gebhart/patrepeval huggingface dataset:
Characterization of hematopoietic lineage-specific gene expression by ES cell in vitro differentiation induction system (2000)

The continuous generation of mature blood cells from hematopoietic progenitor cells requires a highly complex series of molecular events. To examine lineage-specific gene expression during the differentiation process, we developed a novel method combining LacZ reporter gene analysis with in vitro hematopoietic differentiation induction from mouse embryonic stem cells. For a model system using this method, we chose the erythroid and megakaryocytic differentiation pathways. Although erythroid and megakaryocytic cells possess distinct functional and morphologic features, these 2 lineages originate from bipotential erythro-megakaryocytic progenitors and share common lineage-restricted transcription factors. A portion of the 5' flanking region of the human glycoprotein IIb (alphaIIb) integrin gene extending from base -598 to base +33 was examined in detail. As reported previously, this region is sufficient for megakaryocyte-specific gene expression. However, previous reports that used human erythro-megakaryocytic cell lines suggested that one or more negative regulatory regions were necessary for megakaryocyte-specific gene expression. Our data clearly showed that an approximately 200-base enhancer region extending from -598 to -400 was sufficient for megakaryocyte-specific gene expression. This experimental system has advantages over those using erythro-megakaryocytic cell lines because it recapitulates normal hematopoietic cell development and differentiation. Furthermore, this system is more efficient than transgenic analysis and can easily examine gene expression with null mutations of specific genes.
Migraine and beyond: cardiovascular therapeutic potential for CGRP modulators (2001)

CGRP is a potent vasodilator that has been shown to have a physiological and/or pathological role in neurogenic inflammation, headaches including migraine, thermal injury, circulatory shock, pregnancy and menopause, hypertension and heart failure and is known to be cardioprotective. CGRP is also a positive inotrope and increases heart rate. Clinical trials have shown beneficial effects of the vasodilatory action of CGRP in hypertension, angina, heart failure, Raynaud's disease and venous stasis ulcers. However, the clinical potential of CGRP is limited as it has to be given by infusion and is quickly broken down. Oral long acting CGRP-mimetics may have potential in disorders in which CGRP has been shown to be beneficial. CGRP-mimetics include capsaicin/vanilloid receptor agonists and gene transfer of an adenoviral vector that encodes prepro-CGRP. CGRP inhibitors have therapeutic potential in conditions in which excessive CGRP-mediated vasodilatation is present; neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock and flushing in menopause. CGRP inhibitors include capsaicin, antagonists at capsaicin/vanilloid receptors, civamide, CGRP receptor antagonists and 5-HT1D-receptor agonists. Drugs that are 5-HT1D-receptor agonists, the 'triptans' are already commonly used in migraine and the first small molecule CGRP antagonist, BIBN4096BS, is under clinical investigation for the treatment of migraine.
Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells (2015)

Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells <i>in vivo</i> is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells <i>in vitro</i> and <i>in vivo</i> using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests <i>in vitro</i> to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells <i>in vivo</i>. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells <i>in vitro</i>. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.
Gene Transfer Moves Ahead (1980)

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Presynaptic Cholinergic Dysfunction in Patients with Dementia (1983)

Indices of presynaptic cholinergic nerve endings were assayed in neocortical biopsy samples from patients with presenile dementia. For those patients in whom Alzheimer's disease was histologically confirmed, [14C]acetylcholine synthesis, choline acetyltransferase activity and choline uptake were all found to be markedly reduced (at least 40%) below mean control values. The changes occurred in samples from both the frontal and temporal lobes and for [14C]acetylcholine synthesis the decrease was similar under conditions of high and low neuronal activity (as assessed by incubations in 31 mM and 5 mM K+ respectively). Samples from other demented patients, in whom the histological features of Alzheimer's disease were not detected, produced values for all three biochemical parameters which were similar to controls. For the total group of patients with presenile dementia there were correlations between values for the three markers of presynaptic cholinergic nerve endings suggestive of a loss of functional activity at these sites in Alzheimer's disease.
Etiology and management of community-acquired pneumonia in Asia (2002)

The causative organisms of community-acquired pneumonia, especially in Japan and Korea, are essentially similar to those in Western countries. If there are any differences, these are due to the laboratory tests and criteria used to define pathogenicity. Overall, Streptococcus pneumoniae is the most frequently occurring pathogen and Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae and viruses follow. Legionella spp. look likely to be low frequency pathogens in Asian countries, but a reason for this might be limitations of the laboratory tests used. A high frequency of Gram-negative bacilli as pathogens of community-acquired pneumonia in some Asian countries may be due to different criteria used to identify disease-causing organisms. A small number of papers about antibiotic resistance have shown no large differences between Asian countries, but considerable differences to Western countries, such as frequency of macrolide-resistant S. pneumoniae. Some Asian countries have their own guidelines for community-acquired pneumonia, but these are written in their own languages.
Double muscling in cattle due to mutations in the myostatin gene (1997)

