gebhart/patrepeval huggingface dataset:
Pharmacokinetics and Hematological Effects of the PEGylated Thrombopoietin Peptide Mimetic GW395058 in Rats and Monkeys After Intravenous or Subcutaneous Administration (1999)

GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (<twofold) in cynomolgus monkeys following a 25 microg/kg s.c. dose and twofold following a 100 microg/kg s.c. dose. Because the plasma t1/2 of GW395058 is long in mouse, rat, dog, and monkey, yet the dose required to double platelet levels in monkeys is 50-fold that required in rats, differences in hematological responses may be due to interspecies differences in the interaction of GW395058 with the TPOr.
Ineffective Vaccination against Solid Tumors Can Be Enhanced by Hematopoietic Cell Transplantation (2009)

Vaccination with tumor Ags has not been an effective treatment for solid tumors. The goal of the current study was to determine whether a combination of vaccination and hematopoietic cell transplantation (HCT) can effectively treat primary, disseminated, or metastatic CT26 and MC38 murine colon tumors. Vaccination of tumor-bearing mice with irradiated tumor cells and CpG adjuvant failed to alter progressive tumor growth. However, mice bearing primary, disseminated lung, or metastatic liver tumors were uniformly cured after administration of total body irradiation, followed by the transplantation of hematopoietic progenitor cells and T cells from syngeneic, but not allogeneic vaccinated donors. Requirements for effective treatment of tumors included irradiation of hosts, vaccination of donors with both tumor cells and CpG, transfer of both CD4(+) and CD8(+) T cells along with progenitor cells, and ability of donor cells to produce IFN-gamma. Irradiation markedly increased the infiltration of donor T cells into the tumors, and the combined irradiation and HCT altered the balance of tumor-infiltrating cells to favor CD8(+) effector memory T cells as compared with CD4(+)CD25(+)FoxP3(+) T regulatory cells. The combination of vaccination and autologous hematopoietic cell transplantation was also effective in treating tumors. In conclusion, these findings show that otherwise ineffective vaccination to solid nonhematologic tumors can be dramatically enhanced by HCT.
Evaluation of the CO2 rebreathing cardiac output method in seriously ill patients. (1977)

The CO2 rebreathing cardiac output method is a totally noninvasive Fick procedure needing validation in various disease states to become clinically applicable. Simultaneous measurements of cardiac output by CO2 rebreathing and dye-dilution or direct Fick techniques were performed in 53 patients. In nine patients with pulmonary disease rebreathing cardiac output averaged 4.85 L/min compared to 5.18 L/min by dye-dilution or Fick (r = 0.16). In 14 instances of acute myocardial infarction cardiac output was 5.53 L/min by rebreathing and 5.87 L/min by dye-dilution (r = 0.95), while in nine shock cases it averaged 3.98 L/min by dye-dilution or Fick and 3.75 L/min by CO2 rebreathing (r = 0.94). In five heart failure cases with mitral insufficiency, which may distort dye durves, correlation between standard and rebreathing methods was r = 0.09, but in 16 cases without mitral regurgitation, r = 0.89. Acute interventions in ten patients increased dye-dilution cardiac output by 0.92 L/min and rebreathing outputs by 0.60 L/min (r = 0.87). The data suggest that the CO2 rebreathing cardiac output method may be useful in the CCU-MICU setting.
Moving Forward – Essential Questions for the Next 10 Years (2009)

The future is bright for migraine sufferers. For acute treatment, CGRP antagonists and combination products will provide more complete, longer lasting, and safer relief. "Designer drugs" for migraine prevention will be identified based on their ability to block cortical spreading depression and will improve migraine treatment. Genetic and environmental risk factors that promote migraine progression will be identified and preventing progression will become a standard goal in treatment. Some of the devices intended to treat migraine will be approved and will provide important options for sufferers seeking to avoid drugs. Clinical trials that evaluate behavioral and pharmacologic interventions and their impact on patient centered outcomes will emerge. The emergence of novel treatments, when coupled with strategies for individualizing and optimizing treatment while maximizing adherence, will result in ever improving patient outcomes.
Evidence for the microbicidal activity of a chlorine dioxide-containing oral rinse formulation in vivo. (2001)

