CiteULike: jyuh's Weinstein

PDZBase: a protein-protein interaction database for PDZ-domains.

T Beuming — 2006-11-07T22:54:22-00:00

Bioinformatics, Vol. 21, No. 6. (March 2005), pp. 827-828.

SUMMARY: PDZBase is a database that aims to contain all known PDZ-domain-mediated protein-protein interactions. Currently, PDZBase contains approximately 300 such interactions, which have been manually extracted from > 200 articles. The database can be queried through both sequence motif and keyword-based searches, and the sequences of interacting proteins can be visually inspected through alignments (for the comparison of several interactions), or as residue-based diagrams including schematic secondary structure information (for individual complexes).

Biochemistry. A postgenomic visual icon.

JN Weinstein — 2008-06-25T05:39:48-00:00

Science (New York, N.Y.), Vol. 319, No. 5871. (28 March 2008), pp. 1772-1773.

Ensuring the comparability of comparison groups: is randomization enough?

VW Berger — 2008-06-11T08:17:56-00:00

Controlled clinical trials, Vol. 25, No. 5. (October 2004), pp. 515-524.

BACKGROUND: It is widely believed that baseline imbalances in randomized trials must necessarily be random. In fact, there is a type of selection bias that can cause substantial, systematic and reproducible baseline imbalances of prognostic covariates even in properly randomized trials. It is possible, given complete data, to quantify both the susceptibility of a given trial to this type of selection bias and the extent to which selection bias appears to have caused either observable or unobservable baseline imbalances. Yet, in articles reporting on randomized trials, it is uncommon to find either these assessments or the information that would enable a reader to conduct them. Nevertheless, there have been a few published reports that contain descriptions of either this type of selection bias or indicators that it may have occurred. OBJECTIVE: To document that the same type of selection bias has been described in numerous randomized trials and therefore that it represents a problem deserving of greater attention. STUDY SELECTION: Computerized searches were not useful in locating trials with one or more elements that contribute to or are indicative of selection bias in randomized trials. We limit our treatment to trials that were previously questioned for susceptibility to selection bias or for large baseline imbalances. RESULTS: We found 14 randomized trials that appear to be suspicious for selection bias. This may represent only the tip of the iceberg, because the status of other trials is inconclusive. CONCLUSIONS: Authors of clinical trial reports should be required to disclose sufficient details to allow for an assessment of both allocation concealment and selection bias. The extent to which a randomized study was susceptible to selection bias should be considered in determining the relative contribution it makes to any subsequent meta-analysis, policy or decision.

Does Preventive Care Save Money? Health Economics and the Presidential Candidates

Joshua Cohen — 2008-05-30T09:19:12-00:00

N Engl J Med, Vol. 358, No. 7. (14 February 2008), pp. 661-663.

10.1056/NEJMp0708558

Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices--Modeling Studies.

MC Weinstein — 2008-05-20T02:38:56-00:00

Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, Vol. 6, No. 1. (b 2003), pp. 9-17.

OBJECTIVES: Mathematical modeling is used widely in economic evaluations of pharmaceuticals and other health-care technologies. Users of models in government and the private sector need to be able to evaluate the quality of models according to scientific criteria of good practice. This report describes the consensus of a task force convened to provide modelers with guidelines for conducting and reporting modeling studies. METHODS: The task force was appointed with the advice and consent of the Board of Directors of ISPOR. Members were experienced developers or users of models, worked in academia and industry, and came from several countries in North America and Europe. The task force met on three occasions, conducted frequent correspondence and exchanges of drafts by electronic mail, and solicited comments on three drafts from a core group of external reviewers and more broadly from the membership of ISPOR. RESULTS: Criteria for assessing the quality of models fell into three areas: model structure, data used as inputs to models, and model validation. Several major themes cut across these areas. Models and their results should be represented as aids to decision making, not as statements of scientific fact; therefore, it is inappropriate to demand that models be validated prospectively before use. However, model assumptions regarding causal structure and parameter estimates should be continually assessed against data, and models should be revised accordingly. Structural assumptions and parameter estimates should be reported clearly and explicitly, and opportunities for users to appreciate the conditional relationship between inputs and outputs should be provided through sensitivity analyses. CONCLUSIONS: Model-based evaluations are a valuable resource for health-care decision makers. It is the responsibility of model developers to conduct modeling studies according to the best practicable standards of quality and to communicate results with adequate disclosure of assumptions and with the caveat that conclusions are conditional upon the assumptions and data on which the model is built.

