bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesenchymal stem cells avoid allogeneic rejection
Authors: Ryan Jennifer M , Barry Frank P , Murphy J Mary , Mahon Bernard P
Published: July 2005

Adult bone marrow derived mesenchymal stem cells offer the potential to open a new frontier in medicine. Regenerative medicine aims to replace effete cells in a broad range of conditions associated with damaged cartilage, bone, muscle, tendon and ligament. However the normal process of immune rejection of mismatched allogeneic tissue would appear to prevent the realisation of such ambitions. In fact mesenchymal stem cells avoid allogeneic rejection in humans and in animal models. These finding are supported by in vitro co-culture studies. Three broad mechanisms contribute to this effect. Firstly, mesenchymal stem cells are hypoimmunogenic, often lacking MHC-II and costimulatory molecule expression. Secondly, these stem cells prevent T cell responses indirectly through modulation of dendritic cells and directly by disrupting NK as well as CD8+ and CD4+ T cell function. Thirdly, mesenchymal stem cells induce a suppressive local microenvironment through the production of prostaglandins and interleukin-10 as well as by the expression of indoleamine 2,3,-dioxygenase, which depletes the local milieu of tryptophan. Comparison is made to maternal tolerance of the fetal allograft, and contrasted with the immune evasion mechanisms of tumor cells. Mesenchymal stem cells are a highly regulated self-renewing population of cells with potent mechanisms to avoid allogeneic rejection.
Adrenal metastasis as first presentation of hepatocellular carcinoma
Authors: Tsalis Kostas , Zacharakis Emmanouil , Sapidis Nikolaos , Lambrou Ioannis , Zacharakis Evangelos , Betsis Dimitrios
Published: July 2005

Background

Metastases from hepatocellular carcinoma (HCC) can be found in the lung and adrenal gland. We report case of a patient who presented with adrenal metastasis as the first clinical manifestation of HCC.

Case presentation

A patient was referred for surgical treatment for a tumor in retro-peritoneal space. The computerized tomography (CT) scan revealed a mass originating from the left adrenal gland. The patient underwent left adrenalectomy and the exploration of abdominal cavity did not reveal any other palpable lesions. Histologically, the resected lesion was a poorly differentiated metastatic tumor from HCC. Seven months later patient was readmitted complaining of cachexia, icterus, and significant weight loss. CT scan revealed hyperdense lesions of the liver

Conclusion

HCC may have atypical presentations like in present case. Fine needle aspiration/tru-cut® biopsy might be useful in the investigation of an accidentally discovered adrenal mass regardless of the size and can lead to the detection of a primary tumor.
A novel combination of multiple primary carcinomas: Urinary bladder transitional cell carcinoma, prostate adenocarcinoma and small cell lung carcinoma- report of a case and review of the literature
Authors: Koutsopoulos Anastassios V , Dambaki Konstantina I , Datseris George , Giannikaki Elpida , Froudarakis Marios , Stathopoulos Efstathios
Published: July 2005

Background

The incidence of multiple primary malignant neoplasms increases with age and they are encountered more frequently nowadays than before, the phenomenon is still considered to be rare.

Case presentation

We report a case of a man in whom urinary bladder transitional cell carcinoma, metachronous prostate adenocarcinoma and small cell lung carcinoma were diagnosed within an eighteen-month period. The only known predisposing factor was that he was heavy smoker (90–100 packets per year). The literature on the phenomenon of multiple primary malignancies in a single patient is reviewed and the data is summarized.

Conclusion

It is important for the clinicians to keep in mind the possibility of a metachronous (successive) or a synchronous (simultaneous) malignancy in a cancer patient. It is worthy mentioning this case because clustering of three primary malignancies (synchronous and metachronous) is of rare occurrence in a single patient, and, to our knowledge, this is the first report this combination of three carcinomas appearing in the same patient.
Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels
Authors: Borna Catharina , Lazarowski Eduardo , van Heusden Catharina , Öhlin Hans , Erlinge David
Published: July 2005

Background

To be fully activated platelets are dependent on two positive feedback loops; the formation of thromboxane A2 by cyclooxygenase in the platelets and the release of ADP. We wanted to evaluate the effect of aspirin on platelet function in patients with acute coronary syndromes and we hypothesized that increased levels of ADP in patients with acute coronary syndromes could contribute to aspirin resistance.

