gebhart/patrepeval huggingface dataset:
Abstract 2856: Pyrrolobenzodiazepine (PBD) dimers - potent next generation warheads in antibody drug conjugates (ADCs) targeted at both solid and haematological tumors. (2013)

Abstract The pyrrolobenzodiazepine (PBD) dimers are a class of rationally designed DNA minor groove, sequence selective, cross-linking agents. The non-distortive nature of PBD interstrand cross-links results in their persistence compared to those produced by conventional agents such as the nitrogen mustards and platinum drugs. Members of this class can exhibit picomolar or sub-picomolar activity against a range of human tumour cell lines and demonstrate curative activity in human tumour xenograft models. The fully synthetic PBD dimers are ideally suited for a role in strategies aimed at targeting and releasing highly cytotoxic agents directly at a tumour site such as antibody drug conjugates (ADCs). They combine exquisite potency with a demonstrated therapeutic index (unlike other warheads such as calicheamycin), are not cross-resistant with widely used chemotherapy agents, and their unique mode of action sets them apart from the tubulin binders (maytansinoids and auristatins) that currently dominate the ADC arena but which have the limitation that some tumour types lack sensitivity. Four PBD dimer drug linkers representing different PBD dimer warheads and two different attachment sites (N10 and C2) for the linker on the drug were synthesised. Trastuzumab-ADCs were prepared using these drug linkers with a drug-antibody ratio (DAR) below 3 and with attachment of the cleavable valine-alanine dipeptide linker to cysteine residues. Efficacy was evaluated in vitro against Her2 +ve and -ve cell lines and in vivo against human breast cancer Her2-expressing BT474 xenografts. All four ADCs showed durable complete regressions at 1mg/kg (i.v., qwk x 3) and significant growth delays at 0.3 mg/kg. A PBD-containing ADC was further evaluated against a haematological target. In vitro, the ADC gave a greater than 6-log differential cell killing between an expressing and a non-expressing cell line. In vivo, using the qwk x 3 treatment schedule, durable complete regressions were achieved at a dose of 0.1 mg/kg, whereas the naked antibody had no activity at a dose of 2.5 mg/kg. These data clearly demonstrate that antibody delivery of PBD dimers can result in curative antitumor activity against both solid and haematological tumor targets at low doses and DARs and represent the most promising next-generation ADCs for clinical development. Citation Format: John A. Hartley, Luke Masterson, Stephen Gregson, Thais Cailleau, Ebole Ezeadi, Jean-Noel Levy, Gary Kemp, Arnaud Tiberghien, Elizabeth Dunny, Francois D'Hooge, Lauren Adams, David Williams, Patrick van Berkel, Philip W. Howard. Pyrrolobenzodiazepine (PBD) dimers - potent next generation warheads in antibody drug conjugates (ADCs) targeted at both solid and haematological tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2856. doi:10.1158/1538-7445.AM2013-2856
Residual periodontal defects distal to the mandibular second molar 6–36 months after impacted third molar extraction (2002)

The results suggest that periodontal breakdown initiated and established on the distal surface of a mandibular second molar in the vicinity of a 'mesio-angular' impacted third molar evidenced by pre-extraction crestal radiolucency in association with inadequate plaque control after extraction can predispose to a persistent localised periodontal problem.
A Novel Approach for Preparation of Thermoresponsive Polymer Magnetic Microspheres with Core–Shell Structure (2003)

Dual‐responsive polymer microspheres with well‐defined core–shell structure (see Figure) have been prepared via a template polymerization process. The resulting microspheres consist of a silica‐coated magnetite core and a cross‐linked poly( N ‐isopropylacrylamide) shell, which enable them to exhibit both magnetic response and thermoresponse.
Rate constants for abstraction of bromine from bromotrichloromethane by butyl, cyclopropylmethyl, and phenyl radicals in solution (1988)

