tbuckley/cabot-search huggingface dataset:
Late Extended Adjuvant Treatment With Letrozole Improves Outcome in Women With Early-Stage Breast Cancer Who Complete 5 Years of Tamoxifen
Authors: Paul E. Goss, James N. Ingle, Joseph L. Pater, Silvana Martino, Nicholas J. Robert, Hyman B. Muss, Martine J. Piccart, Monica Castiglione, Lois E. Shepherd, Kathleen I. Pritchard, Robert B. Livingston, Nancy E. Davidson, Larry Norton, Edith A. Perez, Jeffrey S. Abrams, David A. Cameron, Michael J. Palmer, Dongsheng Tu
Journal: Journal of Clinical Oncology (2008)

The National Cancer Institute of Canada Clinical Trials Group MA.17 trial examined the efficacy of letrozole (LET) started within 3 months of 5 years of adjuvant tamoxifen in postmenopausal hormone receptor-positive early-stage breast cancer. When the trial was unblinded, patients who received placebo (PLAC) were offered LET.This cohort analysis describes the outcomes of women assigned PLAC at the initial random assignment after unblinding. Efficacy outcomes of women who chose LET (PLAC-LET group) were compared with those who did not (PLAC-PLAC group) by the hazard ratios and by P values calculated from Cox models that adjusted for imbalances between the groups. Toxicity analyses included only events that occurred after unblinding.There were 1,579 women in the PLAC-LET group (median time from tamoxifen, 2.8 years) and 804 in the PLAC-PLAC group. Patients in the PLAC-LET group were younger; had a better performance status; and were more likely to have had node-positive disease, axillary dissection, and adjuvant chemotherapy than those in the PLAC-PLAC group. At a median follow-up of 5.3 years, disease-free survival (DFS; adjusted hazard ratio [HR], 0.37; 95% CI, 0.23 to 0.61; P < .0001) and distant DFS (HR, 0.39; 95% CI, 0.20 to 0.74; P = .004) were superior in the PLAC-LET group. More self-reported new diagnoses of osteoporosis and significantly more clinical fractures occurred in the women who took LET (5.2% v 3.1%, P = .02).Interpretation of this cohort analysis suggests that LET improves DFS and distant DFS even when there has been a substantial period of time since the discontinuation of prior adjuvant tamoxifen.
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
Authors: Timothy S Maughan, Richard A Adams, Christopher G Smith, Angela M Meade, Matthew T Seymour, Richard H Wilson, Shelley Idziaszczyk, Rebecca Harris, David Fisher, Sarah L Kenny, Edward Kay, Jenna K Mitchell, Ayman Madi, Bharat Jasani, Michelle D James, John Bridgewater, M John Kennedy, Bart Claes, Diether Lambrechts, Richard Kaplan, Jeremy P Cheadle
Journal: The Lancet (2011)
Survivin Deregulation in β-Tubulin Mutant Ovarian Cancer Cells Underlies Their Compromised Mitotic Response to Taxol
Authors: Jun Zhou, Aurora O’Brate, Amelia Zelnak, Paraskevi Giannakakou
Journal: Cancer Research (2004)

Abstract Taxol is one of the most successful drugs for the treatment of cancer because of its ability to target tubulin, block cell cycle progression at mitosis, and induce apoptosis. Despite the success of Taxol, the development of drug resistance hampers its clinical applicability. Herein we report that β-tubulin mutant, Taxol-resistant ovarian cancer cells exhibit defective mitotic response to Taxol, even at high concentrations that are sufficient to trigger apoptosis. This mitotic response-defective phenotype is independent of p53 status. We have found that survivin, the mitosis regulator and inhibitor of apoptosis protein, is deregulated in these Taxol-resistant cancer cells; Taxol fails to induce survivin levels and survivin phosphorylation in these cells, in contrast to their parental drug-sensitive counterparts. Exogenous expression of wild-type survivin is able to restore the mitotic response of the resistant cells to Taxol treatment. On the other hand, exogenous expression of dominant-negative survivin abrogates the Taxol-induced mitotic response in drug-sensitive cancer cells. We have also found that overexpression of the mitotic kinase Cdk1, which phosphorylates survivin, is unable to restore the Taxol-induced mitotic response in the resistant cells. Our results show the importance of survivin for the mitotic response in the context of Taxol resistance and provide novel insights into the mechanisms of mitotic arrest and apoptosis induced by microtubule-targeting agents.
Effect of testosterone on post-myocardial infarction remodeling and function
Authors: M Nahrendorf
Journal: Cardiovascular Research (2003)

