tbuckley/cabot-search huggingface dataset:
Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive Metastatic Breast Cancer
Authors: Stephen Johnston, John Pippen, Xavier Pivot, Mikhail Lichinitser, Saeed Sadeghi, Veronique Dieras, Henry Leonidas Gomez, Gilles Romieu, Alexey Manikhas, M. John Kennedy, Michael F. Press, Julie Maltzman, Allison Florance, Lisa O'Rourke, Cristina Oliva, Steven Stein, Mark Pegram
Journal: Journal of Clinical Oncology (2009)

Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC).Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.
Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours
Authors: A. Miyanaga, K. Honda, K. Tsuta, M. Masuda, U. Yamaguchi, G. Fujii, A. Miyamoto, S. Shinagawa, N. Miura, H. Tsuda, T. Sakuma, H. Asamura, A. Gemma, T. Yamada
Journal: Annals of Oncology (2012)
Chronic cough--not such a heartsink
Authors: A H Morice
Journal: Thorax (2003)

Knowledge of the pathophysiology of the different conditions which cause chronic cough is vital to achieving a correct diagnosis and successful treatment

Patients present with symptoms. Doctors are trained to recognise disease. There is no better illustration of these two different paradigms than cough. Unfortunately for the patient, the sensory input triggering the cough reflex may arise from anywhere in the territory of the vagus nerve. Thus, chronic cough may be caused by conditions treated by at least three different specialists—the ENT surgeon, the gastroenterologist, and the chest physician. Because of our speciality led view of the world, the doctor may not have received training in the condition causing the symptom. There is a …
A childhood asthma death in a clinical trial: potential indicators of risk
Authors: JO Warner, WH Nikolaizik, CR Besley, JA Warner
Journal: European Respiratory Journal (1998)

A 9 yr old girl with a history of eczema and asthma was admitted to our specialist asthma service and recruited into a trial designed to investigate systemic as well as therapeutic benefits of inhaled corticosteroids. Eight months after referral the patient died from an acute asthma attack. This childhood asthma death during an inhaled steroid trial has facilitated identification of risk factors. Despite good clinical response to inhaled corticosteroids, the patient was distinguishable from the other patients by: increased variability of the morning and evening peak flow rates; increased reactivity, though not sensitivity, to histamine; and an unprecedented rise in serum soluble interleukin-2 receptor levels immediately after commencing inhaled steroids. The immunological basis for corticosteroid resistance and immunohistochemical studies on postmortem specimens from asthma deaths suggest that T-cell activation markers may be indicators of the fatality prone asthmatic.
Interleukin 6 and its soluble receptor in a central role at the neuroimmunoendocrine interface in Sjögren syndrome: an explanatory interventional study
Authors: H Forsblad d'Elia, C Bjurman, E Rehnberg, G Kvist, Y T Konttinen
Journal: Annals of the Rheumatic Diseases (2009)

Sjogren syndrome (SS) is characterised by focal adenitis and fatigue, the latter often the most important symptom.1 Host reactions and responses to disease and disease-associated fatigue consists of stimulation of cytokine network, which involves tumour necrosis factor (TNF)α and interleukin (IL)1β, with IL6 often acting as the end stage effector cytokine in this cascade.2 Stimulation of host IL6 stimulates protective host responses such as acute phase response and hypothalamus–pituitary–adrenal (HPA) axis. IL6 stimulates hypothalamic corticotropin releasing hormone, pituitary corticotropin and adrenal steroid hormone synthesis.3 4 Soluble IL6 receptor (sIL6R) is an agonist to IL6 as IL6 upon binding to sIL6R further binds to signal transducing gp130 protein activating cells that lack membrane bound IL6R. Thus, sIL6R may function as a powerful enhancer of IL6.5

The hypothesis of the present study was that IL6 and the …
Molecular Profiling of Inflammatory Breast Cancer
Authors: Ivan Bièche, Florence Lerebours, Sengül Tozlu, Marc Espie, Michel Marty, Rosette Lidereau
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. The molecular mechanisms responsible for IBC are largely unknown. Experimental Design: To obtain further insight into the molecular pathogenesis of IBC, we used real-time quantitative reverse transcription (RT)-PCR to quantify the mRNA expression of 538 selected genes in IBC relative to non-IBC. Results: Twenty-seven (5.0%) of the 538 genes were significantly up-regulated in IBC compared with non-IBC. None were down-regulated. The 27 up-regulated genes mainly encoded transcription factors (JUN, EGR1, JUNB, FOS, FOSB, MYCN, and SNAIL1), growth factors (VEGF, DTR/HB-EGF, IGFBP7, IL6, ANGPT2, EREG, CCL3/MIP1A, and CCL5/RANTES) and growth factor receptors (TBXA2R, TNFRSF10A/TRAILR1, and ROBO2). We also identified a gene expression profile, based on MYCN, EREG, and SHH, which discriminated subgroups of IBC patients with good, intermediate, and poor outcome. Conclusion: Our study has identified a limited number of signaling pathways that require inappropriate activation for IBC development. Some of the up-regulated genes identified here could offer useful diagnostic or prognostic markers and could form the basis of novel therapeutic strategies.
Inferring admixture proportions from molecular data
Authors: G. Bertorelle, L. Excoffier
Journal: Molecular Biology and Evolution (1998)

We derive here two new estimators of admixture proportions based on a coalescent approach that explicitly takes into account molecular information as well as gene frequencies. These estimators can be applied to any type of molecular data (such as DNA sequences, restriction fragment length polymorphisms [RFLPs], or microsatellite data) for which the extent of molecular diversity is related to coalescent times. Monte Carlo simulation studies are used to analyze the behavior of our estimators. We show that one of them (mY) appears suitable for estimating admixture from molecular data because of its absence of bias and relatively low variance. We then compare it to two conventional estimators that are based on gene frequencies. mY proves to be less biased than conventional estimators over a wide range of situations and especially for microsatellite data. However, its variance is larger than that of conventional estimators when parental populations are not very differentiated. The variance of mY becomes smaller than that of conventional estimators only if parental populations have been kept separated for about N generations and if the mutation rate is high. Simulations also show that several loci should always be studied to achieve a drastic reduction of variance and that, for microsatellite data, the mean square error of mY rapidly becomes smaller than that of conventional estimators if enough loci are surveyed. We apply our new estimator to the case of admixed wolflike Canid populations tested for microsatellite data.
When Is Osteonecrosis Not Osteonecrosis?: Adjudication of Reported Serious Adverse Joint Events in the Tanezumab Clinical Development Program
Authors: Marc C. Hochberg, Leslie A. Tive, Steven B. Abramson, Eric Vignon, Kenneth M. Verburg, Christine R. West, Michael D. Smith, David S. Hungerford
Journal: Arthritis & Rheumatology (2015)

Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the tanezumab clinical program.The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis.The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus.Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.
Specification, information, and the loss of receptor systems
Authors: Barry Hughes
Journal: Behavioral and Brain Sciences (2001)

Claims made in the target article that information-that-specifies is contained in relations among structured energy arrays, considered as wholes, may well be true, but claims that information-that-specifies is only contained in irreducible relations among structured energy arrays, considered as wholes, fail to persuade, at least in the case of the blind.
The emerging issue of cardiac dysfunction induced by antineoplastic angiogenesis inhibitors
Authors: Carlo G. Tocchetti, Giuseppina Gallucci, Carmela Coppola, Giovanna Piscopo, Clemente Cipresso, Carlo Maurea, Aldo Giudice, Rosario V. Iaffaioli, Claudio Arra, Nicola Maurea
Journal: European Journal of Heart Failure (2013)
Outcomes at 3 Months After Planned Cesarean vs Planned Vaginal Delivery for Breech Presentation at Term&lt;SUBTITLE&gt;The International Randomized Term Breech Trial&lt;/SUBTITLE&gt;
Authors: Mary E. Hannah
Journal: JAMA (2002)

<h3>Context</h3>The Term Breech Trial found a significant reduction in adverse perinatal outcomes without an increased risk of immediate maternal morbidity with planned cesarean delivery compared with planned vaginal birth. No randomized controlled trial of planned cesarean delivery has measured benefits and risks of postpartum outcomes months after the birth.<h3>Objective</h3>To compare maternal outcomes of planned cesarean delivery and planned vaginal birth at 3 months post partum.<h3>Design</h3>Follow-up study to the Term Breech Trial, a randomized controlled trial conducted between January 9, 1997, and April 21, 2000.<h3>Setting and Participants</h3>a total of 1596 of 1940 women from 110 centers worldwide who had a singleton fetus in breech presentation at term responded to a follow-up questionnaire at 3 months post partum.<h3>Main Outcome Measures</h3>Breastfeeding; infant health; ease of caring for infant and adjusting to being a new mother; sexual relations and relationship with husband/partner; pain; urinary, flatal, and fecal incontinence; depression; and views regarding childbirth experience and study participation.<h3>Results</h3>Baseline information was similar for both the cesarean and vaginal delivery groups. Women in the planned cesarean delivery group were less likely to report urinary incontinence than those in the planned vaginal birth group (36/798 [4.5%] vs 58/797 [7.3%]; relative risk, 0.62; 95% confidence interval, 0.41-0.93). Incontinence of flatus was not different between groups but was less of a problem in the planned cesarean delivery group when it occurred (p = .006). There were no differences between groups in other outcomes.<h3>Conclusions</h3>Planned cesarean delivery for pregnancies with breech presentation at term may result in a lower risk of incontinence and is not associated with an increased risk of other problems for women at 3 months post partum, although the effect on longer-term outcomes is uncertain.
Glucocorticoid-Binding Proteins in Human Acute Lymphoblastic Leukemic Blast Cells
Authors: Marc E. Lippman, Roger H. Halterman, Bridgid G. Leventhal, Seymour Perry, E. Brad Thompson
Journal: Journal of Clinical Investigation (1973)

