Gene/Protein Disease Symptom Drug Enzyme Compound
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We prospectively assessed and compared the usefulness of 11C-choline positron emission tomography (PET) with that of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET for the differentiation between benign and malignant tumors. A total of 126 patients with 130 lesions were studied (25 brain tumors, 51 head and neck tumors, 15 bone tumors, 16 lung tumors, and 23 soft tissue tumors). 11C-choline PET and FDG PET were performed from 5 and 40 min, respectively, after injection of 275-370 MBq tracer. PET data were evaluated using the standardized uptake value (SUV) and were analyzed in accordance with the pathologic data. The 11C-choline uptake in malignancies was 3.9+/-2.3 (n=81), which was significantly higher than that in benign lesions (n=49) (2.6+/-1.7, P<0.005). The FDG uptake in malignancies was 5.9+/-3.8 (n=81) and was also significantly higher than that in benign lesions (2.8+/-2.0, P<0.0001). The 11C-choline uptake in the lesions correlated with FDG uptake (r=0.65, P<0.003). According to an ROC analysis, the areas under the ROC curves (AUCs) for 11C-choline PET were more than 0.8 in bone, head and neck, lung, and soft tissue tumors, while the AUC was 0.79 in brain tumors. The AUCs for FDG PET were similarly more than 0.8 in bone, head and neck, lung, and soft tissue tumors, but had a lower value of 0.585 in brain tumors. In brain, head and neck, bone, and soft tissue tumors, 11C-choline showed higher contrast than FDG. In conclusion, it is feasible to use 11C-choline PET for differentiation between malignant and benign tumours, especially of the brain, head and neck, bone, and soft tissue. However, attention needs to be drawn to the high uptake of 11C-choline in some benign tumors and tumour-like lesions, as this will be of significance in clinical practice.
Eur J Nucl Med Mol Imaging 2004 Aug
PMID:Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors. 1501 3

Antigenic peptide is presented to a T-cell receptor through the formation of a stable complex with a Major Histocompatibility Complex (MHC) molecule. Various predictive algorithms have been developed to estimate a peptide's capacity to form a stable complex with a given MHC Class II allele, a technique integral to the strategy of vaccine design. These have previously incorporated such computational techniques as quantitative matrices and neural networks. We have developed a novel predictive technique that uses molecular modeling of predetermined crystal structures to estimate the stability of an MHC Class II peptide complex. This is the 1st structure-based technique, as previous methods have been based on binding data. ROC curves are used to quantify the accuracy of the molecular modeling technique. The novel predictive technique is found to be comparable with the best predictive software currently available.
Mol Med
PMID:A novel predictive technique for the MHC class II peptide-binding interaction. 1520 43

Stimulation of the tracheal muscle bundle by acetylcholine (ACh) results in the generation of asynchronous repetitive Ca2+ waves (ACW) in intact tracheal smooth muscle (TSM) cells. We showed previously that ACW underlie cholinergic excitation-contraction coupling in porcine TSM and that Ca2+ entry through the L-type voltage-gated Ca2+ channel (VGCC) contributes partially to maintenance of the ACW. However, the mechanism of the ACW remains undefined. In this study, we pharmacologically characterized the mechanism of ACh-induced ACW in the intact porcine tracheal muscle bundle. We found that inhibition of receptor-operated channels/store-operated channels (ROC/SOC) by SKF-96365 completely abolished the nifedipine-insensitive component of ACh-mediated ACW and tonic contraction. Blockade of Na+/Ca2+ exchange with KB-R7943 or 2',4'-dichlorobenzamil or removal of extracellular Na+ resulted in nearly complete inhibition of the nifedipine-insensitive component of ACh-mediated ACW and tonic contraction. Inhibition of the sarco(endo)plasmic reticulum Ca2+-ATPase by cyclopiazonic acid abolished the ongoing ACW. Application of 2-aminoethoxydiphenyl borate (2-APB) or xestospongin C to inhibit the inositol 1,4,5-trisphosphate-sensitive sarcoplasmic reticulum (SR) Ca2+ release channels produced no effect on ACh-mediated ACW and tonic contraction. However, pretreatment with caffeine or ryanodine inhibited ACh-induced ACW. Furthermore, application of procaine or tetracaine prevented the generation and abolished the ongoing ACh-mediated ACW and tonic contraction. Collectively, these results indicate that the ACh-stimulated ACW in porcine TSM are produced by repetitive cycles of Ca2+ release from SR through 2-APB- and xestospongin C-insensitive Ca2+ release channels, and plasmalemmal Ca2+ entry involving reverse-mode Na+/Ca2+ exchange, ROC/SOC, and L-type VGCC is required to refill the SR via SERCA to support the ongoing ACW.
Am J Physiol Lung Cell Mol Physiol 2006 Mar
PMID:Mechanism of ACh-induced asynchronous calcium waves and tonic contraction in porcine tracheal muscle bundle. 1621 18

