gebhart/patrepeval huggingface dataset:
Dose Proportionality and Steady-State Pharmacokinetics of Serdexmethylphenidate/Dexmethylphenidate, a Novel Prodrug Combination to Treat Attention-Deficit/Hyperactivity Disorder (2022)

<b><i>Objective:</i></b> The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH. <b><i>Methods:</i></b> Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis. <b><i>Results:</i></b> Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (± standard deviation) maximum concentrations (<i>C</i><sub>max</sub>) were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC<sub>0-last</sub>) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized <i>C</i><sub>max</sub>, AUC<sub>0-last</sub>, and AUC<sub>0-inf</sub> for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that <i>C</i><sub>max</sub> and AUC<sub>0-inf</sub> proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose. <b><i>Conclusion:</i></b> The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional <i>C</i><sub>max</sub> and AUC<sub>0-inf</sub> across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.
The interaction of CD4 with CD3/Ti regulates tyrosine phosphorylation of substrates during T cell activation. (1990)

Phosphorylation of proteins on tyrosine residues during activation was studied in CD3+ CEM T cells. Crosslinking of either CD4 alone or CD3/Ti alone induced weak and transient responses, but the patterns of induced tyrosine-phosphorylated proteins were different. A synergistic but still transient response occurred by the specific interaction of CD4 with CD3/Ti, whereas simultaneous but separate ligation of CD3/Ti and CD4 decreased rather than increased tyrosine phosphorylation of proteins in comparison to CD3/Ti stimulation alone. Stimulation of T cells with immobilized anti-CD3 induced strong and prolonged tyrosine phosphorylation of distinct substrates. CD4 therefore regulates protein tyrosine kinase activation by specific interaction with CD3/Ti, whereas immobilized anti-CD3 may differ from anti-CD3 in solution in the activation of protein tyrosine phosphatase(s) such as CD45.
Automated identification of temporal pattern with high initial enhancement in dynamic MR lesions using fuzzy c-means algorithm (2004)

In contrast-enhanced (CE) MRI of the breast, signal-intensity time curves have been proven useful in differentiating between benign and malignant lesions. Due to uptake heterogeneity in the breast lesion, however, the signal-intensity time curve obtained from a specific region in the lesion may outperform that from the entire lesion. In this study, we propose the use of fuzzy c-means (FCM) clustering algorithms to reveal different temporal patterns within the breast lesion. The algorithm finds fuzzy cluster centers (i.e., temporal patterns) and assigns membership values to each voxel. The temporal pattern with maximum initial enhancement is selected as the representative curve of the lesion and the thresholded membership map is the identified region of fast enhancement. The approach was applied to the analysis of 121 lesions (77 malignant and 44 benign). The resulting representative curves were classified with linear discriminant analysis (LDA). The differentiation performance of LDA output in leave-one-out cross evaluation was assessed using receiver operating characteristic (ROC) analysis. Our results show that the use of FCM significantly improved the performance of signal-intensity time curves in the task of distinguishing between malignant and benign lesions.
Evidence for the adsorption of oriented nido-R2C2B4H6 carborane cluster molecules on silicon(111) surfaces (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEvidence for the adsorption of oriented nido-R2C2B4H6 carborane cluster molecules on silicon(111) surfacesSunwoo Lee, Dongqi Li, P. A. Dowben, F. Keith Perkins, M. Onellion, and James T. SpencerCite this: J. Am. Chem. Soc. 1991, 113, 22, 8444–8447Publication Date (Print):October 1, 1991Publication History Published online1 May 2002Published inissue 1 October 1991https://pubs.acs.org/doi/10.1021/ja00022a036https://doi.org/10.1021/ja00022a036research-articleACS PublicationsRequest reuse permissionsArticle Views65Altmetric-Citations19LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Lumen-apposing covered self-expanding metal stent for management of benign gastrointestinal strictures (2015)

Lumen-apposing, fully covered SEMS appear to be safe and effective for management of selected benign gastrointestinal strictures.
An evaluation of benthic nutrient regeneration in a projected flood control impoundment (1979)

