gebhart/patrepeval huggingface dataset:
Liquid extraction surface analysis mass spectrometry (LESA‐MS) as a novel profiling tool for drug distribution and metabolism analysis: the terfenadine example (2011)

Liquid extraction surface analysis mass spectrometry (LESA-MS) is a novel surface profiling technique that combines micro-liquid extraction from a solid surface with nano-electrospray mass spectrometry. One potential application is the examination of the distribution of drugs and their metabolites by analyzing ex vivo tissue sections, an area where quantitative whole body autoradiography (QWBA) is traditionally employed. However, QWBA relies on the use of radiolabeled drugs and is limited to total radioactivity measured whereas LESA-MS can provide drug- and metabolite-specific distribution information. Here, we evaluate LESA-MS, examining the distribution and biotransformation of unlabeled terfenadine in mice and compare our findings to QWBA, whole tissue LC/MS/MS and MALDI-MSI. The spatial resolution of LESA-MS can be optimized to ca. 1 mm on tissues such as brain, liver and kidney, also enabling drug profiling within a single organ. LESA-MS can readily identify the biotransformation of terfenadine to its major, active metabolite fexofenadine. Relative quantification can confirm the rapid absorption of terfendine after oral dosage, its extensive first pass metabolism and the distribution of both compounds into systemic tissues such as muscle, spleen and kidney. The elimination appears to be consistent with biliary excretion and only trace levels of fexofenadine could be confirmed in brain. We found LESA-MS to be more informative in terms of drug distribution than a comparable MALDI-MS imaging study, likely due to its favorable overall sensitivity due to the larger surface area sampled. LESA-MS appears to be a useful new profiling tool for examining the distribution of drugs and their metabolites in tissue sections.
Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule (1992)

The third variable (V3) domain has been implicated in determining the human immunodeficiency virus (HIV) phenotype, including fusion capacity and monocytotropism. In a large set of primary HIV type 1 (HIV-1) isolates, V3 sequence analysis revealed that fast-replicating, syncytium-inducing isolates contained V3 sequences with a significantly higher positive charge than those of slow-replicating, non-syncytium-inducing monocytotropic isolates. It appeared that these differences in charge could be attributed to highly variable amino acid residues located on either side of the V3 loop, midway between the cysteine residues and the central GPG motif. In non-syncytium-inducing monocytotropic isolates, these residues were negatively charged or uncharged, whereas in syncytium-inducing nonmonocytotropic isolates, either one or both were positively charged. The substitutions at these positions result in changes in the predicted secondary structure of the V3 loop. Our data suggest that two amino acid residues in the highly variable V3 domain are responsible for phenotype differences and point to conformational differences in V3 loops from phenotypically distinct HIV-1 isolates.
Statins for acutely hospitalized patients: randomized controlled trials are long overdue (2010)

From the earliest studies of statins for control of plasma cholesterol, observations have been made that the reductions in mortality observed occurred in a manner seemingly independent from what could be anticipated from cholesterol lowering alone. Over the last decade, the pleiotropic effects of statins have been increasingly elucidated. Perhaps most intriguing are the effects statins appear to have on the immune system, especially the modulation of diffuse or systemic inflammation. There is a growing body of observational literature suggesting that statins can actually reduce hospital mortality through mechanisms far beyond those that can be explained by reductions in cardiovascular events.
Mesenchymal Stem Cells: Cell Biology and Potential Use in Therapy (2004)

