tbuckley/cabot-search huggingface dataset:
International Randomized Phase III Study of Elacytarabine Versus Investigator Choice in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Authors: Gail J. Roboz, Todd Rosenblat, Martha Arellano, Marco Gobbi, Jessica K. Altman, Pau Montesinos, Casey O'Connell, Scott R. Solomon, Arnaud Pigneux, Norbert Vey, Robert Hills, Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, Sylvia Vetrhusand, Francis J. Giles
Journal: Journal of Clinical Oncology (2014)

Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care.A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS).There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respectively. There was no significant difference in OS among any of the investigator's choice regimens. Prolonged survival was only achieved in a few patients in both study arms whose disease responded and who underwent allogeneic stem-cell transplantation.Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.
G-CSF enables completion of tuberculosis therapy associated with iatrogenic neutropenia
Authors: L.J. Cormican, S. Schey, H.J. Milburn
Journal: European Respiratory Journal (2004)

Neutropenia is a rare complication of anti-tuberculous therapy and is usually due to a single agent, most frequently isoniazid. The current case describes a previously healthy immunocompetent patient with tuberculosis of the lymph nodes who developed neutropenia due to a number of first line antibiotics (rifampicin, isoniazid and ethambutol) and streptomycin when introduced in combination and individually thus resulting in repeated treatment disruption. The introduction of twice-weekly subcutaneous granulocyte-colony stimulating factor to correct iatrogenic neutropenia facilitated the continuation and eventual completion of therapy without adverse effect. This is the first description of the use of granulocyte-colony stimulating factor to correct iatrogenic neutropenia due to anti-tuberculous antibiotics and the second description of the occurrence of iatrogenic neutropenia to more than anti-tuberculous antibiotic in an individual.
Interleukin 1 of the central nervous system is produced by ameboid microglia.
Authors: D Giulian, T J Baker, L C Shih, L B Lachman
Journal: The Journal of Experimental Medicine (1986)

By screening specific populations of rat brain cells, we found that ameboid microglia secrete an 18 kD peptide with IL-1 biological activity. The IL-1 activity released by microglia was found to be identical to rat macrophage IL-1 on fractionation by gel filtration and high pressure liquid anion-exchange chromatography, and it was neutralized by an antiserum specific for murine IL-1. When added to astroglia grown in culture, microglial IL-1 increased the cell number of five- to sevenfold, and increased astroglial incorporation of [3H]thymidine by three- to fivefold. We propose that the proliferation of astroglia in specific brain regions may be regulated by the signaled release of IL-1 from activated microglial cells.
Time-intensified dexamethasone/cisplatin/cytarabine:an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease
Authors: A. Josting, C. Rudolph, M. Reiser, M. Mapara, M. Sieber, H.H. Kirchner, B. Dörken, D.K. Hossfeld, V. Diehl, A. Engert
Journal: Annals of Oncology (2002)
Excessive Toxicity When Treating Central Tumors in a Phase II Study of Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Lung Cancer
Authors: Robert Timmerman, Ronald McGarry, Constantin Yiannoutsos, Lech Papiez, Kathy Tudor, Jill DeLuca, Marvene Ewing, Ramzi Abdulrahman, Colleen DesRosiers, Mark Williams, James Fletcher
Journal: Journal of Clinical Oncology (2006)

Surgical resection is standard therapy in stage I non-small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population.Eligible patients included clinically staged T1 or T2 (< or = 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks.All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have died as a result of cancer (n = 5), treatment (n = 6), or comorbid illnesses (n = 17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in a total of 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors.High rates of local control are achieved with this SBRT regimen in medically inoperable patients with stage I NSCLC. Both local recurrence and toxicity occur late after this treatment. This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.
Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.
Authors: A L Moreira, E P Sampaio, A Zmuidzinas, P Frindt, K A Smith, G Kaplan
Journal: The Journal of Experimental Medicine (1993)

