bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of contractile prostaglandins and Rho-kinase in growth factor-induced airway smooth muscle contraction
Authors: Schaafsma Dedmer , Gosens Reinoud , Bos I Sophie T , Meurs Herman , Zaagsma Johan , Nelemans S Adriaan
Published: July 2005

Background

In addition to their proliferative and differentiating effects, several growth factors are capable of inducing a sustained airway smooth muscle (ASM) contraction. These contractile effects were previously found to be dependent on Rho-kinase and have also been associated with the production of eicosanoids. However, the precise mechanisms underlying growth factor-induced contraction are still unknown. In this study we investigated the role of contractile prostaglandins and Rho-kinase in growth factor-induced ASM contraction.

Methods

Growth factor-induced contractions of guinea pig open-ring tracheal preparations were studied by isometric tension measurements. The contribution of Rho-kinase, mitogen-activated protein kinase (MAPK) and cyclooxygenase (COX) to these reponses was established, using the inhibitors Y-27632 (1 μM), U-0126 (3 μM) and indomethacin (3 μM), respectively. The Rho-kinase dependency of contractions induced by exogenously applied prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2) was also studied. In addition, the effects of the selective FP-receptor antagonist AL-8810 (10 μM) and the selective EP1-antagonist AH-6809 (10 μM) on growth factor-induced contractions were investigated, both in intact and epithelium-denuded preparations. Growth factor-induced PGF2α-and PGE2-release in the absence and presence of Y-27632, U-0126 and indomethacin, was assessed by an ELISA-assay.

Results

Epidermal growth factor (EGF)-and platelet-derived growth factor (PDGF)-induced contractions of guinea pig tracheal smooth muscle preparations were dependent on Rho-kinase, MAPK and COX. Interestingly, growth factor-induced PGF2α-and PGE2-release from tracheal rings was significantly reduced by U-0126 and indomethacin, but not by Y-27632. Also, PGF2α-and PGE2-induced ASM contractions were largely dependent on Rho-kinase, in contrast to other contractile agonists like histamine. The FP-receptor antagonist AL-8810 (10 μM) significantly reduced (approximately 50 %) and the EP1-antagonist AH-6809 (10 μM) abrogated growth factor-induced contractions, similarly in intact and epithelium-denuded preparations.

Conclusion

The results indicate that growth factors induce ASM contraction through contractile prostaglandins – not derived from the epithelium – which in turn rely on Rho-kinase for their contractile effects.
Evaluation of normalization methods for cDNA microarray data by k-NN classification
Authors: Wu Wei , Xing Eric P , Myers Connie , Mian I Saira , Bissell Mina J
Published: July 2005

Background

Non-biological factors give rise to unwanted variations in cDNA microarray data. There are many normalization methods designed to remove such variations. However, to date there have been few published systematic evaluations of these techniques for removing variations arising from dye biases in the context of downstream, higher-order analytical tasks such as classification.

Results

Ten location normalization methods that adjust spatial- and/or intensity-dependent dye biases, and three scale methods that adjust scale differences were applied, individually and in combination, to five distinct, published, cancer biology-related cDNA microarray data sets. Leave-one-out cross-validation (LOOCV) classification error was employed as the quantitative end-point for assessing the effectiveness of a normalization method. In particular, a known classifier, k-nearest neighbor (k-NN), was estimated from data normalized using a given technique, and the LOOCV error rate of the ensuing model was computed. We found that k-NN classifiers are sensitive to dye biases in the data. Using N ONRM and GMEDIAN as baseline methods, our results show that single-bias-removal techniques which remove either spatial-dependent dye bias (referred later as spatial effect) or intensity-dependent dye bias (referred later as intensity effect) moderately reduce LOOCV classification errors; whereas double-bias-removal techniques which remove both spatial- and intensity effect reduce LOOCV classification errors even further. Of the 41 different strategies examined, three two-step processes, IG LOESS-SL FILTERW7, IST SPLINE-SL LOESS and IG LOESS-SL LOESS, all of which removed intensity effect globally and spatial effect locally, appear to reduce LOOCV classification errors most consistently and effectively across all data sets. We also found that the investigated scale normalization methods do not reduce LOOCV classification error.

Conclusion

Using LOOCV error of k-NNs as the evaluation criterion, three double-bias-removal normalization strategies, IG LOESS-SL FILTERW7, IST SPLINE-SL LOESS and IG LOESS-SL LOESS, outperform other strategies for removing spatial effect, intensity effect and scale differences from cDNA microarray data. The apparent sensitivity of k-NN LOOCV classification error to dye biases suggests that this criterion provides an informative measure for evaluating normalization methods. All the computational tools used in this study were implemented using the R language for statistical computing and graphics.
Storing, linking, and mining microarray databases using SRS
Authors: Veldhoven Antoine , Lange Don de , Smid Marcel , de Jager Victor , Kors Jan A , Jenster Guido
Published: July 2005

Background

SRS (Sequence Retrieval System) has proven to be a valuable platform for storing, linking, and querying biological databases. Due to the availability of a broad range of different scientific databases in SRS, it has become a useful platform to incorporate and mine microarray data to facilitate the analyses of biological questions and non-hypothesis driven quests. Here we report various solutions and tools for integrating and mining annotated expression data in SRS.

