tbuckley/cabot-search huggingface dataset:
Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome
Authors: Azra Raza, Naomi Galili, Natalie Callander, Leonel Ochoa, Lawrence Piro, Peter Emanuel, Stephanie Williams, Howard Burris, Stefan Faderl, Zeev Estrov, Peter Curtin, Richard A Larson, James G Keck, Marsha Jones, Lisa Meng, Gail L Brown
Journal: Journal of Hematology & Oncology (2009)

Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle. 54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed. Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development. Clinicaltrials.gov: NCT00035867
Ritualized behavior in sport
Authors: Robin C. Jackson, Rich S. W. Masters
Journal: Behavioral and Brain Sciences (2006)

We consider evidence for ritualized behavior in the sporting domain, noting that such behavior appears commonplace both before a competitive encounter and as part of pre-performance routines. The specific times when ritualized behaviors are displayed support the supposition that they provide temporary relief from pre-competition anxiety and act as thought suppressors in the moments preceding skill execution.
Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma
Authors: N G Carroll
Journal: Thorax (2002)

<b>Background:</b> Mucus plugging of the airways is invariably seen in cases of fatal asthma, mucus production is associated with asthma attacks, and the area of submucosal glands is increased in asthma. Mediators secreted from mast cells and neutrophils can stimulate mucous gland secretion. A study was undertaken to count the mast cells and neutrophils in submucosal glands and to relate cell numbers to the presence of mucus in the airway lumen. <b>Methods:</b> Cartilaginous airways obtained at necropsy from cases of fatal asthma (n=8), non-fatal asthma (n=8), and control cases (n=8) were examined. Contiguous transverse sections were stained for mast cell tryptase and neutrophil elastase, and with Periodic Acid Schiff solution to identify mucus. Mucous gland area, lumen area, and the percentage of the relaxed lumen area occupied by mucus (mucus occupying ratio, MOR) were measured. Mast cells (intact and degranulated) and neutrophils per area of submucosal gland were calculated. <b>Results:</b> Compared with controls, the cases of fatal asthma had increased mucous gland area, MOR, percentage of degranulated mast cells, and numbers of neutrophils in the submucosal glands (p&lt;0.05). In cases of non-fatal asthma the MOR and the numbers of mast cells and neutrophils in the submucosal glands were increased (p&lt;0.05). When all cases were pooled together, the MOR correlated with the total number of mast cells (<i>r</i>=0.55, p=0.005) and with the number of degranulated mast cells in the submucosal glands (<i>r</i>=0.51, p=0.013), but not with the number of neutrophils (<i>r</i>=0.21, p=0.121). <b>Conclusion:</b> These results show that mucous gland area, MOR, and mucous gland inflammation are increased in asthma and that degranulation of mast cells may contribute to secretion of mucus into the lumen in cases of fatal asthma.
Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients
Authors: M. Ronzoni, M. Manzoni, S. Mariucci, F. Loupakis, S. Brugnatelli, K. Bencardino, B. Rovati, C. Tinelli, A. Falcone, E. Villa, M. Danova
Journal: Annals of Oncology (2010)
Over-The-Counter Statins Are Worth Considering in Primary Prevention of Cardiovascular Disease
Authors: Antonio M. Gotto
Journal: Circulation (2006)

uch has already been written outlining the advantages and disadvantages of over-the-counter (OTC) access to low-dose therapy with a 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitor, or statin, for individuals at intermediate risk for coronary heart disease (CHD). 1,2After the United Kingdom's approval in 2004 of an OTC, low-dose formulation of simvastatin, a pharmaceutical company in the United States reapplied to the US Food and Drug Administration (FDA) for a nonprescription preparation of lovastatin, which the FDA had first rejected in 2000. 3reviously, low-dose pravastatin also had failed to secure OTC approval.The sponsors of the application proposed that individuals who meet the following criteria may be those most likely to gain from access to OTC statin treatment: (1) those who qualify for primary prevention under the third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program, 4 (2) those with multiple (Ն2) risk factors and a 10-year CHD risk Յ20%, (3) those with no contraindications to statins, and (4) those with a favorable likelihood of experiencing benefit versus risk.
A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at<i>RBX1-EP300</i>
Authors: Antonio Julià, Eugeni Domènech, Elena Ricart, Raül Tortosa, Valle García-Sánchez, Javier P Gisbert, Pilar Nos Mateu, Ana Gutiérrez, Fernando Gomollón, Juan Luís Mendoza, Esther Garcia-Planella, Manuel Barreiro-de Acosta, Fernando Muñoz, Maribel Vera, Cristina Saro, Maria Esteve, Montserrat Andreu, Arnald Alonso, María López-Lasanta, Laia Codó, Josep Lluís Gelpí, Andres C García-Montero, Jaume Bertranpetit, Devin Absher, Julián Panés, Sara Marsal
Journal: Gut (2012)

