gebhart/patrepeval huggingface dataset:
Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads (2020)

Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, a receptor tyrosine kinase highly expressed in a number of solid tumors, identified a number of Bicycle families with low nanomolar affinity. A Bicycle toxin conjugate (BTC) was generated by derivatization of one of these Bicycles with the potent cytotoxin DM1 via a cleavable linker. This BTC demonstrated potent antitumor activity <i>in vivo</i> but was poorly tolerated, which was hypothesized to be the result of undesired liver uptake caused by poor physicochemical properties. Chemical optimization of a second Bicycle, guided by structural biology, provided a high affinity, metabolically stable Bicycle with improved physicochemical properties. A BTC incorporating this Bicycle also demonstrated potent antitumor activity and was very well tolerated when compared to the initial BTC. Phage display selection followed by chemical optimization of Bicycles can deliver potent drug conjugates with favorable pharmaceutical properties.
Side Effects of Minocycline: Different Dosage Regimens (1977)

The incidence of side effects due to two dosage regimens of minocycline was examined over a 5-day period. A total of 60 normal women volunteers were randomly assigned in a double-blind manner to either a group who took 100 mg of minocycline twice a day or a group who took 75 mg of minocycline twice a day for 5 days. Both groups were comparable from the standpoints of age, size, race, and the use of oral contraception, nicotine, and ethanol. They were seen on a daily basis, and symptoms were evaluated by both volunteers (from diaries) and physicians. Minocycline serum concentrations were determined on blood samples taken 2 h after the a.m. dose. Volunteers taking 150 mg of minocycline per day had significantly lower serum antibiotic concentrations than those taking 200 mg per day. However, both low- and high-dose groups exhibited similar incidence and prevalence of recorded symptoms, with the single exception of nausea, where the low-dose group had fewer symptoms than the high-dose group (P = 0.035). Symptomatic volunteers did not have higher serum concentrations of minocycline than their asymptomatic counterparts. When either weight or surface area was examined with antibiotic serum concentration there was a significant inverse correlation between the two on day 2 for both groups and also on day 4 for the low-dose group. It is concluded that, in women, a dose of 150 mg of minocycline per day is associated with the same degree of side effects as a dose of 200 mg per day.
Autophagy as a therapeutic target in cancer (2011)

Autophagy is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival under stress via lysosomal degradation of cytoplasmic constituents and recycling of amino acids and energy. Autophagy is intricately involved in many aspects of human health and disease, including cancer. Autophagy is a double-edged sword in tumorigenesis, acting both as a tumor suppressor and a protector of cancer cell survival, and elucidation of its exact role at different stages of cancer progression and in treatment responsiveness is a complex and challenging task. Better understanding of autophagy regulation and its impact on treatment outcome will potentially allow us to identify novel therapeutic targets in cancer. In this review, we summarize current knowledge on the regulation and dual function of autophagy in tumorigenesis, as well as ongoing efforts in modulating autophagy for cancer treatment and prevention. This is a very exciting and highly promising area of cancer research, as pharmacologic modulation of autophagy appears to augment the efficacy of currently available anticancer regimens and opens the way to the development of new combinatorial therapeutic strategies that will hopefully contribute to cancer eradication.
Cholesterol sulfate in human physiology: what's it all about? (2003)

Cholesterol sulfate is quantitatively the most important known sterol sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DHEA) sulfate. Although these sulfolipids have similar production and metabolic clearance rates, they arise from distinct sources and are metabolized by different pathways. While the function of DHEA sulfate remains an enigma, cholesterol sulfate has emerged as an important regulatory molecule. Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion. As a result of its ability to regulate the activity of selective protein kinase C isoforms and modulate the specificity of phosphatidylinositol 3-kinase, cholesterol sulfate is involved in signal transduction. Cholesterol sulfate functions in keratinocyte differentiation, inducing genes that encode for key components involved in development of the barrier. The accumulating evidence demonstrating a regulatory function for cholesterol sulfate appears solid; the challenge now is to work out the molecular mechanisms whereby this interesting molecule carries out its various roles.
Phenotypic and Molecular Analysis of Oleate Content in the Mutant Soybean Line M23 (2005)

