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PubMed1993

A unified framework for using neural networks to build QSARs.

We propose a new neural network architecture that explicitly separates linear and nonlinear contributions to the biological activity. To facilitate the use of neural networks as a regular tool we demonstrate that (1) a perceptron with linear output units is equivalent to multiple linear regression and (2) one hidden unit at a time can be added to the network so that QSAR data can be modeled by everything from the simplest linear hypersurfaces to complicated ones. The significant improvements accrued by the use of weight decay are demonstrated. We conclude that models built without attempting weight decay may not be reliable either for interpretation or extrapolation. Finally we compare models generated by neural networks, rank regression, and standard regression on non-normally distributed data and conclude that neural networks like rank regression bring out many facets of the data that are inaccessible to multiple linear regression. All the experiments were done on either triazine inhibition of pure DHFR from L1210 leukemia cells and on the inhibition of intact L1210 leukemia cells sensitive and resistant to methotrexate or on steroid binding to progesterone.

Animals↗
PubMed2000

Deriving a quantitative chirality measure from molecular similarity indices.

A versatile new method has been developed as a continuous symmetry measure for chiral compounds. The application of principal component analysis (PCA) to the complete N x N pairwise similarity matrices (electrostatic potential and shape indices) of a series of dihydropyridine calcium channel antagonists allowed to single out a chirality component and to compute a chirality score in terms of the between-enantiomers difference on the component value. The possibility to have chirality defined continuously at the series level could be of importance in eudismic analyses where the relative potency of two enantiomers is studied as well as in QSAR studies dealing with chiral molecules in order to improve the power of the generated models.

Calcium Channel Blockers↗
PubMed1991

Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase.

The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.

Angiotensin II↗
PubMed2002

Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents.

We report the inhibition of a human recombinant geranylgeranyl diphosphate synthase (GGPPSase) by 23 bisphosphonates and six azaprenyl diphosphates. The IC50 values range from 140 nM to 690 microM. None of the nitrogen-containing bisphosphonates that inhibit farnesyl diphosphate synthase were effective in inhibiting the GGPPSase enzyme. Using three-dimensional quantitative structure-activity relationship/comparative molecular field analysis (CoMFA) methods, we find a good correlation between experimental and predicted activity: R2 = 0.938, R(cv)2 = 0.900, R(bs)2 = 0.938, and F-test = 86.8. To test the predictive utility of the CoMFA approach, we used three training sets of 25 compounds each to generate models to predict three test sets of three compounds. The rms pIC50 error for the nine predictions was 0.39. We also investigated the pharmacophore of these GGPPSase inhibitors using the Catalyst method. The results demonstrated that Catalyst predicted the pIC50 values for the nine test set compounds with an rms error of 0.28 (R2 between experimental and predicted activity of 0.948).

Alkyl and Aryl Transferases↗
PubMed1996

Synthesis and contractile activities of cyclic thrombin receptor-derived peptide analogues with a Phe-Leu-Leu-Arg motif: importance of the Phe/Arg relative conformation and the primary amino group for activity.

Based on the minimal peptide sequence (Phe-Leu-Leu-Arg) that has been found to exhibit biological activity in a gastric smooth muscle contractile assay for thrombin receptor-activating peptides, the cyclic peptide analogues cyclo(Phe-Leu-Leu-Arg-Acp) (1), cyclo(Phe-Leu-Leu-Arg-epsilon Lys) (2), and cyclo(Phe-Leu-Leu-Arg-Gly) (3) have been synthesized by the solid-phase method using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoroborate or 2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate as cyclization reagents. The contractile activities of compounds 1-3 have been compared with that of the linear thrombin receptor-activating peptide (TRAP) Ser-Phe-Leu-Leu-Arg-NH2 (compound 4) using a gastric smooth muscle strip assay. Compound 2, wherein the epsilon-amino group of lysine was coupled to the alpha-carboxyl of arginine, exhibited a contractile activity comparable to that of the linear TRAP, compound 4. However compound 1, wherein the aminocaproic linker group yielded a ring size the same as for compound 2 but without a primary amino group, exhibited a contractile activity 600-1000-fold lower than compounds 2 and 4. Compound 3, which exhibited partial agonist activity, was about 100-fold less potent than either compound 2 or 4. NMR spectroscopy of compound 2 revealed a proximity of the Phe and Arg side chains, leading to a molecular model generated by distance geometry and molecular dynamics, wherein the Phe and Arg residues are shown in proximity on the same side of the peptide ring. We conclude that the Phe and Arg side chains along with the primary amino group form an active recognition motif that is augmented by the presence of a primary amino group in the cyclic peptide. We suggest that a comparable cyclic conformation may be responsible for the interaction of linear TRAPs with the thrombin receptor.

