bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term prognostic significance of response in multiple myeloma after stem cell transplantation
Authors: Martinez-Lopez Joaquin , Blade Joan , Mateos María-Victoria , Grande Carlos , Alegre Adrián , García-Laraña José , Sureda Anna , de la Rubia Javier , Conde Eulogio , Martinez Rafael , de Arriba Felipe , Viguria Maria C. , Besalduch Joan , Cabrera Rafael , Gonzalez-San Miguel José D. , Guzman-Zamudio José Luis , Gomez del Castillo Maria Carmen , Moraleda José Maria , García-Ruiz Juan C. , San Miguel Jesús , Lahuerta Juan José ,   for the GEM (Grupo Español de MM) and PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatía Maligna) Cooperative Study Groups
Published: April 2011

For establishing the true effect of different response categories in patients with multiple myeloma (MM) treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with MM who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10−5); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR+VGPR+PR group are alive at 17 years; 2 cases had relapsed in the nCR+VGPR+PR group. In conclusion, MM achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.
Statistical Test of Expression Pattern (STEPath): a new strategy to integrate gene expression data with genomic information in individual and meta-analysis studies
Authors: Martini Paolo , Risso Davide , Sales Gabriele , Romualdi Chiara , Lanfranchi Gerolamo , Cagnin Stefano
Published: April 2011

Background

In the last decades, microarray technology has spread, leading to a dramatic increase of publicly available datasets. The first statistical tools developed were focused on the identification of significant differentially expressed genes. Later, researchers moved toward the systematic integration of gene expression profiles with additional biological information, such as chromosomal location, ontological annotations or sequence features. The analysis of gene expression linked to physical location of genes on chromosomes allows the identification of transcriptionally imbalanced regions, while, Gene Set Analysis focuses on the detection of coordinated changes in transcriptional levels among sets of biologically related genes.

In this field, meta-analysis offers the possibility to compare different studies, addressing the same biological question to fully exploit public gene expression datasets.

Results

We describe STEPath, a method that starts from gene expression profiles and integrates the analysis of imbalanced region as an a priori step before performing gene set analysis. The application of STEPath in individual studies produced gene set scores weighted by chromosomal activation. As a final step, we propose a way to compare these scores across different studies (meta-analysis) on related biological issues. One complication with meta-analysis is batch effects, which occur because molecular measurements are affected by laboratory conditions, reagent lots and personnel differences. Major problems occur when batch effects are correlated with an outcome of interest and lead to incorrect conclusions. We evaluated the power of combining chromosome mapping and gene set enrichment analysis, performing the analysis on a dataset of leukaemia (example of individual study) and on a dataset of skeletal muscle diseases (meta-analysis approach).

In leukaemia, we identified the Hox gene set, a gene set closely related to the pathology that other algorithms of gene set analysis do not identify, while the meta-analysis approach on muscular disease discriminates between related pathologies and correlates similar ones from different studies.

Conclusions

STEPath is a new method that integrates gene expression profiles, genomic co-expressed regions and the information about the biological function of genes. The usage of the STEPath-computed gene set scores overcomes batch effects in the meta-analysis approaches allowing the direct comparison of different pathologies and different studies on a gene set activation level.
Detection of viral sequence fragments of HIV-1 subfamilies yet unknown
Authors: Unterthiner Thomas , Schultz Anne-Kathrin , Bulla Jan , Morgenstern Burkhard , Stanke Mario , Bulla Ingo
Published: April 2011

Background

Methods of determining whether or not any particular HIV-1 sequence stems - completely or in part - from some unknown HIV-1 subtype are important for the design of vaccines and molecular detection systems, as well as for epidemiological monitoring. Nevertheless, a single algorithm only, the Branching Index (BI), has been developed for this task so far. Moving along the genome of a query sequence in a sliding window, the BI computes a ratio quantifying how closely the query sequence clusters with a subtype clade. In its current version, however, the BI does not provide predicted boundaries of unknown fragments.

Results

We have developed Unknown Subtype Finder (USF), an algorithm based on a probabilistic model, which automatically determines which parts of an input sequence originate from a subtype yet unknown. The underlying model is based on a simple profile hidden Markov model (pHMM) for each known subtype and an additional pHMM for an unknown subtype. The emission probabilities of the latter are estimated using the emission frequencies of the known subtypes by means of a (position-wise) probabilistic model for the emergence of new subtypes. We have applied USF to SIV and HIV-1 sequences formerly classified as having emerged from an unknown subtype. Moreover, we have evaluated its performance on artificial HIV-1 recombinants and non-recombinant HIV-1 sequences. The results have been compared with the corresponding results of the BI.