Results

We devised an Auto-Upload Tool by which microarray data can be automatically imported into SRS. The dataset can be linked to other databases and user access can be set. The linkage comprehensiveness of microarray platforms to other platforms and biological databases was examined in a network of scientific databases. The stored microarray data can also be made accessible to external programs for further processing. For example, we built an interface to a program called Venn Mapper, which collects its microarray data from SRS, processes the data by creating Venn diagrams, and saves the data for interpretation.

Conclusion

SRS is a useful database system to store, link and query various scientific datasets, including microarray data. The user-friendly Auto-Upload Tool makes SRS accessible to biologists for linking and mining user-owned databases.
Total blood lymphocyte counts in hemochromatosis probands with HFEC282Y homozygosity: relationship to severity of iron overload and HLA-A and -B alleles and haplotypes
Authors: Barton James C , Wiener Howard W , Acton Ronald T , Go Rodney CP
Published: July 2005

Background

It has been reported that some persons with hemochromatosis have low total blood lymphocyte counts, but the reason for this is unknown.

Methods

We measured total blood lymphocyte counts using an automated blood cell counter in 146 hemochromatosis probands (88 men, 58 women) with HFE C282Y homozygosity who were diagnosed in medical care. Univariate and multivariate analyses of total blood lymphocyte counts were evaluated using these variables: sex; age, transferrin saturation, and serum ferritin concentration at diagnosis; units of blood removed by phlebotomy to achieve iron depletion; and human leukocyte antigen (HLA)-A and -B alleles and haplotypes.

Results

The mean age at diagnosis was 49 ± 14 years (range 18 – 80 years) in men and 50 ± 13 years (range 22 – 88 years) in women. The correlations of total blood lymphocyte counts with sex, age, transferrin saturation, and serum ferritin concentration at diagnosis, and units of blood removed by phlebotomy to achieve iron depletion were not significant at the 0.05 level. Univariate analyses revealed significant associations between total blood lymphocyte counts and presence of the HLA-A*01, -B*08, and -B*14 alleles, and the A*01-B*08 haplotype. Presence of the A*01 allele, B*08 allele, or A*01-B*08 haplotype were associated with a lower total blood lymphocyte count, whereas presence of the B*14 allele was associated with a greater total blood lymphocyte count. There was an inverse association of total blood lymphocyte count with units of phlebotomy to achieve iron depletion, serum ferritin concentration, and with presence of the A*01-B*08 haplotype.

Conclusion

We conclude that there is a significant inverse relationship of total blood lymphocyte counts and severity of iron overload in hemochromatosis probands with HFE C282Y homozygosity. The presence of the HLA-A*01 allele or the -B*08 allele was also associated with significantly lower total blood lymphocyte counts, whereas presence of the -B*14 allele was associated with significantly higher total blood lymphocyte counts. In univariate and multivariate analyses, total blood lymphocyte counts were significantly lower in probands with the HLA-A*01-B*08 haplotype than in probands without this haplotype.
Calcitonin-producing well-differentiated neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder: case report
Authors: Mascolo Massimo , Altieri Vincenzo , Mignogna Chiara , Napodano Giorgio , De Rosa Gaetano , Insabato Luigi
Published: July 2005

Background

The occurrence of calcitonin-secreting primary carcinoid tumor of the urinary bladder is extremely rare.

Case presentation

The case of a 68-year-old male with carcinoid tumor arising in the urinary bladder is presented. Transurethral resection of a polypoid small tumor 0.4 cm in diameter was performed. Immunohistochemical study using neuroendocrine markers allowed a straightforward diagnosis of a low-grade neuroendocrine carcinoma (carcinoid tumor) of the urinary bladder. Immunohistochemistry demonstrated calcitonin immunoreactivity in the most of the tumor cells.

Conclusion

This tumor shows specific clinical, macroscopical and histological features and must be considered in the differential diagnosis of bladder neoplasms.
The influence of methylphenidate on the power spectrum of ADHD children – an MEG study
Authors: Wienbruch Christian , Paul Isabella , Bauer Susanne , Kivelitz Hermann
Published: July 2005

Background

The present study was dedicated to investigate the influence of Methylphenidate (MPH) on cortical processing of children who were diagnosed with different subtypes of Attention Deficit Hyperactivity Disorder (ADHD). As all of the previous studies investigating power differences in different frequency bands have been using EEG, mostly with a relatively small number of electrodes our aim was to obtain new aspects using high density magnetoencephalography (MEG).

