tbuckley/cabot-search huggingface dataset:
GROWTH CHARACTERISTICS OF INFLUENZA VIRUS
Authors: W. Wilbur Ackermann, Hunein F. Maassab
Journal: The Journal of Experimental Medicine (1954)

An analysis of the growth curve obtained in vitro for influenza virus in chorioallantoic membrane has been made using two known viral inhibitors, methoxinine and alpha-amino-alpha p-methoxyphenylmethanesulfonic acid. The action of these compounds has been shown to be specific for particular phases of viral development. Further, this action is sequential indicating that the inhibited phases do not occur concurrently. The sulfonic acid interferes with the initiation of infection and with the release of newly formed virus from the host-cell. The former effect is dependent upon the relative concentrations of viral inoculum and sulfonic acid. The latter effect is prevented by the action of the receptor-destroying enzyme obtained from cholera vibrio extracts. It is proposed that a function of the viral enzyme is to facilitate the release of virus from the host-cell. The intracellular concentration of virus necessary to initiate this release is increased in the presence of alpha-amino-alpha p-methoxyphenylmethanesulfonic acid. It was found that infection can be initiated in the presence of methoxinine under which condition viral increase is disallowed. The function in viral development of one biochemical process which is inhibited by methoxinine was found to be completed at an interval after initiation of infection and before the appearance of the infectious form of the virus. It is possible to define four stages of viral development in terms of sensitivity to methoxinine and alpha-amino-alpha-p-methoxyphenylmethanesulfonic acid.
Heparin-binding protein targeted to mitochondrial compartments protects endothelial cells from apoptosis
Authors: A. Maria Olofsson, Mikael Vestberg, Heiko Herwald, Jørgen Rygaard, Guido David, Karl-E. Arfors, Viggo Linde, Hans Flodgaard, Jürgen Dedio, Werner Müller-Esterl, Evy Lundgren-′«kerlund
Journal: Journal of Clinical Investigation (1999)

Neutrophil-borne heparin-binding protein (HBP) is a multifunctional protein involved in the progression of inflammation. HBP is stored in neutrophil granules and released upon stimulation of the cells in proximity to endothelial cells. HBP affects endothelial cells in multiple ways; however, the molecular and cellular mechanisms underlying the interaction of HBP with these cells are unknown. Affinity isolation and enzymatic degradation demonstrated that HBP released from human neutrophils binds to endothelial cell-surface proteoglycans, such as syndecans and glypican. Flow cytometry indicated that a significant fraction of proteoglycan-bound HBP is taken up by the endothelial cells, and we used radiolabeled HBP to determine the internalization rate of surface-bound HBP. Confocal and electron microscopy revealed that internalized HBP is targeted to perinuclear compartments of endothelial cells, where it colocalizes with mitochondria. Western blotting of isolated mitochondria from HBP-treated endothelial cells showed that HBP is present in 2 forms — 28 and 22 kDa. Internalized HBP markedly reduced growth factor deprivation–induced caspase-3 activation and protected endothelial cells from apoptosis, suggesting that uptake and intracellular routing of exogenous HBP to mitochondria contributes to the sustained viability of endothelial cells in the context of locally activated neutrophils.
Deregulated Cyclin D1 Expression Is Associated with Decreased Efficacy of the Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cell Lines
Authors: Larry H. Kalish, Rhonda A. Kwong, Ian E. Cole, Richard M. Gallagher, Robert L. Sutherland, Elizabeth A. Musgrove
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Despite promising initial results, recent Phase III trials of the selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (“Iressa”; AstraZeneca, Wilmington, Delaware) in advanced head and neck squamous cell carcinoma (HNSCC) have been equivocal. Cyclin D1, an EGFR target gene, is frequently overexpressed in HNSCC, has been implicated in its pathogenesis, and is strongly associated with poor prognosis in this disease. Therefore, we examined the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib. Experimental Design: A panel of six EGFR-overexpressing HNSCC cell lines was used to correlate CCND1 gene copy number, cyclin D1 expression, and response to gefitinib. The effect of constitutive overexpression of cyclin D1 was assessed by establishing stably transfected clonal SCC-9 cell lines. Results: Three of six cell lines displayed cyclin D1 amplification and/or overexpression, and these cell lines were resistant to gefitinib. SCC 9 clones overexpressing cyclin D1 continued to proliferate and maintained their S-phase fraction when treated with gefitinib, whereas empty vector control clones and the parental SCC 9 cells were profoundly inhibited and displayed marked reductions in S-phase. The resistance of cyclin D1-overexpressing clones and cyclin D1-amplified cell lines was associated with maintenance of cyclin D1 expression after gefitinib treatment. Conclusions: These data suggest that deregulated cyclin D1 overexpression may be associated with resistance of HNSCC to EGFR inhibitors. Therefore, the role of cyclin D1 as a marker of therapeutic response and its utility as a prognostic marker in HNSCC warrant additional analysis.
Abnormal Ca <sup>2+</sup> Release, but Normal Ryanodine Receptors, in Canine and Human Heart Failure
Authors: Ming Tao Jiang, Andrew J. Lokuta, Emily F. Farrell, Matthew R. Wolff, Robert A. Haworth, Héctor H. Valdivia
Journal: Circulation Research (2002)

