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Biomedical subjects

S K Thompson

Publications and source records attributed to S K Thompson.

At least 19 recordsLinked to original sources
PubMed2000

Performance analysis of a new semiorthogonal spline wavelet compression algorithm for tonal medical images.

Lossy image compression is thought to be a necessity as radiology moves toward a filmless environment. Compression algorithms based on the discrete cosine transform (DCT) are limited due to the infinite support of the cosine basis function. Wavelets, basis functions that have compact or nearly compact support, are mathematically better suited for decorrelating medical image data. A lossy compression algorithm based on semiorthogonal cubic spline wavelets has been implemented and tested on six different image modalities (magnetic resonance, x-ray computed tomography, single photon emission tomography, digital fluoroscopy, computed radiography, and ultrasound). The fidelity of the reconstructed wavelet images was compared to images compressed with a DCT algorithm for compression ratios of up to 40:1. The wavelet algorithm was found to have generally lower average error metrics and higher peak-signal-to-noise ratios than the DCT algorithm.

Algorithms↗
PubMed1999

Structure-based design of non-peptide, carbohydrazide-based cathepsin K inhibitors.

Using binding models which were based on the X-ray crystal structure of an amino acid-based active site-spanning inhibitor complexed with cathepsin K, Cbz-leucine mimics have been developed, leading ultimately to the design of a potent cathepsin K inhibitor free of amino acid components. These mimics, which consist of alpha-substituted biphenylacetyl groups in place of Cbz-leucine moieties, effectively mimic all aspects of the Cbz-leucine moieties which are important for inhibitor binding. The predicted directions of binding for the inhibitors were confirmed by mass spectral analysis of their complexes with cathepsin K, which gave results consistent with acylation of the enzyme and loss of the acylhydrazine portion of the inhibitor which binds on the S' side of the active site. The binding models were found to be very predictive of relative inhibitor potency as well as direction of inhibitor binding. These results strengthen the validity of a strategy involving iterative cycles of structure-based design and inhibitor synthesis and evaluation for the discovery of non-peptide inhibitors.

Cathepsin K↗
PubMed1999

Potent dipeptidylketone inhibitors of the cysteine protease cathepsin K.

Cathepsin K (EC 3.4.22.38) is a cysteine protease of the papain superfamily which is selectively expressed within the osteoclast. Several lines of evidence have pointed to the fact that this protease may play an important role in the degradation of the bone matrix. Potent and selective inhibitors of cathepsin K could be important therapeutic agents for the control of excessive bone resorption. Recently a series of peptide aldehydes have been shown to be potent inhibitors of cathepsin K. In an effort to design more selective and metabolically stable inhibitors of cathepsin K, a series of electronically attenuated alkoxymethylketones and thiomethylketones inhibitors have been synthesized. The X-ray co-crystal structure of one of these analogues in complex with cathepsin K shows the inhibitor binding in the primed side of the enzyme active site with a covalent interaction between the active site cysteine 25 and the carbonyl carbon of the inhibitor.

Cathepsin B↗
PubMed1998

Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.

Papain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes.

Binding Sites↗
PubMed1998

Structure-based design of cathepsin K inhibitors containing a benzyloxy-substituted benzoyl peptidomimetic.

Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid-based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.

Benzoates↗
PubMed1997

Design of potent and selective human cathepsin K inhibitors that span the active site.

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.

Binding Sites↗
PubMed1997

Identification of a loop outside the active site cavity of the human immunodeficiency virus proteases which confers inhibitor specificity.

We have investigated the inhibitor specificity for the proteases of the human immunodeficiency viruses, types 1 and 2. Using a series of related inhibitors, the P1' side chain was confirmed to play a significant role in determining both the absolute and relative affinity for the enzymes. To further define the residues in the enzymes responsible for the difference in affinity, chimeric proteins were constructed in which domains of the respective proteases were exchanged at the genetic level. The results of these studies demonstrated that inhibitor affinity is conferred by a combination of the active site residues (32, 47, and 82) along with a loop comprised of residues 31 and 33-37, which lies outside of the active site cavity. These results are discussed in terms of existing structural data.

