tbuckley/cabot-search huggingface dataset:
Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology.
Authors: K Schmiegelow, H Schrøder, G Gustafsson, J Kristinsson, A Glomstein, T Salmi, L Wranne
Journal: Journal of Clinical Oncology (1995)

PURPOSE During maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), the cytotoxic metabolites of methotrexate (MTX polyglutamates) and mercaptopurine (6MP) (thioguanine nucleotides [6TGN]) accumulate intracellularly, including in erythrocytes (E-MTX and E-6TGN) with large interindividual variations. In the present Nordic Society for Pediatric Hematology and Oncology (NOPHO) study, the relation of E-MTX and E-6TGN to relapse risk was explored. PATIENTS AND METHODS Two hundred ninety-seven patients with non-B-cell ALL, aged 1 to 14 years, on oral MTX and 6MP had E-MTX and E-6TGN levels measured three to 35 (median, eight) and three to 75 (median, nine) times, respectively. For each patient, a mean of all E-MTX (mE-MTX) and E-6TGN (mE-6TGN) measurements was calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX-6TGN), since MTX and 6MP may have synergistic action. RESULTS For patients in remission, the median mE-MTX and mE-6TGN values were 4.7 nmol/mmol hemoglobin (Hgb) (range, 0.4 to 10.3) and 173 nmol/mmol Hgb (range, 58 to 846). With a median follow-up duration of 66 months for patients in remission, 64 patients relapsed. Cox regression analysis identified mE-MTX-6TGN and sex to be the most significant parameters to predict relapse (global P = .001). Factors that predicted a better prognosis were high mE-MTX 6TGN and female sex. Patients who had a mE-MTX-6TGN less than the product of the median mE-MTX and median mE-6TGN (813 [nmol/mmol Hgb]2) had a significantly poorer event-free survival (EFS) than did patients with higher values (5-year probability of EFS [pEFS5y], 0.70 v 0.86; P = .001). CONCLUSION The pharmacokinetics of MTX and 6MP may have significant influence on the risk of relapse. The value of dose adjustments by E-MTX and E-6TGN remains to be determined.
Protein Phosphorylation Catalyzed by Cyclic AMP-Dependent and Cyclic GMP-Dependent Protein Kinases
Authors: D B Glass, E G Krebs
Journal: The Annual Review of Pharmacology and Toxicology (1980)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Chronic Obstructive Pulmonary Disease: Risk Factors, Pathophysiology and Pathogenesis
Authors: G L Snider
Journal: Annual Review of Medicine (1989)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Extreme mutational selectivity of axitinib limits its potential use as a targeted therapeutic for BCR-ABL1-positive leukemia
Authors: M S Zabriskie, C A Eide, D Yan, N A Vellore, A D Pomicter, S L Savage, B J Druker, M W Deininger, T O'Hare
Journal: Leukemia (2015)

Extreme mutational selectivity of axitinib limits its potential use as a targeted therapeutic for BCR-ABL1-positive leukemia
Peripheral T Cell Tolerance
Authors: Jacques F. A. P. Miller, Grant Morahan
Journal: Annual Review of Immunology (1992)

The most efficient way to ensure self-tolerance in the T-cell repertoire is by intrathymic deletion of self-reactive clones. Antigens not present intrathymically may, however, influence the peripheral T-cell pool in various ways. They may of course activate T cells, provided that these have the correct specificity and affinity and that the antigens are presented in sufficient amounts on professional antigen-presenting cells. They may be ignored by T cells if some of these conditions are not met. In some forms, the antigen may be toleragenic for mature T cells. If the antigens persist in an immunogcnic form, unresponsiveness may eventually be imposed as the end result of a powerful immune response. Extrathymic self-antigenic components are generally encountered early in development, and the way in which these influence peripheral T lymphocytes has been studied by transgenic technology. They may be ignored by T cells if they are sequestered from the immune system, or if they are present in low amounts or on nonprofessional antigen-presenting cells which lack the appropriate accessory molecules or signals needed to activate the relevant T-cell subset. On the other hand, some of these self-antigens readily induce anergy in peripheral T cells, which may or may not involve downregulation of antigen receptors and coreceptors. Tolerance in the T-cell repertoire is therefore achieved not only by intrathymic deletion of self-reactive clones but also by several postthymic mechanisms
Nutritional Consequences of Vegetarianism
Authors: J T Dwyer
Journal: Annual Review of Nutrition (1991)