Conclusions

Our results demonstrate that USF is suitable for detecting segments in HIV-1 sequences stemming from yet unknown subtypes. Comparing USF with the BI shows that our algorithm performs as good as the BI or better.
Gene expression profiles in rat mesenteric lymph nodes upon supplementation with Conjugated Linoleic Acid during gestation and suckling
Authors: Selga Elisabet , Pérez-Cano Francisco J , Franch Àngels , Ramírez-Santana Carolina , Rivero Montserrat , Ciudad Carlos J , Castellote Cristina , Noé Véronique
Published: April 2011

Background

Diet plays a role on the development of the immune system, and polyunsaturated fatty acids can modulate the expression of a variety of genes. Human milk contains conjugated linoleic acid (CLA), a fatty acid that seems to contribute to immune development. Indeed, recent studies carried out in our group in suckling animals have shown that the immune function is enhanced after feeding them with an 80:20 isomer mix composed of c9,t11 and t10,c12 CLA. However, little work has been done on the effects of CLA on gene expression, and even less regarding immune system development in early life.

Results

The expression profile of mesenteric lymph nodes from animals supplemented with CLA during gestation and suckling through dam's milk (Group A) or by oral gavage (Group B), supplemented just during suckling (Group C) and control animals (Group D) was determined with the aid of the specific GeneChip®Rat Genome 230 2.0 (Affymettrix). Bioinformatics analyses were performed using the GeneSpring GX software package v10.0.2 and lead to the identification of 89 genes differentially expressed in all three dietary approaches. Generation of a biological association network evidenced several genes, such as connective tissue growth factor (Ctgf), tissue inhibitor of metalloproteinase 1 (Timp1), galanin (Gal), synaptotagmin 1 (Syt1), growth factor receptor bound protein 2 (Grb2), actin gamma 2 (Actg2) and smooth muscle alpha actin (Acta2), as highly interconnected nodes of the resulting network. Gene underexpression was confirmed by Real-Time RT-PCR.

Conclusions

Ctgf, Timp1, Gal and Syt1, among others, are genes modulated by CLA supplementation that may have a role on mucosal immune responses in early life.
The role of reactive oxygen intermediates in experimental coccidioidomycois in mice
Authors: Margolis David A , Viriyakosol Suganya , Fierer Joshua , Kirkland Theo N
Published: April 2011

Background

Coccidioidomycosis is usually a self-limited infection in immunocompentent people. In immunocompentent human beings second infections due toCoccidioidesare very rare, indicating that recovery from infection results in protective immunity. In experimental animals, immunization with several different proteins or attenuated mutants protects against a virulent challenge. To explore what mechanisms are responsible for protective immunity, we investigated the course ofCoccidioidesinfection in the gp91phoxknock out mouse that has a defect in the oxidative burst that results in chronic granulomatous disease.

Results

We found that the gp91phoxknock out mice were somewhat more resistant to intraperitoneal infection and equally as resistant to low dose intranasal infection, but slightly more susceptible to high dose intranasal infection compared to control mice. The gp91phoxknock out mice made a more robust inflammatory response to infection than controls, as measured by histology and production of inflammatory cytokines. The gp91phoxknock out mice were as protected by immunization with the recombinantCoccidioidesprotein Ag2/PRA as the controls were against either intraperitoneal or intranasal infection.Coccidioides immitisarthroconidia and spherules were significantly more resistant to H2O2treatment in vitro thanAspergillus fumigatusspores.

Conclusion

These data suggest that oxidative burst may not be required for protective immunity to coccidioidomycois.
Clinical management and burden of bipolar disorder: a multinational longitudinal study (WAVE-bd Study)
Authors: Vieta Eduard , Blasco-Colmenares Elena , Figueira Maria Luisa , Langosch Jens M , Moreno-Manzanaro Miriam , Medina Esteban ,   WAVE-bd Study Group
Published: April 2011

Background

Studies in bipolar disorder (BD) to date are limited in their ability to provide a whole-disease perspective - their scope has generally been confined to a single disease phase and/or a specific treatment. Moreover, most clinical trials have focused on the manic phase of disease, and not on depression, which is associated with the greatest disease burden. There are few longitudinal studies covering both types of patients with BD (I and II) and the whole course of the disease, regardless of patients' symptomatology. Therefore, the Wide AmbispectiVE study of the clinical management and burden of Bipolar Disorder (WAVE-bd) (NCT01062607) aims to provide reliable information on the management of patients with BD in daily clinical practice. It also seeks to determine factors influencing clinical outcomes and resource use in relation to the management of BD.

Methods

WAVE-bd is a multinational, multicentre, non-interventional, longitudinal study. Approximately 3000 patients diagnosed with BD type I or II with at least one mood event in the preceding 12 months were recruited at centres in Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela. Site selection methodology aimed to provide a balanced cross-section of patients cared for by different types of providers of medical aid (e.g. academic hospitals, private practices) in each country. Target recruitment percentages were derived either from scientific publications or from expert panels in each participating country. The minimum follow-up period will be 12 months, with a maximum of 27 months, taking into account the retrospective and the prospective parts of the study. Data on demographics, diagnosis, medical history, clinical management, clinical and functional outcomes (CGI-BP and FAST scales), adherence to treatment (DAI-10 scale and Medication Possession Ratio), quality of life (EQ-5D scale), healthcare resources, and caregiver burden (BAS scale) will be collected. Descriptive analysis with common statistics will be performed.