Methods

35 children (6 female, 29 male) participated in this study. Mean age was 11.7 years (± 1.92 years). 17 children were diagnosed of having an Attention-Deficit/Hyperactivity Disorder of the combined type (ADHDcom, DSM IV code 314.01); the other 18 were diagnosed for ADHD of the predominantly inattentive type (ADHDin, DSM IV code 314.0). We measured the MEG during a 5 minute resting period with a 148-channel magnetometer system (MAGNES™ 2500 WH, 4D Neuroimaging, San Diego, USA). Power values were averaged for 5 bands: Delta (D, 1.5–3.5 Hz), Theta (T, 3.5–7.5 Hz), Alpha (A, 7.5–12.5 Hz), Beta (B, 12.5–25 Hz) and Global (GL, 1.5–25 Hz).). Additionally, attention was measured behaviourally using the D2 test of attention with and without medication.

Results

The global power of the frequency band from 1.5 to 25 Hz increased with MPH. Relative Theta was found to be higher in the left hemisphere after administration of MPH than before. A positive correlation was found between D2 test improvement and MPH-induced power changes in the Theta band over the left frontal region. A linear regression was computed and confirmed that the larger the improvement in D2 test performance, the larger the increase in Theta after MPH application.

Conclusion

Main effects induced by medication were found in frontal regions. Theta band activity increased over the left hemisphere after MPH application. This finding contradicts EEG results of several groups who found lower levels of Theta power after MPH application. As relative Theta correlates with D2 test improvement we conclude that MEG provide complementary and therefore important new insights to ADHD.
Biomechanics of bone-fracture fixation by stiffness-graded plates in comparison with stainless-steel plates
Authors: Ganesh VK , Ramakrishna K , Ghista Dhanjoo N
Published: July 2005

Background

In the internal fixation of fractured bone by means of bone-plates fastened to the bone on its tensile surface, an on-going concern has been the excessive stress-shielding of the bone by the excessively-stiff stainless-steel plate. The compressive stress-shielding at the fracture-interface immediately after fracture-fixation delays callus formation and bone healing. Likewise, the tensile stress-shielding of the layer of the bone underneath the plate can cause osteoporosis and decrease in tensile strength of this layer.

Method

In order to address this problem, we propose to use stiffness-graded plates. Accordingly, we have computed (by finite-element analysis) the stress distribution in the fractured bone fixed by composite plates, whose stiffness is graded both longitudinally and transversely.

Results

It can be seen that the stiffness-graded composite-plates cause less stress-shielding (as an example: at 50% of the healing stage, stress at the fracture interface is compressive in nature i.e. 0.002 GPa for stainless steel plate whereas stiffness graded plates provides tensile stress of 0.002 GPa. This means that stiffness graded plate is allowing the 50% healed bone to participate in loadings). Stiffness-graded plates are more flexible, and hence permit more bending of the fractured bone. This results in higher compressive stresses induced at the fractured faces accelerate bone-healing. On the other hand, away from the fracture interface the reduced stiffness and elastic modulus of the plate causes the neutral axis of the composite structure to be lowered into the bone resulting in the higher tensile stress in the bone-layer underneath the plate, wherein is conducive to the bone preserving its tensile strength.

Conclusion

Stiffness graded plates (with in-built variable stiffness) are deemed to offer less stress-shielding to the bone, providing higher compressive stress at the fractured interface (to induce accelerated healing) as well as higher tensile stress in the intact portion of the bone (to prevent bone remodeling and osteoporosis).
Effect of short schemes on body composition measurements using Air-Displacement Plethysmography
Authors: Hull Holly R , Fields David A
Published: July 2005

Background

Air-displacement plethysmography (ADP) is becoming a popular method to assess body composition. Several studies have shown certain types of clothing can affect measurements of body density, however no study has specifically investigated the effect of cotton gym shorts and spandex bicycle shorts on body density.

Methods

Thirty-seven males (23.0 ± 3.2 yr., 177.3 ± 5.4 cm., 74.8 ± 7.5 kg.) and thirty-eight females (23.7 ± 5.3 yr., 163.6 ± 8.4 cm., 57.1 ± 7.0 kg.) had their body density measured by ADP in three clothing schemes: 1) a tight fitting Speedo® swim suit (criterion measure), 2) cotton gym shorts, and 3) spandex bicycle shorts. The clothing was provided by the University of Oklahoma Body Composition Laboratory and the testing schemes were performed in random order.

Results

The regression of body density by the criterion measure against body density while wearing cotton gym shorts for the entire group (y = 0.001 + 0.991x, SEE = 0.003 g/cm3) and the females (y = 0.059 + 0.934x, SEE = 0.003 g/cm3) did not significantly deviate from the line of identity. However in males the regression significantly deviated from the line of identity (y = 0.052 + 0.944x, SEE = 0.002 g/cm3). Body density by the criterion measure and body density while wearing spandex bicycle shorts did not significantly differ from the line of identity for the entire group (y = -0.018 + 1.013x SEE = 0.003 g/cm3), in males (y = -0.002 + 1.001x, SEE = 0.003 g/cm3), or females (y = 0.073 + 0.925x, SEE = 0.003 g/cm3). Residual plot analysis revealed no group or gender bias in either the cotton gym shorts or in the spandex bicycle shorts.