Background: Men and women are differently affected by coronary artery disease, suggesting an important role of sex steroids. Moreover, testosterone (T) treatment is increasingly used in elderly males. Therefore, we examined effects of chronic anabolic T administration on left ventricular (LV) remodeling after myocardial infarction (MI). Methods: Adult male rats were treated with intramuscular placebo, testosterone undecanoate (T), or were orchiectomized. After 2 weeks, animals underwent sham-operation (sham) or left coronary artery ligation. Left ventricular remodeling and function was assessed by serial magnetic resonance imaging (MRI) at weeks 2 and 8 and hemodynamic investigation at week 8. Results: In sham operated animals T administration increased serum T levels and led to cardiac hypertrophy, but not to an upregulation of ANP mRNA. The α/β-MHC ratio was significantly higher after T treatment due to an increase in α-MHC. As a potential mechanism for this "physiologic" form of hypertrophy, IGF-1 mRNA expression was significantly increased in T treated animals. After coronary artery ligation, infarct size and mortality were similar among the groups. Left ventricular hypertrophy was enhanced by T treatment. However, in vivo LV end-diastolic pressure and wall stress were decreased by T, whereas other hemodynamic parameters (mean arterial pressure, cardiac output, etc.) remained unchanged. Conclusion: Chronic anabolic T treatment led to a specific "physiologic" pattern of myocardial hypertrophy with a significant increase in LV weight, but without differences in ANP and with an upregulation in α/β-MHC, possibly mediated by IGF-1. Testosterone treatment had no detrimental effects following MI. Reduced wall stress and LVEDP may even improve long-term outcome.
<i>In Utero</i> Exposure to Dioxins and Polychlorinated Biphenyls and Its Relations to Thyroid Function and Growth Hormone in Newborns
Authors: Shu-Li Wang, Pen-Hua Su, Shiang-Bin Jong, Yueliang L. Guo, Wei-Ling Chou, Olaf Päpke
Journal: Environmental Health Perspectives (2005)

The aim of this study is to examine the association between transplacental exposure to dioxins/polychlorinated biphenyls (PCBs) and thyroid and growth hormones in newborns. We recruited 118 pregnant women, between 25 and 34 years of age, at the obstetric clinic. Personal data collected included reproductive and medical histories and physical factors. Clinicians gathered placental and umbilical cord serum upon delivery and carefully scored the 118 newborns, making both structural and functional assessments. We analyzed placentas for 17 polychlorinated dibenzo-p-dioxins and dibenzofurans and 12 dioxin-like PCB congeners with the World Health Organization–defined toxic equivalent factors, and six indicator PCBs by high-resolution gas chromatography and high-resolution mass spectrometry. We analyzed thyroid and growth hormones from cord serum using radioimmunoassay. Insulin-like growth factor (IGF)-1, IGF-binding globulin-3, and thyroxine × yroid-stimulating hormone (T4 × TSH) were significantly associated with increased placental weight and Quetelet index (in kilograms per square meter; correlation coefficient r = 0.2–0.3; p < 0.05). Multivariate analyses showed independently and significantly decreased free T4 (FT4) × TSH with increasing non-ortho PCBs (r = −0.2; p < 0.05). We suggest that significant FT4 feedback alterations to the hypothalamus result from in utero exposure to non-ortho PCBs. Considering the vast existence of bioaccumulated dioxins and PCBs and the resultant body burden in modern society, we suggest routine screening of both thyroid hormone levels and thyroid function in newborns.
Hepatocyte levels of CD73 contribute to Mallory-Denk body formation
Authors: Samuel French
Journal: Hepatology (2013)