Methods

Platelet activity in 135 patients admitted for chest pain was assessed with PFA-100. An epinephrine-collagen cartridge (EPI-COLL) was used for the detection of aspirin resistance together with an ADP-collagen cartridge (ADP-COLL). ADP was measured with hplc from antecubital vein samples. Three subgroups were compared: chest pain with no sign of cardiac disease (NCD), NonST-elevation myocardial infarction (NSTEMI) and STEMI.

Results

Platelet activation was increased for the STEMI group compared NCD. Aspirin resistance defined as <193 sec in EPI-COLL was 9.7 % in NCD, and increased to 26.0 % (n.s.) in NSTEMI and 83.3 % (p < 0.001) in STEMI. Chronic aspirin treatment significantly reduced platelet aggregation in NCD and NSTEMI, but it had no effect in STEMI. Plasma levels of ADP were markedly increased in STEMI (905 ± 721 nmol/l, p < 0.01), but not in NSTEMI (317 ± 245), compared to NCD (334 ± 271, mean ± SD). ADP levels correlated with increased platelet activity measured with ADP-COLL (r = -0.30, p < 0.05). Aspirin resistant patients (EPI-COLL < 193 sec) had higher ADP levels compared to aspirin responders (734 ± 807 vs. 282 ± 187 nmol/l, mean ± SD, p < 0.05).

Conclusion

Platelets are activated and aspirin resistance is more frequent in STEMI, probably due to a general activation of platelets. ADP levels are increased in STEMI and correlates with platelet activation. Increased levels of ADP could be one reason for increased platelet activity and aspirin resistance.
RNA amplification for successful gene profiling analysis
Authors: Wang Ena
Published: July 2005

The study of clinical samples is often limited by the amount of material available to study. While proteins cannot be multiplied in their natural form, DNA and RNA can be amplified from small specimens and used for high-throughput analyses. Therefore, genetic studies offer the best opportunity to screen for novel insights of human pathology when little material is available. Precise estimates of DNA copy numbers in a given specimen are necessary. However, most studies investigate static variables such as the genetic background of patients or mutations within pathological specimens without a need to assess proportionality of expression among different genes throughout the genome. Comparative genomic hybridization of DNA samples represents a crude exception to this rule since genomic amplification or deletion is compared among different specimens directly. For gene expression analysis, however, it is critical to accurately estimate the proportional expression of distinct RNA transcripts since such proportions directly govern cell function by modulating protein expression. Furthermore, comparative estimates of relative RNA expression at different time points portray the response of cells to environmental stimuli, indirectly informing about broader biological events affecting a particular tissue in physiological or pathological conditions. This cognitive reaction of cells is similar to the detection of electroencephalographic patterns which inform about the status of the brain in response to external stimuli. As our need to understand human pathophysiology at the global level increases, the development and refinement of technologies for high fidelity messenger RNA amplification have become the focus of increasing interest during the past decade. The need to increase the abundance of RNA has been met not only for gene specific amplification, but, most importantly for global transcriptome wide, unbiased amplification. Now gene-specific, unbiased transcriptome wide amplification accurately maintains proportionality among all RNA species within a given specimen. This allows the utilization of clinical material obtained with minimally invasive methods such as fine needle aspirates (FNA) or cytological washings for high throughput functional genomics studies. This review provides a comprehensive and updated discussion of the literature in the subject and critically discusses the main approaches, the pitfalls and provides practical suggestions for successful unbiased amplification of the whole transcriptome in clinical samples.
A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma
Authors: Geiger Christiane , Regn Sybille , Weinzierl Andreas , Noessner Elfriede , Schendel Dolores J
Published: July 2005

We present a generic dendritic cell (DC) vaccine strategy for patients with renal cell carcinoma (RCC) based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs). Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells) as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs.

Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs) specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP)-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease.
Artificial neural networks allow the use of simultaneous measurements of Alzheimer Disease markers for early detection of the disease
Authors: Di Luca Monica , Grossi Enzo , Borroni Barbara , Zimmermann Martina , Marcello Elena , Colciaghi Francesca , Gardoni Fabrizio , Intraligi Marco , Padovani Alessandro , Buscema Massimo
Published: July 2005

Background

Previous studies have shown that in platelets of mild Alzheimer Disease (AD) patients there are alterations of specific APP forms, paralleled by alteration in expression level of both ADAM 10 and BACE when compared to control subjects. Due to the poor linear relation among each key-element of beta-amyloid cascade and the target diagnosis, the use of systems able to afford non linear tasks, like artificial neural networks (ANNs), should allow a better discriminating capacity in comparison with classical statistics.

