tbuckley/cabot-search huggingface dataset:
Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis
Authors: J. Nagano
Journal: European Respiratory Journal (2006)

Idiopathic pulmonary fibrosis has a poor prognosis and few efficacious treatments. The immunosuppressant cyclosporin A has been shown to inhibit tumour growth factor (TGF)-beta-induced collagen deposition in vitro, and is widely used in Japan as a potent antifibrotic agent. Tacrolimus (FK506) is another attractive immunosuppressant, which may be useful in the treatment of pulmonary fibrosis. The aim of the present study was to elucidate the antifibrotic effect of FK506. The inhibitory effect of FK506 on collagen synthesis in cultured lung fibroblastic cells, TIG-3-20, and its antifibrotic effect on bleomycin (BLM)-induced pulmonary fibrosis in mice was investigated. FK506 inhibited TGF-beta-induced collagen synthesis, and suppressed the expression of TGF-beta type I receptor (TbetaR-I) in TIG-3-20 cells. Consistent with the in vitro findings, FK506 treatment starting on day 6 attenuated BLM-induced pulmonary fibrosis, in part, via reduced TbetaR-I expression. FK506 treatment in the acute BLM injury phase unexpectedly increased pro-inflammatory cytokine levels in bronchoalveolar lavage fluid and enhanced lung injury, resulting in poor survival. In conclusion, the present results suggest that FK506 has a potent antifibrotic effect and may be useful for the treatment of pulmonary fibrosis, although its use in the acute inflammatory phase may exacerbate lung injury.
Response to Letter Regarding Article “Diesel Exhaust Inhalation Causes Vascular Dysfunction and Impaired Endogenous Fibrinolysis”
Authors: Nicholas L. Mills, Simon D. Robinson, Nicholas A. Boon, David E. Newby, Håkan Törnqvist, Manuel Gonzalez, Anders Blomberg, Thomas Sandstrom, Kareen Darnley, William MacNee, Ken Donaldson
Journal: Circulation (2006)

We thank Dr Brook and colleagues for their interest in our study, 1 in which we describe an acute impairment of vascular and endogenous fibrinolytic function after exposure to dilute diesel exhaust.Brook et al propose that vascular dysfunction may cause vasoconstriction and increase blood pressure to explain the cardiovascular risk associated with air pollution exposure.This is an interesting and potentially important hypothesis.They comment that, in our study, there appeared to be small differences (6 to 8 mm Hg) in both diastolic and systolic pressure 2 hours after diesel exhaust exposure.However, although these differences could potentially be clinically important, they were not statistically significant.There have been previous reports of increases in diastolic pressure after a 2-hour exposure to ambient particles in supine volunteers. 2 In our study, 1 volunteers exercised intermittently during the exposure, and arterial pressure was measured in resting conditions after the exposure.This protocol design may have obscured any potential hypertensive effects, and we do not believe the study had sufficient power to detect meaningful differences in blood pressure.However, although vasoconstriction could have occurred in other vascular beds, we did not observe any effect on resting forearm blood flow.Conditions associated with endothelial dysfunction, such as hypercholesterolemia, 3 often do not cause hypertension or alterations in basal vascular tone, and our findings are consistent with the absence of hypertensive or peripheral vasoconstrictive effects.This does not preclude the induction of other mechanisms, such as alterations in autonomic nervous system activity that may be operating in addition to vascular dysfunction.We agree with Dr Brook and colleagues and suggest that there is a need for further appropriately designed and powered studies to determine whether exposure to diesel exhaust increases arterial pressure.These studies will need to consider the role of the autonomic nervous system, as well as constitutive nitric oxide, as important potential modulators of arterial pressure.
Tumor and Host-Mediated Pathways of Resistance and Disease Progression in Response to Antiangiogenic Therapy
Authors: John M. L. Ebos, Christina R. Lee, Robert S. Kerbel
Journal: Clinical Cancer Research (2009)

