tbuckley/cabot-search huggingface dataset:
alpha-Fetoprotein Levels in Maternal Serum During Pregnancy and Maternal Breast Cancer Incidence
Authors: M. Melbye
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: A full-term pregnancy is associated with a reduced risk of breast cancer, but the underlying biologic mechanism has not been elucidated. During pregnancy, maternal serum levels of α-fetoprotein, an estradiol-binding protein, rise sharply. In culture, α-fetoprotein inhibits the growth of estrogen-sensitive cells, including estrogen-sensitive breast cancer cells. Thus, we investigated whether a high level of α-fetoprotein in maternal serum during pregnancy is associated with a reduced risk of breast cancer. Methods: From a population-based cohort of 42057 pregnant women in Denmark, enrolled in an α-fetoprotein-screening program from 1978 through 1996, we obtained a complete reproductive history, vital status, and a possible diagnosis of breast cancer (in 117 women) to the end of follow-up on September 1, 1998. Results: During pregnancy, women with an α-fetoprotein level greater than or equal to the median value had a 41% lower risk of breast cancer than women with an α-fetoprotein level below the median value (relative risk [RR] = 0.59; 95% confidence interval [CI] = 0.41–0.85). RRs for breast cancer by mother's age at childbirth were as follows: 29 years or younger, RR = 0.21 (95% CI = 0.08–0.56); 30–34 years, RR = 0.61 (95% CI = 0.32–1.14); 35–37 years, RR = 0.96 (95% CI = 0.49–1.89); and 38 years or older, RR = 0.71 (95% CI = 0.29–1.75) (P for trend = .02). Further analyses suggested that high levels of α-fetoprotein were associated with a reduced incidence of aggressive disease. The most striking finding was that women with high levels of serum α-fetoprotein, compared with women with low levels of serum α-fetoprotein, showed a particularly reduced incidence of large tumors (>2 cm; RR = 0.24 [95% CI = 0.11–0.50]). Conclusion: A high level of α-fetoprotein in maternal serum during any pregnancy is associated with a low overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer at diagnosis. This association appears particularly strong for a pregnancy occurring at a young age.
Clinical Research and the Physician–Patient Relationship
Authors: Donna T. Chen
Journal: Annals of Internal Medicine (2003)

All practicing physicians should be prepared to respond to requests from patients for advice about participating in clinical trials research. Even physicians who choose not to conduct clinical trials but rather devote their practice to clinical care may have patients who consider volunteering for research. In advising patients about clinical research, physicians enhance the physician–patient relationship and contribute to the overall goals of evidence-based medicine. We discuss several ethical and practical challenges facing physicians who wish to help their patients make decisions about volunteering for clinical trials. In addition, we suggest how preparation for advising patients about clinical research participation can be incorporated into the medical education process.
Comparative effects of deoxycholate and 7-methyl-deoxycholate in the hamster
Authors: Syoji Kuroki, Erwin H. Mosbach, Richard J. Stenger, Bertram I. Cohen, Charles K. McSherry
Journal: Hepatology (1987)

The metabolism and effect on biliary lipids of a new bile acid analog, 7-methyl-deoxycholic acid, were studied and compared with those of deoxycholic acid in the hamster. 14C-Labeled 7-methyl-deoxycholic acid and deoxycholic acid were administered intravenously or intraduodenally to bile fistula hamsters at 1.0 or 4.0 mumoles per min X kg, and hepatic bile was analyzed for radioactive metabolites and biliary lipid outputs. Deoxycholic acid and 7-methyl-deoxycholic acid were efficiently absorbed from the intestine, extracted by the liver and excreted into bile as taurine and glycine conjugates. Twenty per cent of deoxycholic acid was 7 alpha-hydroxylated to cholic acid while 7-methyl-deoxycholic acid did not undergo hydroxylation. During deoxycholic acid infusion, the biliary secretion of phospholipid did not increase, and the bile became more lithogenic. In contrast, 7-methyl-deoxycholic acid stimulated phospholipid secretion, and bile became less lithogenic. Although pathologic changes in the liver were inconstant and mostly mild, both bile acids were toxic in the hamster; hemolysis and death due to respiratory distress were observed.
Retained Orthologous Relationships of the MHC Class I Genes during Euteleost Evolution
Authors: Mayumi I. Nonaka, Kouichi Aizawa, Hiroshi Mitani, Hidemi P. Bannai, Masaru Nonaka
Journal: Molecular Biology and Evolution (2011)