Conclusion

It would appear bicycle spandex shorts are an acceptable alternative to a Speedo® like swim suit, however we advise that subjects adhere to the strict clothing protocol that is recommended by the manufacturer.
Intracardiac thrombus in Behçet's disease: Two case reports
Authors: Hammami Sonia , Mahjoub Silvia , Ben-Hamda Khaldoun , Brahem Radhia , Gamra Habib , Ben Farhat Mohamed
Published: July 2005

Intracardiac thrombus in Behçet's disease is an extremely rare manifestation. We report two such cases. A 20-year-old man presented with dyspnoea, cough and haemoptysis. Right heart thrombus associated with pulmonary artery aneurysm and thromboembolism was identified by helical CT and transoesophageal echocardiography. The second case was a 29-year-old male admitted for fever and chest pain. A diagnosis of right atrial thrombosis associated with pulmonary embolism and hyperhomocysteinemia was made. Due to the absence of haemodynamic compromise, medical management consisting of immunosupressive and anticoagulation therapy was adopted which resulted in complete dissolution of the thrombus with dramatic clinical improvement in both cases of clinical status.

Conclusion

intracardiac thrombus is a rare complication of Behçet's disease. As shown in our patients, medical treatment should be considered as the first line.
Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex
Authors: Guillemin Gilles J , Wang Lily , Brew Bruce J
Published: July 2005

There is evidence that the kynurenine pathway (KP) and particularly one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neuroinflammatory diseases, and more particularly AIDS dementia complex (ADC). We hypothesized that QUIN may be involved in astrocyte apoptosis because: 1) apoptotic astrocytes have been observed in the brains of ADC patients, 2) ADC patients have elevated cerebrospinal fluid QUIN concentrations, and 3) QUIN can induce astrocyte death. Primary cultures of human fetal astrocytes were treated with three pathophysiological concentrations of QUIN. Numeration of apoptotic cells was assessed using double immunocytochemistry for expression of active caspase 3 and for nucleus condensation. We found that treatment of human astrocytes with QUIN induced morphological (cell body shrinking) and biochemical changes (nucleus condensation and over-expression of active caspase 3) of apoptosis. After 24 hours of treatment with QUIN 500 nM and 1200 nM respectively 10 and 14% of astrocytes were undergoing apoptosis. This would be expected to lead to a relative lack of trophic support factors with consequent neuronal dysfunction and possibly death. Astroglial apoptosis induced by QUIN provides another potential mechanism for the neurotoxicity of QUIN during ADC.
Induction of compulsive-like washing by blocking the feeling of knowing: an experimental test of the security-motivation hypothesis of Obsessive-Compulsive Disorder
Authors: Woody Erik Z , Lewis Victoria , Snider Lisa , Grant Hilary , Kamath Markad , Szechtman Henry
Published: July 2005

Background

H. Szechtman and E. Woody (2004) hypothesized that obsessive-compulsive disorder results from a deficit in the feeling of knowing that normally terminates thoughts or actions elicited by security motivation. To test the plausibility of this proposed mechanism, an experiment was conducted to produce an analog of washing in obsessive-compulsive disorder by eliciting a scenario of potential harm and using hypnosis to block changes in internally generated feelings that would normally occur during washing.

Results

Participants reacted with increased disgust, anxiety, and heart rate to their mental images of contamination and potential danger. As predicted, high but not low hypnotizable participants showed a significant prolongation of washing when change in feelings during washing was blocked hypnotically.

Conclusion

Results show that blocking the affective signal that is normally generated during security-related behaviors, such as washing, leads to prolonged performance of these behaviors. This finding lends support to the plausibility of the proposed model of obsessive-compulsive disorder.
The color of a Dalmatian's spots: Linkage evidence to support the TYRP1gene
Authors: Cargill Edward J , Famula Thomas R , Schnabel Robert D , Strain George M , Murphy Keith E
Published: July 2005

Background

The distinctive coat pattern of a Dalmatian is the result of the interaction of several loci. While the encoded function of these genes is not fully understood, it is known the Piebald, Ticking, and Flecking loci interact to produce the Dalmatian's classic pigmented spots on a white background. The color of the pigmented spots in purebred Dalmatians can either be black or liver, but the locus responsible for color determination is unknown. Studies have been conducted to determine the underlying genes involved in coat color determination in the dog, e.g., in the Labrador Retriever, but none to date have addressed black versus liver in the Dalmatian.

Results

A genome scan was conducted in a multi-generational kindred of Dalmatians segregating black and liver spot color. Linkage analysis was performed using a total of 113 polymorphic microsatellite markers from the kindred. Linkage was found between spot color and a single microsatellite marker, FH2319 (LOD = 12.5) on chromosome 11.

