CiteULike: jyuh's Reeves

Integrating biological data - the Distributed Annotation System

Andrew Jenkinson — 2008-07-31T06:44:03-00:00

BMC Bioinformatics, Vol. 9, No. Suppl 8. (2008)

BACKGROUND:The Distributed Annotation System (DAS) is a widely adopted protocol for dynamically integrating a wide range of biological data from geographically diverse sources. DAS continues to expand its applicability and evolve in response to new challenges facing integrative bioinformatics.RESULTS:Here we describe the various infrastructure components of DAS and present a new extended version of the DAS specification. Version 1.53E incorporates several recent developments, including its extension to serve new data types and an ontology for protein features.CONCLUSION:Our extensions to the DAS protocol have facilitated the integration of new data types, and our improvements to the existing DAS infrastructure have addressed recent challenges. The steadily increasing numbers of available data sources demonstrates further adoption of the DAS protocol.

Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

K Rikova — 2008-01-24T11:57:39-00:00

Cell, Vol. 131, No. 6. (14 December 2007), pp. 1190-1203.

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity

Binzhi Zhang — 2008-04-29T04:14:58-00:00

J Am Soc Nephrol, Vol. 19, No. 5. (1 May 2008), pp. 923-932.

The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(-/-)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(-/-) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(-/-) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-alpha and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans. 10.1681/ASN.2007090982

Netrin-1 is an early biomarker of acute kidney injury.

W Brian Reeves — 2008-03-04T08:55:44-00:00

Am J Physiol Renal Physiol (30 January 2008)

Acute kidney injury is an important complication in hospitalized patients often diagnosed late and associated with high mortality and morbidity. Although biomarkers for nephrotoxicity are available, they often lack sensitivity and specificity for detecting tubular injury. Netrin-1 is a laminin like molecule highly expressed in many organs including kidney. To determine the value of netrin-1 as a biomarker of renal injury, we analyzed its urinary excretion following ischemia reperfusion, cisplatin, folic acid and endotoxin induced renal injury in mice. Urinary netrin-1 levels increased markedly within 3 hours of ischemia reperfusion (40+/-14 fold, p0.01 vs. baseline), reached a peak level at 6 hours and decreased thereafter, returning to near baseline by 72 hours. Serum creatinine significantly increased only after 24 hours of reperfusion. Similarly, in cisplatin, folic acid and lipopolysaccharide treated mice, urine netrin-1 excretion increased as early as 1 hour and reached a peak level at 6 hours after injection. However, serum creatinine was raised significantly after 6, 24 and 72 hours after folic acid, lipopolysaccharide and cisplatin administration respectively. NGAL excretion in folic acid and lipopolysaccharide treated mice urine samples could only be detected by 24 hours after drug administration. Furthermore, urinary netrin-1 excretion increased dramatically in 13 acute renal failure patients whereas none was detected in 6 healthy volunteer urine samples. Immunohistochemical localization showed that netrin-1 is highly expressed in tubular epithelial cells in transplanted human kidney. We conclude that urinary netrin-1 is a promising early biomarker of renal injury. Key words: Netrin-1, Biomarker, Acute renal failure, cisplatin, Folic Acid.

caCORE version 3: Implementation of a model driven, service-oriented architecture for semantic interoperability.

George A Komatsoulis — 2007-07-30T15:49:18-00:00

J Biomed Inform (2 April 2007)

One of the requirements for a federated information system is interoperability, the ability of one computer system to access and use the resources of another system. This feature is particularly important in biomedical research systems, which need to coordinate a variety of disparate types of data. In order to meet this need, the National Cancer Institute Center for Bioinformatics (NCICB) has created the cancer Common Ontologic Representation Environment (caCORE), an interoperability infrastructure based on Model Driven Architecture. The caCORE infrastructure provides a mechanism to create interoperable biomedical information systems. Systems built using the caCORE paradigm address both aspects of interoperability: the ability to access data (syntactic interoperability) and understand the data once retrieved (semantic interoperability). This infrastructure consists of an integrated set of three major components: a controlled terminology service (Enterprise Vocabulary Services), a standards-based metadata repository (the cancer Data Standards Repository) and an information system with an Application Programming Interface (API) based on Domain Model Driven Architecture. This infrastructure is being leveraged to create a Semantic Service-Oriented Architecture (SSOA) for cancer research by the National Cancer Institute's cancer Biomedical Informatics Grid (caBIGtrade mark).

Cerebrospinal fluid analysis.

DA Seehusen — 2006-09-07T08:10:04-00:00

Am Fam Physician, Vol. 68, No. 6. (15 September 2003), pp. 1103-1108.

Lumbar puncture is frequently performed in primary care. Properly interpreted tests can make cerebrospinal fluid (CSF) a key tool in the diagnosis of a variety of diseases. Proper evaluation of CSF depends on knowing which tests to order, normal ranges for the patient's age, and the test's limitations. Protein level, opening pressure, and CSF-to-serum glucose ratio vary with age. Xanthochromia is most often caused by the presence of blood, but several other conditions should be considered. The presence of blood can be a reliable predictor of subarachnoid hemorrhage but takes several hours to develop. The three-tube method, commonly used to rule out a central nervous system hemorrhage after a "traumatic tap," is not completely reliable. Red blood cells in CSF caused by a traumatic tap or a subarachnoid hemorrhage artificially increase the white blood cell count and protein level, thereby confounding the diagnosis. Diagnostic uncertainty can be decreased by using accepted corrective formulas. White blood cell differential may be misleading early in the course of meningitis, because more than 10 percent of cases with bacterial infection will have an initial lymphocytic predominance and viral meningitis may initially be dominated by neutrophils. Culture is the gold standard for determining the causative organism in meningitis. However, polymerase chain reaction is much faster and more sensitive in some circumstances. Latex agglutination, with high sensitivity but low specificity, may have a role in managing partially treated meningitis. To prove herpetic, cryptococcal, or tubercular infection, special staining techniques or collection methods may be required.

