gebhart/patrepeval huggingface dataset:
Evaluation of Inflammatory Cytokine Secretion by Human Alveolar Macrophages (1999)

The alveolar macrophage (AM) secretes interleukin 1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8), all of them inflammatory cytokines involved in the pathogenesis of many lung diseases. The aim of the present work was to evaluate the basal and stimulated secretion of these cytokines by human AMs. Human AMs were collected by bronchoalveolar lavage (BAL) from four healthy controls and 13 patients with diffuse interstitial lung disease (five cases of sarcoidosis, three of hypersensitivity pneumonitis and five of idiopathic pulmonary fibrosis). AMs were cultured in the presence or absence of different concentrations of lipopolysaccharide (LPS), phorbolmyristate and gamma-interferon. IL-1beta, TNF-alpha, IL-6 and IL-8 levels were measured in BAL fluid and culture supernatant using specific enzyme-linked immunosorbent assays. The substance found to stimulate the secretion of inflammatory cytokines to the greatest extent was LPS at a concentration of 10 microg/ml. Regarding the secretion of IL-1beta, four observations were of interest: basal secretion was very low; LPS exerted a potent stimulatory effect; considerable within-group variability was observed; and there were no significant differences in the comparisons among groups. With respect to TNF-alpha secretion, the results were similar. The only striking finding was the higher basal secretion of this cytokine with respect to that of IL-1beta. Regarding the secretion of IL-6, the same pattern followed by TNF-alpha was found. However, it should be stressed that the increase induced by LPS was smaller than in the two previous cytokines. Regarding the secretion of IL-8, three findings were patent: the strong basal secretion of this cytokine; the moderate increase induced by LPS; and the existence of significant differences among the different groups with respect to the stimulated secretion of this cytokine, which reached maximum values in patients with idiopathic pulmonary fibrosis. Finally, it should be noted that the pattern of cytokines observed in the BAL fluid was similar to that found in cultured AM supernatants. The pattern of inflammatory cytokine secretion by AMs differs from that of other cells of the mononuclear phagocyte system (MPS). In this sense. AMs secrete low amounts of IL-1, moderate amounts of TNF-alpha and IL-6, and high quantities of IL-8. Adherence is an important stimulus in the secretion of these molecules and LPS elicits an increased secretion inverse to the basal secretion. There is considerable individual variability in the secretion of inflammatory cytokines by the AMs of patients with interstitial lung disease and the AMs of these patients are primed in vivo for the secretion of these cytokines. The results of our study, carried out in vitro, can be extrapolated to the in vivo setting.
Improved Isolation and Culture of Embryonic Stem Cells from Chinese Miniature Pig (2004)

Pigs serve as a better research model for human beings than other species. The Chinese laboratory miniature pig is a new laboratory animal and is expected to be applicable in many medical research fields. This study was to establish effective technologies to isolate and culture ES cells in Chinese miniature pigs. For isolation of the inner cell mass from blastocysts, an enzyme-digestive method was compared with the traditional immunosurgery. Isolated ICM were cultured in three feeder cell layers: mouse embryonic fibroblasts (MEF), porcine embryonic fibroblasts (PEF) and a continuous cell line of mouse embryonic fibroblasts (STO). Microtubule activity of the three feeder cells was further examined by immunofluorescence. ICM were successfully isolated from 85% of blastocysts by the enzyme-digestive method, compared to only 40% by immunosurgery. When ICM were cultured in three feeder layers for two to three days, 75%, 65% and 20% of ICMs formed primary cell colonies in MEF, PEF and STO, respectively. Colonies were also formed during subcultures after 9, 5 and 1 passage in MEF, PEF and STO, respectively. Microtubules in STO cells were significantly fewer than those in MEF and PEF. When the ES-like cells were cultured in a differentiation medium, they differentiated to neuron-like cells and other types of cells. These results indicate that healthier ICM can be obtained with the enzyme-digestive method. Successful culture of ICM to ES-like cells has been achieved not only in MEF, but also in homologous (pig) feeder layer. The ES cells obtained in the present study were pluripotent.
Modern Amination Methods (2000)

