tbuckley/cabot-search huggingface dataset:
Breast Cancer Risk Perception Among Women Who Have Undergone Prophylactic Bilateral Mastectomy
Authors: K. A. Metcalfe
Journal: JNCI Journal of the National Cancer Institute (2002)

Prophylactic bilateral mastectomy is a preventive option for women who are at high risk of developing breast cancer. We compared the perceptions of breast cancer risk among women who had previously undergone prophylactic bilateral mastectomy with objective estimates of their breast cancer risk.We asked 75 women in the Canadian province of Ontario who had undergone prophylactic bilateral mastectomy between 1991 and 2000 to provide a complete family history of the cancers that had occurred by the time of their surgery and to indicate their BRCA1 and BRCA2 gene mutation status. This information was used to generate estimates of each woman's risk for breast cancer by using the Gail model, the Claus model, and the BRCAPRO model. Sixty of the women also provided their own estimates of their lifetime risks of developing breast cancer before and after they had prophylactic mastectomy. Risk estimates were compared using Wilcoxon's signed-rank test and Pearson's product-moment correlation analysis. All statistical tests were two-sided.The women estimated that their lifetime risk of developing breast cancer before surgery was, on average, 76% (range = 20%-100%) and after surgery was 11.4% (range = 0%-60%). The mean estimated absolute risk reduction the women attributed to prophylactic mastectomy was 64.8%. The average computer-generated risk estimates were 59% for the 14 women who reported that they carried a BRCA1 or BRCA2 gene mutation and 17% for the other women (of whom 43 had a strong family history of breast cancer and 18 had a limited family history). Breast cancer risk was statistically significantly overestimated by all women except for the known BRCA1 and BRCA2 gene mutation carriers.Women who undergo prophylactic bilateral mastectomy have an exaggerated perception of their breast cancer risk before surgery. Formal genetic counseling and genetic testing may result in more accurate risk perceptions to guide women in choosing other preventive options.
Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study
Authors: Atsushi Ohtsu, Jaffer A. Ajani, Yu-Xian Bai, Yung-Jue Bang, Hyun-Cheol Chung, Hong-Ming Pan, Tarek Sahmoud, Lin Shen, Kun-Huei Yeh, Keisho Chin, Kei Muro, Yeul Hong Kim, David Ferry, Niall C. Tebbutt, Salah-Eddin Al-Batran, Heind Smith, Chiara Costantini, Syed Rizvi, David Lebwohl, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2013)

Purpose The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients and Methods Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Results Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Conclusion Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.
Effect of Tamoxifen on Venous Thromboembolic Events in a Breast Cancer Prevention Trial
Authors: Andrea Decensi, Patrick Maisonneuve, Nicole Rotmensz, Donato Bettega, Alberto Costa, Virgilio Sacchini, Alessandro Salvioni, Roberto Travaglini, Pasquale Oliviero, Giuseppe D’Aiuto, Marcella Gulisano, Giacomo Gucciardo, Marco Rosselli del Turco, Maria Antonietta Pizzichetta, Serafino Conforti, Bernardo Bonanni, Peter Boyle, Umberto Veronesi
Journal: Circulation (2005)

Tamoxifen, a selective estrogen-receptor modulator, increases venous thromboembolic events (VTE), but the factors explaining this risk are unclear. Atherosclerosis may induce VTE, or the 2 conditions may share common risk factors. We assessed the effect of tamoxifen on VTE in a breast cancer prevention trial and studied its association with risk factors for VTE.The incidence of VTE was studied in 5408 hysterectomized women randomly assigned to tamoxifen 20 mg/d or placebo for 5 years. There were 28 VTEs on placebo and 44 on tamoxifen therapy (hazard ratio [HR]=1.63; 95% confidence interval [CI], 1.02 to 2.63), 80% of which were superficial phlebitis, accounting for all of the excess due to tamoxifen within 18 months from randomization. Compared with placebo, the risk of VTE on tamoxifen was higher in women aged 55 years or older, women with a body mass index > or =25 kg/m2, elevated blood pressure, total cholesterol > or =250 mg/dL, current smoking, and a family history of coronary heart disease (CHD). Of the 685 women with a CHD risk score > or =5 who entered the trial, 1 in the placebo arm and 13 in the tamoxifen arm developed VTE (log-rank P=0.0013). In multivariate regression analysis, age > or =60 years, height > or =165 cm, and diastolic blood pressure > or =90 mm Hg had independent detrimental effects on VTE risk during tamoxifen therapy, whereas transdermal estrogen therapy concomitant with tamoxifen was not associated with any excess of VTE (HR=0.64; 95% CI, 0.23 to 1.82).Women with conventional risk factors for atherosclerosis have a higher risk of VTE during tamoxifen therapy. This information should be incorporated into counseling women on its risk-benefit ratio, particularly in the prevention setting.
Monogamy Evolves through Multiple Mechanisms: Evidence from V1aR in Deer Mice
Authors: Leslie M. Turner, Adrian R. Young, Holger Römpler, Torsten Schöneberg, Steven M. Phelps, Hopi E. Hoekstra
Journal: Molecular Biology and Evolution (2010)