Soybean [ Glycine max (L.) Merr.] oil with elevated oleate content would be useful for food and industrial applications that require increased oxidative stability. The first objective of this study was to determine if molecular selection for the Fad2‐1 deletion associated with the ol allele in the mid‐oleate mutant line M23 could be used to identify mid‐oleate individuals in a breeding program. The second objective was to determine if modifying genes affect phenotypic expression of oleate content in individuals homozygous for the deletion from a cross between M23 and Archer, a cultivar with normal oleate content. The segregation among 88 F 2 plants from the cross satisfactorily fit a ratio of 1:2:1 homozygous normal ( OlOl )/heterozygous ( Olol )/homozygous ( olol ) for the Fad2‐1 deletion on the basis of Southern analysis. A PCR‐based marker Fad2‐1‐ ol identified the same olol individuals as the Southern analysis. The PCR‐based marker would be a more rapid and less labor intensive method for molecular selection of olol individuals than Southern analysis. The olol individuals had the highest mean oleate content, the Olol individuals were intermediate, and the OlOl individuals had the lowest mean oleate content. There was significant variation among the olol individuals and their distribution overlapped that of the OlOl and Olol individuals, which indicated that modifying genes had an important influence on the trait. It would be necessary to test the fatty acid profile of olol individuals to select those with the highest oleate content.
Identification of a peptide sequence involved in homophilic binding in the neural cell adhesion molecule NCAM. (1992)

The neural cell adhesion molecule NCAM is capable of mediating cell-cell adhesion via homophilic interactions. In this study, three strategies have been combined to identify regions of NCAM that participate directly in NCAM-NCAM binding: analysis of domain deletion mutations, mapping of epitopes of monoclonal antibodies, and use of synthetic peptides to inhibit NCAM activity. Studies on L cells transfected with NCAM mutant cDNAs using cell aggregation and NCAM-covasphere binding assays indicate that the third immunoglobulin-like domain is involved in homophilic binding. The epitopes of four monoclonal antibodies that have been previously shown to affect cell-cell adhesion mediated by NCAM were also mapped to domain 3. Overlapping hexapeptides were synthesized on plastic pins and assayed for binding with these monoclonal antibodies. One of them (PP) reacted specifically with the sequence KYSFNY. Synthetic oligopeptides containing the PP epitope were potent and specific inhibitors of NCAM binding activity. A substratum containing immobilized peptide conjugates also exhibited adhesiveness for neural retinal cells. Cell attachment was specifically inhibited by peptides that contained the PP-epitope and by anti-NCAM univalent antibodies. The shortest active peptide has the sequence KYSFNYDGSE, suggesting that this site is directly involved in NCAM homophilic interaction.
Deletion in Cysteine-Rich Region of LDL Receptor Impedes Transport to Cell Surface in WHHL Rabbit (1986)

The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal with familial hypercholesterolemia, produces a mutant receptor for plasma low-density lipoprotein (LDL) that is not transported to the cell surface at a normal rate. Cloning and sequencing of complementary DNA's from normal and WHHL rabbits, shows that this defect arises from an in-frame deletion of 12 nucleotides that eliminates four amino acids from the cysteine-rich ligand binding domain of the LDL receptor. A similar mutation, detected by S1 nuclease mapping of LDL receptor messenger RNA, occurred in a patient with familial hypercholesterolemia whose receptor also fails to be transported to the cell surface. These findings suggest that animal cells may have fail-safe mechanisms that prevent the surface expression of improperly folded proteins with unpaired or improperly bonded cysteine residues.
Two Phase 3 Clinical Trials Comparing the Safety and Efficacy of Netarsudil to Timolol in Patients With Elevated Intraocular Pressure: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2) (2017)

In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of this molecule suggest it may be a useful addition to the armamentarium of ocular hypotensive medications.
Absorption, Distribution, Metabolism, and Excretion of a Respirable Antisense Oligonucleotide for Asthma (2001)

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selectively attenuates discordantly overexpressed adenosine A(1) receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [(35)S]-labeled EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administered to normal rabbits by endotracheal tube to assess biodistribution, route of elimination, and potential cardiovascular toxicity. The animals were killed at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliquots from different tissues and samples were solubilized and assessed for radioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was deposited into the lung. The concentration of the drug in the lung at 0, 6, 24, 48, and 72 h was 64.0 +/- 1.5, 67.0 +/- 4.4, 32.0 +/- 3.7, 23.4 +/- 1.4, and 2.1 +/- 0.5 microg equivalents, respectively. Only a small amount of the radioactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the administered dose was excreted in the urine, which represented the major pathway of elimination. In postlabeling studies, intact full-length EPI-2010 could only be detected in the lung. Autoradiographic analysis after inhalation of [(35)S]-labeled EPI-2010 showed a relatively uniform deposition of drug throughout the lung. The aerosolized EPI-2010 did not have any significant systemic effects on the cardiovascular system as determined by Cardiomax-II analysis. This pattern of distribution and the lack of effect on cardiovascular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic bioavailability may be contraindicated.
Suppression of cell-mediated and humoral immune responses by an interleukin-2-immunoglobulin fusion protein in mice. (1996)

Interleukin-2 (IL-2) plays a pivotal role in the cellular and humoral immune responses directed against foreign antigens. We characterized the in vitro and in vivo properties of a chimeric protein consisting of mouse IL-2 fused to the mouse IgG2b Fc domains. This fusion protein binds to IL-2 and Fc receptors and supports IL-2-dependent cell proliferation but does not mediate lysis of IL-2 receptor-positive cells in the presence of murine complement in vitro. However, in vivo the IL2-IgG2b fusion protein suppresses both cellular and humoral immune responses after immunization with sheep erythrocytes. Surprisingly, delayed hypersensitivity is inhibited despite a dramatic increase of splenic CD3+ and NK1.1+ lymphocytes, indicating that altered homing of IL2-IgG2b-activated lymphocytes rather than cytolysis prevents these cells from accumulating in areas of inflammation. Although in vitro the IL2-IgG2b fusion protein does not alter proliferation of B cells in response to mitogenic stimulation, IgM production in response to sheep erythrocytes is profoundly inhibited in mice treated with the IL2-IgG2b fusion protein. Since no side effects are observed, the IL2-IgG2b fusion protein may expand the therapeutic repertoire of reagents used for the treatment of allograft rejection and autoimmune diseases.
Globular amyloid β‐peptide1−42 oligomer − a homogenous and stable neuropathological protein in Alzheimer's disease (2005)

Amyloid beta-peptide (Abeta)(1-42) oligomers have recently been discussed as intermediate toxic species in Alzheimer's disease (AD) pathology. Here we describe a new and highly stable Abeta(1-42) oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and Abeta(1-42)-overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water-soluble globular 60-kDa oligomer which we named 'Abeta(1-42) globulomer'. Our data indicate that Abeta(1-42) globulomer is a persistent structural entity formed independently of the fibrillar aggregation pathway. It is a potent antigen in mice and rabbits eliciting generation of Abeta(1-42) globulomer-specific antibodies that do not cross-react with amyloid precursor protein, Abeta(1-40) and Abeta(1-42) monomers and Abeta fibrils. Abeta(1-42) globulomer binds specifically to dendritic processes of neurons but not glia in hippocampal cell cultures and completely blocks long-term potentiation in rat hippocampal slices. Our data suggest that Abeta(1-42) globulomer represents a basic pathogenic structural principle also present to a minor extent in previously described oligomer preparations and that its formation is an early pathological event in AD. Selective neutralization of the Abeta globulomer structure epitope is expected to have a high potential for treatment of AD.
Electrostatic Multilayer Deposition of a Gold−Dendrimer Nanocomposite (1999)

Poly(amidoamine) (PAMAM) dendrimers can be used as a polymeric template/stabilizer/reservoir to prepare stable gold−dendrimer nanocomposites by reducing PAMAM−tetrachloroaurate polysalts using hydrazine. In the gold−dendrimer nanocomposite, the presence of elemental gold is indicated by its characteristic plasmon absorption peak at 529 nm in aqueous solution and is visualized by transmission electron microscopy (TEM) equipped with energy-dispersive X-ray spectroscopy (EDXS). Electrostatic layer-by-layer assembly of the gold−dendrimer nanocomposite using poly(sodium 4-styrenesulfonate) (PSS) as the oppositely charged polyelectrolyte leading to nanoscale uniform multilayers of gold−dendrimer nanoclusters is reported. UV−vis absorption spectra from the consecutive multilayers indicated that each bilayer growth is regular, even though a 20 nm absorption bathochromic shift takes place in the film. TEM of PSS/gold−dendrimer nanocomposite film demonstrates that gold nanoparticles (5−20 nm) appear as aggregates within a gold−dendrimer nanocomposite monolayer, an observation borne out by crystalline gold electron diffraction patterns obtained from PSS/gold−dendrimer nanocomposite. Atomic force microscopy (AFM) of PSS/gold−dendrimer nanocomposite film indicates that the nanoclusters are arrayed with high uniformity at the nanometer scale.
Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? (1999)

The remarkable difference in success rates between clinical pancreas transplantation and islet transplantation is poorly understood. Despite the same histocompatibility barrier and similar immunosuppressive treatments in both transplantation procedures, human intraportal islet transplantation has a much inferior success rate than does vascularized pancreas transplantation. Thus far, little attention has been directed to the possibility that islets transplanted into the blood stream may elicit an injurious incompatibility reaction. We have tested this hypothesis in vitro with human islets and in vivo with porcine islets. Human islets were exposed to nonanticoagulated human ABO-compatible blood in surface-heparinized polyvinyl chloride tubing loops. Heparin and/or the soluble complement receptor 1 (sCR1) TP10 were tested as additives. Adult porcine islets were transplanted intraportally into pigs, and the liver was recovered after 60 min for immunohistochemical staining. Human islets induced a rapid consumption and activation of platelets. Neutrophils and monocytes were also consumed, and the coagulation and complement systems were activated. Upon histological examination, islets were found to be embedded in clots and infiltrated with CD11+ leukocytes. Furthermore, the cellular morphology was disrupted. When heparin and sCR1 were added to the blood, these events were avoided. Porcine islets retrieved in liver biopsies after intraportal islet allotransplantation showed a morphology similar to that of human islets perifused in vitro. Thus, exposure of isolated islets of Langerhans to allogenic blood resulted in significant damage to the islets, a finding that could explain the unsatisfactory clinical results obtained with intraportal islet transplantation. Because administration of heparin in combination with a soluble complement receptor abrogated these events, such treatment would presumably improve the outcome of clinical islet transplantation by reducing both initial islet loss and subsequent specific immune responses.
Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome (2004)

Several correlated phenotypes, alcohol dependence, major depressive syndrome, and an endophenotype of electrophysiological measurements, event-related oscillations (EROs), have demonstrated linkage on the long arm of chromosome 7. Recently, we reported both linkage and association between polymorphisms in the gene encoding the muscarinic acetylcholine receptor M2 (CHRM2) and EROs. In this study, we evaluated whether genetic variation in the CHRM2 gene is also a risk factor for the correlated clinical characteristics of alcoholism and depression. The CHRM2 gene contains a single coding exon and a large 5' untranslated region encoded by multiple exons that can be alternatively spliced. Families were recruited through an alcohol dependent proband, and multiplex pedigrees were selected for genetic analyses. We examined 11 single nucleotide polymorphisms (SNPs) spanning the CHRM2 gene in these families. Using the UNPHASED pedigree disequilibrium test (PDTPHASE), three SNPs (one in intron 4 and two in intron 5) showed highly significant association with alcoholism (P=0.004-0.007). Two SNPs (both in intron 4) were significantly associated with major depressive syndrome (P=0.004 and 0.017). Haplotype analyses revealed that the most common haplotype (>40% frequency), T-T-T (rs1824024-rs2061174-rs324650), was under-transmitted to affected individuals with alcohol dependence and major depressive syndrome. Different complementary haplotypes were over-transmitted in alcohol dependent and depressed individuals. These findings provide strong evidence that variants within or close to the CHRM2 locus influence risk for two common psychiatric disorders.
Mathematical modeling of power DC/DC converters (2005)

Mathematical modelling of power DC/DC converters is a historical problem accompanying with the development of the DC/DC conversion technology since 1940's. The traditional mathematical modelling is successful to describe fundamental converters, but not available for complex structure converters since the differential equation order increases very high. We have to search other way to establish mathematical modelling for power DC/DC converters.
Progenitor Cells in Pulmonary Vascular Remodeling (2011)

Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow-derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow-derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure.
Binding of a Fluorescent Nucleotide Analog to Hsc70 (1995)

2'-Deoxy-3'-anthraniloyladenosine-5-triphosphate(Ant-dATP) was used as an environmentally sensitive probe of the nucleotide-binding site of the molecular chaperone Hsc70. When coordinated to the lanthanide ion Tb3+, Ant-dATP is not hydrolyzed by Hsc70. The lanthanide ion acts as strong competitive inhibitor with respect to Mg2+ (Ki = 0.1 microM). Tb.Ant-dATP recognizes the nucleotide site of Hsc70 as revealed by an increase in the emission anisotropy from 0.03 to 0.21 and by a change in the fluorescence-decay time from 2.52 ns to 3.75 ns. Sensitized luminescence arising from resonance energy transfer from the anthraniloyl group to Tb3+ is substantially enhanced in the presence of Hsc70. Binding of a 20-amino-acid-residue peptide (Rnase-S peptide) to Hsc70 causes a blue shift in the fluorescence spectrum of Ant-dATP and enhances Tb3+ luminescence upon excitation at 330 nm. It is postulated that binding of the peptide to the COOH-terminal domain of Hsc70 initiates domain movement and the structural changes might extend to the nucleotide-binding site.