Both inflammatory and anti-inflammatory cytokines have been reported to be associated with acute graft-versus-host disease (aGVHD). However, their role and possible mutual interactions during aGVHD are not well understood. Eight patients with aGVHD and eight without who had undergone allogeneic HLA-identical peripheral blood stem cell transplantation were studied. The patients had no other complications known to affect serum concentration of cytokines, including infection. Serum concentrations of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma were concurrently measured by a new technique, the cytometric bead array (CBA). We found that serum concentrations of IL-5, IL-6 and IL-10 were significantly higher in patients with aGVHD than in patients without it. By ratiometric analysis, the ratios of IL-5/IL-2, IL-5/IL-4, IL-6/IL-4 in patients with aGVHD were increased compared to the patients with no evidence of aGVHD. ROC analysis demonstrated that the ratio of IL-5/IL-4 was the most sensitive parameter associated with aGVHD. The second best marker of aGVHD was increased IL-5 concentration. Thus, our results indicate that the ratio of a particular cytokine/cytokine could be a potential diagnostic marker for aGVHD, more sensitive that the serum level of a given cytokine. This observation is consistent with a cross-talk among some cytokines and their possible interactions via respective receptors on cytokine-producing cells; these interactions may play an important role in pathogenesis of aGVHD. Further studies including a large number of patients and concurrent measurement of a variety of cytokines are needed to fully assess the diagnostic value of the cytokine ratiometric analysis. The CBA methodology provides a convenient and useful tool in such studies.
Int J Mol Med 2006 May
PMID:Serum cytokine concentrations and acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: concurrent measurement of ten cytokines and their respective ratios using cytometric bead array. 1659 75

In this paper, we propose a novel method for sparse logistic regression with non-convex regularization Lp (p <1). Based on smooth approximation, we develop several fast algorithms for learning the classifier that is applicable to high dimensional dataset such as gene expression. To the best of our knowledge, these are the first algorithms to perform sparse logistic regression with an Lp and elastic net (Le) penalty. The regularization parameters are decided through maximizing the area under the ROC curve (AUC) of the test data. Experimental results on methylation and microarray data attest the accuracy, sparsity, and efficiency of the proposed algorithms. Biomarkers identified with our methods are compared with that in the literature. Our computational results show that Lp Logistic regression (p <1) outperforms the L1 logistic regression and SCAD SVM. Software is available upon request from the first author.
Stat Appl Genet Mol Biol 2007
PMID:Sparse logistic regression with Lp penalty for biomarker identification. 1740 21

Saquinavir (SQV) was the first HIV-1 PR inhibitor licensed for clinical use and widely used for acquired immunodeficiency syndrome (AIDS) therapy. Its effectiveness, however, has been hindered by the emergence of resistant mutations. The two most important HIV-1 PR mutants are G48V and G48V/L90M. Inhibition studies of SQV on these mutants demonstrated 13.5- and 419-fold reductions of susceptibility, respectively. In this study, an analysis of energetic binding affinity between saquinavir and the HIV-1 PR wild-type and these two mutants has been performed in detail based on density functional theory and the hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. We have found that the interaction of SQV with flap residue 48 of the mutants is significantly perturbed, as shown by the reduced stability of binding between SQV and residue 48 for the G48V and G48V/L90M mutants over the wild-type. This was associated with conformational changes of the inhibitor and the enzyme, leading to the loss of hydrogen bonding between the binding subsite P2 and the backbone carbonyl of residue 48. Moreover, the G48V/L90M mutations cause the repositioning of the residues close to residues 48 and 90, at important locations as a part of the flap and catalytic regions, respectively. The repositioning of these residues consequently perturbed the binding affinity of SQV in the pocket as indicated by the decreasing interaction energies. In addition to the loss of inhibitor/enzyme binding, it is interesting to observe that the mutation leads significantly to an increase of the stability of the enzyme.
J Mol Graph Model 2007 Nov
PMID:Insight into analysis of interactions of saquinavir with HIV-1 protease in comparison between the wild-type and G48V and G48V/L90M mutants based on QM and QM/MM calculations. 1754 58

Although lysophosphatidic acid (LPA) is known to increase intracellularfree calcium concentration ([Ca(2+)](i)) in different cell types, the effect of LPA on the skeletal muscle cells is not known. The present study was therefore undertaken to examine the effect of LPA on the [Ca(2+)](i) in C2C12 cells. LPA induced a concentration and time dependent increase in [Ca(2+)](i), which was inhibited by VPC12249, VPC 32183 and dioctanoyl glycerol pyrophosphate, LPA1/3 receptor antagonists. Pertussis toxin, a G(i) protein inhibitor, also inhibited the LPA-induced increase in [Ca(2+)](i). Inhibition of tyrosine kinase activities with tyrphostin A9 and genistein also prevented the increase in [Ca(2+)](i) due to LPA. Likewise, wortmannin and LY 294002, phosphatidylinositol 3-kinase (PI3-K) inhibitors, inhibited [Ca(2+)](i) response to LPA. The LPA effect was also attenuated by ethylene glycolbis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), an extracellular Ca(2+) chelator, Ni(2+) and KB-R7943, inhibitors of the Na(+)-Ca(2+) exchanger; the receptor operated Ca(2+) channel (ROC) blockers, 2-aminoethoxydiphenyl borate and SK&F 96365. However, the L-type Ca(2+) channel blockers, verapamil and diltiazem; the store operated Ca(2+) channel blockers, La(3+) and Gd(3+); a sarcoplasmic reticulum calcium pump inhibitor, thapsigargin; an inositol trisphosphate receptor antagonist, xestospongin and a phospholipase C inhibitor, U73122, did not prevent the increase [Ca(2+)](i) due to LPA. Our data suggest that the LPA-induced increase in [Ca(2+)](i) might occur through G(i)-protein coupled LPA(1/3) receptors that may be linked to tyrosine kinase and PI3-K, and may also involve the Na(+)-Ca(2+) exchanger as well as the ROC. In addition, LPA stimulated C2C12 cell proliferation via PI3-K. Thus, LPA may be an important phospholipid in the regulation of [Ca(2+)](i) and growth of skeletal muscle cells.
J Cell Mol Med 2008 Jun
PMID:Mechanisms of the lysophosphatidic acid-induced increase in [Ca(2+)](i) in skeletal muscle cells. 1849 35