Major histocompatibility complex (MHC) class I molecules play a pivotal role in immune defense system, presenting the antigen peptides to cytotoxic CD8+ T lymphocytes. Most vertebrates possess multiple MHC class I loci, but the analysis of their evolutionary relationships between distantly related species has difficulties because genetic events such as gene duplication, deletion, recombination, and/or conversion have occurred frequently in these genes. Human MHC class I genes have been conserved only within the primates for up to 46–66 My. Here, we performed comprehensive analysis of the MHC class I genes of the medaka fish, Oryzias latipes, and found that they could be classified into four groups of ancient origin. In phylogenetic analysis using these genes and the classical and nonclassical class I genes of other teleost fishes, three extracellular domains of the class I genes showed quite different evolutionary histories. The α1 domains generated four deeply diverged lineages corresponding to four medaka class I groups with high bootstrap values. These lineages were shared with salmonid and/or other acanthopterygian class I genes, unveiling the orthologous relationships between the classical MHC class I genes of medaka and salmonids, which diverged approximately 260 Ma. This suggested that the lineages must have diverged in the early days of the euteleost evolution and have been maintained for a long time in their genome. In contrast, the α3 domains clustered by species or fish groups, regardless of classical or nonclassical gene types, suggesting that this domain was homogenized in each species during prolonged evolution, possibly retaining the potential for CD8 binding even in the nonclassical genes. On the other hand, the α2 domains formed no apparent clusters with the α1 lineages or with species, suggesting that they were diversified partly by interlocus gene conversion, and that the α1 and α2 domains evolved separately. Such evolutionary mode is characteristic to the teleost MHC class I genes and might have contributed to the long-term conservation of the α1 domain.
Implications of Upstream Glycoprotein IIb/IIIa Inhibition and Coronary Artery Stenting in the Invasive Management of Unstable Angina/Non–ST-Elevation Myocardial Infarction
Authors: Marc S. Sabatine, David A. Morrow, Robert P. Giugliano, Sabina A. Murphy, Laura A. Demopoulos, Peter M. DiBattiste, William S. Weintraub, Carolyn H. McCabe, Elliott M. Antman, Christopher P. Cannon, Eugene Braunwald
Journal: Circulation (2004)

Background— TIMI IIIB and TACTICS-TIMI 18 were 2 trials of an early invasive strategy in unstable angina (UA)/non–ST-elevation myocardial infarction (NSTEMI) that were conducted nearly a decade apart but with virtually identical enrollment criteria and designs, except that upstream glycoprotein IIb/IIIa inhibition was mandated and coronary artery stenting was routinely used in TACTICS-TIMI 18. We sought to examine the effect of these advances on clinical outcomes and the benefits of an early invasive strategy in UA/NSTEMI. Methods and Results— Patients were stratified on the basis of their TIMI risk score into low-, intermediate-, and high-risk categories. Within each risk category, the rates of clinical outcomes and the benefit of an early invasive strategy were compared. Compared with patients in TIMI IIIB and adjusting for baseline risk, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for acute coronary syndromes (OR, 0.62; P &lt;0.0001). Across both trials, the benefit of an early invasive strategy was significantly greater with increasing baseline risk: OR, 1.39 in low-risk, 0.80 in intermediate-risk, and 0.57 in high-risk patients ( P ≤0.004 for interactions). After adjustment for baseline risk, an early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB (OR, 0.79; 95% CI, 0.56 to 1.11). Conclusions— Advances in the care of patients with UA/NSTEMI, including glycoprotein IIb/IIIa inhibition and stenting, were associated with lower rates of death, MI, and rehospitalization for acute coronary syndromes and a trend toward a greater benefit of an early invasive strategy.
Effects of increasing left ventricular filling pressure in patients with acute myocardial infarction
Authors: Richard O. Russell, Charles E. Rackley, Jaoquin Pombo, David Hunt, Constantine Potanin, Harold T. Dodge
Journal: Journal of Clinical Investigation (1970)

