gebhart/patrepeval huggingface dataset:
Clinical Evaluation of Psychotropic Drugs: Principles and Guidelines (1994)

Part 1 Historical perspectives: history and role of guidelines and guidance of drug evaluation, Jerome Levine decision processes in establishing the efficacy and safety of psychotropic drugs, Louis Lasagna. Part 2 General principles in the evaluation of psychotropic drugs: design issues for the clinical evaluation of psychotropic drugs, Eugene M. Laska et al classification issues in patient selection and description, Jean Endicott et al assessment and measurement of clinical change, A. John Rush et al pharmacologic considerations, David J. Grenblatt et al statistical issues for the clinical evaluation of psychotropic drugs, Philip W. Lavori et al clinical trial implementation, Ronald Kartzinel et a premarketing safety evaluation of psychotropic drugs, Thomas P. Laughren et al post-marketing surveillance of drugs, Leo E. Hollister et al documenting and reporting the study results of a randomized clinical trial (spicy meatballs, not pabulum), David J. Kupfer et al ethical and legal considerations in drug trials, Don Gallant and Susan Krinsky. Part 3 Specific patient groups - application of general methodologic principles: evaluating drug treatments of depressive disorders, Gerals L. Klerman et al evaluating pharmacologic treatments for bipolar disorder, Alan J. Gelenberg et al methods for clinical evaluation of pharmacologic treatments of schizophrenia, John M. Kane et al evaluating drug treatments of generalized anxiety disorder and adjustment disorders with anxious mood, Karl Rickels et al evaluation of psychotropic drug treatment of panic-related disorders and social phobia, Donald F. Klein et al obsessive-compulsive disorder, Wayne K. Goodman et al methods for the evaluation of pharmacologic agents in the treatment of cognitive and other deficits in dementia, Samuel Gershon et al clinical trials in children and adolescents, Rachel G. Klein et al evaluation of pharmacolocig treatments in eating disorders, Katherine A. Hamli et al evaluation of hypnotic medications, Thomas Roth et al establishing the efficacy and safety of medications for the treatment of drug dependence and abuse - methodologic issues, Jack D. Blaine et al evaluation of pharmacological treatments for alcohol abuse, dependence and their complications, Markku Linnoila et al evaluation of pharmacologic treatments in personality disorders, Paul H. Soloff et al.
Conducting polymers grown in hydrogel scaffolds coated on neural prosthetic devices (2004)

The conducting polymer polypyrrole (PPy) was electrochemically grown on hydrogel scaffolds deposited on the surface of microfabricated neural prosthetic devices. It is shown that the pyrrole monomer can be grown vertically through the hydrogel layer up to the surface without affecting the adjacent sites on the probes. The electrochemical properties of the conducting polymer-modified hydrogels were studied by impedance spectroscopy and cyclic voltammetry. It is also found that the conducting polymers could still be readily grown through the hydrogel after the microstructure is disrupted by freeze drying. Impedance measurements at the biologically important frequency of 1 kHz showed that the minimum impedance of this polymer-modified hydrogel was 7 kOmega. This is much lower than the minimum impedance of polypyrrole film ( approximately 100 kOmega).
New molecular targets in angiogenic vessels of glioblastoma tumours (2008)

Antiangiogenesis approaches have the potential to be particularly effective in the treatment of glioblastoma tumours. These tumours exhibit extremely high levels of neovascularisation, which may contribute to their extremely aggressive behaviour, not only by providing oxygenation and nutrition, but also by establishing a leaky vasculature that lacks a blood-brain barrier. This leaky vasculature enables migration of tumour cells, as well as the build up of fluid, which exacerbates tissue damage due to increased intracranial pressure. Here, we discuss the considerable progress that has been made in the identification of the pro- and antiangiogenic factors produced by glioblastoma tumours and the effects of these molecules in animal models of the disease. The safety and efficacy of some of these approaches have now been demonstrated in clinical trials. However, the ability of tumours to overcome these therapies and to re-establish angiogenesis requires further clinical research regarding potential multimodality therapies, as well as basic research into the regulation of angiogenesis by as yet unidentified factors. Optimisation of noninvasive procedures for monitoring of angiogenesis would greatly facilitate such research.
Three-Dimensional Structure of Cholera Toxin Penetrating a Lipid Membrane (1988)