Modern Allylic Amination Methods (K. Jorgensen) Eletrophilic Amination Routes from Alkenes (E. Fernandez & J. Brown) Stereoselective Electrophilic Amination with Sulfonyloxycarbamates and Azodicarboxylates (J.-P. Genet, et al.) Glycosylamines as Auxiliaries in Stereoselective Syntheses of Chiral Amino Compounds (H. Tietgen, et al.) Syntheses of Transition Metal Nitride Complexes (C. Tomooka, et al.) Asymmetric Nitrogen Transfer with Nitridomanganese Complexes (S. Minakata & M. Komatsu) Palladium-Catalyzed Amination of Aryl Halides and Sulfonates (J. Hartwig) Index.
Testosterone and Libido in Surgically and Naturally Menopausal Women (2006)

The assessment and then treatment of a change in libido, or a change in the desire to partake in sexual activity, during the menopausal transition and beyond has been a challenging and elusive area of clinical research. This is partly due to the multidimensional nature of female sexuality, the difficulties of measuring testosterone in women in a reliable and accurate manner, and the complexity of the neurobiology and neurobehavior of female sexual desire. In addition, there is a lack of evidence for diagnostic specificity of low free testosterone levels for the symptom of low libido in women for whom there are no confounding interpersonal or psychological factors; although, in the symptomatic population of surgically or naturally menopausal women, a low level of free testosterone often accompanies a complaint of reduced desire/libido. The randomized clinical trial research on testosterone replacement for naturally and/or surgically menopausal women with sexual dysfunction has been criticized for a high placebo response rate, supraphysiological replacement levels of testosterone, the perception of modest clinical outcome when measuring objective data such as the frequency of sexual intercourse relative to placebo, and the unknown safety of long-term testosterone replacement in the estrogen-replete surgically or naturally menopausal woman. A careful review of current evidence from randomized, controlled trials lends support to the value of the replacement of testosterone in the estrogen-replete menopausal woman for whom libido and desire has declined. The issue of long-term safety remains to be answered.
Role of Reactive Oxygen Species in Gallic Acid-Induced Apoptosis. (2000)

We earlier demonstrated that gallic acid (3,4,5-trihydroxybenzoic acid) induced apoptosis in promyelocytic leukemia HL-60RG cells, which was inhibited by catalase and intracellular Ca2+ chelator. In this study, we further studied the involvement of reactive oxygen species (ROS) and intracellular Ca2+ in gallic acid-induced apoptosis. The enhancement of intracellular ROS in HL-60RG cells was detected dose-dependently as early as 5 min after stimulation with gallic acid by using 5,6-carboxy-2',7'-dichlorofluorescin diacetate (DCFH-DA). Further studies that used various antioxidants and ROS scavengers showed that the intracellular peroxide level was well correlated with the potency to induce apoptosis and that the increased intracellular peroxides after gallic acid treatment seemed likely to result from the influx of H2O2 derived from superoxide which were generated extracellularly. In addition, gallic acid, HX/XO, and H2O2-induced apoptosis was completely inhibited by pretreatment with intracellular Ca2+ chelator 1,2-bis(2-aminophenoxyethane)-N,N,N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), but increase of intracellular peroxide levels by gallic acid were suppressed only slightly. It is suggested that intracellular ROS induced by gallic acid plays an important role in eliciting an early signal in apoptosis. Especially, H2O, which is derived from superoxide anion generated extracellularly may increase intracellular Ca2+ levels or cooperate with intracellular Ca2+, thus resulting in apoptosis induction.
Molecular targeted therapies in hepatocellular carcinoma† (2008)

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.
Optical Sensor for the Detection of Caspase-9 Activity in a Single Cell (2004)