Myostatin (GDF-8) is a member of the transforming growth factor beta superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.
Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists (2010)

Stromal cell derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are involved in the directional homing to the bone marrow niches and in peripheral mobilization of normal and transformed hematopoietic stem and myeloid progenitor cells. Elevated CXCR4 expression confers poor prognosis, whereas inhibition of CXCR4 signaling overcomes stroma-mediated chemoresistance in acute myeloid leukemia (AML). Here, we demonstrate that treatment with the pan-histone deacetylase inhibitor panobinostat (PS) depleted the mRNA and protein levels of CXCR4 in the cultured and primary AML cells. PS-induced acetylation of the heat shock protein (hsp) 90 reduced the chaperone association between CXCR4 and hsp90, directing CXCR4 to degradation by the 20S proteasome. PS treatment also depleted G protein-coupled receptor kinase 3, as well as attenuated the phosphorylation of AKT and ERK1/2 in AML cells, which was not affected by cotreatment with CXCL12. Compared with each agent alone, cotreatment with PS and CXCR4 antagonist AMD3100 or FC-131 synergistically induced apoptosis of cultured and primary AML cells. PS and FC-131 exerted more lethal effects on primary AML versus normal CD34(+) bone marrow progenitor cells. These findings support the rationale to test the in vivo efficacy of PS in enhancing the lethal effects of CXCR4 antagonists against AML cells.
Inkjet Gene Printing: A Novel Approach to Achieve Gene Modified Cells for Tissue Engineering (2008)

Abstract : In this study a novel method of simultaneous gene transfection and cell delivery based on inkjet printing technology is described. Plasmids encoding green fluorescent protein (GFP) were co-printed with living cells (porcine aortic endothelial (PAE) cells) through the ink cartridge nozzles of modified commercial inkjet printers. Agaorse gel electrophoresis analysis showed there was no obvious structural alteration or damage to these plasmids after printing. Transfection efficiency of the printed cells, determined by GFP expression, was over 10% and post-transfection cell viability was over 90%. We showed that printing conditions, such as plasmid concentration, cartridge model, and plasmid size influenced gene transfection efficiency. Moreover, genetically modified PAE cells were accurately delivered to target sites within a three dimensional fibrin gel scaffold and expressed GFP in vitro and in vivo when implanted into mice. These results demonstrate that inkjet printing technology is able to simultaneously transfect genes into cells as well as precisely deliver these cell populations to target sites. This technology may facilitate the development of effective cell-based therapies by combining gene therapy with living cells that can be delivered to target sites.
Does abscisic acid affect strigolactone biosynthesis? (2010)

*Strigolactones are considered a novel class of plant hormones that, in addition to their endogenous signalling function, are exuded into the rhizosphere acting as a signal to stimulate hyphal branching of arbuscular mycorrhizal (AM) fungi and germination of root parasitic plant seeds. Considering the importance of the strigolactones and their biosynthetic origin (from carotenoids), we investigated the relationship with the plant hormone abscisic acid (ABA). *Strigolactone production and ABA content in the presence of specific inhibitors of oxidative carotenoid cleavage enzymes and in several tomato ABA-deficient mutants were analysed by LC-MS/MS. In addition, the expression of two genes involved in strigolactone biosynthesis was studied. *The carotenoid cleavage dioxygenase (CCD) inhibitor D2 reduced strigolactone but not ABA content of roots. However, in abamineSG-treated plants, an inhibitor of 9-cis-epoxycarotenoid dioxygenase (NCED), and the ABA mutants notabilis, sitiens and flacca, ABA and strigolactones were greatly reduced. The reduction in strigolactone production correlated with the downregulation of LeCCD7 and LeCCD8 genes in all three mutants. *The results show a correlation between ABA levels and strigolactone production, and suggest a role for ABA in the regulation of strigolactone biosynthesis.
The Effect of Dietary Energy Restriction on Body Weight Gain and the Development of Noninsulin‐Dependent Diabetes Mellitus (NIDDM) in Psammomys obesus (1997)

