tbuckley/cabot-search huggingface dataset:
The Lifetime Risk of Developing Breast Cancer
Authors: E. J. Feuer, L.-M. Wun, C. C. Boring, W. D. Flanders, M. J. Timmel, T. Tong
Journal: JNCI Journal of the National Cancer Institute (1993)

Background : The lifetime risk of developing breast cancer in U.S. women, often quoted as one in nine, is a commonly cited cancer statistic. However, many estimates have used cancer rates derived from total rather than the cancer-free population and have not properly accounted for multiple cancers in the same individual. Purpose : Our purpose was to provide a revised method for calculating estimates of the lifetime risk of developing breast cancer and to aid in interpretation of the estimates. Methods : A multiple decrement life table was derived by applying age-specific incidence and mortality rates from cross-sectional data to a hypothetical cohort of women. Incidence, mortality, and population data from 1975–1988 were used, representing the geographic areas of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. The incidence rates reflected only the first breast primary cancer; mortality rates reflected causes other than breast cancer. The population denominator used in calculating incidence rates was adjusted to reflect only those women without previously diagnosed breast cancers in the hypothetical cohort. Results : Our calculations showed an overall lifetime risk for developing invasive breast cancer of approximately one in eight with use of 1987–1988 SEER data, although up to age 85, it was still the commonly quoted one in nine. Conclusion : Our estimate was calculated assuming constant age-specific rates derived from 1987–1988 SEER data. Because incidence and mortality rates change over time, conditional risk estimates over the short term (10 or 20 years) may be more reliable. A large portion of the rise in the lifetime risk of breast cancer estimated using 1975–1977 data (one in 10.6) to an estimate using 1987–1988 data (one in eight) may be attributed to 1) early detection of prevalent cases due to increased use of mammographic screening and 2) lower mortality due to causes other than breast cancer. A common misperception is that the lifetime risk estimate assumes that all women live to a particular age (e.g., 85 or 95). In fact, the calculation assumes that women can die from causes other than breast cancer at any possible age. Cutting off the lifetime risk calculation at age 85 assumes that no women develop breast cancer after that age. While the lifetime risk of developing breast cancer rose over the period 1976–1977 to 1987–1988, the lifetime risk of dying of breast cancer increased from one in 30 to one in 28, reflecting generally flat mortality trends. [J Natl Cancer Inst 85:892–897, 1993]
Pragmatic trials: how to adjust for the ‘Hawthorne effect’?
Authors: George N Konstantinou
Journal: Thorax (2011)

Hashimoto et al 1 have conducted an interesting study to offer a practical and pragmatic insight into steroid-dependent asthma therapeutics in real-world practice. They proposed a strategy based on internet monitoring of objective (spirometry and fraction of exhaled nitric oxide) and subjective (asthma control and asthma-related quality of life questionnaires) measurements to adjust the dose of oral corticosteroids in patients with severe, uncontrolled asthma. However, how ‘pragmatic’ is …
Inhibition by Pentosan Polysulfate (PPS) of Heparin-Binding Growth Factors Released From Tumor Cells and Blockage by PPS of Tumor Growth in Animals
Authors: G. Zugmaier, M. E. Lippman, A. Wellstein
Journal: JNCI Journal of the National Cancer Institute (1992)