The ability of an oral rinse preparation, containing an admixture of the oxohalogen oxidants chlorite anion and chlorine dioxide, to diminish salivary levels of Streptococcus mutans, lactobacilli and Candida albicans was investigated in a group of 33 dental patients. Patients underwent oral rinsing episodes with the above product (20 ml for a period of 60 seconds, three times daily) for a total of 14 days, and subsequently repeated this exercise with mineral water in place of the oral rinse formulation. A group of 10 dental student volunteers, conducting the same oral rinsing regimens with mineral water in place of the oral health care product, served as a control group. Salivary microorganism levels were determined both prior and subsequent to the above trial period. The results demonstrated that biocidal oxohalogen oxidants present in the oral rinse formulation tested gave rise to a substantial reduction in salivary S. mutans and lactobacilli levels (p < 0.001 and 0.005, respectively), although the decrease observed in C. albicans failed to reach statistical significance. As expected, mineral water employed as an oral rinsing system by the same group of patients, or the student control group, exerted no influence on the salivary levels of each of these microorganisms. The therapeutic, microbial and biochemical ramifications of the results obtained are discussed.
N-(Acyloxyalkyl)pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Factor Antagonist (1994)

Pyrrolothiazole 4 is a potent antagonist of platelet activating factor-mediated effects in a variety of in vitro and in vivo assays. Despite its positive activity in models of inflammation and septic shock, 4 lacks the aqueous solubility necessary for intravenous administration. This deficit was overcome by conversion of 4 to water-soluble pyridinium prodrugs. A two-step procedure was used to prepare a series of N-(acyloxyalkyl)pyridinium salts, all of which exhibited aqueous solubility of greater than 20 mg/mL. The rate of conversion of these prodrugs to 4 was faster in human plasma than in pH 7 aqueous buffer. This rate difference was shown to be due to serum enzymes since the conversion in plasma was significantly slower in the presence of a serine esterase inhibitor. A strong correlation between prodrug structure and buffer/plasma half-life was established. The N-(acetyloxymethyl)pyridinium prodrug 11 (ABT-299) is currently undergoing clinical evaluation for the treatment of sepsis.
Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities (2009)

Redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. This review will present an update on drug discovery, target identification, and mechanisms of action of experimental redox chemotherapeutics with a focus on pro- and antioxidant redox modulators now in advanced phases of preclinal and clinical development. Recent research indicates that numerous oncogenes and tumor suppressor genes exert their functions in part through redox mechanisms amenable to pharmacological intervention by redox chemotherapeutics. The pleiotropic action of many redox chemotherapeutics that involves simultaneous modulation of multiple redox sensitive targets can overcome cancer cell drug resistance originating from redundancy of oncogenic signaling and rapid mutation.Moreover, some redox chemotherapeutics may function according to the concept of synthetic lethality (i.e., drug cytotoxicity is confined to cancer cells that display loss of function mutations in tumor suppressor genes or upregulation of oncogene expression). The impressive number of ongoing clinical trials that examine therapeutic performance of novel redox drugs in cancer patients demonstrates that redox chemotherapy has made the crucial transition from bench to bedside.
Sphenopalatine ganglion block for postdural puncture headache (2009)