Objective

To evaluate the accuracy of ANNs in AD diagnosis.

Methods

37 mild-AD patients and 25 control subjects were enrolled, and APP, ADM10 and BACE measures were performed. Fifteen different models of feed-forward and complex-recurrent ANNs (provided by Semeion Research Centre), based on different learning laws (back propagation, sine-net, bi-modal) were compared with the linear discriminant analysis (LDA).

Results

The best ANN model correctly identified mild AD patients in the 94% of cases and the control subjects in the 92%. The corresponding diagnostic performance obtained with LDA was 90% and 73%.

Conclusion

This preliminary study suggests that the processing of biochemical tests related to beta-amyloid cascade with ANNs allows a very good discrimination of AD in early stages, higher than that obtainable with classical statistics methods.
Dephosphorylation of CDK9 by protein phosphatase 2A and protein phosphatase-1 in Tat-activated HIV-1 transcription
Authors: Ammosova Tatyana , Washington Kareem , Debebe Zufan , Brady John , Nekhai Sergei
Published: July 2005

Background

HIV-1 Tat protein recruits human positive transcription elongation factor P-TEFb, consisting of CDK9 and cyclin T1, to HIV-1 transactivation response (TAR) RNA. CDK9 is maintained in dephosphorylated state by TFIIH and undergo phosphorylation upon the dissociation of TFIIH. Thus, dephosphorylation of CDK9 prior to its association with HIV-1 preinitiation complex might be important for HIV-1 transcription. Others and we previously showed that protein phosphatase-2A and protein phosphatase-1 regulates HIV-1 transcription. In the present study we analyze relative contribution of PP2A and PP1 to dephosphorylation of CDK9 and to HIV-1 transcription in vitro and in vivo.

Results

In vitro, PP2A but not PP1 dephosphorylated autophosphorylated CDK9 and reduced complex formation between P-TEFb, Tat and TAR RNA. Inhibition of PP2A by okadaic acid inhibited basal as well as Tat-induced HIV-1 transcription whereas inhibition of PP1 by recombinant nuclear inhibitor of PP1 (NIPP1) inhibited only Tat-induced transcription in vitro. In cultured cells, low concentration of okadaic acid, inhibitory for PP2A, only mildly inhibited Tat-induced HIV-1 transcription. In contrast Tat-mediated HIV-1 transcription was strongly inhibited by expression of NIPP1. Okadaic acid induced phosphorylation of endogenous as well transiently expressed CDK9, but this induction was not seen in the cells expressing NIPP1. Also the okadaic acid did not induce phosphorylation of CDK9 with mutation of Thr 186 or with mutations in Ser-329, Thr-330, Thr-333, Ser-334, Ser-347, Thr-350, Ser-353, and Thr-354 residues involved in autophosphorylation of CDK9.

Conclusion

Our results indicate that although PP2A dephosphorylates autophosphorylated CDK9 in vitro, in cultured cells PP1 is likely to dephosphorylate CDK9 and contribute to the regulation of activated HIV-1 transcription.
Gait dynamics in mouse models of Parkinson's disease and Huntington's disease
Authors: Amende Ivo , Kale Ajit , McCue Scott , Glazier Scott , Morgan James P , Hampton Thomas G
Published: July 2005

Background

Gait is impaired in patients with Parkinson's disease (PD) and Huntington's disease (HD), but gait dynamics in mouse models of PD and HD have not been described. Here we quantified temporal and spatial indices of gait dynamics in a mouse model of PD and a mouse model of HD.

Methods

Gait indices were obtained in C57BL/6J mice treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg/day for 3 days) for PD, the mitochondrial toxin 3-nitropropionic acid (3NP, 75 mg/kg cumulative dose) for HD, or saline. We applied ventral plane videography to generate digital paw prints from which indices of gait and gait variability were determined. Mice walked on a transparent treadmill belt at a speed of 34 cm/s after treatments.

Results

Stride length was significantly shorter in MPTP-treated mice (6.6 ± 0.1 cm vs. 7.1 ± 0.1 cm, P < 0.05) and stride frequency was significantly increased (5.4 ± 0.1 Hz vs. 5.0 ± 0.1 Hz, P < 0.05) after 3 administrations of MPTP, compared to saline-treated mice. The inability of some mice treated with 3NP to exhibit coordinated gait was due to hind limb failure while forelimb gait dynamics remained intact. Stride-to-stride variability was significantly increased in MPTP-treated and 3NP-treated mice compared to saline-treated mice. To determine if gait disturbances due to MPTP and 3NP, drugs affecting the basal ganglia, were comparable to gait disturbances associated with motor neuron diseases, we also studied gait dynamics in a mouse model of amyotrophic lateral sclerosis (ALS). Gait variability was not increased in the SOD1 G93A transgenic model of ALS compared to wild-type control mice.

Conclusion

The distinct characteristics of gait and gait variability in the MPTP model of Parkinson's disease and the 3NP model of Huntington's disease may reflect impairment of specific neural pathways involved.
Too much or too little step width variability is associated with a fall history in older persons who walk at or near normal gait speed
Authors: Brach Jennifer S , Berlin Jaime E , VanSwearingen Jessie M , Newman Anne B , Studenski Stephanie A
Published: July 2005

Background

Decreased gait speed and increased stride time, stride length, double support time, and stance time variability have consistently been associated with falling whereas step width variability has not been strongly related to falls. The purpose was to examine the linear and nonlinear associations between gait variability and fall history in older persons and to examine the influence of gait speed.

Methods

Gait characteristics and fall history were obtained in 503 older adults (mean age = 79; 61% female) participating in the Cardiovascular Health Study who could ambulate independently. Gait characteristics were recorded from two trials on a 4 meter computerized walkway at the subject's self-selected walking speed. Gait variability was calculated as the coefficient of variation. The presence of a fall in the past 12 months was determined by interview. The nonlinear association between gait variability and fall history was examined using a simple three level classification derived from the distribution of the data and from literature based cut-points. Multivariate logistic regression was used to examine the association between step width variability (extreme or moderate) and fall history stratifying by gait speed (1.0 m/s) and controlling for age and gender.

Results

Step length, stance time, and step time variability did not differ with respect to fall history (p > .33). Individuals with extreme step width variability (either low or high step width variability) were more likely to report a fall in the past year than individuals with moderate step width variability. In individuals who walked ≥ 1.0 m/s (n = 281), after controlling for age, gender, and gait speed, compared to individuals with moderate step width variability individuals with either low or high step width variability were more likely to have fallen in the past year (OR and 95% CI 4.38 [1.79–10.72]). The association between step width variability and fall history was not significant in individuals who walked < 1.0 m/s (n = 224).

Conclusion

Extreme (either too little or too much) step width variability is associated with falls in the past year in older persons who walk at or near normal gait speed and not in older persons who walk slowly (<1.0 m/s).
Can context justify an ethical double standard for clinical research in developing countries?
Authors: Landes Megan
Published: July 2005

Background

The design of clinical research deserves special caution so as to safeguard the rights of participating individuals. While the international community has agreed on ethical standards for the design of research, these frameworks still remain open to interpretation, revision and debate. Recently a breach in the consensus of how to apply these ethical standards to research in developing countries has occurred, notably beginning with the 1994 placebo-controlled trials to reduce maternal to child transmission of HIV-1 in Africa, Asia and the Caribbean. The design of these trials sparked intense debate with the inclusion of a placebo-control group despite the existence of a 'gold standard' and trial supporters grounded their justifications of the trial design on the context of scarcity in resource-poor settings.

Discussion

These 'contextual' apologetics are arguably an ethical loophole inherent in current bioethical methodology. However, this convenient appropriation of 'contextual' analysis simply fails to acknowledge the underpinnings of feminist ethical analysis upon which it must stand. A more rigorous analysis of the political, social, and economic structures pertaining to the global context of developing countries reveals that the bioethical principles of beneficence and justice fail to be met in this trial design.

Conclusion

Within this broader, and theoretically necessary, understanding of context, it becomes impossible to justify an ethical double standard for research in developing countries.
The epidemiology of low back pain in primary care
Authors: Kent Peter M , Keating Jennifer L
Published: July 2005

This descriptive review provides a summary of the prevalence, activity limitation (disability), care-seeking, natural history and clinical course, treatment outcome, and costs of low back pain (LBP) in primary care.

