gebhart/patrepeval huggingface dataset:
Abstract 15925: Newt Exosomes are Bioactive on Mammalian Heart, Enhancing Proliferation of Rat Cardiomyocytes and Improving Recovery After Myocardial Infarction (2015)

Introduction: Adult newts can regenerate amputated cardiac tissue (and whole limbs) without fibrosis, unlike adult mammals which lack such regenerative capacity. Exosomes are nanoparticles which mediate intercellular communication and play a critical role in therapeutic regeneration. Hypothesis: We isolated exosomes from a newt mesodermal cell line, and evaluated their bioactivity in rat models. Methods: A1 cells, derived from the amputated limb buds of Notopthalmus viridescense (Brockes JP, 1988), were expanded in culture. Exosomes were isolated by polyethylene glycol precipitation of A1-conditioned serum-free media (or media conditioned by human dermal fibroblasts [DF] as a control) followed by centrifugation. Bioactivity was tested in vitro on neonatal rat ventricular myocytes (NRVM), and in vivo on acute myocardial infarction in Wistar-Kyoto rats (250μg or 500μg of A1-exosomes or vehicle [placebo] injected intramyocardially). Functional and histological analyses were performed 3 weeks after therapy. Results: A1-conditioned media yielded ~2.8±1Billion particles/ml of 129±1.1 nm diameter. In vitro, A1-exosomes increased the proliferative capacity of NRVM compared to DF-exosomes (4.98±0.89% vs 0.77±0.33%, p=0.035). Priming of DFs with A1-exosomes increased SDF-1 secretion compared to DF-exosomes (755±117pg/ml vs.368±21pg/ml, p=0.03). In vivo, both A1-exosome doses increased cardiac function compared to placebo (EF= 46±1% in 250μg, 49±4% in 500μg vs 36±1% in placebo, p=0.045 by ANOVA). Scar size was markedly decreased (11±1% in 250μg, 9±2% in 500μg vs 18±2% in placebo, p=0.006 by ANOVA), and infarct wall thickness was increased after A1-exosome treatment (1.7±0.11mm in 250μg, 1.85±0.16mm in 500μg vs 1.17±0.11mm in Placebo, p=0.01 by ANOVA). Donor-specific antibodies were present at barely detectable levels in the serum of animals that had been injected with A1-exosomes. Conclusions: Newt exosomes stimulate rat cardiomyocyte proliferation and improve functional and structural outcomes in rats with myocardial infarction. Characterization of the RNA and protein content of newt exosomes, now in progress, may provide clues regarding conserved (or newt-unique) molecular mediators of therapeutic benefit.
Endothelin is a potent long-lasting vasoconstrictor in men (1989)

Endothelin, a 21-amino acid peptide synthesized by cultured porcine aortic endothelial cells, has recently been identified and shown to produce a potent and prolonged constriction of mammalian blood vessels in vitro. We have studied the effect of local infusion of this peptide on resistance and capacitance vessels of normal volunteers. Infusion of endothelin (5 pmol/min) reduced forearm blood flow by 39 +/- 7% from control observations. The maximum response was seen after approximately 55 min of infusion. After stopping the infusion, return of flow to basal values took approximately 120 min. This contrasts with the short onset and duration of action observed when angiotensin II was infused. During coinfusion studies, reversal by nicardipine (0.3-10 micrograms/min) occurred at similar concentrations in both endothelin-induced and angiotensin-induced flow reduction. This observation suggests that nicardipine nonspecifically antagonizes the flow-reducing effects of endothelin. A pattern of slow onset of constriction was found on local infusion of endothelin (5 pmol/min) into dorsal hand veins. During coinfusion of nicardipine (1.5 microgram/min), no reversal of endothelin-induced (5 pmol/min) constriction of dorsal hand veins occurred. The pharmacological profile of this peptide in the peripheral circulation of humans suggests that it may be involved in long-term regulation of vascular tone.
Monocyte Chemotactic Protein-1 Expression Is Associated With the Development of Vein Graft Intimal Hyperplasia (1997)