Discussion

This study will provide detailed descriptions of the management of BD in different countries, particularly in terms of clinical outcomes and resources used. Thus, it should provide psychiatrists with reliable and up-to-date information about those factors associated with different management patterns of BD.

Trial registration no

ClinicalTrials.gov: NCT01062607
Surface display of Salmonella epitopes in Escherichia coli and Staphylococcus carnosus
Authors: Nhan Nguyen Thanh , de Valdivia Ernesto Gonzalez , Gustavsson Martin , Hai Truong Nam , Larsson Gen
Published: April 2011

Background

Salmonella entericaserotype Enteritidis (SE) is considered to be one of the most potent pathogenicSalmonellaserotypes causing food-borne disease in humans. Since a live bacterial vaccine based on surface display of antigens has many advantages over traditional vaccines, we have studied the surface display of the SE antigenic proteins, H:gm and SefA inEscherichia coliby the β-autotransporter system, AIDA. This procedure was compared to protein translocation inStaphylococcus carnosus, using a staphylococci hybrid vector earlier developed for surface display of other vaccine epitopes.

Results

Both SefA and H:gm were translocated to the outer membrane inEscherichia coli. SefA was expressed to full length but H:gm was shorter than expected, probably due to a proteolytic cleavage of the N-terminal during passage either through the periplasm or over the membrane. FACS analysis confirmed that SefA was facing the extracellular environment, but this could not be conclusively established for H:gm since the N-terminal detection tag (His6) was cleaved off. Polyclonal salmonella antibodies confirmed the sustained antibody-antigen binding towards both proteins. The surface expression data fromStaphylococcus carnosussuggested that the H:gm and SefA proteins were transported to the cell wall since the detection marker was displayed by FACS analysis.

Conclusion

Apart from the accumulated knowledge and the existence of a wealth of equipment and techniques, the results indicate the selection ofE. colifor further studies for surface expression of salmonella antigens. Surface expression of the full length protein facing the cell environment was positively proven by standard analysis, and the FACS signal comparison to expression inStaphylococcus carnosusshows that the distribution of the surface protein on each cell was comparatively very narrow inE. coli, theE. coliouter membrane molecules can serve as an adjuvant for the surface antigenic proteins and multimeric forms of the SefA protein were detected which would probably be positive for the realisation of a strong antigenic property. The detection of specific and similar proteolytic cleavage patterns for both the proteins provides a further starting point for the investigation and development of theEscherichia coliAIDA autotransporter efficiency.
Quantitative analysis of nanoparticle internalization in mammalian cells by high resolution X-ray microscopy
Authors: Chen Hsiang-Hsin , Chien Chia-Chi , Petibois Cyril , Wang Cheng-Liang , Chu Yong S , Lai Sheng-Feng , Hua Tzu-En , Chen Yi-Yun , Cai Xiaoqing , Kempson Ivan M , Hwu Yeukuang , Margaritondo Giorgio
Published: April 2011

Background

Quantitative analysis of nanoparticle uptake at the cellular level is critical to nanomedicine procedures. In particular, it is required for a realistic evaluation of their effects. Unfortunately, quantitative measurements of nanoparticle uptake still pose a formidable technical challenge. We present here a method to tackle this problem and analyze the number of metal nanoparticles present in different types of cells. The method relies on high-lateral-resolution (better than 30 nm) transmission x-ray microimages with both absorption contrast and phase contrast -- including two-dimensional (2D) projection images and three-dimensional (3D) tomographic reconstructions that directly show the nanoparticles.

Results

Practical tests were successfully conducted on bare and polyethylene glycol (PEG) coated gold nanoparticles obtained by x-ray irradiation. Using two different cell lines, EMT and HeLa, we obtained the number of nanoparticle clusters uptaken by each cell and the cluster size. Furthermore, the analysis revealed interesting differences between 2D and 3D cultured cells as well as between 2D and 3D data for the same 3D specimen.