In a previous letter [1] we reported our experience with the application of sphenopalatine ganglion block for headache and backache for our obstetric patients. We would like to report our experience with the application of this technique for 13 patients with moderate to severe postdural puncture headache. It has been our practice over the last 8 years to offer patients with postdural puncture headache a sphenopalatine ganglion block with a cotton tip applicator filled with lignocaine 4% topical ointment as the first treatment of choice. These patients always have the option of a blood patch as backup treatment. Patients can receive this treatment once a day for up to a week, either by attending our pain clinic, or by performing the block themselves at home, following our instructions. The success of this treatment is somewhat unpredictable. Some patients have dramatic and complete relief of the headache following a single treatment. Others have improvement or transient relief of their symptoms, and continue the treatment themselves at home for up to a week, many not requiring a blood patch. Of the 13 patients mentioned above, 11 had immediate and/or complete relief of the headache and only two required a blood patch. We suggest that patients with postdural puncture headache could receive this minimally invasive technique which has minimal side effects. In most cases its use can avoid the need for a blood patch with its attendant side effects and potential complications.
Practice, Practice, Practice (2005)

In the early 1990s the NYU/Wagner School undertook an effort to reform the curriculum of one of the oldest and largest public administration programs in the nation to make its graduates more job ready and better prepared to be “reflective practitioners.” While the reform applied to all parts of the School, the design of the public policy analysis specialization at Wagner School embraces all the elements of the “Clinical Initiative.” The curriculum was revised to provide the three “Es”: Exploration, Exercise and Experience. The crowning feature of the reform brought by the Clinical Initiative is the year-long, team capstone project, which replaces the comprehensive examination and the master’s thesis in the MPA program. Instead of taking an examination in the specialization, students now enroll in a two-semester course organized around student-team policy projects involving either consulting for public and nonprofit organization clients, or policy research studies. The projects integrate the knowledge, understanding and skills covered in public policy courses, and test the ability of students to meet the challenges of working in teams. The presentation of the Wagner Clinical Initiative pays special attention to the international capstone course, taught by the author, that often involves fieldwork abroad and teams of Wagner students working with students in partner universities in developing countries. In addition to providing effective policy analysis training, Wagner capstones constitute a significant public service.
FOCAL DESTRUCTION OF NERVOUS TISSUE BY FOCUSED ULTRASOUND: BIOPHYSICAL FACTORS INFLUENCING ITS APPLICATION (1956)

Ultrasound at frequencies of 1.0 mcps and 2.5 mcps can be focused by a suitable lens system to produce a small region of high vibrational intensity. The concentrated energy within and around the focal region can be used to destroy structures of the central nervous system. The extent of destruction depends upon: (a) the size of the focal region, which varies inversely with the frequency, (b) the ultrasonic intensity, (c) the duration of exposure, and (d) the physical and physiologic characteristics of the tissue under irradiation. With proper choice of ultrasonic dosage, mice were rendered monoplegic by destruction of one-half of the spinal cord without demonstrable injury to the skin or subcutaneous tissues through which the converging ultrasonic beam had been transmitted. In similar fashion, focal lesions were produced in the basal ganglia of living cats by stereotaxic transdural application of a focused ultrasonic beam delivered through the superior aspect of the cerebral hemispheres. Histologic studies of mouse spinal cords and cat brains offered evidence that the fiber tracts of the central nervous system are more vulnerable to ultrasonic irradiation than aggregates of cell nuclei or vascular structures. The destructive action of the ultrasound is apparently a result of mechanical strain combined with a rise in temperature at the focus of the beam. The heating factor was found to assume greater importance under conditions of high intensity and continuous (rather than pulsed) irradiation. Trypan blue staining and radioautography using P(32) have been employed to identify the lesions 1 hour after irradiation. This has been a valuable adjunct in our attempts to determine the accuracy of placement of the lesions and their size. Perhaps more important, however, is the indication from these studies that ultrasonically produced lesions may offer a useful method for investigation of the nature of the blood-brain barrier. "Target studies" were undertaken to determine the precision with which lesions of predetermined size could be placed at predetermined sites in the basal ganglia of the cat. Results to date have been promising, but it is our opinion that further technical improvement will be necessary before ultrasound can be used as an accurate method for placing discrete lesions within the human brain.
Nitrite Therapy After Cardiac Arrest Reduces Reactive Oxygen Species Generation, Improves Cardiac and Neurological Function, and Enhances Survival via Reversible Inhibition of Mitochondrial Complex I (2009)

