tbuckley/cabot-search huggingface dataset:
Sensory impairments and incident disability in older men living in a British community: a 2 year follow-up study
Authors: Ann E M Liljas, S Goya Wannamethee, Peter H Whincup, Olia Papacosta, Kate Walters, Steve Iliffe, Lucy T Lennon, Livia A Carvalho, Sheena E Ramsay
Journal: The Lancet (2015)
A phase I and pharmacokinetic study with 21-day continuous infusion of epirubicin.
Authors: E G de Vries, J Greidanus, N H Mulder, M B Nieweg, P E Postmus, D L Schipper, D T Sleijfer, D R Uges, P H Willemse
Journal: Journal of Clinical Oncology (1987)

A phase I study with continuous administration of epirubicin for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two patients entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no toxicity (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one patient had leukopenia grade 3. Two others had some hair loss. At 7 mg/m2/d (four patients), all patients developed mucositis (two grade 3). Three patients had bone marrow depression (one grade 3 anemia, one grade 4 leukocytopenia), and one patient developed the hand-foot syndrome. No other toxicity occurred in the patients. One patient obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One patient developed cellulitis around the port, responding to antibiotic treatment; one patient developed a vena cava superior syndrome that resolved with urokinase and removal of the access port. No septicemia occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between epirubicin dose administered and epirubicin level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with epirubicin may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.
Phenoscape: Identifying Candidate Genes for Evolutionary Phenotypes
Authors: Richard C. Edmunds, Baofeng Su, James P. Balhoff, B. Frank Eames, Wasila M. Dahdul, Hilmar Lapp, John G. Lundberg, Todd J. Vision, Rex A. Dunham, Paula M. Mabee, Monte Westerfield
Journal: Molecular Biology and Evolution (2015)

Phenotypes resulting from mutations in genetic model organisms can help reveal candidate genes for evolutionarily important phenotypic changes in related taxa. Although testing candidate gene hypotheses experimentally in nonmodel organisms is typically difficult, ontology-driven information systems can help generate testable hypotheses about developmental processes in experimentally tractable organisms. Here, we tested candidate gene hypotheses suggested by expert use of the Phenoscape Knowledgebase, specifically looking for genes that are candidates responsible for evolutionarily interesting phenotypes in the ostariophysan fishes that bear resemblance to mutant phenotypes in zebrafish. For this, we searched ZFIN for genetic perturbations that result in either loss of basihyal element or loss of scales phenotypes, because these are the ancestral phenotypes observed in catfishes (Siluriformes). We tested the identified candidate genes by examining their endogenous expression patterns in the channel catfish, Ictalurus punctatus. The experimental results were consistent with the hypotheses that these features evolved through disruption in developmental pathways at, or upstream of, brpf1 and eda/edar for the ancestral losses of basihyal element and scales, respectively. These results demonstrate that ontological annotations of the phenotypic effects of genetic alterations in model organisms, when aggregated within a knowledgebase, can be used effectively to generate testable, and useful, hypotheses about evolutionary changes in morphology.
Lumacaftor/ivacaftor for patients homozygous for Phe508del-CFTR: should we curb our enthusiasm?
Authors: A. M. Jones, P. J. Barry
Journal: Thorax (2015)

Cystic fibrosis (CF) is a success story of modern medicine, with advances in care transforming a disease previously associated with early childhood death into a chronic condition with a predicted median survival of nearly 50 years for patients born in this current decade.1 This has been achieved through a model of multidisciplinary care with the successive advent of supportive therapies that tackled the consequences of the condition, such as replacement pancreatic enzymes, inhaled antibiotics and agents to improve mucociliary clearance. The quest for treatments that address the underlying basic defect has been a hope for the CF community since the discovery of the CF gene, which codes for the dysfunctional channel protein, the CF transmembrane conductance regulator (CFTR), in 1989.2 The Cystic Fibrosis Foundation supported an ambitious pipeline to identify molecules that could allow correction of the dysfunctional CFTR protein, which began to bear the fruits of investment with the treatment of CF patients with Gly551Asp (G551D) mutation with ivacaftor.