The first known step in steroid hormone action is the association of the steroid with specific cytoplasmic steroid-binding proteins (SBP). Using a competitive binding assay, we detected, quantified, and partially characterized such a SBP in cytosol from glucocorticoid-sensitive human lymphoblastic leukemic blasts. The affinity of steroids for the SBP was directly related to their known killing potency. For example, steroids without glucocorticoid effect such as androstenedione, etiocholanolone, and tetrahydrocortisol were unable to displace radiolabeled dexamethasone from the SBP in the binding reaction. The dose-response curve for in vitro inhibition of [(3)H]thymidine uptake in leukemic blasts correlated closely with the binding affinity of glucocorticoids to the SBP, providing additional support for an essential physiologic role for SBP in steroid action. SBP activity was either greatly diminished or absent in glucocorticoid-resistant cells. Six patients who intially had SBP in their blasts and were responsive to combinations of drugs including glucocorticoids no longer had SBP activity detectable at a time when they no longer responded to combinations of drugs including glucocorticoids. In vitro [(3)H]thymidine uptake was not inhibited by steroids in leukemic blast cells lacking SBP activity. Other patients who had received some antileukemic therapy including glucocorticoids and who still had SBP in their leukemic blasts, were still responsive to drug combinations that included glucocorticoids. This appears to be the first study demonstrating glucocorticoid receptors in a human tissue.
Effects of 17β-estradiol and progesterone on migration of human monocytic THP-1 cells stimulated by minimally oxidized low-density lipoprotein in vitro
Authors: M Okada
Journal: Cardiovascular Research (1997)

Many epidemiological studies have shown that postmenopausal hormone replacement therapy (HRT) has a beneficial effect on atherosclerotic cardiovascular disease. The aim of this study was to investigate the effects of estrogen and progestin on the migration of monocytes induced by minimally oxidized low-density lipoprotein (m-ox-LDL) in vitro.Human monocytic THP-1 cells were used for the study. Migration assay was performed using a modified Boyden chamber.The presence of estrogen receptors was determined in THP-1 cells by Western and Northern blot analysis. Although native LDL had no significant effects on the migration of THP-1 cells, m-ox-LDL increased the migration of THP-1 cells in a dose-dependent manner. Although 17 beta-estradiol (E2, 10(-9)-10(-6) M) inhibited the 10 micrograms/ml-induced migration of THP-1 cells in a dose-dependent manner, estrone (E1), estriol (E3) and progesterone (P) had no significant effects. The combination of P (10(-9)-10(-6) M) did not show any effect on the inhibitory effect of 10(-7) M E2. Preincubation of THP-1 cells with the anti-estrogenic agent, tamoxifen (10(-6) M), significantly antagonized the inhibitory effect of 10(-7) M E2. m-ox-LDL stimulated MCP-1 secretion from THP-1 cells, which was reduced by E2. Anti-human MCP-1 neutralizing antibody inhibited the migration of THP-1 cells stimulated by m-ox-LDL. E2 also inhibited the 10 ng/ml MCP-1-induced migration of THP-1 cells in a dose-dependent manner.These findings suggest that the inhibitory effect of E2 on the migration of monocytes might be one of the factors involved in the decreased incidence of atherosclerotic cardiovascular disease in premenopausal women and postmenopausal HRT.
Mediastinoscopy: A clinical evaluation of 400 consecutive cases
Authors: C. L. Sarin, H. C. Nohl-Oser
Journal: Thorax (1969)

Mediastinoscopy was carried out in 400 cases, including 296 of bronchogenic carcinoma. At the time of presentation the new growth had already spread to involve the mediastinal lymph nodes in slightly more than 50% of these. The incidence of involvement was 76% in oat-cell and 35% in squamous-cell carcinoma. Non-resectability at thoracotomy was encountered in seven out of 120 patients. We advocate this procedure in every case of bronchogenic carcinoma which is considered operable on other counts. In patients in whom the mediastinal lymph nodes are invaded by growth we prefer radical radiotherapy to surgery, as the long-term survival of the two methods is comparable. This procedure may be the only source of positive histological proof of diagnosis, not only in carcinoma but in other types of intrathoracic disease. We believe that this procedure reduces the number of unnecessary exploratory thoracotomies.
Phylogenetic reconstruction of the Drosophila obscura group, on the basis of mitochondrial DNA.
Authors: E Barrio, A Latorre, A Moya, F J Ayala
Journal: Molecular Biology and Evolution (1992)