Left ventricular performance in 19 patients with acute myocardial infarction has been evaluated by measuring left ventricular response in terms of cardiac output, stroke volume, work, and power to progressive elevation of filling pressure accomplished by progressive expansion of blood volume with rapid infusion of low molecular weight dextran. Such infusion can elevate the cardiac output, stroke volume, work, and power and thus delineate the function of the left ventricle by Frank-Starling function curves. Left ventricular filling pressure in the range of 20-24 mm Hg was associated with the peak of the curves and when the filling pressure exceeded this range, the curves became flattened or decreased. An increase in cardiac output could be maintained for 4 or more hr. Patients with a flattened function curve had a high mortality in the ensuing 8 wk. The function curve showed improvement in myocardial function during the early convalescence. When left ventricular filling pressure is monitored directly or as pulmonary artery end-diastolic pressure, low molecular weight dextran provides a method for assessment of left ventricular function.
Mechanism of S-T Segment Alteration During Acute Myocardial Injury
Authors: WERNER E. SAMSON, ALLEN M. SCHER
Journal: Circulation Research (1960)

Electrocardiograms recorded with a direct-coupled amplifier and recordings of intramyocardial and intracellular potentials were used to determine the nature of the S-T segment shift after myocardial injury. Immediately after coronary artery ligation in the dog, both true S-T and T-Q changes are produced. Lack of responsiveness to the activation wave in the injured area does not account for the initial change in the S-T segment. Changes in the intracellular action potential can be correlated with the electrocardiographic changes. Immediately after injury, cells in the injured area usually repolarize more rapidly than normal cells and this change is significantly correlated with S-T segment shifts. A decrease in resting potential, generally oc curring later than the action potential changes, is similarly correlated with T-Q segment changes.
Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma
Authors: Hardev S. Pandha, Lucy Heinemann, Guy R. Simpson, Alan Melcher, Robin Prestwich, Fiona Errington, Matt Coffey, Kevin J. Harrington, Richard Morgan
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To test combination treatment schedules of reovirus and cisplatin chemotherapy in human and murine melanoma cell lines and murine models of melanoma and to investigate the possible mechanisms of synergistic antitumor effects. Experimental Design: The effects of reovirus ± chemotherapy on in vitro cytotoxicity and viral replication were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and plaque assay. Interactions between agents were assessed by combination index analysis. Mode of cell death was assessed by Annexin V/propidium iodide fluorescence-activated cell sorting–based assays; gene expression profiling of single versus combination treatments was completed using the Agilent microarray system. Single agent and combination therapy effects were tested in vivo in two immunocompetent models of murine melanoma. Results: Variable degrees of synergistic cytotoxicity between live reovirus and several chemotherapy agents were observed in B16.F10 mouse melanoma cells, most significantly with cisplatin (combination index of 0.42 ± 0.03 at ED50). Combination of cisplatin and reovirus exposure led to increased late apoptotic/necrotic cell populations. Cisplatin almost completely abrogated the inflammatory cytokine gene up-regulation induced by reovirus. Combination therapy led to significantly delayed tumor growth and improved survival in vivo (P &amp;lt; 0.0001 and P = 0.0003, respectively). Cisplatin had no effect on the humoral response to reovirus in mice. However, cisplatin treatment suppressed the cytokine and chemokine response to reovirus in vitro and in vivo. Conclusion: The combination of reovirus and several chemotherapeutic agents synergistically enhanced cytotoxicity in human and murine melanoma cell lines in vitro and murine tumors in vivo. The data support the current reovirus/chemotherapy combination phase I clinical studies currently ongoing in the clinic. (Clin Cancer Res 2009;15(19):6158–66)
One hour of myocardial ischemia decreases the activity of the stimulatory guanine-nucleotide regulatory protein Gs.
Authors: E E Susanni, W T Manders, D R Knight, D E Vatner, S F Vatner, C J Homcy
Journal: Circulation Research (1989)