Conclusion

The TYRP1 (Brown) locus is located at position 50.1 Mb on chromosome 11, which is approximately 0.4 Mb from marker FH2319. Given the recent characterization of TYRP1 genetic variations in the dog and the linkage evidence reported here, TYRP1 is likely responsible for the spot color variation of black versus liver seen in the Dalmatian.
Tumour necrosis factor activates the mitogen-activated protein kinases p38α and ERK in the synovial membrane in vivo
Authors: Görtz Birgit , Hayer Silvia , Tuerck Birgit , Zwerina Jochen , Smolen Josef S , Schett Georg
Published: July 2005

Tumour necrosis factor (TNF) is considered to be a major factor in chronic synovial inflammation and is an inducer of mitogen-activated protein kinase (MAPK) signalling. In the present study we investigated the ability of TNF to activate MAPKs in the synovial membrane in vivo. We studied human TNF transgenic mice – an in vivo model of TNF-induced arthritis – to examine phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) and p38MAPKα in the inflamed joints by means of immunoblot and immunohistochemistry. In addition, the effects of systemic blockade of TNF, IL-1 and receptor activator of nuclear factor-κB (RANK) ligand on the activation of MAPKs were assessed. In vivo, overexpression of TNF induced activation of p38MAPKα and ERK in the synovial membrane, whereas activation of JNK was less pronounced and rarely observed on immunohistochemical analysis. Activated p38MAPKα was predominantly found in synovial macrophages, whereas ERK activation was present in both synovial macrophages and fibroblasts. T and B lymphocytes did not exhibit major activation of any of the three MAPKs. Systemic blockade of TNF reduced activation of p38MAPKα and ERK, whereas inhibition of IL-1 only affected p38MAPKα and blockade of RANK ligand did not result in any decrease in MAPK activation in the synovial membrane. These data indicate that TNF preferentially activates p38MAPKα and ERK in synovial membrane exposed to TNF. This not only suggests that targeted inhibition of p38MAPKα and ERK is a feasible strategy for blocking TNF-mediated effects on joints, but it also shows that even currently available methods to block TNF effectively reduce activation of these two MAPKs.
Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer
Authors: Yamashita Hiroko , Nishio Mariko , Kobayashi Shunzo , Ando Yoshiaki , Sugiura Hiroshi , Zhang Zhenhuan , Hamaguchi Maho , Mita Keiko , Fujii Yoshitaka , Iwase Hirotaka
Published: July 2005

Introduction

Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified.

Methods

Using immunohistochemical techniques, we focused on the expression and phosphorylation of hormone receptors themselves and examined the phosphorylation of ER-α Ser118 and ER-α Ser167 and the expression of ER-α, ER-β1, ER-βcx/β2, progesterone receptor (PR), PRA, and PRB in the primary breast carcinomas of 75 patients with metastatic breast cancer who received first-line treatment with endocrine therapy after relapse.

Results

Phosphorylation of ER-α Ser118, but not Ser167, was positively associated with overexpression of HER2, and HER2-positive tumors showed resistance to endocrine therapy. The present study has shown for the first time that phosphorylation of ER-α Ser167, but not Ser118, and expression of PRA and PRB, as well as ER-α and PR in primary breast tumors are predictive of response to endocrine therapy, whereas expression of ER-β1 and ER-βcx/β2 did not affect response to the therapy. In addition, patients with either high phosphorylation of ER-α Ser167, or high expression of ER-α, PR, PRA, or PRB had a significantly longer survival after relapse.

Conclusion

These data suggest that phosphorylation of ER-α Ser167 is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer.
Evolution of selenium utilization traits
Authors: Romero Héctor , Zhang Yan , Gladyshev Vadim N , Salinas Gustavo
Published: July 2005

Background

The essential trace element selenium is used in a wide variety of biological processes. Selenocysteine (Sec), the 21st amino acid, is co-translationally incorporated into a restricted set of proteins. It is encoded by an UGA codon with the help of tRNASec (SelC), Sec-specific elongation factor (SelB) and a cis-acting mRNA structure (SECIS element). In addition, Sec synthase (SelA) and selenophosphate synthetase (SelD) are involved in the biosynthesis of Sec on the tRNASec. Selenium is also found in the form of 2-selenouridine, a modified base present in the wobble position of certain tRNAs, whose synthesis is catalyzed by YbbB using selenophosphate as a precursor.

Results

We analyzed completely sequenced genomes for occurrence of the selA, B, C, D and ybbB genes. We found that selB and selC are gene signatures for the Sec-decoding trait. However, selD is also present in organisms that do not utilize Sec, and shows association with either selA, B, C and/or ybbB. Thus, selD defines the overall selenium utilization. A global species map of Sec-decoding and 2-selenouridine synthesis traits is provided based on the presence/absence pattern of selenium-utilization genes. The phylogenies of these genes were inferred and compared to organismal phylogenies, which identified horizontal gene transfer (HGT) events involving both traits.