We have constructed restriction-site maps of the mtDNAs in 13 species and one subspecies of the Drosophila obscura group. The traditional division of this group into two subgroups (affinis and obscura) does not correspond to the phylogeny of the group, which shows two well-defined clusters (the Nearctic affinis and pseudoobscura subgroups) plus a very heterogeneous set of anciently diverged species (the Palearctic obscura subgroup). The mtDNA of Drosophila exhibits a tendency to evolve toward high A+T values. This leads to a "saturation" effect that (1) begets an apparent decrease in the rate of evolution as the time since the divergence of taxa increases and (2) reduces the value that mtDNA restriction analysis has for the phylogenetic reconstruction of Drosophila species that are not closely related.
Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a marine model of airway sensitization.
Authors: E Hamelmann, A Oshiba, J Paluh, K Bradley, J Loader, T A Potter, G L Larsen, E W Gelfand
Journal: The Journal of Experimental Medicine (1996)

To study the role of CD8+ T cells in allergic sensitization, we examined the effects of in vivo depletion of CD8+ T cells prior to sensitization on IgE production, immediate type cutaneous hypersensitivity and development of altered airway responsiveness. BALB/c mice were thymectomized and treated with anti-CD8 antibody resulting in depletion of CD8+ T cells (&amp;lt;1%) in spleen and lymphoid tissues. In these mice, sensitization to ovalbumin (OVA) via the airways still resulted in IgE anti-OVA responses and immediate cutaneous reactions to OVA, but the animals were unable to develop airway hyperresponsiveness, eosinophil infiltration of the lung parenchyma, or IL-5 production in the local lymph nodes of the airway. Transfer of CD8+ T cells from naive animals during sensitization (on day 8 of the 10-d protocol) fully restored the ability to develop airway hyperresponsiveness and this was accompanied by IL-5 production and eosinophil accumulation in the lung. These data indicate a critical role for CD8+ T cells in the production of IL-5 and the development of altered airway responsiveness after antigen sensitization through the airways.
Cerebral Blood Flow and Personality: A Positron Emission Tomography Study
Authors: Debra L. Johnson, John S. Wiebe, Sherri M. Gold, Nancy C. Andreasen, Richard D. Hichwa, G. Leonard Watkins, Laura L. Boles Ponto
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: This study sought to describe brain regions associated with the personality dimension of introversion/extraversion. METHOD: Measures of cerebral blood flow (CBF) were obtained from 18 healthy subjects by means of [15O]H2O positron emission tomography. Correlations of regional CBF with introversion/extraversion were calculated, and a three-dimensional map of those correlations was generated. RESULTS: Overall, introversion was associated with increased blood flow in the frontal lobes and in the anterior thalamus. Regions in the anterior cingulate gyrus, the temporal lobes, and the posterior thalamus were found to be correlated with extraversion. CONCLUSIONS: The findings of the study lend support to the notion that introversion is associated with increased activity in frontal lobe regions. Moreover, the study suggests that individual differences in introversion and extraversion are related to differences in a fronto-striato-thalamic circuit.
Comparison of dextran and hematocrit effects in the pulmonary microcirculation.
Authors: J U Raj, J Anderson
Journal: Circulation Research (1991)

We have compared the effects of an increase in perfusate viscosity induced by dextran and by hematocrit (Hct) on segmental vascular resistance in the pulmonary circulation and the effect of flow on microvascular resistance in lungs perfused with dextran and red blood cells. We isolated and perfused lungs of 39 neonatal rabbits weighing 670 +/- 250 g. To determine the effect of dextran, group 1 (n = 8) lungs were perfused with both 5% and 20% dextran 70 solutions (Hct, approximately 25%); to determine the effect of Hct, group 2 (n = 5) lungs were perfused alternately with 5% and 40% Hct solutions (5% dextran 70). In group 1 and group 2 lungs, experiments were done at constant flow and pressure. Group 3 and group 4 (each n = 4) lungs were perfused with 5% and 20% dextran 70, respectively (0 Hct); group 5 (n = 5), with 10% dextran 70; group 6 (n = 7), with 5% dextran 500; and group 7 (n = 6), with 20% dextran 70 (Hct, approximately 5%). All lungs were perfused in zone 3; airway and left atrial pressures were 6 and 8 cm H2O, respectively. To partition the circulation, we measured pressures in the pulmonary artery and left atrium continuously and pressures in 20-50-microns arterioles and 20-50-microns venules by micropuncture. We found that an increase in both the concentration and molecular weight of dextran increased perfusate viscosity and the resistance in all three longitudinal vascular segments: arteries, microvessels, and veins.(ABSTRACT TRUNCATED AT 250 WORDS)