Abstract A flood control impoundment, which would also serve as a recreational facility, was proposed as part of the Upper Quaboag River watershed in western Massachusetts. To predict the impact exerted by a muck substrate on water quality and recreational benefits, a physical model was constructed in the laboratory. From the experiment, it was determined that the rate of nutrient release across the mud‐water interface was sufficient to encourage algal blooms, restrict secondary productivity, and thereby limit the use of the proposed impoundment for recreational purposes.
Effect of Body Fluids and Macromolecular Substances on the Lysis of Group A Streptococci by Muramidases of Streptomyces albus (1975)

The lysis of group A streptococci by muramidases of Streptomyces albus is strongly inhibited by human, rabbit, and calf serum as well as by human synovial fluids and pus. Rabbit antisera to heat-killed streptococci were no more inhibitory to the lysis of the streptococci by the lytic enzyme than normal rabbit serum. The results indicate that muramidases of S. albus will not be useful for the in vivo treatment of chronic granulomatous lesions which had been induced by insoluble cell wall components of streptococci.
Supplementary Figure 2 from Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis (2023)

&lt;p&gt;Correlation of mortalin expression with cell migration capacity. Expression level of mortalin in different cancer cells as determined by Western blotting (A). Correlation of mortalin expression with migration potential of cancer cells as determined by wound-scratch assay (B). A549 showed highest level of mortalin expression and migration capacity.&lt;/p&gt;
Tunable Transmission Resonant Filter and Modulator with Vertical Gratings (2006)

In this paper, we extend our approach to implement a resonant filter and resonant modulator using lithographically defined nanostructures on sidewalls of a waveguide in silicon on insulator (SOI) material system
Modification of the defect structure and electrophysical properties in zinc selenide crystals under the action of an alternating electric field (2003)

Modifications in the structure and electrophysical properties of ZnSe crystals subjected to a high alternating electric field of industrial frequency are investigated. It is established that such an action changes their defect structure and dielectric parameters. The latter exhibit different dependences on temperature and photoexcitation wavelength. The modifications are caused by ionic conduction, which is associated with local anomalies in the electric and elastic subsystems of the crystals.
Induction of Cardiac Cytochrome P450 in Cocaine-Treated Mice (2002)

Cytochrome P450 (P450) is a ubiquitous family of enzymes responsible for the metabolism of a wide variety of drugs and their metabolites, including cocaine. To investigate the effects of cocaine on myocardial injuries and cardiac P450 expression, BALB/c mice were injected daily intraperitoneally with cocaine (30 mg/kg) or cocaine plus pretreatment of P450 inhibitors for 14 days. Tumor necrosis factor-alpha (TNF-alpha) content and creatine phosphokinase (CPK) activity in mice hearts and serums were significantly increased after long-term treatment with cocaine. Pretreatment with the P450 inhibitor, cimetidine (Cime, 50 mg/kg) or metyrapone (Mety, 40 mg/kg) abolished or significantly attenuated the effects of cocaine on TNF-alpha and CPK activity. Western blot analysis shows that mouse cardiac tissues express the P450 isoforms CYP1A1, CYP1A2, and CYP2J2. The protein levels normalized with cyclophilin A were 1.20 plus minus 0.07, 0.67 plus minus 0.03, and 1.48 plus minus 0.01 for CYP1A1, CYP1A2, and CYP 2J2, respectively. After cocaine administration, CYP2J2 increased by 43.6% and CYP1A1 increased by 108.5%, but CYP1A2 was not significantly altered. However, the cytochrome P450 inhibitors Cime and Mety suppressed the cocaine-induced increase in CYP1A1 and CYP2J2 expression. Moreover, application of Cime or Mety alone did not alter the level of cardiac TNF-alpha or the expression of P450. Our results demonstrate that long-term exposure to cocaine causes an increase in cardiac CYP1A1 and CYP2J2 concentration. We speculate that induction of P450 isoforms may cause cardiac injury due to cocaine metabolites locally catalyzed by P450 or the increase in P450 expression itself.
Inactivation of Escherichia coli l-Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic Acid Reveals “A Tale of Two Mechanisms”, (2007)