In a proliferating tumor, locally secreted polypeptide growth factors, which have autocrine and paracrine functions, induce vascularization essential for tumor growth and metastasis. These growth factors may serve as targets for tumor therapy. We have shown that the heparinoid pentosan polysulfate (PPS) can block growth of subcutaneous human tumor xenografts in nude mice and angiogenesis induced by the heparin-binding, Kaposi's sarcoma-derived fibroblast growth factor (K-FGF). The purpose of this study was to determine whether PPS might also interfere with stimulation of endothelial cells by other growth factors released from tumor cells and whether the promising antitumor effects of PPS extend to other human tumor cell lines. We studied the effects of PPS on stimulation by heparin-binding growth factors released from seven human tumor cell lines in vitro and on tumors growing from these cell lines in athymic nude mice. Seven human cell lines established from breast, prostate, epidermoid, and lung carcinomas and rhabdomyosarcoma were used in in vivo as well as in vitro studies of the effects of PPS. We also studied in vitro the effects of PPS on growth factor-induced colony formation of normal rat kidney fibroblasts and human adrenal carcinoma cells. The tumor cell lines released growth factors into their media that stimulated growth of endothelial and epithelial cells as well as fibroblasts. Heparin-affinity chromatography showed that heparin-binding growth factors contributed substantially to this paracrine activity and that PPS inhibited this stimulus. Six of the seven tumor cell lines were resistant to PPS in soft-agar cloning assays and hence did not appear to depend on autocrine stimulation by the heparin-binding growth factors. In contrast to this in vitro resistance, subcutaneous growth of tumors from all cell lines in athymic nude mice was inhibited in a dose-dependent fashion by daily intraperitoneal injections of PPS. We conclude that heparin-binding growth factors contribute substantially to tumor growth in vivo and that PPS acts by blocking the paracrine effects of heparin-binding growth factors released from the tumor cells. PPS could become a novel treatment tool targeting tumor growth factors. (J Natl Cancer Inst 84:1716–1724, 1992)
Effects of the Direct Lipoprotein-Associated Phospholipase A <sub>2</sub> Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque
Authors: Patrick W. Serruys, Héctor M. García-García, Pawel Buszman, Paul Erne, Stefan Verheye, Michael Aschermann, Henrikus Duckers, Oyvind Bleie, Dariusz Dudek, Hans Erik Bøtker, Clemens von Birgelen, Don D'Amico, Tammy Hutchinson, Andrew Zambanini, Frits Mastik, Gerrit-Anne van Es, Antonius F.W. van der Steen, D. Geoffrey Vince, Peter Ganz, Christian W. Hamm, William Wijns, Andrew Zalewski
Journal: Circulation (2008)

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture.This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA(2) inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers.=0.37). In contrast, Lp-PLA(2) activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5+/-17.9 mm(3); P=0.009), whereas darapladib halted this increase (-0.5+/-13.9 mm(3); P=0.71), resulting in a significant treatment difference of -5.2 mm(3) (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95).Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA(2) inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA(2) inhibition may represent a novel therapeutic approach.
A multiclinic, placebo-controlled, double-blind study of prostaglandin E1 in Raynaud's syndrome.
Authors: J S Mohrland, J M Porter, E A Smith, J Belch, M H Simms
Journal: Annals of the Rheumatic Diseases (1985)

Prostaglandin E1 (alprostadil, Prostin VR Sterile Solution, PGE1) was evaluated in patients with Raynaud9s syndrome in a multiclinic, placebo-controlled, double-blind study. A total of 55 patients with either primary Raynaud9s disease or Raynaud9s disease secondary to systemic sclerosis were randomly assigned to receive either PGE1 administered intravenously at 10 ng/kg/min for 72 hours or placebo administered in the same manner. The frequency and severity of Raynaud9s attacks were then monitored for up to four weeks by use of in-clinic questionnaires and patients9 daily diaries. Haemodynamic assessments included measurements of skin temperature and the finger systolic pressure response to localised digital cooling. Immediately after the infusion the overall symptoms in both the PGE1 and the placebo group showed marked improvement; by four weeks after infusion, in some cases, values had not returned to pretreatment levels. There was, however, no marked benefit of PGE1 treatment over that of placebo. Although PGE1 significantly increased skin temperature during and immediately after infusion, the effect did not persist at two- and four-week follow-up evaluations. The finger systolic pressure response to localised digital cooling (15 degrees C) increased more in the PGE1-treated group than in the placebo-treated group, but the difference was not statistically significant. There was no difference in ulcer healing between the two treatment groups. These results failed to substantiate earlier open-label reports that a 72-hour intravenous infusion of PGE1 in patients with Raynaud9s syndrome produced significant clinical benefit.
Improvement of Insulin-Induced Glucose Disposal in Obese Patients With NIDDM After 1-Wk Treatment With <i>d</i>-Fenfluramine
Authors: André J Scheen, Giuseppe Paolisso, Teresa Salvatore, Pierre J Lefèbvre
Journal: Diabetes Care (1991)

Objective To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulininduced glucose disposal. Research Design and Methods A randomized double-blind placebocontrolled crossover trial with 1-wk treatment periods (2 × 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U · kg−1 · h−1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U · kg−1 · h−1) insulin delivery rates. Results In the n·ndiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (−1.2 ± 0.5 kg, P &amp;lt; 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 ± 0.8 vs. 9.4 ± 1.1 mM, P &amp;lt; 0.005) and plasma free fatty acid concentrations (1150 ± 227 vs. 1640 ± 184 µM, P &amp;lt; 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after cMenfluramine (average increase of glucose MCR 35 ± 12%, P &amp;lt; 0.02). Conclusions Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.
Mesangial cell immune injury
Authors: B A Bresnahan, R J Roman, W M Bagchus, E A Lianos
Journal: Journal of the American Society of Nephrology (1991)

