tbuckley/cabot-search huggingface dataset:
DNA methylation profiling of non-small cell lung cancer reveals a COPD-driven immune-related signature
Authors: Els Wauters, Wim Janssens, Johan Vansteenkiste, Herbert Decaluwé, Nele Heulens, Bernard Thienpont, Hui Zhao, Dominiek Smeets, Xavier Sagaert, Johan Coolen, Marc Decramer, Adrian Liston, Paul De Leyn, Matthieu Moisse, Diether Lambrechts
Journal: Thorax (2015)

<h3>Introduction</h3> Non-small cell lung cancer (NSCLC) is a heterogeneous disorder consisting of distinct molecular subtypes each characterised by specific genetic and epigenetic profiles. Here, we aimed to identify novel NSCLC subtypes based on genome-wide methylation data, assess their relationship with smoking behaviour, age, COPD, emphysema and tumour histopathology, and identify the molecular pathways underlying each subtype. <h3>Methods</h3> Methylation profiling was performed on 49 pairs of tumour and adjacent lung tissue using Illumina 450 K arrays. Transcriptome sequencing was performed using Illumina HiSeq2000 and validated using expression data from The Cancer Genome Atlas (TCGA). Tumour immune cell infiltration was investigated by immunohistochemistry. <h3>Results</h3> Unsupervised hierarchical clustering of tumour methylation data revealed two subgroups characterised by a significant association between cluster membership and presence of COPD (p=0.024). Ontology analysis of genes containing differentially methylated CpGs (false discovery rate, FDR-adjusted p&lt;0.05) revealed that immune genes were strongly enriched in COPD tumours, but not in non-COPD tumours. This COPD-specific immune signature was attributable to methylation changes in immune genes expressed either by tumour cells or tumour-infiltrating immune cells. No such differences were observed in adjacent tissue. Transcriptome profiling similarly revealed that genes involved in the immune response were differentially expressed in COPD tumours (FDR-adjusted p&lt;0.05), an observation that was independently replicated using TCGA data. Immunohistochemistry validated these findings, revealing fewer CD4-positive T lymphocytes in tumours derived from patients with COPD. <h3>Conclusions</h3> Lung tumours of patients with COPD differ from those of patients without COPD, with differentially methylated and expressed genes being mainly involved in the immune response.
CONSTITUENTS OF ELEMENTARY BODIES OF VACCINIA
Authors: Charles L. Hoagland, S. M. Ward, Joseph E. Smadel, Thomas M. Rivers
Journal: The Journal of Experimental Medicine (1941)

A search by means of spectroscopic and enzymatic techniques has failed to demonstrate either cytochrome or cytochrome oxidase in purified elementary bodies of vaccinia. A constituent of the virus which catalyzes the oxidation of cystein has been found and identified as copper in a concentration amounting to 0.05 per cent of the dry weight of the virus. The copper constituent was not removed by repeated washing, ultrafiltration, dialysis against 0.1 molar potassium cyanide, or by electrodialysis over a pH range which did not inactivate the virus. During the process of purification of the virus a 25-fold increase of the copper constituent was observed. Emission spectra obtained from the dry virus also revealed copper but no significant traces of other metallic substances. No biological rôle can yet be ascribed to the copper component of virus.
Physician Characteristics and Variability of Erythropoiesis-Stimulating Agent Use Among Medicare Patients With Cancer
Authors: Jason D. Wright, Alfred I. Neugut, Elizabeth T. Wilde, Donna L. Buono, Jennifer Malin, Wei Y. Tsai, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2011)

Purpose Drugs are usually approved for a specific indication on the basis of randomized trials. However, once approved, these treatments are often used differently than as tested in trials. We performed an analysis to determine the patterns of use of erythropoiesis-stimulating agents (ESAs). Methods We used the Surveillance, Epidemiology, and End Results–Medicare database to identify patients age 65 years or older with breast, lung, or colon cancer diagnosed between 1995 and 2005 who had one ESA and chemotherapy claim. Associations of patient, tumor, and physician-related factors with receipt of ESAs were analyzed. Results Of 21,091 patients analyzed, 5,099 (24.2%) received ESAs for 1 week or less (misuse), and 1,601 (7.6%) received ESAs for more than 14 weeks (prolonged use). Receipt of ESAs while not actively receiving chemotherapy (off label) occurred in 2,876 patients (13.6%). In a multivariable analysis, ESA misuse was associated with MD degree, female sex of physician, and earlier year of medical school graduation. Private practice physicians (odds ratio [OR], 0.78; 95% CI, 0.72 to 0.84) and high-volume physicians (OR, 0.78; 95% CI, 0.72 to 0.85) were less likely to use 1 week or less of ESA treatment. Treatment by high-volume oncologists (OR, 1.33; 95% CI, 1.14 to 1.55) and by oncologists who graduated from US medical schools (OR, 1.26; 95% CI, 1.12 to 1.42) predicted prolonged-duration ESA use, whereas female oncologists (OR, 0.79; 95% CI, 0.68 to 0.93) were less likely to prescribe prolonged ESA treatment. Private practice physicians (OR, 1.18; 95% CI, 1.02 to 1.38) and high-volume providers (OR, 1.58; 95% CI, 1.33 to 1.87) were more likely to prescribe more than 24 weeks of ESA treatment. Conclusion Our study demonstrated widespread variability in the use of ESAs. Physician characteristics exerted substantial influence on ESA use. Policies to discourage inappropriate use of cancer therapies are needed.
Harnessing the potential of epigenetic therapy to target solid tumors
Authors: Nita Ahuja, Hariharan Easwaran, Stephen B. Baylin
Journal: Journal of Clinical Investigation (2014)

Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer.
The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum
Authors: P.E. Lønning
Journal: Annals of Oncology (2010)

The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2-3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1-98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology.
The Acetaminophen Enigma in Asthma
Authors: Stephen T. Holgate
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Acetaminophen (APAP or paracetamol) was first synthesized in 1878 and used as an antipyretic in 1887. However, it was rapidly superseded by phenacetin until renal papillary necrosis precluded its use. In 1949, this led to the rediscovery of APAP, the principal active metabolite of phenacetin. APAP is by far the most popular analgesic and antipyretic in worldwide use, especially in children on account of fears over the occurrence of Reye syndrome with aspirin. APAP mediates its beneficial analgesic and antipyretic effects on the central nervous system via selective inhibition of cyclooxygenase (COX) 3 (a splice variant of COX1) and its CNS arachidonic acid metabolite, arachidonyl phenolamine (AM404). AM404 is both an agonist of the transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid 1 (CB1) receptors and a re-uptake inhibitor of cannabinoids. Endocannabinoids mediate their antinocioceptive effects in the brain and spinal cord via activation of CB1 receptors to release opioid peptides. APAP is principally degraded in the liver by the cytochrome P450 oxidases, CYP2E1 and CYP1A2, to the reactive intermediate N-acetyl-p-benzoquinone-imine (NAPQI) that is conjugated by glutathione-S-transferase (GST) and excreted in the urine. The liver toxicity of NAPQI resides in the combination of rapid depletion of glutathione and induction of mitochondrial injury which forms the rationale for the use of N-acetylcysteine as the antidote for APAP poisoning.
SEQUELAE OF BRUCELLA ABORTUS INFECTION IN MAN
Authors: R. C. Affleck
Journal: BMJ (1930)

<b>Background:</b> Prostate cancer has the second highest cancer incidence and mortality in European men. Most prostate cancers are diagnosed after lower urinary tract symptoms (LUTS) are presented to primary care, but such symptoms more often have a benign cause. A general practitioner (GP) has to try and identify which of these patients have prostate cancer. <b>Aims:</b> To review the presenting features of symptomatic prostate cancer. <b>Design of study:</b> Structured review. <b>Method:</b> We searched Medline from 1980 to 2003 for symptoms, signs, and investigations reported in prostate cancer. This list was then expanded by secondary searches of reference lists. We excluded studies on post-diagnostic topics, such as staging, treatment, and prognosis; studies on non-Western patients; and studies on investigations that are not available in primary care. A second cycle of exclusions removed studies whose results would not guide a GP in deciding whether a patient has prostate cancer. <b>Results:</b> No studies from primary care compared prostate cancer patients directly with controls. Two secondary care studies had enough information to allow a comparison of symptoms in cases compared with controls. In these studies, symptoms were generally more prevalent in cases, but the differences were small. Screening and secondary care studies suggest that early prostate cancer is symptomless, and that locally advanced cancer has LUTS that are similar to those for benign prostatic hypertrophy. <b>Conclusion:</b> There is a very weak evidence base for the primary care diagnosis of prostate cancer in men with lower urinary tract symptoms.
Independent Susceptibility Markers for Atrial Fibrillation on Chromosome 4q25
Authors: Steven A. Lubitz, Moritz F. Sinner, Kathryn L. Lunetta, Seiko Makino, Arne Pfeufer, Rosanna Rahman, Caroline E. Veltman, John Barnard, Joshua C. Bis, Stephan P. Danik, Akshata Sonni, Marisa A. Shea, Federica del Monte, Siegfried Perz, Martina Müller, Annette Peters, Steven M. Greenberg, Karen L. Furie, Charlotte van Noord, Eric Boerwinkle, Bruno H.C. Stricker, Jacqueline Witteman, Jonathan D. Smith, Mina K. Chung, Susan R. Heckbert, Emelia J. Benjamin, Jonathan Rosand, Dan E. Arking, Alvaro Alonso, Stefan Kääb, Patrick T. Ellinor
Journal: Circulation (2010)

Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
Analysis of Factors Associated With Outcome in Patients With Malignant Peritoneal Mesothelioma Undergoing Surgical Debulking and Intraperitoneal Chemotherapy
Authors: Andrew L. Feldman, Steven K. Libutti, James F. Pingpank, David L. Bartlett, Tatiana H. Beresnev, Sharon M. Mavroukakis, Seth M. Steinberg, David J. Liewehr, David E. Kleiner, H. Richard Alexander
Journal: Journal of Clinical Oncology (2003)

Malignant mesothelioma (MM) arising in the peritoneal cavity is a rare neoplasm characterized by peritoneal progression and for which there are limited therapeutic options. We evaluated the peritoneal progression-free and overall survival (PFS and OS, respectively) for patients with peritoneal MM after surgical resection and regional chemotherapy.Forty-nine patients (28 males, 21 females; median age, 47 years; range, 16 to 76 years) with MM underwent laparotomy, tumor resection, continuous hyperthermic peritoneal perfusion with cisplatin (median dose 250 mg/m2), and a single postoperative intraperitoneal dwell of fluorouracil and paclitaxel (n = 35) on protocols approved by the Institutional Review Board. Standard techniques for actuarial analyses of potential prognostic variables (Kaplan-Meier method with two-tailed log-rank test and Cox proportional hazards model) were performed.At a median potential follow-up of 28.3 months, median actuarial PFS is 17 months and actuarial OS is 92 months. Factors associated with improved PFS and OS by the Cox proportional hazards model were a history of previous debulking surgery, absence of deep tissue invasion, minimal residual disease after surgical resection (OS only), and age younger than 60 years (OS only).Surgical resection and regional chemotherapy for MM results in durable PFS and OS. Favorable outcome is associated with age, tumor biology (selection of patients with a history of previous debulking), lack of invasive tumor growth, and minimal residual disease after tumor resection.
A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling
Authors: Gerold M. Grodsky
Journal: Journal of Clinical Investigation (1972)

Phases of insulin release were studied in the perfused pancreas during a variety of glucose stimulation patterns. Patterns included staircase stimulations, constant prolonged single steps, restimulations, and ramp functions. Except at low concentrations, prolonged single steps of glucose elicited early spikes of insulin and a slowly rising second phase. Total insulin in the initial spikes increased with higher glucose concentrations. However, the time-related pattern of these spikes was similar in all cases; ratios of initial secretion rate to total insulin released were constant. Total insulin released in this early phase approximated a sigmoidal function of glucose concentration; mathematical differentiation of this function gave a skewed bell-shaped distribution curve. Staircase stimulations caused insulin to be released as a series of transient spikes which did not correlate with the increment of glucose but rather to the available insulin for a given glucose concentration minus that released in previous steps. The sum of total insulin released as spikes in a staircase series leading to a given glucose concentration was the same as when that concentration was used as a single step. Interrupted prolonged glucose infusions indicated the second phase of insulin release could prime the pancreas and that the first and second phases were interrelated. When glucose was perfused as ramp functions of slow, increasing, concentration, phasic response disappeared.A previous two-compartmental model was expanded to include a threshold or sensitivity distribution hypothesis. This hypothesis proposes that labile insulin is not stored in a homogeneous form but as packets with a bell-shaped distribution of thresholds to glucose. These packets respond quickly when their threshold levels to glucose are reached or exceeded. Data from single step stimulations were utilized for constructing a mathematical model which simulated satisfactorily the various stimulation patterns.
Effect of Quinidine and Pronethalol on Acetylstrophanthidin-Induced Ventricular Arrhythmia in Cats Treated with Reserpine
Authors: BARRIE LEVITT, JAY ROBERTS
Journal: Circulation Research (1966)

With pronethalol, quinidine, and reserpine it was necessary to increase the dose of acetylstrophanthidin which produced arrhythmia in combination with vagal stimulation. However, in reserpine-treated animals, quinidine and pronethalol were ineffective. The capability of large doses of acetylstrophanthidin to produce ventricular arrhythmia was not diminished by quinidine, pronethalol, or reserpine. While pronethalol decreased the S-A nodal rate in normal animals, it failed to produce an effect on rate after reserpine pretreatment. Since after catecholamine depletion by reserpine, pronethalol and quinidine did not affect acetylstrophanthidin-induced ventricular arrhythmia, it is suggested that the antidigitalis effect of these agents is related to their actions to diminish adrenergic nervous activity.
Cortical GABAergic excitation contributes to epileptic activities around human glioma
Authors: Johan Pallud, Michel Le Van Quyen, Franck Bielle, Christophe Pellegrino, Pascale Varlet, Marianne Labussiere, Noémie Cresto, Marie-Joseph Dieme, Michel Baulac, Charles Duyckaerts, Nazim Kourdougli, Geneviève Chazal, Bertrand Devaux, Claudio Rivera, Richard Miles, Laurent Capelle, Gilles Huberfeld
Journal: Science Translational Medicine (2014)