Abstract Despite early benefits seen in cancer patients treated with antivascular endothelial growth factor (VEGF) pathway-targeted drugs, the clinical benefits obtained in terms of progression-free or overall survival have been more modest than expected. This outcome is, at least in part, due to antiangiogenic drug resistance mechanisms that involve pathways mediated largely by the tumor, whether intrinsic or acquired in response to therapy, or by the host, which is either responding directly to therapy or indirectly to tumoral cues. The focus of this review is to distinguish, where possible, between such host and tumor-mediated pathways of resistance and discuss key challenges facing the preclinical and clinical development of antiangiogenic agents, including potential differences in drug efficacies when treating primary tumors or various stages of metastatic disease. (Clin Cancer Res 2009;15(16):5020–5)
Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current.
Authors: D Fedida, B Wible, Z Wang, B Fermini, F Faust, S Nattel, A M Brown
Journal: Circulation Research (1993)

In human myocardium, the nature of the K+ currents mediating repolarization of the action potential is still speculative. Delayed rectifier channels have recently been cloned from human myocardium, but it is unclear whether or not these currents are involved in the termination of the cardiac action potential plateau. In intact human atrial myocytes, we have identified a rapid delayed rectifier K+ current with properties and kinetics identical to those expressed by a K+ channel clone (fHK) isolated from human heart and stably incorporated into a human cell line for the first time. The myocyte current amplitude was 3.6 +/- 0.2 pA/pF (at +20 mV, n = 15) and activated with a time constant of 13.1 +/- 2 milliseconds at 0 mV (n = 15). The half-activation potential (V0.5) was -6 +/- 2.5 mV (n = 10) with a slope factor (k) of 8.6 +/- 2.2 (n = 10). The heterologously expressed fHK current amplitude was 136 pA/pF (at +20 mV, n = 9) with an activation time constant of 11.8 +/- 4.6 milliseconds at 0 mV; V0.5 was 4.1 +/- 2.4 mV (mean +/- SEM, n = 8); and k was 7.0. The conductance of single fHK channels was 16.9 picosiemens in 5 mM bath K+. Both native and cloned channel currents inactivated partially during sustained depolarizing pulses. Both currents were blocked by micromolar concentrations of 4-aminopyridine and were relatively insensitive to tetraethylammonium ions and class III antiarrhythmic agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Immunohistochemical Prognostic Markers in Diffuse Large B-Cell Lymphoma: Validation of Tissue Microarray As a Prerequisite for Broad Clinical Applications—A Study From the Lunenburg Lymphoma Biomarker Consortium
Authors: Daphne de Jong, Andreas Rosenwald, Mukesh Chhanabhai, Philippe Gaulard, Wolfram Klapper, Abigail Lee, Birgitta Sander, Christoph Thorns, Elias Campo, Thierry Molina, Andrew Norton, Anton Hagenbeek, Sandra Horning, Andrew Lister, John Raemaekers, Randy D. Gascoyne, Gilles Salles, Edie Weller
Journal: Journal of Clinical Oncology (2007)