As a mechanism-based inactivator of PLP-enzymes, (S)-4-amino-4,5-dihydro-2-thiophenecarboxylic acid (SADTA) was cocrystallized with Escherichia coli aspartate aminotransferase (l-AspAT) at a series of pH values ranging from 6 to 8. Five structural models with high resolution (1.4-1.85 A) were obtained for l-AspAT-SADTA complexes at pH 6.0, 6.5, 7.0, 7.5, and 8.0. Electron densities of the models showed that two different adducts had formed in the active sites. One adduct was formed from SADTA covalently linked to pyridoxal 5'-phosphate (PLP) while the other adduct was formed with the inhibitor covalently linked to Lysine246,1 the active site lysine. Moreover, there is a strong indication based on the electron densities that the occurrence of the two adducts is pH dependent. We conclude that SADTA inactivates l-AspAT via two different mechanisms based on the binding direction of the inactivator. Additionally, the structural models also show pH dependence of the protein structure itself, which provided detailed mechanistic implications for l-AspAT.
Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques (2018)

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27<sup>Gag</sup> and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIV<sub>mac239</sub> which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8<sup>+</sup> T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.
Ultrasonographic detection of testicular ischemia in a canine model using phospholipid coated microbubbles (MRX-115). (1997)

The purpose of this study was to determine if the sonographic contrast agent MRX-115 could improve the accuracy of Doppler ultrasonographic diagnosis of testicular ischemia. Testicular duplex ultrasonography was performed on six dogs before and after surgical ligation of the testicular artery, and before and after intravenous injection of MRX-115. Six radiologists blinded to experimental conditions rated the testicular blood flow. Receiver operating characteristics curves for conditions with and without administration of contrast agent were compared using Student's t-test for paired observations. Statistically significant differences were found both for the tests viewed individually (P = 0.003) and for the testes in comparison to the contralateral side (P = 0.0001). MRX-115 therefore is found to improve duplex sonographic evaluation of testicular ischemia.
An automated workflow for patient-specific quality control of contour propagation (2016)

Contour propagation is an essential component of adaptive radiotherapy, but current contour propagation algorithms are not yet sufficiently accurate to be used without manual supervision. Manual review of propagated contours is time-consuming, making routine implementation of real-time adaptive radiotherapy unrealistic. Automated methods of monitoring the performance of contour propagation algorithms are therefore required. We have developed an automated workflow for patient-specific quality control of contour propagation and validated it on a cohort of head and neck patients, on which parotids were outlined by two observers. Two types of error were simulated-mislabelling of contours and introducing noise in the scans before propagation. The ability of the workflow to correctly predict the occurrence of errors was tested, taking both sets of observer contours as ground truth, using receiver operator characteristic analysis. The area under the curve was 0.90 and 0.85 for the observers, indicating good ability to predict the occurrence of errors. This tool could potentially be used to identify propagated contours that are likely to be incorrect, acting as a flag for manual review of these contours. This would make contour propagation more efficient, facilitating the routine implementation of adaptive radiotherapy.
Mammalian pharmacokinetics of carbon nanotubes using intrinsic near-infrared fluorescence (2006)

Individualized, chemically pristine single-walled carbon nanotubes have been intravenously administered to rabbits and monitored through their characteristic near-infrared fluorescence. Spectra indicated that blood proteins displaced the nanotube coating of synthetic surfactant molecules within seconds. The nanotube concentration in the blood serum decreased exponentially with a half-life of 1.0 +/- 0.1 h. No adverse effects from low-level nanotube exposure could be detected from behavior or pathological examination. At 24 h after i.v. administration, significant concentrations of nanotubes were found only in the liver. These results demonstrate that debundled single-walled carbon nanotubes are high-contrast near-infrared fluorophores that can be sensitively and selectively tracked in mammalian tissues using optical methods. In addition, the absence of acute toxicity and promising circulation persistence suggest the potential of carbon nanotubes in future pharmaceutical applications.
Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population (2015)