Amino Acid Sequence↗
PubMed2004

Effect of surface composition on the adsorption of photosystem I onto alkanethiolate self-assembled monolayers on gold.

We have used self-assembled monolayers (SAMs) prepared from omega-terminated alkanethiols on gold to generate model surfaces and examine the effect of surface composition on the adsorption of Photosystem I (PSI), stabilized in aqueous solution by Triton X-100. Triton-stabilized PSI adsorbs to high-energy surfaces prepared from HO- and HO2C-terminated alkanethiols but does not adsorb to low-energy surfaces. The inhibition of PSI adsorption at low-energy surfaces is consistent with the presence of a layer of Triton X-100 that adsorbs atop the hydrophobic SAM and presents a protein-resistant poly(ethylene glycol) (PEG) surface. While the presence of the PEG surface prevents the adsorption of PSI, the displacement of the inhibiting layer of Triton X-100 by dodecanol, a more active surfactant, greatly enhances the adsorption of PSI. This inhibiting effect by Triton X-100 can be extended to other protein systems such as bovine serum albumin.

Journal Article↗
PubMed2000

What drove changes in the use of breast conserving surgery since the early 1980s? The role of the clinical trial, celebrity action and an NIH consensus statement.

BACKGROUND: Three important events in the history of breast cancer treatment occurred between 1983 and 1995: a large clinical trial, first lady Nancy Reagan's choice of mastectomy and the publishing of an NIH consensus statement. OBJECTIVE: To assess the effects of these events on use of breast conserving surgery (BCS). RESEARCH DESIGN: Data from the cohort study of the surveillance, epidemiology and end results (SEER) Program from 1983 to 1995 were divided into four periods: Baseline, Trial, Celebrity, and Consensus. SUBJECTS: Of the women, 169,466 diagnosed with early stage breast cancer in nine SEER areas. MEASURES: Monthly percentages of BCS. RESULTS: A linear regression model generated a separate intercept and slope term for four time periods, adjusting for demographic characteristics of breast cancer patients. For the Baseline, Celebrity and Consensus Periods, slopes indicated an increasing use of BCS which varied between 0.24% and 0.28% per month. Slopes for these three periods were not statistically different (p = 0.120). In contrast, there was no change in use of BCS during the trial period (p = 0.247). We tested the magnitude of discontinuity between periods. At the beginning of the trial, celebrity and consensus periods, there were increases in BCS of 5.54% (p < 0.001), -3.55% (p < 0.001), and 2.37% (p < 0.001), respectively. CONCLUSIONS: The use of BCS was substantially affected by the reports of a clinical trial of BCS and by celebrity action. These effects were abrupt but transient. The NIH consensus statement stimulated a small change in use of BCS and may be an important intervention for maintaining the increasing trend in use of BCS since the 1990s.

Adult↗
PubMed1999

Regulation of the apolipoprotein B in heterozygous hypobetalipoproteinemic knock-out mice expressing truncated apoB, B81. Low production and enhanced clearance of apoB cause low levels of apoB.

Low levels of cholesterol are protective against development of coronary artery disease. Heterozygous hypobetalipoproteinemic individuals expressing truncated apolipoprotein (apo)B as a result of mutation in the apob gene have low levels of cholesterol and apoB in their plasma. To study the molecular mechanism of low levels of apoB in these individuals, we employed a previously reported knock out mouse model generated by targeted modification of the apob gene. The heterozygous, apoB-100/B-81, mice express full length and truncated apoB, B-81, and have 20 and 35% lower levels of total cholesterol and apoB, respectively, when compared to WT (apoB-100/B-100) mice. The majority of the truncated apoB, B-81, fractionated in the VLDL- density range. The mechanism of low levels of apoB in B-100/B-81 mice was examined. Total hepatic apoB mRNA levels decreased by 15%, primarily due to lower levels of apoB-81 mRNA. Since apoB mRNA transcription rates were similar in B-100/B-100 and B-100/B-81 mice, low levels of mutant apoB-81 mRNA occurred by enhanced degradation of apoB mRNA transcript containing premature translational stop codon. ApoB synthesis measured on isolated hepatocytes decreased in B-100/B-81 mice by 35%, while apoB-48, apoE, and apoAI syntheses remained unchanged. Metabolic studies using whole animal showed a 32% decrease in triglyceride secretion rates, consistent with the apoB secretion rates. Inhibition of receptor-mediated clearance of apoB-81-containing particles resulted in greater relative accumulation of apoB-81 in plasma than apoB-100, suggesting enhanced clearance of apoB-81-containing particles. These results demonstrate that low levels of apoB in heterozygous hypobetalipoproteinemic mice occurs by low rates of apoB secretion, and increased clearance of truncated apoB. Similar mechanisms appear to contribute to low levels of apoB in hypobetalipoproteinemic humans.