Nitrite therapy after resuscitation from 12 minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction, death, and neurological impairment in survivors.
De novo design of heterotrimeric coiled coils (1996)

The three-helix bundle is a common structural motif among natural proteins. It has been observed in numerous important proteins, such as fibrinogen, laminin, spectrin, dystrofin, hemagglutinin, and mannose binding proteins. The three-helix bundle is a simple structure in which three α-helices pack against each other, with a slight left-handed twist. Because of its simplicity relative to other structural motifs, the three-helix bundle can be conveniently used both to clarify the forces responsible for the protein folding and stability, and for the design of novel proteins. In this paper we describe the design, synthesis, and characterization of three peptides that self-assemble into antiparallel, heterotrimeric coiled coils. The experimental results, obtained from CD spectroscopy and ultracentrifugation equilibrium sedimentation, indicate that the mixture of the three peptides preferentially forms heterotrimers; moreover, these aggregates represent attractive systems for combinatorial design of libraries of pseudo C3 symmetric ligands or binding sites. © 1997 John Wiley & Sons, Inc. Biopoly 40: 495–504, 1996
TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses (2007)

Naive murine B cells are known to proliferate and differentiate in response to LPS or CpG, which bind to TLR4 and TLR9, respectively. However, the naive murine B cell compartment is heterogeneous and comprises four different B cell subsets: B-1a, B-1b, marginal zone (MZ), and follicular (FO) B cells. B-1a, B-1b, and MZ B cells are specialized in the response to thymus-independent Ag, and FO B cells are involved in the response to thymus-dependent Ag. This study was undertaken to compare those four naive B cell subsets for their responses to TLR agonists. Quantitative RT-PCR analysis revealed that expression of TLR transcripts differs quantitatively but not qualitatively from one subset to the other. All TLR agonists, with the exception of flagellin and poly(I:C), stimulate B cell proliferation whatever the subset considered. However, TLR ligation leads to massive differentiation of B-1 and MZ B cells into mature plasma cells (PC) but only marginally promotes PC differentiation of FO B cells. Moreover, TLR stimulation strongly up-regulates expression of Blimp-1 and XBP-1(S), two transcription factors known to be instrumental in PC differentiation, in B-1 and MZ B cells but not in FO B cells. Altogether, our findings suggest that B-1 and MZ B cells are poised to PC differentiation in response to the microbial environment and that TLR agonists can be instrumental in stimulating Ab-mediated innate immune protection during microbial infections.
Binding Motifs of Copolymer 1 to Multiple Sclerosis- and Rheumatoid Arthritis-Associated HLA-DR Molecules (1999)

Copolymer 1 (Cop 1, poly (Y, E, A, K)) is a random synthetic amino acid copolymer effective in the treatment of relapsing forms of multiple sclerosis (MS). Cop 1 binds promiscuously, with high affinity and in a peptide-specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and rheumatoid arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules. In the present work at least 95% of added Cop 1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins. Amino acid composition, HPLC profiles, and sequencing patterns of Cop 1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop 1. Protruding N-terminal ends of Cop 1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with aminopeptidase I, followed by elution, HPLC, and pool sequencing. In contrast to untreated or unbound Cop 1, this material exhibited distinct motifs at some positions with increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed. No preference was seen at the following cycles that were mainly A. These first pooled HLA-DR binding epitopes provide clues to the components of Cop 1 that are biologically active in suppressing MS and possibly rheumatoid arthritis.
Effects of 434 MHz microwave hyperthermia applied to the rat in the region of the cervical spinal cord (1987)