The radical chain decomposition of cyclopropylmethyl (1-hydroxy-1-methylethyl)-diazene [Formula: see text] at 253–341 K in hexafluorobenzene or in dichloromethane solution containing bromotrichloromethane affords cyclopropylmethyl bromide, 4-bromo-1-butene, 1-bromo-5,5,5-trichloro-2-pentene, and 3,5-dibromo-1,1,1-trichloropentane from the cyclopropylmethyl portion of 1. Other major products are nitrogen, acetone, and chloroform. The rate constant for formation of cyclopropylmethyl bromide by attack of cyclopropylmethyl free radicals from 1 at bromine of BrCCl 3 [Formula: see text] was calculated from the product composition using the known rate constant for rearrangement of cyclopropylmethyl radicals to 3-buten-1-yl radicals. At 25 °C,[Formula: see text] and the temperature dependence is given by [Formula: see text], where θ = 2.3RT kcal/mol −1 . Non-chain decomposition of (CH 3 ) 2 C(OH)N=N—R (2, R = Bu, and 3, R = Ph) in the presence of excess 1,1,3,3-tetramethylisoindolin-2-yloxyl (4) and bromotrichloromethane afforded BuBr and PhBr, respectively, in yields determined by the relative concentrations of 4 and BrCCl 3 . Rate constants for coupling (k c ) of Bu• and Ph• with 4 were assumed to be proportional to rate constants for diffusion controlled reactions, k d , which were estimated from measured viscosities. Values of [Formula: see text] and[Formula: see text], calculated from k c and product yields for reactions at 80 °C, are 0.26 × 10 9 and 1.55 × 10 9 M −1 s −1 , respectively. The relative radical reactivities toward BrCCl 3 at 80 °C are Ph, 6; cpm, 5; Bu, 1.
Peptide models of protein folding initiation sites. 1. Secondary structure formation by peptides corresponding to the G- and H-helixes of myoglobin (1993)

Myoglobin has been extensively studied as a model system for protein folding in vitro. As part of an ongoing study of myoglobin folding, we have synthesized a series of peptide fragments corresponding to portions of the sequence of the sperm whale protein. The conformational preferences of these peptides have been investigated by circular dichroism and nuclear magnetic resonance spectroscopy in aqueous solution. In this paper we describe the folding propensities of two peptides (Mb-G and Mb-H), corresponding to the G- and H-helix segments of the myoglobin sequence. The Mb-G peptide shows evidence of a very small population of helical conformations in aqueous solution, both by CD and NMR. By contrast, the monomeric Mb-H peptide is found by CD to adopt a significant population (ca. 30%) of ordered helix and by NMR to populate helical conformations in rapid dynamic equilibrium with unfolded states. The Mb-H peptide undergoes a well-characterized, concentration-dependent monomer-tetramer equilibrium. At peptide concentrations greater than 1 mM there is an increase in the population of helix, to approximately 85% according to the CD spectrum, through self-association to form a tetramer. Both medium-range NOE connectivities and a CD spectrum characteristic of ordered helix are observed at low peptide concentrations, establishing that helical conformations are present in the monomeric state of Mb-H. The relative helicity at various sites throughout the Mb-H peptide has been estimated using a novel method for assessing the distribution of helical populations based on the relative magnitudes of medium-range d alpha beta (i,i+3) NOE connectivities. The population of ordered helix is seen to be highest in the center of the peptide sequence; the ends of the peptide show evidence of pronounced fraying.
Novel cyclic peptide inhibits intercellular adhesion molecule‐1‐mediated cell aggregation (2001)