LBP is a common problem affecting both genders and most ages, for which about one in four adults seeks care in a six-month period. It results in considerable direct and indirect costs, and these costs are financial, workforce and social. Care-seeking behaviour varies depending on cultural factors, the intensity of the pain, the extent of activity limitation and the presence of co-morbidity. Care-seeking for LBP is a significant proportion of caseload for some primary-contact disciplines. Most recent-onset LBP episodes settle but only about one in three resolves completely over a 12-month period. About three in five will recur in an on-going relapsing pattern and about one in 10 do not resolve at all. The cases that do not resolve at all form a persistent LBP group that consume the bulk of LBP compensable care resources and for whom positive outcomes are possible but not frequent or substantial.
Identification of kinectin as a novel Behçet's disease autoantigen
Authors: Lu Yu , Ye Ping , Chen Shun-le , Tan Eng M , Chan Edward KL
Published: July 2005

There has been some evidence that Behçet's disease (BD) has a significant autoimmune component but the molecular identity of putative autoantigens has not been well characterized. In the initial analysis of the autoantibody profile in 39 Chinese BD patients, autoantibodies to cellular proteins were uncovered in 23% as determined by immunoblotting. We have now identified one of the major autoantibody specificities using expression cloning. Serum from a BD patient was used as a probe to immunoscreen a λZAP expression cDNA library. Candidate autoantigen cDNAs were characterized by direct nucleotide sequencing and their expressed products were examined for reactivity to the entire panel of BD sera using immunoprecipitation. Reactivity was also examined with normal control sera and disease control sera from patients with lupus and Sjögren's syndrome. Six independent candidate clones were isolated from the cDNA library screen and were identified as overlapping partial human kinectin cDNAs. The finding that kinectin was an autoantigen was verified in 9 out of 39 (23%) BD patient sera by immunoprecipitation of the in vitro translation products. Sera from controls showed no reactivity. The significance of kinectin as a participant in autoimmune pathogenesis in BD and the potential use of autoantibody to kinectin in serodiagnostics are discussed.
Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen
Authors: Bajtner Estelle , Nandakumar Kutty S , Engström Åke , Holmdahl Rikard
Published: July 2005

Antibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/c×B10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/c×B10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.
Proteomic identification of heat shock protein 90 as a candidate target for p53 mutation reactivation by PRIMA-1 in breast cancer cells
Authors: Rehman Abdur , Chahal Manpreet S , Tang Xiaoting , Bruce James E , Pommier Yves , Daoud Sayed S
Published: July 2005

Introduction

A loss of p53 function resulting from mutation is prevalent in human cancers. Thus, restoration of p53 function to mutant p53 using small compounds has been extensively studied for cancer therapy. We previously reported that PRIMA-1 (for 'p53 reactivation and induction of massive apoptosis') restored the transcriptional activity of p53 target genes in breast cancer cells with a p53 mutation. By using functional proteomics approach, we sought to identify molecular targets that are involved in the restoration of normal function to mutant p53.

Methods

PRIMA-1 treated cell lysates were subjected to immunoprecipitation with DO-1 primary antibody against p53 protein, and proteins bound to p53 were separated on a denaturing gel. Bands expressed differentially between control and PRIMA-1-treated cells were then identified by matrix-assisted laser desorption ionization-time-of-flight spectrometry. Protein expression in whole cell lysates and nuclear extracts were confirmed by Western blotting. The effect of combined treatment of PRIMA-1 and adriamycin in breast cancer cells was determined with a cytotoxicity assay in vitro.

Results

PRIMA-1 treated cells distinctly expressed a protein band of 90 kDa that was identified as heat shock protein 90 (Hsp90) by the analysis of the 90 kDa band tryptic digest. Immunoblotting with isoform-specific antibodies against Hsp90 identified this band as the α isoform of Hsp90 (Hsp90α). Co-immunoprecipitation with anti-Hsp90α antibody followed by immunoblotting with DO-1 confirmed that p53 and Hsp90α were interacting proteins. PRIMA-1 treatment also resulted in the translocation of Hsp90α to the nucleus by 8 hours. Treatment of cells with PRIMA-1 alone or in combination with adriamycin, a DNA-targeted agent, resulted in increased sensitivity of tumor cells.

Conclusion

The studies demonstrate that PRIMA-1 restores the p53-Hsp90α interaction, enhances the translocation of the p53-Hsp90α complex and reactivates p53 transcriptional activity. Our preliminary evidence also suggests that PRIMA-1 could be considered in combination therapy with DNA-targeted agents for the treatment of breast cancer, especially for tumors with aberrant p53 function.
Strong evidence that the common variant S384F in BRCA2has no pathogenic relevance in hereditary breast cancer
Authors: Wappenschmidt B , Fimmers R , Rhiem K , Brosig M , Wardelmann E , Meindl A , Arnold N , Mallmann P , Schmutzler RK
Published: July 2005

Introduction

Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10).