Conclusion

These results provide evidence for the ancient origin of these traits, their independent maintenance, and a highly dynamic evolutionary process that can be explained as the result of speciation, differential gene loss and HGT. The latter demonstrated that the loss of these traits is not irreversible as previously thought.
Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content
Authors: Haddrill Penelope R , Charlesworth Brian , Halligan Daniel L , Andolfatto Peter
Published: July 2005

Background

Introns comprise a large fraction of eukaryotic genomes, yet little is known about their functional significance. Regulatory elements have been mapped to some introns, though these are believed to account for only a small fraction of genome wide intronic DNA. No consistent patterns have emerged from studies that have investigated general levels of evolutionary constraint in introns.

Results

We examine the relationship between intron length and levels of evolutionary constraint by analyzing inter-specific divergence at 225 intron fragments in Drosophila melanogaster and Drosophila simulans, sampled from a broad distribution of intron lengths. We document a strongly negative correlation between intron length and divergence. Interestingly, we also find that divergence in introns is negatively correlated with GC content. This relationship does not account for the correlation between intron length and divergence, however, and may simply reflect local variation in mutational rates or biases.

Conclusion

Short introns make up only a small fraction of total intronic DNA in the genome. Our finding that long introns evolve more slowly than average implies that, while the majority of introns in the Drosophila genome may experience little or no selective constraint, most intronic DNA in the genome is likely to be evolving under considerable constraint. Our results suggest that functional elements may be ubiquitous within longer introns and that these introns may have a more general role in regulating gene expression than previously appreciated. Our finding that GC content and divergence are negatively correlated in introns has important implications for the interpretation of the correlation between divergence and levels of codon bias observed in Drosophila.
Theory of true-amplitude one-way wave equations and true-amplitude common-shot migration
Authors: Zhang Yu , Zhang Guanquan , Bleistein Norman
Published: July 2005

One-way wave operators are powerful tools for forward modeling and migration. Here, we describe a recently developed true-amplitude implementation of modified one-way operators and present some numerical examples. By “true-amplitude” one-way forward modeling we mean that the solutions are dynamically correct as well as kinematically correct. That is, ray theory applied to these equations yields the upward- and downward-traveling eikonal equations of the full wave equation, and the amplitude satisfies the transport equation of the full wave equation. The solutions of these equations are used in the standard wave-equation migration imaging condition. The boundary data for the downgoing wave is also modified from the one used in the classic theory because the latter data is not consistent with a point source for the full wave equation. When the full wave-form solutions are replaced by their ray-theoretic approximations, the imaging formula reduces to the common-shot Kirchhoff inversion formula. In this sense, the migration is true amplitude as well. On the other hand, this new method retains all of the fidelity features of wave equation migration. Computer output using numerically generated data confirms the accuracy of this inversion method. However, there are practical limitations. The observed data must be a solution of the wave equation. Therefore, the data must be collected from a single common-shot experiment. Multiexperiment data, such as common-offset data, cannot be used with this method as presently formulated.
On the use of quasi-static deformation to understand reservoir fluid flow
Authors: Vasco Don W. , Ferretti Alessandro
Published: July 2005

Deformation above a producing reservoir provides a valuable source of information concerning fluid flow and flow properties. Quasi-static deformation occurs when the displacements are so slow that we may neglect inertial terms in the equations of motion. We present a method for inferring reservoir volume change and flow properties, such as permeability, from observations of quasi-static deformation. Such displacements may represent surface deformation such as tilt, leveling, interferometric synthetic aperture radar (InSAR), or bathymetry observations or subsurface deformation, as inferred from time-lapse seismic surveys. In our approach, the equation for fluid flow in a deforming reservoir provides a mapping from estimated fractional volume changes to reservoir permeability variations. If the reservoir behaves poroelastically over the interval of interest, all the steps in this approach are linear. Thus, the inference of reservoir permeability from deformation data becomes a linear inverse problem. In an application to the Wilmington oil field in California, we find that observed surface displacements, obtained by leveling and InSAR, are indeed compatible with measured reservoir volume fluxes. We find that the permeability variations in certain layers coincide with fault-block boundaries suggesting that, in some cases, faults are controlling fluid flow at depth.
3D electrical imaging of an archaeological site using electrical and electromagnetic methods
Authors: Osella Ana , Vega Matías de la , Lascano Eugenia
Published: July 2005

Floridablanca is an 18th century archaeological site located in southern Argentina. Archaeological investigations at the site began in 1998, and in 2000 we started a project to perform geophysical studies there. In this paper, we report the implementation of electrical and electromagnetic (EM) methods in a sector of the site that corresponds to the settlers' houses. The objective of the project was to characterize the zone and the buried archaeological structures (adobe walls, tiles from a collapsed roof) with 2D and 3D electrical and EM techniques. We first applied an EM induction method covering a 600-[Formula: see text] area with a frequency ranging from 1000 to 19 000 Hz. A 3D visualization of the in-phase and quadrature components gave an initial description of anomalies possibly associated with buried structures. We then performed dipole-dipole profiles and inverted the data to obtain the corresponding 2D and 3D electrical images. Finally, after correlating the information obtained from the analysis of both EM and electrical data, we performed a more localized 3D dipole-dipole mesh (25 [Formula: see text]) to achieve the final electrical image of the most representative buried structure. The combination of both techniques allowed us to map two entire houses and to identify three types of walls: main, separating, and inner. These results have been confirmed by an archaeological excavation.
Performance of time-delay estimators
Authors: Bagaini Claudio
Published: July 2005

