tbuckley/cabot-search huggingface dataset:
Lovastatin Protects Human Endothelial Cells from Killing by Ionizing Radiation without Impairing Induction and Repair of DNA Double-Strand Breaks
Authors: Tobias Nübel, Julia Damrot, Wynand P. Roos, Bernd Kaina, Gerhard Fritz
Journal: Clinical Cancer Research (2006)

Abstract Purpose: 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) are frequently used lipid-lowering drugs. Moreover, they are reported to exert pleiotropic effects on cellular stress responses, proliferation, and apoptosis. Whether statins affect the sensitivity of primary human cells to ionizing radiation (IR) is still unknown. The present study aims at answering this question. Experimental Design: The effect of lovastatin on IR-provoked cytotoxicity was analyzed in primary human umbilical vein endothelial cells (HUVEC). To this end, cell viability, proliferation, and apoptosis as well as DNA damage–related stress responses were investigated. Results: The data show that lovastatin protects HUVEC from IR-induced cell death. Lovastatin did not confer radioresistance to human fibroblasts. The radioprotective, antiapoptotic effect of lovastatin was observed at low, physiologically relevant dose level (1 μmol/L). Lovastatin affected various IR-induced stress responses in HUVEC: It attenuated the increase in p53/p21 protein level and impaired the activation of nuclear factor-κB, Chk-1, and Akt kinase but did not inhibit extracellular signal-regulated kinase activation. Exposure of HUVEC to IR did not change the level of Bax and Bcl-2 and did not cause activation of caspase-3, indicating that radioprotection by lovastatin does not depend on the modulation of the mitochondrial death pathway. Also, IR-induced DNA double-strand break formation and repair were not influenced by lovastatin. Conclusions: The data show that lovastatin has multiple inhibitory effects on IR-stimulated DNA damage–dependent stress responses in HUVEC. Because lovastatin causes radioresistance, it might be useful in the clinic for attenuating side effects of radiation therapy that are related to endothelial cell damage.
Standardization of bleeding assessment in immune thrombocytopenia: report from the International Working Group
Authors: Francesco Rodeghiero, Marc Michel, Terry Gernsheimer, Marco Ruggeri, Victor Blanchette, James B. Bussel, Douglas B. Cines, Nichola Cooper, Bertrand Godeau, Andreas Greinacher, Paul Imbach, Mehdi Khellaf, Robert J. Klaassen, Thomas Kühne, Howard Liebman, Maria Gabriella Mazzucconi, Adrian Newland, Ingrid Pabinger, Alberto Tosetto, Roberto Stasi
Journal: Blood (2013)
Sequential Use of the Androgen Synthesis Inhibitors Ketoconazole and Abiraterone Acetate in Castration-Resistant Prostate Cancer and the Predictive Value of Circulating Androgens
Authors: Won Kim, Li Zhang, John H. Wilton, Gerald Fetterly, James L. Mohler, Vivian Weinberg, Allison Morse, Russell Z. Szmulewitz, Terence W. Friedlander, Lawrence Fong, Amy M. Lin, Andrea L. Harzstark, Arturo Molina, Eric J. Small, Charles J. Ryan
Journal: Clinical Cancer Research (2014)

Patients previously treated with ketoconazole were excluded from phase III trials of abiraterone acetate due to potential overlapping mechanism of action. The purpose of this study was to determine the clinical utility of abiraterone and its impact on circulating androgens following ketoconazole.Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. The primary endpoint was the proportion of patients with PSA response, defined as ≥30% PSA decline at 12 weeks. H0 = 0.30 versus H1 = 0.50 (α = 0.05, power = 0.83). Circulating androgen levels were measured using liquid chromatography tandem mass spectrometry.Thirty-nine patients were included in the final analysis. Twenty (51%; 95% confidence interval, 36%-66%) patients had ≥30% PSA decline; the null hypothesis was rejected. Sixteen (41%) had ≥50% PSA decline. Median PFS (progression-free survival) was 16 weeks; median radiographic PFS (rPFS) was 36 weeks. Samples for measurement of baseline androgens were available in 37 patients. The PSA response proportion was 59% in 29 patients with DHEA ≥ limit of quantitation (LOQ), compared with 13% in 8 patients with DHEA < LOQ (P = 0.042). Median PFS was 6 and 16 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P = 0.017); median rPFS was 14 and 36 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P < 0.001).Abiraterone demonstrates modest clinical efficacy in mCRPC patients previously treated with ketoconazole. Patients with DHEA ≥ LOQ were more likely to demonstrate PSA responses and longer PFS. Analysis of circulating androgens merits further investigation as a biomarker for response to androgen synthesis inhibitor therapy.
Effect of prazosin on microvascular perfusion during middle cerebral artery ligation in the rat.
Authors: M Anwar, E Buchweitz-Milton, H R Weiss
Journal: Circulation Research (1988)