Sarcoplasmic reticulum (SR) Ca 2+ transport proteins, especially ryanodine receptors (RyR) and their accessory protein FKBP12.6, have been implicated as major players in the pathogenesis of heart failure (HF), but their role remain controversial. We used the tachycardia-induced canine model of HF and human failing hearts to investigate the density and major functional properties of RyRs, SERCA2a, and phospholamban (PLB), the main proteins regulating SR Ca 2+ transport. Intracellular Ca 2+ is likely to play a role in the contractile dysfunction of HF because the amplitude and kinetics of the [Ca 2+ ] i transient were reduced in HF. Ca 2+ uptake assays showed 44±8% reduction of V max in canine HF, and Western blots demonstrated that this reduction was due to decreased SERCA2a and PLB levels. Human HF showed a 30±5% reduction in SERCA2a, but PLB was unchanged. RyRs from canine and human HF displayed no major structural or functional differences compared with control. The P o of RyRs was the same for control and HF over the range of pCa 7 to 4. Subconductance states, which predominate in FKBP12.6-stripped RyRs, were equally frequent in control and HF channels. An antibody that recognizes phosphorylated RyRs yields equal intensity for control and HF channels. Further, phosphorylation of RyRs by PKA did not appear to change the RyR/FKBP12.6 association, suggesting minor β-adrenergic stimulation of Ca 2+ release through this mechanism. These results support a role for SR in the pathogenesis of HF, with abnormal Ca 2+ uptake, more than Ca 2+ release, contributing to the depressed and slow Ca 2+ transient characteristic of HF.
Development of a Diagnostic Genetic Test for Simplex and Autosomal Recessive Retinitis Pigmentosa
Authors: Graeme Richard Clark, Paul Crowe, Dorota Muszynska, Dominic O'Prey, Justin O'Neill, Sharon Alexander, Colin Eric Willoughby, Gareth John McKay, Giuliana Silvestri, David Arthur Simpson
Journal: Ophthalmology (2010)
Vascular complications associated with arteriotomy closure devices in patients undergoing percutaneous coronary procedures
Authors: Eugenia Nikolsky, Roxana Mehran, Amir Halkin, Eve D. Aymong, Gary S. Mintz, Zoran Lasic, Manuela Negoita, Martin Fahy, Shoshana Krieger, Issam Moussa, Jeffrey W. Moses, Gregg W. Stone, Martin B. Leon, Stuart J. Pocock, George Dangas
Journal: Journal of the American College of Cardiology (2004)
HA22 (R490A) Is a Recombinant Immunotoxin with Increased Antitumor Activity without an Increase in Animal Toxicity
Authors: SookHee Bang, Satoshi Nagata, Masanori Onda, Robert J. Kreitman, Ira Pastan
Journal: Clinical Cancer Research (2005)