Methods

For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated.

Results

We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 × 10-8 in favour of neutrality of the variant.

Conclusion

Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated)
Authors: Levy Howard , Laterre Pierre-Francois , Bates Becky , Qualy Rebecca L
Published: July 2005

Introduction

In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC).

Methods

Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window.

Results

Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and drotrecogin alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41–1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and drotrecogin alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62–0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and drotrecogin alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54–1.06).

Conclusion

Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with drotrecogin alfa (activated).
The molecular portrait of in vitro growth by meta-analysis of gene-expression profiles
Authors: Sandberg Rickard , Ernberg Ingemar
Published: July 2005

Background

Cell lines as model systems of tumors and tissues are essential in molecular biology, although they only approximate the properties of in vivo cells in tissues. Cell lines have been selected under in vitro conditions for a long period of time, affecting many specific cellular pathways and processes.

Results

To identify the transcriptional changes caused by long term in vitro selection, we performed a gene-expression meta-analysis and compared 60 tumor cell lines (of nine tissue origins) to 135 human tissue and 176 tumor tissue samples. Using significance analysis of microarrays we demonstrated that cell lines showed statistically significant differential expression of approximately 30% of the approximately 7,000 genes investigated compared to the tissues. Most of the differences were associated with the higher proliferation rate and the disrupted tissue organization in vitro. Thus, genes involved in cell-cycle progression, macromolecule processing and turnover, and energy metabolism were upregulated in cell lines, whereas cell adhesion molecules and membrane signaling proteins were downregulated.

Conclusion

Detailed molecular understanding of how cells adapt to the in vitro environment is important, as it will both increase our understanding of tissue organization and result in a refined molecular portrait of proliferation. It will further indicate when to use immortalized cell lines, or when it is necessary to instead use three-dimensional cultures, primary cell cultures or tissue biopsies.
The Dictyostelium genome encodes numerous RasGEFs with multiple biological roles
Authors: Wilkins Andrew , Szafranski Karol , Fraser Derek J , Bakthavatsalam Deenadayalan , Müller Rolf , Fisher Paul R , Glöckner Gernot , Eichinger Ludwig , Noegel Angelika A , Insall Robert H
Published: July 2005

Background

Dictyostelium discoideum is a eukaryote with a simple lifestyle and a relatively small genome whose sequence has been fully determined. It is widely used for studies on cell signaling, movement and multicellular development. Ras guanine-nucleotide exchange factors (RasGEFs) are the proteins that activate Ras and thus lie near the top of many signaling pathways. They are particularly important for signaling in development and chemotaxis in many organisms, including Dictyostelium.

Results

We have searched the genome for sequences encoding RasGEFs. Despite its relative simplicity, we find that the Dictyostelium genome encodes at least 25 RasGEFs, with a few other genes encoding only parts of the RasGEF consensus domains. All appear to be expressed at some point in development. The 25 genes include a wide variety of domain structures, most of which have not been seen in other organisms. The LisH domain, which is associated with microtubule binding, is seen particularly frequently; other domains that confer interactions with the cytoskeleton are also common. Disruption of a sample of the novel genes reveals that many have clear phenotypes, including altered morphology and defects in chemotaxis, slug phototaxis and thermotaxis.

Conclusion

These results suggest that the unexpectedly large number of RasGEF genes reflects an evolutionary expansion of the range of Ras signaling rather than functional redundancy or the presence of multiple pseudogenes.
New standards for reducing gravity data: The North American gravity database
Authors: Hinze William J. , Aiken Carlos , Brozena John , Coakley Bernard , Dater David , Flanagan Guy , Forsberg René , Hildenbrand Thomas , Keller G. Randy , Kellogg James , Kucks Robert , Li Xiong , Mainville Andre , Morin Robert , Pilkington Mark , Plouff Donald , Ravat Dhananjay , Roman Daniel , Urrutia-Fucugauchi Jamie , Véronneau Marc , Webring Michael , Winester Daniel
Published: July 2005