The purpose of this study was to evaluate the effects of prazosin, an alpha 1-adrenoceptor antagonist, on morphometric indexes of the total and perfused cerebral microvascular bed 1 hour after middle cerebral artery (MCA) ligation in pentobarbital-anesthetized rats. We hypothesized that this agent would prevent catecholamine-induced vasoconstriction in the ischemic brain. Cerebral blood flow (CBF) was determined with 14C-iodoantipyrine, and the perfused microvascular bed was visualized using fluorescein isothiocyanate-dextran. MCA occlusion did not alter systemic hemodynamic or blood gas parameters. CBF averaged 29 +/- 15 (mean +/- SD) ml/min/100 g in the MCA-ligated cortex and 49 +/- 18 in the other examined brain regions. Prazosin did not significantly alter these CBF values, averaging 26 +/- 14 and 48 +/- 10, respectively. There were no significant regional differences in total capillaries/mm2 in either group. The percent of the capillaries/mm2 perfused (51 +/- 6%) was similar in the two groups in all examined regions except the ischemic cortex. In the MCA-ligated cortex, 22 +/- 8% of the capillary volume was perfused in comparison with 49 +/- 8% in the prazosin-treated group. Prazosin-treated rats had an increased percentage of their microvasculature perfused despite a similarly reduced CBF. Prazosin appeared to reduce diffusion distances in the ischemic cortex. This might be due to its alpha 1-adrenoceptor blocking activity.
P105 Direct access pulmonary function testing for primary care
Authors: K. E. Backler, L. Leech, M. Purdon, D. Roberts, Z. Lord, R. C. Buttery
Journal: Thorax (2011)

<h3></h3> Hinchingbrooke Hospital is a Diagnostic pilot site for the NHS Lung Improvement Programme, providing direct access from local GP Practices to Respiratory Physiology. Hitherto, patients have been referred to Respiratory Clinic; most have Pulmonary Function Testing in a linked appointment on the same day. An audit of these patients showed 30% of referrals were immediately discharged back to the GP and could have been diagnosed and managed in primary care (estimated total saving of £10 000 a year). <h3>Aims for the LIP service</h3> More accurate diagnosis of respiratory disease in primary care. More appropriate management pathways for respiratory patients, with enhanced access to smoking cessation services, COPD respiratory nurse specialists and pulmonary rehabilitation services. Ultimately, this will result in a reduction in hospital admissions due to better diagnosis and management in primary care. The aim was to reduce referrals to the Chest Clinic by 25%. To provide a quality service to the GPs and patients. <h3>Methods</h3> Referrals for pulmonary function testing were received directly from Primary Care. Quality assured tests were performed: spirometry, gas diffusion and static lung volumes. At the point of testing, patients received detailed information regarding their results and diagnosis from a trained respiratory physiologist, giving an opportunity to have one to one conversations regarding fears or concerns about their diagnosis. Tests were reviewed by a respiratory consultant and a fully interpreted report Faxed to referring team. If Chest Clinic referral was advised, the cost of the services was deducted from the Chest Consultation tariff. Therefore the service is at least cost neutral. <h3>Results</h3> (See Abstract P105 table 1). <h3>Conclusions</h3> This service has been successfully set up, with a steady referral stream of patients from primary care. The main difficulty encountered has been awareness levels in primary care, despite promotion through standard channels. Outcomes show a high level of satisfaction with the service from both patients and GPs. 75% of patients who used this service have subsequently been managed within primary care, with an estimated cost saving of £1800 to the health economy.
Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells
Authors: Yasuhiro Nemoto, Takanori Kanai, Masahiro Takahara, Shigeru Oshima, Tetsuya Nakamura, Ryuichi Okamoto, Kiichiro Tsuchiya, Mamoru Watanabe
Journal: Gut (2012)