The Gly551Asp mutation produces a CFTR protein that localises to the epithelial cell membrane but fails to open. Ivacaftor acts as a CFTR potentiator that increases channel opening probability and has demonstrated remarkable improvements in lung function, nutritional status, patient-reported outcome measures and biomarkers of CFTR function in clinical studies of patients with the Gly551Asp gene mutation.3 ,4 The initial promise of these significant clinical benefits seen in pre-licensing clinical studies has been fulfilled in subsequent postmarketing phase IV studies.5–7 In addition, published case reports and anecdotal comments from patients have exemplified the benefits of such therapy beyond the respiratory system in addressing the dysfunction that CF causes in other organs and systems.8–10

The unprecedented success of ivacaftor treatment for the Gly551Asp CF patient population has created immense excitement within the CF community with anticipation …
Lymphokine Control of In Vivo Immunoglobulin Isotype Selection
Authors: F D Finkelman, J Holmes, I M Katona, J F Urban, M P Beckmann, L S Park, K A Schooley, R L Coffman, T R Mosmann, W E Paul
Journal: Annual Review of Immunology (1990)

Several specific conclusions can be drawn from these studies: 1. IL-4 is required for the generation of both primary polyclonal and secondary antigen-specific IgE responses in vivo. 2. IL-4 is required to maintain established, ongoing, antigen-specific and polyclonal IgE responses. 3. Most, but not all, polyclonal IgE production during a secondary immune response is IL-4-dependent. Memory B cells that have already switched to IgE at the DNA level may no longer require stimulation with IL-4 to be induced to secrete IgE. 4. The generation of a secondary IgE response is not dependent upon the presence of IL-4 during primary immunization. However, if IL-4 is not present during primary immunization, it is required during secondary immunization for the generation of an IgE response. 5. IL-4 does not appear to be required for the generation of in vivo IgG1 responses, and in at least some instances, does not contribute significantly to the generation of IgG1 responses in vivo. 6. A late-acting form of T-cell help other than IL-4 appears to be required for the generation of an IgE, but not an IgG1 response. 7. An antibody that inhibits IL-4 binding to IL-4 receptors affects Ig isotype selection in the same way as an antibody that neutralizes IL-4. 8. IFN-gamma can act in both spontaneous and induced immune responses to suppress IgE production. 9. IFN-gamma can also suppress IgG1 production and stimulate IgG2a production. However, IFN-gamma appears to suppress polyclonal IgG1 responses more than antigen-specific IgG1 responses, and it enhances, but is not required for, the generation of IgG2a responses. 10. IFN-alpha appears to resemble IFN-gamma in its ability to inhibit IgE and enhance IgG2a responses in GaM delta-injected mice, but it requires the presence of IFN-gamma to suppress IgG1 production in these mice. 11. Both IFN-alpha and IFN-gamma appear to be able to decrease IgE production in some human patients. 12. There is no direct evidence that IL-5 contributes to the generation of in vivo antibody responses. Two general conclusions may also be drawn.(ABSTRACT TRUNCATED AT 400 WORDS)
Hybridization Approaches to the Study of Neuropeptides
Authors: J P Schwartz, E Costa
Journal: Annual Review of Neuroscience (1986)

During the course of evolution, species have increased in complexity, and their nervous systems have evolved correspondingly with an increase in the diversity of their capabilities to respond. Part of that diversity has resulted from an increase in cell types and numbers and their interconnections. In addition, much of it comes from the panoply of neurotransmitters available, of which the neuropeptides represent a major portion. The application of the techniques of molecular biology to the nervous system has led to an appreciation of some of the genetic means by which such diversity can be generated. The cloning and sequencing of peptide precursor genes has shown the existence of gene families, genes with duplications of internal sequences, and genes evolutionarily related to one another, suggesting that one response to the increasing complexity of the organism has been a genetic diversification of the precursor population for peptides. As the precursor genes evolved and thereby provided increasing numbers of peptides, the receptor genes may have evolved simultaneously to provide diversification in the responses to these peptides (for example, the opioid peptide precursors) (Comb et al 1983). The precursor sequences obtained have led not only to the predictions of new peptides but also to the discovery of alternative methods of generating diversity from a single gene. At one extreme, the gene is translated into a polyprotein containing several peptides, which are produced in and released from the same cell. At the other extreme, the nuclear transcript of the gene is differentially spliced such that one peptide is expressed in one tissue and another in a different tissue (Calcitonin-CGRP), or one peptide may be expressed with or without a second peptide in different cells (substance P-substance K). The net result is either one neuron producing a multiplicity of responses to several co-released peptides derived from a polyprotein (POMC or PE) or a tissue- or cell-specificity in terms of which peptide is produced and released. Numerous applications have been made utilizing the cDNA probes generated from the cloning of neuropeptide precursors. Hybridization analyses, including in vitro transcription run-off, have demonstrated that the transcription of neuropeptide genes is regulated by transsynaptic activation of transmitter receptors located in the neuronal membrane, or by hormones, or by as yet unveiled mechanisms. Hybridization techniques have allowed assessment of the dynamic state of neuropeptides functioning as neuromodulators.(ABSTRACT TRUNCATED AT 400 WORDS)
Postherpetic Neuralgia
Authors: Robert W. Johnson, Andrew S.C. Rice
Journal: New England Journal of Medicine (2014)