We assessed the renal hemodynamic changes occurring acutely after glomerular mesangial cell immune injury and the effects of thromboxane receptor antagonism on these changes. A single intravenous proteinuric dose of a monoclonal antibody raised against the rat thymocyte antigen Thy 1.1 (ER4), which is also expressed in rat mesangial cells, induced acute decrements in glomerular filtration rate and in renal blood flow in male Munich-Wistar rats. One hour after administration of 4 to 6 mg/kg of ER4 antibody, glomerular filtration rate and renal blood flow decreased by 80 and 36%, respectively. These decrements were associated with significant increments in basal thromboxane B2 synthesis in isolated glomeruli and no changes in glomerular prostaglandin E2 synthesis. Pretreatment of animals with the thromboxane receptor antagonist SQ-29,548 (2 mg/kg) significantly ameliorated decrements in glomerular filtration rate and renal blood flow. Pretreatment with a structurally dissimilar thromboxane receptor antagonist, L-670,596 (3 mg/kg) had no effect. Both antagonists at the doses employed abolished the decrements in renal blood flow induced by systemic administration of the thromboxane mimetic U-46619. Whereas the SQ-29,548 antagonist had no effect on glomerular leukotriene B4 and 12-hydroxyeicosatetraenoic acid synthesis, the L-670,596 thromboxane receptor antagonist significantly inhibited glomerular synthesis of these eicosanoids in immunologically injured glomeruli. These observations indicate that in mesangial cell immune injury the protective effect of thromboxane A2 receptor antagonism on glomerular filtration rate and renal blood flow is not solely due to inhibition of the vasoconstrictor effects of thromboxane A2. An effect on the synthesis of arachidonate lipoxygenation products may also play a role.
Will the Pig Solve the Transplantation Backlog?
Authors: David K. C. Cooper, Bernd Gollackner, David H. Sachs
Journal: Annual Review of Medicine (2002)

▪ Abstract The increasing shortage of human cadaveric organs for purposes of transplantation has become the critical limiting factor in the number of transplants performed each year. Some of this deficit is being met by the use of organs or partial organs from living donors, but this source is insufficient. Xenotransplantation—the transplantation of organs between species, namely from the pig to human—could provide a solution if immunologic and other associated problems could be solved. When a pig organ is transplanted into a primate, hyperacute rejection, induced by anti-pig antibody and mediated by complement and the coagulation system, develops rapidly. This immediate problem can now be overcome, but the return or persistence of anti-pig antibody leads to a delayed form of humoral rejection, acute humoral xenograft rejection, which leads to destruction of the organ within days or weeks. We review the various approaches being investigated to overcome this barrier. Whether they will also prevent subsequent acute cellular rejection remains unknown. Brief mention is made of the potential physiologic incompatibilities between pig and human organs, as well as the microbiologic safety aspects of xenotransplantation. Finally, the question of patient and societal acceptance of xenotransplantation is discussed.
Antitumor activity of motesanib alone and in combination with cisplatin or docetaxel in multiple human non–small-cell lung cancer xenograft models
Authors: Angela Coxon, Beth Ziegler, Stephen Kaufman, Man Xu, Hongyu Wang, Dawn Weishuhn, Joanna Schmidt, Heather Sweet, Charlie Starnes, Douglas Saffran, Anthony Polverino
Journal: Molecular Cancer (2012)

Non–small-cell lung cancer (NSCLC) is categorized into various histologic subtypes that play an important role in prognosis and treatment outcome. We investigated the antitumor activity of motesanib, a selective antagonist of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit, alone and combined with chemotherapy in five human NSCLC xenograft models (A549, Calu-6, NCI-H358, NCI-H1299, and NCI-H1650) containing diverse genetic mutations. Motesanib as a single agent dose-dependently inhibited tumor xenograft growth compared with vehicle in all five of the models (P < 0.05). When combined with cisplatin, motesanib significantly inhibited the growth of Calu-6, NCI-H358, and NCI-H1650 tumor xenografts compared with either single agent alone (P < 0.05). Similarly, the combination of motesanib plus docetaxel significantly inhibited the growth of A549 and Calu-6 tumor xenografts compared with either single agent alone (P < 0.05). In NCI-H358 and NCI-H1650 xenografts, motesanib with and without cisplatin significantly decreased tumor blood vessel area (P < 0.05 vs vehicle) as assessed by anti-CD31 staining. Motesanib alone or in combination with chemotherapy had no effect on tumor cell proliferation in vitro. These data demonstrate that motesanib had antitumor activity against five different human NSCLC xenograft models containing diverse genetic mutations, and that it had enhanced activity when combined with cisplatin or docetaxel. These effects appeared to be mediated primarily by antiangiogenic mechanisms.
Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families
Authors: J Hull
Journal: Thorax (2000)