The results of immunohistochemical class prediction and prognostic stratification of diffuse large B-cell lymphoma (DLBCL) have been remarkably various thus far. Apart from biologic variations, this may be caused by differences in laboratory techniques, scoring definitions, and inter- and intraobserver variations. In this study, an international collaboration of clinical lymphoma research groups from Europe, United States, and Canada concentrated on validation and standardization of immunohistochemistry of the currently potentially interesting prognostic markers in DLBCL.Sections of a tissue microarray from 36 patients with DLBCL were stained in eight laboratories with antibodies to CD20, CD5, bcl-2, bcl-6, CD10, HLA-DR, MUM1, and MIB-1 according to local methods. The study was performed in two rounds firstly focused on the evaluation of laboratory staining variation and secondly on the scoring variation.Different laboratory staining techniques resulted in unexpectedly highly variable results and very poor reproducibility in scoring for almost all markers. No single laboratory stood out as uniformly poor or excellent. With elimination of variation due to staining, high agreement was found for CD20, HLA-DR, and CD10. Poor agreement was found for bcl-6 and Ki-67. Optimization of techniques and uniformly agreed on scoring criteria improved reproducibility.This study shows that semiquantitative immunohistochemistry for subclassification of DLBCL is feasible and reproducible, but exhibits varying rates of concordance for different markers. These findings may explain the wide variation of biomarker prognostic impact reported in the literature. Harmonization of techniques and centralized consensus review appears mandatory when using immunohistochemical biomarkers for treatment stratification.
Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update
Authors: Santhi K. Ganesh, Donna K. Arnett, Themistocles L. Assimes, Craig T. Basson, Aravinda Chakravarti, Patrick T. Ellinor, Mary B. Engler, Elizabeth Goldmuntz, David M. Herrington, Ray E. Hershberger, Yuling Hong, Julie A. Johnson, Steven J. Kittner, Deborah A. McDermott, James F. Meschia, Luisa Mestroni, Christopher J. O’Donnell, Bruce M. Psaty, Ramachandran S. Vasan, Marc Ruel, Win-Kuang Shen, Andre Terzic, Scott A. Waldman
Journal: Circulation (2013)
Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study
Authors: Angela Dispenzieri, Jerry A Katzmann, Robert A Kyle, Dirk R Larson, L Joseph Melton, Colin L Colby, Terry M Therneau, Raynell Clark, Shaji K Kumar, Arthur Bradwell, Rafael Fonseca, DF Jelinek, S Vincent Rajkumar
Journal: The Lancet (2010)
Ketamine and Cancer Pain: The Reports of My Death Have Been Greatly Exaggerated
Authors: Kate Jackson, Michael Franco, Leeroy William, Peter Poon, Maria Pisasale, David Kenner, David Brumley, Greg Mewett, Michael Ashby, Melissa Viney, David Kerr
Journal: Journal of Clinical Oncology (2013)

Theauthorsaretobecongratulated on successfully completing a placebo-controlled, ran-domized controlled trial in 185 patients receiving palliative care—nomean feat.However,wequestionwhethertheauthors’sweepingconclusionthat “Ketamine does not have net clinical beneﬁt when used as anadjunct to opioids and standard coanalgesics in cancer pain”
FDA advisers warn of more deaths if drug is relaunched
Authors: R. Moynihan
Journal: BMJ (2002)

Advisers to the US Food and Drug Administration are warning of more serious injuries and drug related deaths if alosetron (Lotronex)—a drug for bowel disorders manufactured by GlaxoSmithKline—returns to the market later this year.

Once considered a potentially top selling drug, it was first approved in February 2000 for women with “diarrhoea- predominant” irritable bowel syndrome. It was withdrawn nine months later after reports of serious side effects leading to admission to hospital, surgery, and death.

Urged by patient groups, the FDA and the manufacturer worked together to bring alosetron back to the market, and in April this year a special FDA advisory committee …
The Ratio of FEV<sub>1</sub> to FVC as a Basis for Establishing Chronic Obstructive Pulmonary Disease
Authors: Carlos A. Vaz Fragoso, John Concato, Gail McAvay, Peter H. Van Ness, Carolyn L. Rochester, H. Klar Yaggi, Thomas M. Gill
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: The lambda-mu-sigma (LMS) method is a novel approach that defines the lower limit of normal (LLN) for the ratio of FEV1/FVC as the fifth percentile of the distribution of Z scores. The clinical validity of this threshold as a basis for establishing chronic obstructive pulmonary disease is unknown.Objective: To evaluate the association between the LMS method of determining the LLN for the FEV1/FVC, set at successively higher thresholds, and clinically meaningful outcomes.Methods: Using data from a nationally representative sample of 3,502 white Americans aged 40–80 years, we stratified the FEV1/FVC according to the LMS-LLN, with thresholds set at the 5th, 10th, 15th, 20th, and 25th percentiles (i.e., LMS-LLN5, LMS-LLN10, etc.). We then evaluated whether these thresholds were associated with an increased risk of death or prevalence of respiratory symptoms. Spirometry was not specifically completed after a bronchodilator.Measurements and Main Results: Relative to an FEV1/FVC greater than or equal to LMS-LLN25 (reference group), the risk of death and the odds of having respiratory symptoms were elevated only in participants who had an FEV1/FVC less than LMS-LLN5, with an adjusted hazard ratio of 1.68 (95% confidence interval, 1.34–2.12) and an adjusted odds ratio of 2.46 (95% confidence interval, 2.01–3.02), respectively, representing 13.8% of the cohort. Results were similar for persons aged 40–64 years and those aged 65–80 years.Conclusions: In white persons aged 40–80 years, an FEV1/FVC less than LMS-LLN5 identifies persons with an increased risk of death and prevalence of respiratory symptoms. These results support the use of the LMS-LLN5 threshold for establishing chronic obstructive pulmonary disease.
Pre-entry screening programmes for tuberculosis in migrants to low-incidence countries: a systematic review and meta-analysis
Authors: Robert W Aldridge, Tom A Yates, Dominik Zenner, Peter J White, Ibrahim Abubakar, Andrew C Hayward
Journal: The Lancet Infectious Diseases (2014)