We demonstrate for the first time, the application and utility of a unique optical sensor having a nanoprobe for monitoring the onset of the mitochondrial pathway of apoptosis in a single living cell by detecting enzymatic activities of caspase-9. Minimally invasive analysis of single live MCF-7 cells for caspase-9 activity is demonstrated using the optical sensor which employs a modification of an immunochemical assay format for the immobilization of nonfluorescent enzyme substrate, Leucine-GlutamicAcid-Histidine-AsparticAcid-7-amino-4-methylcoumarin (LEHD-AMC). LEHD-AMC covalently attached on the nanoprobe tip of an optical sensor is cleaved during apoptosis by caspase-9 generating free AMC. An evanescent field is used to excite cleaved AMC and the resulting fluorescence signal is detected. By quantitatively monitoring the changes in fluorescence signals, caspase-9 activity within a single living MCF-7 cell was detected. By comparing of the fluorescence signals from apoptotic cells induced by photodynamic treatment and nonapoptotic cells, we successfully detected caspase-9 activity, which indicates the onset of apoptosis in the cells.
Purification and properties of citrate lyase from Escherichia coli (1983)

Citrate lyase (EC 4.1.3.6) has been purified from Escherichia coli and the homogeneity of the preparation established from the three-component subunits obtained on sodium dodecyl sulfate/polyacrylamide gel electrophoresis. The purified enzyme has a specific activity of 120 mumol min-1 mg-1 and requires optimally 10 mM Mg2+ and a pH of 8.0 for the cleavage reaction. The native enzyme is polydispersed in the ultracentrifuge and in polyacrylamide gel electrophoresis. The enzyme complex is composed of three different polypeptide chains of 85 000, 54 000, 32 000 daltons. An estimate of subunit stoichiometry indicates that 1 mol of the largest polypeptide chain is associated with 6 mol each of the smaller ones. The polypeptide subunits have been isolated in pure state and their biological functions characterize. The 54 000-dalton subunit functions as the acyltransferase alpha subunit catalyzing the formation of citryl coenzyme A from citrate in the presence of acetyl coenzyme A and ethylenediaminetetraacetic acid. The 32 000-dalton subunit functions as the acyllyase beta subunit catalyzing the cleavage of (3S)-citryl coenzyme A to oxal-acetate and acetyl coenzyme A. The 85 000-dalton subunit, which carries exclusively the prosthetic group components, functions as the acyl-carrier protein gamma subunit in the cleavage of citrate in the presence of mg2+ and the alpha and beta subunits. The presence of a large ACP subunit and the unusual stoichiometry of the different subunits distinguish the complex from other citrate lyases. A ligase which acetylates the deacetyl[citrate lyase] in the presence of acetate and ATP has ben shown to be present in the organism.(ABSTRACT TRUNCATED AT 250 WORDS)
Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules (2004)

We identified and characterized a human orthologue of Rif1 protein, which in budding yeast interacts in vivo with the major duplex telomeric DNA binding protein Rap1p and negatively regulates telomere length. Depletion of hRif1 by RNA interference in human cancer cells impaired cell growth but had no detectable effect on telomere length, although hRif1 overexpression in S. cerevisiae interfered with telomere length control, in a manner specifically dependent on the presence of yeast Rif1p. No localization of hRif1 on normal human telomeres, or interaction with the human telomeric proteins TRF1, TRF2, or hRap1, was detectable. However, hRif1 efficiently translocated to telomerically located DNA damage foci in response to the synthesis of aberrant telomeres directed by mutant-template telomerase RNA. The hRif1 level rose during late S/G2 but hRif1 was not visible on chromosomes in metaphase and anaphase; however, notably, specifically during early anaphase, hRif1 aligned along a subset of the midzone microtubules between the separating chromosomes. In telophase, hRif1 localized to chromosomes, and in interphase, it was intranuclear. These results define a novel subcellular localization behavior for hRif1 during the cell cycle.
Viral-induced remission in chronic lymphocytic leukemia? (1979)