Respiratory syncytial virus (RSV) infects nearly all children by the end of their second winter. Why some develop bronchiolitis is poorly understood; it is not known whether there is a genetic component. The pathological features include neutrophil infiltration and high levels of interleukin 8 (IL-8), a potent neutrophil chemoattractant.Common genetic variants of the promoter region of the IL-8 gene were identified by sequencing DNA from 36 healthy individuals. Genetic correlates of IL-8 production were assessed using whole blood from 50 healthy subjects. To investigate genetic correlates of disease severity 117 nuclear families were recruited in which a child had required hospital admission for RSV bronchiolitis.A common single nucleotide polymorphism (allele frequency 0.44) was identified 251 bp upstream of the IL-8 transcription start site. The IL8-251A allele tended to be associated with increased IL-8 production by lipopolysaccharide stimulated whole blood (p=0.07). Using the transmission disequilibrium test, the frequency of this allele was significantly increased in infants with bronchiolitis (transmission = 62% (95% confidence interval (CI) 53 to 71), p=0.014) and particularly in those without known risk factors (transmission = 78% (95% CI 62 to 93), p=0.004).Disease severity following RSV infection appears to be determined by a genetic factor close to the IL-8 gene. Further analysis of this effect may elucidate causal processes in the pathogenesis of RSV bronchiolitis.
IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis
Authors: Shigeru Kotake, Nobuyuki Udagawa, Naoyuki Takahashi, Kenichiro Matsuzaki, Kanami Itoh, Shigeru Ishiyama, Seiji Saito, Kazuhiko Inoue, Naoyuki Kamatani, Matthew T. Gillespie, T. John Martin, Tatsuo Suda
Journal: Journal of Clinical Investigation (1999)

IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.
Endothelin blockers and renal protection: a new strategy to prevent end-organ damage in cardiovascular disease?
Authors: T. J. Rabelink, E. S. G. Stroes, K. P. Bouter, P. Morrison
Journal: Cardiovascular Research (1998)

Time for primary review 27 days. 

The endothelin (ET) family comprises three 21-amino acid peptides: ET-1, ET-2 and ET-3. Endothelin-1 has been identified as the major cardiovascular isopeptide. Release of the active peptide ET-1 requires cleavage of a Trp21–Val22 bond in the carboxyterminal of the precursor molecule, big ET-1 [1]. This reaction is catalyzed by a membrane bound metalloprotease, endothelin converting enzyme (ECE-1) [1, 2]. An intracellularly located ECE (ECE-2) has been identified as well [3]. Endothelin release is increased transcriptionally when the endothelium is exposed to vasoconstrictor peptides, inflammatory cytokines and physical factors (e.g. angiotensin II, thrombin, TGF-β). Although the human kidney contains mRNA for all three isoforms of endothelin (ET), ET-1 appears to be the only peptide expressed at the protein level [4]. Expression of ET-1, its precursor, big ET-1, and the ECE in the non-diseased kidney is largely confined to the glomerular and vascular endothelium [4, 5]. However, when proteinuria is present, there is tubular expression of ET-1 as well [6]. ET-1 released by the renal vasculature or nephron segments mainly acts on cells in the immediate vicinity in an autocrine/paracrine fashion. ET-1 mediates its biological effects by interacting with two receptors, the ETA and ETB receptors, which have been cloned and well characterized. The ETA receptor is preferentially expressed in vascular smooth muscle cells and mediates the potent constrictor actions of ET-1 [7]. The ETB receptor is primarily expressed in endothelial cells and binds all three ET isoforms. When this receptor is activated, nitric oxide and prostacyclin are released, possibly as a feedback loop to the constrictor actions of ET-1. This is exemplified by recent observations where both administration of a selective ETB antagonist in animals as well as specific knock-out … 

* Corresponding author. Tel: +31-30-250-7329; Fax: +31-30-254-3492; E-mail: t.rabelink@digd.azu.nl