Animals↗
PubMed2001

Data mining with decision trees for diagnosis of breast tumor in medical ultrasonic images.

To increase the ability of ultrasonographic (US) technology for the differential diagnosis of solid breast tumors, we describe a novel computer-aided diagnosis (CADx) system using data mining with decision tree for classification of breast tumor to increase the levels of diagnostic confidence and to provide the immediate second opinion for physicians. Cooperating with the texture information extracted from the region of interest (ROI) image, a decision tree model generated from the training data in a top-down, general-to-specific direction with 24 co-variance texture features is used to classify the tumors as benign or malignant. In the experiments, accuracy rates for a experienced physician and the proposed CADx are 86.67% (78/90) and 95.50% (86/90), respectively.

Breast Neoplasms↗
PubMed2003

Factor structure of the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire evaluated in patients with heartburn predominant reflux disease.

AIM: To test whether the original factor structure of the Quality of Life in Reflux and Dyspepsia (QOLRAD) can be replicated in Nordic patients and English speaking patients. PATIENTS AND METHODS: Clinical trial patients with heartburn without esophagitis completed the Swedish, Norwegian, Finnish and Danish versions (n = 634) and the English version (n = 1185). The factor structure was examined using models generated by exploratory and confirmatory factor analysis. RESULTS: The exploratory factor analysis suggested that the original five-factor structure solution was the most optimal. The Nordic versions explained 67% and the English version 72% of the variance. The factor loading of 22 out of 25 items was >0.55. In the confirmatory factor analysis, because of the sample size, only the Swedish and Norwegian data were used. Confirmatory factor analysis indicated an acceptable goodness of fit of the five-factor solution to the data with a goodness of fit index of 0.85 in the Swedish, 0.77 in the Norwegian and 0.91 in the English speaking population. The internal consistency reliability ranged from 0.70 to 0.94 (in the Nordic translations) and from 0.85 to 0.92 (in the English version), supporting the homogeneity of the items within the factors and thus their construct validity. The QOLRAD distinguished severity and frequency of heartburn, thereby documenting its known-group validity to distinguish between groups of patients. CONCLUSIONS: The factor structure and dimensionality of the English version and the Swedish and Norwegian translations of the QOLRAD could be replicated by the exploratory and confirmed by the confirmatory factor analysis. The QOLRAD is a valid and reliable instrument for use in clinical trials.

Adolescent↗
PubMed2001

[Measuring fatigue of cancer patients in the German-speaking region: development of the Fatigue Assessment Questionnaire].

UNLABELLED: Fatigue is recognised as one of the most frequent and distressing symptoms of patients with cancer. Whilst causal relationships mainly remain unclear, researchers meanwhile acknowledge its multidimensional nature. Causes and manifestations are complex and multifaceted and therefore, measurement in the past has been difficult. In recent years, some instruments have been developed in the English language. It is the aim of this article to describe the development of a new fatigue measurement instrument in the German language, the Fatigue Assessment Questionnaire. The following steps are described: 1. Concept analysis, 2. Identification of measurement criteria, 3. Comparison of these criteria with those described in the literature available, 4. Construction of a measurement scale, 5. Testing the new instrument, 6. Use of the instrument in a large study population. Steps 5 and 6 primarily deal with validity and reliability testing while step 6 also tests the hypothesis that patients with some types and stages of cancer suffer more from distressing fatigue than patients with other types and stages. CONCLUSION: Validity of the measurement items in the Fatigue Assessment Questionnaire was supported by the fact that they were derived from qualitative interviews with cancer patients. The first test with 77 cancer patients and 77 healthy individuals led to small adaptations and the following study, including 592 cancer patients, supported the reliability and validity of the Fatigue Assessment Questionnaire. It was able to distinguish between different populations. Factor analyses supported the earlier generated model of physical, affective and cognitive fatigue. Internal consistency of the questionnaire was supported by the Alpha Coefficient 0.90 (Cronbach). A difference was found in physical tiredness for patients with different types of cancer (p = 0.008) but this was not the case for affective and cognitive tiredness. More fatigue feelings were experienced by cancer patients with advanced disease than by patients in remission and this was true for physical fatigue (p = 0.0001), affective fatigue (p = 0.01), cognitive fatigue (p = 0.02) as well as for fatigue intensity (p = 0.0001) and distress (p = 0.0001). This group of patients also experienced significantly higher levels of depression and anxiety (p = 0.0001). The Fatigue Assessment Questionnaire, developed in the German speaking part of Switzerland, can be used for further activities in the field of quality of life and nursing care in oncology. The instrument and a proposed scoring system are published as an addendum to this article.

Adolescent↗
PubMed1997

Predictors of the generation of episodic stress: a longitudinal study of late adolescent women.

The effects of depression and Axis I comorbidity on subsequent self-generated life stress were examined in a longitudinal sample of 134 late adolescent women. The results indicated that specific forms of psychopathology constitute a risk factor for future self-generated episodic stress, even when controlling for prior chronic stress. Comorbid depression had a particularly salient effect in the prediction of stress related to interpersonal conflicts. The effects of family psychopathology and sociotropy were mediated through participant psychiatric status, whereas autonomy made an independent contribution to the prediction of episodic stress. These results support C. Hammen's (1991b) stress generation model in a community sample, demonstrating how individuals with depression play a role in the creation of stress, and also refine prior work by showing that only the comorbid form of depression is associated with subsequent conflict-related stress.

Adolescent↗
PubMed1996

Magnitude estimation of perceived odor intensity: empirical and theoretical properties.

Four subjects judged the odor intensities of 7 pyridine concentrations and a blank. Computer simulations of a judgment model were compared with the empirical data. The model generates data patterns that closely mimic empirical findings. The following patterns were confirmed: (a) A power function relates magnitude estimates and concentration with an exponent in the range of 0.7 to 1.0 (b) The exponent fluctuates so that the level constant is negatively correlated with the exponent. (c) The standard deviation of the responses is a negatively accelerated function of the mean. (d) The skewness of the responses is relatively high for low concentrations and declines toward zero with increasing concentration. (e) The correlation between responses to successive stimuli is highest when successive concentrations are similar.

Adult↗
PubMed2001

New Tonopen XL: comparison with the Goldmann tonometer.

PURPOSE: To compare the intraocular pressure (IOP) values obtained using a Goldmann tonometer (Haag-Streit) with those obtained with the new Tonopen XL (Mentor), which has certain differences compared with first- and second-generation models. METHODS: The IOPs of 104 patients were assessed by Goldmann tonometer and Tonopen XL tonometer. Goldmann measurements was done first in 145 eyes and Tonopen measurements were done first in 53 eyes. Four observers measured the IOP. Observers A, B and C used the Goldmann tonometer first and then the Tonopen XL, while observer D used the Tonopen XL first and then the Goldmann tonometer. The results were analysed by descriptive analysis and, when the distribution of the data was normal, paired t-test and Pearson's r coefficient were used to compare and correlate IOP measurements between Goldmann and Tonopen measurements. When the distribution of the data was non-normal, the Wilcoxon matched-pair test and Spearman coefficient were used. The agreement between Goldmann and Tonopen values was also calculated. ANOVA test was used to compare the difference obtained by 'Goldmann minus Tonopen' measurements among the three different observers. RESULTS: A statistically significant difference (p < 0.0001) was found between the IOP readings obtained by Goldmann tonometer and the Tonopen XL and a significant correlation was found between the Goldmann values and Tonopen XL values (p < 0.001). When the Goldmann IOP was more than 20 mmHg the Tonopen XL measurements were lower than the Goldmann values. Also in this group this difference was statistically significant. No significant difference was found between Goldmann values and Tonopen values among the three observers, even though a significant difference was found between Goldmann values and Tonopen values for observer B. When the values obtained by first the Goldmann tonometer and then the Tonopen XL were compared with those obtained by first the Tonopen XL and then the Goldmann tonometer, no significant difference was found between the two groups. CONCLUSION: The new Tonopen XL provides similar results to the Goldmann tomometer in 62% of the cases and was slightly less accurate than the Goldmann tonometer for extreme values, just like the previous Tonopen. Nevertheless the precision is good enough for the purpose of adequate screening.

Analysis of Variance↗
PubMed2026

Enhancing pan-cancer spatial transcriptomics at single-cell resolution with stPainter.