The effect of 1 hour of myocardial ischemia on the function of the stimulatory guanine-nucleotide-binding protein Gs was examined. This study follows our recent finding that myocardial ischemia increases the density of beta-adrenoreceptors in a conscious canine model while having the opposite effect on the activity of adenylate cyclase. Coronary artery occlusion was induced in five conscious dogs and verified by measurement of blood flow using the Doppler and microsphere techniques. Alterations in the level and function of Gs were examined in sarcolemmal membranes prepared from ischemic and nonischemic regions of the left ventricle. After 1 hour of coronary artery occlusion, the functional activity of sarcolemmal Gs, as determined by reconstitution with cyc- membranes, decreased by 27 +/- 7% in the ischemic zone. Cholera toxin labeling performed in parallel with the reconstitution studies demonstrated a similar decrease of 28 +/- 7%. This was associated with decreases in basal activity and decreases in adenylate cyclase activity stimulated by GTP, GTP plus isoproterenol, sodium fluoride, and forskolin. Thus, a defect distal to the beta-adrenoreceptor occurs in the transduction of adrenergic signals to the heart as a consequence of 1 hour of ischemia.
Mutations in SEPT9 cause hereditary neuralgic amyotrophy
Authors: Gregor Kuhlenbäumer, Mark C Hannibal, Eva Nelis, Anja Schirmacher, Nathalie Verpoorten, Jan Meuleman, Giles D J Watts, Els De Vriendt, Peter Young, Florian Stögbauer, Hartmut Halfter, Joy Irobi, Dirk Goossens, Jurgen Del-Favero, Benjamin G Betz, Hyun Hor, Gert Kurlemann, Thomas D Bird, Eila Airaksinen, Tarja Mononen, Adolfo Pou Serradell, José M Prats, Christine Van Broeckhoven, Peter De Jonghe, Vincent Timmerman, E Bernd Ringelstein, Phillip F Chance
Journal: Nature Genetics (2005)
Targeting children through school-based education and policy strategies: Comprehensive cancer control activities in melanoma prevention
Authors: Julie S. Townsend, Beth Pinkerton, Sharon A. McKenna, Sue M. Higgins, Eric Tai, C. Brooke Steele, Susan R. Derrick, Christine Brown
Journal: Journal of the American Academy of Dermatology (2011)

Primary school-based educational strategies are proven interventions to raise children's awareness and knowledge about sun safety. We highlight barriers and facilitators to implementing interventions across multiple populations in 3 state comprehensive cancer control programs/partnerships that implemented primary school-based sun-safety educational programs. Using a case study approach, we collected semistructured program information and evaluation results from New Mexico's Raising Awareness in Youth about Sun Safety Project, the Sun Protection in Florida Project, and the Arizona SunWise Program. Each program used different strategies for implementing school-based educational programs in their respective state based on local needs, funding constraints, and unique characteristics of their populations. Barriers to implementation included difficulties reaching schools and school administrators and changes in staff workload. Facilitators to implementation included using innovative recruitment approaches (mini grants, school assemblies), having community partners, reaching out to educators in various settings, and having program advocates within schools. Each program placed emphasis on supplementing educational programs with sun-safety policies. We only present a case study from 3 comprehensive cancer control programs/partnerships. Rigorous evaluation methods are needed to test the effectiveness of the various strategies that were used to implement these programs on a population-based level. Partnerships and program advocates are important for successfully implementing and sustaining sun-safety programs. Innovative strategies for reaching school administrators are likely needed to effectively implement sun-safety programs and policies. School policy and environmental change are important and valued components of sun-safety programs.
Promoter CpG Island Methylation of Genes in Key Cancer Pathways Associates with Clinical Outcome in High-Grade Serous Ovarian Cancer
Authors: Wei Dai, Constanze Zeller, Nahal Masrour, Nadeem Siddiqui, James Paul, Robert Brown
Journal: Clinical Cancer Research (2013)