Conclusions

We demonstrated the feasibility and effectiveness of our method, proving that it is accurate enough to measure the nanoparticle uptake differences between cells as well as the sizes of the formed nanoparticle clusters. The differences between 2D and 3D cultures and 2D and 3D images stress the importance of the 3D analysis which is made possible by our approach.
Validation of the Japanese version of the Pediatric Quality of Life Inventory (PedsQL) Cancer Module
Authors: Tsuji Naoko , Kakee Naoko , Ishida Yasushi , Asami Keiko , Tabuchi Ken , Nakadate Hisaya , Iwai Tsuyako , Maeda Miho , Okamura Jun , Kazama Takuro , Terao Yoko , Ohyama Wataru , Yuza Yuki , Kaneko Takashi , Manabe Atsushi , Kobayashi Kyoko , Kamibeppu Kiyoko , Matsushima Eisuke
Published: April 2011

Background

The PedsQL 3.0 Cancer Module is a widely used instrument to measure pediatric cancer specific health-related quality of life (HRQOL) for children aged 2 to 18 years. We developed the Japanese version of the PedsQL Cancer Module and investigated its reliability and validity among Japanese children and their parents.

Methods

Participants were 212 children with cancer and 253 of their parents. Reliability was determined by internal consistency using Cronbach's coefficient alpha and test-retest reliability using intra-class correlation coefficient (ICC). Validity was assessed through factor validity, convergent and discriminant validity, concurrent validity, and clinical validity. Factor validity was examined by exploratory factor analysis. Convergent and discriminant validity were examined by multitrait scaling analysis. Concurrent validity was assessed using Spearman's correlation coefficients between the Cancer Module and Generic Core Scales, and the comparison of the scores of child self-reports with those of other self-rating depression scales for children. Clinical validity was assessed by comparing the on- and off- treatment scores using Kruskal-Wallis and Mann-Whitney U tests.

Results

Cronbach's coefficient alpha was over 0.70 for the total scale and over 0.60 for each subscale by age except for the 'pain and hurt' subscale for children aged 5 to 7 years. For test-retest reliability, the ICC exceeded 0.70 for the total scale for each age. Exploratory factor analysis demonstrated sufficient factorial validity. Multitrait scaling analysis showed high success rates. Strong correlations were found between the reports by children and their parents, and the scores of the Cancer Module and the Generic Core Scales except for 'treatment anxiety' subscales for child reports. The Depression Self-Rating Scale for Children (DSRS-C) scores were significantly correlated with emotional domains and the total score of the cancer module. Children who had been off treatment over 12 months demonstrated significantly higher scores than those on treatment.

Conclusions

The results demonstrate the reliability and validity of the Japanese version of the PedsQL Cancer Module among Japanese children.
Size-dependent visible absorption and fast photoluminescence decay dynamics from freestanding strained silicon nanocrystals
Authors: Dhara Soumen , Giri PK
Published: April 2011

In this article, we report on the visible absorption, photoluminescence (PL), and fast PL decay dynamics from freestanding Si nanocrystals (NCs) that are anisotropically strained. Direct evidence of strain-induced dislocations is shown from high-resolution transmission electron microscopy images. Si NCs with sizes in the range of approximately 5-40 nm show size-dependent visible absorption in the range of 575-722 nm, while NCs of average size <10 nm exhibit strong PL emission at 580-585 nm. The PL decay shows an exponential decay in the nanosecond time scale. The Raman scattering studies show non-monotonic shift of the TO phonon modes as a function of size because of competing effect of strain and phonon confinement. Our studies rule out the influence of defects in the PL emission, and we propose that owing to the combined effect of strain and quantum confinement, the strained Si NCs exhibit direct band gap-like behavior.
Plasma creatinine in dogs: intra- and inter-laboratory variation in 10 European veterinary laboratories
Authors: Ulleberg Tina , Robben Joris , Nordahl Kathrine M , Ulleberg Thomas , Heiene Reidun
Published: April 2011

Background

There is substantial variation in reported reference intervals for canine plasma creatinine among veterinary laboratories, thereby influencing the clinical assessment of analytical results. The aims of the study was to determine the inter- and intra-laboratory variation in plasma creatinine among 10 veterinary laboratories, and to compare results from each laboratory with the upper limit of its reference interval.

Methods

Samples were collected from 10 healthy dogs, 10 dogs with expected intermediate plasma creatinine concentrations, and 10 dogs with azotemia. Overlap was observed for the first two groups. The 30 samples were divided into 3 batches and shipped in random order by postal delivery for plasma creatinine determination. Statistical testing was performed in accordance with ISO standard methodology.

Results

Inter- and intra-laboratory variation was clinically acceptable as plasma creatinine values for most samples were usually of the same magnitude. A few extreme outliers caused three laboratories to fail statistical testing for consistency. Laboratory sample means above or below the overall sample mean, did not unequivocally reflect high or low reference intervals in that laboratory.

Conclusions

In spite of close analytical results, further standardization among laboratories is warranted. The discrepant reference intervals seem to largely reflect different populations used in establishing the reference intervals, rather than analytical variation due to different laboratory methods.
Acute appendicitis caused by endometriosis: a case report
Authors: Laskou Styliani , Papavramidis Theodossis S , Cheva Angeliki , Michalopoulos Nick , Koulouris Charilaos , Kesisoglou Isaak , Papavramidis Spiros
Published: April 2011

Introduction

Endometriosis is a well-recognized gynecological condition in the reproductive age group. Surgical texts present the gynecological aspects of the disease in detail, but the published literature on unexpected manifestations, such as appendiceal disease, is inadequate. The presentation to general surgeons may be atypical and pose diagnostic difficulty. Thus, a definitive diagnosis is likely to be established only by the histological examination of a specimen.