In a significant work, Dobson and Doig (J Mol Biol 2003, 330, 771) illustrated protein prediction as enzymatic or not from spatial structure without resorting to alignments. They used 52 protein features and a nonlinear support vector machine model to classify more than 1000 proteins collected from the PDB with a 77% overall accuracy. The most useful features were: the secondary-structure content, the amino acid frequencies, the number of disulphide bonds, and the largest cleft size. Working on the same dataset used by D&D, in this article we reported a good and simple model, based on the Markov chain models (MCM), to classify protein 3D structures as enzymatic or not, taking into consideration the spatial structure without resorting to alignments. Here we define, for the first time, a general MCM to calculate the electrostatic potential, molecular vibrations, van der Waals (vdw) interactions, and hydrophobic interactions (HINT) and use them in comparative studies of potential fields and/or protein function prediction. The dataset is composed of 1371 proteins divided into 689 enzymes and 682 nonenzymes, all proteins were collected from the PDB. The best model we found was a linear model carried out with the linear discriminant analysis; it was able to classify 74.18% of the proteins using only two electrostatic potentials. In the work described here, we define 3D-HINT potentials (mu(k)) and use them for the first time to derive a classifier for protein enzymes. We analyzed ROC curves, domain of applicability, parametric assumptions, desirability maps, and also tested other nonlinear artificial neural network models which did not improve the linear model. In closing, this MCM allows a fast calculation and comparison of different potentials deriving into accurate protein 3D structure-function relationships, notably simpler than the previous.
 ...
PMID:Computational chemistry study of 3D-structure-function relationships for enzymes based on Markov models for protein electrostatic, HINT, and van der Waals potentials. 1908 60

New parameters that could be used as tumor markers for lung cancer would be valuable. Our aim was to analyze the fatty acid profiles of total lipids from erythrocytes and platelets from patients with advanced non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD) and asthma to reveal the fatty acids that could be used as NSCLC biomarkers. In our study, 50, 15 and 15 patients with advanced NSCLC, COPD and asthma and 50 healthy subjects were enrolled. Fatty acid profiles were investigated using gas chromatography/mass spectrometry followed by ROC (receiver operating characteristics) curves analysis to gain information about biomarkers. Sialic acid (SA) and cytokeratins were measured by the thiobarbituric acid and immunoradiometric methods respectively. Useful fatty acid markers were as follows: erythrocytes, 22:0 and linoleic acid (LA, 18:2n6); platelets, 16:0, 18:0, and LA. At the cutoff value to obtain maximum accuracy, the best biomarker was platelet LA, with higher diagnostic yields than the commonly used markers SA or cytokeratins (100%, 76%, 75% and 86% sensitivity, specificity, positive predictive value and accuracy, respectively). These findings suggest that platelet LA might be used as a biomarker of NSCLC in relation to different aspects of the disease process that now needs to be explored.
Exp Mol Pathol 2009 Dec
PMID:Platelet linoleic acid is a potential biomarker of advanced non-small cell lung cancer. 1973 67

Rapid overlay of chemical structures (ROCS) is a method that aligns molecules based on shape and/or chemical similarity. It is often used in 3D ligand-based virtual screening. Given a query consisting of a single conformation of an active molecule ROCS can generate highly enriched hit lists. Typically the chosen query conformation is a minimum energy structure. Can better enrichment be obtained using conformations other than the minimum energy structure? To answer this question a methodology has been developed called CORAL (COnformational analysis, Rocs ALignment). For a given set of molecule conformations it computes optimized conformations for ROCS screening. It does so by clustering all conformations of a chosen molecule set using pairwise ROCS combo scores. The best representative conformation is that which has the highest average overlap with the rest of the conformations in the cluster. It is these best representative conformations that are then used for virtual screening. CORAL was tested by performing virtual screening experiments with the 40 DUD (Directory of Useful Decoys) data sets. Both CORAL and minimum energy queries were used. The recognition capability of each query was quantified as the area under the ROC curve (AUC). Results show that the CORAL AUC values are on average larger than the minimum energy AUC values. This demonstrates that one can indeed obtain better ROCS enrichments with conformations other than the minimum energy structure. As a result, CORAL analysis can be a valuable first step in virtual screening workflows using ROCS.
J Comput Aided Mol Des 2009 Dec
PMID:Computation of 3D queries for ROCS based virtual screens. 1982 Sep 2


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