gebhart/patrepeval huggingface dataset:
Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects (2002)

Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.
Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs (2020)

Abstract COVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA-approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM &lt; IC 50 &lt; 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.
Retaining Key People in Troubled Companies (2002)

High performance of dedicated workers is the key approach in accelerating recovery through a company’s slowdown. Unfortunately, most companies are forgetting important lessons and practices that can help them stay afloat through tough economic times. It is essential to recognize key employees and their contributions to the company. This article outlines some strategies for companies to stay on course. First and foremost, companies should retain top talent in troubled times. The larger challenge is then helping businesses toward recovery. The way that companies respond to troubled times determines which of them will dominate the next economic cycle. Maintaining a high performance ethic may help companies stay out of trouble in the future.
A Need for Speed: Genetic Encoding of Rapid Cycloaddition Chemistries for Protein Labelling in Living Cells (2012)

Rapid reactions: Several reactants for strain-promoted cycloaddition reactions have been genetically encoded as the side chains of noncanonical amino acids. This results in decisive improvements for the fluorescent labelling of intracellular proteins such as quantitative turnover, completion of labelling reactions within minutes, fluorogenic effects and even partial orthogonality for multicolour labelling.
Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs (2003)

The role of thrombopoietin (Tpo) in promoting hematopoiesis has been extensively studied in late fetal, neonatal, and adult mice. However, the effects of Tpo on early yolk sac hematopoiesis have been largely unexplored. We examined whole embryos or the cells isolated from embryo proper and yolk sacs and identified both Tpo and c-mpl (Tpo receptor) mRNA transcripts in tissues as early as embryonic day 6.5 (E6.5). Presomite whole embryos and somite-staged yolk sac and embryo proper cells were plated in methylcellulose cultures and treated with selected hematopoietic growth factors in the presence or absence of Tpo. Tpo alone failed to promote colony-forming unit (CFU) formation. However, in the presence of other growth factors, Tpo caused a substantial dose-dependent reduction in primitive and definitive erythroid CFU growth in cultures containing E7.5 and E8.0 whole embryos and E8.25 to 9.5 yolk sac-derived cells. Meanwhile, Tpo treatment resulted in a substantial dose-dependent increase in CFU-mixed lineage (CFU-Mix) and CFU-megakaryocyte (CFU-Meg) formation in cultures containing cells from similar staged tissues. Addition of Tpo to cultures of sorted E9.5 yolk sac c-Kit(+)CD34(+) hematopoietic progenitors also inhibited erythroid CFU growth but augmented CFU-Mix and CFU-Meg activity. Effects of Tpo on CFU growth were blocked in the presence of a monoclonal antibody with Tpo-neutralizing activity but not with control antibody. Thus, under certain growth factor conditions, Tpo directly inhibits early yolk sac erythroid CFU growth but facilitates megakaryocyte and mixed lineage colony formation.
Bacilysin from Bacillus amyloliquefaciens FZB42 Has Specific Bactericidal Activity against Harmful Algal Bloom Species (2014)

Harmful algal blooms, caused by massive and exceptional overgrowth of microalgae and cyanobacteria, are a serious environmental problem worldwide : In the present study, we looked for Bacillus strains with sufficiently strong anticyanobacterial activity to be used as biocontrol agents. Among 24 strains, Bacillus amyloliquefaciens FZB42 showed the strongest bactericidal activity against Microcystis aeruginosa, with a kill rate of 98.78%. The synthesis of the anticyanobacterial substance did not depend on Sfp, an enzyme that catalyzes a necessary processing step in the nonribosomal synthesis of lipopeptides and polyketides, but was associated with the aro gene cluster that is involved in the synthesis of the sfp-independent antibiotic bacilysin. Disruption of bacB, the gene in the cluster responsible for synthesizing bacilysin, or supplementation with the antagonist N-acetylglucosamine abolished the inhibitory effect, but this was restored when bacilysin synthesis was complemented. Bacilysin caused apparent changes in the algal cell wall and cell organelle membranes, and this resulted in cell lysis. Meanwhile, there was downregulated expression of glmS, psbA1, mcyB, and ftsZ-genes involved in peptidoglycan synthesis, photosynthesis, microcystin synthesis, and cell division, respectively. In addition, bacilysin suppressed the growth of other harmful algal species. In summary, bacilysin produced by B. amyloliquefaciens FZB42 has anticyanobacterial activity and thus could be developed as a biocontrol agent to mitigate the effects of harmful algal blooms.
Elastic tissue abnormalities resembling pseudoxanthoma elasticum in β thalassemia and the sickling syndromes (2002)