HEALTH ASPECTS OF VEGETARIANISM     ......... . . The Range of Eating Styles Compatible with Health   . . DIETARY INADEQUACIES THAT MAY ARISE ON VEGETARIAN DIETS ...... . . Iron Deficiency Anemia     , . . . . . . . . . . . . . . Megaloblastic Anemias Due to Vitamin B/2 and Folic Acid Deficiencies   . Calcium-Deficient Diets    . . . . . . . . . .. . . . . . . . .. . . , . . Vitamin D, Rickets, and Osteomalacia   . Zinc Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . , . . . . . . . . . . . . . . . . . Vitamin B6 ... , . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . Other Nutrients Possibly Low in Vegetarian Diets .. . DECREASED RISKS OF CHRONIC DEGENERATIVE DISEASES ON VEGETARIAN DIETS     . .
Paclitaxel and cardiotoxicity.
Authors: E A Perez
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.11.3481 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9817263 Paclitaxel and cardiotoxicity. E A PerezxE A PerezSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.11.3481 PDF "Paclitaxel and cardiotoxicity.." Journal of Clinical Oncology, 16(11), pp. 3481–3482© 1998 by American Society of Clinical Oncology
Association of Serum Antibodies to Heat-Shock Protein 65 With Carotid Atherosclerosis
Authors: Qingbo Xu, Stefan Kiechl, Manuel Mayr, Bernhard Metzler, Georg Egger, Friedrich Oberhollenzer, Johann Willeit, Georg Wick
Journal: Circulation (1999)

Background —Previous work has proved that increased titers of antibodies against heat-shock protein (hsp) 65 are associated with atherosclerotic lesions independently of other established risk factors. The present follow-up study was designed to further scrutinize the association of hsp antibodies and atherosclerosis and evaluate the possible predictive value of these antibodies for the development and/or progression of lesions in the same population. Methods and Results —A total of 750 subjects 45 to 74 years old were recruited, and the rate of participation was 93.6%; 58 subjects died between 1990 and 1995. All participants were subjected to determination of serum antibodies against hsp65 and sonography to assess carotid atherosclerotic lesions and evaluate other risk factors, ie, age, sex, body mass index, blood cholesterol, apolipoprotein B, apolipoprotein A, triglycerides, lipoprotein(a), fibrinogen, leukocyte number, antithrombin III, ESR, ferritin, hypertension, smoking, and diabetes mellitus. Our data show that hsp65 antibody titers in the population emerged as highly consistent over a 5-year observation period ( r =0.78, P &lt;0.0001). Titers were significantly elevated in subjects with progressive carotid atherosclerosis and correlated with intima/media thickness. Multiple linear regression analysis documented these associations to be independent of age, sex, and other risk factors. Subanalyses revealed a preferential association of hsp65 antibody titers with advanced lesions (odds ratio, 1.42; 95% CI, 1.02 to 1.98; P =0.039). Other risk factors neither confounded nor modified this association. Finally, hsp65 antibody titers significantly predicted the 5-year mortality (hazard ratio, 1.52; 95% CI, 1.14 to 2.03; P &lt;0.001). Conclusions —These findings indicate a sustained existence of anti-hsp65 antibodies in subjects with severe atherosclerosis, which is predictive for mortality.
Non-Equilibrium Behavior of Some Brain Enzyme and Receptor Systems
Authors: A J Mandell
Journal: The Annual Review of Pharmacology and Toxicology (1984)

The previous article in this review dealing with the regulatory properties of brain tyrosine (TOH) and tryptophan hydroxylase (TPOH) systems (1 ) empha­ sized (a) multidimensional ity: almost all the components present under phys ­ iological and assay conditions, ranging from electromagnetic fields through hydrophobic ligands to reducing equivalents, influence in one way or another the rate functions representing catalytic activities; (b) nonlinearity: critical zones of ligand concentration, curvilinear, even intermittent amount-effect functions, and inconsistencies among results depending on small differences in parameter values are consonant with the prominent role of cooperative interac­ tions among the many stated and unstated dimensions (coordinates) regulating catalytic systems; (c) conformational instability: in the protein macromolecular components of TOH and TPOH, conformational instabilities are evidenced by 20 years offailure to purify the enzyme proteins in amounts useful for systemat­ ic extensive kinetic characterization , by their extreme friability under condi­ tions of storage, by their multiplicity of reported molecular weigh ts and kinetic constants, and by their markedly increased ease of denaturation and precipita­ tion after the removal of components from their normal milieu by dialysis and enrichment procedures. That article expressed hope that a multivariate approach to studies of TOH and TPOH regulation could be developed to allow data reduction through pattern analysis in place of one-or two-variable kinetic experiments and quantification by Michaelis or Hill constants (1 ). This review updates the 1978 one with respect to research on the regulatory properties of TOH and TPOH as reported in the literature through early 1983 with the exception of the cyclic nucleotide-prote in phosphorylati on schemata (recently involving calmodulin), the current status of which is reviewed else
Very Early Molecular Responses During The First Two Months Of Therapy Are Highly Predicitive Of Deep Molecular Responses In Newly-Diagnosed Chronic Myeloid Leukemia In Chronic Phase( CML-CP) Patients Treated Upfront With Nilotinib. The Spanish Substudy Of The ENEST1st Trial
Authors: Juan Luis Steegmann, Luis Felipe Casado Montero, Maria Teresa Gomez-Casares, Maria Rozman, Maria Asunción Echeveste, J Valentin Garcia-Gutierrez, Jose Luis Sastre, Angel Ramirez Payer, Eduardo Olavarria, Ferran Vall, Blanca Xicoy, Pilar Giraldo, Eulogio Conde, Rolando Omar Vallansot, Jose Luis Lopez-Lorenzo, Luis Palomera, Soraya Ruiz, Laura Casas, Claudia Walasek, Dolors Colomer
Journal: Blood (2013)
Purinergic Neurotransmission and Neuromodulation
Authors: C Su
Journal: The Annual Review of Pharmacology and Toxicology (1983)

Conflicting views abound on the peripheral neurotransmitter and neuromodulator roles of purine compounds. Substantial organ- and species-related variations have become apparent. There is, however, a body of compelling evidence for such roles, if not so broad and ubiquitous as those envisioned (7) for the central nervous system. The variations may in part be attributable to the neuroeffector synaptic geometry. The transmitter concentration found at the postsynaptic membrane drops precipitously with increase in the synaptic cleft (85). Where the cleft is narrow, a purine may serve as the primary or sole transmitter (purinergic nerve) and presynaptic modulator. Alternatively, from nonpurinergic (e.g. adrenergic) nerves a purine may be released, possibly ATP by exocytosis, to act as a cotransmitter. It may also serve as pre- and post-synaptic modulator, potentially with a contribution from postsynaptic release (Figure 1). The purine could conceivably diffuse and affect other varicosities. Where the cleft is wide, the postsynaptic concentration of the neurogenic purine may be too low to permit a transmitter or postsynaptic modulator function. The concentration of the nonpurine transmitter may also be insufficient to elicit a significant postsynaptic purine release. The neuronally released purine may, however, presynaptically exert inhibition of transmitter release much as in a narrow cleft. It seems, therefore, that the origin of synaptic purines and their function, be it transmitter, cotransmitter, or modulator, are dictated at least in part by the characteristics of the purine pools, purinergic receptors, and synaptic configuration, which await further assessment.
The Neurotrophins and CNTF: Two Families of Collaborative Neurotrophic Factors
Authors: Nancy Y. Ip, George D. Yancopoulos
Journal: Annual Review of Neuroscience (1996)

Because the actions of neurotrophic factors appear distinct from those of traditional growth factors and cytokines, it was long assumed that the neurotrophic factors utilized receptors and signaling systems fundamentally different from those used by growth factors operating elsewhere in the body. Recent advances in the understanding of the structure of the receptors for neurotrophic factors have unexpectedly revealed that they are in fact similar to the receptors used by the traditional growth factors and cytokines. The expression of the receptors for the neurotrophic factors is exclusively or predominantly in the nervous system; activation of these receptors in the context of the neuron allows these factors to display distinctive actions. While the precise roles of the neurotrophic factors and their therapeutic potential in various disease states still remain to be elucidated, this review describes studies on their receptor systems, their notable biological activities in the nervous system, and recent insights provided by targeted gene disruptions.
Apples and oranges: building a consensus for standardized eligibility criteria and end points in prostate cancer clinical trials.
Authors: N A Dawson
Journal: Journal of Clinical Oncology (1998)

To survey eligibility and response criteria for clinical trials in hormone-refractory prostate cancer (HRPC).Thirty-five established investigators of HRPC completed a 125-question survey.There was a general consensus that criteria for clinical trial entry would include progression based on an increasing prostate-specific antigen (PSA) level (94% of investigators), an increase in measurable disease (91%), and/or appearance of new bone lesions on bone scan (83%). Most believed that castrate levels of testosterone (77%) and progression after antiandrogen withdrawal (97%) should be documented before study enrollment. Continuation of testicular androgen suppression would be required by 82%. Seventy-seven percent favored separate reports on response rates in bone, measurable disease, symptoms, and biochemical markers (primarily PSA levels), rather than a composite response. Ninety-four percent of the investigators accepted changes in PSA level as a surrogate end point of response. However, interpretation by these investigators of a PSA data set similar to what might be observed in a clinical trial showed marked discordance. Survival is the end point of most importance to 94% of these investigators. Response based on changes in measurable disease, time to progression, response duration, PSA level decrease, or quality-of-life improvement were of similar weighted value as a clinical trial end point and were rated as less important to these investigators than survival (P < 10(-8)).This survey indicates some consensus on eligibility and concomitant treatments for clinical studies in HRPC. The use of multiparameter assessment of response and PSA level as a surrogate end point have been widely adopted.
Abstract 12011: Severe Heterozygous Familial Hypercholesterolaemia in the Netherlands: Prevalence and Risk for Cardiovascular Disease
Authors: Joost Besseling, Gerard K Hovingh, Barbara A Hutten, John J Kastelein
Journal: Circulation (2013)

Introduction: Low-density lipoprotein cholesterol (LDL-C) levels vary widely amongst patients with heterozygous familial hypercholesterolaemia (HeFH), and patients with the highest LDL-C levels are...
Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle
Authors: Miles A. Miller, Suresh Gadde, Christina Pfirschke, Camilla Engblom, Melissa M. Sprachman, Rainer H. Kohler, Katherine S. Yang, Ashley M. Laughney, Gregory Wojtkiewicz, Nazila Kamaly, Sushma Bhonagiri, Mikael J. Pittet, Omid C. Farokhzad, Ralph Weissleder
Journal: Science Translational Medicine (2015)

Magnetic nanoparticles predict the efficacy of drug-loaded polymeric nanoparticles in vivo, helping select for tumors more responsive to nanomedicine.
Does interleukin-2 have a role in the management of acute leukemia?
Authors: R Foa
Journal: Journal of Clinical Oncology (1993)