RFB4 (dsFv)-PE38 (BL22) is a recombinant immunotoxin containing an anti-CD22 (Fv) fused to truncated Pseudomonas exotoxin A, which induces a high complete remission rate in patients with purine analogue-resistant hairy cell leukemia. HA22 is a mutant of BL22 with mutations in heavy-chain CDR3 resulting in increased cytotoxic activity. Our goal was to improve the activity of HA22.Arg(490), which is located in the catalytic domain (III) of the immunotoxin HA22, was mutated to alanine. Purified immunotoxins were produced and tested for cytotoxic activity in cell culture and for antitumor activity and nonspecific toxicity in mice. ADP-ribosylation activity was also measured.HA22 (R490A) is approximately 2-fold more cytotoxic than HA22 on several CD22-positive cell lines. When injected i.v., HA22 (R490A) has more potent antitumor activity than HA22 against CA46 tumors in mice. HA22 and HA22 (R490A) have similar LD(50)s (approximately 1.3 mg/kg) and similar plasma half-lives. The R490A mutation also improved the cytotoxicity of the antimesothelin recombinant immunotoxin SS1 (dsFv)-PE38 (SS1P). In vitro ADP-ribosylation assays show that HA22 R490A has increased activity. Increased cytotoxic activity is probably related to this increase in ADP-ribosylation activity.Protein engineering can be used to increase the efficacy of recombinant immunotoxins. Because HA22 (R490A) has increased antitumor activity without increased animal toxicity, immunotoxins with this mutation are candidates for clinical development.
Sulphasalazine and male infertility: reversibility and possible mechanism.
Authors: S Toovey, E Hudson, W F Hendry, A J Levi
Journal: Gut (1981)

Earlier observations on infertility related to sulphasalazine treatment were extended and semen samples obtained from 28 patients with inflammatory bowel disease on treatment with sulphasalazine at 2-4 g per day. Semen was examined for changes in density, motility, and morphology before, during, and after withdrawal of sulphasalazine. Gross semen abnormalities were seen in 18 patients on this drug for more than two months. Semen quality improved after sulphasalazine had been withdrawn for more than two months and 10 pregnancies are reported after sulphasalazine withdrawal. Preliminary endocrine and acetylator phenotype studies do not elucidate the mechanism of this important new side-effect of this drug. The time course of the drug9s effect on semen quality is consistent with the hypothesis that sulphasalazine or a metabolite, possibly sulphapyridine, is directly toxic to developing spermatozoa. These studies confirmed the preliminary report and suggest that prolonged treatment with sulphasalazine may universally depress semen quality and cause reversible infertility.
Where are they now? Four years after the completion of a maintenance exercise program in people with COPD
Authors: Lissa Spencer, Zoe Mckeough, Jennifer Alison
Journal: European Respiratory Journal (2012)

Introduction: To determine if quality of life and exercise capacity had been maintained four years after the completion of a12-months maintenance exercise program (MEP) that followed an eight-week pulmonary rehabilitation program (PRP), in people with COPD.   Methods:  At the completion of the 12 month MEP, participants had maintained exercise capacity and quality of life and were instructed to continue with unsupervised exercise without further follow-up. Four years later participants were invited to be reassessed with spirometry, two six-minute walk tests (6MWT), St George9s Respiratory Questionnaire (SGRQ) and the Health and Activity Survey (HAAS). Daily Physical Activity (PA) was also measured using the SenseWear Pro 3 armband.  Results: Thirty-seven of the 48 (79%) who completed the MEP were reassessed at four years [mean (SD): age 70 (8); males 22; BMI 26 (6); smokers 14%]. Results compared to the end of the MEP [mean difference (95%CI)] showed a maintenance of SGRQ [2.5 (-4 to 9), p=0.43] with a decline in 6MWT [-56m (-25 to -86) p   Conclusion:  Four years following a PRP plus a12-month MEP people with COPD had maintained quality of life but showed a significant decline in exercise capacity.
ADHD, Values, and the Self
Authors: Paul Litton
Journal: The American Journal of Bioethics (2005)

*The opinions expressed are the views of the author and do not necessarily reflect the policy of the National Institutes of Health, the Public Health Service, or the U.S. Department of Health and Human Services. Notes *The opinions expressed are the views of the author and do not necessarily reflect the policy of the National Institutes of Health, the Public Health Service, or the U.S. Department of Health and Human Services. 2. Alternatively, one has reason to realize her authentic self if it is good to realize one's authentic self regardless of whether it is a desirable self. 3. I owe this paragraph's points to Larry Temkin.
Grand Multiparity Is Associated With Type 2 Diabetes in Filipino American Women, Independent of Visceral Fat and Adiponectin
Authors: Maria Rosario G. Araneta, Elizabeth Barrett-Connor
Journal: Diabetes Care (2009)