<h3>Objective</h3> Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn9s disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. <h3>Design</h3> We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. <h3>Results</h3> We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the <i>RBX1</i> and <i>EP300</i> genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the <i>IFNGR2</i> (21q22.11), <i>FOXP2</i> (7q31), <i>MACROD2</i> (20p12.1) and <i>AIF1</i> (6p21.3) loci with CD risk. <h3>Conclusions</h3> In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between <i>RBX1</i> and <i>EP300</i>. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.
<i>In vitro</i> Stimulation of CD8 and CD4 T Cells by Dendritic Cells Loaded with a Complex of Cholesterol-Bearing Hydrophobized Pullulan and NY-ESO-1 Protein: Identification of a New HLA-DR15–Binding CD4 T-Cell Epitope
Authors: Kosei Hasegawa, Yuji Noguchi, Fumihito Koizumi, Akiko Uenaka, Motoyuki Tanaka, Michihide Shimono, Hideo Nakamura, Hiroshi Shiku, Sacha Gnjatic, Roger Murphy, Yuji Hiramatsu, Lloyd J. Old, Eiichi Nakayama
Journal: Clinical Cancer Research (2006)

Abstract Purpose: NY-ESO-1 belongs to a class of cancer/testis antigens and has been shown to be immunogenic in cancer patients. We synthesized a complex of cholesterol-bearing hydrophobized pullulan and NY-ESO-1 protein (CHP/ESO) and investigated the in vitro stimulation of CD8 and CD4 T cells from peripheral blood mononuclear cells in healthy donors with autologous CHP/ESO-loaded dendritic cells as antigen-presenting cells. Experimental Design: In vitro stimulation of CD8 or CD4 T cells was determined by IFNγ ELISPOT assays against autologous EBV-B cells infected with vaccinia/NY-ESO-1 recombinant virus or wild-type vaccinia virus as targets and by ELISA measuring secreted IFNγ. Results: NY-ESO-1–specific CD8 and CD4 T cells were induced. In a donor expressing HLA-A2, CD8 T cells stimulated with CHP/ESO-loaded dendritic cells recognized naturally processed NY-ESO-1157-165, an HLA-A2–binding CD8 T cell epitope. NY-ESO-1 CD4 T cells were Th1-type. We identified a new HLA-DR15–binding CD4 T cell epitope, NY-ESO-137-50. Conclusions: These findings indicate that CHP/ESO is a promising polyvalent cancer vaccine targeting NY-ESO-1.
The coexpression of the migration inhibiting factor 1-alpha with CD401 in human atherosclerotic plaques is associated with advanced plaque stages and extent of intraplaque inflammation
Authors: Alexander Schmeisser, Thomas Illmer, Christiane Graffy, Herribert Loesel-Sadee, Dittmar Boeckler, Dittmar Menschikowski, Gerhard Ehninger, Christoph Garlichs, Werner G. Daniel, Ruth H. Strasser
Journal: Journal of the American College of Cardiology (2003)
Catheter Ablation of Ventricular Epicardial Tissue
Authors: André d’Avila, Christopher Houghtaling, Paulo Gutierrez, Olivera Vragovic, Jeremy N. Ruskin, Mark E. Josephson, Vivek Y. Reddy
Journal: Circulation (2004)