Several high-income countries have pre-entry screening programmes for tuberculosis. We aimed to establish the yield of pre-entry screening programmes to inform evidence-based policy for migrant health screening.We searched six bibliographic databases for experimental or observational studies and systematic reviews, which reported data on migrant screening for active or latent tuberculosis by any method before migration to a low-incidence country. Primary outcomes were principal reported screening yield of active tuberculosis, yield of culture-confirmed cases, and yield of sputum smear for acid-fast bacilli cases. Where appropriate, fixed-effects models were used to summarise the yield of pre-entry screening across included studies.We identified 15 unique studies with data for 3 739 266 migrants screened pre-entry for tuberculosis between 1982 and 2010. Heterogeneity was high for all primary outcomes. After stratification by prevalence in country of origin, heterogeneity was reduced for culture-confirmed and smear-confirmed cases. Yield of culture-confirmed cases increased with prevalence in the country of origin, and summary estimates ranged from 19·7 (95% CI 10·3-31·5) cases identified per 100 000 individuals screened in countries with a prevalence of 50-149 cases per 100 000 population to 335·9 (283·0-393·2) per 100 000 in countries with a prevalence of greater than 350 per 100 000 population.Targeting high-prevalence countries could result in the highest yield for active disease. Pre-entry screening should be considered as part of a broad package of measures to ensure early diagnosis and effective management of migrants with active tuberculosis, and be integrated with initiatives that address the health needs of migrants.Wellcome Trust, UK National Institute for Health Research, Medical Research Council, Public Health England.
Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid
Authors: T. Marinkovic, A. Garin, Y. Yokota, Y.-X. Fu, N. H. Ruddle, G. C. Furtado, S. A. Lira
Journal: Journal of Clinical Investigation (2006)

Ectopic expression of CC chemokine ligand 21 (CCL21) in the thyroid leads to development of lymphoid structures that resemble those observed in Hashimoto thyroiditis. Deletion of the inhibitor of differentiation 2 (Id2) gene, essential for generation of CD3-CD4+ lymphoid tissue-inducer (LTi) cells and development of secondary lymphoid organs, did not affect formation of tertiary lymphoid structures. Rather, mature CD3+CD4+ T cells were critical for the development of tertiary lymphoid structures. The initial stages of this process involved interaction of CD3+CD4+ T cells with DCs, the appearance of peripheral-node addressin-positive (PNAd+) vessels, and production of chemokines that recruit lymphocytes and DCs. These findings indicate that the formation of tertiary lymphoid structures does not require Id2-dependent conventional LTis but depends on a program initiated by mature CD3+CD4+ T cells.
Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture.
Authors: P A Jones, Z Werb
Journal: The Journal of Experimental Medicine (1980)