OBJECTIVE To determine whether multiparity is associated with type 2 diabetes, independent of visceral adipose tissue (VAT) and adipokines. RESEARCH DESIGN AND METHODS Participants were from the University of California San Diego Filipino Women's Health Study with at least one live birth. A 2-h 75-g oral glucose tolerance test was administered; adiponectin, leptin, ghrelin, reproductive history, family history of diabetes, VAT, and lifestyle behaviors were measured between 1995 and 2002. RESULTS Among 152 women, mean age was 59.5 years (range 48–73 years) and mean parity was 4.3 (range 1–12 births). Type 2 diabetes prevalence increased by parity group (low parity, 1–2 births, 25%; medium parity, 3–5 births, 30.3%; and grand multiparity: 6–12 births, 50%; P = 0.048). Family history of diabetes, exercise, insulin resistance, and leptin and ghrelin levels did not differ by parity group. Compared with women in the low parity group, women with ≥6 births were significantly older (62 vs. 57 years), had lower college completion (22 vs. 58%, P = 0.006), more hypertension (72 vs. 55%), higher VAT (74.9 vs. 58.4 cm3), and lower adiponectin concentration (5.79 vs. 7.61 μg/ml). In multivariate analysis adjusting for adiponectin, VAT, family history of diabetes, age, education, hypertension, and estrogen use, grand multiparous women had a threefold higher odds of type 2 diabetes (adjusted odds ratio 3.40 [95% CI 1.13–10.2]) compared with low parity women. No differences were observed in the odds of diabetes between women in the medium (1.10 [0.41–2.91]) and low parity groups. CONCLUSIONS Having ≥6 children was associated with type 2 diabetes, independent of adiponectin, VAT, family history, and other measured diabetes risk factors.
Changes in hepatocyte water volume affect protein synthesis
Authors: Robert Wondergem
Journal: Hepatology (1993)

Protein synthesis in isolated rat hepatocytes was determined from the incorporation of [ 3 H]leucine (4 mM) into acid-precipitable material in the presence of amino acids at twice their physiological concentration. Protein synthesis increased linearly with time and incubated cell protein, and was inhibited by cycloheximide by more than 95%. In normo-osmotic incubations containing amino acids at twice the physiological concentrations the rate of [ 3 H]leucine incorporation was 5.8 ± 0.2 nmol/h per mg cell protein (n = 26). Hyperosmotic cell shrinkage due to addition of 60 mM-NaCl or 120 mM-raffinose inhibited [ 3 H]leucine incorporation into acid-precipitable material by 60% and 74%, respectively, whereas hypo-osmotic cell swelling was ineffective. Inhibition of protein synthesis by adding 120 mM-raffinose was largely counteracted by simultaneous lowering of the NaCl concentration by 60 mM. Glutamine (10 mM) had no effect on protein synthesis in normo-osmotic incubations (320 mosm), but stimulated protein synthesis in hyperosmotically (440 mosm) pre-shrunken cells almost to rates found in normo-osmotic (320 mosm) control incubations. Cyclic AMP and vasopressin inhibited protein synthesis by 23% and 8%, respectively, whereas insulin and phenylephrine were ineffective. However, inhibition of protein synthesis by cyclic AMP was about twice as strong in the presence of vasopressin or phenylephrine. When protein synthesis was preinhibited by cyclic AMP, [ 3 H]leucine incorporation was stimulated by glutamine (10 mM), insulin or hypoosmotic exposure. There was a close relationship between the inhibition of protein synthesis and the extent of hepatocyte shrinkage induced by the abovementioned effectors, suggesting a role of cell volume in the regulation of hepatic protein synthesis.
Expanding Evidence for the Multiple Dangers of Epidemic Abdominal Obesity
Authors: Adrian J. Cameron, Paul Z. Zimmet
Journal: Circulation (2008)

of America has been expanding now for decades, 1 largely as a consequence of an obesogenic environment, with a car-worshipping culture and take-away lifestyle par excellence. 2 No upper limit to the prevalence or extent of obesity is yet apparent, and many countries and communities worldwide are busily following the American lead.Accumulating research evidence suggests that the personal and economic costs of the obesity epidemic are immense, 3 driven by the obesity-related increases in risk for conditions such as type 2 diabetes mellitus, the metabolic syndrome, cardiovascular disease (CVD), kidney disease, arthritis, cancer, asthma, and sleep-disordered breathing.In addition, decreases are apparent in self-esteem and quality of life.
Molecular analysis of heritable mouse mutations.
Authors: E M Rinchik
Journal: Environmental Health Perspectives (1987)