Two-dimensional crystals of cholera toxin bound to receptors in a lipid membrane give diffraction extending to 15 A resolution. Three-dimensional structure determination reveals a ring of five B subunits on the membrane surface, with one-third of the A subunit occupying the center of the ring. The remaining mass of the A subunit appears to penetrate the hydrophobic interior of the membrane. Cleavage of a disulfide bond in the A subunit, which activates the toxin, causes a major conformational change, with the A subunit mostly exiting from the B ring.
Allele-specific competitive blocker PCR: A one-step method with applicability to pool screening (1995)

We have developed a novel one-step pool screening PCR procedure which is based on the principles of amplification refractory mutation system (ARMS) and competitive oligonuleotide priming (COP) PCR. In addition to the usual primers, this approach uses two allele-specific competitive oligonucleotides, one of which is 3'-end labeled with a dideoxynucleotide and blocks amplification of the wild-type allele. An allele-specific product is generated only in the presence of the mutation. The introduction of an allele-specific competitive blocker oligonucleotide improves the specificity and robustness of ARMS-PCR. Further its sensitivity is dramatically increased, which allows detection of one mutant allele in a large excess of wild-type-bearing genomic DNA by electrophoresis in an ethidium bromide-stained agarose gel (up to 1 in 10(4) alleles). This makes the method ideal for nonradioactive pool screening. The successful application of the method has been demonstrated for four different point mutations, two in the apolipoprotein B gene (R3500Q, R3531C) which result in familial defective apolipoprotein B-100, one in the CFTR gene (R1162X), and one in the gene for lipoprotein lipase (G188E).
Benzo[ b ]quinolizinium Derivatives Have a Strong Antimalarial Activity and Inhibit Indoleamine Dioxygenase (2015)

The heme-containing enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and IDO-2 catalyze the conversion of the essential amino acid tryptophan into kynurenine. Metabolites of the kynurenine pathway and IDO itself are involved in immunity and the pathology of several diseases, having either immunoregulatory or antimicrobial effects. IDO-1 plays a central role in the pathogenesis of cerebral malaria, which is the most severe and often fatal neurological complication of infection with Plasmodium falciparum. Mouse models are usually used to study the underlying pathophysiology. In this study, we screened a natural compound library against mouse IDO-1 and identified 8-aminobenzo[b]quinolizinium (compound 2c) to be an inhibitor of IDO-1 with potency at nanomolar concentrations (50% inhibitory concentration, 164 nM). Twenty-one structurally modified derivatives of compound 2c were synthesized for structure-activity relationship analyses. The compounds were found to be selective for IDO-1 over IDO-2. We therefore compared the roles of prominent amino acids in the catalytic mechanisms of the two isoenzymes via homology modeling, site-directed mutagenesis, and kinetic analyses. Notably, methionine 385 of IDO-2 was identified to interfere with the entrance of l-tryptophan to the active site of the enzyme, which explains the selectivity of the inhibitors. Most interestingly, several benzo[b]quinolizinium derivatives (6 compounds with 50% effective concentration values between 2.1 and 6.7 nM) were found to be highly effective against P. falciparum 3D7 blood stages in cell culture with a mechanism independent of IDO-1 inhibition. We believe that the class of compounds presented here has unique characteristics; it combines the inhibition of mammalian IDO-1 with strong antiparasitic activity, two features that offer potential for drug development.
The effect of intravenous medetomidine on pupil size and intraocular pressure in normotensive dogs (2000)