Adolescent idiopathic scoliosis.

SL Weinstein — 2008-05-09T03:00:55-00:00

Lancet, Vol. 371, No. 9623. (3 May 2008), pp. 1527-1537.

Adolescent idiopathic scoliosis (AIS) affects 1-3% of children in the at-risk population of those aged 10-16 years. The aetiopathogensis of this disorder remains unknown, with misinformation about its natural history. Non-surgical treatments are aimed to reduce the number of operations by preventing curve progression. Although bracing and physiotherapy are common treatments in much of the world, their effectiveness has never been rigorously assessed. Technological advances have much improved the ability of surgeons to safely correct the deformity while maintaining sagittal and coronal balance. However, we do not have long-term results of these changing surgical treatments. Much has yet to be learned about the general health, quality of life, and self-image of both treated and untreated patients with AIS.

Recent developments in decision-analytic modelling for economic evaluation.

MC Weinstein — 2008-04-07T01:51:05-00:00

PharmacoEconomics, Vol. 24, No. 11. (2006), pp. 1043-1053.

The past few years have seen rapid changes in the methods of decision-analytic modelling of healthcare programmes for the purposes of economic evaluation. This paper focuses on four developments in modelling that have emerged over the past few years or have become more widely used. First, no one optimal method for extrapolating outcomes from clinical trials has yet been established. Modellers may draw from a set of varied assumptions about survival extrapolation that encompass a range of possibilities from highly optimistic to extremely cautious. Secondly, the practicality and appeal of microsimulation as a method for analysing healthcare decision problems has increased dramatically with the speed of computing technology. Individual instantiations of a system are generated by using a random process to draw from probability distributions a large number of times (also known as Monte Carlo or probabilistic simulation). Microsimulation is moving in new directions, such as discrete-event simulations that simulate sequences of events by drawing directly from probability distributions of event times; this approach is now being broadly applied to model situations where populations of patients interact with healthcare delivery systems. Microsimulation modelling of transmission systems at the population level is also rapidly developing. Thirdly, model calibration is emerging as a new tool that may offer health scientists a means of generating important fundamental knowledge about disease processes. Model calibration allows evidence synthesis in which observations on observable quantities are used to draw inferences about unobservable quantities. The methodology of model calibration has advanced considerably, drawing on theories of numerical analysis and mathematical programming such as gradient methods, intelligent grid search algorithms, and many more. As a fourth issue, an area of extraordinary activity is in the use of transmission models to analyse interventions for infectious diseases, including population-wide effects of vaccination. Transmission models use differential equations to simulate, deterministically for the most part, transitions among infection-related health states. Only recently have modelling methodologies been combined so that cost-effectiveness analyses can consider explicitly not only the patient-level benefits of interventions but also the secondary benefits through transmission dynamics. Advances in technology allow more realistic and complex healthcare models to be simulated more rapidly. However, decision makers will not readily accept results from models unless they can understand them intuitively and explain them to others in relatively simple terms. The challenge for the next generation of modellers is not only to harness the power available from these newly accessible methods, but also to extract from the new generation of models the insights that will have the power to influence decision makers.

VennMaster: Area-proportional Euler diagrams for functional GO analysis of microarrays

Hans Kestler — 2008-01-30T07:46:41-00:00

BMC Bioinformatics, Vol. 9, No. 1. (2008)

BACKGROUND:Microarray experiments generate vast amounts of data. The functional context of differentially expressed genes can be assessed by querying the Gene Ontology (GO) database via GoMiner. Directed acyclic graph representations, which are used to depict GO categories enriched with differentially expressed genes, are difficult to interpret and, depending on the particular analysis, may not be well suited for formulating new hypotheses. Additional graphical methods are therefore needed to augment the GO graphical representation. RESULTS:We present an alternative visualization approach, area-proportional Euler diagrams, showing set relationships with semi-quantitative size information in a single diagram to support biological hypothesis formulation. The cardinalities of sets and intersection sets are represented by area-proportional Euler diagrams and their corresponding graphical (circular or polygonal) intersection areas. Optimally proportional representations are obtained using swarm and evolutionary optimization algorithms. CONCLUSIONS:VennMasteras area-proportional Euler diagrams effectively structure and visualize the results of a GO analysis by indicating to what extent flagged genes are shared by different categories. In addition to reducing the complexity of the output, the visualizations facilitate generation of novel hypotheses from the analysis of seemingly unrelated categories that share differentially expressed genes.

Inhibition of interleukin-10 by the immunomodulator AS101 reduces mesangial cell proliferation in experimental mesangioproliferative glomerulonephritis: association with dephosphorylation of STAT3.

Y Kalechman — 2008-01-21T14:06:55-00:00

J Biol Chem, Vol. 279, No. 23. (4 June 2004), pp. 24724-24732.

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of glomerular disease. Using an acute model of mesangial proliferative glomerulonephritis (Thy1 GN), we show that neutralization of interleukin (IL)-10 greatly ameliorated the disease as expressed by both decreased MC expansion and proteinuria. Treatment with the tellurium compound AS101 (ammonium trichloro(dioxoethylene-o,o')tellurate) resulted in favorable effects provided that the compound was administered 24 h before insult, whereas partial effects were obtained when administered after insult. We identified STAT3 as playing a pivotal role in IL-10-induced MC proliferation in vitro and in vivo. IL-10 activates MC STAT3 in vitro as expressed by its phosphorylation and nuclear translocation. The role of STAT3 in MC proliferation induced by IL-10 was deduced from results showing that IL-10-induced proliferation was abrogated if MC transfected with STAT3 antisense oligonucleotides were used or if cells were incubated with inhibitors of STAT3. AS101 deactivates STAT3 in control but not in MC transfected with IL-10 antisense oligonucleotides. Inactivation of STAT3 prevents reduction of MC proliferation by AS101. We further demonstrate the role of STAT3 in the regulation of cell cycle and survival regulatory proteins by AS101 in MC via inhibition of IL-10. IL-10 increased MC expression of Bcl-2 and Bcl-X1 and simultaneously decreased the levels of p27kip1. These survival factors were decreased by AS101 in a STAT3- and IL-10-dependent manner, whereas p27kip1 was similarly increased. In Thy1 GN, phosphorylated STAT3 in glomerular MC peaked at day 6 and correlated with MC expansion. Neutralization of IL-10 or its inhibition by AS101 abolished phosphorylation of STAT3. This effect positively correlated with amelioration of the disease. These in vitro and in vivo studies indicate that the autocrine MC growth factor IL-10 induces MC proliferation via STAT3. We suggest that IL-10 or its downstream target STAT3 might be therapeutic targets for kidney diseases induced by mesangial proliferation.

Mechanisms of Disease: oncogene addiction: a rationale for molecular targeting in cancer therapy

Bernard Weinstein — 2008-01-01T03:29:49-00:00

Nat Clin Prac Oncol, Vol. 3, No. 8. (2006), pp. 448-457.

Guidelines on the use of therapeutic apheresis in clinical practice - Evidence-based approach from the apheresis applications committee of the American society for apheresis

Zbigniew Szczepiorkowski — 2007-12-10T02:38:35-00:00

Journal of Clinical Apheresis, Vol. 22, No. 3. (2007), pp. 106-175.

The American Society for Apheresis (ASFA) Apheresis Applications Committee is charged with a review and categorization of indications for therapeutic apheresis. This elaborate process had been undertaken every 7 years resulting in three prior publications in 1986, 1993, and 2000 of ?The ASFA Special Issues.? This article is the integral part of the Fourth ASFA Special Issue. The Fourth ASFA Special Issue is significantly modified in comparison to the previous editions. A new concept of a fact sheet has been introduced. The fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis. A detailed description of the fact sheet is provided. The article consists of 53 fact sheets devoted to each disease entity currently categorized by the ASFA. Categories I, II, and III are defined as previously in the Third Special Issue. However, a few new therapeutic apheresis modalities, not yet approved in the United States or are currently in clinical trials, have been assigned category P (pending) by the ASFA Clinical Categories Subcommittee. The diseases assigned to category IV are discussed in a separate article in this issue. J. Clin. Apheresis., 2007 © 2007 Wiley-Liss, Inc.

Effectiveness of chlorhexidine bathing to reduce catheter-associated bloodstream infections in medical intensive care unit patients.

SC Bleasdale — 2007-10-25T14:56:41-00:00

Arch Intern Med, Vol. 167, No. 19. (22 October 2007), pp. 2073-2079.

OBJECTIVE: To determine whether patients bathed daily with chlorhexidine gluconate (CHG) have a lower incidence of primary bloodstream infections (BSIs) compared with patients bathed with soap and water. METHODS: The study design was a 52-week, 2-arm, crossover (ie, concurrent control group) clinical trial with intention-to-treat analysis. The study setting was the 22-bed medical intensive care unit (MICU), which comprises 2 geographically separate, similar 11-bed units, of the John H. Stroger Jr (Cook County) Hospital, a 464-bed public teaching hospital in Chicago, Illinois. The study population comprised 836 MICU patients. During the first of 2 study periods (28 weeks), 1 hospital unit was randomly selected to serve as the intervention unit in which patients were bathed daily with 2% CHG-impregnated washcloths (Sage 2% CHG cloths; Sage Products Inc, Cary, Illinois); patients in the concurrent control unit were bathed daily with soap and water. After a 2-week wash-out period at the end of the first period, cleansing methods were crossed over for 24 more weeks. Main outcome measures included incidences of primary BSIs and clinical (culture-negative) sepsis (primary outcomes) and incidences of other infections (secondary outcomes). RESULTS: Patients in the CHG intervention arm were significantly less likely to acquire a primary BSI (4.1 vs 10.4 infections per 1000 patient days; incidence difference, 6.3 [95% confidence interval, 1.2-11.0). The incidences of other infections, including clinical sepsis, were similar between the units. Protection against primary BSI by CHG cleansing was apparent after 5 or more days in the MICU. CONCLUSION: Daily cleansing of MICU patients with CHG-impregnated cloths is a simple, effective strategy to decrease the rate of primary BSIs.

Transcript and protein expression profiles of the NCI-60 cancer cell panel: an integromic microarray study.

UT Shankavaram — 2007-07-03T15:57:06-00:00

Mol Cancer Ther, Vol. 6, No. 3. (March 2007), pp. 820-832.

To evaluate the utility of transcript profiling for prediction of protein expression levels, we compared profiles across the NCI-60 cancer cell panel, which represents nine tissues of origin. For that analysis, we present here two new NCI-60 transcript profile data sets (A based on Affymetrix HG-U95 and HG-U133A chips; Affymetrix, Santa Clara, CA) and one new protein profile data set (based on reverse-phase protein lysate arrays). The data sets are available online at http://discover.nci.nih.gov in the CellMiner program package. Using the new transcript data in combination with our previously published cDNA array and Affymetrix HU6800 data sets, we first developed a "consensus set" of transcript profiles based on the four different microarray platforms. Using that set, we found that 65% of the genes showed statistically significant transcript-protein correlation, and the correlations were generally higher than those reported previously for panels of mammalian cells. Using the predictive analysis of microarray nearest shrunken centroid algorithm for functional prediction of tissue of origin, we then found that (a) the consensus mRNA set did better than did data from any of the individual mRNA platforms and (b) the protein data seemed to do somewhat better (P = 0.027) on a gene-for-gene basis in this particular study than did the consensus mRNA data, but both did well. Analysis based on the Gene Ontology showed protein levels of structure-related genes to be well predicted by mRNA levels (mean r = 0.71). Because the transcript-based technologies are more mature and are currently able to assess larger numbers of genes at one time, they continue to be useful, even when the ultimate aim is information about proteins.

Multiplexing siRNAs to compress RNAi-based screen size in human cells.

Scott E Martin — 2007-04-12T12:31:57-00:00

Nucleic Acids Res (28 March 2007)

Here we describe a novel strategy using multiplexes of synthetic small interfering RNAs (siRNAs) corresponding to multiple gene targets in order to compress RNA interference (RNAi) screen size. Before investigating the practical use of this strategy, we first characterized the gene-specific RNAi induced by a large subset (258 siRNAs, 129 genes) of the entire siRNA library used in this study ( approximately 800 siRNAs, approximately 400 genes). We next demonstrated that multiplexed siRNAs could silence at least six genes to the same degree as when the genes were targeted individually. The entire library was then used in a screen in which randomly multiplexed siRNAs were assayed for their affect on cell viability. Using this strategy, several gene targets that influenced the viability of a breast cancer cell line were identified. This study suggests that the screening of randomly multiplexed siRNAs may provide an important avenue towards the identification of candidate gene targets for downstream functional analyses and may also be useful for the rapid identification of positive controls for use in novel assay systems. This approach is likely to be especially applicable where assay costs or platform limitations are prohibitive.

AbMiner: a bioinformatic resource on available monoclonal antibodies and corresponding gene identifiers for genomic, proteomic, and immunologic studies.

SM Major — 2007-08-18T04:30:15-00:00

BMC Bioinformatics, Vol. 7 (2006)

BACKGROUND: Monoclonal antibodies are used extensively throughout the biomedical sciences for detection of antigens, either in vitro or in vivo. We, for example, have used them for quantitation of proteins on "reverse-phase" protein lysate arrays. For those studies, we quality-controlled > 600 available monoclonal antibodies and also needed to develop precise information on the genes that encode their antigens. Translation among the various protein and gene identifier types proved non-trivial because of one-to-many and many-to-one relationships. To organize the antibody, protein, and gene information, we initially developed a relational database in Filemaker for our own use. When it became apparent that the information would be useful to many other researchers faced with the need to choose or characterize antibodies, we developed it further as AbMiner, a fully relational web-based database under MySQL, programmed in Java. DESCRIPTION: AbMiner is a user-friendly, web-based relational database of information on > 600 commercially available antibodies that we validated by Western blot for protein microarray studies. It includes many types of information on the antibody, the immunogen, the vendor, the antigen, and the antigen's gene. Multiple gene and protein identifier types provide links to corresponding entries in a variety of other public databases, including resources for phosphorylation-specific antibodies. AbMiner also includes our quality-control data against a pool of 60 diverse cancer cell types (the NCI-60) and also protein expression levels for the NCI-60 cells measured using our high-density "reverse-phase" protein lysate microarrays for a selection of the listed antibodies. Some other available database resources give information on antibody specificity for one or a couple of cell types. In contrast, the data in AbMiner indicate specificity with respect to the antigens in a pool of 60 diverse cell types from nine different tissues of origin. CONCLUSION: AbMiner is a relational database that provides extensive information from our own laboratory and other sources on more than 600 available antibodies and the genes that encode the antibodies' antigens. The data will be made freely available at http://discover.nci.nih.gov/abminer.