I analyze the problem of estimating differences in the arrival times of a seismic wavefront recorded by an array of sensors. The two-sensor problem is tackled first, showing that even an approximate knowledge of the wavelet, such as its power spectrum, can substantially increase the accuracy of the time-delay estimate and reduce the signal-to-noise ratio (S/N) threshold for reliable time-delay estimation. The use of the complex trace, although beneficial for time-delay estimates in the presence of frequency-independent phase shifts, reduces the estimation accuracy in poor S/N conditions. I compare the performance of five time-delay estimators for arrays of sensors. Four of five estimators are based on crosscorrelation with a reference signal derived according to one of the following criteria: one trace in the array randomly selected, the stack of all array traces, the stack of all array traces iteratively updated, and (possible only for synthetic data) the noise-free wavelet. Another method, which is referred to as integration of differential delays, is based on the solution of an overdetermined system of linear equations built using the time delays between each pair of sensors. In all the situations considered, the performance of crosscorrelation with a trace of the array randomly selected is significantly worse than the other methods. Integration of differential delays proved to be the best-performing method for a large range of S/N conditions, particularly in the presence of large fluctuations in time delays and large bandwidth. However, for small time delays with respect to the wavelet duration, or if a priori knowledge of the moveout can be used to detrend the original data, crosscorrelation with a stacked trace performs similarly to integration of differential delays.
Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Thrombospondin-1–Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Cancer
Authors: Hoekstra Ronald , de Vos Filip Y.F.L. , Eskens Ferry A.L.M. , Gietema Jourik A. , van der Gaast Ate , Groen Harry J.M. , Knight Raymond A. , Carr Robert A. , Humerickhouse Rod A. , Verweij Jaap , de Vries Elisabeth G.E.
Published: July 2005

Purpose

ABT-510 is an angiogenesis inhibitor derived from thrombospondin-1, a naturally occurring inhibitor of angiogenesis. We investigated ABT-510, which was administered subcutaneously in patients with advanced solid malignancies, to assess safety, pharmacokinetics, and serum markers of angiogenesis.

Patients and Methods

ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 h) and bolus injections (100, 200, and 260 mg once daily; 50 and 100 mg twice daily) in 28-day cycles.

Results

Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. Maximum-tolerated dose was not defined, but 260 mg was defined as the maximum clinically practical dose. ABT-510 pharmacokinetics were linear across the dosage ranges tested, and the potential therapeutic threshold (plasma concentrations > 100 ng/mL > 3 h/d) was achieved with all dose regimens. Median serum basic fibroblast growth factor (bFGF) levels decreased from 14.1 pg/mL (range, 0.5 to 77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2 to 29.4 pg/mL) after 56 days of treatment (P = .003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. Stable disease lasting for six cycles or more was seen in six patients.

Conclusion

ABT-510 demonstrated a favorable toxicity profile and linear and time-independent pharmacokinetics with biologically relevant plasma concentrations. The significant number of patients with prolonged stable disease and the convenient method of dosing merit further studies with this angiogenesis inhibitor.
Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas: Evidence of Diminished Cognitive and Adaptive Functioning in National Collaborative Research Studies (CCG 9891/POG 9130)
Authors: Beebe Dean W. , Ris M. Douglas , Armstrong F. Daniel , Fontanesi John , Mulhern Raymond , Holmes Emi , Wisoff Jeffrey H.
Published: July 2005

Purpose

Clinicians often assume that children with posterior fossa tumors are at minimal risk for cognitive or adaptive deficits if they do not undergo cranial irradiation. However, small case series have called that assumption into question, and have also suggested that nonirradiated cerebellar tumors can cause location-specific cognitive and adaptive impairment. This study (1) assessed whether resected but not irradiated pediatric cerebellar tumors are associated with cognitive and adaptive functioning deficits, and (2) examined the effect of tumor location and medical complications on cognitive and adaptive functioning.

Patients and Methods

The sample was composed of 103 children aged 3 to 18 years with low-grade cerebellar astrocytomas, who underwent only surgical treatment as part of Children's Cancer Group protocol 9891 or Pediatric Oncology Group protocol 9130. The sample was divided into three groups based on primary tumor location: vermis, left hemisphere, or right hemisphere. Data were collected prospectively on intelligence, academic achievement, adaptive skills, behavioral functioning, and pre-, peri-, and postsurgical medical complications.