Case presentation

We report a case of endometriosis of the appendix in a 25-year-old Caucasian woman who presented with symptoms of acute appendicitis and was treated by appendectomy, which resulted in a good outcome.

Conclusions

We discuss special aspects of acute appendicitis caused by endometriosis to elucidate the pathologic entity of this variant of acute appendicitis.
Expression of MICA, MICB and NKG2D in human leukemic myelomonocytic and cervical cancer cells
Authors: Weiss-Steider Benny , Soto-Cruz Isabel , Martinez-Campos Christian A , Mendoza-Rincon Jorge Flavio
Published: April 2011

Background

Cancer cells are known to secrete the stress molecules MICA and MICB that activate cytotoxicity by lymphocytes and NK cells through their NKG2D receptor as a mechanism of immunological defense. This work was undertaken to evaluate if cancer cells can also express this receptor as a possible mechanisms of depletion of MIC molecules and thus interfere with their immune recognition.

Methods

Myelomonocytic leukemic (TPH-1 and U-937) and cervical cancer (CALO and INBL) cell lines were evaluated by Western Blot, ELISA, flow cytometry and immunocytochemistry to evaluate their capacity to express and secrete MICA and MICB and to be induced to proliferate by these molecules as well as to express their receptor NKG2D. Statistical analysis was performed by two-way ANOVA for time course analysis and Student's t-test for comparison between groups. Values were considered significantly different if p < 0.05.

Results

THP-1 and U-937 produce and secrete the stress MICA and MICB as shown by Western Blot of lysed cells and by ELISA of their conditioned media. By Western Blot and flow cytometry we found that these cells also express the receptor NKG2D. When THP-1 and U-937 were cultured with recombinant MICA and MICB they exhibited a dose dependent induction for their proliferation. CALO and INBL also produce MICA and MICB and were induced to proliferate by these stress molecules. By Western Blot, flow cytometry and immunocytochemistry we also found that these cells express NKG2D.

Conclusions

Our novel results that tumor cells can simultaneously secrete MIC molecules and express their receptor, and to be induced for proliferation by these stress molecules, and that tumor epithelial cells can also express the NKG2D receptor that was thought to be exclusive of NK and cytotoxic lymphocytes is discussed as a possible mechanism of immunological escape and of tumor growth induction.
Bathymetric effects and corrections in marine CSEM data
Authors: Sasaki Yutaka
Published: April 2011

The effect of seafloor topographic variations on controlled-source electromagnetic (CSEM) responses is investigated using a finite-difference modeling approach for both petroleum and gas-hydrate exploration scenarios. In a deepwater reservoir model, distortions in the inline electric field responses are mainly due to galvanic effects, particularly at long transmitter-receiver (Tx-Rx) offsets, and are characterized by persistent short-wavelength anomalies at all Tx-Rx offsets in the amplitude profiles. In a shallow-water reservoir model, the contribution of inductive effects to bathymetric distortions is large at short Tx-Rx offsets compared to the deepwater case, whereas at long offsets, the distortion pattern is mainly determined by the source-receiver geometry relative to the sea surface because of the airwave effect rather than by the resistivity variations associated with the seafloor topography. A simple correction technique, which is an extension of the topographic correction procedure for magnetotelluric data, is effective in removing the bathymetric distortions for the deep marine case, but cannot be used for the shallow-water case because of the airwave effect. For a gas-hydrate exploration model, it is shown that the bathymetric response can be large enough to mask the target response, because higher frequencies and shorter offsets need to be used to detect the shallow targets. However, the modeling study suggests that the shallow target response can be separated from the bathymetric distortions using the correction method.
Signal extraction from 4D transient electromagnetic surveys using the equivalent source method
Authors: MacLennan Kristopher , Li Yaoguo
Published: April 2011