Transthoracic epicardial catheter ablation is an emerging catheter ablation strategy being used clinically at increasing frequency. However, the efficacy of standard RF ablation on the epicardial surface of the heart is hindered by (1) the lack of convective cooling of the ablation electrode and (2) the varying presence of epicardial adipose tissue interposed between the ablation electrode and the target site. This experimental animal study examines the biophysical characteristics of radiofrequency (RF) ablation lesions generated by either standard or cooled-tip ablation of the ventricular epicardium.Nonsurgical subxyphoid pericardial access was achieved in 10 normal goats and 7 pigs with healed myocardial infarctions. A 4-mm cooled-tip RF ablation catheter (continuous 0.9% saline circulation at 0.6 mL/s; goal temperature, 40 degrees C; 60 seconds) was used to deliver epicardial ventricular lesions: 47 in normal tissue and 22 in infarcted tissue. Standard RF ablation lesions (n=33) using a 4-mm top catheter (goal temperature, 70 degrees C; 60 seconds) were also placed on normal epicardial tissue. Lesions created with standard and cooled-tip RF ablation were 3.7+/-1.3 mm (25+/-16.8 W) and 6.7+/-1.7 mm (44.8+/-6.8 W) in depth, respectively. On scar tissue, lesions made with the cooled-tip catheter measured 14.6+/-2.7 mm in length, 11.8+/-2.9 mm in width, and 5.6+/-1.2 mm in depth (35.6+/-7.1 W). In areas covered by epicardial fat (3.1+/-1.2 mm thick), standard RF energy did not generate any appreciable lesions, but cooled-tip RF lesions were 4.1+/-2 mm in depth (45+/-4.4 W).Cooled-tip RF ablation can generate epicardial lesions more effectively than standard RF ablation and appears to be of particular benefit in ablating areas with overlying epicardial fat.
Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials
Authors: Guglielmo Ronco, Joakim Dillner, K Miriam Elfström, Sara Tunesi, Peter J F Snijders, Marc Arbyn, Henry Kitchener, Nereo Segnan, Clare Gilham, Paolo Giorgi-Rossi, Johannes Berkhof, Julian Peto, Chris J L M Meijer
Journal: The Lancet (2013)
Medullary Epithelial Cells of the Human Thymus Express a Highly Diverse Selection of Tissue-specific Genes Colocalized in Chromosomal Clusters
Authors: Jörn Gotter, Benedikt Brors, Manfred Hergenhahn, Bruno Kyewski
Journal: The Journal of Experimental Medicine (2004)

Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (&amp;gt;400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.
Multifactorial Approach to Predicting Resistance to Anthracyclines
Authors: Christine Desmedt, Angelo Di Leo, Evandro de Azambuja, Denis Larsimont, Benjamin Haibe-Kains, Jean Selleslags, Suzette Delaloge, Caroline Duhem, Jean-Pierre Kains, Birgit Carly, Marie Maerevoet, Anita Vindevoghel, Ghislane Rouas, Françoise Lallemand, Virginie Durbecq, Fatima Cardoso, Roberto Salgado, Rodrigo Rovere, Gianluca Bontempi, Stefan Michiels, Marc Buyse, Jean-Marie Nogaret, Yuan Qi, Fraser Symmans, Lajos Pusztai, Véronique D'Hondt, Martine Piccart-Gebhart, Christos Sotiriou
Journal: Journal of Clinical Oncology (2011)

Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines.The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes.A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00).Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.
Congenital Absence of Gall-bladder Associated with a High Caecum and Absence of Ascending Colon
Authors: D. A. Reid
Journal: BMJ (1959)

Women Uncorrected levels .. 89.44% (13.24 g./100 ml.)Corrected levels .. 91.90% (13.60 g./100 ml.) with a standard deviation of 7.07 and a standard error d the mean of 0.57
Short- and long-term clinical and quantitative angiographic results with the new, less shortening wallstent for vessel reconstruction in chronic total occlusion: A quantitative angiographic study
Authors: Yukio Ozaki, Andonis G. Violaris, Jaap Hamburger, Rein Melkert, David Foley, David Keane, Pim de Feyter, Patrick W. Serruys
Journal: Journal of the American College of Cardiology (1996)
CDKN2A Variants in a Population-Based Sample of Queensland Families With Melanoma
Authors: J. Aitken, J. Welch, D. Duffy, A. Milligan, A. Green, N. Martin, N. Hayward
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Mutations in the CDKN2A gene confer susceptibility to cutaneous malignant melanoma (CMM); however, the population incidence of such mutations is unknown. Polymorphisms in CDKN2A have also been described, but it is not known whether they influence melanoma risk. We investigated the association of CDKN2A mutations and polymorphisms with melanoma risk in a population-based sample of families ascertained through probands with melanoma. METHODS: The 482 Queensland, Australia, families in our sample were characterized previously as having high, intermediate, or low family risk of CMM. Unrelated individuals (n = 200 families/individuals) drawn from the Australian Twin Registry served as control subjects. For individuals in the high-risk group, the entire CDKN2A gene coding region was screened for mutations by use of the polymerase chain reaction, agarose gel electrophoresis, allele-specific oligonucleotide (ASO) hybridization, and single-strand conformation polymorphism analysis. The intermediate- and low-risk families and control subjects were analyzed by ASO hybridization for a total of six recurring mutations as well as for polymorphisms at nucleotides (Nts) 442, 500, and 540. RESULTS: CDKN2A mutations were found only in the high-risk families (nine [10.3%] of 87). The prevalence of the Nt500G (guanosine) polymorphism increased linearly with increasing familial risk (two-sided P = .02) and was highest in the nine (primarily Celtic) families with CDKN2A mutations. After adjustment for ethnic origin, the relationship between risk group and the frequency of the Nt500G allele was weakened ( P = .25); however, there was no relationship between ethnic origin and Nt500-polymorphism frequency among the control subjects. CONCLUSIONS: CDKN2A mutations are rare in this population (approximately 0.2% of all melanoma cases in Queensland) and appear to be associated with melanoma in only the most affected families. The Nt500G allele appears to be associated with familial risk, but this association probably reflects Celtic ancestry.
Treatment of Hyperthyroidism
Authors: M R McClung, M A Greer
Journal: Annual Review of Medicine (1980)