Subcellular spatial transcriptomics can resolve tissue architecture at cellular scale, but sparse gene panels and limited detection sensitivity constrain downstream analysis. Existing enhancement methods often require tissue-matched single-cell RNA sequencing (scRNA-seq) references and dataset-specific retraining. Here we show that stPainter, a conditional generative model pretrained on a pan-cancer scRNA-seq atlas, can enhance spatial transcriptomics data without matched references or retraining. Using a latent diffusion architecture guided by Stochastic Differential Equations (SDE), stPainter&#xa0;reconstructs expanded expression profiles from sparse measurements and produces latent representations for clustering and cell-state analysis. When we apply stPainter&#xa0;upon 6 spatial transcriptomics datasets of different cancer types, we demonstrate that our model empowers downstream biological analyses, including fine-grained subpopulation clustering and pathway enrichment. Comparison with spatially resolved proteomics (CODEX) provided independent support for regional agreement between imputed cellular compositions and protein-level tissue organization. These results establish stPainter&#xa0;as a scalable approach for analyzing tumor microenvironments without auxiliary sequencing data.

Spatial Transcriptomics↗
PubMed2001

Anti-neutrophil cytoplasmic antibodies (ANCA) from patients with systemic vasculitis recognize restricted epitopes of proteinase 3 involving the catalytic site.

ANCA with specificity for proteinase 3 (PR3), a neutrophil primary granule enzyme, are of diagnostic value in Wegener's granulomatosis (WG) and certain other forms of systemic vasculitis. There is evidence to suggest that they play a pathogenic role in disease, and that the interaction of ANCA with PR3 is likely to be important. We showed, using a resonant mirror biosensor, that C-ANCA from different patients recognized the same or closely related epitopes on PR3. Studies using linear peptides in the SPOT system confirmed the highly restricted nature of this interaction and identified five linear epitopes. Fluid-phase inhibition studies, using a different set of peptides, validated the sequences involved. Using a computer-generated model of the structure of PR3, four of five epitopes were shown to be intimately linked with the catalytic site. The restricted number of epitopes, and their location at the catalytic site, has important implications for the role of C-ANCA in the pathogenesis of vasculitis.

Amino Acid Sequence↗
PubMed1999

Critical reflective inquiry for knowledge development in nursing practice.

This paper presents a method of inquiry which uses nurses' situated, individual instances of nursing practice as the basis for developing knowledge for nursing and improving practice. This method of inquiry is founded upon the ideas in action science and reflective practice, and critical philosophy. Nursing practice is viewed as a rich source of new knowledge as practitioners are engaged in creating as well as modifying knowledge to respond to specific clinical situations. At the same time, practitioners may be in practice without recognizing deficiencies or ineffectiveness. As a method to tap these two aspects of practice, the inquiry is designed to encompass three phases, i.e. descriptive, reflective and critical/emancipatory, and is oriented to provide understanding to practitioners of the nature and meaning of their own practice, to correct and improve practice through self-reflection and critique, and to generate models of 'good' practice and theories of application as well as to discover processes of practice as played out in clinical situations. This method of inquiry can be used by nurses and nursing students in collaboration with researches or mentors to develop nursing knowledge about practice, improve individual practice, and engage in shared learning.

Communication↗
PubMed2001

Antisense RNA regulation of the par post-segregational killing system: structural analysis and mechanism of binding of the antisense RNA, RNAII and its target, RNAI.

The par stability determinant of the Enterococcus faecalis plasmid pAD1 is the first antisense RNA regulated post-segregational killing system (PSK) identified in a Gram-positive organism. Par encodes two small, convergently transcribed RNAs, designated RNAI and RNAII, which are the toxin and antitoxin of the par PSK system respectively. RNAI encodes an open reading frame for a 33 amino acid toxin called Fst. Expression of fst is regulated post-transcriptionally by RNAII. RNAII interacts with RNAI by a unique antisense RNA mechanism involving binding at the 5' and 3' ends of both RNAs. Par RNA interaction requires a complementary transcriptional terminator stem-loop and a set of direct repeat sequences, DRa and DRb, located at the 5' end of both RNAs. The secondary structures of RNAI, RNAII and the RNAI-RNAII complex were analysed by partial digestion with Pb(II) and ribonucleases. Probing data for RNAI and RNAII are consistent with previously reported computer generated models, and also confirm that complementary direct repeat and terminator sequences are involved in the formation of the RNAI-RNAII complex. Mutant par RNAs were used to show that the binding reaction occurs in at least two steps. The first step is the formation of an initial kissing interaction between the transcriptional terminator stem-loops of both RNAs. The subsequent step(s) involves an initial pairing of the complementary direct repeat sequences followed by complete hybridization of the 5' nucleotides to stabilize the RNAI-RNAII complex.

Amino Acid Sequence↗