<h3>To the Editor.—</h3> Hansen and Libnoch have recently described in theArchives(138:1137-1138, 1978) a patient with chronic lymphocytic leukemia (CLL) who attained a complete remission after smallpox vaccination. Proposed mechanisms for this remission included spontaneous regression, direct viral destruction of lymphocytes, and lymphocyte destruction through viral-induced host immune defenses. A trial of vaccinia oncolysate therapy for CLL was proposed. We wish to propose another mechanism for this remission: induction of endogenous interferon production. Interferon preparations have been shown to have both antiviral and antimitotic properties.<sup>1,2</sup>Viral infection induces host production of interferon. It has been shown that lymphocyte interferon production is increased in response to vaccinia antigen challenge.<sup>3</sup>Inhibition of the proliferation of tumor cells by interferon has been demonstrated with in vitro and in vivo animal systems.<sup>2</sup>Human malignancies have also responded to exogenous interferon treatment.<sup>4</sup>Interferon has been used as adjuvant therapy for
Characterization of a Novel Src-like Adapter Protein That Associates with the Eck Receptor Tyrosine Kinase (1995)

The Eph family of receptor protein tyrosine kinases (RPTKs) is the largest family of RPTKs. The signal transduction pathways initiated by this family have only recently begun to be explored. Using a yeast two-hybrid screen to identify molecules that interact with the cytoplasmic domain of Eck, it was previously shown that activated Eck RPTK bound to and stimulated phosphatidylinositol 3-kinase (Pandey, A., Lazar, D.F., Saltiel, A. R., and Dixit, V.M. (1994) J. Biol. Chem. 269, 30154-30157). Also isolated from this same screen was a novel protein containing SH3 and SH2 adapter modules that had striking homology to those found in the Src family of non-receptor tyrosine kinases. However, unlike other Src family members, it lacked a catalytic tyrosine kinase domain. Hence, this protein was designated SLAP for Src-like adapter protein. Using glutathione S-transferase fusion Proteins, it was demonstrated that SLAP bound to activated Eck receptor tyrosine kinase. Therefore, SLAP is a novel candidate downstream signaling intermediate and the first member of the Src family that resembles an adapter molecule.
Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-Substituted-4-(phenylamino)quinolines (1992)

Previously, gastric (H+/K+)-ATPase inhibitors such as 2 have been prepared as analogues of 1a on the presumption that the 3-carbethoxy substituent plays a key role in establishing the orientation of the 4-arylamino group. In this paper we explore further the contribution made to activity by the quinoline 3-substituent. We show that, for compounds bearing such a substituent, only a particular combination of properties provides high activity, both in vitro and as inhibitors of gastric acid secretion in vivo. The ability of the substituent to affect activity by restricting rotation about the Cquin-N bond through a combination of both a pi-electron withdrawal and hydrogen bonding is supported by the current study. However, high activity is only achieved if the effect of this group on the quinoline pK(a) is kept to a minimum. 3-Acyl substituents provide an optimum combination of electronic properties. From this series, compound 17c (SK&F 96067) was shown to be a potent inhibitor of histamine-stimulated gastric acid secretion after oral dosing in the Heidenhain pouch dog and was selected for further development and evaluation in man.
Single cell multiplex PCR amplification of five dystrophin gene exons combined with gender determination (2001)

Large deletions in the dystrophin gene account for > 60% of mutations responsible for Duchenne muscular dystrophy (DMD). We have developed a genetic test that can be used directly for the preimplantation genetic diagnosis (PGD) of a majority of couples at risk of transmitting DMD. The test, a double nested multiplex polymerase chain reaction assay for the amplification of exons 8, 19, 45, 47 and 51 allows the detection of over 70% of all DMD deletions. Amelogenin sequences on the X and the Y chromosomes were also co-amplified to provide a correlation between embryo gender and deletion status. The setting up of reliable single cell assays for preimplantation genetic diagnosis is delicate and time consuming. Assays have to be validated on a large number of single cells for each specific mutation to assess efficiency and accuracy before being applied clinically. The multiplex procedure permitted the validation of all tested loci in the same series of isolated lymphocytes rather than in separate series for each exon. One hundred single lymphocytes, 50 female and 50 male cells, were analysed with an overall amplification rate of 98% and an amplification failure of 2% per exon. We suggest that this test is reliable, easy to set up and much preferable to a mere sex determination with the selective transfer of female embryos.
Economic impact of existing and prospective weight restrictions on older bridges in England and Wales (1988)

It is estimated that there are some 49,000 bridges throughout Great Britain which were not built to comply with national loading standards, introduced in 1922, or were built before the standards were introduced. Some of these bridges were assessed for their load‐carrying capacity in the early 1970s in a programme called ‘Operation Bridgeguard’. The Department of Transport is once more assessing older bridges in a three part programme to:
Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide-I(7-37) in mouse insulinoma beta TC-1 cells. (1992)

The neuropeptide hormone galanin, released by sympathetic stimulation of nerve terminals in the endocrine pancreas, inhibits insulin secretion via a receptor-linked pertussis toxin-sensitive (Gi) transmembrane signaling pathway. Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal hormone shown to have potent insulin-releasing activities in pancreatic B-cells and is believed to serve a physiological role in the augmentation of nutrient-induced insulin release. GLP-I(7-37) binds to specific Gs- and adenylate cyclase-coupled receptors on pancreatic B-cells and directly stimulates proinsulin gene transcription, thereby increasing cellular levels of proinsulin messenger RNA (mRNA) and proinsulin biosynthesis. This study examines the effects of galanin on GLP-I(7-37)-stimulated proinsulin gene expression in mouse beta TC1 cells. The degree of proinsulin gene transcription was assessed by measuring the activity of chloramphenicol acetyl transferase (CAT) expressed from a CAT reporter plasmid linked to the rat insulin-1 gene promoter transferred to beta TC1 cells and by measuring proinsulin mRNA levels by Northern blot analysis. Galanin inhibited both CAT activity and the rise in proinsulin mRNA levels stimulated by either GLP-I(7-37) or forskolin (0.1 microM). Notably, galanin was without effect on CAT activity induced by the cAMP analog, 8-bromo-cAMP, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, or higher concentrations of forskolin. The inhibitory effects of galanin on GLP-I(7-37) and forskolin-induced CAT activity were reversed by the addition of pertussis toxin, a toxin that inactivates inhibitory G-proteins (Gi). We conclude that galanin inhibits GLP-I(7-37)-stimulated proinsulin gene expression by inhibiting the activation of adenylate cyclase by GLP-I(7-37) and subsequently the production of cAMP in B-cells. Further, our data suggest that these actions of galanin are mediated by a pertussis toxin sensitive pathway involving one or more Gis that inhibit adenylate cyclase. Thus, in addition to its well known inhibitory effects on insulin secretion galanin can inhibit proinsulin gene expression stimulated by GLP-I(7-37) activation of the cAMP signaling pathway. These findings may be a unique demonstration of the inhibition of proinsulin gene expression by a substance (galanin) released endogenously within the pancreas.
In Search of Safe and Effective Oral Anticoagulation (2005)

There is a large gap between the need for anticoagulation and the use of drug therapy for this purpose in ambulatory care. Major lower-extremity orthopedic surgery such as total hip replacement and total knee replacement are associated with an increased risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to symptomatic outcomes such as pulmonary embolism (PE). Prophylaxis and treatment of patients with symptomatic VTE occurs in 2 phases. Initial therapy focuses on rapid achievement of effective anticoagulation and usually involves subcutaneous low-molecular-weight heparin. Long-term prophylaxis with the vitamin K antagonist, warfarin, reduces the risk of recurrent VTE from about 27% (without prophylaxis or inadequate prophylaxis) to 4% during the first 3 months of observation.