<h3>Objective</h3> Interleukin (IL)-7 is mainly produced in bone marrow (BM) that forms the niche for B cells. We previously demonstrated that BM also retains pathogenic memory CD4 T cells in murine models of inflammatory bowel disease (IBD). However, it remains unknown whether BM-derived IL-7 is sufficient for the development of IBD and which cells form the niche for colitogenic memory CD4 T cells in BM. <h3>Design</h3> To address these questions, we developed mice in which IL-7 expression was specific for BM, and identified colitis-associated IL-7-expressing mesenchymal stem cells (MSC) in the BM. <h3>Results</h3> IL-7<sup>–/–</sup>×RAG-1<sup>–/–</sup> mice injected with BM cells from IL-7<sup>+/+</sup>×RAG-1<sup>–/–</sup> mice, but not from IL-7<sup>–/–</sup>×RAG-1<sup>–/–</sup> mice, expressed IL-7 in BM, but not in their colon, and developed colitis when injected with CD4<sup>+</sup>CD45RB<sup>high</sup> T cells. Cultured BM MSC stably expressed a higher level of IL-7 than that of primary BM cells. IL-7-sufficient, but not IL-7-deficient, BM MSC supported upregulation of Bcl-2 in, and homeostatic proliferation of, colitogenic memory CD4 T cells in vitro<i>.</i> Notably, IL-7<sup>–/–</sup>×RAG-1<sup>–/–</sup> mice transplanted with IL-7-sufficient, but not IL-7-deficient, BM MSC expressed IL-7 in BM, but not in their colon, and developed colitis when transplanted with CD4<sup>+</sup>CD45RB<sup>high</sup> T cells. <h3>Conclusions</h3> We demonstrate for the first time that BM MSC are a major source of IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in BM.
Unexpected severe systemic allergic reaction after hymenoptera sting in well controlled asthma during treatment with omalizumab
Authors: Gabriella Guarnieri, Patrizia Bonadonna, Michele Schiappoli, Piero Maestrelli
Journal: European Respiratory Journal (2014)

Omalizumab has been used as add-on therapy for patients at high risk of anaphylaxis during specific venom immunotherapy (1). We reported the case of a 64-year-old man, suffering from severe allergic asthma since 1986. In February 2008 he started treatment with Omalizumab (300 mg twice per month), added to high doses of inhaled corticosteroids and long-acting bronchodilators and montelukast. Omalizumabwaswell tolerated. Respiratory symptoms, lung function and quality of life improved. He remained stable until August 2012, when he experienced a severe systemic allergic reaction after a wasp sting (grade III according Mueller classification). The intradermal skin tests and the specific IgE level were positive to all hymenoptera venom. CAP-inhibition assays showed that Vespula was the main venom responsible for the adverse reaction. Tryptase level was normal (9 μg/l). Venom immunotherapy for Vespula was started according to a rush modified regimen, continuing with Omalizumab therapy. Maintenance dose was reached in 7 weeks and well tolered. The mechanism for which severe systemic allergic reaction to hymenoptera venom occurred despite concomitant anti-IgE therapy remains unknown. It may be assumed that the dose of Omalizumab used for asthma treatment was not sufficient to prevent reactions to hymenoptera venom or was given at excessive interval from the wasp sting (2 weeks before). Another explanation could be that the systemic reaction was elicited by a non IgE-mediated release of mediators.  1. Galera C et al. J Investig Allergol Clin Immunol 2009; 19(3):225-9.
The mycobacterial mystery
Authors: N. Schönfeld
Journal: European Respiratory Journal (2006)

Before the advent of HIV, which led to an increased awareness of Mycobacterium avium complex disease, followed by the first prospective comparison studies on treatment regimens 1, 2, the topic of nontuberculous mycobacterial disease was a true example of Aristotelian science. Previously, only a few experts worldwide had compiled empirical data and disseminated knowledge on the subject, which was based upon meticulous observations in small series or case studies from the 1950s onwards 3. These studies demonstrated the manifold particularities of M. avium complex disease and others as compared with tuberculosis, and also showed how even nontuberculous mycobacterial lung diseases alone, quite apart from manifestations in other organs, appear in widely varying forms. To this day, an ever increasing number of reports on uncommon or recently detected and potentially pathogenic species with strange names deepen the impression that we are dealing with an intricate matter.

In 1979, Wolinsky 4 published his legendary review on nontuberculous mycobacteria (NTM) and associated diseases, which is still worth reading and citing: “The pathogenesis of adult pulmonary disease is obscure. Does it represent primary infection after inhalation of aerosolized infected droplet nuclei that then localize and proliferate in specific areas of damaged lung? Or is it a reactivation of dormant bacilli that had been acquired previously?” 4. Meanwhile, the history of HIV especially, and the growing number of patients with transplants, have helped in understanding the role, and some mechanisms, of systemic immunosuppression as an important factor in the development of both disseminated and pulmonary disease. Have we, however, deepened our understanding of the pathophysiology of localised lung disease in non-HIV patients, this being a key issue?