Leukocyte adherence mediated by intercellular adhesion molecule-1 (ICAM-1) binding to leukocyte function-associated antigen (LFA-1) is required for proper inflammatory and immune function. Inhibition of ICAM-1\LFA-1 binding using monoclonal antibodies (mAb) has been shown to be efficacious at inhibiting lymphoma metastasis as well as leukocyte emigration into tissue in a number of inflammatory diseases such as ischemia-reperfusion injury, septic shock and rheumatoid arthritis. In this report, we describe the development and characterization of a small peptide antagonist of ICAM-1-dependent cell aggregation. By using repeated selection of a cyclic nonapeptide phage display library on purified ICAM-1, we identified phage that were competitively eluted with anti-ICAM-1 mAb. The peptide sequences were determined by nucleotide sequencing, and the peptide sequence (C*LLRMRSIC*) (IP01) that occurred most frequently was chosen for further study. Phage expressing this peptide sequence specifically bound ICAM-1 over a range of 5 x 10(6) to 1 x 10(8) phage/microL. A cyclic IP01 peptide, linear IP01 peptide, a cyclic nonapeptide with a scrambled IP01 sequence, and a random, cyclic nonapeptide were synthesized. The cyclic and linear IP01 peptides were able to inhibit ICAM-1-mediated cell aggregation at a concentration of 1 mM, whereas the random and scrambled peptide sequences did not alter aggregation. Cyclic IP01 had a half-maximal inhibitory concentration of approximately 970 microM. Cyclic IP01 did not inhibit cellular aggregation that was dependent on ICAM-2 or ICAM-3. Alanine substitutions in the cyclic IP01 identified at least four amino acids necessary for inhibition of ICAM-1 dependent cell aggregation; leucine 2, leucine 3, methionine 5, and arginine 6. Finally, we showed that cyclic IP01 can inhibit firm adhesion of neutrophils to endothelium, a critical event in inflammatory diseases, in an assay that recapitulates physiologic flow conditions. Homology of IP01 with the primary amino acid sequences of the alpha or beta subunit of LFA-1 was not identified. Thus, we identified a unique molecule that inhibits ICAM-1 dependent cell adhesion, but is not related to the primary sequence of the ICAM-1 ligand LFA-1. Due to the small size and ability to block cell-cell adhesion, IP01 may serve as a useful tool for study of ICAM-1 and LFA-1 biology as well as for the development of small molecule therapeutics.
Hydroxamic acid inhibitors of 5-lipoxygenase (1987)

The hydroxamic acid functionality can be incorporated in a variety of simple molecules to produce potent inhibitors of 5-lipoxygenase. As an example of this, the structure-activity relationships in a series of omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids are presented. Among the features described are the influence of hydrophobicity, aryl substitution, and modifications of the hydroxamate group on enzyme inhibitory potency. To assist in the selection of more potent hydroxamic acid inhibitors, a simple hypothesis about the nature of enzyme-inhibitor binding was devised. In this hypothesis, the structures of compounds were matched to a proposed geometry of arachidonic acid when bound to the enzyme. Compounds that match best without extending into disfavored regions were predicted to be the best inhibitors. Three series of hydroxamates selected according to this approach are described. Within these series are some of the most potent inhibitors of 5-lipoxygenase reported to date.
Horizontal coseismic deformation of the 2003 Bam (Iran) earthquake measured from SPOT‐5 THR satellite imagery (2005)

On 26 December 2003, a destructive Mw 6.5 earthquake occurred in Kerman province, Iran, killing more than 30,000 people around the ancient city of Bam. We map the fault zone and determine the slip distribution using sub‐pixel correlation of images taken by the SPOT‐5 THR sensor before and after the main shock. Our results show that the surface displacement occurred on a blind fault oriented N174 and located South of Bam. A 15 km along‐strike profile depicts a distribution with a maximum displacement of 1.2 ± 0.15 m near the centre of the fault. The mean slip that we infer (∼0.77 ± 0.05 m) is much higher than the ground displacement measured in the field (∼0.2 m). We suggest that field‐measured displacements are underestimated due to slip accommodation within an 500 m wide shear zone. Furthermore, we demonstrate for the first time the relevancy of 2.5 m SPOT‐5 THR images for sub‐pixel ground displacement measurements.
Genetic advances for studying Mycobacterium tuberculosis pathogenicity (1998)

Tuberculosis remains the greatest cause of death worldwide because of a single pathogen. Despite its importance, the genetic basis of the pathogenicity of Mycobacterium tuberculosis remains poorly understood, mainly because the most productive investigative approach, molecular genetic analysis, has been severely hampered by a lack of efficient tools. However, significant advances, including the development of methods for inactivating genes and studying their expression with reporter genes, have been recently made. This progress may lead to opportunities for developing new vaccines and antituberculous drugs. The aim of this review is to examine the present state of the art in mycobacterial molecular genetics and pinpoint some expected or promising areas for future research.
Personal Factors Affecting Therapeutic Responses to BCG Vaccination in Asthmatics (2011)