Abstract Purpose: We aimed to identify DNA methylation biomarkers of progression-free survival (PFS) to platinum-based chemotherapy in high-grade serous ovarian cancer (HGSOC) within biologically relevant ovarian cancer-associated pathways. Experimental Design: Association with PFS of CpG island (CGI) promoter DNA methylation at genes in the pathways Akt/mTOR, p53, redox, and homologous recombination DNA repair was sought with PFS as the primary objective in a prospectively collected ovarian cancer cohort (n = 150). Significant loci were validated for associations between PFS, methylation, and gene expression in an independent The Cancer Genome Atlas (TCGA) data set of HGSOC (n = 311). Results: DNA methylation at 29 CGI loci linked to 28 genes was significantly associated with PFS, independent from conventional clinical prognostic factors (adjusted P &amp;lt; 0.05). Of 17 out of the 28 genes represented in the TCGA data set, methylation of VEGFB, VEGFA, HDAC11, FANCA, E2F1, GPX4, PRDX2, RAD54L, and RECQL4 was prognostic in this independent patient cohort (one-sided P &amp;lt; 0.05, false discovery rate &amp;lt; 10%). A multivariate Cox model was constructed, with clinical parameters (age, stage, grade, and histologic type) and significant loci. The final model included NKD1, VEGFB, and PRDX2 as the three best predictors of PFS (P = 6.62 × 10−6, permutation test P &amp;lt; 0.05). Focussing only on known VEGFs in the TCGA cohort showed that methylation at promoters of VEGFA, VEGFB, and VEGFC was significantly associated with PFS. Conclusions: A three loci model of DNA methylation could identify two distinct prognostic groups of patients with ovarian cancer (PFS: HR = 2.29, P = 3.34 × 10−5; overall survival: HR = 1.87, P = 0.007) and patients more likely to have poor response to chemotherapy (OR = 3.45, P = 0.012). Clin Cancer Res; 19(20); 5788–97. ©2013 AACR.
The effect of recombinant α-interferon treatment on serum levels of hepatitis B virus-encoded proteins in man
Authors: Georg Hess, Wolfram Gerlich, Guido Gerken, Michael Manns, Thomas H. Hütteroth, Karl-Hermann Meyer Zum Büschenfelde
Journal: Hepatology (1987)

The effect of alpha-interferon treatment on serum levels of hepatitis B virus-encoded proteins was analyzed in eight patients with chronic type B hepatitis who participated in a pilot study of interferon therapy. Three individuals became HBsAg-negative, 4 lost HBeAg but remained HBsAg-positive and 1 remained positive for both HBsAg and HBeAg. Initiation of interferon treatment was rapidly followed by reduction or loss of hepatitis B virus DNA in the serum but by little immediate change in hepatitis B virus antigen levels. Changes in hepatitis B virus antigens were usually delayed. Loss of HBsAg from the serum was preceded by the sequential disappearance of pre-S-encoded proteins (pre-S1 and polymerized human serum albumin) and HBeAg. In patients who lost HBeAg but remained HBsAg-positive, serum levels of pre-S1 and polymerized human serum albumin usually, but did not always, decrease. The individual who remained HBsAg- and HBeAg-positive had unchanged serum levels of pre-S1, polymerized human serum albumin and HBsAg. These results suggest that alpha-interferon inhibits hepatitis B virus DNA replication but has little direct effect on synthesis of hepatitis B virus gene products.
Cross-Reactive Neuraminidase Antibodies Afford Partial Protection against H5N1 in Mice and Are Present in Unexposed Humans
Authors: Matthew R Sandbulte, Gretchen S Jimenez, Adrianus C. M Boon, Larry R Smith, John J Treanor, Richard J Webby
Journal: PLoS Medicine (2007)

A pandemic H5N1 influenza outbreak would be facilitated by an absence of immunity to the avian-derived virus in the human population. Although this condition is likely in regard to hemagglutinin-mediated immunity, the neuraminidase (NA) of H5N1 viruses (avN1) and of endemic human H1N1 viruses (huN1) are classified in the same serotype. We hypothesized that an immune response to huN1 could mediate cross-protection against H5N1 influenza virus infection.Mice were immunized against the NA of a contemporary human H1N1 strain by DNA vaccination. They were challenged with recombinant A/Puerto Rico/8/34 (PR8) viruses bearing huN1 (PR8-huN1) or avN1 (PR8-avN1) or with H5N1 virus A/Vietnam/1203/04. Additional naïve mice were injected with sera from vaccinated mice prior to H5N1 challenge. Also, serum specimens from humans were analyzed for reactivity with avN1. Immunization elicited a serum IgG response to huN1 and robust protection against the homologous challenge virus. Immunized mice were partially protected from lethal challenge with H5N1 virus or recombinant PR8-avN1. Sera transferred from immunized mice to naïve animals conferred similar protection against H5N1 mortality. Analysis of human sera showed that antibodies able to inhibit the sialidase activity of avN1 exist in some individuals.These data reveal that humoral immunity elicited by huN1 can partially protect against H5N1 infection in a mammalian host. Our results suggest that a portion of the human population could have some degree of resistance to H5N1 influenza, with the possibility that this could be induced or enhanced through immunization with seasonal influenza vaccines.