Myocardial infarction (MI) is divided into either ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI), differing in a number of clinical characteristics. We sought to identify genetic variants conferring risk to NSTEMI or STEMI by conducting a genome-wide association study (GWAS) of MI stratified into NSTEMI and STEMI in a consecutive sample of 1,579 acute MI cases with 1,576 controls. Subsequently, we followed the results in an independent population-based sample of 562 cases and 566 controls, a partially independent prospective cohort (N = 16,627 with 163 incident NSTEMI cases), and examined the effect of disease-associated variants on gene expression in 513 healthy participants. Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with NSTEMI (rs656843; odds ratio 1.57, P = 3.11 × 10(-10)) in the case-control analysis with a consistent but not statistically significant effect in the prospective cohort (rs656843; hazard ratio 1.13, P = 0.43). These variants were not associated with STEMI (rs656843; odds ratio, 1.11, P = 0.20; hazard ratio 0.97, P = 0.87), appearing to have a pronounced effect on NSTEMI risk. A majority of the variants at 1p13.3 associated with NSTEMI were also associated with the expression level of DRAM2 in blood leukocytes of healthy controls (top-ranked variant rs325927, P = 1.50 × 10(-12)). The results suggest that genetic factors may in part influence whether coronary artery disease results in NSTEMI rather than STEMI.
Symmetric positive definite matrices, e.g. covariance matrices, are constrained by their symmetry, the strict positivity of the diagonal elements (variance) and the Cauchy-Schwarz inequalities bounding the absolute value of the off-diagonal elements: |Cov(x<sub>i</sub>x<sub>j</sub>)|≤[Var(x<sub>j</sub>)Var(x<sub>j</sub>)]<sup>1/2</sup>, for all i,j∈{1,…,N}. (2015)

&lt;p&gt;This topology is easily visualized in case of 2x2 matrices; any 2x2 covariance matrix can be seen as a point in 3D Euclidean space, with two coordinates given by the two variances (diagonal elements) and the third coordinate given by the covariance (either one of the off-diagonal element). By construction a covariance matrix must stay within the cone boundaries. As soon as the point touches the boundary of the cone, the matrix is no more positive definite.&lt;/p&gt;
Pseudomonas cepacia Typing Systems: Collaborative Study to Assess Their Potential in Epidemiologic Investigations (1989)

To determine the utility of available Pseudomonas cepacia typing systems for confirming the relatedness of isolates, we applied these methods to isolates associated with previously investigated nosocomial outbreaks. We compared chromosome analysis, serologic reactions, biochemical tests, bacteriocin production and susceptibility, and antimicrobial susceptibility in their ability to determine outbreak relatedness. Chromosome analysis, serologic reactions, and biochemical tests were each demonstrated to be epidemiologically useful methods for typing isolates. Determination of the sensitivity and specificity of these typing techniques will facilitate their application in the epidemiologic study of this increasingly important nosocomial pathogen.
Design and investigation of multivalent ligands for the detection and treatment of diseases (2013)

D of drugs for the detection and treatment of degenerative diseases such as cancer, prolonged and neuropathic pain, diabetes, etc. has proved to be very difficult. Most current treatments are inadequate, treat mostly symptoms, and have toxicities and development of tolerance that prevent effective long term use. Recent genomic and proteomic studies have shown that in many cases the diseases result from multiple changes in the expressed genome. These findings present opportunities for the development of new approaches to drug design and development. In particular it is possible to design multivalent ligands that can address 2 or more targets for the disease state, all in a single molecule. Depending on the nature of the target, different strategies are required so as to assure that each of the pharmacophores can act at their particular targets (receptor, accepter, enzyme, etc.) without interfering with the actions of the other pharmacophore. We illustrate these principles and this new approach for two different diseases. In the first case, we address the problem for designing ligands which can treat the most ubiquitous disease in the world, prolonged and neuropathic pain, without toxic side effects, for which there is no current effective treatment. We have designed bivalent and trivalent ligands that can act as antagonists at neurokinin-1 or bradykinin receptors and/or as agonists at the mu and delta opioid receptors in a single molecule. We can demonstrate that these ligands can treat neuropathic pain in vivo without toxicities or development of tolerance. In another example, we demonstrate the development of novel multivalent scaffolds that can target cancer cells but not normal cells, and thus can be used for the early detection and treatment of cancer. Victor J. Hruby, Med chem 2013, 3:4 http://dx.doi.org/10.4172/2161-0444.S1.007