Amino Acid Sequence↗
PubMed1997

Cytologic diagnosis of Ki-1 lymphoma in pleural and peritoneal effusions: a case report.

This is a report of a case of Ki-1-positive large-cell anaplastic lymphoma in an 87-year-old man diagnosed on pleural and peritoneal fluids by cytomorphologic and immunohistochemical examination. Papanicolaou-stained smears revealed many single, large neoplastic cells containing one or two nuclei with occasional multinucleated cells having a wreath-like nuclear arrangement. The tumor cells expressed Ki-1 antigen and epithelial membrane antigen. This is the first known report of Ki-1 lymphoma diagnosed initially on cytologic examination of pleural and peritoneal fluids.

Aged↗
PubMed1997

Adaptive sampling in behavioral surveys.

Studies of populations such as drug users encounter difficulties because the members of the populations are rare, hidden, or hard to reach. Conventionally designed large-scale surveys detect relatively few members of the populations so that estimates of population characteristics have high uncertainty. Ethnographic studies, on the other hand, reach suitable numbers of individuals only through the use of link-tracing, chain referral, or snowball sampling procedures that often leave the investigators unable to make inferences from their sample to the hidden population as a whole. In adaptive sampling, the procedure for selecting people or other units to be in the sample depends on variables of interest observed during the survey, so the design adapts to the population as encountered. For example, when self-reported drug use is found among members of the sample, sampling effort may be increased in nearby areas. Types of adaptive sampling designs include ordinary sequential sampling, adaptive allocation in stratified sampling, adaptive cluster sampling, and optimal model-based designs. Graph sampling refers to situations with nodes (for example, people) connected by edges (such as social links or geographic proximity). An initial sample of nodes or edges is selected and edges are subsequently followed to bring other nodes into the sample. Graph sampling designs include network sampling, snowball sampling, link-tracing, chain referral, and adaptive cluster sampling. A graph sampling design is adaptive if the decision to include linked nodes depends on variables of interest observed on nodes already in the sample. Adjustment methods for nonsampling errors such as imperfect detection of drug users in the sample apply to adaptive as well as conventional designs.

Behavior↗
PubMed1997

Spatial sampling.

Sampling in a spatial setting is typically done for the purpose of estimating or predicting a population quantity such as the total of a variable in a study region, to predict a new value at an unobserved site, or to find regions of high values for further study. Spatial covariance and conditional variance patterns have led to the use of designs such as systematic and stratified arrangements to increase precision and cluster or multistage sampling to increase cost effectiveness. In addition, adaptive procedures can be used to take advantage of patterns not discovered prior to the survey. An adaptive sampling design is one in which the procedure for selecting sites or units to include in the sample can depend on values of the variable of interest observed during the survey. For example, in a survey of an unevenly distributed insect species, neighbouring sites may be added to the sample whenever high abundance of the insects is encountered. Examples of adaptive designs include adaptive cluster sampling and adaptive allocation. Issues of design optimality or effectiveness and choice of inference methods with different types of designs will be discussed.

Agriculture↗
PubMed1996

Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification.

Human cathepsin K is a recently identified protein with high primary sequence homology to members of the papain cysteine protease superfamily including cathepsins S, L, and B and is selectively expressed in osteoclasts (Drake, F.H., Dodds, R., James I., Connor J., Debouck, C., Richardson, S., Lee, E., Rieman, D., Barthlow, R., Hastings, G., and Gowen, M. (1996) J. Biol., Chem. 271, 12511-12516). To characterize its catalytic properties, cathepsin K has been expressed in baculovirus-infected SF21 cells and the soluble recombinant protein isolated from growth media was purified. Purified protein includes an inhibitory pro-leader sequence common to this family of protease. Conditions for enzyme activation upon removal of the pro-sequence have been identified. Fluorogenic peptides have been identified as substrates for mature cathepsin K. In addition, two protein components of bone matrix, collagen and osteonectin, have been shown to be substrates of the activated protease. Cathepsin K is inhibited by E-64 and leupeptin, but not for by pepstatin, EDTA, phenylmethylsulfonyl fluoride, or phenanthroline, consistent with its classification within the cysteine protease class. Leupeptin has been characterized as a slow binding inhibitor of cathepsin K (kobs/[I] = 273,000 m(-1).s(-1)). Cathepsin K may represent the elusive protease implicated in degradation of protein matrix during bone resorption and represents a novel molecular target in treatment of disease states associated with excessive bone loss such as osteoporosis.