Infiltration of immunologically active cells into vein grafts is concomitant with the development of intimal hyperplasia (IH) and often leads to obliterative stenosis and graft failure. Previous work has demonstrated the prolonged presence of monocytes and macrophages in vein grafts. The stimuli attracting these macrophages remain unidentified. Monocyte chemotactic protein-1 (MCP-1), a potent and specific chemokine for monocytes/macrophages, is secreted by smooth muscle cells, endothelial cells, fibroblasts, and leukocytes, all of which are present in grafted veins. In this study, we examined the temporal profile of MCP-1 gene expression in rat vein grafts by using reverse transcription-polymerase chain reaction (PCR) and immunohistochemistry. Epigastric vein-to-femoral artery bypass grafts were microsurgically placed and harvested at various time points after grafting. Histological analysis confirmed the consistent development of IH. PCR was performed and relative levels of MCP-1 quantified by autoradiography. Our results show that MCP-1 mRNA levels increased 28-fold by 4 hours after grafting and up to 117-fold by 1 week. After this time MCP-1 mRNA levels decreased; nonetheless, even at 8 weeks after grafting, message levels remained elevated 7-fold above baseline. Immunoreactive MCP-1 protein and ED1+ macrophages were detected at all time points; the degree of immunostaining correlated with MCP-1 mRNA levels. Our results support the hypothesis that upregulation of MCP-1 gene expression in vein grafts results in the recruitment of monocytes and tissue macrophages to the vein wall, which leads to IH. The correlation between monocyte/ macrophage infiltration and IH suggests a critical role for these cells in IH development.
Microbial Fuel Cell Cathodes With Poly(dimethylsiloxane) Diffusion Layers Constructed around Stainless Steel Mesh Current Collectors (2010)

A new and simplified approach for making cathodes for microbial fuel cells (MFCs) was developed by using metal mesh current collectors and inexpensive polymer/carbon diffusion layers (DLs). Rather than adding a current collector to a cathode material such as carbon cloth, we constructed the cathode around the metal mesh itself, thereby avoiding the need for the carbon cloth or other supporting material. A base layer of poly(dimethylsiloxane) (PDMS) and carbon black was applied to the air-side of a stainless steel mesh, and Pt on carbon black with Nafion binder was applied to the solution-side as catalyst for oxygen reduction. The PDMS prevented water leakage and functioned as a DL by limiting oxygen transfer through the cathode and improving coulombic efficiency. PDMS is hydrophobic, stable, and less expensive than other DL materials, such as PTFE, that are commonly applied to air cathodes. Multiple PDMS/carbon layers were applied in order to optimize the performance of the cathode. Two PDMS/carbon layers achieved the highest maximum power density of 1610 +/- 56 mW/m(2) (normalized to cathode projected surface area; 47.0 +/- 1.6 W/m(3) based on liquid volume). This power output was comparable to the best result of 1635 +/- 62 mW/m(2) obtained using carbon cloth with three PDMS/carbon layers and a Pt catalyst. The coulombic efficiency of the mesh cathodes reached more than 80%, and was much higher than the maximum of 57% obtained with carbon cloth. These findings demonstrate that cathodes can be constructed around metal mesh materials such as stainless steel, and that an inexpensive coating of PDMS can prevent water leakage and lead to improved coulombic efficiencies.
Different Isoforms of HPV-16 E7 Protein are Present in Cytoplasm and Nucleus (2008)

The E7 protein of high risk HPV types has been found with different molecular weights, mainly because of phosphorylation, an event that changes protein charge and mobility in SDS-PAGE. Distribution of E7 protein in the cellular compartments has also been subject of debate as some groups report the protein in nucleus and others in cytoplasm. The different subcellular distribution and molecular weights reported for the E7 protein suggest the presence of isoforms. We examined this possibility by using several antibodies that recognize different epitopes on the HPV-16 E7 protein. We showed that E7 is processed in 3 isoforms with different molecular weights and isoelectric points (IEP), and described as E7a1 (17.5 kDa, IEP 4.68), E7a (17 kDa, IEP 6.18) and E7b (16 kDa, IEP 6.96). The immunofluorescense results also showed that E7 is distributed into different compartments (ER, Golgi and nucleus), which suggest the presence of other posttranslational modifications, besides phosphorylation.
Hazard communication: challenges in the pharmaceutical industry. (1997)

Several of the major regulations mandating hazard communication programs around the world are reviewed and their applicability to the pharmaceutical industry is discussed. Regulation distinctions that are key to compliance activities are highlighted.
Calcitonin Gene-Related Peptide-Targeted Therapies for Migraine and Cluster Headache: A Review (2017)

Abstract Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from activated trigeminal sensory afferents in headache and facial pain disorders. There are a handful of CGRP-targeted therapies currently in phase 3 studies for migraine acute treatment or prevention. Currently, 4 monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in clinical trials for cluster headache prevention as well. Several other small-molecular CGRP receptor antagonists are in earlier stages of development for acute migraine treatment or prevention. In this review, we will discuss the growing body of clinical trials studying CGRP-targeted therapies for migraine and cluster headache.
Progression of Late-Onset Stargardt Disease (2016)

We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high.
Evidence for a natural gene transfer from the ponyfish to its bioluminescent bacterial symbiont Photobacter leiognathi. The close relationship between bacteriocuprein and the copper-zinc superoxide dismutase of teleost fishes. (1981)

The copper and zinc-containing superoxide dismutases of six teleost fish species and of the bioluminescent bacterium Photobacter leiognathi were isolated and characterized, as was the iron-containing superoxide dismutase of P. leiognathiThe amino acid composition of the CuZn enzyme from P. leiognathi was more closely related to the corresponding fish enzymes than it was to any other yet described CuZn superoxide dismutase.Rank order correlation analysis o f amino acid difference indices, computed for all pairwise comparisons of bacteriocuprein and the ponyfish enzyme with other CuZn-superoxide dismutases, suggested that the bacterid and ponytish enzymes occupy similar phylogenetic positions, being most closely related to the superoxide dismutases of teleost fish.Discriminant functions analysis of all available superoxide dismutase amino acid compositions demonstrated that correct group classification could be achieved on the sole basis of amino acid composition.Thus, Fe and Mn superoxide dismutase groups could be delineated and both groups differed dramatically from the CuZn-superoxide dismutases, Bacteriocuprein was classified with the CuZn-superoxide dismutase group.Moreover, this analytical method subdivided the CuZn group into three subgroups made up of the avian plus mammalian, plant plus fungal, and the fish enzymes, with the P. €eeiognuthi enzyme placed in the fish subgroup.The physicochemical properties of the P. leiognuthi CuZn-superoxide dismutases were very similar to those of the comparable CuZn enzymes from other sources, especially those of teleost fish.In view of the long standing symbiosis between P.Zeiognathi and its teleost hosts, the leiognathid fishes, these results suggest that the gene specifying the CuZnsuperoxide dismutase was transferred from the fish to the bacterium, during their coevolutionary history.Three major types of superoxide dismutases have been described.The first of these contains Cu and Zn, the second
Spinal muscular atrophy: molecular genetics and diagnostics (2004)

Spinal muscular atrophy is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN genes, SMN1 and SMN2. Due to a single nucleotide polymorphism (840C>T), SMN2 produces less full-length transcript than SMN1 and cannot entirely prevent neuronal cell death at physiologic gene dosages. The 38-kDa SMN protein comprises 294 amino acids and is involved in the biogenesis of uridine-rich small nuclear ribonucleoproteins, facilitating their cytoplasmic assembly into the spliceosome. Various animal models have been developed to study the pathogenesis of spinal muscular atrophy, as well as to test novel therapeutics. Common PCR-restriction fragment length polymorphism assays can detect the homozygous absence of SMN1 in approximately 94% of patients with clinically typical spinal muscular atrophy. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counseling are particularly important. Comprehensive SMA genetic testing, combined with appropriate genetic counseling and risk assessment, provides the most complete evaluation of patients and their families at this time. New technologies, such as monosomal analysis techniques, may be widely available in the future.
GENE THERAPY: Twenty-First Century Medicine (2005)

Broadly defined, the concept of gene therapy involves the transfer of genetic material into a cell, tissue, or whole organ, with the goal of curing a disease or at least improving the clinical status of a patient. A key factor in the success of gene therapy is the development of delivery systems that are capable of efficient gene transfer in a variety of tissues, without causing any associated pathogenic effects. Vectors based upon many different viral systems, including retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses, currently offer the best choice for efficient gene delivery. Their performance and pathogenicity has been evaluated in animal models, and encouraging results form the basis for clinical trials to treat genetic disorders and acquired diseases. Despite some initial success in these trials, vector development remains a seminal concern for improved gene therapy technologies.
Fatigue properties of carbon‐ and porous‐coated Ti6Al4V alloy (1984)

A porous metal coating applied to a solid substrate implant has been shown, in vivo, to offer advantages over current polymethylmethacrylate cement fixation in orthopedic devices. These advantages may be lost, however, in devices requiring a sintering heat treatment to apply the coating since these treatments may have a detrimental effect on the substrate material mechanical properties. In addition, more biocompatible interface coating materials have come of interest with recent literature reports of metal ion release. These coatings may be of particular use in porous-coated systems since the surface area of implant in contact with the surrounding tissues is greatly increased. This study investigated the effects that both a porous Ti- 6Al -4V alloy coating and a ULTI carbon coating have on the fatigue properties of a Ti- 6Al -4V alloy substrate system. The fatigue properties of uncoated as-received, uncoated sinter heat treated and notched Ti- 6Al -4V material were also investigated. The results of this study revealed endurance limits for Ti- 6Al -4V alloy tested with a rotating beam system of 617 MN/m2 (uncoated as-received), 624 MN/m2 ( ULTI carbon-coated), 377 MN/m2 ( sinter heat treated), 220 MN/m2 (notched) and 138 MN/m2 (porous-coated). No effects on fatigue properties were observed when testing the material in saline compared with air. The slight increase in fatigue strength for the carbon-coated material is thought to be due to the increase in surface hardness resulting from the formation of titanium carbides on the surface. The low-endurance limit of the porous-coated material is due to both the transition from the as-received equiaxed microstructure to a lamellar microstructure upon sintering and to the notch effect created by the porous coating.
Tumor Antigen Expression in Melanoma Varies According to Antigen and Stage (2006)

This large series describes patterns of antigen expression in melanoma and their evolution over time. This will help inform decisions about selection of patients and target antigens for melanoma immunotherapy clinical trials.
Vascular endothelial growth factor (VEGF)–C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy (2002)

Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4(+) leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.
Activation of the TRPV4 Ion Channel Is Enhanced by Phosphorylation (2009)

The TRPV4 (transient receptor potential vanilloid 4) ion channel, a member of the vanilloid subfamily of the transient receptor potential channels, is activated by membrane stretch, by non-noxious warm temperatures, and by a range of chemical activators. In the present study we examined the role of phosphorylation in modulating the activation of TRPV4. We expressed TRPV4 in HEK293 cells and activated the channel by cell swelling in a hypotonic solution. TRPV4 channel activation and serine phosphorylation were enhanced by exposure to the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate or by application of bradykinin, which activates PKC via a G-protein-coupled mechanism. The enhancement was inhibited by the PKC inhibitors staurosporine, bisindolylmaleimide I, and rottlerin or by mutation of the serine/threonine residues Ser(162), Thr(175), and Ser(189). The adenylate cyclase activator forskolin also enhanced activation of TRPV4, and the enhancement was antagonized by the selective cyclic AMP-dependent protein kinase (PKA) inhibitor H89 or by mutation of serine residue Ser(824). Sensitization of TRPV4 by both PKC and PKA depended on the scaffolding protein AKAP79, because channel activation and phosphorylation were enhanced by co-transfection of AKAP79 and were antagonized by removal of AKAP79 using small interfering RNA. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.
A Closer Look at SNPs Suggests Difficulties (1998)

SKOKLOSTER, SWEDEN--
 During the past year, researchers, both public and private, have scrambled to accumulate the single-base variations in the human genetic code called single-nucleotide polymorphisms, or SNPs, because they believed that SNPs would be extremely helpful in tracking disease genes and understanding human genetic diversity. But new results presented here earlier this month at the first international meeting devoted to SNPs suggest that using SNPs to achieve these goals could prove more difficult than initially thought. In some cases, SNPs might fail to pick up disease genes, or researchers will need to have many more SNPs located in and around the suspected disease gene to make their case than first anticipated. Other work suggests that researchers will also need more information about the history of the people being studied, such as their migration patterns, to make sense of their SNP data.
M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and nonalcoholic fatty liver disease (2013)

These data uncover a novel mechanism regulating the M1/M2 balance that relies on apoptotic effects of M2 KCs towards their M1 counterparts. They suggest that promoting M2-induced M1 KC apoptosis might prove a relevant strategy to limit alcohol- and high fat-induced inflammation and hepatocyte injury.
Influence of Amino Acid Substitutions Related to Inherited Human Prion Diseases on the Thermodynamic Stability of the Cellular Prion Protein (1999)

Transmissible spongiform encephalopathies (TSEs) are caused by a unique infectious agent which appears to be identical with PrPSc, an oligomeric, misfolded isoform of the cellular prion protein, PrPC. All inherited forms of human TSEs, i.e., familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia, segregate with specific point mutations or insertions in the gene coding for human PrP. Here we have tested the hypothesis that these mutations destabilize PrPC and thus facilitate its conversion into PrPSc. Eight of the disease-specific amino acid replacements are located in the C-terminal domain of PrPC, PrP(121-231), which constitutes the only part of PrPC with a defined tertiary structure. Introduction of all these replacements into PrP(121-231) yielded variants with the same spectroscopic characteristics as wild-type PrP(121-231) and similar to full-length PrP(23-231), which excludes the possibility that the exchanges a priori induce a PrPSc-like conformation. The thermodynamic stabilities of the variants do not correlate with specific disease phenotypes. Five of the amino acid replacements destabilize PrP(121-231), but the other variants have the same stability as the wild-type protein. These data suggest that destabilization of PrPC is neither a general mechanism underlying the formation of PrPSc nor the basis of disease phenotypes in inherited human TSEs.