gebhart/patrepeval huggingface dataset:
Therapeutic Drug Monitoring of Escitalopram in an Outpatient Setting (2007)

The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring; and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S-didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S-citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.
PSP expression in murine lacrimal glands and function as a bacteria binding protein in exocrine secretions (1997)

Nonobese diabetic (NOD) mice, an animal model for type I autoimmune diabetes and autoimmune sialoadenitis, abnormally express parotid secretory protein (PSP) in the submandibular glands (Robinson, C. P., H. Yamamoto, A. B. Peck, and M. G. Humphreys-Beher. Clin. Immunol. Immunopathol. 79: 50-59, 1996). To evaluate possible PSP gene dysregulation in the NOD mouse, we have examined a number of organs and tissues for PSP mRNA transcripts and protein expression. Results indicate that PSP is produced in the lacrimal glands of NOD mice as well as most laboratory mouse strains. Although purified salivary PSP from C3H/HeJ or BALB/c mice fails to affect amylase enzyme activity in in vitro assays, PSP bound to whole bacteria in a Zn2+-dependent manner. Additionally, radiolabeled protein bound to specific bacterial membrane proteins using a ligand binding assay. PSP gene transcription, but not protein production, was observed in the heart and pancreas from NOD mice, indicating abnormal transcription of the PSP gene. Sequence analysis of PSP cDNA from NOD mice revealed numerous base differences (compared with the published PSP sequence) capable of leading to significant amino acid substitutions, suggestive of strain-specific differences for the protein in mice. Together these results suggest that there exists in the NOD mouse a dysregulation of PSP transcription in various tissues. However, except for C3H/HeJ mice, PSP appears as a normal product of the lacrimal glands where, as in saliva, it may function as a nonimmune antimicrobial agent in the protection of tissue surfaces exposed to the external environment.
Stem Cells and Cartilage Development: Complexities of a Simple Tissue (2010)

Cartilage is considered to be a simple tissue that should be easy to engineer because it is avascular and contains just one cell type, the chondrocyte. Despite this apparent simplicity, regenerating cartilage in a form that can function effectively after implantation in the joint has proven difficult. This may be because we have not fully appreciated the importance of different structural regions of articular cartilage or of understanding the origins of chondrocytes and how this cell population is maintained in the normal tissue. This review considers what is known about different regions of cartilage and the types of stem cells in articulating joints and emphasizes the potential importance of regeneration of the lamina splendens at the joint surface and calcified cartilage at the junction with bone for long-term survival of regenerated tissue in vivo.
New somatic cell hybrids for physical mapping in distal Xq and the fragile X region (1991)

Somatic cell hybrids were constructed from 3 patients carrying X chromosome abnormalities with breakpoints in distal Xq: 1) 94-3, from a patient with 46,XX,t(X;15)(q25 or q26;q25), 2) 8121-A1, from a patient with 46,X,del(X)(q26), and 3) 2384-A2, from a patient with 46,X,del(X)(q27). The breakpoint of patient 94 is proximal to HPRT in q26, a significant distance from the fragile X locus. The breakpoint of patient 8121 is distal to F9, but proximal to DXS98, and is thus proximal to the fragile site region. The breakpoint of 2384 is distal to DXS98 but proximal to DXS52, placing it within the region of the fragile site. Use of these physical mapping reference points will aid in the rapid localization of new DNA markers to distal Xq and the fragile X region.
Importance-Driven Focus of Attention (2006)

This paper introduces a concept for automatic focusing on features within a volumetric data set. The user selects a focus, i.e., object of interest, from a set of pre-defined features. Our system automatically determines the most expressive view on this feature. A characteristic viewpoint is estimated by a novel information-theoretic framework which is based on the mutual information measure. Viewpoints change smoothly by switching the focus from one feature to another one. This mechanism is controlled by changes in the importance distribution among features in the volume. The highest importance is assigned to the feature in focus. Apart from viewpoint selection, the focusing mechanism also steers visual emphasis by assigning a visually more prominent representation. To allow a clear view on features that are normally occluded by other parts of the volume, the focusing for example incorporates cut-away views.
Plasma Clearance, Tissue Distribution and Catabolism of Cationized Albumins with Increasing Isoelectric Points in the Rat (1984)

The infusion of cationic substances produces acute renal failure and proteinuria, and an experimental disease very similar to disseminated coagulopathy. The purpose of this work was to investigate further, in the rat, the plasma disappearance rate, the tissue distribution and the catabolism of albumins with modified isoelectric points. Human serum albumin was cationized with hexanediamine and labelled with 125I or 131I. During 10-180 min after their intravenous injection into the rat, these modified 125I-labelled albumins were cleared from the plasma at a rate which increased with their isoelectric point. At 1 and 3 h after the injection of highly cationic proteins (isoelectric point higher than 9.5) the tissue protein bound 125I concentration was greatest (approximately 3.5% of the injected activity/g) in the spleen and liver. A significant amount of the basic proteins was found in the kidney and in the lung (0.75-1%/g). Their concentration was much lower in other tissues. The whole body radioactivity was significantly lower 24 h after the injection of 131I-labelled cationized albumins than after similarly labelled native albumin. However, expressed as a percentage of the retention at 24 h, the body radioactivity at later times was higher for cationic than for native albumin. We conclude that cationized albumins are cleared from the plasma, mainly by the reticuloendothelial system, at a rate directly related to their isoelectric point. The cationized albumins are catabolized very rapidly initially, but a fraction of the injected protein remains in the body for a longer time than native albumin.
Potential Targets and Their Relevant Inhibitors in Anti-influenza Fields (2009)

Influenza is a disease for deeply affecting millions of people every year. Recently, there has been considerable concern regarding the highly pathogenic H5N1 avian influenza virus, and its human pandemic potential. With developments in viral biology, there are more novel antiviral strategies targeting these viruses. In this review, we will discuss several proven and potential anti-influenza targets, including viral factors (such as hemagglutinin (HA), M2 ion channel protein, RNA-dependent RNA polymerase (RdRp), nucleoprotein (NP), non-structural protein (NS) and neuraminidase (NA)) and host factors (such as v-ATPase, protease, inosine monophosphate dehydrogenase (IMPDH) and intracellular signalling cascades), and their relevant inhibitors.
Single and Bis Peptide Nucleic Acids as Triplexing Agents: Binding and Stoichiometry (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSingle and Bis Peptide Nucleic Acids as Triplexing Agents: Binding and StoichiometryMichael C. Griffith, Lisa M. Risen, Michael J. Greig, Elena A. Lesnik, Kelly G. Sprankle, Rich H. Griffey, John S. Kiely, and Susan M. FreierCite this: J. Am. Chem. Soc. 1995, 117, 2, 831–832Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://pubs.acs.org/doi/10.1021/ja00107a033https://doi.org/10.1021/ja00107a033research-articleACS PublicationsRequest reuse permissionsArticle Views538Altmetric-Citations119LEARN 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-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
Novel DNA vaccine based on hepatitis B virus core gene induces specific immune responses in Balb/c mice (2005)

AIM: To investigate the immunogenicity of a novel DNA vaccine,pSW3891/HBc, based on HBV core gene in Balb/c mice.METHODS: A novel DNA vaccine, pSW3891/HBc, encoding HBV core gene was constructed using a vector plasmid pSW3891. Balb/c mice were immunized with either pSW3891/HBc or empty vector DNA via gene gun. IgG anti-HBc responses in mouse sera were demonstrated by ELISA. Specific cytotoxicity of cytotoxic T lymphocytes (CTLs) of mice was quantitatively measured by lactate dehydrogenase release assay.RESULTS: HBcAg was expressed effectively in 293T cell line transiently transfected with pSW3891/HBc. Strong IgG anti-HBc responses were elicited in mice immunized with pSW3891/HBc. The end-point titers of anti-HBc reached the highest 1:97 200, 4 wk after the third immunization. The specific CTL killing with the highest specific lysis reached 73.25% at effector:target ratio of 20:1 in mice that received pSW3891/HBc DNA vaccine.CONCLUSION: pSW3891/HBc vaccination elicits specific anti-HBc response and induces HBc-specific CTL response in immunized Balb/c mice.
Fabrication and Test of Integrated Micro-Scale Vibration Based Electromagnetic Generator (2007)

This paper discusses the design, fabrication and testing of electromagnetic microgenerators on silicon. Two different designs of power generators are micro-fabricated, Prototype A having a wire-wound copper coil and Prototype B, an electrodeposited copper coil both on a Deep Reactive Ion etched (DRIE) silicon paddle. The devices were fabricated using standard Micro-Electro-Mechanical Systems (MEMS) processing techniques. For Prototype A, the maximum measured power output was 148 nW at 8.08 kHz resonant frequency and 3.9 m/s acceleration. For prototype B, the microgenerator gave a maximum load power of 23 nW for an acceleration of 9.8 m/s , at a resonant frequency of 9.83 kHz.
HIV Type 1 Nef Is Released from Infected Cells in CD45 + Microvesicles and Is Present in the Plasma of HIV-Infected Individuals (2010)

HIV-1 Nef has been demonstrated to be integral for viral persistence, infectivity, and the acceleration of disease pathogenesis (AIDS) in humans. Nef has also been detected in the plasma of HIV-infected individuals and is released from infected cells. The form in which Nef is released from infected cells is unknown. However, Nef is a myristoylated protein and has been shown to interact with the intracellular vesicular trafficking network. Here we show that Nef is released in CD45-containing microvesicles. This microvesicular Nef (mvNef) is detected in the plasma of HIV-infected individuals at relatively high concentrations (10 ng/ml). It is also present in tissue culture supernatants of Jurkat cells infected with HIV(MN). Interestingly, plasma mvNef levels in HIV(+) patients did not significantly correlate with viral load or CD4 count. Microvesicular Nef levels persisted in the plasma of HIV-infected individuals despite the use of antiretroviral therapy, even in individuals with undetectable viral loads. Using cell lines, we found Nef microvesicles induce apoptosis in Jurkat T-lymphocytes but had no observed effect on the U937 monocytic cell line. Given the large amount of mvNef present in the plasma of HIV-infected individuals, the apoptotic effect of mvNef on T cells, and the observed functions of extracellular soluble Nef in vitro, it seems likely that in vivo mvNef may play a significant role in the pathogenesis of AIDS.
A Mechanistic Study of Tumor-Targeted Corrole Toxicity (2011)

HerGa is a self-assembled tumor-targeted particle that bears both tumor detection and elimination activities in a single, two-component complex (Agadjanian et al. Proc. Natl. Acad. Sci. U.S.A.2009, 106, 6105-6110). Given its multifunctionality, HerGa (composed of the fluorescent cytotoxic corrole macrocycle, S2Ga, noncovalently bound to the tumor-targeted cell penetration protein, HerPBK10) has the potential for high clinical impact, but its mechanism of cell killing remains to be elucidated, and hence is the focus of the present study. Here we show that HerGa requires HerPBK10-mediated cell entry to induce toxicity. HerGa (but not HerPBK10 or S2Ga alone) induced mitochondrial membrane potential disruption and superoxide elevation, which were both prevented by endosomolytic-deficient mutants, indicating that cytosolic exposure is necessary for corrole-mediated cell death. A novel property discovered here is that corrole fluorescence lifetime acts as a pH indicator, broadcasting the intracellular microenvironmental pH during uptake in live cells. This feature in combination with two-photon imaging shows that HerGa undergoes early endosome escape during uptake, avoiding compartments of pH < 6.5. Cytoskeletal disruption accompanied HerGa-mediated mitochondrial changes whereas oxygen scavenging reduced both events. Paclitaxel treatment indicated that HerGa uptake requires dynamic microtubules. Unexpectedly, low pH is insufficient to induce release of the corrole from HerPBK10. Altogether, these studies identify a mechanistic pathway in which early endosomal escape enables HerGa-induced superoxide generation leading to cytoskeletal and mitochondrial damage, thus triggering downstream cell death.
Influence of the Disintegrant on the Drug Percolation Threshold in Tablets (1997)

Previous papers studied ternary tablets containing different concentrations of polyvinylpyrrolidone cross-link (PVP-CL) as disintegrant. The drug percolation threshold, pcl, for these tablets was estimated to fall in the range 0.26-0.31 of total porosity. The aim of the present paper is to study if the presence of the disintegrant agent (PVP-CL) in these tablets, exerts an important effect on the drug percolation threshold obtained. For this purpose, binary tablets containing the same model drug and excipient have been prepared in identical technological conditions. The drug percolation threshold in these matrix tablets has been calculated following the method of Bonny and Leuenberger (5). The results obtained show no significant difference between pcl in the binary matrix tablets and the drug percolation threshold found in the tablets containing the disintegrant agent. This result supposes a stimulus for the application of the principles of percolation theory to a great number of pharmaceutical systems containing disintegrant agents or substances which cause a strong change in its release behavior.
Graphene-Based Ambipolar RF Mixers (2010)

The combination of the unique properties of graphene with new device concepts and nanotechnology can overcome some of the main limitations of traditional electronics in terms of maximum frequency, linearity, and power dissipation. In this letter, we demonstrate the use of the ambipolar-transport properties of graphene for the fabrication of a new kind of RF mixer device. Due to the symmetrical ambipolar conduction in graphene, graphene-based mixers can effectively suppress odd-order intermodulations and lead to lower spurious emissions in the circuit. The mixer operation was demonstrated at a frequency of 10 MHz using graphene grown by chemical vapor deposition on a Ni film and then transferred to an insulating substrate. The maximum operating frequency was limited by the device geometry and the measurement setup, and a high-quality factor was observed with a third-order intercept point of +13.8 dBm.
Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway (2008)

Identification of unique features of cancer cells is important for defining specific and efficient therapeutic targets. Mutant p53 is present in nearly half of all cancer cases, forming a promising target for pharmacological reactivation. In addition to being defective for the tumor-suppressor function, mutant p53 contributes to malignancy by blocking a p53 family member p73. Here, we describe a small-molecule RETRA that activates a set of p53-regulated genes and specifically suppresses mutant p53-bearing tumor cells in vitro and in mouse xenografts. Although the effect is strictly limited to the cells expressing mutant p53, it is abrogated by inhibition with RNAi to p73. Treatment of mutant p53-expressing cancer cells with RETRA results in a substantial increase in the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects similar to the functional reactivation of p53. RETRA is active against tumor cells expressing a variety of p53 mutants and does not affect normal cells. The results validate the mutant p53-p73 complex as a promising and highly specific potential target for cancer therapy.
784 BDC-2034: discovery of a CEA-targeting immune-stimulating antibody conjugate (ISAC) for solid tumors (2021)

<h3>Background</h3> CEA (CEACAM5) is a well-validated cell-surface antigen that is highly expressed in multiple solid tumors. Bolt9s immune-stimulating antibody conjugates (ISACs) direct a TLR7/8 agonist into tumors to activate tumor-infiltrating myeloid cells and initiate a broad innate and adaptive anti-tumor immune response.<sup>1</sup> The favorable properties of CEA, including robust cell surface expression, low internalization rate, and limited normal tissue expression, suggest that the antigen may be a suitable ISAC target. We are evaluating an anti-CEA ISAC, BDC-2034, as a multi-functional approach to treat CEA-expressing cancers. <h3>Methods</h3> Anti-CEA antibodies were tested for binding affinity and specificity, CEA-targeted antibody-dependent cellular phagocytosis (ADCP), and myeloid-mediated tumor cell killing. Selected antibodies were conjugated to proprietary TLR7/8 agonists, and the resulting CEA ISACs were evaluated for in vitro myeloid activation and in vivo efficacy against xenograft tumors. <h3>Results</h3> Antibody CEA1 binds to the CEA protein with high affinity (EC50 = 0.25 nM), binds selectively to CEA-positive tumor cell lines, and mediates ADCP more efficiently than a reference anti-CEA antibody, labetuzumab (figure 1). We generated BDC-2034 by conjugating a potent TLR7/8 agonist to CEA1. BDC-2034 tumor cell binding drives myeloid effector cell ADCP, agonist delivery to TLR7 and TLR8 in endosomes, and secretion of cytokines critical for innate and adaptive immunity (including IL-12p70, CXCL10, and TNFa). In the HPAF II + cDC co-culture model, IL-12p70 is induced with EC50 = 1.2 nM, and the level of induction is at least ten-fold higher than with ISACs using labetuzumab (figure 2). Potent cellular activity is strictly dependent on tumor cell CEA expression; in whole blood, in the absence of CEA-expressing tumor cells, cytokine induction was only observed at approximately 100-fold higher concentrations. BDC-2034 inhibits the growth of HPAF II xenograft tumors in SCID/beige mice with a minimal efficacious dose (MED) of 1 mg/kg, demonstrating anti-tumor activity solely through innate immune activation (figure 3). The TLR7/8 agonist in BDC-2034 has relatively poor activity in mice; a surrogate CEA1 ISAC with a mouse TLR7-activating agonist achieved MED = 0.5 mg/kg in the HPAF II model, with eradication of all tumors at the 5 mg/kg dose. <h3>Conclusions</h3> These pre-clinical data demonstrate the potential of BDC-2034 to treat CEA-expressing human cancers. Most importantly, the antigen-dependent induction of immune-stimulating cytokines promises a robust immune response that combines the activation of innate and adaptive arms. <h3>Reference</h3> Ackerman S, Pearson C, Gregorio J. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. <i>Nature Cancer</i> 2021;<b>2</b>:18–33. https://doi.org/10.1038/s43018-020-00136-x