Results

The sample as a whole displayed an elevated risk for cognitive and adaptive impairment that was not associated consistently with medical complications. Within this group of children with cerebellar tumors, tumor location had little effect on cognitive, adaptive, or medical outcome.

Conclusion

We did not replicate previous findings of location-specific effects on cognitive or adaptive outcome. However, the elevated risk of deficits in this population runs contrary to clinical lore, and suggests that clinicians should attend to the functional outcomes of children who undergo only surgical treatment for cerebellar tumors.
Fertility- and Menopause-Related Information Needs of Younger Women With a Diagnosis of Early Breast Cancer
Authors: Thewes B. , Meiser B. , Taylor A. , Phillips K.A. , Pendlebury S. , Capp A. , Dalley D. , Goldstein D. , Baber R. , Friedlander M.L.
Published: July 2005

Purpose

The use of chemotherapy and endocrine therapies in the treatment of premenopausal women carries with it reproductive and gynecologic implications that young women may find distressing and discordant with plans for childbearing. This multicenter study aimed to investigate fertility- and menopause-related information needs among young women with a diagnosis of early-stage breast cancer.

Patients and Methods

Two hundred twenty-eight women with a diagnosis of early-stage breast cancer who were aged 40 years or younger at diagnosis and who were 6 to 60 months after diagnosis were entered onto the trial. Participants completed a mailed self-report questionnaire that included a purposely designed fertility- and menopause-related information needs survey and standardized measures of distress, anxiety, quality of life, menopausal symptoms, and information-seeking style.

Results

Seventy-one percent of participants discussed fertility-related issues with a health professional as part of their breast cancer treatment, and 86% discussed menopause-related issues. Consultation with a fertility or menopause specialist was the most preferred method of obtaining this information. Receiving fertility-related information was rated as being significantly more important than receiving menopause-related information at time of diagnosis (P < .001) and at treatment decision making (P = .058). Receiving menopause-related information was rated as being significantly more important than receiving fertility-related information during adjuvant treatment (P < .05), at completion of adjuvant treatment (P < .001), and during follow-up (P < .001). Common questions, sources of information, and correlates of perceived importance were identified.

Conclusion

The results of this study suggest that younger women have unmet needs for fertility- and menopause-related information and provide preliminary empirical data to guide the development of better fertility- and menopause-related patient education materials for younger women with a diagnosis of early breast cancer.
Identifying Patients at Risk for Significant Versus Clinically Insignificant Postoperative Prostate-Specific Antigen Failure
Authors: D'Amico Anthony V. , Chen Ming-Hui , Roehl Kimberly A. , Catalona William J.
Published: July 2005

Purpose

We evaluated whether men at risk for significant versus clinically insignificant prostate-specific antigen (PSA) failure after radical prostatectomy could be identified using information available at diagnosis.

Patients and Methods

A prospective prostate cancer screening study that enrolled, diagnosed, and treated 1,011 men with radical prostatectomy at Barnes-Jewish Hospital (St Louis, MO) from January 1, 1989, to June 1, 2002, for localized prostate cancer formed the study cohort. Preoperative predictors of a postoperative PSA doubling time (DT) of less than 3 months and more than 12 months or no PSA failure were identified using logistic regression.

Results

A preoperative PSA velocity more than 2.0 ng/mL/yr (P = .001) and biopsy Gleason score 7 (P = .006) or 8 to 10 (P = .003) were significantly associated with having a postoperative PSA DT less than 3 months. A PSA level less than 10 ng/mL (P = .005), a nonpalpable cancer (P = .001) with a Gleason score ≤ 6 (P = .0002), and a preoperative PSA increase that did not exceed 0.5 ng/mL/yr (P = .03) were significantly associated with a postoperative PSA DT of at least 12 months or no PSA failure. Most men with these preoperative characteristics and a postoperative PSA DT of 12 months or more had a persistent postoperative PSA level of at least 0.2 ng/mL that did not exceed 0.25 ng/mL after a median follow-up of 3.6 years.

Conclusion

A postoperative PSA DT less than 3 months is associated with a preoperative PSA velocity more than 2.0 ng/mL/yr and high-grade disease. Select men with a postoperative PSA DT more than 12 months may not require salvage radiation therapy.
Randomized Trial Comparing Cyclophosphamide, Epirubicin, and Fluorouracil With Cyclophosphamide, Methotrexate, and Fluorouracil in Premenopausal Women With Node-Positive Breast Cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA5
Authors: Levine Mark N. , Pritchard Kathleen I. , Bramwell Vivien H.C. , Shepherd Lois E. , Tu Dongsheng , Paul Nancy
Published: July 2005

Purpose

Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer.

Patients and Methods

Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node–positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m2 orally days 1 through 14, epirubicin 60 mg/m2 intravenously days 1 and 8, and fluorouracil 500 mg/m2 intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m2 orally days 1 through 14, methotrexate 40 mg/m2 intravenously days 1 and 8, and fluorouracil 600 mg/m2 intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF.

Results

The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group).

Conclusion

The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.