Emerging applications of transient electromagnetic (TEM) surveys, such as monitoring of groundwater aquifers or tracking fluid movement within petroleum reservoirs, require the acquisition of high resolution time-lapsed (4D) data sets, using three-component receivers to maximize information. However, separating signal from noise in TEM surveys can be difficult, and the magnitude of the time-lapse difference is often on the order of the noise. A method is developed for extracting signal from noisy three-component TEM data sets collected in fixed-loop, multiple-receiver surveys using a novel application of the equivalent source technique. This method takes advantage of the relationship between the three components of the observed decaying magnetic field to improve data contaminated by uncorrelated random noise, such as that due to receiver coil misalignment and location errors. Both synthetic and field three-component TEM data are used to demonstrate the viability of the technique. The results suggest it is feasible to use the method in processing time-lapsed TEM data, allowing for an improved signal to noise ratio in 4D survey data.
Low-Dose Decitabine Versus Best Supportive Care in Elderly Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group
Authors: Lübbert Michael , Suciu Stefan , Baila Liliana , Rüter Björn Hans , Platzbecker Uwe , Giagounidis Aristoteles , Selleslag Dominik , Labar Boris , Germing Ulrich , Salih Helmut R. , Beeldens Filip , Muus Petra , Pflüger Karl-Heinz , Coens Corneel , Hagemeijer Anne , Eckart Schaefer Hans , Ganser Arnold , Aul Carlo , de Witte Theo , Wijermans Pierre W.
Published: April 2011

Purpose

To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy.

Patients and Methods

Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m2) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles.

Results

OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) –free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters.

Conclusion

Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.
Validation of a Novel Staging System for Disease-Specific Survival in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy
Authors: Mittendorf Elizabeth A. , Jeruss Jacqueline S. , Tucker Susan L. , Kolli Aparna , Newman Lisa A. , Gonzalez-Angulo Ana M. , Buchholz Thomas A. , Sahin Aysegul A. , Cormier Janice N. , Buzdar Aman U. , Hortobagyi Gabriel N. , Hunt Kelly K.
Published: April 2011

Purpose

We previously described a novel breast cancer staging system for assessing prognosis after neoadjuvant chemotherapy on the basis of pretreatment clinical stage (CS), estrogen receptor status (E), grade (G), and post-treatment pathologic stage (PS). This clinical-pathologic stage (CPS) + EG staging system assigned and summed points for each factor, allowing for better determination of breast cancer–specific survival than CS or PS alone. The current study was undertaken to validate this staging system using internal and external cohorts.

Methods

We identified an internal cohort of 804 patients treated with neoadjuvant chemotherapy at our institution from 2003 to 2005 and an external cohort of 165 patients treated at another institution. Clinicopathologic characteristics, treatment regimens, and patient outcomes were assessed. Outcomes were stratified by CPS + EG score.

Results

Five-year disease-specific survival (DSS) for the internal cohort was 77% (95% CI, 72 to 82) at a median follow-up of 3.4 years (range, 0.3 to 5.9 years). Five-year DSS for the external cohort was 86% (95% CI, 79 to 91) at a median follow-up of 4.7 years (range, 0.5 to 10.5 years). The ability of the CPS + EG score to stratify outcomes was confirmed in both the internal and external cohorts. Application of the CPS + EG staging system facilitated more refined categorization of patients into prognostic subgroups by outcome than presenting CS or final PS as defined by the American Joint Committee on Cancer (AJCC) staging system.

Conclusion

The current study validates the CPS + EG staging system in two independent cohorts. We recommend that biologic markers and response to treatment be incorporated into revised versions of the AJCC staging system for patients receiving neoadjuvant chemotherapy.
Role of Functional Imaging in the Management of Lymphoma
Authors: Cheson Bruce D.
Published: April 2011

18-F-fluorodeoxyglucose (FDG) –positron emission tomography (PET), and more recently PET/computed tomography (CT), is the most sensitive and specific imaging technique currently available for patients with lymphoma. Nevertheless, despite being increasingly used in pretreatment assessment, midtreatment evaluation of response, post-treatment restaging, and surveillance during follow-up of patients with lymphoma, its impact on clinical outcome in most clinical situations remains to be confirmed. PET/CT provides its greatest clinical benefit in the post-treatment evaluation of Hodgkin's lymphoma and diffuse large B-cell lymphoma; however, the role of metabolic imaging in other indications and in other histologies remains to be demonstrated. Ongoing risk-adapted studies will hopefully provide evidence for clinical improvement on the basis of altering treatment as a result of interim PET results. Efforts are ongoing to better standardize the conduct and interpretation of FDG-PET scans. FDG-PET has the potential to improve lymphoma patient management; however, its usefulness will likely vary by histology, stage, therapy, and clinical setting.
Advances in Imaging and the Management of Myeloma Bone Disease
Authors: Terpos Evangelos , Moulopoulos Lia A. , Dimopoulos Meletios A.
Published: April 2011

Osteolytic disease is a major complication of multiple myeloma that may lead to devastating skeletal-related events (SREs). Conventional radiography remains the gold standard for the evaluation of bone disease in patients with myeloma. However, whole-body magnetic resonance imaging (MRI) is recommended in patients with normal conventional radiography and should be performed as part of staging in all patients with a solitary plasmacytoma of bone. Urgent MRI is also the diagnostic procedure of choice to assess suspected cord compression, whereas computed tomography can guide tissue biopsy. Positron emission tomography with computed tomography can provide complementary information to MRI, but its use in multiple myeloma must be better defined by further studies. The incorporation of abnormal MRI findings into the definition of symptomatic myeloma also needs to be clarified. Bisphosphonates remain the cornerstone for the management of myeloma bone disease. Intravenous pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future.
Transformation of Indolent B-Cell Lymphomas
Authors: Montoto Silvia , Fitzgibbon Jude
Published: April 2011