Focusing on treatment, in 1985 another pioneer in the field of tuberculosis and nontuberculous mycobacterial diseases, Karl Ludwig Radenbach (1918–1986), wrote: “Clinically, treatment cannot …
Directed Mutagenesis Confirms the Functional Importance of Positively Selected Sites in Polygalacturonase Inhibitor Protein
Authors: John G. Bishop
Journal: Molecular Biology and Evolution (2005)

Polygalacturonase inhibitor proteins (PGIPs) protect plants against invasion by diverse microbial and invertebrate enemies that use polygalacturonase (PG) to breach the plant cell wall. Directed mutagenesis has identified specific natural mutations conferring novel defensive capability in green bean PGIP against a specific fungal PG. These same sites are identified as positively selected by phylogenetic codon-substitution models, demonstrating the utility of such models for connecting retrospective comparative analyses with contemporary, ecologically relevant variation.
Emotional Hygiene in Pregnancy
Authors: J. S. Horsley
Journal: BMJ (1964)

coincidental, must result from a failure of aseptic techniques.Any interference in a patient with a foetal death has some risk, and this risk must be weighed against that of conservative treat- nent.At a scientific meeting of the Royal College of Obstetricians and Gynaecologists Dr. Geoghegan, of Dublin, reported a maternal death resulting from amniotic embolus immediately after abdominal amni- otomy in a patient with polyhydramnios; this must also be recognized as a rare but definite risk of the procedure.If induction of labour is thought necessary in a patient with foetal death intravenous oxytocin is probably the safest initial procedure.How- ever, induction may fail in these circum- stances, and it would still seem reasonable to use intra-amniotic hypertonic glucose or saline rather than prolong oxytocin therapy for more than two days.-Weare, etc.,
The role of HTLV-1 clonality, proviral structure, and genomic integration site in adult T-cell leukemia/lymphoma
Authors: Lucy B. Cook, Anat Melamed, Heather Niederer, Mikel Valganon, Daniel Laydon, Letizia Foroni, Graham P. Taylor, Masao Matsuoka, Charles R. M. Bangham
Journal: Blood (2014)
Future Treatment of Bone Metastases
Authors: Allan Lipton
Journal: Clinical Cancer Research (2006)

Abstract All bone surfaces are periodically remodeled by the coupled and balanced action of osteoclasts and osteoblasts, of which the activities are regulated by a variety of cytokines and growth factors. Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which the actions of osteoclasts and osteoblasts remain coupled, but become imbalanced in sites adjacent to the tumor. The result is net bone loss. Many cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called “vicious cycle,” there are multiple sites that are targets for new bone-directed therapies. A variety of new agents for the treatment and prevention of osteolytic bone metastasis are currently being developed. These include new agents that inhibit osteoclast differentiation, bone adhesion, and osteoclast function. These new strategies have evolved from a better understanding of the interaction between tumor cells and cells in the bone marrow microenvironment. There is great promise that these new bone-targeted therapies can decrease the frequent skeletal-related events that greatly diminish quality of life of patients with bone metastases.
Use of different exhaled nitric oxide multiple flow rate models in COPD
Authors: K. Roy, Z. L. Borrill, C. Starkey, A. L. Hazel, J. Morris, J. Vestbo, D. Singh
Journal: European Respiratory Journal (2007)

Multiple flow rates of exhaled nitric oxide (eNO) fraction ( F e,NO ) data can be modelled to estimate airway wall concentration of nitric oxide ( C aw,NO ), diffusing capacity of nitric oxide ( D aw,NO ), alveolar nitric oxide concentration ( C alv,NO ) and total maximal flux of nitric oxide in the airway compartment ( J ′ aw,NO ). F e,NO at 10, 30, 50, 100 and 200 mL·s −1 from 50 chronic obstructive pulmonary disease (COPD) patients and 35 healthy controls (smokers and nonsmokers) modelled using five different methods was compared and the effect of the number of flow rates was investigated. All methods showed that current smoking reduced C &amp;SetFont Italic="0"; aw,NO in COPD patients, with some methods showing that smoking reduced J ′ aw,NO . Smoking did not affect C alv,NO or D aw,NO . The methods gave similar results for C aw,NO but there was variability between methods for J ′ aw,NO , C alv,NO and D aw,NO &amp;SetFont Italic="0";. The median error by least squares fitting between modelled and actual data was significantly lower for the nonlinear method (1.96) compared with the mixed methods (3.31 and 3.62). Parameters calculated using the nonlinear method using five and four flow rates were significantly different. The ratio (95% confidence interval) of C aw,NO was 2.02 (1.45–2.83). Nitric oxide models give different results, although airway conductance of nitric oxide is relatively model independent. Nonlinear modelling has the least error, suggesting it is the best method. The number of flow rates should be standardised.
Successful control of lymphangioma circumscriptum by superficial X-rays
Authors: S. O'CATHAIL, A.Y. ROSTOM, M.L. JOHNSON
Journal: British Journal of Dermatology (1985)