Snider et al.1 reported low levels of CD73 in hepatitis C and nonalcoholic steatohepatitis (NASH) livers, where Mallory-Denk bodies (MDBs) formed. In a mouse model (C57BL), low levels of CD73 developed when fed 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) and MDBs formed. Thus, both human and mouse livers with reduced levels of CD73 correlated with increased MDB formation. Paradoxically, Snider et al.1 observed that CD73−/− mice fed DDC failed to form MDBs. They offer no mechanism to explain this paradox. "If low levels of CD73 increase MDB formation, isn't it logical to expect that, in the absence of CD73 in CD73−/− mice, they would form even more MDBs?" They do show that some of the CD73−/− mice fed DDC formed a lower amount of high molecular weight (HMW) proteins and ubiquitinated HMW proteins (their fig. 4D). The normal K8 blot, on the other hand, was greatly increased by DDC feeding in the CD73−/− mice. This did not occur in the wild-type mice where MDBs were formed. These paradoxical observations are hard to reconcile. One explanation could be that low levels of CD73 somehow causes a decrease in 26S proteasome activity. However, the absence of CD73 does the opposite, that is, it prevents the loss of 26s proteasome activity. MDBs form when a shift occurs in the formation of the 26s proteasome. This shift is to the formation of the immunoproteasome.2, 3 The shift to form the immunoproteasome is the result of the response of interferon (IFN) sequence response element on the UbD (FAT10 in humans) promoter stimulated by IFNγ and tumor necrosis factor alpha (TNFα).4 UbD is markedly induced in the DDC mouse model of MBD formation.5 SAMe prevents this DDC induction of UbD, MDB formation, and the induction of immunoproteasome formation.3, 5 UbD−/− mice fed DDC cannot form MDBs.6 Samuel French, M.D. Harbor-UCLA Medical Center Torrance, CA
Bronchial hyperreactivity in patients who cough after receiving angiotensin converting enzyme inhibitors
Authors: C. E Bucknall, J B. Neilly, R. Carter, R. D Stevenson, P. F Semple
Journal: BMJ (1988)

Angiotensin converting enzyme inhibitors cause cough in some patients, but the mechanism of this effect is not known. Six patients in whom these inhibitors had caused cough and a further two patients in whom they were suspected to have caused worsening of bronchial asthma were studied. Nine patients in whom angiotensin converting enzyme inhibitors had not been associated with cough served as controls. In the controls lung function and bronchial reactivity were measured once; for the study patients these and the cough index were measured twice before rechallenge for two weeks with an angiotensin enzyme inhibitor and once afterwards. Rechallenge with drug for two weeks caused a significant decrease in the mean concentration of histamine causing a 35% fall in airways conductance and a significant increase in the cough index. Patients with cough showed bronchial hyperactivity compared with the controls, which increased after rechallenge with the inhibitors. Cough associated with converting enzyme inhibitors may be a variant of the cough in asthma.
A Role for the Cyclin Box in the Ubiquitin-Mediated Degradation of Cyclin G1
Authors: Denise M. Piscopo, Philip W. Hinds
Journal: Cancer Research (2008)

Abstract Cyclin G1 was identified as a transcriptional target of p53 that encodes a protein with strong homology to the cyclin family of cell cycle regulators. We show that either ectopically expressed or endogenous cyclin G1 protein is very unstable, undergoes modification with ubiquitin, and is likely degraded by the proteasome. Ectopic cyclin G1 protein stability is increased by cyclin box mutation or by association with inactive cyclin-dependent kinase (CDK) subunits, suggesting that a function of cyclin G1 as a CDK regulator may be required for its rapid turnover. Furthermore, cyclin G1 and the cyclin box mutant interact with and are ubiquitinated by MDM2, another transcriptional target of p53 that acts as a negative regulator of p53 stability. These data suggest that the cyclin box has a role in the proteasome-mediated degradation of cyclin G1 and thus suggest a putative role for a CDK in cyclin G1 metabolism and function. [Cancer Res 2008;68(14):5581–90]
Isolation and characterization of the cytoplasmic and outer membranes of the Legionnaires' disease bacterium (Legionella pneumophila).
Authors: J E Gabay, M A Horwitz
Journal: The Journal of Experimental Medicine (1985)

Legionella pneumophila, the etiologic agent of Legionnaires' disease, is phagocytized in an unusual way and multiplies in human mononuclear phagocytes in a novel phagosome. As a first step toward understanding these L. pneumophila-phagocyte interactions, we have studied the envelope of L. pneumophila Philadelphia 1 strain. We isolated cell envelopes by treating whole bacterial cells with lysozyme and EDTA to convert them to spheroplasts, then lysing the spheroplasts osmotically or sonically. We resolved the cell envelopes into two membrane fractions by isopycnic centrifugation. We localized NADH oxidase to the fraction of buoyant density 1.145, which we designated cytoplasmic membrane, and lipopolysaccharide (LPS) to the fraction of density 1.222, which we designated outer membrane. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed that the L. pneumophila outer membrane contains a single major protein species migrating at 28,000 mol wt; this is the major protein of the bacterium. The cytoplasmic membrane also contains a single major protein species migrating at 65,000 mol wt. Surface iodination of the bacteria and agglutination and immunofluorescence studies with rabbit antibody produced against the purified major outer membrane protein (MOMP) revealed that this protein is exposed at the cell surface. We isolated LPS from L. pneumophila membranes by SDS-EDTA treatment. The pattern obtained by subjecting the LPS to SDS-PAGE and staining the gel with silver nitrate suggests that L. pneumophila LPS might be atypical. We studied patient serologic responses to cell envelope components of L. pneumophila Philadelphia 1, a serogroup 1 organism. Sera from patients with evidence of infection with serogroup 1 L. pneumophila contained large amounts of antibody to this strain. Few of these antibodies recognized the MOMP of L. pneumophila. In contrast, greater than 98% of these antibodies were directed against the LPS. This indicates that LPS is the dominant serogroup antigen and the major antigen responsible for the reactivity of patient sera in the indirect fluorescent antibody assay, currently the principal diagnostic assay for Legionella infection.
Normal and Pathologic Concentrations of Uremic Toxins
Authors: Flore Duranton, Gerald Cohen, Rita De Smet, Mariano Rodriguez, Joachim Jankowski, Raymond Vanholder, Angel Argiles
Journal: Journal of the American Society of Nephrology (2012)

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.
Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies
Authors: G Vargas-Alarcon
Journal: Annals of the Rheumatic Diseases (2002)

To investigate the role of HSP70 genes as contributors to genetic susceptibility of the spondyloarthropathies (SpA) in the Mexican population.The study included 150 patients with SpA (undifferentiated spondyloarthropathy (uSpA) 68, ankylosing spondylitis (AS) 60, and reactive arthritis 22) and 158 healthy controls. HSP70-1, HSP70-2 and HSP70-hom genotypes were analysed by the polymerase chain reaction-restriction fragment length polymorphism technique. Statistical methods included the Mantel-Haenzel, chi(2), Fisher's exact test, and Woolf's method for odds ratio (OR).HSP70-2 B/B genotype frequency was increased in the whole group of patients with SpA (pC<0.05, OR=4.3), as well as in the different clinical subgroups (pC<0.05, OR=4.2 for AS; pC<0.05, OR=4.4 for uSpA; and pC<0.05, OR=4.1 for ReA). This frequency remained significantly increased when the patients with B27 negative SpA were analysed. On the other hand, HSP70-hom locus analysis showed significantly increased frequency of A allele in the whole group of SpA (pC<0.05, OR=3.4), as well as in the groups with AS (pC<0.05, OR=5.6) and with uSpA (pC<0.05, OR=3.1), when compared with healthy controls. In this case, also, the genotype A/A was increased in the whole group of SpA (pC<0.05, OR=4.5), as well as in patients with AS (pC<0.05, OR=6.4) and with uSpA (pC<0.05, OR=3.7). When the patients with B27 negative SpA were analysed the frequencies of HSP70-hom A allele and A/A genotype remained significantly increased in the whole group of SpA (pC<0.05, OR=3.2 for the A allele and pC<0.05, OR=4.2 for the A/A genotype) and in the uSpA subgroup (pC<0.05, OR=3.8 for the A allele and pC<0.05, OR=4.3 for the A/A genotype).In addition to the association of SpA with HLA-B27, there is a significant association of HSP70-2 and HSP70-hom alleles with SpA in Mexicans. This association seems to be independent of the susceptibility conferred by HLA-B27 in the group of patients with uSpA.
Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B
Authors: John J.P. Kastelein, Mark K. Wedel, Brenda F. Baker, John Su, JoAnn D. Bradley, Rosie Z. Yu, Emil Chuang, Mark J. Graham, Rosanne M. Crooke
Journal: Circulation (2006)