Amino Acid Sequence↗
PubMed1996

Design and evaluation of small peptides mapping the exposed surface of IL-8.

In an effort to determine which regions of IL-8 are involved in interactions with its receptors, eight peptides were designed to correspond to distinct exposed regions of the IL-8 monomer, using the proton NMR-derived structure of the dimer as a basis. The peptides were evaluated singularly, and as equimolar mixtures of two to six peptides, in an IL-8 receptor binding assay and found to have no binding interaction with either alpha or beta IL-8 receptor as single peptides or mixtures of two peptides. In contrast, one of these peptides having the sequence AVLPRSAKEL, which corresponds to the N-terminal 10 amino acid residues of the 77 amino acid form of IL-8, exhibited potent chemotactic activity in human neutrophils. These results indicate that there is no contiguous ligand that can be designed based on the NMR and X-ray determined structure of IL-8 and that there may be multiple receptors responsible for neutrophil activation and chemotaxis.

Acetylation↗
PubMed1994

Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere.

The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-101/HIV-1 protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'--P2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of/Fc parallel/sigma magnitude of), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as an isosteric replacement for the P1'--P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.

Amides↗
PubMed1994

Paranuclear blue inclusions: an aid in the cytopathologic diagnosis of primary and metastatic pulmonary small-cell carcinoma.

Accurate diagnosis of small-cell carcinoma of the lung (SCLC) is clinically important because of the therapeutic implications. SCLC must be distinguished from non-small-cell carcinoma (NSCLC) and lymphoma. Paranuclear blue inclusions (PBIs) were recently described as a feature of metastatic SCLC on air-dried Wright-stained bone marrow aspirate smears. To determine the utility of PBIs in distinguishing SCLC from NSCLC and lymphoma, we evaluated air-dried Diff-Quik-stained smears from 103 fine-needle aspiration (FNA) specimens and 14 touch imprint specimens. PBIs were identified in 24 (89%) of 27 cases of SCLC, in 6 (9%) of 64 non-small-cell carcinomas (P < 0.00001), and in two (8%) of the 26 lymphoma cases (P < 0.00001). No PBIs were seen on any of the alcohol-fixed Papanicolaou or hematoxylin-eosin (H&E) stained smears examined. In conclusion, PBIs appear to be a feature of SCLC on air-dried cytologic material stained with Romanowsky type stains. In the presence of cytologic features of SCLC, the identification of PBIs provides a useful diagnostic feature for differentiating between SCLC and NSCLC carcinomas, and between SCLC and lymphomas in FNA specimens and touch imprints from surgical specimens.

Carcinoma, Non-Small-Cell Lung↗
PubMed1994

Detectability in conventional and adaptive sampling.

In this paper a simple but very general method is given for estimating a population total with any sampling design when objects in sampled units are observed with imperfect detectability--a problem characteristic of many surveys of natural and human populations. In the most general case, the method consists of dividing the value of the variable of interest associated with each detected object by the detection probability for that object and then proceeding to use the estimation method that would ordinarily be used under the design if there were no detectability problems. Examples illustrating the method include simple random sampling, conventional unequal probability sampling, and adaptive cluster sampling.

Analysis of Variance↗
PubMed1992

Radiation-induced changes in the breast: a potential diagnostic pitfall on fine-needle aspiration.

The authors report a case of fine-needle aspiration (FNA) of a breast mass in a 36-year-old woman with previous history of lumpectomy and therapeutic radiation for breast carcinoma. The changes seen were interpreted as recurrent carcinoma, while subsequent biopsy showed only radiation changes. Radiation-induced changes in breast tissue are a potential diagnostic pitfall. The characteristic cytopathologic changes and their differential diagnosis are discussed.

Adult↗