During the past decade, our understanding of thyroid pathophysiology has expanded greatly. Recent advances include insights into the mechanisms of thyroid hormone action, the peripheral metabolism of thyroid hormones, and immunologic aspects of thyroid disease. Refinements in thyroid hor­ mone assays and the availability of thyrotropin-releasing hormone (TRH) have provided more direct and definitive approaches to the diagnosis of hyperthyroidism. Using these new laboratory aids, researchers recently demonstrated that hyperthyroidism is more common than was formerly believed, occurring in as much as 2% of the adult female population (1, 2). However, the therapeutic tools with which we approach hyperthyroid pa­ tients have changed little in the past 30 years. Each of the three principal methods, antithyroid drugs, radioiodine, and surgery, can be used effec­ tively and each has its advantages, its advocates, and its tradition in the therapy of hyperthyroid individuals. The management of a specific patient will be influenced by the nature and severity of the hyperthyroidism, the patient's age and general health, the experience of the responsible physician, the availability of expert nuclear medicine and surgical colleagues, and by the patient's own feelings regarding therapy.
Autoantibodies to the constitutive 73-kD member of the hsp70 family of heat shock proteins in systemic lupus erythematosus.
Authors: S Minota, B Cameron, W J Welch, J B Winfield
Journal: The Journal of Experimental Medicine (1988)

Serum from patients with systemic lupus erythematosus (SLE) frequently contain IgM and IgG autoantibodies to the constitutively expressed 73-kD/pI 5.5 member of the hsp70 family of heat shock proteins, as determined by one-dimensional (SDS-PAGE) and two-dimensional (IEF/SDS-PAGE) immunoblotting, and by solid-phase SLE Ig immunoprecipitation experiments using hsp70 protein-specific mAbs as probes. Autoantibodies to hsp70 also were detected in a minority of sera from patients with other rheumatic or viral diseases, but not in normal sera. These data may provide additional insight into etiologic and pathophysiologic mechanisms in this and related autoimmune disorders.
5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes.
Authors: J W Woods, J F Evans, D Ethier, S Scott, P J Vickers, L Hearn, J A Heibein, S Charleson, I I Singer
Journal: The Journal of Experimental Medicine (1993)

The intracellular distribution of the enzyme 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) in resting and ionophore-activated human leukocytes has been determined using immuno-electronmicroscopic labeling of ultrathin frozen sections and subcellular fractionation techniques. 5-LO is a 78-kD protein that catalyzes the conversion of arachidonic acid to leukotrienes. FLAP is an 18-kD membrane bound protein that is essential for leukotriene synthesis in cells. In response to ionophore stimulation, 5-LO translocates from a soluble to a sedimentable fraction of cell homogenates. In activated leukocytes, both FLAP and 5-LO were localized in the lumen of the nuclear envelope. Neither protein could be detected in any other cell compartment or along the plasma membrane. In resting cells, the FLAP distribution was identical to that observed in activated cells. In addition, subcellular fractionation techniques showed > 83% of immunoblot-detectable FLAP protein and approximately 64% of the FLAP ligand binding activity was found in the nuclear membrane fraction. A fractionation control demonstrated that a plasma membrane marker, detected by a monoclonal antibody PMN13F6, was not detectable in the nuclear membrane fraction. In contrast to FLAP, 5-LO in resting cells could not be visualized along the nuclear envelope. Except for weak labeling of the euchromatin region of the nucleus, 5-LO could not be readily detected in any other cellular compartment. These results demonstrate that the nuclear envelope is the intracellular site at which 5-LO and FLAP act to metabolize arachidonic acid, and that ionophore activation of neutrophils and monocytes results in the translocation of 5-LO from a nonsedimentable location to the nuclear envelope.