The development of clinical and histopathologic manifestations of a diffuse elastic tissue defect, resembling inherited pseudoxanthoma elasticum (PXE), has been encountered with a notable frequency in patients with beta thalassemia, sickle cell disease, and sickle thalassemia. The PXE-like clinical syndrome, consisting of skin, ocular, and vascular manifestations, has a variable severity in these hemoglobinopathies and it is age-dependent, with a generally late onset, after the second decade of life. The defect is believed to be acquired rather than inherited and related to the consequences of the primary disease. The high prevalence of the findings implicates the elastic tissue injury as one of the main comorbid abnormalities encountered in beta thalassemia and the sickling syndromes. In these patients a number of complications, sometimes serious, has been recognized to be related to ocular and vascular elastic tissue defects. Because several organ systems are involved, each medical specialty should be aware of the phenomenon. This coexistence, on the other hand, introduces a novel pathogenetic aspect of PXE and an important research challenge.
Platelet-derived growth factor improves cardiac function in a rodent myocardial infarction model (2004)

These studies demonstrate that PDGF pretreatment improves cardiac function following acute coronary occlusion. Strategies based on the cardioprotective actions of PDGF may provide a significant advance in the treatment of myocardial infarction.
The National Cancer Data Base report on longitudinal observations on prostate cancer (1996)

These data show that the clinical patterns of prostate cancer have changed markedly in recent years.
A peer-to-peer discovery protocol for semantic Web services in industrial embedded controllers (2005)

One of the significant challenges for current and future manufacturing systems is that of providing rapid reconfigurability in order to evolve and adapt to mass customization. Service-oriented architecture has been proposed as a technology facilitator to create systems by encapsulating, composing and reconfiguring machines and devices rather than reprogramming the hard code. The SOA paradigm holds the promise of being applicable across the entire spectrum of manufacturing systems and devices, down to sensors and actuators. One of the pillars of SOA is the mechanism by which service advertisements are published by providers and subsequently discovered and selected by requestors. This paper presents a protocol for the dynamic discovery of services in industrial environments. The protocol is designed for operation in embedded industrial controllers, and operates in a peer-to-peer topology without a need for centralized service registries. Furthermore, the protocol enables conveying information regarding services that are semantically interoperable but that use different invocation syntax. In order to infer such semantic relationships between services, the OWL-S semantic Web services ontology is used. The protocol was deployed in embedded industrial controllers in order to facilitate the reconfiguration of assembly systems that employ CAMX standards for communications.
Aprotinin Dosing: How Much Is Enough? (2004)

Coagulopathy and postoperative bleeding continue to be a major concern for patients undergoing cardiac surgery with cardiopulmonary bypass. Pharmacologic attenuation of this morbidity has been one area that clinicians have held in high interest. Aprotinin, a serine protease inhibitor, has been shown to be effective in reducing bleeding as well as the need for blood component transfusions. Although effective, aprotinin is an expensive drug and this, in conjunction with a cost-conscious community, has led clinicians to determine what is the lowest effective dose of aprotinin. From these studies, various aprotinin dosing regimens have been studied with differing results. The purpose of this work is to review the effectiveness of the various dosing strategies and to examine potential benefits of a dosing regimen based on a patient's weight, which may allow clinicians to achieve the maximal benefits from aprotinin without overdosing patients.
RGD-conjugated albumin nanoparticles as a novel delivery vehicle in pancreatic cancer therapy (2012)