Food intake was restricted to 75% of ad libitum levels in 37 male Psammomys obesus (Israeli Sand Rats) from the ages of 4 (weaning) to 10 weeks. Energy restriction reduced the mean bodyweight at 10 weeks by 29% compared with 44 ad libitum fed controls. Hyperglycemia was prevented completely in the food-restricted group, and mean blood glucose concentrations were significantly reduced (3.8 +/- 0.2 vs. 5.5 +/- 0.4 mumol/L; p < 0.05) compared with control animals. Plasma insulin concentrations were also decreased significantly compared with ad libitum fed controls (105 +/- 13 vs. 241 +/- 29 mU/L; p < 0.05). Although energy restriction prevented hyperglycemia from developing in 10-week-old P. obesus, 19% of the food restricted animals still developed hyperinsulinemia. We concluded that hyperphagia between the ages of 4 to 10 weeks may be essential for the development of noninsulin-dependent diabetes mellitus in P. obesus, but that hyperinsulinemia may still occur in the absence of hyperphagia and hyperglycemia, suggesting a significant genetic influence on the development of hyperinsulinemia in this animal model.
Short‐term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis (1996)

Progressive lung disease in patients with cystic fibrosis (CF) is caused by thick secretions, which cause airway obstruction and subsequent colonization and infection by inhaled pathogenic microorganisms. Recently, recombinant human DNase has been shown to reduce the viscoelasticity of sputum in patients with cystic fibrosis and to improve lung function. Ultrasonically nebulized hypertonic saline (HS) has been demonstrated to enhance mucociliary clearance and sputum expectoration by rehydrating airway secretions, and may therefore provide a low cost alternative. We studied the changes in pulmonary function and symptoms in a group of patients with CF who have moderate to severe lung disease. The patients were evaluated following 2 weeks of treatment with HS in an open-label study. Subjects were randomly allocated to receive 10 ml of either 0.9% NaCl (IS) or 6% NaCl (HS). Twice daily, prior to physiotherapy, treatments were delivered by a portable ultrasonic nebulizer. To prevent bronchoconstriction, 600 mg of salbutamol was administered prior to the nebulized solutions. A symptom score was recorded and spirometry was performed on day 0 before therapy was started, on day 14 (the last day of therapy), and on day 28 (14 days after the last treatment with either IS or HS). Fifty-two patients (32 males), with a mean age of 16.2 (range 7–36) years completed the study. There was no difference in baseline characteristics between the two groups. Following 2 weeks of treatment, there was a significant improvement from baseline in FEV1 of 15.0 ± 16.0% (mean ± SD) in patients treated with HS, compared with a change of 2.8 ± 13% in those on IS therapy (P = 0.004). Furthermore, there was a subjective improvement in the effectiveness of chest physiotherapy as reported by those using HS (P = 0.02). The treatment was well tolerated. We conclude that in patients with CF, ultrasonically nebulized hypertonic saline improves lung function in a way similar to that reported for human recombinant DNase when inhaled over a 2 week period. Nebulized saline also enhances the perception of effectiveness of chest physiotherapy. Pediatr Pulmonol. 1996; 21:77–83. © 1996 Wiley-Liss, Inc.
Hypertension (2008)

W e are happy to report continued progress during the past year in achieving the goals outlined previously for Hypertension.
Stability of flucytosine 50 mg/mL in extemporaneous oral liquid formulations (2002)

Journal Article Stability of flucytosine 50 mg/mL in extemporaneous oral liquid formulations Get access Heather L. VandenBussche, Pharm.D., Heather L. VandenBussche, Pharm.D. Associate Professor College of Pharmacy, Ferris State University; at the time of this study she was Clinical Pharmacist—Pediatric Infectious Diseases, University of Michigan Hospitals and Health Centers (UMHHC), Ann Arbor, and Clinical Assistant Professor, College of Pharmacy, University of Michigan (UM), Ann Arbor Search for other works by this author on: Oxford Academic Google Scholar Cary E. Johnson, Pharm.D., Cary E. Johnson, Pharm.D. Professor of Pharmacy College of Pharmacy, UM, and Clinical Pharmacist— Pediatrics, UMHHC Address correspondence to Dr. Johnson at the College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065. Search for other works by this author on: Oxford Academic Google Scholar Jin Yun, Pharm.D., Jin Yun, Pharm.D. degree candidates College of Pharmacy, UM Search for other works by this author on: Oxford Academic Google Scholar Sima A. Patel, Pharm.D. Sima A. Patel, Pharm.D. degree candidates College of Pharmacy, UM Search for other works by this author on: Oxford Academic Google Scholar American Journal of Health-System Pharmacy, Volume 59, Issue 19, 1 October 2002, Pages 1853–1855, https://doi.org/10.1093/ajhp/59.19.1853 Published: 01 October 2002
The Eilat Connection (1999)

The developments analysed in the previous chapter necessitated a new look at Israel’s oil supply. The long-term solution to that problem obviously lay in the development by Israel of sufficient crude oil production in its own territory, and the reinstating of the normal supply Une from Iraq. As that was impossible to achieve, the main objective of Israel’s oil policy for the time being was to have admission to crude oil markets with maximum flexibility in normal times to buy at the lowest possible price, and in times of crisis to have access to reliable sources of supply.1 This meant, in practice, that oil supplies should not be dependent on any one country or area, however advantageous such supply might appear in normal times, for reasons of price, but that the alternative options should be maintained. Israeli policy-makers well understood that the overriding problem was to assure safe sources of supply. Still, when pressing for that assurance, they were equally aware that in ‘normal’ times all oil companies were interested in selling oil and when negotiating with them should not be allowed to assume the stance of benefactors. On the other hand, in order to gain their cooperation in a crisis situation, it was essential, especially in the case of Israel, to grant the companies equitable terms in normal times. The inevitable operational consequences of such reasoning were the efforts to obtain a substantial fraction of Israel’s oil supplies either directly or indirectly from a number of international major oil companies who were the only bodies with sufficient flexibility of oil sources.
Effect of Enzymatic Hydrolysis on Polylactic Acid Fabrics by Lipases from Different Origins (2012)

This study measured the effect of general pre-treatment on PLA fabrics to confirm the benefits of enzymatic processing on PLA fabrics in the textile industry as well as evaluated the hydrolytic activities of three lipases. The effects of lipase hydrolysis were analyzed through moisture regain, dyeing ability, tensile strength, and surface morphology. As a result, PLA fibers were easily damaged by a low concentration of sodium hydroxide and a low treatment temperature. The optimal treatment conditions of Lipase from Candida cylindracea were pH 8.0, <TEX>$40^{\circ}C$</TEX>, and 1,000 U. The optimal treatment conditions for Lipase from Candida rugosa were pH 7.2, <TEX>$37^{\circ}C$</TEX>, and 1,000 U. The optimal treatment conditions for Lipase from Porcine pancreas were pH 8.0, <TEX>$37^{\circ}C$</TEX>, and 2,000 U. The moisture regain and dyeing ability of PLA fabrics increased and the tensile strength of PLA fabrics decreased. The results of surface morphology revealed that there were some cracks due to hydrolysis on the surface of the fiber.
Surgery for faecal incontinence in adults (2010)

Despite more studies being included in this update, the continued small number of relevant trials identified together with their small sample sizes and other methodological weaknesses continue to limit the usefulness of this review for guiding practice. It was impossible to identify or refute clinically important differences between the alternative surgical procedures. Larger rigorous trials are still needed. However, it should be recognised that the optimal treatment regime may be a complex combination of various surgical and non-surgical therapies.
BindingDB Entry 5122: [3H]RY 80: A high-affinity, selective ligand for gamma-aminobutyric acidA receptors containing alpha-5 subunits. (2012)

The radiochemical synthesis and pharmacological properties are described of [3H]RY 80 (ethyl-8-acetylene-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1, 4]benzodiazepine-3-carboxylate, [ethyl-3H]). This compound is one of a series of 8-substituted imidazobenzodiazepines that exhibits both high affinity and selectivity for gamma-aminobutyric acid (GABA)A receptors containing alpha-5 subunits. Saturable, high-affinity (Kd approximately 0.7 nM) binding of [3H]RY 80 was observed in hippocampal membranes. The maximum number (Bmax) of [3H]RY 80 binding sites was approximately 18% of that obtained with [3H]flunitrazepam, a radioligand that labels all "diazepam-sensitive" GABAA receptors. This value is consistent with previous estimates (10-20%) of the proportion of rat hippocampal GABAA receptors containing alpha-5 subunits determined by immunoprecipitation with selective antibodies and competition experiments using an alpha-5-selective ligand. In recombinant GABAA receptors composed of alpha-5 beta-3 gamma-2 subunits, the Kd of [3H]RY 80 (approximately 0.5 nM) was consistent with the value obtained in hippocampus, whereas the Bmax value was not significantly different from that obtained with [3H]flunitrazepam. The potencies of several benzodiazepine site ligands to inhibit [3H]RY 80 binding to hippocampal membranes were in agreement with the values obtained in recombinant (alpha-5 beta-3 gamma-2) GABAA receptors. [3H]RY 80 was used both in a "GABA shift" assay to correctly predict the in vivo actions of a novel, alpha-5-selective ligand and to characterize a population of GABAA receptors containing alpha-5 subunits in neonatal rat cortex. These findings demonstrate that [3H]RY 80 can be used as a radioligand to examine the properties of GABAA receptors containing alpha-5 subunits.