic cyclins for destruction in mitosis and G1 phase and is then inactivated at S phase, thereby generating the alternating states of high and low cyclin-Cdk activity required for the alternation of mitosis and DNA replication. Two key questions are how the APC/C is held in check by the spindle-assembly checkpoint to delay cells in mitosis in the presence of improperly attached chromosomes, and how the APC/C is inactivated once cells exit mitosis. The ubiquitin-conjugating protein UbcH10 has been proposed to be crucial in the answers to both questions. However, here we show that the behaviour of UbcH10 is inconsistent with both a crucial role in the spindle checkpoint and in inactivating the APC/C as part of an autonomous oscillator. Instead, we find that the rate-limiting role of UbcH10 is only at the end of G1 phase, just before DNA replication begins.
Structural basis for hygromycin B inhibition of protein biosynthesis
Authors: Borovinskaya Maria A. , Shoji Shinichiro , Fredrick Kurt , Cate Jamie H.D.
Published: June 2008

Aminoglycosides are one of the most widely used and clinically important classes of antibiotics that target the ribosome. Hygromycin B is an atypical aminoglycoside antibiotic with unique structural and functional properties. Here we describe the structure of the intactEscherichia coli70S ribosome in complex with hygromycin B. The antibiotic binds to the mRNA decoding center in the small (30S) ribosomal subunit of the 70S ribosome and induces a localized conformational change, in contrast to its effects observed in the structure of the isolated 30S ribosomal subunit in complex with the drug. The conformational change in the ribosome caused by hygromycin B binding differs from that induced by other aminoglycosides. Also, in contrast to other aminoglycosides, hygromycin B potently inhibits spontaneous reverse translocation of tRNAs and mRNA on the ribosome in vitro. These structural and biochemical results help to explain the unique mode of translation inhibition by hygromycin B.
3′-cyclic phosphorylation of U6 snRNA leads to recruitment of recycling factor p110 through LSm proteins
Authors: Licht Konstantin , Medenbach Jan , Lührmann Reinhard , Kambach Christian , Bindereif Albrecht
Published: June 2008

Pre-mRNA splicing proceeds through assembly of the spliceosome complex, catalysis, and recycling. During each cycle the U4/U6.U5 tri-snRNP is disrupted and U4/U6 snRNA base-pairing unwound, releasing separate post-spliceosomal U4, U5, and U6 snRNPs, which have to be recycled to the splicing-competent tri-snRNP. Previous work implicated p110—the human ortholog of the yeast Prp24 protein—and the LSm2-8 proteins of the U6 snRNP in U4/U6 recycling. Here we show in vitro that these proteins bind synergistically to U6 snRNA: Both purified and recombinant LSm2-8 proteins are able to recruit p110 protein to U6 snRNA via interaction with the highly conserved C-terminal region of p110. Furthermore, the presence of a 2′,3′-cyclic phosphate enhances the affinity of U6 snRNA for the LSm2-8 proteins and inversely reduces La protein binding, suggesting a direct role of the 3′-terminal phosphorylation in RNP remodeling during U6 biogenesis.
Compositional properties and thermal adaptation of 18S rRNA in vertebrates
Authors: Varriale Annalisa , Torelli Giuseppe , Bernardi Giorgio
Published: June 2008

In order to investigate the influence of temperature on the GC level of the paired sequences of ribosomal 18S RNAs in vertebrates, we have studied their base composition in cold- and warm-blooded vertebrates using a stem-by-stem comparison. We observed that a number of stems of 18S ribosomal RNAs (rRNAs) are variable among species and that the majority of such stems are GC richer in warm-blooded than in cold-blooded vertebrates. We also constructed the secondary structures of the 18S rRNAs of a polar fish, a marsupial, and a monotreme to compare them with those of temperate/tropical fishes and of eutherians, respectively. In these cases, differences similar to those already mentioned were found. We conclude that there is a correlation between stem stability and body temperature even within the relatively limited temperature range of vertebrates.
Norms and Descriptions
Authors: Vareman Niklas
Published: June 2008

This article addresses the problem of identifying conditions according to which it is possible to distinguish between a descriptive theory and a normative theory. What makes a descriptive theory descriptive and a normative theory normative? The focus is on subjective expected utility theories where it seems open to debate whether the appropriate use is normative or descriptive. My discussion, which takes arguments by Isaac Levi and Hugh Mellor as points of departure, is mostly negative, showing that there are no obvious distinguishing features of theories qua theories. Rather, the theories can be used normatively or descriptively without making them theories of one kind or the other. I also point to situations in prescriptive decision analysis where one should be observant of in what way theories are used.
Eliciting Subjective Probabilities Through Exchangeable Events: An Advantage and a Limitation
Authors: Baillon Aurélien
Published: June 2008

Two events are exchangeable for an agent when she is indifferent to permutations of their outcomes. Such events are thus revealed to be equally likely. If they are complementary, the subjective probability associated with each event should be 1/2 (assuming the additivity of the probability measure). This paper reports the results of an experiment that elicits probabilities through exchangeable events. The experiment shows that this method does not suffer from source dependence, i.e., the preference for betting on some events based on knowledge about the mechanism that generates them. However, it also highlights how additivity might be violated. This paper deduces the practical implications of these results.
Incorporating Path Dependency into Decision-Analytic Methods: An Application to Global Climate-Change Policy
Authors: Webster Mort
Published: June 2008

Climate policy decisions are necessarily sequential decisions over time under uncertainty, given the magnitude of uncertainty in both economic and scientific processes, the decades-to-centuries time scale of the phenomenon, and the ability to reduce uncertainty and revise decisions along the way. Thus, an appropriate choice of analytical method is decision analysis. However, applying decision analysis in the context of idealized government decision makers over a century raises the question of how to deal with the fact that political systems tend to exhibit path dependency, a force that makes large policy shifts difficult and rare, and limits most decisions to small incremental changes. This paper explores the effect of considering path dependency in an application of decision analysis to climate-change policy decisions, presenting two alternative methods for modeling path dependency. I demonstrate that consideration of path dependence in the context of climate policy justifies greater near-term emissions reductions. The more general result of path-dependency is to shift the near-term strategy towards a more moderate hedging strategy, because drastic shifts later will be difficult.
Exact and Asymptotically Exact Solutions for a Class of Assortment Problems
Authors: Arbib C. , Marinelli F.
Published: June 2008

Mass customization requires us to select a few types of resources to produce heterogeneous classes of products. In the assortment problem addressed here, a resource unit of type j yields, at a cost cij, a batch of aij product units of type i. The problem, a generalization of the p-median, calls for (i) choosing a restricted subset of resource types and (ii) assigning resource units to products so as to fulfill a given demand vector at a minimum cost. For this problem, we develop a branch-and-price scheme that can either be used to find optimal solutions, or tuned by choosing columns in a suitable class so as to get approximate solutions. The solutions obtained in the second case approach the optimum by a ratio that asymptotically reduces to zero as the demand of the least-required product increases. A comparative analysis of the features of the algorithm is discussed for a wide set of large problem instances.
Rejoinder—Can Behavioral WOM Measures Provide Insight into the Net Promoter© Concept of Customer Loyalty?
Authors: Morgan Neil A. , Rego Lopo L.
Published: June 2008

We examine the ability of the “Net Promoter” of Morgan and Rego (2006) measure constructed using behavioral word-of-mouth (WOM) data to provide insights into the Net Promoter© customer loyalty concept popularized by Reichheld (2003), which is indicated by a score constructed using attitudinal “intention-to-recommend” data. We show that despite differences in data and operationalization, the two measures are very closely correlated and behave remarkably similarly when examined relative to a third related variable, customer satisfaction.
A Bargaining Framework in Supply Chains: The Assembly Problem
Authors: Nagarajan Mahesh , Bassok Yehuda
Published: June 2008

We examine a decentralized supply chain in which a single assembler buys complementary components from n suppliers and assembles the final product in anticipation of demand. Players take actions in the following sequence. First (stage 1), the suppliers form coalitions among themselves. Second (stage 2), the coalitions compete for a position in the negotiation sequence. Finally (stage 3), the coalitions negotiate with the assembler on allocations of the supply chain's profit. We model the multilateral negotiations between the suppliers and the assembler sequentially, i.e., the assembler negotiates with one coalition at a time. Each of these negotiations is modeled using the Nash bargaining concept. Further, in forming coalitions we assume that players are farsighted. We then predict at equilibrium the structure of the supply chain as a function of the players' relative negotiation powers. In particular, we show that the assembler always prefers the outcome where suppliers do not form coalitions. However, when the assembler is weak (low negotiation power) the suppliers join forces as a grand coalition, but when the assembler is powerful the suppliers stay independent, which is the preferred outcome to the assembler.
A 2-Approximation Algorithm for Stochastic Inventory Control Models with Lost Sales
Authors: Levi Retsef , Janakiraman Ganesh , Nagarajan Mahesh
Published: June 2008

In this paper, we describe the first computationally efficient policies for stochastic inventory models with lost sales and replenishment lead times that admit worst-case performance guarantees.

In particular, we introduce dual-balancing policies for lost-sales models that are conceptually similar to dual-balancing policies recently introduced for a broad class of inventory models in which demand is backlogged rather than lost. That is, in each period, we balance two opposing costs: the expected marginal holding costs against the expected marginal lost-sales cost. Specifically, we show that the dual-balancing policies for the lost-sales models provide a worst-case performance guarantee of two under relatively general demand structures. In particular, the guarantee holds for independent (not necessarily identically distributed) demands and for models with correlated demands such as the AR(1) model and the multiplicative autoregressive demand model. The policies and the worst-case guarantee extend to models with capacity constraints on the size of the order and stochastic lead times. Our analysis has several novel elements beyond the balancing ideas for backorder models.
A Geometrical Characterization of Multidimensional Hausdorff Polytopes with Applications to Exit Time Problems
Authors: Helmes Kurt , Röhl Stefan
Published: June 2008

We present a formula for the corner points of the multidimensional Hausdorff polytopes and show how this result can be used to improve linear programming models for computing, e.g., moments of exit time distributions of diffusion processes. Specifically, we compute the mean exit time of two-dimensional Brownian motion from the unit square, as well as higher moments of the exit time of time-space Brownian motion, i.e., the two-dimensional process composed of a one-dimensional Wiener process and the time component, from a rectangle. The corner point formula is complemented by a convergence result, which provides the analytical underpinning of the numerical method that we use.
Truncation Strategies in Matching Markets
Authors: Ehlers Lars
Published: June 2008

Roth and Rothblum [Roth, A. E., U. G. Rothblum. 1999. Truncation strategies in matching markets—In search of advice for participants. Econometrica 67 21–43] showed that for matching markets using the deferred acceptance algorithm a physician with symmetric (incomplete) information possibly gains only by truncating her true ranking. We show that in symmetric information environments this result is identical for all priority mechanisms and all linear programming mechanisms introduced in British entry-level medical markets and in public school choice in some American cities.