The therapeutic effect of BCG in asthma may differ according to patient clinical characteristics. The greatest benefit occurred in young atopic females. Asthma activity indices, such as eosinophilia and FEV1 % best, were more predictive of a good/fair response in males; this may have been related to cigarette smoking.
Argonaute--a database for gene regulation by mammalian microRNAs (2005)

MicroRNAs (miRNAs) constitute a recently discovered class of small non-coding RNAs that regulate expression of target genes either by decreasing the stability of the target mRNA or by translational inhibition. They are involved in diverse processes, including cellular differentiation, proliferation and apoptosis. Recent evidence also suggests their importance for cancerogenesis. By far the most important model systems in cancer research are mammalian organisms. Thus, we decided to compile comprehensive information on mammalian miRNAs, their origin and regulated target genes in an exhaustive, curated database called Argonaute (http://www.ma.uni-heidelberg.de/apps/zmf/argonaute/interface). Argonaute collects latest information from both literature and other databases. In contrast to current databases on miRNAs like miRBase::Sequences, NONCODE or RNAdb, Argonaute hosts additional information on the origin of an miRNA, i.e. in which host gene it is encoded, its expression in different tissues and its known or proposed function, its potential target genes including Gene Ontology annotation, as well as miRNA families and proteins known to be involved in miRNA processing. Additionally, target genes are linked to an information retrieval system that provides comprehensive information from sequence databases and a simultaneous search of MEDLINE with all synonyms of a given gene. The web interface allows the user to get information for a single or multiple miRNAs, either selected or uploaded through a text file. Argonaute currently has information on 839 miRNAs from human, mouse and rat.
[Progress in pathogenesis and therapeutic research in retinitis pigmentosa and age-related macular degeneration]. (2004)

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are designated special targeted eye diseases by the Welfare and Labor Ministry of Japan. We have been studying the pathogenesis, diagnosis, treatment, and evaluation of these diseases. The development of molecular genetic analyses of RP revealed that the type and frequency of mutations varied with the ethnic population. In our present study, we focused on the genetic analysis and clinical examinations for autosomal dominant retinitis pigmentosa (ADRP). We screened 96 unrelated ADRP families with 9 genes, which included rhodopsin, peripherin/RDS, RP 1, NRL, FSCN 2, PRPF 31, PRPC 8, HPRP 3, IMPDH 1. We also showed the correlations we have found between the phenotype and genotype of hereditary retinal diseases in Japanese patients. Our mutation screenings suggested that Japanese patients with ADRP might have a unique mutation, because the mutation in the FSCN 2 gene has been found only in Japanese patients. On the other hand, the Pro347Leu and Pro23His mutations in the rhodopsin, the Arg677X mutation in the RP 1, and the Asp226Asn mutation in the IMPDH 1 genes are representative mutations for ADRP, and are not found or are very rare in Japanese patients with ADRP. The results of randomized controlled trials of low-dose radiation for wet-type age-related macular degeneration located at the fovea centralis indicate the effectiveness of this treatment for maintaining visual acuity and regression of choroidal neovascular membrane (CNV) for at least one-year. Simple surgical removal of CNV or transplantation of autologous cultured iris pigment epithelium (IPE) with vitreous surgery showed some improvement of vision. In either RP or AMD, photoreceptors die, in most cases by apoptosis. Neurotrophic factors (NT) are effective for reducing these processes and preventing photoreceptor cell death in animal models. To apply these methods to humans, the procedures are as follows: 1) obtaining IPE by peripheral iridectomy, 2) culturing it with autologous serum and transfecting the cDNA of NT, and then 3) transplantation of these cells under the retina. We used cDNA of brain-derived neurotrophic factor (BDNF) with adeno-associated virus (AAV) as a vector. These ex vivo procedures were safe and very effective for preventing photoreceptor cell death in animal models, such as RCS rats and light-damaged rats. In the future, these procedures could be applied for RP or AMD and might show some clinical effects for maintaining or improving the vision of patients.
Expression of Functional Ricin B Chain using the Baculovirus System (1995)

The ricin B chain (RTB) was expressed using a baculovirus expression system. The RTB coding sequence downstream of the preproricin signal sequence was inserted in the baculovirus transfer vector pM34T. After cotransfection of Spodoptera frugiperda Sf9 cells with linearized baculovirus DNA, recombinant viruses were selected, cloned and amplified. Upon infection of Sf9 cells with these recombinant baculoviruses, RTB production was revealed by immunoblotting. RTB expression using this system was optimum 72 h after infection of the cells at a multiplicity of infection of 3. RTB produced was glycosylated and had an apparent molecular mass of 34 kDa. Most of the signal sequence was removed, but the resulting recombinant RTB had a 13-residue N-terminus extension. Immunofluorescence analysis showed that this protein was located in the endoplasmic reticulum/Golgi region of the cell. RTB was not present at the plasma membrane. Secretion was enhanced by the addition of lactose to the cell-culture medium up to 50 mM. Purification was achieved from both cells and media using immobilized lactose and the lectin activity of RTB. Results obtained with the purified recombinant protein (more than 2 mg/l culture) were identical to those obtained with native RTB in all assays for biological activity; binding, internalization and reassociation with the ricin A chain to produce toxic ricin. Moreover, the RTB translocation capacity was not altered by the N-terminal peptide, showing that recombinant RTB could be used to deliver antigenic peptides to the cytosol for the induction of cell-mediated immunity.
Cloning of Two Putative Ecdysteroid Receptor Isoforms from Tenebrio Molitor and their Developmental Expression in the Epidermis during Metamorphosis (1997)

Using the Drosophila EcR-B1 cDNA as a probe, we have cloned the putative ecdysteroid receptor from the mealworm Tenebrio molitor. We have isolated two cDNAs with different 5' termini that contain a complete open reading frame. These two cDNAs encode two proteins with distinct N-terminal regions corresponding to two isoforms. The coleopteran receptor is obviously related to the ecdysteroid receptor of other insects, but shares only 89% and 61% amino acid identities with the DNA-binding and ligand-binding domains of the Drosophila receptor, respectively. Its expression pattern has been examined in the epidermis during the last larval instar and pupal stage of T. molitor, in correlation with the hemolymph ecdysteroid titer. Hybridizations revealed two transcripts of 7 kb and 6.5 kb detected in most stages during metamorphosis and corresponding to the A and B1 isoforms. These two mRNAs are highly evident just before the rise of each ecdysteroid peak both in prepupae and in pupae. They show almost the same expression pattern in epidermis except for the second part of the pupal stage, during which only the A isoform is detected.
Attomole Microarray Detection of MicroRNAs by Nanoparticle-Amplified SPR Imaging Measurements of Surface Polyadenylation Reactions (2006)

Multiple microRNAs (miRNAs) are detected in a microarray format using a novel approach that combines a surface enzyme reaction with nanoparticle-amplified SPR imaging (SPRI). The surface reaction of poly(A) polymerase creates poly(A) tails on miRNAs hybridized onto locked nucleic acid (LNA) microarrays. DNA-modified nanoparticles are then adsorbed onto the poly(A) tails and detected with SPRI. This ultrasensitive nanoparticle-amplified SPRI methodology can be used for miRNA profiling at attomole levels.
Electrochemical hydrogenation of canola oil using a hydrogen transfer agent (2003)

Abstract A novel low‐temperature process for the electrochemical hydrogenation of canola oil is described. An emulsion of oil and water containing formic acid and a nickel hydrogenation catalyst, placed in the cathode compartment of an electrolysis cell and subjected to an electrical current, underwent hydrogenation at temperatures as low as 45°C. At these low temperatures of hydrogenation, the trans FA content of the hydrogenated canola oil was very low as compared with that of the edible oils hydrogenated by commercial processes using high temperature and high partial pressure of hydrogen gas. Because of its adverse health effects, a high trans FA content in edbile oils is viewed as undesirable. In addition to the commercially available nickel supported on silica, amorphous nickelphosphorus alloys supported on a variety of substrates were also used. Amorphous alloys are generally very corrosion resistant because of the absence of grain boundaries. A mechanism for hydrogenation using the hydrogen transfer agent of formic acid and its continuous regeneration at the cathode was evoked to explain the experimental data.
α2-Adrenoreceptors Profile Modulation. 4. From Antagonist to Agonist Behavior (2008)

The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors.