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Biomedical subjects

D C Sullivan

Publications and source records attributed to D C Sullivan.

At least 19 recordsLinked to original sources
PubMed2003

New molecular pathways in angiogenesis.

Angiogenesis has developed into a major area of cancer research. Recently, several newly identified signalling pathways have been shown to play a role in both normal and pathological (including tumour) angiogenesis. Several of the molecules involved in these pathways have potential as novel anti-cancer therapeutic targets including members of the ephrin/Eph receptor, Notch/delta, sprouty, hedgehog and roundabout/slit families. These developments are reviewed.

Ephrins↗
PubMed2001

Conformation spaces of proteins.

We report a simple method for measuring the accessible conformational space explored by an ensemble of protein structures. The method is useful for diverse ensembles derived from molecular dynamics trajectories, molecular modeling, and molecular structure determinations. It can be used to examine a wide range of time scales. The central tactic we use, which has been previously employed, is to replace the true mechanical degrees of freedom of a molecular system with the conformationally effective degrees of freedom as measured by the root-mean squared cartesian distances among all pairs of conformations. Each protein conformation is treated as a point in a high dimensional euclidean space. In this article, we model this space in a novel way by representing it as an N-dimensional hypercube, describable with only two parameters: the number of dimensions and the edge length. To validate this approach, we provide a number of elementary test cases and then use the N-cube method for measuring the size and shape of conformational space covered by molecular dynamics trajectories spanning 10 orders of magnitude in time. These calculations were performed on a small protein, the villin headpiece subdomain, exploring both the native state and the misfolded/folding regime. Distinct features include single, vibrationally averaged, substate minima on the 0.1-1-ps time scale, thermally averaged conformational states that persist for 1-100 ps and transitions between these local minima on nanosecond time scales. Large-scale refolding modes appear to become uncorrelated on the microsecond time scale. Associated length scales for these events are 0.2 A for the vibrational minima; 0.5 A for the conformational minima; and 1-2 A for the nanosecond events. We find that the conformational space that is dynamically accessible during folding of villin has enough volume for approximately 10(9) minima of the variety that persist for picoseconds. Molecular dynamics trajectories of the native protein and experimentally derived solution ensembles suggest the native state to be composed of approximately 10(2) of these thermally accessible minima. Thus, based on random exploration of accessible folding space alone, protein folding for a small protein is predicted to be a milliseconds time scale event. This time can be compared with the experimental folding time for villin of 10-100 micros. One possible explanation for the 10-100-fold discrepancy is that the slope of the "folding funnel" increases the rate 1-2 orders of magnitude above random exploration of substates.

Algorithms↗
PubMed2001

National Cancer Institute initiative: Lung image database resource for imaging research.

Preliminary clinical studies suggest that spiral computed tomography (CT) of the lungs can improve early detection of lung cancer in high-risk individuals. More clinical studies are needed, however, before public health recommendations can be proposed for population-based screening. Spiral CT generates large-volume data sets and thus poses problems in terms of implementation of efficient and cost-effective screening methods. Image processing algorithms such as computer assisted diagnostic (CAD) methods have the potential to assist in lesion (eg, nodule) detection on spiral CT studies. CAD methods may also be used to characterize nodules by either assessing the stability or change in size of lesions based on evaluation of serial CT studies, or quantitatively measuring the temporal parameters related to contrast dynamics when using contrast material-enhanced CT studies. CAD methods therefore have the potential to enhance the sensitivity and specificity of spiral CT lung screening studies. Lung cancer screening studies now under investigation create an opportunity to develop an image database that will allow comparison and optimization of CAD algorithms. This database could serve as an important national resource for the academic and industrial research community that is currently involved in the development of CAD methods. The National Cancer Institute request for applications (RFA) (CA-01-001) has already been announced (April 2000) to establish and support a consortium of academic centers to develop this database, the consortium to be referred to as the Lung Image Database Consortium (LIDC). This RFA is now closed. Five academic sites have been selected to be members of the LIDC, the first meeting of this consortium is planned for spring of 2001, and a public meeting is to be held in 2002. This report is abstracted from the previously published RFA to serve as an example of how an initiative is developed by the National Cancer Institute to support a research resource. For specific details of the RFA, please access the following Internet site: http://www. nci.nih.gov/bip/NCI-DIPinisumm.htm#a11.

Algorithms↗
PubMed2001

In vivo imaging of gene expression.

Imaging of gene expression is increasingly essential for cancer diagnosis, prediction of tumor response to various available therapies, and for monitoring response to therapy, whether it is gene or nongene therapy. Most of the work on developing techniques and methodologies for imaging gene expression has been performed in mice. Sophisticated small animal imaging technologies have been developed for this purpose. Imaging of gene expression in humans is still very limited. Nuclear medicine, positron-emission tomography, magnetic resonance imaging, and optical methods are the modalities that have shown preliminary utility in imaging gene expression. Two major imaging strategies have been investigated: using marker genes encoding either intracellular enzymes or cell-surface receptors. The first approach exploits the ability of certain enzymes to modify imaging prodrugs, so that tissue accumulation of such drugs reflects the expression. The second approach uses cell-surface expression of ligand-binding receptors that can be detected using imaging tracers. In this review, we summarize some of the imaging techniques that have been developed to detect gene expression.

Animals↗
PubMed1999

A sequential chart for the audit-based evaluation of screening mammogram interpretation.

RATIONALE AND OBJECTIVES: Auditing has received much attention recently as a method for radiologists to use to evaluate their interpretation of screening mammograms. U.S. Food and Drug Administration regulations require that some sort of audit be in place before a mammography screening facility can receive accreditation. Auditing presents a unique opportunity to monitor accuracy continually and identify problems early. Audit data present unique challenges, however, and appropriate methods must be used to control the risk of errors. MATERIALS AND METHODS: This article introduces a simple method for the task of deciding if a radiologist yields an acceptable positive predictive value based on audit. The method is based on "sequential" decision-making techniques that have found wide application in quality control problems. These techniques are developed for diagnostic radiology and embodied in an easy-to-use decision-making chart. RESULTS: Several examples, based on audit data from actual mammography facilities, provide insights into the use of these charts and the influence of (a) the selection of standards, (b) the selection of error risks, and (c) radiologist variability. The examples also serve to demonstrate another important property of this method--that is, it specifies the minimum amount of data that has to be collected before any decision can reliably be made. CONCLUSION: The chart presented in this article provides a method by which audit data can be used objectively to evaluate the accuracy of screening mammogram interpretation. The method controls the risk of either falsely accepting an unqualified radiologist or falsely rejecting a qualified radiologist. It should be a useful tool to radiologists who must evaluate their own practices.

Female↗
PubMed1999

How experience and training influence mammography expertise.

RATIONALE AND OBJECTIVES: The authors evaluated the influence of perceptual and cognitive skills in mammography detection and interpretation by testing three groups representing different levels of mammography expertise in terms of experience, training, and talent with a mammography screening-diagnostic task. MATERIALS AND METHODS: One hundred fifty mammograms, composed of unilateral cranial-caudal and mediolateral oblique views, were displayed in pairs on a digital workstation to 19 radiology residents, three experienced mammographers, and nine mammography technologists. One-third of the mammograms showed malignant lesions; two-thirds were malignancy-free. Observers interacted with the display to indicate whether each image contained no malignant lesions or suspicious lesions indicating malignancy. Decision time was measured as the lesions were localized, classified, and rated for decision confidence. RESULTS: Compared with performance of experts, alternative free response operating characteristic performance for residents was significantly lower and equivalent to that of technologists. Analysis of overall performance showed that, as level of expertise decreased, false-positive results exerted a greater effect on overall decision accuracy over the time course of image perception. This defines the decision speed-accuracy relationship that characterizes mammography expertise. CONCLUSION: Differences in resident performance resulted primarily from lack of perceptual-learning experience during mammography training, which limited object recognition skills and made it difficult to determine differences between malignant lesions, benign lesions, and normal image perturbations. A proposed solution is systematic mentor-guided training that links image perception to feedback about the reasons underlying decision making.

Analysis of Variance↗
PubMed1999

BI-RADS categorization as a predictor of malignancy.

PURPOSE: To determine the positive predictive value (PPV) of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories 0, 2, 3, 4, and 5 by using BI-RADS terminology and by auditing data on needle localizations. MATERIALS AND METHODS: Between April 1991 and December 1996, 1,400 mammographically guided needle localizations were performed in 1,109 patients. Information entered into the mammographic database included where the initial mammography was performed (inside vs outside the institution), BI-RADS category, mammographic finding, and histopathologic findings. A recorded recommendation was available for 1,312 localizations in 1,097 patients, who composed the study population. RESULTS: The 1,312 localizations yielded 449 (34%) cancers (139 [31%] were ductal carcinoma in situ [DCIS]; 310 [69%] were invasive cancers) and 863 (66%) benign lesions. There were 15 (1%) category 0 lesions; the PPV was 13% (two of 15 lesions). There were 50 (4%) category 2 lesions; the PPV was 0% (0 of 40 lesions). There were 141 (11%) category 3 lesions; the PPV was 2% (three of 141 lesions). The three cancers in this group were all non-comedotype DCIS. There were 936 (71%) category 4 lesions; the PPV was 30% (279 of 936 lesions). There were 170 (13%) category 5 lesions; the PPV was 97% (165 of 170 lesions). CONCLUSION: Placing mammographic lesions into BI-RADS categories is useful for predicting the presence of malignancy. Perhaps, most important, a lesion placed into BI-RADS category 3 is highly predictive of benignity, and short-term interval follow-up as an alternative to biopsy would decrease the number of biopsies performed in benign lesions.

Biopsy↗
PubMed1998

Susceptibilities of clinical and laboratory isolates of Blastomyces dermatitidis to ketoconazole, itraconazole, and fluconazole.

Eighteen isolates of Blastomyces dermatitidis were evaluated for their in vitro susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges were 0.1 to 0.4 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 2.5 to 4.0 microg/ml for fluconazole. The ranges for the minimal lethal concentrations were 0.2 to 0.8 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 10 to 40 microg/ml for fluconazole. Itraconazole was the most active agent against B. dermatitidis in vitro, while fluconazole was the least active. These results correlate with the clinical efficacies noted to date with doses of these agents used to treat blastomycosis.

Antifungal Agents↗