Histologic transformation (HT) to an aggressive lymphoma is a well-described event in the natural history and clinical course of patients with so-called indolent lymphomas. This phenomenon has been studied most extensively in patients with follicular lymphoma and subsequent transformation to a diffuse large B-cell lymphoma, with little literature on HT in nonfollicular lymphomas. Despite a considerable body of information on the pathologic and molecular events associated with HT, its pathogenesis has remained elusive and the molecular information available has not been translated into clinical advances. It remains unclear if there is already a predisposition to HT and whether this can be detected at the time of diagnosis. The rituximab era has been characterized by a significant improvement in the prognosis of patients with B-cell lymphomas, but HT remains one of the most important challenges in the management of patients with indolent lymphoma, the difficulties starting with the diagnosis and definition of HT and ending with the appropriate management and treatment of the event. Going forward, it is crucial to incorporate HT as a major end point in clinical trials and to include patients with HT as subject of such studies if we are to see meaningful progress in the future.
The Gray Zone Between Burkitt's Lymphoma and Diffuse Large B-Cell Lymphoma From a Genetics Perspective
Authors: Salaverria Itziar , Siebert Reiner
Published: April 2011

It has long been recognized that the border between classical Burkitt's lymphoma (BL) and classical diffuse large B-cell lymphoma (DLBCL) is hard to determine. Instead, both classical lymphoma entities seem to be the extreme ends of a spectrum of diseases that contains a group of lymphomas characterized predominately by the fact that they are hard to assign to the one or the other group. This gray zone has been recently termed “lymphoma, unclassifiable, with features intermediate between DLBCL and BL” by the updated WHO classification. The term “intermediate” resembles that from a recent gene-expression study of mature aggressive B-cell lymphomas, although, notably, it is used differently. Intermediate lymphomas according to the WHO classification clearly are a temporary container of different biologic subtypes of aggressive lymphoma, from which several might be associated with an unfavorable clinical outcome. The present review aims at describing the morphologic, clinical, and biologic heterogeneity of the intermediate lymphomas and, moreover, attempts to propose testable subgroups based on age and presence of genetic aberrations.
Pathogenesis of Non-Hodgkin's Lymphoma
Authors: Nogai Hendrik , Dörken Bernd , Lenz Georg
Published: April 2011

The understanding of the molecular pathogenesis of non-Hodgkin's lymphomas (NHL) has significantly improved in recent years. Advances in molecular biology and genetics lead to the identification and characterization of several oncogenic pathways involved in lymphomagenesis. This knowledge will ultimately lead to improved diagnostic and therapeutic strategies for patients with NHL. This review summarizes current concepts of the molecular pathogenesis of the most common NHL subtypes, with a special emphasis on diffuse large B-cell lymphoma, the most common lymphoma subtype.
TheDrosophilaSTUbL protein Degringolade limits HES functions during embryogenesis
Authors: Barry Kevin C. , Abed Mona , Kenyagin Dorit , Werwie Timothy R. , Boico Olga , Orian Amir , Parkhurst Susan M.
Published: April 2011

Degringolade (Dgrn) encodes a Drosophila SUMO-targeted ubiquitin ligase (STUbL) protein similar to that of mammalian RNF4. Dgrn facilitates the ubiquitylation of the HES protein Hairy, which disrupts the repressive activity of Hairy by inhibiting the recruitment of its cofactor Groucho. We show that Hey and all HES family members, except Her, interact with Dgrn and are substrates for its E3 ubiquitin ligase activity. Dgrn displays dynamic subcellular localization, accumulates in the nucleus at times when HES family members are active and limits Hey and HES family activity during sex determination, segmentation and neurogenesis. We show that Dgrn interacts with the Notch signaling pathway by it antagonizing the activity of E(spl)-C proteins. dgrn null mutants are female sterile, producing embryos that arrest development after two or three nuclear divisions. These mutant embryos exhibit fragmented or decondensed nuclei and accumulate higher levels of SUMO-conjugated proteins, suggesting a role for Dgrn in genome stability.
Ion Formation Processes in Laser Ablation of Multicomponent Inorganic Particles Relevant to Single Particle Laser Analysis of Atmospheric Aerosols
Authors: Yabushita Akihiro , Kinugawa Takashi , Narukawa Masahiro , Takahashi Kenshi , Kawasaki Masahiro , Matsumi Yutaka
Published: April 2011