Genetic variation in Avpr1a, the locus encoding the arginine vasopressin receptor 1A (V1aR), has been implicated in pair-bonding behavior in voles (genus Microtus) and humans, raising the possibility that this gene may contribute commonly to mating-system variation in mammals. In voles, differential expression of V1aR in the brain is associated with male partner–preference behavior in a comparison of a monogamous (Microtus ochrogaster) and promiscuous (Microtus montanus) species. This expression difference is correlated, in turn, with a difference in length of a 5′ regulatory microsatellite in Avpr1a. Here, we use a combination of comparative sequencing of coding and regulatory regions, analysis of neural expression patterns, and signaling assays to test for differences in V1aR expression and function among eight species of deer mice (genus Peromyscus). Despite well-documented variation in Peromyscus social behavior, we find no association between mating system and length variation in the microsatellite locus linked to V1aR expression in voles. Further, there are no consistent differences in V1aR expression pattern between monogamous and promiscuous species in regions of the brain known to influence mating behavior. We do find statistical evidence for positive selection on the V1aR coding sequence including several derived amino acid substitutions in a monogamous Peromyscus lineage, yet these substitutions have no measurable effect on V1aR signaling activity. Together, these results suggest that mating-system variation in rodents is mediated by multiple genetic mechanisms.
Computational prediction of human metabolic pathways from the complete human genome.
Authors: Pedro Romero, Jonathan Wagg, Michelle L Green, Dale Kaiser, Markus Krummenacker, Peter D Karp
Journal: Genome biology (2004)

Abstract Background We present a computational pathway analysis of the human genome that assigns enzymes encoded therein to predicted metabolic pathways. Pathway assignments place genes in their larger biological context, and are a necessary first step toward quantitative modeling of metabolism. Results Our analysis assigns 2,709 human enzymes to 896 bioreactions; 622 of the enzymes are assigned roles in 135 predicted metabolic pathways. The predicted pathways closely match the known nutritional requirements of humans. This analysis identifies probable omissions in the human genome annotation in the form of 203 pathway holes (missing enzymes within the predicted pathways). We have identified putative genes to fill 25 of these holes. The predicted human metabolic map is described by a Pathway/Genome Database called HumanCyc, which is available at http://HumanCyc.org/ . We describe the generation of HumanCyc, and present an analysis of the human metabolic map. For example, we compare the predicted human metabolic pathway complement to the pathways of Escherichia coli and Arabidopsis thaliana and identify 35 pathways that are shared among all three organisms. Conclusions Our analysis elucidates a significant portion of the human metabolic map, and also indicates probable unidentified genes in the genome. HumanCyc provides a genome-based view of human nutrition that associates the essential dietary requirements of humans with a set of metabolic pathways whose existence is supported by the human genome. The database places many human genes in a pathway context, thereby facilitating analysis of gene expression, proteomics, and metabolomics datasets through a publicly available online tool called the Omics Viewer.
Immune responses to the hepatitis B surface antigen and liver-specific lipoprotein in acute type B hepatitis.
Authors: W M Lee, W D Reed, C G Osman, J Vahrman, A J Zuckerman, A L Eddleston, R Williams
Journal: Gut (1977)

A serial prospective study of cellular immunity to HBsAg and liver-specific membrane lipoprotein was undertaken in 21 adults with acute hepatitis type B. Cellular immunity to HBsAg as determined by leucocyte migration inhibition with partially purified HBsAg as antigen was detected in all the patients during the recovery phase of the illness and was already detectable at the time of admission in 13 (62%) of the cases. In five of the remaining eight the titre of HBsAg in the serum at this time was high and in the whole series there was an inverse correlation between the degree of migration inhibition on admission and the peak HBsAg titre suggesting that antigen or possibly antigen/antibody complexes might be interfering with the demonstration of cellular immunity in vitro. Using a combination of minimum migration index recorded during the recovery period peak HBsAg titre, it was possible to compute the peak aspartate aminotransferase level with reasonable accuracy, a finding consistent with the hypothesis that the severity of the illness is related to both the number of infected hepatocytes and the vigour of the immune response to HBsAg. Evidence of an immune response to the liver-specific hepatocyte membrane lipoprotein was present in 50% of the patients tested at the time of admission, but was transient, having disappeared in every case by four weeks. The minimum migration index recorded with HBsAg as antigen was significantly lower in those with detectable sensitisation to the lipoprotein and it is possible that this autoimmune reaction is also generated by the interaction of T cells with viral antigenic determinants on the liver cell surface.
Mannose-binding lectin and mannose-binding lectin–associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults
Authors: M. Isabel Garcia-Laorden, Jordi Sole-Violan, Felipe Rodriguez de Castro, Javier Aspa, M. Luisa Briones, Ayoze Garcia-Saavedra, Olga Rajas, Jose Blanquer, Araceli Caballero-Hidalgo, J. Alberto Marcos-Ramos, Javier Hernandez-Lopez, Carlos Rodriguez-Gallego
Journal: Journal of Allergy and Clinical Immunology (2008)
Macrophage Inflammatory Responses in Rats and Mice With Autochthonous and Transplanted Tumors Induced by 3-Methylcholanthrene23
Authors: Sigurd J. Normann, Martin C. Schardt, Ernst Sorkin
Journal: JNCI Journal of the National Cancer Institute (1984)