AffyProbeMiner: a web resource for computing or retrieving accurately redefined Affymetrix probe sets.

Hongfang Liu — 2007-08-18T04:19:50-00:00

Bioinformatics (27 July 2007)

MOTIVATION: Affymetrix microarrays are widely used to measure global expression of mRNA transcripts. That technology is based on the concept of a probe set. Individual probes within a probe set were originally designated by Affymetrix to hybridize with the same unique mRNA transcript. Because of increasing accuracy in knowledge of genomic sequences, however, a substantial number of the manufacturer's original probe groupings and mappings are now known to be inaccurate and must be corrected. Otherwise, analysis and interpretation of an Affymetrix microarray experiment will be in error. RESULTS: AffyProbeMiner is a computationally-efficient platform-independent tool that uses all RefSeqs and validated complete coding sequences in GenBank to (1) regroup the individual probes into consistent probe sets and (2) remap the probe sets to the correct sets of mRNA transcripts. The individual probes are grouped into probe sets that are 'transcript-consistent' in that they hybridize to the same mRNA transcript (or transcripts) and, therefore, measure the same entity (or entities). About 65.6% of the probe sets on the HG-U133A chip were affected by the remapping. Pre-computed regrouped and remapped probe sets for many Affymetrix microarrays are made freely available at the AffyProbeMiner web site. Alternatively, we provide a web service that enables the user to perform the remapping for any type of short-oligo commercial or custom array that has an Affymetrix-format Chip Definition File (CDF). Important features that differentiate AffyProbeMiner from other approaches are flexibility in the handling of splice variants, computational efficiency, extensibility, customizability, and user-friendliness of the interface. AVAILABILITY: The web interface and software (GPL open source license), are publicly-accessible at http://discover.nci.nih.gov/affyprobeminer. CONTACT: hl224@georgetown.edu or barry@discover.nci.nih.gov.

Low back pain.

RA Deyo — 2007-06-22T08:40:11-00:00

N Engl J Med, Vol. 344, No. 5. (1 February 2001), pp. 363-370.

Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts.

E Piek — 2007-07-25T07:19:25-00:00

J Biol Chem, Vol. 276, No. 23. (8 June 2001), pp. 19945-19953.

A prominent pathway of transforming growth factor (TGF)-beta signaling involves receptor-dependent phosphorylation of Smad2 and Smad3, which then translocate to the nucleus to activate transcription of target genes. To investigate the relative importance of these two Smad proteins in TGF-beta1 signal transduction, we have utilized a loss of function approach, based on analysis of the effects of TGF-beta1 on fibroblasts derived from mouse embryos deficient in Smad2 (S2KO) or Smad3 (S3KO). TGF-beta1 caused 50% inhibition of cellular proliferation in wild-type fibroblasts as assessed by [(3)H]thymidine incorporation, whereas the growth of S2KO or S3KO cells was only weakly inhibited by TGF-beta1. Lack of Smad2 or Smad3 expression did not affect TGF-beta1-induced fibronectin synthesis but resulted in markedly suppressed induction of plasminogen activator inhibitor-1 by TGF-beta1. Moreover, TGF-beta1-mediated induction of matrix metalloproteinase-2 was selectively dependent on Smad2, whereas induction of c-fos, Smad7, and TGF-beta1 autoinduction relied on expression of Smad3. Investigation of transcriptional activation of TGF-beta-sensitive reporter genes in the different fibroblasts showed that activation of the (Smad binding element)(4)-Lux reporter by TGF-beta1 was dependent on expression of Smad3, but not Smad2, whereas activation of the activin response element-Lux reporter was strongly suppressed in S2KO fibroblasts but, on the contrary, enhanced in S3KO cells. Our findings indicate specific roles for Smad2 and Smad3 in TGF-beta1 signaling.