Integrin αvβ3 receptor is expressed on several types of cancer cells, including pancreatic cancer cells, and plays an important role in tumor growth and metastasis. The ability to target the integrin αvβ3 receptor on cancer cells increases the efficacy of targeted therapy and reduces the side effects. The aim of this study is to develop a novel arginine-glycine-aspartic acid (RGD) peptide -conjugated albumin nanoparticle to enhance the intracellular uptake of anticancer drug into the pancreatic cancer cells through receptor-mediated endocytosis. In the cellular uptake studies, the fluorescent signal of RGD-conjugated BSANPs in BxPC3 cells was higher than that of BSANPs without RGD conjugation as determined by fluorescence spectrophotometer. We also found that BSANPs bound to BxPC3 cells in a time- and concentration-dependent manner. The uptake of RGD-conjugated BSANPs by pancreatic cancer cells was inhibited by an excess amount of free RGD peptide, indicating that the binding and/or uptake were mediated by the αvβ3 receptor. Furthermore, the nanoparticles were found to be located close to the nuclei by using laser scanning confocal microscopy. Besides, no significant in vitro cytotoxicity was observed as measured with MTT assay. Both in vitro and in vivo antitumor efficacy was improved by targeting gemcitabine-loaded nanoparticles to BxPC-3 cells using RGD peptides. Therefore, the RGD-conjugated BSANPs hold great potential as an effective drug delivery system to deliver therapeutic agents to pancreatic cancer.
Scientific and Ethical Concerns in Neural Fetal Tissue Transplantation (1993)

This report presents a brief overview of the medical and ethical issues involved with the procurement, preparation, safety, efficacy, and subject protection of human fetal central nervous system tissue in the context of neural transplantation. The ethical perspectives from which to view the clinical use of fetal tissue include the following: 1) that fetal tissue from elective abortions is a surgical specimen; 2) that the use of such tissue involves fetal experimentation in which the fetus is a subject; and 3) that fetal tissue is considered as a cadaveric organ specimen, similar to other organs, but with special considerations compared with adult cadaveric tissue. The latter approach appears to be the most applicable and is parallel to the use of cadaveric organs and tissues after a declaration of brain death. Additional issues include the following: 1) the safety and quality of fetal tissue for implantation; 2) the hypothesis that "legitimization" and "redemption" (potentially positive effects of tissue donation in general) may lead to an increase in elective abortion rates; 3) the ethical issues of the validity and value of human experimentation involving neural grafting; and 4) the type of consent to be obtained and the appropriate timing. Elective abortions, however, probably will continue to be the primary source of fetal tissue for grafting for some time, until other tissue sources become available.
Expression and localization of amiloride-sensitivesodium channel indicate a role for non-taste cells in tasteperception. (1994)

Salty taste is blocked by the diuretic amiloride, which inhibits specific sodium channels. We have isolated an amiloride-sensitive sodium channel (ASSC) from taste tissues by polymerase chain reaction and screening of a cDNA library prepared from rat circumvallate papillae. Northern analysis reveals ASSC in taste and non-taste tissues with the highest level of expression of ASSC in the lung. In situ hybridization establishes ASSC localizations in the epithelia of lung and colon as well as tongue epithelial layers containing and lacking taste buds. These results support a model in which ASSC in non-taste cells regulates responses of taste cells to salt as well as other tastants.
Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes (2002)

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.
Characterization of the structural and functional defect in the Escherichia coli single-stranded DNA binding protein encoded by the ssb-1 mutant gene. Expression of the ssb-1 gene under lambda pL regulation. (1984)

The ssb-1 gene encoding a mutant single-stranded DNA binding protein (SSB-1) has been cloned into a vector placing its expression under lambda pL regulation. This construction results in more than 100-fold increased expression of the mutant protein following temperature induction. Tryptic peptide analysis of the mutant protein by high-pressure liquid chromatography and solid-phase protein sequencing has shown that the ssb-1 mutation results in these substitution of tyrosine for histidine at residue 55 of SSB. This change could only occur in one step by a C----T transition in the DNA sequence which has been confirmed. Physicochemical studies of the homogeneous mutant protein have shown that in contrast to that of the wild-type SSB, the tetrameric structure of SSB-1 is unstable and gradually dissociates to monomer as the protein concentration is decreased from about 10 microM to less than 0.5 microM. The SSB-1 tetramer appears to be stable to elevated temperature (45 degrees C) but the monomer is not. We estimate the normal cellular concentration of SSB-1 (single chromosomal gene) to be 0.5-1 microM. Thus, there is a plausible physical explanation for our previous finding that increased expression of ssb-1 reverses the effects of a single gene (chromosomal) copy amount of SSB-1 (Chase, J.W., Murphy, J.B., Whittier, R.F., Lorensen, E., and Sninsky, J.J. (1983) J. Mol. Biol. 164, 193-211). However, even though the in vivo effects of ssb-1 and most of the in vitro defects of SSB-1 protein are reversed simply by increasing SSB-1 protein concentration, the mutant protein is not as effective a helix-destabilizing protein as wild-type SSB as measured by its ability to lower the thermal melting transition of poly[d-(A-T)].
Increased phosphorylation of specific nuclear proteins in superior cervical ganglia and PC12 cells in response to nerve growth factor. (1980)

Treatment of rat superior cervical ganglia in culture with nerve growth factor (NGF) increases the amount of radioactive phosphate incorporated into a nuclear protein band. This band migrates coincidentally with H1 histone on 10% sodium dodecyl sulfate/polyacrylamide gels. The increase in phosphate incorporation is at least 70% and occurs only in tissues known to be responsive to NGF. It is not produced by treatment with related peptides, but is observed after the addition of dibutyryl cyclic AMP. An increase in phosphorylation can be detected after 1 h, and can be seen with as little as 10 ng/ml of NGF in the medium. Neither actinomycin D nor cycloheximide inhibits the effect. When the nuclei are extracted with 0.2 M H2SO4 and the extract analyzed on acid-urea/polyacrylamide gels, two NGF-responsive proteins can be detected. One protein again migrates with the H1 histone marker; the other migrates more slowly than H1. These two NGF-responsive proteins have molecular weights of approximately 30,000 and are chromatin-bound. They are not soluble in 5% perchloric acid, but can be extracted from the nuclei with 0.35 M NaCl. No increase in the phosphorylation of these proteins was seen in ganglia from 6-hydroxydopamine-treated rats. The phosphorylation of the proteins in both control and NGF-treated ganglia occurs almost exclusively on serine residues. The amino acid compositions of the two nuclear proteins show that they are different from the H1 histone and different from each other. Both nerve growth factor (NGF) and epidermal growth factor (EGF) increase the incorporation of radioactive phosphate into a specific nuclear protein in cultures of PC12, a clone of rat pheochromocytoma. Purified NGF antibody blocks the effect of NGF, but not that of EGF; EGF antiserum neutralizes the effect of EGF, but not that of NGF. Insulin, glucagon, and dexamethasone are without effect. The increase in phosphorylation due to NGF can be detected within 1 h. Dibutyryl cyclic AMP increases the phosphorylation of this protein, but dibutyryl cyclic GMP does not. Neither the uptake nor the overall incorporation of [32P]orthophosphate is altered by NGF, EGF, or dibutyryl cAMP under the present experimental conditions. The nuclear protein exhibiting increased radioactivity is similar in solubility, size, and amino acid composition to one of the NGF-responsive nuclear proteins from sympathetic ganglia.
Growth and Characterization of Polycrystalline Silicon (1973)

Polycrystalline silicon is deposited by pyrolysis of silane in an rf heated epitaxial reactor. The grains exhibit a fibrous microstructure having an 〈110〉 preferred orientation in the growth direction. Growth is inhibited in the presence of excess arsine and accelerated in the presence of diborane. The results are explained in terms of catalysis and poisoning of surface adsorption sites responsible for reaction. A simple model for current conduction in polycrystalline silicon is described based on grain size, grain doping, and effective barrier height due to the grain boundary. This model satisfactorily explains the observed temperature dependence of the resistivity of undoped films and also the large values of resistivity which are observed for dopant concentrations .
EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes (2007)

EGFRvIII is a mutant variant of the epidermal growth factor receptor (EGFR) found exclusively in various cancer types. EGFRvIII lacks a large part of the extracellular domain and is unable to bind ligands; however, the receptor is constitutively phosphorylated and able to activate downstream signaling pathways. Failure to attenuate signaling by receptor down-regulation could be one of the major mechanisms by which EGFRvIII becomes oncogenic. Using a cell system expressing either EGFR or EGFRvIII with no expression of other EGFR family members and with endogenous levels of key degradation proteins, we have investigated the down-regulation of EGFRvIII and compared it to that of EGFR. We show that, in contrast to EGFR, EGFRvIII is inefficiently degraded. EGFRvIII is internalized, but the internalization rate of the mutated receptor is significantly less than that of unstimulated EGFR. Moreover, internalized EGFRvIII is recycled rather than delivered to lysosomes. EGFRvIII binds the ubiquitin ligase c-Cbl via Grb2, whereas binding via phosphorylated tyrosine residue 1045 seems to be limited. Despite c-Cbl binding, the receptor fails to become effectively ubiquitinylated. Thus, our results suggest that the long lifetime of EGFRvIII is caused by inefficient internalization and impaired sorting to lysosomes due to lack of effective ubiquitinylation.