Autochthonous and transplanted tumors induced by 3-methylcholanthrene-impregnated paraffin pellets in DA rats and C57BL/6 mice were analyzed for effects on macrophage inflammatory responses. Tumors emerged in 40% of carcinogen-treated rats with a mean latency of 8.1 months. During the latent period, rats treated with carcinogen versus rats treated only with paraffin had a higher frequency of depressed macrophage responses, which, however, did not alter either tumor latency or incidence. Tumors emerged in 70% of carcinogentreated mice with a mean latency of 110 days. Prior to tumor emergence, mice treated with carcinogen or paraffin had a higher frequency of depressed responses than untreated control mice, and such abnormalities in the presence of carcinogen were positively associated with tumor development. Macrophage responses were not altered in rats or mice bearing large autochthonous tumors, although emerging tumors in rats but not in mice were associated with a modest inhibition in macrophage responses. Autochthonous tumors that did not induce macrophage abnormalities did so in syngeneic recipients upon tumor transplantation.
In vitro synergy between linezolid and clarithromycin against Mycobacterium tuberculosis
Authors: Mathieu S. Bolhuis, Tridia van der Laan, Jos G.W. Kosterink, Tjip S. van der Werf, Dick van Soolingen, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2014)

To the Editor: 

Approximately 3% of new tuberculosis cases worldwide represent multidrug-resistant tuberculosis (MDR-TB) [1]. In these MDR-TB cases, resistance of Mycobacterium tuberculosis to the otherwise effective rifampicin and isoniazid forces clinicians to diverge to other antimicrobial agents. Such treatment options include the World Health Organization (WHO) group 5 drugs linezolid and clarithromycin [1]. Linezolid shows excellent efficacy in the treatment of MDR-TB, but its use is often troubled by adverse events [2–4]. Linezolid has shown in vitro bacteriostatic activity against M. tuberculosis and is also effective at achieving culture conversion in drug-resistant cases [5]. In vitro testing revealed that clarithromycin is not very active against M. tuberculosis , as the minimal inhibitory concentrations (MICs) are relatively high. Clinical efficacy seems questionable, as MICs, as reported in the literature, are significantly higher than achievable serum peak levels in vivo [6]. Conversely, clarithromycin reaches adequate local concentrations in alveolar cells and in epithelial lining fluid, where most mycobacteria reside [7], although lower clarithromycin MICs were observed by the Dutch National Mycobacteria Reference Laboratory (Bilthoven, the Netherlands; unpublished data).

Due to the limited number of new treatment options, optimising existing treatment regimens is a conceivable option. Exploring synergy between tuberculosis drugs might help in improving treatment regimens. A study that investigated several antituberculous drugs, such as isoniazid, rifampicin and/or ethambutol, but not linezolid, revealed in vitro synergistic activity with clarithromycin against M. tuberculosis [8]. In this study, we aimed to investigate the possible in vitro synergy between linezolid and clarithromycin in M. tuberculosis isolates obtained from multidrug-resistant, monoresistant and drug-susceptible tuberculosis cases.

We randomly selected a panel of 24 M. tuberculosis isolates from the strain …
The Effects of Changing Weather on Public Health
Authors: Jonathan A. Patz, David Engelberg, John Last
Journal: Annual Review of Public Health (2000)