Medetomidine, a highly specific alpha-2 adrenergic agonist, has been demonstrated to lower intraocular pressure (IOP) in rabbits and cats when applied topically. The purpose of this study was to assess the influence of intravenously injected medetomidine on the pupil size (PS) and the IOP of non glaucomatous dogs. IOP was measured by applanation tonometry and PS was measured using Jameson calipers at t=0 (or time of IV injection of medetomidine (Domitor; Orion) at the dose of 1500 microg/m2 body surface area) and again after 5 minutes (t=5). The IV administration of medetomidine caused miosis in all 14 dogs. The mean PS decreased from 9.0 to 4.0 mm (p<0.001). The IOP was lowered in 10 dogs and in 4 dogs there was a rise in IOP. The mean IOP (mmHg) decreased from 22 to 21 (p>0.2). The data presented above confirm that medetomidine at a dose of 1500 microg/m2 body surface area produces miosis in non glaucomatous dogs, without influencing the IOP.
Improving Software Quality Estimation by Combining Boosting and Feature Selection (2013)

The predictive accuracy of a classification modelis often affected by the quality of training data. However, there are two problems which may affect the quality of the training data: high dimensionality (too many independent attributes in a dataset) and class imbalance (many more instances of one class than the other class in a binary-classification problem). In this study, we present an iterative feature selection approach working with an ensemble learning method to solve both of these problems. The iterative feature selection approach samples the dataset k times and applies feature ranking to each sampled dataset, the k different rankings are then aggregated to create a single feature ranking. The ensemble learning method used is RUSBoost, in which random under sampling(RUS) is integrated into a boosting algorithm. The main purpose of this paper is to investigate the impact of feature selection as well as the RUSBoost approach on the classification performance in the context of software quality prediction. In the experiment, we explore six rankers, each used along with RUS in the iterative feature selection process. Following feature selection, models are built either using a plain learner or byusing the RUSBoost algorithm. We also examine the case of no feature selection and use this as the baseline for comparisons. The experimental results demonstrate that with the exception of one learner, feature selection combined with boosting provides better classification performance than when either is applied alone or when neither are applied.
Cryptococcus neoformans Produces Authentic Prostaglandin E 2 without a Cyclooxygenase (2006)

Many single-celled eukaryotes produce prostaglandin-like molecules, but these have not been absolutely verified by mass spectrometry. We have isolated, and identified by liquid chromatography-tandem mass spectrometry, authentic prostaglandin E(2) from Cryptococcus neoformans. Cyclooxygenase inhibitors did not inhibit prostaglandin synthesis, and the cryptococcal genome lacks a cyclooxygenase homolog. Thus, novel enzymes must exist.
Studies to show that with podophyllotoxin the early replicative stages of herpes simplex virus type 1 depend upon functional cytoplasmic microtubules (1996)

The antiviral activity of podophyllotoxin against herpes simplex type 1 virus (HSV-1) grown in Vero cells was studied by a simple microtitration assay. Antiviral effects were induced at similar concentrations as direct cellular toxicity, as characterised by a time-dependent loss of cell monolayer. Podophyllotoxin-mediated toxicity arises from cytoplasmic microtubular, and hence cytoskeletal, decay. Some degree of selectivity was seen for inhibition of virus replication over direct cellular toxicity. Podophyllotoxin acted against an early viral process, as an antiviral effect was still seen if drug was removed 2 h after infection. Similar effects were seen with colchicine, a classical tubulin-binding compound, but not with bromovinyldeoxyuridine. Podophyllotoxin was capable of inducing a cytoprotective effect in Vero cells, as pre-treatment of cells abrogated virus growth for up to 90 min after removal of drug. This is coincident with the repolymerisation of cellular microtubules and re-formation of the cytoskeleton. We conclude that HSV-1 relies upon a functional cellular cytoskeleton for efficient completion of an early replicative event. Such a process may be the transport of viral material to the nucleus or inhibition of the formation of intranuclear viral 'replication factories', bodies containing cytoskeletal fragments constructed after viral infection.
Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). (2015)