Hyperthermia was applied in the region of the vertebral column between the cervical vertebrae 5 and thoracic 2, using a ring-shaped applicator operating at a microwave frequency of 434 MHz. This region was focally heated, including spinal cord, vertebrae, intervertebral discs and nerve roots. In all experiments temperature was measured at a 'reference' thermocouple probe which was placed against one of the cervical vertebrae 6, 7 or thoracic 1. Temperatures inside the vertebral canal were measured separately and proved to be below the 'reference' temperature: at 42 degrees, 43 degrees, 44 degrees and 45 degrees C (+/- 0.1 degree C) respectively the temperature in the canal was 41.2 degrees, 42.3 degrees, 42.9 degrees and 43.2 degrees C (+/- 0.4 degree C). Temperatures in tissues close to the vertebrae (e.g. within 2 mm lateral to the vertebrae, in the region of the brachial plexus) did not differ significantly from the temperature inside the canal. The temperature inside the intervertebral disc was as high as the 'reference' temperature. Temperatures measured at other sites, e.g. in the oesophagus, rectally and in the cervical muscles 5 or 10 mm lateral from the vertebral column showed that these sites were only slightly heated. The effects of hyperthermia at temperatures inside the spinal canal ranging from 41.2-43.2 degrees C for 30-120 min were investigated. One day after treatment at 41.2 degrees C for 120 min or 42.3 degrees C for 60 min neither neurological symptoms nor deaths were observed. Minor neurological symptoms were observed one day after 75 min at 42.3 degrees C. The incidence and severity of the neurological symptoms (ranging from unco-ordinated use of the forelegs to paralysis) increased with increasing temperature and duration of the hyperthermic treatment. Thermal damage even resulted in lethality: 74 per cent of the rats that died did so between 2 and 42 h after treatment. The LD50 value at 60 days at 43.2 degrees C was 30 min, at 42.9 degrees C, 41 min, and at 42.3 degrees C, 92 min. In most rats with neurological symptoms after treatment, recovery from motor dysfunctions took place within about two weeks. Even severe neurological symptoms which did not lead to lethality recovered completely. At day 60 no neurological symptoms were observed.
NEW FORMULATIONS FOR HYDRAULIC BIOLUBRICANTS BASED ON EPOXIDIZED VEGETABLE OILS: PASSION FRUIT (Passiflora edulis Sims f. flavicarpa Degener) AND MORINGA (Moringa oleifera Lamarck) (2015)

The aim of this work is to develop new biolubricants based on epoxidized vegetable oils, optimizing formulations with an additive package by experimental design. A 2³ factorial design with center points was used to determine optimal conditions for anti-wear, corrosion inhibition, extreme pressure, and antioxidants to be applied with formulations with epoxidized passion fruit and moringa oils. The lubricants obtained were characterized in accordance with DIN 51524 (Part 2 HLP) and DIN 51517 (Part 3 CLP) standards. The epoxidation process improved the oxidative stability and the acid value of both pure vegetable oils. Furthermore, the presence of epoxidized oils improved the solubilisation of the additives, increasing the fluids' performances. Regarding their suitability as lubricants, epoxidized moringa oil with additives presented the best results, followed by epoxidized passion fruit oil with additives, epoxidized moringa oil, epoxidized passion fruit oil, pure moringa oil and, finally, pure passion fruit oil.
Induced stem cells (2011)

Preface Cryopreservation of Pluripotent Stem Cells: From Slow Cooling Protocols to Slow Cooling Protocols Bone Tissue Engineering Approaches & Challenges using Bioactive Ceramic Scaffolds Induced Pluripotent Stem Cell-Derived Hepatocytes as an Alternative to Human Adult Hepatocytes Production of Cells with the Patient's Genotype by Induced Pluripotent Stem Cell Technique Induced Pluripotent Stem Cell Technology for the Study of Neurodegenerative Diseases Generation of Human Induced Pluripotent Stem Cells from Cord Blood Cells Induced Stem Cells Stem Cell Therapy in Alzheimer's Disease Human Somatic Cells of Neural Crest Origin Isolated from Dental Pulp are an Abundant Source for Generation of Induced Pluripotent Stem Cells Induced Stem Cells Index.