▪ Abstract Many diseases are influenced by weather conditions or display strong seasonality, suggestive of a possible climatic contribution. Projections of future climate change have, therefore, compelled health scientists to re-examine weather/disease relationships. There are three projected physical consequences of climate change: temperature rise, sea level rise, and extremes in the hydrologic cycle. This century, the Earth has warmed by about 0.5 degrees centigrade, and the mid-range estimates of future temperature change and sea level rise are 2.0 degrees centigrade and 49 centimeters, respectively, by the year 2100. Extreme weather variability associated with climate change may especially add an important new stress to developing nations that are already vulnerable as a result of environmental degradation, resource depletion, overpopulation, or location (e.g. low-lying coastal deltas). The regional impacts of climate change will vary widely depending on existing population vulnerability. Health outcomes of climate change can be grouped into those of: (a) direct physical consequences, e.g. heat mortality or drowning; (b) physical/chemical sequelae, e.g. atmospheric transport and formation of air pollutants; (c) physical/biological consequences, e.g. response of vector- and waterborne diseases, and food production; and (d) sociodemographic impacts, e.g. climate or environmentally induced migration or population dislocation. Better understanding of the linkages between climate variability as a determinant of disease will be important, among other key factors, in constructing predictive models to guide public health prevention.
Glucocorticoid resistance in a girl with Takayasu's arteritis
Authors: I Drigo
Journal: Annals of the Rheumatic Diseases (2006)

documented a modest ASAS 20 response despite employing a more intensive regimen. 8Similarly, Cairns et al found only modest improvement in the BASDAI (6.8 to 5.75). 9A shorter disease duration (9.2 years present study v 15.1 years Maksymowych et al) as well as slightly lower disease activity cannot explain the observed lack of efficacy.Adverse effects were seen in 16 patients, most of which were minor and well tolerated (post-infusion fever and myalgias in 12, mild uveitis in one).Three patients experienced serious adverse effects (renal disease in two, gastrointestinal problems in one) temporally related to the infusions.Renal adverse events included doubling of the serum creatinine levels and nephrotic range proteinuria, respectively.A relapsing form of glomerulopathy is a rare adverse effect of pamidronate infusions. 10 Our patient did not consent to a renal biopsy, and the proteinuria gradually resolved.The third patient had severe diarrhoea and anorexia lasting for 2 months for which no alternative pathology could be found.One patient developed a severe disease flare after the third infusion (severe bilateral uveitis and peripheral arthritis requiring high dose steroid treatment).This patient had history of mild uveitis and peripheral arthritis 4 years ago.It cannot be ascertained whether pamidronate was responsible for the flare or this represented a lack of efficacy of the drug in this patient.In conclusion, pamidronate infusions did not decrease disease activity significantly in patients with moderately active AS refractory to NSAIDs.The study raises questions about the efficacy of monthly pamidronate infusions as a treatment for AS.
Do universal codon-usage patterns minimize the effects of mutation and translation error?
Authors: Roberto Marquez, Sandra Smit, Rob Knight
Journal: Genome biology (2005)

Abstract Background Do species use codons that reduce the impact of errors in translation or replication? The genetic code is arranged in a way that minimizes errors, defined as the sum of the differences in amino-acid properties caused by single-base changes from each codon to each other codon. However, the extent to which organisms optimize the genetic messages written in this code has been far less studied. We tested whether codon and amino-acid usages from 457 bacteria, 264 eukaryotes, and 33 archaea minimize errors compared to random usages, and whether changes in genome G+C content influence these error values. Results We tested the hypotheses that organisms choose their codon usage to minimize errors, and that the large observed variation in G+C content in coding sequences, but the low variation in G+U or G+A content, is due to differences in the effects of variation along these axes on the error value. Surprisingly, the biological distribution of error values has far lower variance than randomized error values, but error values of actual codon and amino-acid usages are actually greater than would be expected by chance. Conclusion These unexpected findings suggest that selection against translation error has not produced codon or amino-acid usages that minimize the effects of errors, and that even messages with very different nucleotide compositions somehow maintain a relatively constant error value. They raise the question: why do all known organisms use highly error-minimizing genetic codes, but fail to minimize the errors in the mRNA messages they encode?
GENETICS OF SOMATIC MAMMALIAN CELLS
Authors: J. H. Tjio, Theodore T. Puck
Journal: The Journal of Experimental Medicine (1958)

A convenient, reliable method for chromosome delineation of animal cells grown as monolayers on glass has been applied to human, opossum, and Chinese hamster cells. Tissue cultured cells from 5 different, normal organs of 7 different human subjects uniformly displayed the expected chromosome number of 46 and showed no variations in morphology or number other than the expected sex differences and a small incidence of polyploidy. The chromosomes of normal cells from the American opossum were as uniform as those of human cells. Cells of the inbred Chinese hamster demonstrated appreciable karyotype variability, the cause of which is under investigation. The chromosome number and morphology of cells from normal human tissues have remained constant after more than 5 months of continuous, rapid growth in tissue culture involving scores of vessel transfers and a number of generations equivalent to many billions of progeny. By the use of routine recloning, even cells of malignant, aneuploid constitution have been maintained in active growth for 3 years and hundreds of generations, with stable chromosomal and metabolic characteristics. The cells of the American opossum and Chinese hamster which possess only 22 chromosomes have been established in vitro and are especially suitable for genetic studies. The readily recognizeable Y and X chromosomes of the male opossum are particularly favorable as cytological markers. Photomicrographs of the chromosomes of the various cells employed are presented.