The North American gravity database as well as data-bases from Canada, Mexico, and the United States are being revised to improve their coverage, versatility, and accuracy. An important part of this effort is revising procedures for calculating gravity anomalies, taking into account our enhanced computational power, improved terrain databases and datums, and increased interest in more accurately defining long-wavelength anomaly components. Users of the databases may note minor differences between previous and revised database values as a result of these procedures. Generally, the differences do not impact the interpretation of local anomalies but do improve regional anomaly studies. The most striking revision is the use of the internationally accepted terrestrial ellipsoid for the height datum of gravity stations rather than the conventionally used geoid or sea level. Principal facts of gravity observations and anomalies based on both revised and previous procedures together with germane metadata will be available on an interactive Web-based data system as well as from national agencies and data centers. The use of the revised procedures is encouraged for gravity data reduction because of the widespread use of the global positioning system in gravity fieldwork and the need for increased accuracy and precision of anomalies and consistency with North American and national databases. Anomalies based on the revised standards should be preceded by the adjective “ellipsoidal” to differentiate anomalies calculated using heights with respect to the ellipsoid from those based on conventional elevations referenced to the geoid.
Gaussian beam migration of common-shot records
Authors: Gray Samuel H.
Published: July 2005

Gaussian beam migration is a depth migration method whose accuracy rivals that of migration by wavefield extrapolation — so-called “wave-equation migration” — and whose efficiency rivals that of Kirchhoff migration. This migration method can image complicated geologic structures, including very steep dips, in areas where the seismic velocity varies rapidly. However, applications of prestack Gaussian beam migration either have been limited to common-offset common-azimuth data volumes, and thus are inflexible, or suffer from multiarrival inaccuracies in a common-shot implementation. In order to optimize both the flexibility and accuracy of Gaussian beam migration, I present a common-shot implementation that handles multipathing in a natural way. This allows the migration of data sets that can include a variety of azimuths, and it allows a simplified treatment of near-surface issues. Application of this method to model data typical of Canadian Foothills structures and to model data that includes a complicated salt body demonstrates the accuracy and versatility of the migration.
Two-dimensional finite-difference seismic modeling of an open fluid-filled fracture: Comparison of thin-layer and linear-slip models
Authors: Wu Chunling , Harris Jerry M. , Nihei Kurt T. , Nakagawa Seiji
Published: July 2005

Within the context of seismic wave propagation, fractures can be described as thin layers or linear-slip interfaces. In this paper, numerical simulations of elastic wave propagation in a medium with a single fracture represented by these two models are performed by 2D finite-difference codes: a variable-grid isotropic code for the thin-layer model and a regular-grid anisotropic code for the linear-slip model. Numerical results show excellent agreement between the two models for wavefields away from the fracture; the only discrepancy between the two is the presence of a slow wave traveling primarily within the fracture fluid of the thin-layer model. The comparison of the computational cost shows that modeling of the linear-slip model is more efficient than that of the thin-layer model. This study demonstrates that the linear-slip model is an efficient and accurate modeling approach for the remote seismic characterization of fractures.
A moving hum filter to suppress rotor noise in high-resolution airborne magnetic data
Authors: Xia Jianghai , Doll William E. , Miller Richard D. , Gamey T. Jeffrey , Emond Abraham M.
Published: July 2005

A unique filtering approach is developed to eliminate helicopter rotor noise. It is designed to suppress harmonic noise from a rotor that varies slightly in amplitude, phase, and frequency and that contaminates aeromagnetic data. The filter provides a powerful harmonic noise-suppression tool for data acquired with modern large-dynamic-range recording systems. This three-step approach — polynomial fitting, bandpass filtering, and rotor-noise synthesis — significantly reduces rotor noise without altering the spectra of signals of interest. Two steps before hum filtering — polynomial fitting and bandpass filtering — are critical to accurately model the weak rotor noise. During rotor-noise synthesis, amplitude, phase, and frequency are determined. Data are processed segment by segment so that there is no limit on the length of data. The segment length changes dynamically along a line based on modeling results. Modeling the rotor noise is stable and efficient. Real-world data examples demonstrate that this method can suppress rotor noise by more than 95% when implemented in an aeromagnetic data-processing flow.
Imaging depth, structure, and susceptibility from magnetic data: The advanced source-parameter imaging method
Authors: Smith Richard S. , Salem Ahmed
Published: July 2005