Lymphangioma circumscriptum (LC) is usually treated by excision. Radiotherapy is not considered suitable primary treatment (Kinmonth, 1972). We report a case which was treated by superficial X‐rays with almost complete regression. Regression was very slow. Reviewing the literature we discovered that X‐ray therapy has never been properly tested for treating this condition. We conclude that this modality of treatment is rational, effective and warrants further testing.
Cytotoxic T lymphocyte nonresponsiveness to the male antigen H-Y in the H-2Db mutants bm13 and bm14. Complementation of the response in F1 crosses with the I-Ab mutant bm12 nonresponder and failure of B6 or Db mutant mice tolerant of each other to respond to allogeneic male cells.
Authors: L P De Waal, R W Melvold, C J Melief
Journal: The Journal of Experimental Medicine (1983)

The cytotoxic T-lymphocyte (CTL) response against the male-specific antigen H-Y in C57BL/6 (B6, H-2b) mice is regulated by the I-Ab and Db molecules. From previous studies, we concluded that the bm12 I-Ab mutant does not respond to H-Y, because of a deletion in its T-helper-cell repertoire. We now demonstrate that two Db mutants, bm13 and bm14, also fail to generate a CTL response to H-Y. The bm12 class-II mutant on one hand and the bm13 and bm14 class-I mutants on the other complemented each other for the H-Y-specific CTL response in (bm12 X bm13)F1 and (bm 12 X bm 14)F1 hybrids. This indicates that the need for tolerance of the mutant class II and class I molecules in these hybrids does not create deletions in the I-Ab-restricted T helper cell and Db-restricted CTL repertoire for H-Y. This study constitutes the first demonstration with H-2 mutants that a CTL response controlled by class I and class II MHC molecules is complemented in an F1 cross between a class I and a class II nonresponder. (B6 X bm 13)F1 and (B6 X bm 14)F1 hybrids only responded to H-Y when the antigen was presented on F1 or B6 antigen-presenting cells (apc) but not on Db mutant apc. B6 or Db mutant responders rendered neonatally tolerant of each other failed to respond to the H-Y antigen presented on the tolerogenic allogeneic cell. In the tolerized animals, a response was only seen with responder (B6) type T cells and responder type (B6) apc, indicating that both the T cell source and the MHC type of the apc have to be taken into account in this system. Thus, Ir genes may act at the level of both the T cell repertoire and antigen presentation.
Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome.
Authors: B Zwissler, G Kemming, O Habler, M Kleen, M Merkel, M Haller, J Briegel, M Welte, K Peter
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Inhalation of nitric oxide (NO) and prostacyclin (PGI2) may induce selective pulmonary vasodilation and-by improving ventilation-perfusion ratio in ventilated areas of the lung-increase Pao2 in patients with acute lung injury. To assess the therapeutic efficacy of both compounds, dose-response curves were established in patients with adult respiratory distress syndrome (ARDS). Patients received both PGI2 (doses of 1, 10, and 25 ng/kg/min) and NO (concentrations of 1, 4, and 8 ppm). Cardiorespiratory parameters were assessed at control, at each drug concentration, and after withdrawal of NO and PGI2. PGI2 resulted in a significant, dose-dependent and selective reduction of pulmonary artery pressure (PAP) from 35.1 +/- 6.3 mm Hg at control to 33.1 +/- 4.8 (1 ng/kg/min), 31.3 +/- 4.8 mm Hg (10 ng/kg/min) and 29.6 +/- 4.5 mm Hg (25 ng/kg/min), respectively. Inhaled NO reduced PAP from 34.5 +/- 5.6 to 32.1 +/- 5.9 mm Hg at 4 ppm, and to 31.8 +/- 6.1 mm Hg at 8 ppm, respectively, with no effect at 1 ppm. Pao2/Flo2 ratio increased from 105 +/- 37 to 125 +/- 56 mm Hg (range of increase: 0 to 57 mm Hg) at PGI2 10 ng/kg/min and to 131 +/- 63 mm Hg (range: -5 to 89 mm Hg) at 25 ng/kg/min with no effect at 1 ng/kg/min. NO improved Pao2 (e.g., from 116 +/- 47 to 167 +/- 86 mm Hg at 8 ppm) and reduced intrapulmonary shunt at all doses tested. We conclude that both inhaled PGI2 and NO may induce selective pulmonary vasodilation and increase Pao2 in severe ARDS.