Background— Apolipoprotein B (apoB) is an important structural component of low-density lipoprotein cholesterol (LDL-C) and plays a key role in LDL-C transport and removal. Reduction in apoB synthesis is expected to reduce circulating LDL-C, a proven risk factor of cardiovascular disease. In the present study, we describe the outcome of the first-in-humans study on the safety and efficacy of an antisense oligonucleotide inhibitor of apoB. Methods and Results— This study was a double-blind, randomized, placebo-controlled, dose-escalation investigation conducted at a single site in 36 volunteers with mild dyslipidemia. The study utilized an initial single dose of 50 to 400 mg of ISIS 301012, a 20-mer oligonucleotide, followed by a 4-week multiple-dosing regimen with the same assigned dose. Safety was assessed by the incidence, severity, and relationship of adverse events to dose. Efficacy was determined by changes in serum apoB and LDL-C relative to baseline and placebo. The most common adverse event was erythema at the injection site (21 of 29 subjects). ApoB was reduced by a maximum of 50% ( P =0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C ( P =0.001). LDL-C and apoB remained significantly below baseline ( P &lt;0.05) up to 3 months after the last dose. Conclusions— Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apoB and LDL-C. Although injection-site reactions were common, adherence to protocol was unaffected.
Age-Associated Testosterone Decline in Men: Clinical Issues for Psychiatry
Authors: Harvey Sternbach
Journal: American Journal of Psychiatry (1998)

Objective:The author summarizes current knowledge about the diagnosis and treatment of testosterone decline in healthy aging men and the associated clinical issues for psychiatry. Method:A MEDLINE search was conducted in which the search terms "male climacteric," "male menopause," "andropause," "viropause," "low-testosterone syndrome," and "testosterone replacement therapy" were used. Literature published before 1966 was identified by reviewing the reference lists of later publications.Results:Manifestations of testosterone deficiency have included depression, anxiety, irritability, insomnia, weakness, diminished libido, impotence, poor memory, reduced muscle and bone mass, and diminished sexual body hair. Although testosterone levels decline with age, there is great interindividual variability, and the connection between serum testosterone levels and clinical psychiatric signs and symptoms is not clear-cut, since other hormonal changes are implicated as well. Testosterone replacement therapy may offer hypogonadal men benefit, but long-term studies on its efficacy and safety are lacking. Comprehensive biopsychosocial assessment should be a routine part of the evaluation of complaints of low-testosterone syndrome in men.Conclusions:Testosterone decline/deficiency is not a state strictly analogous to female menopause and may exhibit considerable overlap with primary and other secondary psychiatric disorders. Am J Psychiatry 1998; 155: 1310-1318
P94 Do healthcare professionals have sufficient knowledge of inhaler techniques in order to educate their patients effectively in their use?
Authors: M. Baverstock, N. Woodhall, V. Maarman
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Inhalers are widely used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). For patients to gain maximum benefit they need to be educated by competent healthcare professionals (HCPs) whose own competence meets accepted standards. This study looked at HCPs ability to use the commonly prescribed metered dose inhaler (pMDI). <h3>Methods</h3> 150 Healthcare professionals (74 Primary Care Trust; 76 Acute Trust) were asked to demonstrate how they would self-administer a pMDI placebo Inhaler. The Group included hospital doctors, hospital nurses, general practitioners, pratice nurses, hospital and community pharmacy staff. Each professional was marked against a standard set by the manufacturer and Education for Health UK.1 They were also asked to demonstrate the correct inspiratory flow rate using the In-check dial device.2 <h3>Results</h3> Of the <b>150</b> HCPs assessed only <b>11 (7%)</b> could demonstrate all the recognised steps in administration including assessment of inspiratory flow using the in-check device (Abstract P94 Figure 1). <b>113 (75%) of the HCPs</b> said they were involved in the teaching of inhaler technique. Of these 113, <b>11(9%)</b> could demonstrate all the recognised Steps (n=10 PCT n=1 acute trust). Of the <b>150, 72 (48%)</b> were prescribers or were involved in prescribing. <b>94 (63%)</b> had received some training on Inhaler technique in the past of which <b>64 (67%)</b> said the training took place more than a year before. <h3>Conclusion</h3> If we are going to adequately educate our patients with regard to their inhaler usage we as HCPs need to be competent in how each device works. Incorrect teaching and assessment will increase use of healthcare resources, waste medication, and mean worsening symptoms and poor control of airways disease for our patients.