Postherpetic neuralgia is more common with older age. Recommended treatments include topical agents (lidocaine or capsaicin) and systemic agents (in particular, gabapentin, pregabalin, or tricyclic antidepressants), but their efficacy tends to be suboptimal.
THE LANGUAGE OF HEALTH CARE: The British Royal Commission on Tuberculosis
Authors: J. M Grange
Journal: Journal of the Royal Society of Medicine (2006)

In his challenging and erudite article on the risk of animal tuberculosis to human health (JRSM October 2006),1 Peter Davies states that this risk was not debated by the Government until 1929. In fact, the British Government showed great interest and took decisive action as early as 1901.

In that year, Robert Koch astounded his audience at the British Congress on Tuberculosis by claiming that bovine tuberculosis was of no danger to the human population. A vociferous debate ensued and several distinguished veterinary surgeons attending the congress, with the support of Lord Lister, urged the Government to have the issue investigated. The Royal Commission on Tuberculosis was rapidly convened and the Commissioners employed some eminent workers, including Louis Cobbett, Arthur Stanley Griffith, and his brother Fred, more famous for describing transmission of inheritable characteristics from one bacterium to another, thereby paving the way for the discovery of DNA. These workers embarked on an intensive and extensive ten-year project and produced a series of reports, with the final one published in 1911 concluding that ‘Man must therefore be added to the list of animals notably susceptible to bovine tubercle bacilli.’2,3 These workers also developed the test-and-slaughter control method for bovine tuberculosis, but this was not systematically deployed until after the Second World War. This Royal Commission was one of the first examples of state-sponsored medical research and was the precursor of the Tuberculosis Research Council, which in turn was the forerunner of the British Medical Research Council.

Tragically, Fred Griffith was killed in an air-raid in London in the Second World War. Arthur Stanley Griffith devoted 37 years of his life to tuberculosis bacteriology and developed many techniques that are, with only minor modifications, used throughout the world today.
Circulating Blood B Cells in Multiple Myeloma: Analysis and Relationship to Circulating Clonal Cells and Clinical Parameters in a Cohort of Patients Entered on the Eastern Cooperative Oncology Group Phase III E9486 Clinical Trial
Authors: Neil E. Kay, Traci Leong, Robert A. Kyle, Philip Greipp, Daniel Billadeau, Brian Van Ness, Nancy Bone, Martin M. Oken
Journal: Blood (1997)
Measuring the Quality of Care for Patients With Traumatic Brain Injury
Authors: Xiulu Ruan, Alan D. Kaye
Journal: JAMA Surgery (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Oxidative DNA damage and apoptosis induced by docosahexaenoic acid in human colon cells
Authors: Jishen Pan, Fung-Lung Chung
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1386 

The apoptotic effect of ω-3 polyunsaturated fatty acids (PUFAs) attributing to their protection against colon carcinogenesis has been amply documented in various cell lines and animal studies. Although the underlying molecular mechanism is still unclear, some studies have shown that DNA damage caused by lipid peroxidation may be involved in this cell programmed death process. Our previous studies showed that ω-3 PUFAs, particularly docosahexaenoic acid (DHA) due to its high degree of unsaturation with six double bonds, give rise to the acrolein-derived 1,N2-propanodeoxyguanosine adduct (Acr-dG) as a major oxidative DNA adduct formed through lipid peroxidation pathway. In this study, we examined the possible role of oxidative DNA damage in the apoptotic effect of DHA in HT29 and HCT116 human colon cells. Two oxidative DNA lesions, Acr-dG and 8-oxodeoxygunosine (8-oxodG), were measured by the 32P-postlabeling/SPE/HPLC and HPLC-electrochemical detection methods, respectively. The apoptosis was determined by cytoplasmic and nuclear morphological changes, caspase 3 activities, and TUNEL assays. The results showed that levels of Acr-dG and 8-oxodG adducts in these cells are increased by more than twofold in a dose-dependent manner following treatment of DHA from 0 to 300 μM. The apoptosis induced by DHA in these cells were confirmed by increased levels of caspase 3 activity and DNA strand breaks, nuclear shrinkage, and cell membrane blebbing. By contrast, linoleic acid, an ω-6 PUFA with two double bonds, did not significantly change the levels of Acr-dG and 8-oxodG and showed no increase in apoptosis even at much higher concentrations in these cells. In conclusion, these results demonstrate that DHA increases the oxidative DNA damage and apoptosis and suggest that the elevated damage may serve as signal to initiate apoptosis in human colon cells. (supported by NCI grant CA43159)
Synergistic effects of interferon γ and tumour necrosis factor α on T84 cell function
Authors: S M Fish, R Proujansky, W W Reenstra
Journal: Gut (1999)