A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

RR MacLehose — 2007-08-12T09:16:18-00:00

Health Technol Assess, Vol. 4, No. 34. (2000), pp. 1-154.

BACKGROUND: There is controversy about the value of evidence about the effectiveness of healthcare interventions from non-randomised study designs. Advocates for quasi-experimental and observational (QEO) studies argue that evidence from randomised controlled trials (RCTs) is often difficult or impossible to obtain, or is inadequate to answer the question of interest. Advocates for RCTs point out that QEO studies are more susceptible to bias and refer to published comparisons that suggest QEO estimates tend to find a greater benefit than RCT estimates. However, comparisons from the literature are often cited selectively, may be unsystematic and may have failed to distinguish between different explanations for any discrepancies observed. OBJECTIVES: The aim was to investigate the association between methodological quality and the magnitude of estimates of effectiveness by comparing systematically estimates of effectiveness derived from RCTs and QEO studies. Quantifying any such association should help healthcare decision-makers to judge the strength of evidence from non-randomised studies. Two strategies were used to minimise the influence of differences in external validity between RCTs and QEO studies: a comparison of the RCT and QEO study estimates of effectiveness of any intervention, where both estimates were reported in a single paper a comparison of the RCT and QEO study estimates of effectiveness for specified interventions, where the estimates were reported in different papers. The authors also sought to identify study designs that have been proposed to address one or more of the problems often found with conventional RCTs. METHODS: DATA SOURCES: Relevant literature was identified from: The Cochrane Library, MEDLINE, EMBASE, DARE, and the Science Citation Index. References of relevant papers already identified experts. Electronic searches were very difficult to design and yielded few papers for the first strategy and when identifying study designs. CHOICE OF INTERVENTIONS TO REVIEW FOR STRATEGIES 1 AND 2: For strategy 1, any intervention was eligible. For strategy 2, interventions for which the population, intervention and outcome investigated were anticipated to be homogeneous across studies were selected for review: Mammographic screening (MSBC) of women to reduce mortality from breast cancer. Folic acid supplementation (FAS) to prevent neural tube defects in women trying to conceive. DATA EXTRACTION AND QUALITY ASSESSMENT: Data were extracted by the first author and checked by the second author. Disagreements were negotiated with reference to the paper concerned. For strategy 1, study quality was scored using a checklist to assess whether the RCT and QEO study estimates were derived from the same populations, whether the assessment of outcomes was 'blinded', and the extent to which the QEO study estimate took account of possible confounding. For strategy 2, a more detailed instrument was used to assess study quality on four dimensions: the quality of reporting, the generalisability of the results, and the extent to which estimates of effectiveness may have been subject to bias or confounding. All quality assessments were carried out by three people. DATA SYNTHESIS AND ANALYSIS: For strategy 1, pairs of comparisons between RCT and QEO study estimates were classified as high or low quality. Seven indices of the size of discrepancies between estimates of effect size and outcome frequency were calculated, where possible, for each comparison. Distributions of the size and direction of discrepancies were compared for high- and low-quality comparisons. FOR STRATEGY 2, THREE ANALYSES WERE CARRIED OUT: Attributes of the instrument were described by k statistics, percentage agreement, and Cronbach's a values. Regression analyses were used to investigate -variations in study quality. (ABSTRACT TRUNCATED)

Relationship between number of medical conditions and quality of care.

T Higashi — 2007-07-12T10:09:22-00:00

N Engl J Med, Vol. 356, No. 24. (14 June 2007), pp. 2496-2504.

BACKGROUND: There is emerging concern that the methods used to measure the quality of care unfairly penalize providers caring for patients with multiple chronic conditions. We therefore sought to study the relationship between the quality of care and the number of medical conditions a patient has. METHODS: We assessed measurements of the quality of medical care received in three cohorts of community-dwelling adult patients in the Community Quality Index study, the Assessing Care of Vulnerable Elders study, and the Veterans Health Administration project (7680 patients in total). We analyzed the relationship between the quality of care that patients received, defined as the percentage of quality indicators satisfied among those for which patients were eligible, and the number of chronic medical conditions each patient had. We further explored the roles of characteristics of patients, use of health care (number of office visits and hospitalizations), and care provided by specialists as explanations for the observed relationship. RESULTS: The quality of care increased as the number of medical conditions increased. Each additional condition was associated with an increase in the quality score of 2.2% (95% confidence interval [CI], 1.7 to 2.7) in the Community Quality Index cohort, of 1.7% (95% CI, 1.1 to 2.4) in the Assessing Care of Vulnerable Elders cohort, and of 1.7% (95% CI, 0.7 to 2.8) in the Veterans Health Administration cohort. The relationship between the quality of care and the number of conditions was little affected by adjustment for the difficulty of delivering the care recommended in a quality indicator and for the fact that, because of multiple conditions requiring the same care, a patient could be eligible to receive the same care process more than once. Adjustment for characteristics of patients, use of health care, and care provided by specialists diminished the relationship, but it remained positive. CONCLUSIONS: The quality of care, measured according to whether patients were offered recommended services, increases as a patient's number of chronic conditions increases.