PURPOSE To discuss the possibility that interleukin-2 (IL-2)-based immunotherapeutic protocols may have a role in the management of acute leukemia. DESIGN The preclinical results that have led to the clinical use of IL-2 in acute leukemia will be reviewed. The clinical data obtained with the administration of IL-2 to acute leukemia patients in different phases of their disease will be discussed, together with the clinicohematologic and immunologic modifications induced following the infusion of IL-2. Finally, the possibility that limitations associated with the exogenous administration of high-dose IL-2 may be circumvented by engineering techniques aimed at inserting the IL-2 gene directly into the tumor cells, will be addressed. RESULTS The data indicate that high-dose IL-2 may be administered to acute leukemia patients. Toxicity, recorded in all patients, appears to be controllable using a continuous intravenous (i.v.) infusion protocol based on a daily dose-escalating administration. Complete remissions have been documented in acute myeloid leukemias (AMLs) with a limited, but detectable proportion of residual marrow blasts. Numerous phenotypic and functional changes have been recorded within the immune system of the host. Using retroviral vectors, the IL-2 gene may be productively transduced into human acute leukemia cell lines. CONCLUSION IL-2 appears to represent a therapeutic option for AML patients with limited/minimal residual disease. The results of the ongoing randomized trials in patients in first or second remission are awaited.
Zonation of Parenchymal and Nonparenchymal Metabolism in Liver
Authors: Kurt Jungermann, Thomas Keitzmann
Journal: Annual Review of Nutrition (1996)

The enormous number of different liver functions are carried out by parenchymal and four main types of nonparenchymal cells, either alone or in cooperation. Although the liver tissue is uniform on the level of histology, it is heterogenous on the level of morphometry and histochemistry. This heterogeneity is related to the blood supply; cells located in the upstream or periportal zone differ from those in the downstream or perivenous zone in their equipment with key enzymes, translocators, receptors, and subcellular structures and therefore have different functional capacities. This is the basis of the model of metabolic zonation, according to which glucose release from glycogen and via gluconeogenesis, amino acid utilization and ammonia detoxification, protective metabolism, bile formation, and the synthesis of certain plasma proteins such as albumin and fibrinogen occur mainly in the periportal area, whereas glucose utilization, xenobiotic metabolism, and the formation of other plasma proteins such as α 1 -antitrypsin or α-fetoprotein occur predominantly in the perivenous zone. The morphologic and functional heterogeneity is the result of zonal differences in the activation of the cellular genome caused by gradients in oxygen, substrate, hormone, and mediator levels, in innervation, as well as in cell-to-cell and cell-to-biomatrix interactions.
Multiple myeloma as a major cause of false-positive galactomannan tests in adult patients with cancer
Authors: Jae-Hoon Ko, Kyong Ran Peck, Ji Yong Lee, Sun Young Cho, Young Eun Ha, Cheol-In Kang, Doo Ryeon Chung, Kihyun Kim, Eun-Suk Kang, Jae-Hoon Song
Journal: Journal of Infection (2015)
The Rodent Leukemias: Virus-Induced Murine Leukemias
Authors: J B Moloney
Journal: Annual Review of Medicine (1964)

It is the intent of this paper to consider specific studies with certain of the viruses which induce neoplasms of the reticular system of rodents. The physi­ cal and chemical nature of the viruses, their relationship to the neoplastic process, and the interrelationships of the leukemia agents, will be discussed. For recent and more complete reviews on the leukemia viruses, the reader is referred to reports by Gross (1), Dmochowski (2), and Sinkovics (3). The pioneer studies of Gross (4) in 1951 on the viral etiology of rodent leukemias stimulated investigations in this area of research. At present there are many well-defined, and perhaps distinct viruses known to induce leu­ kemia in mice, rats, and, to a more limited extent, in hamsters. Table I lists the viruses as they have been reported in the literature. There are no specific names for these agents; however, to facilitate presentation they are listed under the names of the investigators who first described their properties. The viruses are further grouped and for the most part will be dis­ cussed according to the pathologic classification of the induced neoplasms. It should be emphasized that the table lists only those viruses considered original and those viruses most completely defined. Thus, the leukemia agents described by Precerutti & Law (23), Bather, (24), Pope (25), Mirand & Grace (26) are considered by these authors to be directly related to certain of the agents described in the table.
Regiochemistry of Cytochrome P450 Isozymes
Authors: K Oguri, H Yamada, H Yoshimura
Journal: The Annual Review of Pharmacology and Toxicology (1994)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More