Germ-line mutations of the mouse have for years comprised one class of biological markers for mammalian reproductive and developmental toxicology. Understanding the molecular nature of mutations and the mechanisms by which mutations are translated into specific (and often complex) phenotypes, however, still looms as a major goal of mammalian biology. Molecular genetic analysis of heritable mouse mutations constitutes a significant, experimentally malleable strategy for relating genomic DNA structure to genic expression and function in mammals. The integrated use of recombinant DNA technology, which allows both the identification and analysis of expression of single genes, and classical genetic and cytogenetic analysis, which allow the important correlation between basic DNA defects and the organismic consequences of such defects, has been crucial to this strategy. Some of the approaches (e.g., specific-gene cloning, random-clone analysis of genomic regions, insertional mutagenesis) for studying the nature and effect of both mutations and their wild-type counterparts that have resulted from this integration of genetic analysis and molecular biology have been applied to many loci within the murine genome. Studies of the nature and effects of a complex set of radiation-induced mutations at the dilute-short ear (d-se) region of chromosome 9, a specific example of this type of integrated analysis, are discussed.
Silencing of FLRG, an Antagonist of Activin, Inhibits Human Breast Tumor Cell Growth
Authors: Diane Razanajaona, Stéphanie Joguet, Anne-Sophie Ay, Isabelle Treilleux, Sophie Goddard-Léon, Laurent Bartholin, Ruth Rimokh
Journal: Cancer Research (2007)

Abstract Activin, a member of the transforming growth factor β (TGFβ) superfamily, regulates diverse processes, such as cellular growth and differentiation. There is increasing evidence that TGFβ and its signaling effectors are key determinants of tumor cell behavior. Loss of sensitivity to TGFβ-induced growth arrest is an important step toward malignancy. We previously characterized FLRG as an extracellular antagonist of activin. Here, we show that activin-induced growth inhibition is altered in FLRG-expressing breast cancer lines. Silencing FLRG induced growth inhibition, which is reversible upon addition of exogenous FLRG. We showed that FLRG silencing effects resulted from restoration of endogenous activin functions as shown by increased levels of phosphorylated smad2 and up-regulation of activin target gene transcripts. Furthermore, the growth inhibition induced by FLRG silencing was reversible by treatment with a soluble form of type II activin receptor. Finally, a strong expression of FLRG was observed in invasive breast carcinomas in contrast with the normal luminal epithelial cells in which FLRG was not detected. Our data provide strong evidence that endogenous FLRG contributes to tumor cell proliferation through antagonizing endogenous activin effects. [Cancer Res 2007;67(15):7223–9]
STAT4 single nucleotide polymorphism, rs7574865 G/T, as a risk for antiphospholipid syndrome
Authors: T Horita, T Atsumi, N Yoshida, H Nakagawa, H Kataoka, S Yasuda, T Koike
Journal: Annals of the Rheumatic Diseases (2009)

Genetic factors are hypothesised to play a role in the susceptibility to antiphospholipid syndrome (APS) based on several family studies in patients with anti-phospholipid antibodies (aPL) and/or clinical manifestations of APS. APS can occur alone (primary APS) or in conjunction with systemic lupus erythematosus (SLE). Therefore, APS and SLE may, in part, share a common mechanism for disease onset or progression. Likewise SLE, human leukocyte antigen (HLA) associations have been reported in APS.1 In addition, polymorphisms of target antigens for aPL and thrombotic genetic risk factors have been described.1 Despite the numerous studies on the immunogenetic predisposition to APS, only a few genes …
A duodenal role in gastrin release
Authors: J. R. Hayes, J. Ardill, T. L. Kennedy, K. D. Buchanan
Journal: Gut (1974)

Observations on the plasma gastrin response to feeding protein in patients with the dumping syndrome, patients with pyloric stenosis, and patients asymptomatic after gastric surgery suggested that the duodenum might be important in the mechanism of gastrin release. This duodenal role was confirmed by the finding that when the stimulus was placed directly in the duodenum peak gastrin levels occurred earlier than when the stimulus was placed directly in the stomach.