Thioglycollate-elicited mouse peritoneal macrophages were cultured in contact with the mixture of extracellular matrix proteins produced by rat smooth muscle cells in culture. Both live macrophages and their conditioned media hydrolyzed glycoproteins, elastin, and collagen. Live macrophages also degraded extracellular connective tissue proteins secreted by endothelial cells and fibroblasts. The glycoproteins in the matrix markedly inhibited the rate of digestion of the other macromolecules, particularly elastin. When plasminogen was added to the matrix, activation of plasminogen to plasmin resulted in the hydrolysis of the glycoprotein components, which then allowed the macrophage elastase easier access to its substrate, elastin. Thus, although plasmin has no direct elastinolytic activity, its presence accelerated the rate of hydrolysis of elastin and therefore the rate of matrix degradation. These findings may be important in an understanding of disease states, such as emphysema and atherosclerosis, that are characterized by the destruction of connective tissue.
Interventions to reduce antibiotic prescription for lower respiratory tract infections: Happy Audit study
Authors: Carl Llor, Josep M. Cots, Beatriz G. López-Valcárcel, Javier Arranz, Guillermo García, Jesús Ortega, Manuel Gómez, Gloria Guerra, María J. Monedero, Juan D. Alcántara, José Paredes, Silvia Hernández, Marina Cid, Carolina Pérez, Vicenta Pineda
Journal: European Respiratory Journal (2011)

This before-after study aimed to evaluate the effect of two interventions on lowering the prescription of antibiotics in lower respiratory tract infections (LRTI) in Spain. General practitioners (GPs) registered all cases with LRTIs over 3-week periods before and after an intervention, in 2008 and 2009. Two types of intervention were considered: full-intervention group (FIG), consisting of discussion sessions of the results of the first registry, courses for GPs, guidelines, patient information leaflets, workshops on rapid tests and use of the C-reactive protein (CRP) test; GPs in the partial-intervention group (PIG) underwent all of the above interventions except for the workshop on rapid tests, and they did not have access to CRP. A multilevel logistic regression analysis was performed considering the prescription of an antibiotic as the dependent variable. 210 physicians were assigned to FIG and 70 to PIG. In 2009, 58 new physicians were included as a control group. 5,385 LRTIs were registered. Compared with the control group, the OR of antibiotic prescription after the intervention in the PIG was 0.42 (95% CI: 0.22-0.82) and 0.22 (95% CI: 0.12-0.38) in the FIG. Intervention led to a reduction in the prescription of antibiotics, mainly when CRP testing was available.
Relapsing polychondritis—treatment with cyclosporin A
Authors: A.D. Ormerood, I.J. Clark
Journal: British Journal of Dermatology (1992)

Journal Article Relapsing polychondritis—treatment with cyclosporin A Get access A.D. Ormerood, A.D. Ormerood Department of Dermatology, Aberdeen Rmial Infirmary, Foresterhill, Aberdeen AB9 2ZB, U.K. Search for other works by this author on: Oxford Academic Google Scholar I.J. Clark I.J. Clark Heatson Institute for Cancer Research, Wolfson Laboratory for Molecular Pathology, Bcarsden, Glasgow, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 127, Issue 3, 1 September 1992, Page 300, https://doi.org/10.1111/j.1365-2133.1992.tb00135.x Published: 01 September 1992
Cancer Drug Discovery Faces the FACT
Authors: Giulio F. Draetta, Ronald A. DePinho
Journal: Science Translational Medicine (2011)

In this issue of Science Translational Medicine, Gasparian et al. use a clever cell-based screen to identify a family of DNA-binding small molecules-curaxins-that inhibit tumor cell growth and division. The curaxins' mechanism of action pinpoints a new chromatin-remodeling factor as a therapeutic target for cancer.
Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation
Authors: Daniel E. Spratt, Michael J. Evans, Brian J. Davis, Michael G. Doran, Man Xia Lee, Neel Shah, John Wongvipat, Kathryn E. Carnazza, George G. Klee, William Polkinghorn, Donald J. Tindall, Jason S. Lewis, Charles L. Sawyers
Journal: Cancer Research (2015)

Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy in prostate cancer. ADT sensitizes prostate cancer to radiotherapy-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons, adjuvant ADT provides further survival benefits. Here, we show that androgen receptor (AR) expression and activity are durably upregulated following radiotherapy in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20% of patients after radiotherapy. Furthermore, these men were three-fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that radiotherapy can upregulate AR signaling after therapy to an extent that negatively affects disease progression and/or survival.
Colicky Epigastric and Right Upper Quadrant Pain
Authors: Franck Billmann, Therezia Bokor-Billmann, Christopher Beck
Journal: JAMA Surgery (2014)

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