We have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA. Thus, the half-life of the molecule was reduced from approximately 30 to approximately 17 min in the presence of 50 micrograms/ml of thalidomide. Inhibition of TNF-alpha production was selective, as other LPS-induced monocyte cytokines were unaffected. Pentoxifylline and dexamethasone, two other inhibitors of TNF-alpha production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-alpha synthesis at distinct points of the cytokine biosynthetic pathway. These observations provide an explanation for the synergistic effects of these drugs. The selective inhibition of TNF-alpha production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-alpha-induced toxicities are observed and where immunity must remain intact.
The Battle Against Antimicrobial Resistance
Authors: Rakesh D. Mistry, Peter S. Dayan, Nathan Kuppermann
Journal: JAMA Pediatrics (2015)

This Viewpoint reports on the antimicrobial stewardship programs that have been created in many institutions in response to the overuse of antibiotics that has been implicated as a contributor to childhood morbidities such as asthma and obesity.
Are Drug Companies Living Up to Their Human Rights Responsibilities? The Perspective of the Former United Nations Special Rapporteur (2002-2008)
Authors: Paul Hunt, Rajat Khosla
Journal: PLoS Medicine (2010)

The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.
THE ELECTRICAL CHARGE OF TOXIN AND ANTITOXIN
Authors: Cyrus W. Field, Oscar Teague
Journal: The Journal of Experimental Medicine (1907)

1. Both diphtheria and tetanus toxin and their antitoxins arc electro-positive, that is, they pass to the cathode under the influence of an electric current. 2. The character of the charge is not altered by a change in the reaction of the solvent. 3. The combination of toxin and antitoxin would seem to represent not a true chemical reaction but the adsorption of one colloid by another.
Expression in Human Hepatocellular Carcinoma of Nucleoside Diphosphate Kinase, a Homologue of the nm23 Gene Product
Authors: T. Nakayama, A. Ohtsuru, K. Nakao, M. Shima, K. Nakata, K. Watanabe, N. Ishii, N. Kimura, S. Nagataki
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Expression in Human Hepatocellular Carcinoma of Nucleoside Diphosphate Kinase, a Homologue of the nm23 Gene Product Get access Toshihiro Nakayama, Toshihiro Nakayama The First Department of Internal Medicine, Nagasaki University School of MedicineJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Akira Ohtsuru, Akira Ohtsuru Department of Cell Physiology, Atomic Disease Institute, Nagasaki University School of MedicineJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Kazuhiko Nakao, Kazuhiko Nakao The First Department of Internal Medicine, Nagasaki University School of MedicineJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Masayoshi Shima, Masayoshi Shima The First Department of Internal Medicine, Nagasaki University School of MedicineJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Keisuke Nakata, Keisuke Nakata The First Department of Internal Medicine, Nagasaki University School of MedicineJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Kazutada Watanabe, Kazutada Watanabe Department of Biochemical Engineering of Technology, University of Kyushu Institute of TechnologyJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Nobuko Ishii, Nobuko Ishii Health Center of Nagasaki UniversityJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Narimichi Kimura, Narimichi Kimura Department of Molecular Biology, Tokyo Metropolitan Institute of GerontologyJapan Search for other works by this author on: Oxford Academic PubMed Google Scholar Shigenobu Nagataki Shigenobu Nagataki * The First Department of Internal Medicine, Nagasaki University School of MedicineJapan *Correspondence to : Shigenobu Nagataki, M.D., The First Department of Internal Medicine, Nagasaki University School of Medicine. 7-1. Sakamoto-machi, Nagasaki, 852, Japan. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 17, 2 September 1992, Pages 1349–1354, https://doi.org/10.1093/jnci/84.17.1349 Published: 02 September 1992 Article history Received: 23 December 1991 Revision received: 12 March 1992 Accepted: 19 June 1992 Published: 02 September 1992
P190 Drug Induced Liver Injury In The Treatment Of Tuberculosis In A Busy Uk Centre
Authors: S. Chitty, R. Ghani, J. Roe, H. Davidson, M. Routledge, T. Edwards, C. Hateley, S. Collin, A. Ritchie, J. Dzvova, J. Buckley, R. Davidson, L. John
Journal: Thorax (2014)

<h3>Introduction</h3> We describe the incidence and management of drug induced liver injury (DILI) in active TB at the largest UK centre, using a nurse-led local protocol derived from 1998 BTS guidelines. <h3>Methods</h3> All active TB cases were identified from April 2010 to May 2014. Patients were identified with DILI by following criteria: Type 1 DILI(ALT &gt;3x upper limit normal (ULN-55iu/l), Type 2 DILI (ALP &gt;2x ULN(150 iu/l) and Bilirubin &gt;21 iu/l) or Type 3 DILI (Bilirubin &gt;40 iu/l). Patient demographics, TB treatment (ATT), timing, management and outcomes of DILI were described. Baseline characteristics and ATT doses were matched with controls. <h3>Results</h3> 105 individuals with DILI were identified out of 1529 patients with active TB (6.9%). 81% were on standard first line therapy (Rifampicin (R), Isoniazid (H), Pyrazinamide (Z) and Ethambutol (E)). 7.8% were on Moxifloxacin (M) instead of E and 1.9% were on RHME. Type 1 DILI was most frequent (81%) with median peak ALT 296 iu/l (IQR 227–505). Median time from treatment start to onset of DILI was 12.5 days (7–30). Symptoms at presentation included nausea/vomiting (54%), abdominal pain (18%) and jaundice (12.4%). 45.7% patients had all medication stopped, 7.6% continued ethambutol with amikacin (A), 26.7% continued all medication, 6.7% stopped Z only, 3.8% substituted Z for a quinolone. Median time from stopping to reintroduction was 10 days (6–17). Of 66 reintroduction patients, regimens included H &gt;R &gt;E(45%), H&gt;R&gt;E&gt;M (31%) and R&gt;E&gt;M (15%). Median time from reintroduction to full treatment restart was 14 days (12–18). 81% of patients were uneventfully reintroduced, 5% suffered a 2nd DILI. 32% patients required hospital admission and 4(3.8%) died. DILI cases were matched to 200 controls. Cases more likely (P &lt; 0.05) to; be HIV positive, have quinolones in initial regimen and lower body weight. Quinolone use gave an adjusted hazard ratio 5.41 (2.96, 9.91). <h3>Conclusion</h3> DILI remains the most important toxicity of ATT and usually occurs during the first month. The BTS guideline provides a useful template for the diagnosis and management of DILI which may be largely nurse led and ambulatory. Most patients are successfully reintroduced without pyrazinamide. HIV status, body weight and quinolone use are risk factors.
Kiwifruit Act d 11 is the first member of the ripening-related protein family identified as an allergen
Authors: R. D'Avino, M. L. Bernardi, M. Wallner, P. Palazzo, L. Camardella, L. Tuppo, C. Alessandri, H. Breiteneder, F. Ferreira, M. A. Ciardiello, A. Mari
Journal: Allergy (2011)

Kiwifruit is an important cause of food allergy. A high amount of a protein with a molecular mass compatible with that of Bet v 1 was observed in the kiwifruit extract.To identify and characterize kirola, the 17-kDa protein of green kiwifruit (Act d 11).Act d 11 was purified from green kiwifruit. Its primary structure was obtained by direct protein sequencing. The IgE binding was investigated by skin testing, immunoblotting, inhibition tests, and detection by the ISAC microarray in an Italian cohort and in selected Bet v 1-sensitized Austrian patients. A clinical evaluation of kiwi allergy was carried out.Act d 11 was identified as a member of the major latex protein/ripening-related protein (MLP/RRP) family. IgE binding to Act d 11 was shown by all the applied testing. Patients tested positive for Act d 11 and reporting symptoms on kiwifruit exposure were found within the Bet v 1-positive subset rather than within the population selected for highly reliable history of allergic reactions to kiwifruit. Epidemiology of Act d 11 IgE reactivity was documented in the two cohorts. IgE co-recognition of Act d 11 within the Bet v 1-like molecules is documented using the microarray IgE inhibition assay.Act d 11 is the first member of the MLP/RRP protein family to be described as an allergen. It displays IgE co-recognition with allergens belonging to the PR-10 family, including Bet v 1.
Childhood factors associated with asthma remission after 30 year follow up
Authors: J M Vonk
Journal: Thorax (2004)