BACKGROUND Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation and increased epithelial permeability. Both tumour necrosis factor α (TNF-α) and interferon γ (IFN-γ) have been implicated in IBD. AIMS To understand better the effects of these cytokines on epithelial cell function. METHODS T84 cells were cultured with IFN-γ and TNF-α and changes in transepithelial resistance (TER), fluorescein isothiocyanate (FITC) dextran flux, short circuit current ( I sc ), cystic fibrosis transmembrane conductance regulator (CFTR) protein levels, cell morphology, TNF receptor gene expression, and apoptosis were assayed. RESULTS Relative to controls, significant changes (p&lt;0.05) occurred in cells incubated with IFN-γ for two days: TER was decreased to 20 (6.2)%, FITC–dextran flux was increased by 109 (19)-fold, cAMP and Ca dependent I sc were decreased to 51 (6.4)% and 24 (2.2)%, respectively, and CFTR levels were decreased to 47 (11)%. Cell morphology was altered but cell death was not induced. TNF receptor mRNA levels were increased. When added with IFN-γ, TNF-α accelerated IFN-γ dependent changes. Relative to controls, significant changes occurred after one day of culture with IFN-γ plus TNF-α: TER was decreased to 27 (3.5)%, FITC–dextran flux was increased by 185 (45)-fold, and cAMP and Ca dependent I sc were decreased to 66 (12)% and 35 (6.8)%, respectively. TNF-α also enhanced IFN-γ dependent changes in cell morphology but did not induce cell death. CONCLUSION IFN-γ alters T84 cell epithelial properties and TNF-α can enhance these effects, perhaps due to IFN-γ dependent increases in TNF receptor gene expression. Overall, these studies suggest that in IBD, TNF-α may have synergistic effects on IFN-γ mediated alterations of epithelial cell function.
Porphyria and Porphyrin Metabolism
Authors: J G Straka, J M Rank, J R Bloomer
Journal: Annual Review of Medicine (1990)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies
Authors: J. Naidoo, D.B. Page, B.T. Li, L.C. Connell, K. Schindler, M.E. Lacouture, M.A. Postow, J.D. Wolchok
Journal: Annals of Oncology (2015)
Evaluation of Thrombogenic Effects of Drugs
Authors: G Zbinden
Journal: The Annual Review of Pharmacology and Toxicology (1976)

More than 100 years ago the German pathologist RudolfVirchow recognized that pathological changes of blood vessel walls, thrombotic diathesis, and altered blood flow were the major causes of thrombosis (1). It is remarkable that no fundamentally new pathogenetic factors have since been added to what is now known as Virchow's triad. In recent years biochemical and morphological studies have unraveled many of the processes taking place during hemostasis. As a result, we have also gained a better understanding of the mechanisms contributing to thrombus form­ ation. The notion that drugs play an important role in the development of thrombosis has gained widespread attention. Extensive investigations undertaken in an effort to explain the apparent thrombogenic effect of steroidal oral contraceptives (OC) have revealed a number of unusual toxicological problems: 1. Few chemical substances are known to cause outright thrombosis. However, many agents seem to increase the risk of thrombosis, that is, they create a state of impending thrombosis or thrombophilia. an ill-defined pharmacological endpoint. 2. Drugs may influence several factors involved in thrombus formation. 3. There are at least three fundamentally different forms of thrombosis, arterial and venous thrombosis, and disseminated microcirculatory thrombosis. Drugs may promote one or more of these forms to a variable degree. 4. Most laboratory methods were originally designed to measure defective blood clotting and platelet function. They are not well suited for the demonstration of impending thrombosis. 5. In man, the recognition of a thrombogenic drug effect often rests on epidemio­ logical data. Serious problems of diagnosis. and the existence of disease-related and environmental factors that influence the incidence of thrombosis, render such stud­ ies difficult.