LBA8512 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, May 30, 2015, and in the Annual Meeting Proceedings online supplement to the June 20, 2015, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Agmatine: an Endogenous Clonidine-Displacing Substance in the Brain (1994)

Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors. The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain. This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain. Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells. Its biosynthetic enzyme, arginine decarboxylase, is present in brain. Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.
Downstream Processing: From Egg to Cell Culture‐Derived Influenza Virus Particles (2008)

The establishment of cell culture-derived vaccine production requires the development of appropriate downstream processes. Until today, many of the downstream methods applied originate from egg-derived production processes. These methods have often been slightly modified in order to account for the new demands. However, efforts are currently underway to optimize these processes focusing, for example, on ion exchange or affinity based membrane adsorption chromatography. This review covers the main aspects relevant for the downstream processing of egg and mammalian cell culture-derived whole influenza viruses.
Vaccination with Plasmid DNA Encoding TSA/LmSTI1 Leishmanial Fusion Proteins Confers Protection againstLeishmania majorInfection in Susceptible BALB/c Mice (2002)

We have recently shown that a cocktail containing two leishmanial recombinant antigens (LmSTI1 and TSA) and interleukin-12 (IL-12) as an adjuvant induces solid protection in both a murine and a nonhuman primate model of cutaneous leishmaniasis. However, because IL-12 is difficult to prepare, is expensive, and does not have the stability required for a vaccine product, we have investigated the possibility of using DNA as an alternative means of inducing protective immunity. Here, we present evidence that the antigens TSA and LmSTI1 delivered in a plasmid DNA format either as single genes or in a tandem digene construct induce equally solid protection against Leishmania major infection in susceptible BALB/c mice. Immunization of mice with either TSA DNA or LmSTI1 DNA induced specific CD4(+)-T-cell responses of the Th1 phenotype without a requirement for specific adjuvant. CD8 responses, as measured by cytotoxic-T-lymphocyte activity, were generated after immunization with TSA DNA but not LmSTI1 DNA. Interestingly, vaccination of mice with TSA DNA consistently induced protection to a much greater extent than LmSTI1 DNA, thus supporting the notion that CD8 responses might be an important accessory arm of the immune response for acquired resistance against leishmaniasis. Moreover, the protection induced by DNA immunization was specific for infection with Leishmania, i.e., the immunization had no effect on the course of infection of the mice challenged with an unrelated intracellular pathogen such as Mycobacterium tuberculosis. Conversely, immunization of BALB/c mice with a plasmid DNA that is protective against challenge with M. tuberculosis had no effect on the course of infection of these mice with L. major. Together, these results indicate that the protection observed with the leishmanial DNA is mediated by acquired specific immune response rather than by the activation of nonspecific innate immune mechanisms. In addition, a plasmid DNA containing a fusion construct of the two genes was also tested. Similarly to the plasmids encoding individual proteins, the fusion construct induced both specific immune responses to the individual antigens and protection against challenge with L. major. These results confirm previous observations about the possibility of DNA immunization against leishmaniasis and lend support to the idea of using a single polygenic plasmid DNA construct to achieve polyspecific immune responses to several distinct parasite antigens.
Substrate specificity of Helicobacter pylori histone-like HU protein is determined by insufficient stabilization of DNA flexure points (2004)

The histone-like HU protein is ubiquitous in the eubacteria. A role for Escherichia coli HU in compaction of the bacterial genome has been reported, along with regulatory roles in DNA replication, transposition, repair and transcription. We show here that HU from the human pathogen Helicobacter pylori, which has been implicated in the development of ulcers and gastric cancer, exhibits enhanced thermal stability and distinct DNA substrate specificity. Thermal denaturation of HpyHU (H. pylori HU) measured by CD spectroscopy yields a melting temperature (T(m)) of 56.4+/-0.1 degrees C. HpyHU binds linear duplex DNA with a site size of approximately 19 bp and with low affinity, but in striking contrast to E. coli HU, HpyHU has only modest preference for DNA with mismatches, nicks or gaps. Instead, HpyHU binds stably to four-way DNA junctions with half-maximal saturation of 5 nM. Substitution of two residues adjacent to the DNA-intercalating prolines attenuates both the preference for flexible DNA and the ability to bend and supercoil DNA. These observations suggest that proline intercalation generates hinges that must be stabilized by adjacent residues; insufficient stabilization leads to reduced bending and a failure to bind preferably to DNA with flexure points, such as gaps and mismatches.
Development of Hysteroscopic Insemination of the Uterine Tube in the Mare (1998)

was found to be less than 2 French. The average volume required to fill a uterine tube was 0.3 ml. Complete tracts (n 5 86) were classified as estrus, diestrus, transitional, or anestrus based on ovarian structures. The external appearance of the ostium (opening) was imaged by using an Olympus stereomicroscope a connected to a data-acquisition‐dataanalysis imaging program. b The mean diameter and area of the ostium were determined. A variability in the external morphology but not in the diameter (analysis of variance; p 5 0.25) or area ( p 5 0.39) of the uterine tube was observed, but it was unrelated to physiologic status (chi square; p 5 0.56). There were five main morphologic categories: papilla (36%), complex (32%), diffuse (17%), double ridge (11%), and other (4%). There was a withinmare variability in morphologic type. In the second experiment, 12 mixed-breed light horse mares were selected for a breeding trial based on the following: age (,8 years of age), good endometrial biopsy scores (I or IIA), healthy reproductive tracts, and no history of reproductive problems. The mares were teased
Sequential immunofluorescence staining and image analysis for detection of large numbers of antigens in individual cell nuclei (2001)

The concentration of at least six different antigens in each cell can thus be measured semiquantitatively using sequential immunofluorescence staining and the described image analysis techniques. The number of antigens that can be visualized in a single sample is considerably increased by the presented protocol.
Mapping Receptor Binding Sites in Interleukin (IL)-1 Receptor Antagonist and IL-1β by Site-directed Mutagenesis (1995)

Interleukin-1 receptor antagonist (IL-1ra), an IL-1 family member, binds with high affinity to the type I IL-1 receptor (IL-1RI), blocking IL-1 binding but not inducing an IL-1-like response. Extensive site-directed mutagenesis has been used to identify residues in IL-1ra and IL-1 beta involved in binding to IL-1RI. These analyses have revealed the presence of two discrete receptor binding sites on IL-1 beta. Only one of these sites is present on IL-1ra, consisting of residues Trp-16, Gln-20, Tyr-34, Gln-36, and Tyr-147. Interestingly, the absent second site is at the location of the major structural difference between IL-1ra and IL-1 beta, which are otherwise structurally similar. The two receptor binding sites on IL-1 beta are also present on IL-1 alpha. Thus, it appears that the two IL-1 agonist molecules have two sites for IL-1RI binding, and the homologous antagonist molecule, IL-1ra, has only one. Based on these observations, a hypothesis is presented to account for the difference in activity between the agonist and antagonist proteins. It is proposed that the presence of the two receptor binding sites may be necessary for agonist activity.
Ruthenium-Catalyzed Urea Synthesis Using Methanol as the C1 Source (2015)

An unprecedented protocol for urea synthesis directly from methanol and amine was accomplished. The reaction is highly atom-economical, producing hydrogen as the sole byproduct. Commercially available ruthenium pincer complexes were used as catalysts. In addition, no additive, such as a base, oxidant, or hydrogen acceptor, was required. Furthermore, unsymmetrical urea derivatives were successfully obtained via a one-pot, two-step reaction.