Epileptic discharges in the neocortex surrounding human gliomas are initiated by GABAergic interneurons through alterations of chloride homeostasis in pyramidal cells.
Identification of 5 novel genes methylated in breast and other epithelial cancers
Authors: Victoria K Hill, Luke B Hesson, Temuujin Dansranjavin, Ashraf Dallol, Ivan Bieche, Sophie Vacher, Stella Tommasi, Timothy Dobbins, Dean Gentle, David Euhus, Cheryl Lewis, Reinhard Dammann, Robyn L Ward, John Minna, Eammon R Maher, Gerd P Pfeifer, Farida Latif
Journal: Molecular Cancer (2010)

Abstract Background There are several high throughput approaches to identify methylated genes in cancer. We utilized one such recently developed approach, MIRA (methylated-CpG island recovery assay) combined with CpG island arrays to identify novel genes that are epigenetically inactivated in breast cancer. Results Using this approach we identified numerous CpG islands that demonstrated aberrant DNA methylation in breast cancer cell lines. Using a combination of COBRA and sequencing of bisulphite modified DNA, we confirmed 5 novel genes frequently methylated in breast tumours; EMILIN2, SALL1 , DBC1 , FBLN2 and CIDE-A . Methylation frequencies ranged from between 25% and 63% in primary breast tumours, whilst matched normal breast tissue DNA was either unmethylated or demonstrated a much lower frequency of methylation compared to malignant breast tissue DNA. Furthermore expression of the above 5 genes was shown to be restored following treatment with a demethylating agent in methylated breast cancer cell lines. We have expanded this analysis across three other common epithelial cancers (lung, colorectal, prostate). We demonstrate that the above genes show varying levels of methylation in these cancers. Lastly and most importantly methylation of EMILIN2 was associated with poorer clinical outcome in breast cancer and was strongly associated with estrogen receptor as well as progesterone receptor positive breast cancers. Conclusion The combination of the MIRA assay with CpG island arrays is a very useful technique for identifying epigenetically inactivated genes in cancer genomes and can provide molecular markers for early cancer diagnosis, prognosis and epigenetic therapy.
Why patient safety is such a tough nut to crack
Authors: I. P. Leistikow, C. J. Kalkman, H. d. Bruijn
Journal: BMJ (2011)

It's now more than a decade since the US Institute of Medicine's landmark 1999 report <i>To Err Is Human</i> put patient safety prominently on the international agenda. Despite countless initiatives, publications, and conferences on the topic, improvement has been disappointingly slow. <b>Ian Leistikow and colleagues</b> define the four challenges that make patient safety such a tough nut to crack, and propose a way out of the impasse
The Association of Acetaminophen, Aspirin, and Ibuprofen with Respiratory Disease and Lung Function
Authors: Tricia M. McKeever, Sarah A. Lewis, Henriëtte A. Smit, Peter Burney, John R. Britton, Patricia A. Cassano
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Oxidative stress may increase the risk of asthma, contribute to asthma progression, and decrease lung function. Previous research suggests that use of acetaminophen, which is hypothesized to reduce antioxidant capacity in the lung, is associated with an increased risk of asthma. We hypothesized that acetaminophen use may also be associated with chronic obstructive pulmonary disease (COPD) and decreased lung function.To investigate the associations between use of pain medication, particularly acetaminophen, and asthma, COPD, and FEV1 in adults.A cross-sectional analysis using the Third National Health and Nutrition Examination Survey.Increased use of acetaminophen had a positive, dose-dependent association with COPD (adjusted odds ratio for increasing category of intake, 1.16; 95% confidence interval [CI], 1.09-1.24; p value for trend < 0.001) and an inverse association with lung function (daily user compared with never users, -54.0 ml; 95% CI, -90.3 to -17.7, adjusted). Neither of these associations was explained by overlap between COPD and asthma occurrence. We confirmed a dose-response association of acetaminophen use and asthma (adjusted odds ratio, 1.20; 95% CI, 1.12-1.28; p value for trend < 0.001).This study provides further evidence that use of acetaminophen is associated with an increased risk of asthma and COPD, and with decreased lung function.