Mesenchymal stem cells are clonogenic, non-haematopoietic stem cells present in the bone marrow and are able to differentiate into multiple mesoderm-type cell lineages e.g. osteoblasts, chondrocytes, endothelial-cells and also non-mesoderm-type lineages e.g. neuronal-like cells. Several methods are currently available for isolation of the mesenchymal stem cells based on their physical and immunological characteristics. Because of the ease of their isolation and their extensive differentiation potential, mesenchymal stem cells are among the first stem cell types to be introduced in the clinic. Recent studies have demonstrated that the life span of mesenchymal stem cells in vitro can be extended by increasing the levels of telomerase expression in the cells and thus allowing culture of large number of cells needed for therapy. In addition, it has been shown that it is possible to culture the cells in xeno-free environment without affecting their growth or differentiation potential. Finally, the mesenchymal stem cells seems to be hypoimmunogenic and thus allogenic mesenchymal stem cells transplantation is possible. It is envisaged that mesenchymal stem cells can be used in systemic transplantation for generalized diseases, local implantation for local tissue defects, as a vehicle for genes in gene therapy protocols or to generate transplantable tissues and organs in tissue engineering protocols. The results of these initial trials are very encouraging and several clinical trials are under way to study the efficacy and long-term safety of therapeutics based on mesenchymal stem cells.
Polyglutamyl and polylysyl derivatives of the lysine analogs of folic acid and homofolic acid (1976)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPolyglutamyl and polylysyl derivatives of the lysine analogs of folic acid and homofolic acidLaurence T. Plante, Elizabeth J. Crawford, and Morris FriedkinCite this: J. Med. Chem. 1976, 19, 11, 1295–1299Publication Date (Print):November 1, 1976Publication History Published online1 May 2002Published inissue 1 November 1976https://pubs.acs.org/doi/10.1021/jm00233a008https://doi.org/10.1021/jm00233a008research-articleACS PublicationsRequest reuse permissionsArticle Views128Altmetric-Citations8LEARN 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
Effects of Varying Pacemaker Sites on Left Ventricular Performance (1976)

The hemodynamic effects of the site of the artificial cardiac stimulation were studied in 17 open chest dogs. The right atrium and five ventricular sites (the inflow and outflow tracts and apex of the right ventricle, apex and lateral wall of the left ventricle) were stimulated electronically at a given rate, ranging from 130 to 190 per min. When cardiac performance during ventricular pacing was compared with those during right atrial pacing, the former uniformly caused a diminution of cardiac output and systemic blood pressure, without reduction of left ventricular end-diastolic pressure. Ventricular function curves, in which left ventricular stroke work was related to left ventricular end-diastolic pressure, shifted downwards and to the right during ventricular pacing. Stimulation frequency did not alter these variables. It was considered that the left ventricular dysfunction in ventricular pacing resulted from the absence of atrial contribution to ventricular filling, mitral regurgitation present and asynchronous ventricular contraction. No significant difference of cardiac performance was demonstrated by changing the site of ventricular pacing, suggesting that the mode of ventricular depolarization itself was not relevant to a decrease in cardiac performance.
CYB5A and autophagy-mediated cell death in pancreatic cancer (2014)

The highly invasive and chemoresistant phenotype of pancreatic cancer highlights the urgency to identify prognostic biomarkers and novel therapeutic targets. Recently, we observed a significant correlation between shorter survival and loss of the cytoband 18q22.3. Here we investigated genes encoded by this cytoband, and demonstrated the prognostic value of CYB5A in resected and metastatic patients. Furthermore, our in vitro and in vivo studies clarified CYB5A inhibitory activity of oncogenic phenotypes through autophagy induction. This raises the possibility that inhibition of CYB5A-deregulated downstream pathways, such as those involving TRAF6, may favor autophagy-mediated cancer cell death in selected subgroups of patients.
Physicochemical and Biological Comparison of Recombinant Human Erythropoietin with Human Urinary Erythropoietin1 (1990)

Physicochemical and biological properties of recombinant human erythropoietin (rhEPO) were compared with human urinary erythropoietin (uEPO). uEPO and rhEPO were purified to apparent homogeneity from the urine of patients with aplastic anemia and from the conditioned medium of Chinese hamster ovary (CHO) cells transfected with a cDNA clone for human EPO, respectively. The microheterogeneous nature of both factors, observed on isoelectric focusing, is derived from the difference of the number of terminal sialic acid residues bound to the carbohydrate chains of the EPO molecule. The primary structure of rhEPO, consisting of 165 amino acid residues, was determined, and the C-terminal arginine predicted from the cDNA sequence was confirmed to be missing, as described previously (Recny et al. (1987) J. Biol. Chem. 262, 17156). Three N-glycosylation and one O-glycosylation sites of both factors were determined as Asn24, Asn38, and Asn83 and Ser126, respectively. Two disulfide linkages are located between Cys7 and Cys161, and between Cys29 and Cys33, in both EPOs. Hematogenic potencies of rhEPO and uEPO compared in normal and in partially nephrectomized rats were approximately the same. Both factors also stimulated the colony formation of CFU-E, BFU-E, and CFU-Meg in a dose-dependent manner. From these results, it is concluded that rhEPO produced in CHO cells transfected with cDNA clone for human EPO is indistinguishable from uEPO physicochemically and biologically, and is valuable for further research and for clinical use.
Proficiency testing of Cryptosporidium and Giardia analyses - an Australian case study (2002)

An inter-laboratory proficiency trial was undertaken as a prelude to a survey of Australian drinking source waters for Cryptosporidium and Giardia oo/cysts. Specific aims included measuring the recovery of protozoan control material from representative source waters, identifying laboratory errors and assessing the utility of pre-stained reference oo/cysts. Five experienced laboratories were provided with coded vials containing oo/cysts or blanks for spiking 10 L water samples (11 replicate environmental, 5 filtered) or to be analysed directly (16 Count Control vials). Each laboratory reported both their standard counts and details of how each oo/cyst image was interpreted and confirmed. A sixth laboratory provided flow cytometry prepared seed material and reference analyses. Average recoveries for 10 L samples ranged from 0-67% and 0-72%, for environmental and filtered tap water respectively, depending on laboratory and sample type. The best performing laboratory obtained high recoveries, ranging from 45% to 66% for tap water and 63% to 81% for environmental water. Nonetheless, recovery from tap water and environmental sample analysed simultaneously by the same laboratory could differ markedly (1% v. 48% in one case). Poor recovery and false positives were encountered despite the experience of the participants. Inconsistencies in reporting were introduced by the different procedures for confirming oocysts and cysts. The trial showed that obtaining reliable estimates of environmental protozoan loads is still a concern for water managers.
Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus (1997)

Inflammatory bowel disease (IBD) is thought to result from either an abnormal immunological response to enteric flora or a normal immunological response to a specific pathogen. No study to date has combined both factors. The present studies were carried out with an immunologically manipulated mouse model of IBD. Mice homozygous for the severe combined immunodeficiency (scid) mutation develop IBD with adoptive transfer of CD4+ T cells expressing high levels of CD45RB (CD45RB(high) CD4+ T cells). These mice do not develop IBD in germfree conditions, implicating undefined intestinal flora in the pathogenesis of lesions. In controlled duplicate studies, the influence of a single murine pathogen, Helicobacter hepaticus, in combination with the abnormal immunological response on the development of IBD was assessed. The combination of H. hepaticus infection and CD45RB(high) CD4+ T-cell reconstitution resulted in severe disease expression similar to that observed in human IBD. This study demonstrates that IBD develops in mice as a consequence of an abnormal immune response in the presence of a single murine pathogen, H. hepaticus. The interaction of host immunity and a single pathogen in this murine system provides a novel model of human IBD, an immunity-mediated condition triggered by bacterial infection.
Adaptive responses to antimicrobial agents in biofilms (2005)

Bacterial biofilms demonstrate adaptive resistance in response to antimicrobial stress more effectively than corresponding planktonic populations. We propose here that, in biofilms, reaction-diffusion limited penetration may result in only low levels of antimicrobial exposure to deeper regions of the biofilm. Sheltered cells are then able to enter an adapted resistant state if the local time scale for adaptation is faster than that for disinfection. This mechanism is not available to a planktonic population. A mathematical model is presented to illustrate. Results indicate that, for a sufficiently thick biofilm, cells in the biofilm implement adaptive responses more effectively than do freely suspended cells. Effective disinfection requires applied biocide concentration that increases quadratically or exponentially with biofilm thickness.
Advanced optical sensing techniques using novel fibre gratings (2003)

We describe some recently developed fibre grating sensing devices (Bragg and long-period types) and applications with emphasis on simultaneous measurement of multiple measurands using combinational grating structures, and the realisation of ultra-high sensitivity sensors utilising the quadratic dispersion of long-period grating structure.
Role of chemokines in renal cell carcinoma. (2014)

With new frontiers of pharmaceutical therapies focusing on tumor growth and angiogenesis, understanding the interaction between immune system and tumor microenvironment has become ever more important. Chemokines and chemokine receptors appear to play an integral role in tumor characteristics. Evidence suggests CXCR4, CXCL5, CXCR7, and stromal derived factor-1 appear to be crucial in survival, growth, and metastasis of renal cell carcinoma. As the role of chemokines in renal cancer is becoming more evident, further research will lead to a better understanding of tumor biology and the development of new therapeutic targets to help improve survival.
Mortalin is a novel mediator of erythropoietin signaling (2007)

Erythropoietin (EPO) stimulates erythroid growth by enhancing the proliferation, maturation and survival of late-stage erythroid progenitor cells. However, the entire process of EPO stimulation remains undetermined. To further clarify the intracellular mechanisms by which EPO affects the growth of erythroid progenitor cells, we analyzed proteins obtained from purified human erythroid colony-forming cells (ECFCs) cultured with or without EPO, and one of the proteins apparently related with EPO stimuli was identified as mortalin (mthsp70/PBP74/Grp75/mot-2), which is a member of the heat shock protein 70 family of chaperones. The amount of mortalin mRNA in ECFCs increased in an EPO dose-dependent manner, and ECFC growth was dependent on the amount of mortalin. Furthermore, expression of mortalin in ECFCs was suppressed by a phosphatidylinositol 3-kinase inhibitor. Finally, we analyzed gene expression patterns in ECFCs cultured with or without EPO after treatment with mortalin small interfering RNA (siRNA) using a DNA microarray. When ECFCs treated with mortalin siRNA were cultured with EPO, the expression of several genes overlapped with the profile seen in control ECFCs cultured without EPO. Our data suggest that mortalin is involved in the mediation of EPO signaling and plays an important role in stimulating the growth of erythroid progenitor cells.
Expression of the Erythropoietin Receptor by Trophoblast Cells in the Human Placenta1 (1999)

Nonclassical sites of erythropoietin (EPO) and erythropoietin receptor (EPO-R) expression have been described that suggest new physiological roles for this hormone unrelated to erythropoiesis. The recent finding of EPO expression by trophoblast cells in the human placenta prompted us to consider whether these cells also express EPO-R. With use of immunocytochemistry, EPO-R was identified in villous and extravillous cytotrophoblast cells, as well as in the syncytiotrophoblast at all gestational ages. EPO-R was also expressed by cells within the villous core, including endothelial cells of fetoplacental blood vessels. Placental tissues and isolated and immunopurified trophoblast cells, as well as trophoblast-derived choriocarcinoma Jar cells, expressed immunoreactive EPO-R on Western blot. EPO-R mRNA was also detected in the same placental tissues and trophoblast cells by nested-primer reverse transcription-polymerase chain reaction. Finally, EPO-R was functional insofar as the receptor was phosphorylated on tyrosine residues in response to exogenous EPO treatment of cultured trophoblast or Jar cells. Thus, the present findings support the hypothesis that trophoblast cells of the human placenta express EPO-R. In view of these results, taken together with previous work demonstrating EPO expression by the same cells, an autocrine role for this hormone in the survival, proliferation, or differentiation of placental trophoblast cells is proposed.
Targeting Delavirdine/Atevirdine Resistant HIV-1:  Identification of (Alkylamino)piperidine-Containing Bis(heteroaryl)piperazines as Broad Spectrum HIV-1 Reverse Transcriptase Inhibitors (1996)

A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.
Deficient Platelet-Derived Nitric Oxide and Enhanced Hemostasis in Mice Lacking the NOSIII Gene (1999)

Endothelial nitric oxide synthase (eNOS) has been identified in human platelets. Although platelet-derived nitric oxide (NO) has been shown to inhibit platelet recruitment in vitro, its role in the regulation of the hemostatic response in vivo has not been characterized. To define the role of platelet-derived NO in vivo, we studied mice that lacked a functional eNOS gene (NOSIII). Surface P-selectin expression in platelets from eNOS-deficient mice was not significantly altered; however, bleeding times were markedly decreased in eNOS-deficient versus wild-type mice (77.2+/-3 versus 133.4+/-3 seconds, P<0.00005). To determine the contribution of endothelium- versus platelet-derived NO to the bleeding time, isolated platelets from either eNOS-deficient or wild-type mice were transfused into a thrombocytopenic eNOS-deficient mouse and the bleeding time was measured. The bleeding times in mice transfused with eNOS-deficient platelets were significantly decreased compared with mice transfused with wild-type platelets (Deltableeding time, -24.6+/-9.1 and -3.4+/-5.3 seconds, respectively; P<0.04). Platelet recruitment was studied by measuring serotonin release from a second recruitable population of platelets that were added to stimulated platelets at the peak of NO production. There was 40.3+/-3.7% and 52. 0+/-2.1% serotonin release for platelets added to wild-type or eNOS-deficient platelets, respectively (P<0.05). In summary, mice that lacked eNOS had markedly decreased bleeding times even after endothelial NO production was controlled. These data suggest that the lack of platelet-derived NO alters in vivo hemostatic response by increasing platelet recruitment. Thus, these data support a role for platelet-derived NO production in the regulation of hemostasis.
Drug Targeting to the Brain Using Avidin-Biotin Technology in the Mouse (Blood-Brain Barrier, Monoclonal Antibody, Transferrin Receptor, Alzheimer's Disease) (2000)

A beta1-40 peptide radiopharmaceuticals could be used to image A beta brain amyloid in transgenic mouse models of Alzheimer's disease should the A beta peptide radiopharmaceutical be made transportable through the blood-brain barrier (BBB) in vivo. The present studies used the RI7-217 rat monoclonal antibody to the mouse transferrin receptor as a BBB drug targeting vector for the delivery to brain of A beta1-40 radiolabeled with either 125-Iodine or 111-Indium. The A beta peptide radiopharmaceutical is conjugated to the RI7 MAb using avidin biotin technology, wherein the A beta1-40 peptide radiopharmaceutical is monobiotinylated (bio) and bound to a conjugate of the RI7 MAb and streptavidin (SA). The [125 I]-bio-A beta1-40 or the [111 In]-bio-A beta1-40 either free or bound to the RI7/SA conjugate was injected intravenously into anesthetized adult mice and plasma pharmacokinetics and organ uptake were measured over the next 60 minutes. The A beta1-40 peptide radiopharmaceutical radiolabeled with 111-Indium was the preferred formulation, compared to peptide labeled with 125-Iodine, because there was a greater metabolic stability and reduced artifactual organ uptake of metabolites associated with the use of the 111-Indium nuclide. However, biotinylated A beta1-40 peptide radiopharmaceuticals conjugated to the RI7/SA brain drug targeting system were metabolically unstable in mice in vivo owing to active biotinidase activity. Future work involving brain drug targeting in mice that utilizes avidin biotin technology will need to incorporate biotin analogues that are resistant to biotinidase.