An important problem in the interpretation of magnetic data is quantifying the source parameters that describe the anomalous structure. We present a new method that uses various combinations of the local wavenumbers for estimating the depth and shape (structural index) of the structure. Because the estimates are derived from third derivatives of the magnetic data, they are noisy. However, there are multiple ways of calculating the depth and index, and these solutions can be averaged to give a stable estimate. Even so, a synthetic test shows that the results are erratic away from the locations where the analytic-signal amplitude is large. Hence, when we generate images of the depth and structural index, we make the results most visible where the analytic-signal amplitude is large and less visible where the signal is small. The advantage of the method is that estimates can be obtained at all locations on a profile and used to generate continuous profiles or images of the source parameters. This can be used to help identify the locations where interference might be corrupting the results. The structural index image can be used to determine the most appropriate type of model for an area. Assuming this model, it is possible to calculate the depth that would be consistent with the model and the data. Knowing both the depth and model, the analytic-signal amplitude can be converted to apparent susceptibility. If a vertical-contact model is assumed, the susceptibility contrast across the contact can be imaged. For the thin-sheet and horizontal-cylinder models, we can image the susceptibility-thickness and susceptibility-area products, respectively.
Subsonic near-surface P-velocity and low S-velocity observations using propagator inversion
Authors: Vossen Robbert van , Curtis Andrew , Trampert Jeannot
Published: July 2005

Detailed knowledge of near-surface P- and S-wave velocities is important for processing and interpreting multicomponent land seismic data because (1) the entire wavefield passes through and is influenced by the near-surface soil conditions, (2) both source repeatability and receiver coupling also depend on these conditions, and (3) near-surface P- and S-wave velocities are required for wavefield decomposition and demultiple methods. However, it is often difficult to measure these velocities with conventional techniques because sensitivity to shallow-wave velocities is low and because of the presence of sharp velocity contrasts or gradients close to the earth's free surface. We demonstrate that these near-surface P- and S-wave velocities can be obtained using a propagator inversion. This approach requires data recorded by at least one multicomponent geophone at the surface and an additional multicomponent geophone at depth. The propagator between them then contains all information on the medium parameters governing wave propagation between the geophones at the surface and at depth. Hence, inverting the propagator gives local estimates for these parameters. This technique has been applied to data acquired in Zeist, the Netherlands. The near-surface sediments at this site are unconsolidated sands with a thin vegetation soil on top, and the sediments considered are located above the groundwater table. A buried geophone was positioned 1.05 m beneath receivers on the surface. Propagator inversion yielded low near-surface velocities, namely, 270 ± 15 m/s for the compressional-wave velocity, which is well below the sound velocity in air, and 150 ± 9 m/s for the shear velocity. Existing methods designed for imaging deeper structures cannot resolve these shallow material properties. Furthermore, velocities usually increase rapidly with depth close to the earth's surface because of increasing confining pressure. We suspect that for this reason, subsonic near-surface P-wave velocities are not commonly observed.
Processing of anisotropic data in the τ-pdomain: II — Common-conversion-point sorting
Authors: Baan Mirko van der
Published: July 2005

Common-conversion-point (CCP) sorting of P-SV converted-wave data is conventionally done by first sorting data into common asymptotic-conversion-point (CACP) gathers and then computing the involved CCP shifts from analytic approximations. I explore an alternative method where the latter step is replaced by an entirely data-driven approach. Moveout curves of correlated P-P and P-SV reflections in collocated CMP and CACP gathers are first scanned for points of equal slowness. A common-source slowness indicates that the downgoing branches of the P-P and P-SV waves overlap if the conversion occurs at the reflecting interface. The P-SV conversion point is then assumed to be situated underneath the associated P-P wave midpoint. A migration of amplitudes from CACP to CCP gathers is straightforward once the exact CCP position is known. This data-driven approach requires kinematic information only and is exact for laterally homogeneous media with arbitrary strength of anisotropy if horizontal symmetry planes are present at all depths. Both time-offset and τ-p domain implementations are possible, although the latter are preferred.
Field test of a permanent in-well fiber-optic seismic system
Authors: Hornby Brian E. , Bostick F. X. (Tad) , Williams Brock A. , Lewis Kristen A. , Garossino Paul G.
Published: July 2005

A deviated borehole was drilled and completed to test systems for deployment of permanent in-well three-component fiber-optic seismic sensors. Two systems were developed and tested for deployment of these sensors. The first system involved using a passive mandrel device to enable coupling of the sensors simply using the weight of the tubing. The second system involved use of an active mandrel that incorporates a spring-loaded pad device to isolate the sensor from the tubing vibration. In addition, reference wireline vertical-seismic-profile data were acquired both in the empty cased borehole and through the tubing at the same location as the fiber optic sensor. Analysis of the data showed that best results were obtained using the active design. Tubing-related resonances were noted on data acquired using the passive design, whereas the active design did a good job of discriminating among these undesirable signals.