Nanosecond laser ablation and subsequent ion formation processes of submicron aerosol particles containing multicomponent ammonium and sodium salts relevant to atmospheric aerosols were studied using a laser-ionization single-particle aerosol mass spectrometer. In the case of ammonium salts, chemical species with a low ionization energy are predominately observed in the positive-ion mass spectra, while those having a high electron affinity are predominately observed in the negative-ion mass spectra. Dissociative electron attachment processes take place. However, as far as sodium salts are concerned, the energetically preferred ions are not necessarily dominant, and the ion formation processes are suggested to be more complex than the ammonium salts.
A Möbius Aromatic Pd(II) Complex of [28]Hexaphyrin(2.1.1.0.1.1)
Authors: Moriya Kohei , Yoneda Tomoki , Saito Shohei , Osuka Atsuhiro
Published: April 2011

Pd(II) complex of [28]hexaphyrin(2.1.1.0.1.1) 5 was prepared in 36% yield from [26]hexaphyrin(2.1.1.0.1.1) 3 via reduction with NaBH4 and subsequent metalation of 4 with Pd(OAc)2 in the presence of triethylamine. This molecule constitutes the first example of Möbius aromatic species formed from expanded porphyrins other than the regular meso-aryl expanded porphyrins with the alternate arrangement of pyrroles and methine carbons.
Contracts as Reference Points—Experimental Evidence
Authors: Fehr Ernst , Hart Oliver , Zehnder Christian
Published: April 2011

Hart and John Moore (2008) introduce new behavioral assumptions that can explain long-term contracts and the employment relation. We examine experimentally their idea that contracts serve as reference points. The evidence confirms the prediction that there is a trade-off between rigidity and flexibility. Flexible contracts—which would dominate rigid contracts under standard assumptions—cause significant shading in ex post performance, while under rigid contracts much less shading occurs. The experiment appears to reveal a new behavioral force: ex ante competition legitimizes the terms of a contract, and aggrievement and shading occur mainly about outcomes within the contract. (JEL D44, D86, J41)
Falsifiability
Authors: Olszewski Wojciech , Sandroni Alvaro
Published: April 2011

We examine Popper's falsifiability within an economic model in which a tester hires a potential expert to produce a theory. Payments are contingent on the performance of the theory vis-à-vis data. We show that if experts are strategic, falsifiability has no power to distinguish scientific theories from worthless theories. The failure of falsification in screening informed and uninformed experts motivates questions on the broader concepts of refutation and verification. We demonstrate an asymmetry between the two concepts. Like falsification, verification contracts have no power to distinguish between informed and uninformed experts, but some refutation contracts are capable of screening experts. (JEL B41)
The Cyclical Behavior of Debt and Equity Finance
Authors: Covas Francisco , Haan Wouter J. Den
Published: April 2011

Debt and equity issuance are procyclical for most size-sorted firm categories of listed US firms and the procyclicality of equity issuance decreases monotonically with firm size. At the aggregate level, however, the results for equity issuance are not conclusive due to different behavior of the largest firms, especially those in the top one percent. During a deterioration in economic conditions, firms limit the impact of the reduction in external financing on investment by shedding financial assets. This is true for a worsening in aggregate as well as firm-specific conditions. (JEL E32, G32, L11, L25)
Search Dynamics in Consumer Choice under Time Pressure: An Eye-Tracking Study
Authors: Reutskaja Elena , Nagel Rosemarie , Camerer Colin F , Rangel Antonio
Published: April 2011

We study decisions that involve choosing between different numbers of options under time pressure using eye-tracking to monitor the search process of the subjects. We find that subjects are quite adept at optimizing within the set of items that they see, that the initial search process is random in value, that subjects use a stopping rule to terminate the search process that combines features of optimal search and satisficing, and that subjects search more often in certain focal regions of the display, which leads to choice biases. (JEL C91, D12, M31)
Integrated Sequencing and Scheduling in Coil Coating
Authors: Höhn Wiebke , König Felix G. , Möhring Rolf H. , Lübbecke Marco E.
Published: April 2011

We consider a complex planning problem in integrated steel production. A sequence of coils of sheet metal needs to be color coated in consecutive stages. Different coil geometries and changes of colors necessitate time-consuming setup work. In most coating stages one can choose between two parallel color tanks. This can either reduce the number of setups needed or enable setups concurrent with production. A production plan comprises the sequencing of coils and the scheduling of color tanks and setup work. The aim is to minimize the makespan for a given set of coils. We present an optimization model for this integrated sequencing and scheduling problem. A core component is a graph theoretical model for concurrent setup scheduling. It is instrumental for building a fast heuristic that is embedded into a genetic algorithm to solve the sequencing problem. The quality of our solutions is evaluated via an integer program based on a combinatorial relaxation, showing that our solutions are within 10% of the optimum. Our algorithm is implemented at Salzgitter Flachstahl GmbH, a major German steel producer. This has led to an average reduction in makespan by over 13% and has greatly exceeded expectations.

This paper was accepted by Dimitris Bertsimas, optimization.