Factors contributing to either "complete" or "clinical" remission of asthma are important to know since there is no cure for the disease.A cohort of 119 allergic asthmatic children was examined three times with a mean follow up of 30 years. They were aged 5-14 years at visit 1 (1966-9), 21-33 years at visit 2 (1983-6), and 32-42 years at visit 3 (1995-6). Complete remission of asthma at visit 3 was defined as no asthma symptoms, no use of inhaled corticosteroids, normal lung function (FEV1 >90% predicted), and no bronchial hyperresponsiveness (PC10 >16 mg/ml). Clinical remission was defined as no asthma symptoms and no use of inhaled corticosteroids.22% of the group was in complete remission of asthma at visit 3 and a further 30% was in clinical remission (total 52%); 57% of subjects in clinical remission had bronchial hyperresponsiveness and/or a low lung function. Logistic regression analyses showed that a higher FEV1 in childhood and more improvement in FEV1 from age 5-14 to 21-33 were associated with both complete and clinical asthma remission at age 32-42.Complete remission of asthma was present in a small subset of asthmatics while half the subjects showed clinical remission. Both complete and clinical remission were associated with a higher lung function level in childhood and a higher subsequent increase in FEV1. These results support the view that defining remission only on the basis of symptoms and medication use will overlook subjects with subclinical active disease and possibly associated airway remodelling.
Plasmodium falciparum Genetic Diversity Maintained and Amplified Over 5 Years of a Low Transmission Endemic in the Peruvian Amazon
Authors: O. H. Branch, P. L. Sutton, C. Barnes, J. C. Castro, J. Hussin, P. Awadalla, G. Hijar
Journal: Molecular Biology and Evolution (2010)

Plasmodium falciparum entered into the Peruvian Amazon in 1994, sparking an epidemic between 1995 and 1998. Since 2000, there has been sustained low P. falciparum transmission. The Malaria Immunology and Genetics in the Amazon project has longitudinally followed members of the community of Zungarococha (N = 1,945, 4 villages) with active household and health center-based visits each year since 2003. We examined parasite population structure and traced the parasite genetic diversity temporally and spatially. We genotyped infections over 5 years (2003–2007) using 14 microsatellite (MS) markers scattered across ten different chromosomes. Despite low transmission, there was considerable genetic diversity, which we compared with other geographic regions. We detected 182 different haplotypes from 302 parasites in 217 infections. Structure v2.2 identified five clusters (subpopulations) of phylogenetically related clones. To consider genetic diversity on a more detailed level, we defined haplotype families (hapfams) by grouping haplotypes with three or less loci differences. We identified 34 different hapfams identified. The Fst statistic and heterozygosity analysis showed the five clusters were maintained in each village throughout this time. A minimum spanning network (MSN), stratified by the year of detection, showed that haplotypes within hapfams had allele differences and haplotypes within a cluster definition were more separated in the later years (2006–2007). We modeled hapfam detection and loss, accounting for sample size and stochastic fluctuations in frequencies overtime. Principle component analysis of genetic variation revealed patterns of genetic structure with time rather than village. The population structure, genetic diversity, appearance/disappearance of the different haplotypes from 2003 to 2007 provides a genome-wide "real-time" perspective of P. falciparum parasites in a low transmission region.
Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction
Authors: Edith M. Hessel, Mabel Chu, Jennifer O. Lizcano, Bonnie Chang, Nancy Herman, Sariah A. Kell, Marsha Wills-Karp, Robert L. Coffman
Journal: The Journal of Experimental Medicine (2005)

A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)-mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c(+ )APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E-dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways.